bims-nastce Biomed News
on NASH and T cells
Issue of 2021–11–28
186 papers selected by
Petra Hirsova, Mayo Clinic College of Medicine
  1. T Cell Subsets and Natural Killer Cells in the Pathogenesis of Nonalcoholic Fatty Liver Disease.
  2. Bile acids contribute to the development of non-alcoholic steatohepatitis in mice.
  3. The Hepatic Sinusoid in Chronic Liver Disease: The Optimal Milieu for Cancer.
  4. Promising results for exclusion diet in adults.
  5. Antimetastatic defense by CD8+ T cells.
  6. NAFLD and NASH: The Metabolically Diseased Liver.
  7. Human gut bacterial metabolism drives Th17 activation and colitis.
  8. Narrative review of current and emerging pharmacological therapies for nonalcoholic steatohepatitis.
  9. Intrahepatic immune infiltrate in chronic hepatitis B and chronic hepatitis C: Similar but not the same.
  10. Th17 cell master transcription factor RORC2 regulates HIV-1 gene expression and viral outgrowth.
  11. Models of nonalcoholic steatohepatitis potentiated by chemical inducers leading to hepatocellular carcinoma.
  12. CD226 knockout alleviates high-fat diet induced obesity by suppressing proinflammatory macrophage phenotype.
  13. Mesenchymal Stem Cells Influence Activation of Hepatic Stellate Cells, and Constitute a Promising Therapy for Liver Fibrosis.
  14. Immunotoxins: From Design to Clinical Application.
  15. Linking liver metabolic and vascular disease via bile acid signaling.
  16. Invariant NKT Cells Promote the Development of Highly Cytotoxic Multipotent CXCR3+CCR4+CD8+ T Cells That Mediate Rapid Hepatocyte Allograft Rejection.
  17. Hepatic Response of Magnesium-Restricted Wild Type Mice.
  18. CD63+ and MHC Class I+ Subsets of Extracellular Vesicles Produced by Wild-Type and CD47-Deficient Jurkat T Cells Have Divergent Functional Effects on Endothelial Cell Gene Expression.
  19. Maralixibat relieves chronic cholestasis in children.
  20. Genetics, Immunity and Nutrition Boost the Switching from NASH to HCC.
  21. Administration of aerosolized SARS-CoV-2 to K18-hACE2 mice uncouples respiratory infection from fatal neuroinvasion.
  22. New Horizons in the Treatment of Osteosarcoma.
  23. Anatomy-preserving adjustable intragastric balloon is safe and promotes durable weight loss.
  24. Trans-Ned 19-Mediated Antagonism of Nicotinic Acid Adenine Nucleotide-Mediated Calcium Signaling Regulates Th17 Cell Plasticity in Mice.
  25. Resident and migratory adipose immune cells control systemic metabolism and thermogenesis.
  26. Role of Ferroptosis in Non-Alcoholic Fatty Liver Disease and Its Implications for Therapeutic Strategies.
  27. SP-1154, a novel synthetic TGF-β inhibitor, alleviates obesity and hepatic steatosis in high-fat diet-induced mice.
  28. Gut Microbiota Reshaped by Pectin Treatment Improves Liver Steatosis in Obese Mice.
  29. High-Fat, Western-Style Diet, Systemic Inflammation, and Gut Microbiota: A Narrative Review.
  30. The asymmetric Pitx2 gene regulates gut muscular-lacteal development and protects against fatty liver disease.
  31. Reply to Over-celling fetal microbial exposure.
  32. A high OXPHOS CD8 T cell subset is predictive of immunotherapy resistance in melanoma patients.
  33. Immunological Mechanisms of Sickness Behavior in Viral Infection.
  34. Time-Restricted Feeding Restores Obesity-Induced Alteration in Adipose Tissue Immune Cell Phenotype.
  35. Interrelation Between Fibroblasts and T Cells in Fibrosing Interstitial Lung Diseases.
  36. Two microbiota subtypes identified in irritable bowel syndrome with distinct responses to the low FODMAP diet.
  37. The Batman and Robin of liver-stage immunity to malaria.
  38. The Effect of Mycotoxins and Silymarin on Liver Lipidome of Mice with Non-Alcoholic Fatty Liver Disease.
  39. Activation and Functional Priming of Blood Neutrophils in Non-Alcoholic Fatty Liver Disease Increases in Non-Alcoholic Steatohepatitis.
  40. scCODA is a Bayesian model for compositional single-cell data analysis.
  41. Lipid Metabolism Disorders in the Comorbid Course of Nonalcoholic Fatty Liver Disease and Chronic Obstructive Pulmonary Disease.
  42. A New Potential Strategy for Acute Non-Alcoholic Steatohepatitis (NASH).
  43. Intestinal microbial communities and Holdemanella isolated from HIV+/- men who have sex with men increase frequencies of lamina propria CCR5+ CD4+ T cells.
  44. Identification of Follicular T Cells in the Gut.
  45. Effect of a High-Fat Diet on the Small-Intestinal Environment and Mucosal Integrity in the Gut-Liver Axis.
  46. IL-4-Producing Vγ1+/Vδ6+ γδ T Cells Sustain Germinal Center Reactions in Peyer's Patches of Mice.
  47. An Update on the Role of Extracellular Vesicles in the Pathogenesis of Necrotizing Enterocolitis and Inflammatory Bowel Diseases.
  48. Fatty acid metabolism in adaptive immunity.
  49. Emerging Role of Interleukins for the Assessment and Treatment of Liver Diseases.
  50. Novel Therapeutic Targets in Liver Fibrosis.
  51. Regulation of Tim-3 function by binding to phosphatidylserine.
  52. ILC3s control airway inflammation by limiting T cell responses to allergens and microbes.
  53. Research in metabolic ageing - a tale of mice versus humans?
  54. Overexpression of PDE4D in mouse liver is sufficient to trigger NAFLD and hypertension in a CD36-TGF-β1 pathway: therapeutic role of roflumilast.
  55. Horses for Courses in the Era of CARs: Advancing CAR T and CAR NK Cell Therapies.
  56. Single-Cell Transcriptomic Analysis Reveals a Tumor-Reactive T Cell Signature Associated With Clinical Outcome and Immunotherapy Response In Melanoma.
  57. TM6SF2/PNPLA3/MBOAT7 loss-of-function genetic variants impact on NAFLD development and progression both in patients and in in vitro models.
  58. The Gut-Liver Axis in Chronic Liver Disease: A Macrophage Perspective.
  59. High endogenous CCL2 expression promotes the aggressive phenotype of human inflammatory breast cancer.
  60. Role and Function of T Cell-Derived Exosomes and Their Therapeutic Value.
  61. Identification of an Immunogenic Medulloblastoma-Specific Fusion Involving EPC2 and GULP1.
  62. Inflammatory activity affects the accuracy of liver stiffness measurement by transient elastography, but not by two-dimensional shear wave elastography in nonalcoholic fatty liver disease.
  63. The Role of Neuropeptide Y in Adipocyte-Macrophage Crosstalk during High Fat Diet-Induced Adipose Inflammation and Liver Steatosis.
  64. The Hepatic Stellate Cells (HSTCs) and Adipose-derived Mesenchymal Stem Cells (ASCs) Axis as a Potential Major Driver of Metabolic Syndrome - Novel Concept and Therapeutic Implications.
  65. TICAM-1/TRIF associates with Act1 and suppresses IL-17 receptor-mediated inflammatory responses.
  66. Endoscopic Bariatric Interventions in Patients with Chronic Liver Disease.
  67. High-Resolution Exposomics and Metabolomics Reveals Specific Associations in Cholestatic Liver Diseases.
  68. A 3D primary human cell-based in vitro model of non-alcoholic steatohepatitis for efficacy testing of clinical drug candidates.
  69. CD38 Deficiency Protects Mice from High Fat Diet-Induced Nonalcoholic Fatty Liver Disease through Activating NAD+/Sirtuins Signaling Pathways-Mediated Inhibition of Lipid Accumulation and Oxidative Stress in Hepatocytes.
  70. Comparison of Three CD3-Specific Separation Methods Leading to Labeled and Label-Free T Cells.
  71. High Throughput Interrogation of Human Liver Stellate Cells Reveals Microenvironmental Regulation of Phenotype.
  72. Delphinidin diminishes in vitro interferon-γ and interleukin-17 producing cells in patients with psoriatic disease.
  73. Involvement of Ceramides in Non-Alcoholic Fatty Liver Disease (NAFLD) Atherosclerosis (ATS) Development: Mechanisms and Therapeutic Targets.
  74. Gut-derived systemic inflammation as a driver of depression in chronic liver disease.
  75. Peanut oral immunotherapy differentially suppresses clonally distinct subsets of T helper cells.
  76. Nonalcoholic Fatty Liver Disease and Chronic Kidney Disease: A Review of Links and Risks.
  77. Preclinical testing of chimeric antigen receptor T cells in neuroblastoma mouse models.
  78. Highlights from SfE BES 2021.
  79. Targeting regulatory T cells for immunotherapy in melanoma.
  80. Impact of Helicobacter pylori-Related Metabolic Syndrome Parameters on Arterial Hypertension.
  81. Therapeutic Advances in Gut Microbiome Modulation in Patients with Inflammatory Bowel Disease from Pediatrics to Adulthood.
  82. Aryl Hydrocarbon Receptor (AhR) Activation by 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) Dose-Dependently Shifts the Gut Microbiome Consistent with the Progression of Non-Alcoholic Fatty Liver Disease.
  83. Lung and Gut Microbiota Changes Associated with Pseudomonas aeruginosa Infection in Mouse Models of Cystic Fibrosis.
  84. Estimating Drug Efficacy with a Diet-Induced NASH Model in Chimeric Mice with Humanized Livers.
  85. Non-invasive methods for imaging hepatic steatosis and their clinical importance in NAFLD.
  86. COVID-19 and the forgotten organ: prolonged changes to the metabolic output of the gut microbiome.
  87. Small Molecule Inhibitors of MERTK and FLT3 Induce Cell Cycle Arrest in Human CD8+ T Cells.
  88. [Research progress in metabolic reprogramming of endothelial cells and T cells and potential therapeutic targets for chronic inflammation].
  89. Circadian rhythms in adaptive immunity and vaccination.
  90. In Vivo Bioluminescence Imaging of HBV Replicating Hepatocytes Allows for the Monitoring of Anti-Viral Immunity.
  91. Bile Acid Receptors and the Gut-Liver Axis in Nonalcoholic Fatty Liver Disease.
  92. Innate Immune Mechanisms and Immunotherapy of Myeloid Malignancies.
  93. From Bench to Bedside: How the Tumor Microenvironment Is Impacting the Future of Immunotherapy for Renal Cell Carcinoma.
  94. Hematopoiesis under telomere attrition at the single-cell resolution.
  95. ACC1-expressing pathogenic T helper 2 cell populations facilitate lung and skin inflammation in mice.
  96. From Immune Dysregulations to Therapeutic Perspectives in Myelodysplastic Syndromes: A Review.
  97. In Memoriam of Narayanaswamy Srinivasan (1962-2021).
  98. CORTISTATIN REGULATES FIBROSIS AND MYOFIBROBLAST ACTIVATION IN EXPERIMENTAL HEPATOTOXIC- AND CHOLESTATIC-INDUCED LIVER INJURY.
  99. Single-Cell Multiomics Analysis for Drug Discovery.
  100. A coarse-grained NADH redox model enables inference of subcellular metabolic fluxes from fluorescence lifetime imaging.
  101. Fitness benefits of dietary restriction.
  102. Assessment of non-alcoholic fatty liver disease (NAFLD) severity with novel serum-based markers: A pilot study.
  103. Generation of an NFκB-Driven Alpharetroviral "All-in-One" Vector Construct as a Potent Tool for CAR NK Cell Therapy.
  104. Behind the scenes of extracellular vesicle therapy for skin injuries and disorders.
  105. Analysis of Schistosoma mansoni Extracellular Vesicles Surface Glycans Reveals Potential Immune Evasion Mechanism and New Insights on Their Origins of Biogenesis.
  106. Multicentric Castleman disease and the evolution of the concept.
  107. Nonalcoholic fatty liver disease: The role of quercetin and its therapeutic implications.
  108. New species of the genus Gynaecoserica Brenske, 1896 from Indochina (Coleoptera: Scarabaeidae: Sericini).
  109. Expression of Immune Related Genes and Possible Regulatory Mechanisms in Alzheimer's Disease.
  110. MC3R controls growth and puberty onset.
  111. Physiological Roles of Apoptotic Cell Clearance: Beyond Immune Functions.
  112. Updates on Immunotherapy and Immune Landscape in Renal Clear Cell Carcinoma.
  113. Identification of indole-based activators of insulin degrading enzyme.
  114. Immune ageing at single-cell resolution.
  115. [Obesity-fatty liver: the role of the pediatrician].
  116. The FODMAP diet: more than just a symptomatic therapy?
  117. Quality of life and unmet needs in patients with chronic liver disease: A mixed-method systematic review.
  118. MyD88 in Macrophages Enhances Liver Fibrosis by Activation of NLRP3 Inflammasome in HSCs.
  119. Identification of Non-classical Follicular T Cells.
  120. Cannabis and Its Potential Protective Role Against Inflammatory Bowel Disease: A Scoping Review.
  121. Stereotypic Expansion of T Regulatory and Th17 Cells during Infancy Is Disrupted by HIV Exposure and Gut Epithelial Damage.
  122. LSD1 inhibition sustains T cell invigoration with a durable response to PD-1 blockade.
  123. The Interplay of Vitamin D Deficiency and Cellular Senescence in The Pathogenesis of Obesity-Related Co-Morbidities.
  124. Randomized controlled trials in surgery for inguinal hernias.
  125. CRISPR-enhanced human adipocyte browning as cell therapy for metabolic disease.
  126. Alpha-Synuclein Induced Immune Cells Activation and Associated Therapy in Parkinson's Disease.
  127. Time-restricted feeding and circadian autophagy for long life.
  128. Two new species of Petalophthalmus and Ipirophthalmus (Crustacea: Mysida: Petalophthalmidae), from New Zealand.
  129. Hybrid Clustering of Single-Cell Gene Expression and Spatial Information via Integrated NMF and K-Means.
  130. Mycobiota-host immune interactions in IBD: coming out of the shadows.
  131. Cancer surveillance in non-alcoholic fatty liver disease: A potential role for lipidomics.
  132. Comparison of Guidelines for the Use of Interleukin-17 Inhibitors for Psoriasis in the United States, Britain, and Europe: A Critical Appraisal and Comprehensive Review.
  133. Myeloid cell subsets that express latency-associated peptide promote cancer growth by modulating T cells.
  134. Innate-Immunity Genes in Obesity.
  135. Single-cell analysis identifies dynamic gene expression networks that govern B cell development and transformation.
  136. Single-Cell RNAseq Profiling of Human γδ T Lymphocytes in Virus-Related Cancers and COVID-19 Disease.
  137. Skin fibrosis and recovery is dependent on Wnt activation via DPP4.
  138. Assessing microplastic exposure of large marine filter-feeders.
  139. Diet underlying autism-microbiome association.
  140. Stabilin receptors clear LPS and control systemic inflammation.
  141. Diversity of effects induced by boron-containing compounds on immune response cells and on antibodies in basal state.
  142. A Comparative Proteomic Analysis of Extracellular Vesicles Associated With Lipotoxicity.
  143. More from ASN high-impact trials.
  144. Delivery of IL-2 to the T Cell Surface Through Phosphatidylserine Permits Robust Expansion of CD8 T Cells.
  145. Combining a β3 adrenergic receptor agonist with alpha-lipoic acid reduces inflammation in male mice with diet-induced obesity.
  146. Thinking Quantitatively of RNA-Based Information Transfer via Extracellular Vesicles: Lessons to Learn for the Design of RNA-Loaded EVs.
  147. Time-Restricted Feeding in Mice Prevents the Disruption of the Peripheral Circadian Clocks and Its Metabolic Impact during Chronic Jetlag.
  148. Non-Invasive Analysis of Human Liver Metabolism by Magnetic Resonance Spectroscopy.
  149. Identification and Characterization of Antigen-Specific CD8+ T Cells Using Surface-Trapped TNF-α and Single-Cell Sequencing.
  150. Immune Tolerance in the Oral Mucosa.
  151. Metallothionein 1: A New Spotlight on Inflammatory Diseases.
  152. Leptin Signaling in the Ovary of Diet-Induced Obese Mice Regulates Activation of NOD-Like Receptor Protein 3 Inflammasome.
  153. Consumption of dietary fat causes loss of olfactory sensory neurons and associated circuitry that is not mitigated by voluntary exercise in mice.
  154. Coix Seed Consumption Affects the Gut Microbiota and the Peripheral Lymphocyte Subset Profiles of Healthy Male Adults.
  155. Design, synthesis and activity evaluation of prodrug form JBP485 and Vitamin E for alleviation of NASH.
  156. [Study of abnormal lipid metabolism analysis and significance of fatty acid binding protein expression in patients with hepatocellular carcinoma].
  157. Lipidomics and Redox Lipidomics Indicate Early Stage Alcohol-Induced Liver Damage.
  158. Abstracts From Other Journals.
  159. Neoadjuvant PD-1 blockade induces T cell and cDC1 activation but fails to overcome the immunosuppressive tumor associated macrophages in recurrent glioblastoma.
  160. Why is it worth remembering the lung microbiome in ICU patients?
  161. Hsa-miR-31 Governs T-Cell Homeostasis in HIV Protection via IFN-γ-Stat1-T-Bet Axis.
  162. Seven new Otacilia Thorell, 1897 species from China (Araneae: Phrurolithidae).
  163. A Role for the Bone Marrow Microenvironment in Drug Resistance of Acute Myeloid Leukemia.
  164. Comment on: Assurance of surgical quality within multicenter randomized, controlled trials for bariatric and metabolic surgery: a systematic review.
  165. Cicero's "On Old Age".
  166. T Cell Bispecific Antibodies: An Antibody-Based Delivery System for Inducing Antitumor Immunity.
  167. Ibrutinib protects T cells in patients with CLL from proliferation-induced senescence.
  168. Crosstalk between macrophages and natural killer cells in the tumor microenvironment.
  169. Response to Letter to the Editor.
  170. Neoantigen-reactive CD8+ T cells affect clinical outcome of adoptive transfer with tumor-infiltrating lymphocytes in melanoma.
  171. Intestinal Microbiota as a Contributor to Chronic Inflammation and Its Potential Modifications.
  172. Epigenetic interaction between UTX and DNMT1 regulates diet-induced myogenic remodeling in brown fat.
  173. How dogs became humans' best friends: from Neanderthals to now.
  174. Accumulation of Genetic and Epigenetic Alterations in the Background Liver and Emergence of Hepatocellular Carcinoma in Patients with Non-Alcoholic Fatty Liver Disease.
  175. Assessing causal relationships between COVID-19 and non-alcoholic fatty liver disease.
  176. Non-Alcoholic Fatty Liver Disease (NAFLD) and Potential Links to Depression, Anxiety, and Chronic Stress.
  177. Nonalcoholic Fatty Liver Disease Underdiagnosis in Primary Care: What Are We Missing?
  178. Spatial distribution and functional analysis define the action pathway of Tim-3/Tim-3 ligands in tumor development.
  179. Whole-Body Imaging to Assess Cell-Based Immunotherapy: Preclinical Studies with an Update on Clinical Translation.
  180. Distinct Immunological Features of Inflammatory Demyelinating Diseases of the Central Nervous System.
  181. Additions to the Neoserica calva group from continental South East Asia (Coleoptera: Scarabaeidae: Melolonthinae: Sericini).
  182. High fat diet induced gut dysbiosis alters corneal epithelial injury response in mice.
  183. To walk or not to walk: That is the question.
  184. Metabolic adaptation to the chronic loss of Ca2+ signaling induced by knockout of IP3 receptors or the mitochondrial Ca2+ uniporter.
  185. Hepatocellular Carcinoma in Non-Alcoholic Fatty Liver Disease: From Epidemiology to Diagnostic Approach.
  186. Metabolic Changes in Tumor Microenvironment: How Could They Affect γδ T Cells Functions?
  1. Int J Mol Sci. 2021 Nov 11. pii: 12190. [Epub ahead of print]22(22):
    T Cell Subsets and Natural Killer Cells in the Pathogenesis of Nonalcoholic Fatty Liver Disease.
    Yoseph Asmelash Gebru, Haripriya Gupta, Hyeong Seop Kim, Jung A Eom, Goo Hyun Kwon, Eunju Park, Jin-Ju Jeong, Sung-Min Won, Satya Priya Sharma, Raja Ganesan, Dong Joon Kim, Ki Tae Suk.
      Nonalcoholic fatty liver disease (NAFLD) is a condition characterized by hepatic accumulation of excess lipids. T cells are commonly classified into various subsets based on their surface markers including T cell receptors, type of antigen presentation and pathophysiological functions. Several studies have implicated various T cell subsets and natural killer (NK) cells in the progression of NAFLD. While NK cells are mainly components of the innate hepatic immune system, the majority of T cell subsets can be part of both the adaptive and innate systems. Several studies have reported that various stages of NAFLD are accompanied by the accumulation of distinct T cell subsets and NK cells with different functions and phenotypes observed usually resulting in proinflammatory effects. More importantly, the overall stimulation of the intrahepatic T cell subsets is directly influenced by the homeostasis of the gut microbiota. Similarly, NK cells have been found to accumulate in the liver in response to pathogens and tumors. In this review, we discussed the nature and pathophysiological roles of T cell subsets including γδ T cells, NKT cells, Mucosal-associated invariant T (MAIT) cells as well as NK cells in NAFLD.
    Keywords:  MHC I; MHC II; NK cells; T cells; antigen presenting cell; gut microbiota; nonalcoholic fatty liver disease
    DOI:  https://doi.org/10.3390/ijms222212190
  2. JHEP Rep. 2022 Jan;4(1): 100387
    Bile acids contribute to the development of non-alcoholic steatohepatitis in mice.
    Justine Gillard, Laure-Alix Clerbaux, Maxime Nachit, Christine Sempoux, Bart Staels, Laure B Bindels, Anne Tailleux, Isabelle A Leclercq.
       Background & Aims: Through FXR and TGR5 signaling, bile acids (BAs) modulate lipid and glucose metabolism, inflammation and fibrosis. Hence, BAs returning to the liver after enteric secretion, modification and reabsorption may contribute to the pathogenesis of non-alcoholic steatohepatitis (NASH). Herein, we characterized the enterohepatic profile and signaling of BAs in preclinical models of NASH, and explored the consequences of experimental manipulation of BA composition.
    Methods: We used high-fat diet (HFD)-fed foz/foz and high-fructose western diet-fed C57BL/6J mice, and compared them to their respective controls. Mice received a diet supplemented with deoxycholic acid (DCA) to modulate BA composition.
    Results: Compared to controls, mice with NASH had lower concentrations of BAs in their portal blood and bile, while systemic BA concentrations were not significantly altered. Notably, the concentrations of secondary BAs, and especially of DCA, and the ratio of secondary to primary BAs were strikingly lower in bile and portal blood of mice with NASH. Hence, portal blood was poor in FXR and TGR5 ligands, and conferred poor anti-inflammatory protection in mice with NASH. Enhanced primary BAs synthesis and conversion of secondary to primary BAs in NASH livers contributed to the depletion in secondary BAs. Dietary DCA supplementation in HFD-fed foz/foz mice restored the BA concentrations in portal blood, increased TGR5 and FXR signaling, improved the dysmetabolic status, protected from steatosis and hepatocellular ballooning, and reduced macrophage infiltration.
    Conclusions: BA composition in the enterohepatic cycle, but not in systemic circulation, is profoundly altered in preclinical models of NASH, with specific depletion in secondary BAs. Dietary correction of the BA profile protected from NASH, supporting a role for enterohepatic BAs in the pathogenesis of NASH.
    Lay summary: This study clearly demonstrates that the alterations of enterohepatic bile acids significantly contribute to the development of non-alcoholic steatohepatitis in relevant preclinical models. Indeed, experimental modulation of bile acid composition restored perturbed FXR and TGR5 signaling and prevented non-alcoholic steatohepatitis and associated metabolic disorders.
    Keywords:  ASBT, apical sodium-dependent BA transporter; BA, bile acid; CA, cholic acid; CDCA, chenodeoxycholic acid; CYP27A1, sterol 27-hydroxylase; CYP2A12, bile acid 7α-hydroxylase; CYP7A1, cholesterol 7α-hydroxylase; CYP7B1, oxysterol 7α-hydroxylase; CYP8B1, sterol 12α-hydroxylase; DCA, deoxycholic acid; FABP6, fatty acid binding protein 6; FGF15, fibroblast growth factor 15; FGFR4, fibroblast growth factor receptor 4; FXR; FXR, Farnesoid X receptor; GLP-1, glucagon-like peptide-1; HFD, high-fat diet; LCA, lithocholic acid; LPS, lipopolysaccharide; NAFLD; NAFLD, non-alcoholic fatty liver disease; NAS, NAFLD activity score; NASH; NASH, non-alcoholic steatohepatitis; ND, normal diet; OGTT, oral glucose tolerance test; OST, organic solute transporter; SHP, small heterodimer protein; TGR5; TGR5, Takeda G-protein coupled receptor 5; TLCA, tauro-lithocholic acid; TNFα, tumor necrosis factor α; WDF, western and high-fructose diet; WT, wild-type; metabolic syndrome; αMCA, α-muricholic acid; βMCA, β-muricholic acid; ωMCA, ω-muricholic acid
    DOI:  https://doi.org/10.1016/j.jhepr.2021.100387
  3. Cancers (Basel). 2021 Nov 15. pii: 5719. [Epub ahead of print]13(22):
    The Hepatic Sinusoid in Chronic Liver Disease: The Optimal Milieu for Cancer.
    Albert Gibert-Ramos, David Sanfeliu-Redondo, Peio Aristu-Zabalza, Ana Martínez-Alcocer, Jordi Gracia-Sancho, Sergi Guixé-Muntet, Anabel Fernández-Iglesias.
      The liver sinusoids are a unique type of microvascular beds. The specialized phenotype of sinusoidal cells is essential for their communication, and for the function of all hepatic cell types, including hepatocytes. Liver sinusoidal endothelial cells (LSECs) conform the inner layer of the sinusoids, which is permeable due to the fenestrae across the cytoplasm; hepatic stellate cells (HSCs) surround LSECs, regulate the vascular tone, and synthetize the extracellular matrix, and Kupffer cells (KCs) are the liver-resident macrophages. Upon injury, the harmonic equilibrium in sinusoidal communication is disrupted, leading to phenotypic alterations that may affect the function of the whole liver if the damage persists. Understanding how the specialized sinusoidal cells work in coordination with each other in healthy livers and chronic liver disease is of the utmost importance for the discovery of new therapeutic targets and the design of novel pharmacological strategies. In this manuscript, we summarize the current knowledge on the role of sinusoidal cells and their communication both in health and chronic liver diseases, and their potential pharmacologic modulation. Finally, we discuss how alterations occurring during chronic injury may contribute to the development of hepatocellular carcinoma, which is usually developed in the background of chronic liver disease.
    Keywords:  CLD; HSC; Kupffer cell; LSEC; NASH; cirrhosis; hepatocellular carcinoma; portal hypertension
    DOI:  https://doi.org/10.3390/cancers13225719
  4. Nat Rev Gastroenterol Hepatol. 2021 Nov 23.
    Promising results for exclusion diet in adults.
    Caroline Barranco.
      
    DOI:  https://doi.org/10.1038/s41575-021-00560-z
  5. Trends Cancer. 2021 Nov 20. pii: S2405-8033(21)00223-5. [Epub ahead of print]
    Antimetastatic defense by CD8+ T cells.
    Paulino Tallón de Lara, Héctor Castañón, Michelle Sterpi, Maries van den Broek.
      Metastasis is an intricate process whereby tumor cells migrate from the primary tumor, survive in the circulation, seed distal organs, and proliferate to create metastatic foci. CD8+ T cells can detect and eliminate tumor cells. Research on CD8+ T cell-dependent antitumor immunity has classically focused on its role in the primary tumor. There is increasing evidence, however, that CD8+ T cells have unique antimetastatic functions in various steps of the metastatic cascade. Here, we review the mechanisms whereby CD8+ T cells control metastatic lesions. We discuss their role in each step of metastasis, metastatic dormancy, and metastatic clonal evolution as well as the consequent clinical repercussions.
    Keywords:  CD8(+) T cells; immunoediting; metastasis; metastatic dormancy
    DOI:  https://doi.org/10.1016/j.trecan.2021.10.006
  6. Handb Exp Pharmacol. 2021 Nov 23.
    NAFLD and NASH: The Metabolically Diseased Liver.
    Angelo Armandi, Jörn M Schattenberg.
      Non-Alcoholic Fatty Liver Disease (NAFLD) is the most common chronic liver disease, with a global prevalence of approximately 24% in the general population. It is caused by fat accumulation in the liver secondary to insulin resistance, visceral obesity, and/or features of metabolic syndrome. A genetic susceptibility contributes to the phenotype, accounting for a more severe course of liver disease and the observed clinical variability. In fact, despite liver steatosis being considered a relatively benign entity, inflammation related to oxidative stress and lipid-derived damage may lead to non-alcoholic steatohepatitis (NASH), which constitutes the progressive disease. Accumulation of hepatic fibrosis can lead to cirrhosis and provide the environment for hepatocellular carcinoma. Obese and diabetic individuals represent a well-acknowledged high risk population. The assessment of liver fibrosis plays a crucial role in clinical setting, as liver-related mortality increases parallel to fibrosis stage. A liver biopsy is currently considered the reference standard for the diagnosis of NASH and the fibrosis stage, but many non-invasive tools are used with the aim of replacing histology for diagnosis and prognosis purposes. Blood based scores and liver stiffness are the most widely used and validated tools to assess liver fibrosis. Management of NAFLD resides on environmental interventions, including diet and physical activity to induce weight loss, and avoiding harmful nutrients, including fructose-sweetened beverages and high glycemic index foods, that are directly implied in liver injury. Multiple trials with investigational drugs are currently explored to treat fibrosing NASH, with promising results and it can be expected that a liver direct therapy aiming at steatohepatitis and fibrosis will become available soon.
    Keywords:  Liver fibrosis; Liver stiffness; Medical therapy; Metabolic syndrome; Non-alcoholic fatty liver disease; Non-alcoholic steatohepatitis; Non-invasive fibrosis tests; Obesity; Type 2 diabetes; Weight loss
    DOI:  https://doi.org/10.1007/164_2021_561
  7. Cell Host Microbe. 2021 Nov 18. pii: S1931-3128(21)00507-2. [Epub ahead of print]
    Human gut bacterial metabolism drives Th17 activation and colitis.
    Margaret Alexander, Qi Yan Ang, Renuka R Nayak, Annamarie E Bustion, Moriah Sandy, Bing Zhang, Vaibhav Upadhyay, Katherine S Pollard, Susan V Lynch, Peter J Turnbaugh.
      Bacterial activation of T helper 17 (Th17) cells exacerbates mouse models of autoimmunity, but how human-associated bacteria impact Th17-driven disease remains elusive. We show that human gut Actinobacterium Eggerthella lenta induces intestinal Th17 activation by lifting inhibition of the Th17 transcription factor Rorγt through cell- and antigen-independent mechanisms. E. lenta is enriched in inflammatory bowel disease (IBD) patients and worsens colitis in a Rorc-dependent manner in mice. Th17 activation varies across E. lenta strains, which is attributable to the cardiac glycoside reductase 2 (Cgr2) enzyme. Cgr2 is sufficient to induce interleukin (IL)-17a, a major Th17 cytokine. cgr2+ E. lenta deplete putative steroidal glycosides in pure culture; related compounds are negatively associated with human IBD severity. Finally, leveraging the sensitivity of Cgr2 to dietary arginine, we prevented E. lenta-induced intestinal inflammation in mice. Together, these results support a role for human gut bacterial metabolism in driving Th17-dependent autoimmunity.
    Keywords:  T helper 17 cells; autoimmune disease; dietary supplementation; human gut microbiome; inflammatory bowel disease; microbial metabolism
    DOI:  https://doi.org/10.1016/j.chom.2021.11.001
  8. Transl Gastroenterol Hepatol. 2021 ;6 60
    Narrative review of current and emerging pharmacological therapies for nonalcoholic steatohepatitis.
    Jinendra Satiya, Heather S Snyder, Shivaram Prasad Singh, Sanjaya K Satapathy.
      Nonalcoholic steatohepatitis (NASH) is the most common cause of chronic liver disease today, and it has now emerged as the leading etiology of end-stage liver disease requiring liver transplantation. It is a progressive form of non-alcoholic fatty liver disease which can not only progress to cirrhosis of liver and hepatocellular carcinoma (HCC), but is associated with increased cardiovascular risks too. Despite all the advances in the understanding of the risk factors and the pathogenetic pathways involved in the pathogenesis and progression of NASH, an effective therapy for NASH has not been developed yet. Although lifestyle modifications including dietary modifications and physical activity remain the mainstay of therapy, there is an unmet need to develop a drug or a combination of drugs which can not only reduce the fatty infiltration of the liver, but also arrest the development and progression of fibrosis and advancement to cirrhosis of liver and HCC. The pharmacologic therapies which are being developed target the various components believed to be involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD)/NASH which includes insulin resistance, lipid metabolism oxidative stress, lipid peroxidation, inflammatory and cell death pathways, and fibrosis. In this review, we summarize the current state of knowledge on pharmacotherapy of NASH, and also highlight the recent developments in the field, for optimizing the management and treatment of NASH.
    Keywords:  Cirrhosis; fibrosis; nonalcoholic fatty liver disease (NAFLD); nonalcoholic steatohepatitis (NASH); treatment
    DOI:  https://doi.org/10.21037/tgh-20-247
  9. J Viral Hepat. 2021 Nov 25.
    Intrahepatic immune infiltrate in chronic hepatitis B and chronic hepatitis C: Similar but not the same.
    Cecilia Graciela Giadans, Daniela Alejandra Ríos, Beatriz Ameigeiras, Leila Haddad, Elena Noemí De Matteo, Pamela Valva, María Victoria Preciado.
      In chronic hepatitis B (CHB) and C (CHC) infections the composition of the immune cell microenvironment at the site of infection is poorly understood. Thus, our aim was to characterize and compare liver infiltrates to identify shared and exclusive hepatic immune components. Immunohistochemistry was performed on 26 CHB and 42 CHC liver biopsies to determine Th (CD4+), Th1 (Tbet+), Th17 (IL-17A+), Treg (Foxp3+), and CTL (CD8+) cells frequency in portal/periportal and intralobular areas and relate them to liver damage. CHB and CHC cases shared a portal/periportal CD4+ lymphocyte predominance and a lobular CD8+ lymphocyte majority. However, CHC exhibited a concomitant lobular T-bet+ cell dominance while in CHB FoxP3+ cells prevail. CHC disclosed higher frequencies of P/P FoxP3+, IL-17A+ and T-bet+ cells and intralobular CD4+, IL-17A+ and T-bet+ lymphocytes. HBeAg+ chronic hepatitis and CHC cell frequencies were similar except for lobular T-bet+ that remained higher among CHC cases. Comparison among cases with less severe liver disease revealed lower lymphocyte frequencies in CHB samples, while no differences were observed between patients with more severe stages. Interestingly, in CHB portal/periportal CD4+ and lobular CD4+, CD8+ and IL-17A+ cells were associated to severe hepatitis. Even when all studied populations were identified in both infections preferential lymphocyte frequencies and prevalence at different areas along with their association with liver damage highlighted that CHB and CHC immune responses are not the same.
    Keywords:  CTL; Th lymphocyte; chronic hepatitis B; chronic hepatitis C; immune infiltrate; liver disease
    DOI:  https://doi.org/10.1111/jvh.13635
  10. Proc Natl Acad Sci U S A. 2021 Nov 30. pii: e2105927118. [Epub ahead of print]118(48):
    Th17 cell master transcription factor RORC2 regulates HIV-1 gene expression and viral outgrowth.
    Tomas Raul Wiche Salinas, Yuwei Zhang, Daniele Sarnello, Alexander Zhyvoloup, Laurence Raymond Marchand, Augustine Fert, Delphine Planas, Manivel Lodha, Debashree Chatterjee, Katarzyna Karwacz, Sally Oxenford, Jean-Pierre Routy, David Irlbeck, Heather Amrine-Madsen, Petronela Ancuta, Ariberto Fassati.
      Among CD4+ T cells, T helper 17 (Th17) cells are particularly susceptible to HIV-1 infection and are depleted from mucosal sites, which causes damage to the gut barrier, resulting in a microbial translocation-induced systemic inflammation, a hallmark of disease progression. Furthermore, a proportion of latently infected Th17 cells persist long term in the gastrointestinal lymphatic tract where a low-level HIV-1 transcription is observed. This residual viremia contributes to chronic immune activation. Thus, Th17 cells are key players in HIV pathogenesis and viral persistence. It is, however, unclear why these cells are highly susceptible to HIV-1 infection. Th17 cell differentiation depends on the expression of the master transcriptional regulator RORC2, a retinoic acid-related nuclear hormone receptor that regulates specific transcriptional programs by binding to promoter/enhancer DNA. Here, we report that RORC2 is a key host cofactor for HIV replication in Th17 cells. We found that specific inhibitors that bind to the RORC2 ligand-binding domain reduced HIV replication in CD4+ T cells. The depletion of RORC2 inhibited HIV-1 infection, whereas its overexpression enhanced it. RORC2 was also found to promote HIV-1 gene expression by binding to the nuclear receptor responsive element in the HIV-1 long terminal repeats (LTR). In treated HIV-1 patients, RORC2+ CD4 T cells contained more proviral DNA than RORC2- cells. Pharmacological inhibition of RORC2 potently reduced HIV-1 outgrowth in CD4+ T cells from antiretroviral-treated patients. Altogether, these results provide an explanation as to why Th17 cells are highly susceptible to HIV-1 infection and suggest that RORC2 may be a cell-specific target for HIV-1 therapy.
    Keywords:  HIV-1; RORC2; Th17; gene expression; hormone receptor
    DOI:  https://doi.org/10.1073/pnas.2105927118
  11. Biochem Pharmacol. 2021 Nov 18. pii: S0006-2952(21)00461-5. [Epub ahead of print] 114845
    Models of nonalcoholic steatohepatitis potentiated by chemical inducers leading to hepatocellular carcinoma.
    Linda Vanessa Márquez-Quiroga, Jaime Arellanes-Robledo, Verónica Rocío Vásquez-Garzón, Saul Villa-Treviño, Pablo Muriel.
      Hepatocellular carcinoma (HCC), the most common primary liver cancer, arises after a long period of exposure to etiological factors. Nonalcoholic steatohepatitis (NASH) is ranked as the main risk factor for developing HCC; hence, experimental models of NASH leading to HCC have become key tools both to investigate the molecular mechanisms underlying the pathophysiology and to evaluate new putative drugs for treating chronic liver diseases in humans. Animal models of NASH induced by a high-fat diet (HFD) plus chemical inducers, such as the NASH-HCC (STAM), high-fat diet/diethylnitrosamine (HFD/DEN), choline-deficient high-fat diet/DEN (CDHFD/DEN), and Western diet/carbon tetrachloride (WD/CCl4) models, are promising because they exacerbate liver damage and significantly shorten the experimental time. In this review, we critically summarize and discuss the ability of these models to recapitulate the liver alterations that precede and lead to HCC progression, as well as the impact of the diet in promoting liver injury progression. We also emphasize the strengths and weaknesses of the models' ability to closely mimic the stages of liver injury development that occur in humans. Based on the molecular mechanisms induced by the currently available NASH models leading to HCC, we argue that although several NASH models have importantly contributed to describing the disease chronology, the progress in emulating the progression from NASH to HCC has been partial. Thus, the development of novel NASH/HCC models remains an unmet need.
    Keywords:  STAM; Western diet; diethylnitrosamine; hepatocellular carcinoma; high fatty diet; non-alcoholic steatohepatitis
    DOI:  https://doi.org/10.1016/j.bcp.2021.114845
  12. J Transl Med. 2021 Nov 25. 19(1): 477
    CD226 knockout alleviates high-fat diet induced obesity by suppressing proinflammatory macrophage phenotype.
    Jingchang Ma, Wei Hu, Dongliang Zhang, Jiangang Xie, Chujun Duan, Yitian Liu, Yuling Wang, Xuexue Xu, Kun Cheng, Boquan Jin, Yuan Zhang, Ran Zhuang.
      Obesity is associated with chronic low-grade inflammation, contributing to an increasing prevalence of chronic metabolic diseases, such as insulin resistance, non-alcoholic fatty liver disease (NALFD), and steatohepatitis. Macrophages are the predominant immune cells in adipose tissues. Adipose tissue macrophages (ATMs) would switch to pro-inflammatory M1 state during obesity, causing local and systemic inflammation. However, the regulatory mechanism of ATMs has not yet been well described within this process. Using a high-fat diet (HFD)-induced mouse obesity model, we found that the costimulatory molecule CD226 was highly expressed on ATMs and knockout (KO) of CD226 alleviated obesity caused by HFD. Loss of CD226 reduced the accumulation of ATMs and hindered macrophage M1 polarization, with lower serum proinflammatory cytokine levels. Furthermore, deficiency of CD226 on ATMs decreased the phosphorylation levels of VAV1, AKT, and FOXO1 and thereby upregulated PPAR-γ. Further administration of PPAR-γ inhibitor restored M1 phenotype in CD226KO ATMs. In summary, loss of CD226 alleviates the HFD-induced obesity and systemic inflammation through inhibition of the accumulation and M1 polarization of ATMs in which PPAR-γ-dependent signaling pathway is involved, suggesting that CD226 may be identified as a potential molecular target for the clinical treatment of obesity.
    Keywords:  CD226; HFD; Macrophage; Obesity; Polarization
    DOI:  https://doi.org/10.1186/s12967-021-03150-4
  13. Biomedicines. 2021 Nov 02. pii: 1598. [Epub ahead of print]9(11):
    Mesenchymal Stem Cells Influence Activation of Hepatic Stellate Cells, and Constitute a Promising Therapy for Liver Fibrosis.
    Chanbin Lee, Minju Kim, Jinsol Han, Myunghee Yoon, Youngmi Jung.
      Liver fibrosis is a common feature of chronic liver disease. Activated hepatic stellate cells (HSCs) are the main drivers of extracellular matrix accumulation in liver fibrosis. Hence, a strategy for regulating HSC activation is crucial in treating liver fibrosis. Mesenchymal stem cells (MSCs) are multipotent stem cells derived from various post-natal organs. Therapeutic approaches involving MSCs have been studied extensively in various diseases, including liver disease. MSCs modulate hepatic inflammation and fibrosis and/or differentiate into hepatocytes by interacting directly with immune cells, HSCs, and hepatocytes and secreting modulators, thereby contributing to reduced liver fibrosis. Cell-free therapy including MSC-released secretomes and extracellular vesicles has elicited extensive attention because they could overcome MSC transplantation limitations. Herein, we provide basic information on hepatic fibrogenesis and the therapeutic potential of MSCs. We also review findings presenting the effects of MSC itself and MSC-based cell-free treatments in liver fibrosis, focusing on HSC activation. Growing evidence supports the anti-fibrotic function of either MSC itself or MSC modulators, although the mechanism underpinning their effects on liver fibrosis has not been established. Further studies are required to investigate the detailed mechanism explaining their functions to expand MSC therapies using the cell itself and cell-free treatments for liver fibrosis.
    Keywords:  cell-free therapy; extracellular vesicles; hepatic stellate cells; liver fibrosis; mesenchymal stem cells
    DOI:  https://doi.org/10.3390/biomedicines9111598
  14. Biomolecules. 2021 Nov 15. pii: 1696. [Epub ahead of print]11(11):
    Immunotoxins: From Design to Clinical Application.
    Robert J Kreitman, Ira Pastan.
      The Special Issue of Biomolecules entitled "Immunotoxins, From Design to Clinical Application" contains seven reviews related to immunotoxins [...].
    DOI:  https://doi.org/10.3390/biom11111696
  15. Trends Mol Med. 2021 Nov 20. pii: S1471-4914(21)00277-X. [Epub ahead of print]
    Linking liver metabolic and vascular disease via bile acid signaling.
    Stefano Fiorucci, Eleonora Distrutti.
      Non-alcoholic fatty liver disease (NAFLD) is a metabolic disorder affecting over one quarter of the global population. Liver fat accumulation in NAFLD is promoted by increased de novo lipogenesis leading to the development of a proatherosclerotic lipid profile and atherosclerotic cardiovascular disease (CVD). The CVD component of NAFLD is the main determinant of patient outcome. The farnesoid X receptor (FXR) and the G protein bile acid-activated receptor 1 (GPBAR1) are bile acid-activated receptors that modulate inflammation and lipid and glucose metabolism in the liver and CV system, and are thus potential therapeutic targets. We review bile acid signaling in liver, metabolic tissues, and the CV system, and we propose the development of dual FXR/GPBAR1 ligands, intestine-restricted FXR ligands, or statin combinations to limit side effects and effectively manage the liver and CV components of NAFLD.
    Keywords:  FXR; GPBAR1; bile acid; cardiovascular disease; non-alcoholic fatty liver disease (NAFLD)
    DOI:  https://doi.org/10.1016/j.molmed.2021.10.005
  16. J Immunol. 2021 Nov 22. pii: ji2100334. [Epub ahead of print]
    Invariant NKT Cells Promote the Development of Highly Cytotoxic Multipotent CXCR3+CCR4+CD8+ T Cells That Mediate Rapid Hepatocyte Allograft Rejection.
    Jason M Zimmerer, Bryce A Ringwald, Sachi R Chaudhari, Jing Han, Chelsea M Peterson, Robert T Warren, Madison M Hart, Mahmoud Abdel-Rasoul, Ginny L Bumgardner.
      Hepatocyte transplant represents a treatment for metabolic disorders but is limited by immunogenicity. Our prior work identified the critical role of CD8+ T cells, with or without CD4+ T cell help, in mediating hepatocyte rejection. In this study, we evaluated the influence of invariant NKT (iNKT) cells, uniquely abundant in the liver, upon CD8-mediated immune responses in the presence and absence of CD4+ T cells. To investigate this, C57BL/6 (wild-type) and iNKT-deficient Jα18 knockout mice (cohorts CD4 depleted) were transplanted with allogeneic hepatocytes. Recipients were evaluated for alloprimed CD8+ T cell subset composition, allocytotoxicity, and hepatocyte rejection. We found that CD8-mediated allocytotoxicity was significantly decreased in iNKT-deficient recipients and was restored by adoptive transfer of iNKT cells. In the absence of both iNKT cells and CD4+ T cells, CD8-mediated allocytotoxicity and hepatocyte rejection was abrogated. iNKT cells enhance the proportion of a novel subset of multipotent, alloprimed CXCR3+CCR4+CD8+ cytolytic T cells that develop after hepatocyte transplant and are abundant in the liver. Alloprimed CXCR3+CCR4+CD8+ T cells express cytotoxic effector molecules (perforin/granzyme and Fas ligand) and are distinguished from alloprimed CXCR3+CCR4-CD8+ T cells by a higher proportion of cells expressing TNF-α and IFN-γ. Furthermore, alloprimed CXCR3+CCR4+CD8+ T cells mediate higher allocytotoxicity and more rapid allograft rejection. Our data demonstrate the important role of iNKT cells in promoting the development of highly cytotoxic, multipotent CXCR3+CCR4+CD8+ T cells that mediate rapid rejection of allogeneic hepatocytes engrafted in the liver. Targeting iNKT cells may be an efficacious therapy to prevent rejection of intrahepatic cellular transplants.
    DOI:  https://doi.org/10.4049/jimmunol.2100334
  17. Metabolites. 2021 Nov 06. pii: 762. [Epub ahead of print]11(11):
    Hepatic Response of Magnesium-Restricted Wild Type Mice.
    Vera H Fengler, Tanja Macheiner, Walter Goessler, Maria Ratzer, Johannes Haybaeck, Karine Sargsyan.
      Magnesium-deficiency is implicated in many metabolic disorders, e.g., type 2 diabetes and metabolic syndrome, representing risk factors for non-alcoholic fatty liver disease (NAFLD). This study aims to investigate the contribution of magnesium-restriction to the development of NAFLD. Magnesium-deficiency was induced in C57BL/6 mice by feeding a magnesium-deficient-diet. Metabolic markers as well as markers of inflammation and liver function were assessed. Furthermore, liver tissue was examined histopathologically and compared with specimens from high-fat-diet fed and control mice. Finally, the hepatic inflammatory response was quantified by determining hepatic IL-6, TNFα, and MCP-1. Magnesium-restriction resulted in at least a 2-fold significant reduction of serum magnesium levels compared to the high-fat-diet fed and control mice, whereas the hepatic magnesium content was decreased due to high-fat-diet feeding. No changes in metabolic markers in magnesium-restricted mice were observed, while the cholesterol content was elevated in high-fat-diet fed mice. Magnesium-restricted mice additionally featured inflammation and enlarged hepatocytes in liver histology. Furthermore, magnesium-restricted and high-fat-diet fed mice exhibited elevated hepatic TNFα levels compared to control mice. Accordingly, our data suggest that magnesium is involved in hepatic inflammatory processes and hepatocyte enlargement, key histological features of human NAFLD, and may therefore contribute to development and progression of the disease.
    Keywords:  experimental mouse model; hepatic inflammation; hepatic steatosis; magnesium-deficiency; magnesium-restriction; non-alcoholic fatty liver disease
    DOI:  https://doi.org/10.3390/metabo11110762
  18. Biomedicines. 2021 Nov 17. pii: 1705. [Epub ahead of print]9(11):
    CD63+ and MHC Class I+ Subsets of Extracellular Vesicles Produced by Wild-Type and CD47-Deficient Jurkat T Cells Have Divergent Functional Effects on Endothelial Cell Gene Expression.
    Sukhbir Kaur, Abdel G Elkahloun, Jennifer D Petersen, Anush Arakelyan, Ferenc Livak, Satya P Singh, Leonid Margolis, Joshua Zimmerberg, David D Roberts.
      T cells and endothelial cells engage in bidirectional communication that regulates angiogenesis and T cell transmigration. Extracellular vesicles (EVs) mediate intercellular communication by the transfer of bioactive molecules including RNAs. EVs produced by a given cell type are heterogeneous in their RNA content, but it is unclear how specific EV surface markers relate to their functional effects on target cells. Our previous work established that Jurkat T cell EVs bearing CD63, MHC-I, or CD47 surface markers contain distinct noncoding RNA populations. The present study reveals that CD63+ and MHC-I+ EVs from CD47-deficient Jurkat T cells are enriched in small non-coding RNAs relative to EVs from wild-type Jurkat T cells. CD47-deficient Jurkat T cells secrete more CD63+ and MHC-I+ EVs, but MHC-I+ EVs are selectively taken up more by human umbilical vein endothelial cells. Transcriptomics analysis of endothelial cells treated with CD63+ or MHC-I+ EVs showed surface marker- and CD47-dependent changes in gene expression in the target cells. Gene set enrichment analysis identified CD47-dependent, and surface marker-dependent effects of T cell EVs on VEGF and inflammatory signaling, cell cycle, and lipid and cholesterol metabolism. Thus, subsets of T cell EVs differentially regulate endothelial cell metabolism and inflammatory and angiogenic responses.
    Keywords:  cell-cell communication; extracellular vesicles; non-coding RNAs
    DOI:  https://doi.org/10.3390/biomedicines9111705
  19. Nat Rev Gastroenterol Hepatol. 2021 Nov 23.
    Maralixibat relieves chronic cholestasis in children.
    Caroline Barranco.
      
    DOI:  https://doi.org/10.1038/s41575-021-00558-7
  20. Biomedicines. 2021 Oct 23. pii: 1524. [Epub ahead of print]9(11):
    Genetics, Immunity and Nutrition Boost the Switching from NASH to HCC.
    Paola Dongiovanni, Marica Meroni, Miriam Longo, Silvia Fargion, Anna Ludovica Fracanzani.
      Nonalcoholic fatty liver disease (NAFLD) is the leading contributor to the global burden of chronic liver diseases. The phenotypic umbrella of NAFLD spans from simple and reversible steatosis to nonalcoholic steatohepatitis (NASH), which may worsen into cirrhosis and hepatocellular carcinoma (HCC). Notwithstanding, HCC may develop also in the absence of advanced fibrosis, causing a delayed time in diagnosis as a consequence of the lack of HCC screening in these patients. The precise event cascade that may precipitate NASH into HCC is intricate and it entails diverse triggers, encompassing exaggerated immune response, endoplasmic reticulum (ER) and oxidative stress, organelle derangement and DNA aberrancies. All these events may be accelerated by both genetic and environmental factors. On one side, common and rare inherited variations that affect hepatic lipid remodeling, immune microenvironment and cell survival may boost the switching from steatohepatitis to liver cancer, on the other, diet-induced dysbiosis as well as nutritional and behavioral habits may furtherly precipitate tumor onset. Therefore, dietary and lifestyle interventions aimed to restore patients' health contribute to counteract NASH progression towards HCC. Even more, the combination of therapeutic strategies with dietary advice may maximize benefits, with the pursuit to improve liver function and prolong survival.
    Keywords:  HCC; NAFLD; NASH; heritability; nutrition
    DOI:  https://doi.org/10.3390/biomedicines9111524
  21. Sci Immunol. 2021 Nov 23. eabl9929
    Administration of aerosolized SARS-CoV-2 to K18-hACE2 mice uncouples respiratory infection from fatal neuroinvasion.
    Valeria Fumagalli, Micol Ravà, Davide Marotta, Pietro Di Lucia, Chiara Laura, Eleonora Sala, Marta Grillo, Elisa Bono, Leonardo Giustini, Chiara Perucchini, Marta Mainetti, Alessandro Sessa, José M Garcia-Manteiga, Lorena Donnici, Lara Manganaro, Serena Delbue, Vania Broccoli, Raffaele De Francesco, Patrizia D'Adamo, Mirela Kuka, Luca G Guidotti, Matteo Iannacone.
      [Figure: see text].
  22. N Engl J Med. 2021 Nov 25. 385(22): 2066-2076
    New Horizons in the Treatment of Osteosarcoma.
    Paul S Meltzer, Lee J Helman.
      
    DOI:  https://doi.org/10.1056/NEJMra2103423
  23. Nat Rev Gastroenterol Hepatol. 2021 Nov 23.
    Anatomy-preserving adjustable intragastric balloon is safe and promotes durable weight loss.
    Caroline Barranco.
      
    DOI:  https://doi.org/10.1038/s41575-021-00559-6
  24. Cells. 2021 Nov 05. pii: 3039. [Epub ahead of print]10(11):
    Trans-Ned 19-Mediated Antagonism of Nicotinic Acid Adenine Nucleotide-Mediated Calcium Signaling Regulates Th17 Cell Plasticity in Mice.
    Mikołaj Nawrocki, Niels Lory, Tanja Bedke, Friederike Stumme, Björn-Phillip Diercks, Andreas H Guse, Chris Meier, Nicola Gagliani, Hans-Willi Mittrücker, Samuel Huber.
      Nicotinic acid adenine dinucleotide phosphate (NAADP) is the most potent Ca2+ mobilizing agent and its inhibition proved to inhibit T-cell activation. However, the impact of the NAADP signaling on CD4+ T-cell differentiation and plasticity and on the inflammation in tissues other than the central nervous system remains unclear. In this study, we used an antagonist of NAADP signaling, trans-Ned 19, to study the role of NAADP in CD4+ T-cell differentiation and effector function. Partial blockade of NAADP signaling in naïve CD4+ T cells in vitro promoted the differentiation of Th17 cells. Interestingly, trans-Ned 19 also promoted the production of IL-10, co-expression of LAG-3 and CD49b and increased the suppressive capacity of Th17 cells. Moreover, using an IL-17A fate mapping mouse model, we showed that NAADP inhibition promotes conversion of Th17 cells into regulatory T cells in vitro and in vivo. In line with the results, we found that inhibiting NAADP ameliorates disease in a mouse model of intestinal inflammation. Thus, these results reveal a novel function of NAADP in controlling the differentiation and plasticity of CD4+ T cells.
    Keywords:  Ca2+ signaling; NAADP; T cells; adenine nucleotides; immune regulation; immune therapy; inflammatory diseases
    DOI:  https://doi.org/10.3390/cells10113039
  25. Cell Mol Immunol. 2021 Nov 26.
    Resident and migratory adipose immune cells control systemic metabolism and thermogenesis.
    Kevin Man, Axel Kallies, Ajithkumar Vasanthakumar.
      Glucose is a vital source of energy for all mammals. The balance between glucose uptake, metabolism and storage determines the energy status of an individual, and perturbations in this balance can lead to metabolic diseases. The maintenance of organismal glucose metabolism is a complex process that involves multiple tissues, including adipose tissue, which is an endocrine and energy storage organ that is critical for the regulation of systemic metabolism. Adipose tissue consists of an array of different cell types, including specialized adipocytes and stromal and endothelial cells. In addition, adipose tissue harbors a wide range of immune cells that play vital roles in adipose tissue homeostasis and function. These cells contribute to the regulation of systemic metabolism by modulating the inflammatory tone of adipose tissue, which is directly linked to insulin sensitivity and signaling. Furthermore, these cells affect the control of thermogenesis. While lean adipose tissue is rich in type 2 and anti-inflammatory cytokines such as IL-10, obesity tips the balance in favor of a proinflammatory milieu, leading to the development of insulin resistance and the dysregulation of systemic metabolism. Notably, anti-inflammatory immune cells, including regulatory T cells and innate lymphocytes, protect against insulin resistance and have the characteristics of tissue-resident cells, while proinflammatory immune cells are recruited from the circulation to obese adipose tissue. Here, we review the key findings that have shaped our understanding of how immune cells regulate adipose tissue homeostasis to control organismal metabolism.
    Keywords:  adipose tissue; immune cells; metabolism
    DOI:  https://doi.org/10.1038/s41423-021-00804-7
  26. Biomedicines. 2021 Nov 10. pii: 1660. [Epub ahead of print]9(11):
    Role of Ferroptosis in Non-Alcoholic Fatty Liver Disease and Its Implications for Therapeutic Strategies.
    Han Zhang, Enxiang Zhang, Hongbo Hu.
      Non-alcoholic fatty liver disease (NAFLD) has become the chronic liver disease with the highest incidence throughout the world, but its pathogenesis has not been fully elucidated. Ferroptosis is a novel form of programmed cell death caused by iron-dependent lipid peroxidation. Abnormal iron metabolism, lipid peroxidation, and accumulation of polyunsaturated fatty acid phospholipids (PUFA-PLs) can all trigger ferroptosis. Emerging evidence indicates that ferroptosis plays a critical role in the pathological progression of NAFLD. Because the liver is the main organ for iron storage and lipid metabolism, ferroptosis is an ideal target for liver diseases. Inhibiting ferroptosis may become a new therapeutic strategy for the treatment of NAFLD. In this article, we describe the role of ferroptosis in the progression of NAFLD and its related mechanisms. This review will highlight further directions for the treatment of NAFLD and the selection of corresponding drugs that target ferroptosis.
    Keywords:  NAFLD; ferroptosis; iron metabolism; lipid peroxidation
    DOI:  https://doi.org/10.3390/biomedicines9111660
  27. Biomed Pharmacother. 2021 Nov 20. pii: S0753-3322(21)01227-0. [Epub ahead of print]145 112441
    SP-1154, a novel synthetic TGF-β inhibitor, alleviates obesity and hepatic steatosis in high-fat diet-induced mice.
    Kisoo Pahk, Sang Gil Lee, Chanmin Joung, Eun-Ok Kim, Hyun Woo Kwon, Dong Hwi Kim, Jong-Ik Hwang, Sungeun Kim, Won-Ki Kim.
       OBJECTIVE: Obesity-induced inflamed visceral adipose tissue (VAT) secretes pro-inflammatory cytokines thereby promoting systemic inflammation and insulin resistance which further exacerbate obesity-associated nonalcoholic fatty liver disease (NAFLD). Transforming growth factor (TGF)-β /Smad3 signaling plays a crucial role in the inflammatory events within the VAT. Here, we investigate whether SP-1154, a novel synthetic verbenone derivative, can inhibit TGF-β/Smad3 signaling thereby exhibiting a therapeutic effect against obesity-induced inflamed VAT and subsequent NAFLD in high-fat diet-induced mice.
    METHODS: NAFLD was induced by a high-fat diet (60% fat) for 20 weeks using the male C57BL/6 mice. SP-1154 (50 mg/kg) was orally given daily for 20 weeks. In vivo VAT- and systemic inflammation were measured by using 18F-fluorodeoxyglucose positron emission tomography and C-reactive protein levels. Both insulin tolerance- and glucose tolerance test were performed to assess the status of insulin resistance and glucose intolerance. Histological and molecular analyses were performed on harvested liver and VAT.
    KEY FINDINGS: SP-1154 inhibited TGF-β/Smad3 signaling pathway and remarkably suppressed high-fat diet-induced VAT inflammation and its related systemic inflammation. Furthermore, SP-1154 significantly improved insulin sensitivity with glucose homeostasis and reduced hepatic steatosis. SP-1154 significantly improves VAT inflammation and obesity-related NAFLD.
    CONCLUSION: Our novel findings support the potential use of SP-1154 as a therapeutic drug for obesity and its related NAFLD by targeting the inflamed VAT.
    Keywords:  Inflammation; NAFLD; Obesity; Smad3; TGF-β; Visceral fat
    DOI:  https://doi.org/10.1016/j.biopha.2021.112441
  28. Nutrients. 2021 Oct 22. pii: 3725. [Epub ahead of print]13(11):
    Gut Microbiota Reshaped by Pectin Treatment Improves Liver Steatosis in Obese Mice.
    Camille Houron, Dragos Ciocan, Nicolas Trainel, Françoise Mercier-Nomé, Cindy Hugot, Madeleine Spatz, Gabriel Perlemuter, Anne-Marie Cassard.
      Pectin, a soluble fiber, improves non-alcoholic fatty-liver disease (NAFLD), but its mechanisms are unclear. We aimed to investigate the role of pectin-induced changes in intestinal microbiota (IM) in NAFLD. We recovered the IM from mice fed a high-fat diet, treated or not with pectin, to perform a fecal microbiota transfer (FMT). Mice fed a high-fat diet, which induces NAFLD, were treated with pectin or received a fecal microbiota transfer (FMT) from mice treated with pectin before (preventive FMT) or after (curative FMT) being fed a high-fat diet. Pectin prevented the development of NAFLD, induced browning of adipose tissue, and modified the IM without increasing the abundance of proteobacteria. Preventive FMT also induced browning of white adipose tissue but did not improve liver steatosis, in contrast to curative FMT, which induced an improvement in steatosis. This was associated with an increase in the concentration of short-chain fatty acids (SCFAs), in contrast to preventive FMT, which induced an increase in the concentration of branched SCFAs. Overall, we show that the effect of pectin may be partially mediated by gut bacteria.
    Keywords:  NAFLD; NASH; SCFA; fecal microbiota transplantation; fiber; pectin
    DOI:  https://doi.org/10.3390/nu13113725
  29. Cells. 2021 Nov 14. pii: 3164. [Epub ahead of print]10(11):
    High-Fat, Western-Style Diet, Systemic Inflammation, and Gut Microbiota: A Narrative Review.
    Ida Judyta Malesza, Michał Malesza, Jarosław Walkowiak, Nadiar Mussin, Dariusz Walkowiak, Raisa Aringazina, Joanna Bartkowiak-Wieczorek, Edyta Mądry.
      The gut microbiota is responsible for recovering energy from food, providing hosts with vitamins, and providing a barrier function against exogenous pathogens. In addition, it is involved in maintaining the integrity of the intestinal epithelial barrier, crucial for the functional maturation of the gut immune system. The Western diet (WD)-an unhealthy diet with high consumption of fats-can be broadly characterized by overeating, frequent snacking, and a prolonged postprandial state. The term WD is commonly known and intuitively understood. However, the strict digital expression of nutrient ratios is not precisely defined. Based on the US data for 1908-1989, the calory intake available from fats increased from 32% to 45%. Besides the metabolic aspects (hyperinsulinemia, insulin resistance, dyslipidemia, sympathetic nervous system and renin-angiotensin system overstimulation, and oxidative stress), the consequences of excessive fat consumption (high-fat diet-HFD) comprise dysbiosis, gut barrier dysfunction, increased intestinal permeability, and leakage of toxic bacterial metabolites into the circulation. These can strongly contribute to the development of low-grade systemic inflammation. This narrative review highlights the most important recent advances linking HFD-driven dysbiosis and HFD-related inflammation, presents the pathomechanisms for these phenomena, and examines the possible causative relationship between pro-inflammatory status and gut microbiota changes.
    Keywords:  LPS; NF-κB; TLR4; bile acids; dysbiosis; endoplasmic reticulum stress; endotoxemia; leaky gut; oxidative stress; postprandial inflammation
    DOI:  https://doi.org/10.3390/cells10113164
  30. Cell Rep. 2021 Nov 23. pii: S2211-1247(21)01512-6. [Epub ahead of print]37(8): 110030
    The asymmetric Pitx2 gene regulates gut muscular-lacteal development and protects against fatty liver disease.
    Shing Hu, Aparna Mahadevan, Isaac F Elysee, Joseph Choi, Nathan R Souchet, Gloria H Bae, Alessandra K Taboada, Bhargav Sanketi, Gerald E Duhamel, Carolyn S Sevier, Ge Tao, Natasza A Kurpios.
      Intestinal lacteals are essential lymphatic channels for absorption and transport of dietary lipids and drive the pathogenesis of debilitating metabolic diseases. However, organ-specific mechanisms linking lymphatic dysfunction to disease etiology remain largely unknown. In this study, we uncover an intestinal lymphatic program that is linked to the left-right (LR) asymmetric transcription factor Pitx2. We show that deletion of the asymmetric Pitx2 enhancer ASE alters normal lacteal development through the lacteal-associated contractile smooth muscle lineage. ASE deletion leads to abnormal muscle morphogenesis induced by oxidative stress, resulting in impaired lacteal extension and defective lymphatic system-dependent lipid transport. Surprisingly, activation of lymphatic system-independent trafficking directs dietary lipids from the gut directly to the liver, causing diet-induced fatty liver disease. Our study reveals the molecular mechanism linking gut lymphatic function to the earliest symmetry-breaking Pitx2 and highlights the important relationship between intestinal lymphangiogenesis and the gut-liver axis.
    Keywords:  ASE enhancer; Pitx2; dietary lipid transport; fatty liver disease; gut lymphatic development; lacteal; left-right asymmetry; oxidative stress; portal lipid transport; villus-axial smooth muscle
    DOI:  https://doi.org/10.1016/j.celrep.2021.110030
  31. Cell. 2021 Nov 24. pii: S0092-8674(21)01283-6. [Epub ahead of print]184(24): 5842-5844
    Reply to Over-celling fetal microbial exposure.
    Archita Mishra, Leong Jing Yao, Martin Wasser, Costerwell Khyriem, Benoit Malleret, Naomi McGovern, Salvatore Albani, Jerry Kok Yen Chan, Florent Ginhoux.
      
    DOI:  https://doi.org/10.1016/j.cell.2021.10.028
  32. J Exp Med. 2022 Jan 03. pii: e20202084. [Epub ahead of print]219(1):
    A high OXPHOS CD8 T cell subset is predictive of immunotherapy resistance in melanoma patients.
    Chuan Li, Yee Peng Phoon, Keaton Karlinsey, Ye F Tian, Samjhana Thapaliya, Angkana Thongkum, Lili Qu, Alyssa Joyce Matz, Mark Cameron, Cheryl Cameron, Antoine Menoret, Pauline Funchain, Jung-Min Song, C Marcela Diaz-Montero, Banumathi Tamilselvan, Jackelyn B Golden, Michael Cartwright, Annabelle Rodriguez, Christopher Bonin, Anthony Vella, Beiyan Zhou, Brian R Gastman.
      Immune checkpoint inhibitor (ICI) therapy continues to revolutionize melanoma treatment, but only a subset of patients respond. Major efforts are underway to develop minimally invasive predictive assays of ICI response. Using single-cell transcriptomics, we discovered a unique CD8 T cell blood/tumor-shared subpopulation in melanoma patients with high levels of oxidative phosphorylation (OXPHOS), the ectonucleotidases CD38 and CD39, and both exhaustion and cytotoxicity markers. We called this population with high levels of OXPHOS "CD8+ TOXPHOS cells." We validated that higher levels of OXPHOS in tumor- and peripheral blood-derived CD8+ TOXPHOS cells correlated with ICI resistance in melanoma patients. We then developed an ICI therapy response predictive model using a transcriptomic profile of CD8+ TOXPHOS cells. This model is capable of discerning responders from nonresponders using either tumor or peripheral blood CD8 T cells with high accuracy in multiple validation cohorts. In sum, CD8+ TOXPHOS cells represent a critical immune population to assess ICI response with the potential to be a new target to improve outcomes in melanoma patients.
    DOI:  https://doi.org/10.1084/jem.20202084
  33. Viruses. 2021 Nov 08. pii: 2245. [Epub ahead of print]13(11):
    Immunological Mechanisms of Sickness Behavior in Viral Infection.
    Mia Krapić, Inga Kavazović, Felix M Wensveen.
      Sickness behavior is the common denominator for a plethora of changes in normal behavioral routines and systemic metabolism during an infection. Typical symptoms include temperature, muscle weakness, and loss of appetite. Whereas we experience these changes as a pathology, in fact they are a carefully orchestrated response mediated by the immune system. Its purpose is to optimize immune cell functionality against pathogens whilst minimizing viral replication in infected cells. Sickness behavior is controlled at several levels, most notably by the central nervous system, but also by other organs that mediate systemic homeostasis, such as the liver and adipose tissue. Nevertheless, the changes mediated by these organs are ultimately initiated by immune cells, usually through local or systemic secretion of cytokines. The nature of infection determines which cytokine profile is induced by immune cells and therefore which sickness behavior ensues. In context of infection, sickness behavior is typically beneficial. However, inappropriate activation of the immune system may induce adverse aspects of sickness behavior. For example, tissue stress caused by obesity may result in chronic activation of the immune system, leading to lasting changes in systemic metabolism. Concurrently, metabolic disease prevents induction of appropriate sickness behavior following viral infection, thus impairing the normal immune response. In this article, we will revisit recent literature that elucidates both the benefits and the negative aspects of sickness behavior in context of viral infection.
    Keywords:  T cells; anorexia; appetite; coronavirus; cytokines; cytomegalovirus; diabetes; infection; metabolic disease; metabolism; nausea; sickness behavior
    DOI:  https://doi.org/10.3390/v13112245
  34. Nutrients. 2021 Oct 25. pii: 3780. [Epub ahead of print]13(11):
    Time-Restricted Feeding Restores Obesity-Induced Alteration in Adipose Tissue Immune Cell Phenotype.
    Youngyoon Lee, Yelim Kim, Minam Lee, Dayong Wu, Munkyong Pae.
      Studies suggest that time-restricted feeding (TRF) may prevent obesity and its commodities. At present, little is known about how TRF impacts immune cells, and whether such an effect is linked to altered metabolic parameters under condition of a high-fat diet (HFD)-induced obesity. To address these issues, we conducted a study in which we determined whether TRF has therapeutic efficacy against weight gain, adiposity, as well as associated immune cell disturbance found in obese mice. Six-week-old male C57BL/6 mice were fed a low-fat diet (LFD) or HFD ad libitum for six weeks, after which time a subgroup of HFD mice was switched to the 10 h TRF paradigm (HFD-TRF) for additional eight weeks. We found that TRF intervention reduced HFD-induced weight gain. Even with comparable fat mass and mean adipocyte area, the HFD-TRF group had lower mRNA levels of proinflammatory cytokine Tnfα and chemokine Ccl8, along with reduced numbers of adipose tissue macrophages (ATM), CD11c+ ATM, and CD8+ T cell compared to the HFD group, while maintaining CD8+ to CD4+ ratio at levels similar to those in the LFD group. Furthermore, TRF intervention was effective in improving glucose tolerance and reducing HOMA-IR. Taken together, our findings suggest that TRF restores the obesity-induced alteration in immune cell composition, and this effect may in part contribute to health benefits (including insulin sensitivity) of practicing TRF.
    Keywords:  T cells; insulin resistance; macrophages; obesity; time-restricted feeding
    DOI:  https://doi.org/10.3390/nu13113780
  35. Front Immunol. 2021 ;12 747335
    Interrelation Between Fibroblasts and T Cells in Fibrosing Interstitial Lung Diseases.
    Yunxin Lai, Xinru Wei, Ting Ye, Lilin Hang, Ling Mou, Jin Su.
      Interstitial lung diseases (ILDs) are a heterogeneous group of diseases characterized by varying degrees of inflammation and fibrosis of the pulmonary interstitium. The interrelations between multiple immune cells and stromal cells participate in the pathogenesis of ILDs. While fibroblasts contribute to the development of ILDs through secreting extracellular matrix and proinflammatory cytokines upon activation, T cells are major mediators of adaptive immunity, as well as inflammation and autoimmune tissue destruction in the lung of ILDs patients. Fibroblasts play important roles in modulating T cell recruitment, differentiation and function and conversely, T cells can balance fibrotic sequelae with protective immunity in the lung. A more precise understanding of the interrelation between fibroblasts and T cells will enable a better future therapeutic design by targeting this interrelationship. Here we highlight recent work on the interactions between fibroblasts and T cells in ILDs, and consider the implications of these interactions in the future development of therapies for ILDs.
    Keywords:  ILDs; T cells; fibroblasts; fibrosis; interrelation
    DOI:  https://doi.org/10.3389/fimmu.2021.747335
  36. Gut. 2021 Nov 22. pii: gutjnl-2021-325177. [Epub ahead of print]
    Two microbiota subtypes identified in irritable bowel syndrome with distinct responses to the low FODMAP diet.
    Kevin Vervier, Stephen Moss, Nitin Kumar, Anne Adoum, Meg Barne, Hilary Browne, Arthur Kaser, Christopher J Kiely, B Anne Neville, Nina Powell, Tim Raine, Mark D Stares, Ana Zhu, Juan De La Revilla Negro, Trevor D Lawley, Miles Parkes.
       OBJECTIVE: Reducing FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) can be clinically beneficial in IBS but the mechanism is incompletely understood. We aimed to detect microbial signatures that might predict response to the low FODMAP diet and assess whether microbiota compositional and functional shifts could provide insights into its mode of action.
    DESIGN: We used metagenomics to determine high-resolution taxonomic and functional profiles of the stool microbiota from IBS cases and household controls (n=56 pairs) on their usual diet. Clinical response and microbiota changes were studied in 41 pairs after 4 weeks on a low FODMAP diet.
    RESULTS: Unsupervised analysis of baseline IBS cases pre-diet identified two distinct microbiota profiles, which we refer to as IBSP (pathogenic-like) and IBSH (health-like) subtypes. IBSP microbiomes were enriched in Firmicutes and genes for amino acid and carbohydrate metabolism, but depleted in Bacteroidetes species. IBSH microbiomes were similar to controls. On the low FODMAP diet, IBSH and control microbiota were unaffected, but the IBSP signature shifted towards a health-associated microbiome with an increase in Bacteroidetes (p=0.009), a decrease in Firmicutes species (p=0.004) and normalisation of primary metabolic genes. The clinical response to the low FODMAP diet was greater in IBSP subjects compared with IBSH (p=0.02).
    CONCLUSION: 50% of IBS cases manifested a 'pathogenic' gut microbial signature. This shifted towards the healthy profile on the low FODMAP diet; and IBSP cases showed an enhanced clinical responsiveness to the dietary therapy. The effectiveness of FODMAP reduction in IBSP may result from the alterations in gut microbiota and metabolites produced. Microbiota signatures could be useful as biomarkers to guide IBS treatment; and investigating IBSP species and metabolic pathways might yield insights regarding IBS pathogenic mechanisms.
    Keywords:  diet; intestinal microbiology; irritable bowel syndrome
    DOI:  https://doi.org/10.1136/gutjnl-2021-325177
  37. Trends Parasitol. 2021 Nov 23. pii: S1471-4922(21)00282-8. [Epub ahead of print]
    The Batman and Robin of liver-stage immunity to malaria.
    William R Heath, Lauren E Holz, Daniel Fernandez-Ruiz.
      Malaria parasites replicate within the liver shortly after infection. This stage can be controlled by CD8 T cells, but which subsets undertake this function is unclear. Lefebvre et al. now elegantly show that effector memory T (TEM) cells are avid participants, working as a dynamic duo with liver tissue-resident memory T (TRM) cells to combat infection.
    Keywords:  CD8 T cells; liver; malaria; memory; vaccines
    DOI:  https://doi.org/10.1016/j.pt.2021.11.002
  38. Biomolecules. 2021 Nov 19. pii: 1723. [Epub ahead of print]11(11):
    The Effect of Mycotoxins and Silymarin on Liver Lipidome of Mice with Non-Alcoholic Fatty Liver Disease.
    Kamila Bechynska, Vit Kosek, Marie Fenclova, Lucie Muchova, Vaclav Smid, Jakub Suk, Karel Chalupsky, Eva Sticova, Kamila Hurkova, Jana Hajslova, Libor Vitek, Milena Stranska.
      Milk thistle-based dietary supplements have become increasingly popular. The extract from milk thistle (Silybum marianum) is often used for the treatment of liver diseases because of the presence of its active component, silymarin. However, the co-occurrence of toxic mycotoxins in these preparations is quite frequent as well. The objective of this study was to investigate the changes in composition of liver lipidome and other clinical characteristics of experimental mice fed by a high-fat methionine-choline deficient diet inducing non-alcoholic fatty liver disease. The mice were exposed to (i) silymarin, (ii) mycotoxins (trichothecenes, enniatins, beauvericin, and altertoxins) and (iii) both silymarin and mycotoxins, and results were compared to the controls. The liver tissue extracts were analyzed by ultra-high performance liquid chromatography coupled with high-resolution tandem mass spectrometry. Using tools of univariate and multivariate statistical analysis, we were able to identify 48 lipid species from the classes of diacylglycerols, triacylglycerols, free fatty acids, fatty acid esters of hydroxy fatty acids and phospholipids clearly reflecting the dysregulation of lipid metabolism upon exposure to mycotoxin and/or silymarin.
    Keywords:  lipidome; mass spectrometry; metabolome; mice liver; mycotoxins; silymarin
    DOI:  https://doi.org/10.3390/biom11111723
  39. Clin Exp Gastroenterol. 2021 ;14 441-449
    Activation and Functional Priming of Blood Neutrophils in Non-Alcoholic Fatty Liver Disease Increases in Non-Alcoholic Steatohepatitis.
    Johanne Sloth Lauszus, Peter Lykke Eriksen, Mette Mejlby Hansen, Lotte Lindgreen Eriksen, Debbie Lindsay Shawcross, Hendrik Vilstrup, Karen Louise Thomsen, Sidsel Stoy.
       Introduction: In non-alcoholic fatty liver disease (NAFLD), neutrophils in liver infiltrates are activated, which may contribute to disease progression towards non-alcoholic steatohepatitis (NASH). However, the functional status of the blood neutrophils remains unknown and their role in the disease mechanisms is thus uncertain. We therefore characterized activation and function of blood neutrophils in patients with NAFLD in relation to clinical disease markers and the NAFLD plasma milieu.
    Methods: We studied 20 patients with NAFLD, among these 6 patients with NASH, and 14 healthy persons. Neutrophil activation, interleukin (IL)-8 production and oxidative burst were measured by flow cytometry on participants´ neutrophils and on healthy neutrophils exposed in vitro to plasma from the study participants.
    Results: Blood neutrophils from the NASH patients showed a doubling in their expression of the activation marker CD62L. Also, all NAFLD patients had 50-100% increased expression of CD11b. Functionally, NASH neutrophils had 30% elevated IL-8 production and more than doubled spontaneous oxidative burst. In all NAFLD patients, higher spontaneous oxidative burst was associated with worse liver function. Incubation of healthy neutrophils with NAFLD plasma paradoxically slightly reduced CD62L and CD11b expression, and NASH plasma also reduced the frequency of IL-8-producing neutrophils.
    Conclusion: In NAFLD, blood neutrophils are activated, and in NASH also functionally primed. This suggests a progressive neutrophil aggressiveness already present with liver fat infiltration. However, NAFLD plasma in vitro, if anything, had the opposite effect on the healthy neutrophils so the NAFLD-related neutrophil activation cannot be attributed to humoral factors and remains unexplained.
    Keywords:  CD11b; neutrophil; non-alcoholic fatty liver disease; non-alcoholic steatohepatitis; oxidative burst
    DOI:  https://doi.org/10.2147/CEG.S329424
  40. Nat Commun. 2021 Nov 25. 12(1): 6876
    scCODA is a Bayesian model for compositional single-cell data analysis.
    M Büttner, J Ostner, C L Müller, F J Theis, B Schubert.
      Compositional changes of cell types are main drivers of biological processes. Their detection through single-cell experiments is difficult due to the compositionality of the data and low sample sizes. We introduce scCODA ( https://github.com/theislab/scCODA ), a Bayesian model addressing these issues enabling the study of complex cell type effects in disease, and other stimuli. scCODA demonstrated excellent detection performance, while reliably controlling for false discoveries, and identified experimentally verified cell type changes that were missed in original analyses.
    DOI:  https://doi.org/10.1038/s41467-021-27150-6
  41. Cells. 2021 Nov 01. pii: 2978. [Epub ahead of print]10(11):
    Lipid Metabolism Disorders in the Comorbid Course of Nonalcoholic Fatty Liver Disease and Chronic Obstructive Pulmonary Disease.
    Stanislav Kotlyarov, Aleksei Bulgakov.
      Non-alcoholic fatty liver disease (NAFLD) is currently among the most common liver diseases. Unfavorable data on the epidemiology of metabolic syndrome and obesity have increased the attention of clinicians and researchers to the problem of NAFLD. The research results allow us to emphasize the systemicity and multifactoriality of the pathogenesis of liver parenchyma lesion. At the same time, many aspects of its classification, etiology, and pathogenesis remain controversial. Local and systemic metabolic disorders are also a part of the pathogenesis of chronic obstructive pulmonary disease and can influence its course. The present article analyzes the metabolic pathways mediating the links of impaired lipid metabolism in NAFLD and chronic obstructive pulmonary disease (COPD). Free fatty acids, cholesterol, and ceramides are involved in key metabolic and inflammatory pathways underlying the pathogenesis of both diseases. Moreover, inflammation and lipid metabolism demonstrate close links in the comorbid course of NAFLD and COPD.
    Keywords:  chronic obstructive pulmonary disease; lipid metabolism; metabolism; non-alcoholic fatty liver disease
    DOI:  https://doi.org/10.3390/cells10112978
  42. Am J Case Rep. 2021 Nov 26. 22 e932961
    A New Potential Strategy for Acute Non-Alcoholic Steatohepatitis (NASH).
    Anupamjeet Kaur Sekhon, Aniruddha Gollapalli, Dharamjeet Kaur, Bryan Janssen, Mark L Stevens, Fernando Valerio, Miguel A Sierra-Hoffman.
      BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the United States, and 25% of patients with NAFLD progress to non-alcoholic steatohepatitis (NASH). NAFLD is predicted to be the most common indication for liver transplantation by 2030. Despite associated high morbidity and mortality, there is currently no approved therapy for NASH. PCSK9 inhibitors are approved for reducing LDL in patients who are statin-intolerant or need further LDL reduction. Increased LDL levels are independently associated with an elevated risk of NAFLD. CASE REPORT We present a case of a 39-year-old woman with acute NASH with familial hypercholesterolemia that was refractory to lifestyle modifications and HMG-CoA reductase inhibitors. An episode of rhabdomyolysis warranted a search for alternatives to statin therapy. Results of a liver biopsy showed microvesicular and macrovesicular steatosis with ballooning degeneration, indicating acute NASH. She was started on PCSK9 inhibitors as salvage therapy. Three monthly doses resulted in a more than an 80% reduction in ALT and AST and a 48% reduction in LDL levels. A liver biopsy done 8 months after the first biopsy showed normalization of liver histology. CONCLUSIONS The use of PCSK9 inhibitors showed a dramatic response in this patient who failed conventional therapies, and the encouraging results seen in this case merit further research into the use of PCSK9 inhibitors as first-line therapy for the acute phase of NASH.
    DOI:  https://doi.org/10.12659/AJCR.932961
  43. Gut Microbes. 2021 Jan-Dec;13(1):13(1): 1997292
    Intestinal microbial communities and Holdemanella isolated from HIV+/- men who have sex with men increase frequencies of lamina propria CCR5+ CD4+ T cells.
    Eiko Yamada, Casey G Martin, Nancy Moreno-Huizar, Jennifer Fouquier, C Preston Neff, Sara L Coleman, Jennifer M Schneider, Jonathan Huber, Nichole M Nusbacher, Martin McCarter, Thomas B Campbell, Catherine A Lozupone, Brent E Palmer.
      Men who have sex with men (MSM), regardless of HIV infection status, have an intestinal microbiome that is compositionally distinct from men who have sex with women (MSW) and women. We recently showed HIV-negative MSM have elevated levels of intestinal CD4+ T cells expressing CCR5, a critical co-receptor for HIV. Whether elevated expression of CCR5 is driven by the altered gut microbiome composition in MSM has not been explored. Here we used in vitro stimulation of gut Lamina Propria Mononuclear Cells (LPMCs) with whole intact microbial cells isolated from stool to demonstrate that fecal bacterial communities (FBCs) from HIV-positive/negative MSM induced higher frequencies of CCR5+ CD4+ T cells compared to FBCs from HIV-negative MSW and women. To identify potential microbial drivers, we related the frequency of CCR5+ CD4+ T cells to the abundance of individual microbial taxa in rectal biopsy of HIV-positive/negative MSM and controls, and Holdemanella biformis was strongly associated with increased frequency of CCR5+ CD4+ T cells. We used in vitro stimulation of gut LPMCs with the type strain of H. biformis, a second strain of H. biformis and an isolate of the closely related Holdemanella porci , cultured from either a HIV-positive or a HIV-negative MSM stool. H. porci elevated the frequency of both CCR5+ CD4+ T cells and the ratio of TNF-α/IL-10 Genomic comparisons of the 3 Holdemanella isolates revealed unique cell wall and capsular components, which may be responsible for their differences in immunogenicity. These findings describe a novel mechanism potentially linking intestinal dysbiosis in MSM to HIV transmission and mucosal pathogenesis.
    Keywords:  CCR5; Gut; HIV transmission; MSM; T-cell recruitment; microbiome
    DOI:  https://doi.org/10.1080/19490976.2021.1997292
  44. Methods Mol Biol. 2022 ;2380 85-95
    Identification of Follicular T Cells in the Gut.
    Hristo Georgiev, Georgia Papadogianni, Günter Bernhardt.
      Humoral adaptive immune responses trigger the establishment of plasma B cells secreting antibodies of various isotypes that bind antigen specifically and with high affinity. Moreover, memory B cells will be generated. To accomplish this, B cells need assistance from a special subset of CD4 T cells, the so called follicular T cells that differentiate from naïve T cells in the course of the immune response. Therefore, the study of follicular T cells is of primordial interest when investigating the molecular and cellular determinants of adaptive immune responses. This is done by direct analysis of the cells isolated from mice following an immunological challenge but in many instances such analyses must involve follow-up studies in cell culture requiring living cells. Especially, in vitro experimentation necessitates isolation and sorting of follicular T cells. However, follicular T cells are generally difficult to handle because they are prone to apoptosis and cell death. This is particularly evident when dealing with follicular T cells residing in the gut since we observed that isolation and processing from murine gut notoriously results in very high loss rates when compared for example to cells obtained from immunized peripheral lymph nodes. To bypass these limitations, we developed a protocol that allows for efficient isolation of intact follicular T cells. The protocol introduced here illustrates isolation and handling of follicular T cells using murine Peyer's Patches as an example because they constantly harbor significant amounts of these cells.
    Keywords:  ARTC2; Apoptosis; Cell isolation; Follicular helper T (TFH) cells; Gut; Peyer’s patches (PP); Purinergic receptor P2X7 (P2RX7)
    DOI:  https://doi.org/10.1007/978-1-0716-1736-6_8
  45. Cells. 2021 Nov 14. pii: 3168. [Epub ahead of print]10(11):
    Effect of a High-Fat Diet on the Small-Intestinal Environment and Mucosal Integrity in the Gut-Liver Axis.
    Takashi Nakanishi, Hirokazu Fukui, Xuan Wang, Shin Nishiumi, Haruka Yokota, Yutaka Makizaki, Yoshiki Tanaka, Hiroshi Ohno, Toshihiko Tomita, Tadayuki Oshima, Hiroto Miwa.
      Although high-fat diet (HFD)-related dysbiosis is involved in the development of steatohepatitis, its pathophysiology especially in the small intestine remains unclear. We comprehensively investigated not only the liver pathology but also the microbiome profile, mucosal integrity and luminal environment in the small intestine of mice with HFD-induced obesity. C57BL/6J mice were fed either a normal diet or an HFD, and their small-intestinal contents were subjected to microbial 16S rDNA analysis. Intestinal mucosal permeability was evaluated by FITC-dextran assay. The levels of bile acids in the small-intestinal contents were measured by liquid chromatography/mass spectrometry. The expression of tight junction molecules, antimicrobial peptides, lipopolysaccharide and macrophage marker F4/80 in the small intestine and/or liver was examined by real-time RT-PCR and immunohistochemistry. The abundance of Lactobacillus was markedly increased and that of Clostridium was drastically decreased in the small intestine of mice fed the HFD. The level of conjugated taurocholic acid was significantly increased and those of deconjugated cholic acid/secondary bile acids were conversely decreased in the small-intestinal contents. The expression of occludin, antimicrobial Reg IIIβ/γ and IL-22 was significantly decreased in the small intestine of HFD-fed mice, and the intestinal permeability was significantly accelerated. Infiltration of lipopolysaccharide was significantly increased in not only the small-intestinal mucosa but also the liver of HFD-fed mice, and fat drops were apparently accumulated in the liver. Pathophysiological alteration of the luminal environment in the small intestine resulting from a HFD is closely associated with minimal inflammation involving the gut-liver axis through disturbance of small-intestinal mucosal integrity.
    Keywords:  barrier; bile acid; high-fat diet; microbiome; small intestine
    DOI:  https://doi.org/10.3390/cells10113168
  46. Front Immunol. 2021 ;12 729607
    IL-4-Producing Vγ1+/Vδ6+ γδ T Cells Sustain Germinal Center Reactions in Peyer's Patches of Mice.
    Leon Ullrich, Yvonne Lueder, Anna-Lena Juergens, Anneke Wilharm, Joana Barros-Martins, Anja Bubke, Abdi Demera, Koichi Ikuta, Gwendolyn Elena Patzer, Anika Janssen, Inga Sandrock, Immo Prinz, Francesca Rampoldi.
      The mucosal immune system is the first line of defense against pathogens. Germinal centers (GCs) in the Peyer's patches (PPs) of the small intestine are constantly generated through stimulation of the microbiota. In this study, we investigated the role of γδ T cells in the GC reactions in PPs. Most γδ T cells in PPs localized in the GCs and expressed a TCR composed of Vγ1 and Vδ6 chains. By using mice with partial and total γδ T cell deficiencies, we found that Vγ1+/Vδ6+ T cells can produce high amounts of IL-4, which drives the proliferation of GC B cells as well as the switch of GC B cells towards IgA. Therefore, we conclude that γδ T cells play a role in sustaining gut homeostasis and symbiosis via supporting the GC reactions in PPs.
    Keywords:  IL-4; IgA; Peyer’s patches; Vγ1+ T cells; germinal center; γδ T cells
    DOI:  https://doi.org/10.3389/fimmu.2021.729607
  47. Cells. 2021 Nov 17. pii: 3202. [Epub ahead of print]10(11):
    An Update on the Role of Extracellular Vesicles in the Pathogenesis of Necrotizing Enterocolitis and Inflammatory Bowel Diseases.
    Rafał Filip.
      Some of the most fundamental influences of microorganisms inhabiting the human intestinal tract are exerted during infant development and impact the maturation of intestinal mucosa and gut immune system. The impact of bacteria on the host gut immune system is partially mediated via released extracellular vesicles (EVs). The heterogeneity in EV content, size, and bacterial species origin can have an impact on intestinal cells, resulting in inflammation and an immune response, or facilitate pathogen entry into the gut wall. In mammals, maintaining the integrity of the gut barrier might also be an evolutionary function of maternal milk EVs. Recently, the usage of EVs has been explored as a novel therapeutic approach in several pathological conditions, including necrotizing enterocolitis (NEC) and inflammatory bowel disease (IBD). In this review, we attempt to summarize the current knowledge of EV biology, followed by a discussion of the role that EVs play in gut maturation and the pathogenesis of NEC and IBD.
    Keywords:  extracellular vesicles; gut maturation; inflammatory bowel disease; necrotizing enterocolitis
    DOI:  https://doi.org/10.3390/cells10113202
  48. FEBS J. 2021 Nov 25.
    Fatty acid metabolism in adaptive immunity.
    Xian Zhou, Xingxing Zhu, Hu Zeng.
      Fatty acids not only are a key component of cellular membrane structure, but also have diverse functions in biological processes. Recent years have seen great advances in understanding of how fatty acid metabolism contributes to adaptive immune response. Here, we review 3 key processes, fatty acid biosynthesis, fatty acid oxidation and fatty acid uptake, and how they direct T and B cell functions during immune challenges. Then we will focus on the relationship between microbiota derived fatty acids, short-chain fatty acids, and adaptive immunity. Along the way, we will also discuss the outstanding controversies and challenges in the field.
    Keywords:  B cells; Fatty acid; T cells; Treg; germinal center; memory; mitochondrial; oxidation
    DOI:  https://doi.org/10.1111/febs.16296
  49. Endocr Metab Immune Disord Drug Targets. 2021 Nov 23.
    Emerging Role of Interleukins for the Assessment and Treatment of Liver Diseases.
    Aaliya L Ali, Namrata P Nailwal, Gaurav M Doshi.
       BACKGROUND: The most common liver diseases are fibrosis, alcoholic liver disease, non-alcoholic fatty disease, viral hepatitis, and hepatocellular carcinoma. These liver diseases account for approximately 2 million deaths per year worldwide, with cirrhosis accounting for 2.1% of the worldwide burden. The most widely used liver function tests for diagnosis are alanine transaminase, aspartate transaminase, serum proteins, serum albumin, and serum globulins, whereas antivirals and corticosteroids have been proven to be useful for the treatment of liver diseases. A major disadvantage of these diagnostic measures is the lack of specificity to a particular tissue or cell type, as these enzymes are common to one or more tissues. The major adverse effect of current treatment methods is drug resistance. To overcome these issues, interleukins have been investigated. The balance of these interleukins determines the outcome of an immune response. Interleukins are considered interesting therapeutic targets for the treatment of liver diseases. In this review, we summarize the current state of knowledge regarding interleukins in the diagnosis, treatment, and pathogenesis of different acute and chronic liver diseases.
    OBJECTIVE: To understand the role of interleukins in the assessment and treatment of different types of liver diseases.
    METHODS: A literature search was conducted using PubMed, Science Direct, and NCBI with the following keywords: Interleukins, Acute Liver Failure, Alcoholic Liver Disease, Non-Alcoholic Fatty Liver Disease, Liver Fibrosis, Hepatocellular Carcinoma, Inflammation, Liver injury, Hepatoprotective effect. Clinical trial data on these interleukins have been searched on Clinicaltrials.gov.
    RESULTS: Existing literature and preclinical and clinical trial data demonstrate that interleukins play a crucial role in the pathogenesis of liver diseases.
    CONCLUSION: Our findings indicate that IL-1, IL-6, IL-10, IL-17, IL-22, IL-35, and IL-37 are involved in the progression and control of various liver conditions via the regulation of cell signaling pathways. However, further investigation on the involvement of these interleukins is necessary for their use as a targeted therapy in liver diseases.
    Keywords:  Acute Liver Failure; Alcoholic Liver Disease; Hepatocellular Carcinoma; Hepatoprotective effect; Inflammation; Interleukins; Liver Fibrosis; Liver injury; Non-Alcoholic Fatty Liver Disease
    DOI:  https://doi.org/10.2174/1871530321666211124102837
  50. Front Mol Biosci. 2021 ;8 766855
    Novel Therapeutic Targets in Liver Fibrosis.
    Jinhang Zhang, Qinhui Liu, Jinhan He, Yanping Li.
      Liver fibrosis is end-stage liver disease that can be rescued. If irritation continues due to viral infection, schistosomiasis and alcoholism, liver fibrosis can progress to liver cirrhosis and even cancer. The US Food and Drug Administration has not approved any drugs that act directly against liver fibrosis. The only treatments currently available are drugs that eliminate pathogenic factors, which show poor efficacy; and liver transplantation, which is expensive. This highlights the importance of clarifying the mechanism of liver fibrosis and searching for new treatments against it. This review summarizes how parenchymal, nonparenchymal cells, inflammatory cells and various processes (liver fibrosis, hepatic stellate cell activation, cell death and proliferation, deposition of extracellular matrix, cell metabolism, inflammation and epigenetics) contribute to liver fibrosis. We highlight discoveries of novel therapeutic targets, which may provide new insights into potential treatments for liver fibrosis.
    Keywords:  hepatic stellate cells; liver fibrosis; molecular mechanism; non-alcocholic fatty liver disease; therapeutic targets
    DOI:  https://doi.org/10.3389/fmolb.2021.766855
  51. Biochem J. 2021 Nov 26. 478(22): 3999-4004
    Regulation of Tim-3 function by binding to phosphatidylserine.
    Lawrence P Kane.
      Tim-3 is a transmembrane protein that is highly expressed on subsets of chronically stimulated CD4+ helper and CD8+ cytotoxic T cells, with more transient expression during acute activation and infection. Tim-3 is also constitutively expressed by multiple types of myeloid cells. Like other TIM family members, Tim-3 can bind to phosphatidylserine displayed by apoptotic cells, and this interaction has been shown to mediate uptake of such cells by dendritic cells and cross-presentation of antigens to CD8+ T cells. In contrast, how the recognition of PS by Tim-3 might regulate the function of Tim-3+ T cells is not known. In their recent paper, Lemmon and colleagues demonstrate for the first time that recognition of PS by Tim-3 leads to enhanced T cell activation.
    DOI:  https://doi.org/10.1042/BCJ20210652
  52. Cell Rep. 2021 Nov 23. pii: S2211-1247(21)01537-0. [Epub ahead of print]37(8): 110051
    ILC3s control airway inflammation by limiting T cell responses to allergens and microbes.
    Fei Teng, Roser Tachó-Piñot, Biin Sung, Donna L Farber, Stefan Worgall, Hamida Hammad, Bart N Lambrecht, Matthew R Hepworth, Gregory F Sonnenberg.
      Group 3 innate lymphoid cells (ILC3s) critically regulate host-microbe interactions in the gastrointestinal tract, but their role in the airway remains poorly understood. Here, we demonstrate that lymphoid-tissue-inducer (LTi)-like ILC3s are enriched in the lung-draining lymph nodes of healthy mice and humans. These ILC3s abundantly express major histocompatibility complex class II (MHC class II) and functionally restrict the expansion of allergen-specific CD4+ T cells upon experimental airway challenge. In a mouse model of house-dust-mite-induced allergic airway inflammation, MHC class II+ ILC3s limit T helper type 2 (Th2) cell responses, eosinophilia, and airway hyperresponsiveness. Furthermore, MHC class II+ ILC3s limit a concomitant Th17 cell response and airway neutrophilia. This exacerbated Th17 cell response requires exposure of the lung to microbial stimuli, which can be found associated with house dust mites. These findings demonstrate a critical role for antigen-presenting ILC3s in orchestrating immune tolerance in the airway by restricting pro-inflammatory T cell responses to both allergens and microbes.
    Keywords:  ILC3s; Th17 cells; airway inflammation; antigen presentation; asthma; house dust mite; innate lymhoid cells; microbiota; type 2 immunity
    DOI:  https://doi.org/10.1016/j.celrep.2021.110051
  53. Nat Rev Endocrinol. 2021 Nov 25.
    Research in metabolic ageing - a tale of mice versus humans?
    Susanna M Hofmann, Rüdiger Landgraf.
      
    DOI:  https://doi.org/10.1038/s41574-021-00597-9
  54. Pharmacol Res. 2021 Nov 23. pii: S1043-6618(21)00588-0. [Epub ahead of print] 106004
    Overexpression of PDE4D in mouse liver is sufficient to trigger NAFLD and hypertension in a CD36-TGF-β1 pathway: therapeutic role of roflumilast.
    Xiang Tao, Haiqing He, Jiangtong Peng, Rui Xu, Jing Fu, Yuting Hu, Li Li, Xiaoyan Yang, Xiuling Feng, Chao Zhang, Lingmin Zhang, Xi-Yong Yu, Ao Shen, Kai Huang, Qin Fu.
      Emerging evidence has shown that nonalcoholic fatty liver disease (NAFLD) may be both a consequence and a cause of hypertension. Recent studies have demonstrated that phosphodiesterase 4 (PDE4)-cAMP signaling represents a pathway relevant to the pathophysiology of metabolic disorders. This study aims to investigate the impact and the underlying mechanism of PDE4 in the pathogenesis of NAFLD and its associated hypertension. Here we demonstrated that high-fat-diet (HFD) fed mice developed NAFLD and hypertension, with an associated increase in hepatic PDE4D expression, which can be prevented and even reversed by PDE4 inhibitor roflumilast. Furthermore, we demonstrated that hepatic overexpression of PDE4D drove significant hepatic steatosis and elevation of blood pressure. Mechanistically, PDE4D activated fatty acid translocase CD36 signaling which facilitates hepatic lipid deposition, resulting in TGF-β1 production by hepatocytes and excessive TGF-β1 signaling in vessels and consequent hypertension. Specific silencing of TGF-β1 in hepatocytes by siRNA using poly (β-amino ester) nanoparticles significantly normalized hepatic PDE4D overexpression-activated TGF-β1 signaling in vessels and hypertension. Together, the conclusions indicated that PDE4D plays an important role in the pathogenesis of NAFLD and associated hypertension via activation of CD36-TGF-β1 signaling in the liver. PDE4 inhibitor such as roflumilast, which is clinically approved for chronic obstructive pulmonary disease (COPD) treatment, has the potential to be used as a preventive or therapeutic drug against NAFLD and associated hypertension in the future.
    Keywords:  CD36; Hypertension; Nonalcoholic fatty liver; PDE4D; TGF-β1
    DOI:  https://doi.org/10.1016/j.phrs.2021.106004
  55. J Pers Med. 2021 Nov 11. pii: 1182. [Epub ahead of print]11(11):
    Horses for Courses in the Era of CARs: Advancing CAR T and CAR NK Cell Therapies.
    Sergey Kulemzin, Igor Evsyukov, Tatiana Belovezhets, Alexander Taranin, Andrey Gorchakov.
      The adoptive transfer of allogeneic CAR NK cells holds great promise as an anticancer modality due to the relative ease of manufacturing and genetic modification of NK cells, which translates into affordable pricing. Compared to the pronounced efficacy of CAR T cell therapy in the treatment of B cell malignancies, rigorous clinical and preclinical assessment of the antitumor properties of CAR NK cells has been lagging behind. In this brief review, we summarize the biological features of NK cells that may help define the therapeutic niche of CAR NK cells as well as create more potent NK cell-based anticancer products. In addition, we compare T cells and NK cells as the carriers of CARs using the data of single-cell transcriptomic analysis.
    Keywords:  CAR NK cell; CAR T cell; cancer immunotherapy
    DOI:  https://doi.org/10.3390/jpm11111182
  56. Front Immunol. 2021 ;12 758288
    Single-Cell Transcriptomic Analysis Reveals a Tumor-Reactive T Cell Signature Associated With Clinical Outcome and Immunotherapy Response In Melanoma.
    Min Yan, Jing Hu, Yanyan Ping, Liwen Xu, Gaoming Liao, Zedong Jiang, Bo Pang, Shangqin Sun, Yunpeng Zhang, Yun Xiao, Xia Li.
      The infiltration of tumor-reactive T cells in the tumor site is associated with better survival and immunotherapy response. However, tumor-reactive T cells were often represented by the infiltration of total CD8+ T cells, which was confounded by the presence of bystander T cells. To identify tumor-reactive T cells at the cancer lesion, we performed integration analyses of three scRNA-seq data sets of T cells in melanoma. Extensive heterogeneous functional states of T cells were revealed in the tumor microenvironment. Among these states, we identified a subset of tumor-reactive T cells which specifically expressed tumor-reactive markers and T cell activation signature, and were strongly enriched for larger T cell receptor (TCR) clones. We further identified and validated a tumor-reactive T cell signature (TRS) to evaluate the tumor reactivity of T cells in tumor patients. Patients with high TRS scores have strong immune activity and high mutation burden in the TCGA-SKCM cohort. We also demonstrated a significant association of the TRS with the clinical outcomes of melanoma patients, with higher TRS scores representing better survival, which was validated in four external independent cohorts. Furthermore, the TRS scores exhibited greater performance on prognosis prediction than infiltration levels of CD8+ T cells and previously published prognosis-related signatures. Finally, we observed the capability of TRS to predict immunotherapy response in melanoma. Together, based on integrated analysis of single-cell RNA-sequencing, we developed and validated a tumor-reactive-related signature that demonstrated significant association with clinical outcomes and response to immunotherapy.
    Keywords:  exhausted T cells; immunotherapy; melanoma; tumor reactivity; tumor-infiltrating T cells
    DOI:  https://doi.org/10.3389/fimmu.2021.758288
  57. Cell Mol Gastroenterol Hepatol. 2021 Nov 22. pii: S2352-345X(21)00241-1. [Epub ahead of print]
    TM6SF2/PNPLA3/MBOAT7 loss-of-function genetic variants impact on NAFLD development and progression both in patients and in in vitro models.
    Miriam Longo, Marica Meroni, Erika Paolini, Veronica Erconi, Fabrizia Carli, Francesco Fortunato, Dario Ronchi, Roberto Piciotti, Silvia Sabatini, Chiara Macchi, Anna Alisi, Luca Miele, Giorgio Soardo, Giacomo Pietro Comi, Luca Valenti, Massimiliano Ruscica, Anna L Fracanzani, Amalia Gastaldelli, Paola Dongiovanni.
       BACKGROUND AND AIMS: The I148M PNPLA3, the rs641738 in MBOAT7/TMC4 locus and the E167K TM6SF2 polymorphisms represent the main predisposing factors to non-alcoholic fatty liver disease (NAFLD) development and progression. We previously generated a full knockout of MBOAT7 in HepG2 cells (MBOAT7-/-), homozygous for the I148M PNPLA3. Therefore, we aimed to:1) investigate the synergic impact of the 3 at-risk variants on liver injury and hepatocellular carcinoma (HCC) in a large cohort of NAFLD patients;2) create in vitro models of genetic NAFLD by silencing TM6SF2 in both HepG2 and MBOAT7-/- cells.
    METHODS: NAFLD patients (n=1380) of whom 121 had HCC were stratified with a semi-quantitative score ranging from 0 to 3 according to the number of PNPLA3, TM6SF2 and MBOAT7 at-risk variants. TM6SF2 was silenced in HepG2 (TM6SF2-/-) and MBOAT7-/- (MBOAT7-/-TM6SF2-/-) through CRISPR/Cas9.
    RESULTS: In NAFLD patients, the additive weight of these mutations was associated with liver disease severity and increased risk to develop HCC. In HepG2 cells, TM6SF2 silencing altered lipid composition and induced the accumulation of micro-vesicular LDs, whereas the MBOAT7-/-TM6SF2-/- cells showed a mixed micro/macro pattern of LDs. TM6SF2 deletion strongly affected endoplasmic reticulum (ER) and mitochondria ultrastructures thus increasing ER/oxidative stress. Mitochondrial number raised in both TM6SF2-/- and MBOAT7-/-TM6SF2-/- models, suggesting an unbalancing in mitochondrial dynamics and the silencing of both MBOAT7 and TM6SF2 impaired mitochondrial activity with a shift towards anaerobic glycolysis. MBOAT7-/-TM6SF2-/- cells also showed the highest proliferation rate. Finally, the re-overexpression of MBOAT7 and/or TM6SF2 reverses the metabolic and tumorigenic features observed in the compound knockout model.
    CONCLUSIONS: The co-presence of the 3 at-risk variants impacts on NAFLD course, in both patients and experimental models affecting LDs accumulation, mitochondrial functionality and metabolic reprogramming towards HCC.
    Keywords:  ER stress; HCC; NAFLD; TM6SF2; mitochondrial dynamics
    DOI:  https://doi.org/10.1016/j.jcmgh.2021.11.007
  58. Cells. 2021 Oct 30. pii: 2959. [Epub ahead of print]10(11):
    The Gut-Liver Axis in Chronic Liver Disease: A Macrophage Perspective.
    Kevin De Muynck, Bart Vanderborght, Hans Van Vlierberghe, Lindsey Devisscher.
      Chronic liver disease (CLD) is a growing health concern which accounts for two million deaths per year. Obesity, alcohol overconsumption, and progressive cholestasis are commonly characterized by persistent low-grade inflammation and advancing fibrosis, which form the basis for development of end-stage liver disease complications, including hepatocellular carcinoma. CLD pathophysiology extends to the intestinal tract and is characterized by intestinal dysbiosis, bile acid dysregulation, and gut barrier disruption. In addition, macrophages are key players in CLD progression and intestinal barrier breakdown. Emerging studies are unveiling macrophage heterogeneity and driving factors of their plasticity in health and disease. To date, in-depth investigation of how gut-liver axis disruption impacts the hepatic and intestinal macrophage pool in CLD pathogenesis is scarce. In this review, we give an overview of the role of intestinal and hepatic macrophages in homeostasis and gut-liver axis disruption in progressive stages of CLD.
    Keywords:  chronic liver disease; gut-liver axis; macrophage
    DOI:  https://doi.org/10.3390/cells10112959
  59. Nat Commun. 2021 Nov 25. 12(1): 6889
    High endogenous CCL2 expression promotes the aggressive phenotype of human inflammatory breast cancer.
    Anita Rogic, Ila Pant, Luca Grumolato, Ruben Fernandez-Rodriguez, Andrew Edwards, Suvendu Das, Aaron Sun, Shen Yao, Rui Qiao, Shabnam Jaffer, Ravi Sachidanandam, Guray Akturk, Rosa Karlic, Mihaela Skobe, Stuart A Aaronson.
      Inflammatory Breast Cancer (IBC) is a highly aggressive malignancy with distinct clinical and histopathological features whose molecular basis is unresolved. Here we describe a human IBC cell line, A3250, that recapitulates key IBC features in a mouse xenograft model, including skin erythema, diffuse tumor growth, dermal lymphatic invasion, and extensive metastases. A3250 cells express very high levels of the CCL2 chemokine and induce tumors enriched in macrophages. CCL2 knockdown leads to a striking reduction in macrophage densities, tumor proliferation, skin erythema, and metastasis. These results establish IBC-derived CCL2 as a key factor driving macrophage expansion, and indirectly tumor growth, with transcriptomic analysis demonstrating the activation of multiple inflammatory pathways. Finally, primary human IBCs exhibit macrophage infiltration and an enriched macrophage RNA signature. Thus, this human IBC model provides insight into the distinctive biology of IBC, and highlights potential therapeutic approaches to this deadly disease.
    DOI:  https://doi.org/10.1038/s41467-021-27108-8
  60. Mediators Inflamm. 2021 ;2021 8481013
    Role and Function of T Cell-Derived Exosomes and Their Therapeutic Value.
    Yuanyuan Shao, Xiaofeng Pan, Rong Fu.
      Exosomes are membrane-bound extracellular vesicles that are produced in the endosomal compartment of most eukaryotic cells. Containing proteins, RNA, and DNA, exosomes mediate intercellular communication between different cell types by transferring their contents and thus are involved in numerous physiological and pathological processes. T cells are an indispensable part of adaptive immunity, and the functions of T cell-derived exosomes have been widely studied. In the more than three decades since the discovery of exosomes, several studies have revealed that T cell-derived exosomes play a novel role in cell-to-cell signaling, especially in inflammatory responses, autoimmunity, and infectious diseases. In this review, we will summarize the function of T cell-derived exosomes and their therapeutic potential.
    DOI:  https://doi.org/10.1155/2021/8481013
  61. Cancers (Basel). 2021 Nov 21. pii: 5838. [Epub ahead of print]13(22):
    Identification of an Immunogenic Medulloblastoma-Specific Fusion Involving EPC2 and GULP1.
    Claudia Paret, Nadine Lehmann, Hannah Bender, Maximilian Sprang, Clemens J Sommer, Denis Cana, Larissa Seidmann, Arthur Wingerter, Marie A Neu, Khalifa El Malki, Francesca Alt, Lea Roth, Federico Marini, Malte Ottenhausen, Martin Glaser, Markus Knuf, Alexandra Russo, Joerg Faber.
      Medulloblastoma is the most common malignant brain tumor in children. Immunotherapy is yet to demonstrate dramatic results in medulloblastoma, one reason being the low rate of mutations creating new antigens in this entity. In tumors with low mutational burden, gene fusions may represent a source of tumor-specific neoantigens. Here, we reviewed the landscape of fusions in medulloblastoma and analyzed their predicted immunogenicity. Furthermore, we described a new in-frame fusion protein identified by RNA-Seq. The fusion involved two genes on chromosome 2 coding for the enhancer of polycomb homolog 2 (EPC2) and GULP PTB domain containing engulfment adaptor 1 (GULP1) respectively. By qRT-PCR analysis, the fusion was detected in 3 out of 11 medulloblastoma samples, whereby 2 samples were from the same patients obtained at 2 different time points (initial diagnosis and relapse), but not in other pediatric brain tumor entities. Cloning of the full-length sequence indicated that the fusion protein contains the N-terminal enhancer of polycomb-like domain A (EPcA) of EPC2 and the coiled-coil domain of GULP1. In silico analyses predicted binding of the neoantigen-derived peptide to HLA-A*0201. A total of 50% of the fusions described in the literature were also predicted to produce an immunogenic peptide. The EPC2-GULP1 fusion peptide was able to induce a de novo T cell response characterized by interferon gamma release of CD8+ cytotoxic T cells in vitro. While the functional relevance of this fusion in medulloblastoma biology remains to be clarified, our data support an immunotherapeutic approach for pediatric medulloblastoma patients carrying the EPC2-GULP1 fusion and other immunogenic fusions.
    Keywords:  EPC2; GULP1; fusion; medulloblastoma
    DOI:  https://doi.org/10.3390/cancers13225838
  62. Liver Int. 2021 Nov 25.
    Inflammatory activity affects the accuracy of liver stiffness measurement by transient elastography, but not by two-dimensional shear wave elastography in nonalcoholic fatty liver disease.
    Yuly P Mendoza, Susana G Rodrigues, Maria G Delgado, Giuseppe Murgia, Naomi F Lange, Jonas Schropp, Matteo Montani, Jean-François Dufour, Annalisa Berzigotti.
       BACKGROUND: In patients with non-alcoholic fatty liver disease (NAFLD), the impact of the severity of steatosis and inflammatory activity on the accuracy of liver stiffness measurement (LSM) by transient elastography (TE) and by two-dimensional-shear-wave elastography (2D-SWE) in staging liver fibrosis is still debated and scarce, respectively. We aimed to focus on this aspect.
    METHODS: We prospectively studied 104 patients requiring biopsy for the assessment of NAFLD. We used ordinary least squares regression to test for differences in the association between fibrosis and LSM by TE and 2D-SWE when other factors (steatosis, inflammatory activity) are considered.
    RESULTS: Among 104 patients, 102 had reliable LSM by TE, and 88 had valid LSM by 2D-SWE. The association between fibrosis based on histology and LSM was significantly stronger when 2D-SWE assessed LSM compared to TE (Spearman's correlation coefficient of 0.71; p<0.001 vs. 0.51, p<0.001; Z=2.21, p=0.027). Inflammatory activity was an independent predictor of LSM by TE but not of LSM by 2D-SWE. After controlling for fibrosis, age, sex, and BMI, the inflammatory activity and the interaction between inflammatory activity and fibrosis independently explained 11% and 13% of variance in LSM by TE, respectively. Steatosis did not affect the association of fibrosis and LSM by either method.
    CONCLUSION: Inflammatory activity on histology significantly affects LSM by TE, but not LSM by 2D-SWE in NAFLD. LSM by 2D-SWE reflects liver fibrosis more accurately than LSM by TE. Furthermore, the severity of steatosis on histology did not influence the association of LSM and fibrosis by either elastography method.
    Keywords:  Fibroscan; Liver stiffness measurement; NASH; fibrosis; noninvasive test
    DOI:  https://doi.org/10.1111/liv.15116
  63. Biomedicines. 2021 Nov 22. pii: 1739. [Epub ahead of print]9(11):
    The Role of Neuropeptide Y in Adipocyte-Macrophage Crosstalk during High Fat Diet-Induced Adipose Inflammation and Liver Steatosis.
    Seongjoon Park, Toshimitsu Komatsu, Hiroko Hayashi, Ryoichi Mori, Isao Shimokawa.
      Obesity is associated with an increased risk of non-alcoholic fatty liver disease (NAFLD), which is initiated by adipocyte-macrophage crosstalk. Among the possible molecules regulating this crosstalk, we focused on neuropeptide Y (NPY), which is known to be involved in hypothalamic appetite and adipose tissue inflammation and metabolism. In this study, the NPY-/- mice showed a marked decrease in body weight and adiposity, and lower free fatty acid and adipose inflammation without food intake alteration during a high fat diet (HFD). Moreover, NPY deficiency increased the thermogenic genes expression in brown adipose tissue. Notably, NPY-mRNA expression was upregulated in macrophages from the HFD mice compared to that from the mice on a standard diet. The NPY-mRNA expression also positively correlated with the liver mass/body weight ratio. NPY deletion alleviated HFD-induced adipose inflammation and liver steatosis. Hence, our findings point toward a novel intracellular mechanism of NPY in the regulation of adipocyte-macrophage crosstalk and highlight NPY antagonism as a promising target for therapeutic approaches against obesity and NAFLD.
    Keywords:  brown adipose tissue; fatty liver; macrophage; neuropeptide Y; obesity
    DOI:  https://doi.org/10.3390/biomedicines9111739
  64. Stem Cell Rev Rep. 2021 Nov 25.
    The Hepatic Stellate Cells (HSTCs) and Adipose-derived Mesenchymal Stem Cells (ASCs) Axis as a Potential Major Driver of Metabolic Syndrome - Novel Concept and Therapeutic Implications.
    Krzysztof Marycz, Katarzyna Kornicka-Garbowska, Larry Galuppo, Lynda Bourebaba.
      Herein, we would like to introduce a novel concept for the prevention and treatment of metabolic syndrome, which is based on molecular relationship between liver and adipose tissue. Particularly, we believe, that unravelling the molecular crosstalk between hepatokines and adipokines will allow to better understand the pathophysiology of metabolic diseases and allow to develop novel, effective therapeutic solutions against obesity and metabolic syndrome. Inter-organ communication on the level of stem progenitor cells-hepatic stellate cells (HSTCs) and adipose-derived progenitors (ASCs) could represents a key mechanism involved in controlling glucose tolerance as well as insulin sensitivity.
    Keywords:  A-Reg; ASCs; Adipokines; Crosstalk; HSTCs; Hepatokines; Metabolic syndrome
    DOI:  https://doi.org/10.1007/s12015-021-10304-w
  65. Life Sci Alliance. 2022 Feb;pii: e202101181. [Epub ahead of print]5(2):
    TICAM-1/TRIF associates with Act1 and suppresses IL-17 receptor-mediated inflammatory responses.
    Yusuke Miyashita, Takahisa Kouwaki, Hirotake Tsukamoto, Masaaki Okamoto, Kimitoshi Nakamura, Hiroyuki Oshiumi.
      TICAM-1 (also called TRIF) is the sole adaptor of TLR3 that recognizes double-stranded RNA. Here, we report that TICAM-1 is involved not only in TLR3 signaling but also in the cytokine receptor IL-17RA signaling. We found that TICAM-1 bound to IL-17R adaptor Act1 to inhibit the interaction between IL-17RA and Act1. Interestingly, TICAM-1 knockout promoted IL-17RA/Act1 interaction and increased IL-17A-mediated activation of NF-κB and MAP kinases, leading to enhanced expression of inflammatory cytokines and chemokines upon IL-17A stimulation. Moreover, Ticam-1 knockout augmented IL-17A-mediated CXCL1 and CXCL2 expression in vivo, resulting in accumulation of myeloid cells. Furthermore, Ticam-1 knockout enhanced delayed type hypersensitivity and exacerbated experimental autoimmune encephalomyelitis. Ticam-1 knockout promoted accumulation of myeloid and lymphoid cells in the spinal cord of EAE-induced mice. Collectively, these data indicate that TICAM-1 inhibits the interaction between IL-17RA and Act1 and functions as a negative regulator in IL-17A-mediated inflammatory responses.
    DOI:  https://doi.org/10.26508/lsa.202101181
  66. Clin Liver Dis. 2022 Feb;pii: S1089-3261(21)00070-2. [Epub ahead of print]26(1): 139-148
    Endoscopic Bariatric Interventions in Patients with Chronic Liver Disease.
    Marco A Bustamante-Bernal, Luis O Chavez, Marc J Zuckerman.
      Obesity and its associated comorbidities are rapidly increasing in the US population. Therefore, metabolic associated fatty liver disease (MAFLD), previously known as nonalcoholic fatty liver disease (NAFLD), has become a leading indication for liver transplantation. Lifestyle modifications as a sole therapy have been insufficient to reduce the burden of chronic liver disease secondary to MAFLD. Endoscopic bariatric interventions (EBI) appear to be safe and effective therapies for obesity and chronic liver disease secondary to MAFLD. Gastric EBI include endoscopic sleeve gastroplasty (ESG) and intragastric balloons (IGB). Small bowel EBI are also evolving in the field of bariatric endoscopy.
    Keywords:  Bariatric endoscopy; Chronic liver disease; Endoscopic bariatric interventions; Metabolic associated fatty liver disease
    DOI:  https://doi.org/10.1016/j.cld.2021.08.005
  67. Hepatol Commun. 2021 Nov 26.
    High-Resolution Exposomics and Metabolomics Reveals Specific Associations in Cholestatic Liver Diseases.
    Douglas I Walker, Brian D Juran, Angela C Cheung, Erik M Schlicht, Yongliang Liang, Megan Niedzwiecki, Nicholas F LaRusso, Gregory J Gores, Dean P Jones, Gary W Miller, Konstantinos N Lazaridis.
      Progress in development of prognostic and therapeutic options for the rare cholestatic liver diseases, primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), is hampered by limited knowledge of their pathogeneses. In particular, the potential role of hepatotoxic and/or metabolism-altering environmental chemicals in the pathogenesis of these diseases remains relatively unstudied. Moreover, the extent to which metabolic pathways are altered due to ongoing cholestasis and subsequent liver damage or possibly influenced by hepatotoxic chemicals is poorly understood. In this study, we applied a comprehensive exposomics-metabolomics approach to uncover potential pathogenic contributors to PSC and PBC. We used untargeted high-resolution mass spectrometry to characterize a wide range of exogenous chemicals and endogenous metabolites in plasma and tested them for association with disease. Exposome-wide association studies (EWAS) identified environmental chemicals, including pesticides, additives and persistent pollutants, that were associated with PSC and/or PBC, suggesting potential roles for these compounds in disease pathogenesis. Metabolome-wide association studies (MWAS) found disease-associated alterations to amino acid, eicosanoid, lipid, co-factor, nucleotide, mitochondrial and microbial metabolic pathways, many of which were shared between PSC and PBC. Notably, this analysis implicates a potential role of the 5-lipoxygenase pathway in the pathogenesis of these diseases. Finally, EWAS × MWAS network analysis uncovered linkages between environmental agents and disrupted metabolic pathways that provide insight into potential mechanisms for PSC and PBC. Conclusion: This study establishes combined exposomics-metabolomics as a generalizable approach to identify potentially pathogenic environmental agents and enumerate metabolic alterations that may impact PSC and PBC, providing a foundation for diagnostic and therapeutic strategies.
    DOI:  https://doi.org/10.1002/hep4.1871
  68. Sci Rep. 2021 Nov 23. 11(1): 22765
    A 3D primary human cell-based in vitro model of non-alcoholic steatohepatitis for efficacy testing of clinical drug candidates.
    Simon Ströbel, Radina Kostadinova, Katia Fiaschetti-Egli, Jana Rupp, Manuela Bieri, Agnieszka Pawlowska, Donna Busler, Thomas Hofstetter, Katarzyna Sanchez, Sue Grepper, Eva Thoma.
      Non-alcoholic steatohepatitis (NASH) is a progressive and severe liver disease, characterized by lipid accumulation, inflammation, and downstream fibrosis. Despite its increasing prevalence, there is no approved treatment yet available for patients. This has been at least partially due to the lack of predictive preclinical models for studying this complex disease. Here, we present a 3D in vitro microtissue model that uses spheroidal, scaffold free co-culture of primary human hepatocytes, Kupffer cells, liver endothelial cells and hepatic stellate cells. Upon exposure to defined and clinically relevant lipotoxic and inflammatory stimuli, these microtissues develop key pathophysiological features of NASH within 10 days, including an increase of intracellular triglyceride content and lipids, and release of pro-inflammatory cytokines. Furthermore, fibrosis was evident through release of procollagen type I, and increased deposition of extracellular collagen fibers. Whole transcriptome analysis revealed changes in the regulation of pathways associated with NASH, such as lipid metabolism, inflammation and collagen processing. Importantly, treatment with anti-NASH drug candidates (Selonsertib and Firsocostat) decreased the measured specific disease parameter, in accordance with clinical observations. These drug treatments also significantly changed the gene expression patterns of the microtissues, thus providing mechanisms of action and revealing therapeutic potential. In summary, this human NASH model represents a promising drug discovery tool for understanding the underlying complex mechanisms in NASH, evaluating efficacy of anti-NASH drug candidates and identifying new approaches for therapeutic interventions.
    DOI:  https://doi.org/10.1038/s41598-021-01951-7
  69. Int J Biol Sci. 2021 ;17(15): 4305-4315
    CD38 Deficiency Protects Mice from High Fat Diet-Induced Nonalcoholic Fatty Liver Disease through Activating NAD+/Sirtuins Signaling Pathways-Mediated Inhibition of Lipid Accumulation and Oxidative Stress in Hepatocytes.
    Lin Xie, Ke Wen, Qian Li, Cong-Cong Huang, Jia-Le Zhao, Qi-Hang Zhao, Yun-Fei Xiao, Xiao-Hui Guan, Yi-Song Qian, Lu Gan, Ling-Fang Wang, Ke-Yu Deng, Hong-Bo Xin.
      Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation in hepatocytes. CD38 was initially identified as a lymphocyte surface antigen and then has been found to exist in a variety of cell types. Our previous studies showed that CD38-/- mice were resistant to high-fat diet (HFD)-induced obesity. However, the role and mechanism of CD38 in HFD-induced NAFLD is still unclear. Here, we reported that CD38-/- mice significantly alleviated HFD-induced hepatic steatosis. HFD or oleic acid (OA) remarkably increased the mRNA and protein expressions of CD38 in mouse hepatic tissues and primary hepatocytes or hepatic cell lines in vitro and in vivo, suggesting that CD38 might play a role in HFD-induced hepatic steatosis. We observed that CD38 deficiency markedly decreased HFD- or OA-induced the lipid accumulation and oxidative stress in CD38-/- livers or primary hepatocytes, respectively. In contrast, overexpression of CD38 in Hep1-6 cells aggravated OA-induced lipid accumulation and oxidative stress. Furthermore, CD38 deficiency markedly inhibited HFD- or OA-induced the expressions of NOX4, and increased the expression of PPARα, CPT1, ACOX1 and SOD2 in liver tissue and hepatocytes from CD38-/- mice, indicating that CD38 deficiency-mediated the enhancement of fatty acid oxidation and the inhibition of oxidative stress contributed to protecting NAFLD. More importantly, Ex527 (Sirt1 inhibitor) and 3-TYP (Sirt3 inhibitor) significantly enhanced OA-induced lipid accumulation and oxidative stress in CD38-/- primary hepatocytes, suggesting that the anti-lipid accumulation of CD38 deficiency might be dependent on NAD/Sirtuins-mediated enhancement of FAA β-oxidation and suppression of oxidative stress in hepatocytes. In conclusion, we demonstrated that CD38 deficiency protected mice from HFD-induced NAFLD by reducing lipid accumulation and suppressing oxidative stress via activating NAD/Sirtuins signaling pathways.
    Keywords:  CD38; Sirtuins; lipid accumulation; oxidative stress; peroxisome proliferator-activated receptor α
    DOI:  https://doi.org/10.7150/ijbs.65588
  70. Cells. 2021 Oct 21. pii: 2824. [Epub ahead of print]10(11):
    Comparison of Three CD3-Specific Separation Methods Leading to Labeled and Label-Free T Cells.
    Ronald Weiss, Wilhelm Gerdes, Rommy Berthold, Ulrich Sack, Ulrike Koehl, Sunna Hauschildt, Anja Grahnert.
      T cells are an essential part of the immune system. They determine the specificity of the immune response to foreign substances and, thus, help to protect the body from infections and cancer. Recently, T cells have gained much attention as promising tools in adoptive T cell transfer for cancer treatment. However, it is crucial not only for medical purposes but also for research to obtain T cells in large quantities, of high purity and functionality. To fulfill these criteria, efficient and robust isolation methods are needed. We used three different isolation methods to separate CD3-specific T cells from leukocyte concentrates (buffy coats) and Ficoll purified PBMCs. To catch the target cells, the Traceless Affinity Cell Selection (TACS®) method, based on immune affinity chromatography, uses CD-specific low affinity Fab-fragments; while the classical Magnetic Activated Cell Sorting (MACS®) method relies on magnetic beads coated with specific high affinity monoclonal antibodies. The REAlease® system also works with magnetic beads but, in contrast to MACS®, low-affinity antibody fragments are used. The target cells separated by TACS® and REAlease® are "label-free", while cells isolated by MACS® still carry the cell specific label. The time required to isolate T cells from buffy coat by TACS® and MACS® amounted to 90 min and 50 min, respectively, while it took 150 min to isolate T cells from PBMCs by TACS® and 110 min by REAlease®. All methods used are well suited to obtain T cells in large quantities of high viability (>92%) and purity (>98%). Only the median CD4:CD8 ratio of approximately 6.8 after REAlease® separation differed greatly from the physiological conditions. MACS® separation was found to induce proliferation and cytokine secretion. However, independent of the isolation methods used, stimulation of T cells by anti CD3/CD28 resulted in similar rates of proliferation and cytokine production, verifying the functional activity of the isolated cells.
    Keywords:  CD3; MACS®; REAlease®; T cells; TACS®; isolation; proliferation; separation
    DOI:  https://doi.org/10.3390/cells10112824
  71. Acta Biomater. 2021 Nov 17. pii: S1742-7061(21)00756-X. [Epub ahead of print]
    High Throughput Interrogation of Human Liver Stellate Cells Reveals Microenvironmental Regulation of Phenotype.
    Aidan Brougham-Cook, Ishita Jain, David A Kukla, Faisal Masood, Hannah Kimmel, Hyeon Ryoo, Salman R Khetani, Gregory H Underhill.
      Liver fibrosis is a common feature of progressive liver disease and is manifested as a dynamic series of alterations in both the biochemical and biophysical properties of the liver. Hepatic stellate cells (HSCs) reside within the perisinusoidal space of the liver sinusoid and are one of the main drivers of liver fibrosis, yet it remains unclear how changes to the sinusoidal microenvironment impact HSC phenotype in the context of liver fibrosis. Cellular microarrays were used to examine and deconstruct the impacts of bio-chemo-mechanical changes on activated HSCs in vitro. Extracellular matrix (ECM) composition and stiffness were found to act individually and in combination to regulate HSC fibrogenic phenotype and proliferation. Hyaluronic acid and collagen III promoted elevated collagen I expression while collagen IV mediated a decrease. Previously activated HSCs exhibited reduced lysyl oxidase (Lox) expression as array substrate stiffness increased, with less dependence on ECM composition. Collagens III and IV increased HSC proliferation, whereas hyaluronic acid had the opposite effect. Meta-analysis performed on these data revealed distinct phenotypic clusters (e.g. low fibrogenesis/high proliferation) as a direct function of their microenvironmental composition. Notably, soft microenvironments mimicking healthy tissue (1 kPa), promoted higher levels of intracellular collagen I and Lox expression in activated HSCs, compared to stiff microenvironments mimicking fibrotic tissue (25 kPa). Collectively, these data suggest potential HSC functional adaptations in response to specific bio-chemo-mechanical changes relevant towards the development of therapeutic interventions. These findings also underscore the importance of the microenvironment when interrogating HSC behavior in healthy, disease, and treatment settings. STATEMENT OF SIGNIFICANCE: : In this work we utilized high-throughput cellular microarray technology to systematically interrogate the complex interactions between HSCs and their microenvironment in the context of liver fibrosis. We observed that HSC phenotype is regulated by ECM composition and stiffness, and that these phenotypes can be classified into distinct clusters based on their microenvironmental context. Moreover, the range of these phenotypic responses to microenvironmental stimuli is substantial and a direct consequence of the combinatorial pairing of ECM protein and stiffness signals. We also observed a novel role for microenvironmental context in affecting HSC responses to potential fibrosis therapeutics.
    Keywords:  C1, collagen I; C3, collagen III; C4, collagen IV; C5, collagen V; DC, decorin; ECM, extracellular matrix; FN, fibronectin; HA, hyaluronic acid; HSC, hepatic stellate cell; LN, laminin; LU, lumican; Lox, lysyl oxidase; NASH, non-alcoholic steatohepatitis; PA, polyacrylamide; TC, tenascin C; TFM, traction force microscopy; fibrosis, extracellular matrix, clustering, fibrogenic, heterogeneity List of Abbreviations: NAFLD, non-alcoholic fatty liver disease
    DOI:  https://doi.org/10.1016/j.actbio.2021.11.015
  72. Immunol Res. 2021 Nov 25.
    Delphinidin diminishes in vitro interferon-γ and interleukin-17 producing cells in patients with psoriatic disease.
    Sotirios G Tsiogkas, Αthanasios Mavropoulos, Dimitrios N Skyvalidas, Eleni Patrikiou, Niki Ntavari, Athina Ioanna Daponte, Maria G Grammatikopoulou, Efthimios Dardiotis, Aggeliki-Victoria Roussaki-Schulze, Lazaros I Sakkas, Efterpi Zafiriou, Dimitrios P Bogdanos.
      The anthocyanidin delphinidin reduces psoriasiform lesions and inflammatory mediators in human cell culture systems. Its role in psoriatic disease has not yet been investigated. We assessed delphinidin's in vitro immunomodulatory effect on ex vivo stimulated peripheral blood mononuclear cells (PBMCs) from 50 individuals [26 with psoriasis, 10 with psoriatic arthritis (PsA) and 14 healthy controls (HCs)]. Cells were either left untreated or stimulated with PMA plus ionomycin in the presence or absence of delphinidin. Intracellular production of interferon-γ (IFNγ), interleukin-17A (IL-17A), and interleukin-10 (IL-10) was measured flow cytometrically. Delphinidin dose-dependently reduced IFNγ+ T cells from patients and HCs. The mean IFNγ decrease in CD4+ T subpopulations was 42.5 ± 28% for psoriasis patients, 51.8 ± 21.5% for PsA patients and 49 ± 17% for HCs (p < 0.001 for all). Similarly, IFNγ reduction in CD8+ T cells was 34 ± 21.6% for psoriasis patients, 47.1 ± 22.8% for PsA and 44.8 ± 14.3% for HCs (P < 0.001 for all). An inhibitory effect of delphinidin was also noted in IFNγ producing NKs and NKTs from psoriasis individuals. Delphinidin also significantly decreased IL-17+ CD4+ T cells in all tested subjects, with marginal effect on the increase of IL-10-producing T regulatory subsets. In conclusion, delphinidin exerts a profound in vitro anti-inflammatory effect in psoriasis and psoriatic arthritis by inhibiting IFNγ+ innate and adaptive cells and T helper (Th) 17 cells. If this effect is also exerted in vivo, delphinidin may be regarded as a nutraceutical with immunosuppressive potential.
    Keywords:  Diet supplement; IFNγ; IL-17A; Immunonutrition; Immunoregulation; Inflammation; PBMCs; Psoriasis
    DOI:  https://doi.org/10.1007/s12026-021-09251-y
  73. Diagnostics (Basel). 2021 Nov 05. pii: 2053. [Epub ahead of print]11(11):
    Involvement of Ceramides in Non-Alcoholic Fatty Liver Disease (NAFLD) Atherosclerosis (ATS) Development: Mechanisms and Therapeutic Targets.
    Daniela Maria Tanase, Evelina Maria Gosav, Daniela Petrov, Alina Ecaterina Jucan, Cristina Mihaela Lacatusu, Mariana Floria, Claudia Cristina Tarniceriu, Claudia Florida Costea, Manuela Ciocoiu, Ciprian Rezus.
      Non-alcoholic fatty liver disease (NAFLD) and atherosclerosis (ATS) are worldwide known diseases with increased incidence and prevalence. These two are driven and are interconnected by multiple oxidative and metabolic functions such as lipotoxicity. A gamut of evidence suggests that sphingolipids (SL), such as ceramides, account for much of the tissue damage. Although in humans they are proving to be accurate biomarkers of adverse cardiovascular disease outcomes and NAFLD progression, in rodents, pharmacological inhibition or depletion of enzymes driving de novo ceramide synthesis prevents the development of metabolic driven diseases such as diabetes, ATS, and hepatic steatosis. In this narrative review, we discuss the pathways which generate the ceramide synthesis, the potential use of circulating ceramides as novel biomarkers in the development and progression of ATS and related diseases, and their potential use as therapeutic targets in NAFDL-ATS development which can further provide new clues in this field.
    Keywords:  ATS; NAFLD; SL; atherosclerosis; biomarkers; ceramide; non-alcoholic fatty liver disease; sphingolipids; therapeutic targets
    DOI:  https://doi.org/10.3390/diagnostics11112053
  74. J Hepatol. 2021 Nov 17. pii: S0168-8278(21)02180-2. [Epub ahead of print]
    Gut-derived systemic inflammation as a driver of depression in chronic liver disease.
    Victoria T Kronsten, Thomas H Tranah, Carmine Pariante, Debbie L Shawcross.
      Depression and chronic liver disease (CLD) are important causes of disability, morbidity and mortality worldwide and their prevalence continues to rise. The rate of depression in CLD is high compared to that of the general population and is comparable to the increased rates observed in other medical comorbidities and chronic inflammatory conditions. Notably, a comorbid diagnosis of depression has a detrimental effect on outcomes in cirrhosis. Systemic inflammation is pivotal in cirrhosis-associated immune dysfunction - a phenomenon present in advanced CLD (cirrhosis) and implicated in the development of complications, organ failure, disease progression, increased infection rates and poor outcome. The presence of systemic inflammation is also well documented in a cohort of depressed patients; peripheral cytokine signals can result in neuroinflammation, behavioural change and depressive symptoms via neural mechanisms, cerebral endothelial cell and circumventricular organ signaling, and peripheral immune cell-to-brain signaling. Gut dysbiosis has been observed in both depressed and cirrhotic patients. It leads to intestinal barrier dysfunction resulting in increased bacterial translocation, in turn activating circulating immune cells, leading to cytokine production and systemic inflammation. A perturbed gut-liver-brain axis may therefore explain the high rates of depression in patients with cirrhosis. The underlying mechanisms explaining the critical relationship between depression and cirrhosis remain to be fully elucidated. Several other psychosocial and biological factors are likely to be involved, and therefore the cause is probably multifactorial. However, the role of the dysfunctional gut-liver-brain axis as a driver of gut-derived systemic inflammation requires further exploration and consideration as a target for therapy for depression in patients with cirrhosis.
    Keywords:  Depression; cirrhosis; gut dysbiosis; gut-liver-brain axis; systemic inflammation
    DOI:  https://doi.org/10.1016/j.jhep.2021.11.008
  75. J Clin Invest. 2021 Nov 23. pii: e150634. [Epub ahead of print]
    Peanut oral immunotherapy differentially suppresses clonally distinct subsets of T helper cells.
    Brinda Monian, Ang A Tu, Bert Ruiter, Duncan M Morgan, Patrick M Petrossian, Neal P Smith, Todd M Gierahn, Julia H Ginder, Wayne G Shreffler, J Christopher Love.
      Food allergy affects an estimated 8% of children in the US. Oral immunotherapy (OIT) is a recently approved treatment, with outcomes ranging from sustained tolerance to food allergen to no apparent benefit. The immunological underpinnings that influence clinical outcomes of OIT still remain largely unresolved. Using single-cell RNA sequencing and paired TCRα/β sequencing, we assessed the transcriptomes of CD154+ and CD137+ peanut-reactive T helper cells from 12 peanut-allergic patients longitudinally throughout OIT. We observed expanded populations of cells expressing Th1, Th2, and Th17 signatures that further separated into six clonally distinct subsets. Four of these subsets demonstrated convergence of TCR sequences, suggesting antigen-driven T cell fate. Over the course of OIT, we observed suppression of Th2 and Th1 gene signatures in effector clonotypes but not Tfh-like clonotypes. Positive outcomes were associated with stronger suppression of Th2 signatures in Th2A-like cells, while treatment failure was associated with the expression of baseline inflammatory gene signatures that were present in Th1 and Th17 populations and unmodulated by OIT. These results demonstrate that differential clinical responses to OIT are associated both with pre-existing characteristics of peanut-reactive CD4+ T cells and with suppression of a subset of Th2 cells.
    Keywords:  Allergy; Immunology; T cells
    DOI:  https://doi.org/10.1172/JCI150634
  76. Clin Exp Gastroenterol. 2021 ;14 457-465
    Nonalcoholic Fatty Liver Disease and Chronic Kidney Disease: A Review of Links and Risks.
    Amanda Cheung, Aijaz Ahmed.
      Nonalcoholic fatty liver disease and chronic kidney disease are both chronic conditions with rapidly increasing prevalence and incidence worldwide that have led to a significant burden on health-care systems. The association between these two disease entities is partly attributed to shared cardiometabolic comorbidities including diabetes, hypertension, obesity, and metabolic syndrome. However, independent of these overlapping risks, there are increased rates and more severe CKD in NAFLD patients. Conversely, more progressive NAFLD is seen with advanced stages of kidney injury. In addition to overlapping risk factors, shared pathogenic mechanisms suggest these two disease entities may resemble different manifestations of a single underlying disease process.
    Keywords:  chronic kidney disease; gut-kidney axis; gut-liver axis; liver-kidney axis; metabolic syndrome; mortality; nonalcoholic fatty liver disease
    DOI:  https://doi.org/10.2147/CEG.S226130
  77. STAR Protoc. 2021 Dec 17. 2(4): 100942
    Preclinical testing of chimeric antigen receptor T cells in neuroblastoma mouse models.
    Nan Li, Rosa Nguyen, Carol J Thiele, Mitchell Ho.
      The translation of chimeric antigen receptor (CAR) T cell therapy for pediatric solid tumors is limited by the lack of preclinical models that fully recapitulate solid tumor biology. We describe steps to implement neuroblastoma metastatic and orthotopic mouse models. We delineate an analysis pipeline to quantify the efficacy and determine the immunological characteristics of both CAR T and tumor cells in these models. Both mouse models can be applied to evaluate other experimental therapies for neuroblastoma. For complete details on the use and execution of this protocol, please refer to Li et al. (2021).
    Keywords:  Cancer; Cell culture; Cell-based Assays; Immunology; Model Organisms; Molecular Biology; Neuroscience
    DOI:  https://doi.org/10.1016/j.xpro.2021.100942
  78. Nat Rev Endocrinol. 2021 Nov 24.
    Highlights from SfE BES 2021.
    Shimona Starling.
      
    DOI:  https://doi.org/10.1038/s41574-021-00603-0
  79. Mol Biomed. 2021 ;2(1): 11
    Targeting regulatory T cells for immunotherapy in melanoma.
    Lili Huang, Yeye Guo, Shujing Liu, Huaishan Wang, Jinjin Zhu, Lingling Ou, Xiaowei Xu.
      Regulatory T cells (Tregs) are essential in the maintenance of immunity, and they are also a key to immune suppressive microenvironment in solid tumors. Many studies have revealed the biology of Tregs in various human pathologies. Here we review recent understandings of the immunophenotypes and suppressive functions of Tregs in melanoma, including Treg recruitment and expansion in a tumor. Tregs are frequently accumulated in melanoma and the ratio of CD8+ T cells versus Tregs in the melanoma is predictive for patient survival. Hence, depletion of Tregs is a promising strategy for the enhancement of anti-melanoma immunity. Many recent studies are aimed to target Tregs in melanoma. Distinguishing Tregs from other immune cells and understanding the function of different subsets of Tregs may contribute to better therapeutic efficacy. Depletion of functional Tregs from the tumor microenvironment has been tested to induce clinically relevant immune responses against melanomas. However, the lack of Treg specific therapeutic antibodies or Treg specific depleting strategies is a big hurdle that is yet to be overcome. Additional studies to fine-tune currently available therapies and more agents that specifically and selectively target tumor infiltrating Tregs in melanoma are urgently needed.
    Keywords:  Immune suppression; Immunotherapy; Melanoma; Tregs
    DOI:  https://doi.org/10.1186/s43556-021-00038-z
  80. Microorganisms. 2021 Nov 14. pii: 2351. [Epub ahead of print]9(11):
    Impact of Helicobacter pylori-Related Metabolic Syndrome Parameters on Arterial Hypertension.
    Jannis Kountouras, Apostolis Papaefthymiou, Stergios A Polyzos, Georgia Deretzi, Elisabeth Vardaka, Elpidoforos S Soteriades, Maria Tzitiridou-Chatzopoulou, Paraskevas Gkolfakis, Kyriaki Karafyllidou, Michael Doulberis.
      Arterial hypertension is a risk factor for several pathologies, mainly including cardio-cerebrovascular diseases, which rank as leading causes of morbidity and mortality worldwide. Arterial hypertension also constitutes a fundamental component of the metabolic syndrome. Helicobacter pylori infection is one of the most common types of chronic infection globally and displays a plethora of both gastric and extragastric effects. Among other entities, Helicobacter pylori has been implicated in the pathogenesis of the metabolic syndrome. Within this review, we illustrate the current state-of-the-art evidence, which may link several components of the Helicobacter pylori-related metabolic syndrome, including non-alcoholic fatty liver disease and arterial hypertension. In particular, current knowledge of how Helicobacter pylori exerts its virulence through dietary, inflammatory and metabolic pathways will be discussed. Although there is still no causative link between these entities, the emerging evidence from both basic and clinical research supports the proposal that several components of the Helicobacter pylori infection-related metabolic syndrome present an important risk factor in the development of arterial hypertension. The triad of Helicobacter pylori infection, the metabolic syndrome, and hypertension represents a crucial worldwide health problem on a pandemic scale with high morbidity and mortality, like COVID-19, thereby requiring awareness and appropriate management on a global scale.
    Keywords:  Helicobacter pylori; arterial hypertension; atherosclerosis; diet; inflammation; metabolic syndrome; non-alcoholic fatty liver disease
    DOI:  https://doi.org/10.3390/microorganisms9112351
  81. Int J Mol Sci. 2021 Nov 19. pii: 12506. [Epub ahead of print]22(22):
    Therapeutic Advances in Gut Microbiome Modulation in Patients with Inflammatory Bowel Disease from Pediatrics to Adulthood.
    Adi Eindor-Abarbanel, Genelle R Healey, Kevan Jacobson.
      There is mounting evidence that the gut microbiota plays an important role in the pathogenesis of inflammatory bowel disease (IBD). For the past decade, high throughput sequencing-based gut microbiome research has identified characteristic shifts in the composition of the intestinal microbiota in patients with IBD, suggesting that IBD results from alterations in the interactions between intestinal microbes and the host's mucosal immune system. These studies have been the impetus for the development of new therapeutic approaches targeting the gut microbiome, such as nutritional therapies, probiotics, fecal microbiota transplant and beneficial metabolic derivatives. Innovative technologies can further our understanding of the role the microbiome plays as well as help to evaluate how the different approaches in microbiome modulation impact clinical responses in adult and pediatric patients. In this review, we highlight important microbiome studies in patients with IBD and their response to different microbiome modulation therapies, and describe the differences in therapeutic response between pediatric and adult patient cohorts.
    Keywords:  EEN; FMT; IBD; antibiotics; dietary fibre; microbiome; microbiome modulation; prebiotics; probiotics
    DOI:  https://doi.org/10.3390/ijms222212506
  82. Int J Mol Sci. 2021 Nov 18. pii: 12431. [Epub ahead of print]22(22):
    Aryl Hydrocarbon Receptor (AhR) Activation by 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) Dose-Dependently Shifts the Gut Microbiome Consistent with the Progression of Non-Alcoholic Fatty Liver Disease.
    Russell R Fling, Timothy R Zacharewski.
      Gut dysbiosis with disrupted enterohepatic bile acid metabolism is commonly associated with non-alcoholic fatty liver disease (NAFLD) and recapitulated in a NAFLD-phenotype elicited by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice. TCDD induces hepatic fat accumulation and increases levels of secondary bile acids, including taurolithocholic acid and deoxycholic acid (microbial modified bile acids involved in host bile acid regulation signaling pathways). To investigate the effects of TCDD on the gut microbiota, the cecum contents of male C57BL/6 mice orally gavaged with sesame oil vehicle or 0.3, 3, or 30 µg/kg TCDD were examined using shotgun metagenomic sequencing. Taxonomic analysis identified dose-dependent increases in Lactobacillus species (i.e., Lactobacillus reuteri). Increased species were also associated with dose-dependent increases in bile salt hydrolase sequences, responsible for deconjugation reactions in secondary bile acid metabolism. Increased L. reuteri levels were further associated with mevalonate-dependent isopentenyl diphosphate (IPP) biosynthesis and o-succinylbenzoate synthase, a menaquinone biosynthesis associated gene. Analysis of the gut microbiomes from cirrhosis patients identified an increased abundance of genes from the mevalonate-dependent IPP biosynthesis as well as several other menaquinone biosynthesis genes, including o-succinylbenzoate synthase. These results extend the association of lactobacilli with the AhR/intestinal axis in NAFLD progression and highlight the similarities between TCDD-elicited phenotypes in mice to human NAFLD.
    Keywords:  2,3,7,8-tetrachlorodibenzo-p-dioxin; aryl hydrocarbon receptor; dioxin; fibrosis; gut dysbiosis; gut microbiome; non-alcoholic fatty liver disease; secondary bile acids
    DOI:  https://doi.org/10.3390/ijms222212431
  83. Int J Mol Sci. 2021 Nov 10. pii: 12169. [Epub ahead of print]22(22):
    Lung and Gut Microbiota Changes Associated with Pseudomonas aeruginosa Infection in Mouse Models of Cystic Fibrosis.
    Giovanni Bacci, Alice Rossi, Federica Armanini, Lisa Cangioli, Ida De Fino, Nicola Segata, Alessio Mengoni, Alessandra Bragonzi, Annamaria Bevivino.
      Cystic fibrosis (CF) disease leads to altered lung and gut microbiomes compared to healthy subjects. The magnitude of this dysbiosis is influenced by organ-specific microenvironmental conditions at different stages of the disease. However, how this gut-lung dysbiosis is influenced by Pseudomonas aeruginosa chronic infection is unclear. To test the relationship between CFTR dysfunction and gut-lung microbiome under chronic infection, we established a model of P. aeruginosa infection in wild-type (WT) and gut-corrected CF mice. Using 16S ribosomal RNA gene, we compared lung, stool, and gut microbiota of C57Bl/6 Cftr tm1UNCTgN(FABPCFTR) or WT mice at the naïve state or infected with P. aeruginosa.&nbsp;P. aeruginosa infection influences murine health significantly changing body weight both in CF and WT mice. Both stool and gut microbiota revealed significantly higher values of alpha diversity in WT mice than in CF mice, while lung microbiota showed similar values. Infection with P. aeruginosa did not changed the diversity of the stool and gut microbiota, while a drop of diversity of the lung microbiota was observed compared to non-infected mice. However, the taxonomic composition of gut microbiota was shown to be influenced by P. aeruginosa infection in CF mice but not in WT mice. This finding indicates that P. aeruginosa chronic infection has a major impact on microbiota diversity and composition in the lung. In the gut, CFTR genotype and P. aeruginosa infection affected the overall diversity and taxonomic microbiota composition, respectively. Overall, our results suggest a cross-talk between lung and gut microbiota in relation to P. aeruginosa chronic infection and CFTR mutation.
    Keywords:  CFTR mice; Pseudomonas aeruginosa; animal models; cystic fibrosis; gut; gut-lung axis; lung; microbiome
    DOI:  https://doi.org/10.3390/ijms222212169
  84. Biomedicines. 2021 Nov 09. pii: 1647. [Epub ahead of print]9(11):
    Estimating Drug Efficacy with a Diet-Induced NASH Model in Chimeric Mice with Humanized Livers.
    Keishi Kisoh, Go Sugahara, Yuko Ogawa, Suzue Furukawa, Yuji Ishida, Takeshi Okanoue, Michinori Kohara, Chise Tateno.
      Nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) is the most common liver disorder in developed countries. Although many new therapeutics for NASH are present in the drug development pipeline, there are still no approved drugs. One of the reasons that makes NASH drug development challenging is the lack of appropriate animal NASH models that resolve issues arising from inter-species differences between humans and rodents. In the present study, we developed a choline-deficient, L-amino-acid-defined, high-fat-diet (CDAHFD)-induced human NASH model using human liver chimeric mice. We demonstrated human hepatocyte injury by an elevation of plasma human alanine aminotransferase 1 in mice fed CDAHFD. Histological analysis showed that CDAHFD feeding induced similar histological changes to human NASH patients, including ballooning, inflammation, apoptosis, regeneration of human hepatocytes, and pericellular and perisinusoidal fibrosis. The chimeric mice fed CDAHFD were treated with a peroxisome-proliferator-activated receptor α/δ agonist, Elafibranor. Elafibranor ameliorated steatosis, ballooning of hepatocytes, and preserved fibrosis progression. We developed a novel humanized NASH model that can elucidate pathophysiological mechanisms and predict therapeutic efficacy in human NASH. This model will be useful in exploring new drugs and biomarkers in the early stages of human NASH.
    Keywords:  Mallory–Denk body; NAFLD/NASH; ballooning hepatocytes; human disease animal model; human liver chimeric mice
    DOI:  https://doi.org/10.3390/biomedicines9111647
  85. Nat Rev Endocrinol. 2021 Nov 23.
    Non-invasive methods for imaging hepatic steatosis and their clinical importance in NAFLD.
    Nobuharu Tamaki, Veeral Ajmera, Rohit Loomba.
      Hepatic steatosis is a key histological feature of nonalcoholic fatty liver disease (NAFLD). The non-invasive quantification of liver fat is now possible due to advances in imaging modalities. Emerging data suggest that high levels of liver fat and its temporal change, as measured by quantitative non-invasive methods, might be associated with NAFLD progression. Ultrasound-based modalities have moderate diagnostic accuracy for liver fat content and are suitable for screening. However, of the non-invasive imaging modalities, MRI-derived proton density fat fraction (MRI-PDFF) has the highest diagnostic accuracy and is used for trial enrolment and to evaluate therapeutic effects in early-phase clinical trials in nonalcoholic steatohepatitis (NASH). In patients with NAFLD without advanced fibrosis, high levels of liver fat are associated with rapid disease progression. Furthermore, changes on MRI-PDFF (≥30% decline relative to baseline) are associated with NAFLD activity score improvement and fibrosis regression. However, an inverse association exists between liver fat and complications of cirrhosis. Liver fat decreases as liver fibrosis progresses towards cirrhosis, and the clinical importance of quantitative measurements of liver fat differs by NAFLD status. As such, patients with NAFLD should be stratified by fibrosis severity to investigate the utility of quantitative measurements of liver fat for assessing NAFLD progression and prognosis.
    DOI:  https://doi.org/10.1038/s41574-021-00584-0
  86. Gastroenterology. 2021 Nov 17. pii: S0016-5085(21)03756-2. [Epub ahead of print]
    COVID-19 and the forgotten organ: prolonged changes to the metabolic output of the gut microbiome.
    Mericien Venzon, Ken Cadwell.
      
    DOI:  https://doi.org/10.1053/j.gastro.2021.11.017
  87. Vaccines (Basel). 2021 Nov 08. pii: 1294. [Epub ahead of print]9(11):
    Small Molecule Inhibitors of MERTK and FLT3 Induce Cell Cycle Arrest in Human CD8+ T Cells.
    Richard M Powell, Marlies J W Peeters, Anne Rahbech, Pia Aehnlich, Tina Seremet, Per Thor Straten.
      There is an increasing interest in the development of Receptor Tyrosine Kinases inhibitors (RTKIs) for cancer treatment, as dysregulation of RTK expression can govern oncogenesis. Among the newer generations of RTKIs, many target Mer Tyrosine Kinase (MERTK) and Fms related RTK 3 (FLT3). Next to being overexpressed in many cancers, MERTK and FLT3 have important roles in immune cell development and function. In this study, we address how the new generation and potent RTKIs of MERTK/FLT3 affect human primary CD8+ T cell function. Using ex vivo T cell receptor (TCR)-activated CD8+ T cells, we demonstrate that use of dual MERTK/FLT3 inhibitor UNC2025 restricts CD8+ T proliferation at the G2 phase, at least in part by modulation of mTOR signaling. Cytokine production and activation remain largely unaffected. Finally, we show that activated CD8+ T cells express FLT3 from day two post activation, and FLT3 inhibition with AC220 (quizartinib) or siRNA-mediated knockdown affects cell cycle kinetics. These results signify that caution is needed when using potent RTKIs in the context of antitumor immune responses.
    Keywords:  CD8+ T cells; FLT3; MERTK; T lymphocytes; receptor tyrosine kinases; small molecule inhibitors
    DOI:  https://doi.org/10.3390/vaccines9111294
  88. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2021 Nov;37(11): 1038-1044
    [Research progress in metabolic reprogramming of endothelial cells and T cells and potential therapeutic targets for chronic inflammation].
    Wenqiu Wang, Shiyuan Hou, Mingwei Han, Yiting Zheng, Ruixue Ma, Ziyu Liu, Yunhua Lyu, Xing'an Wu, Rongrong Liu.
      Metabolic reprogramming plays a very important role in the immunoregulatory process, and T cells, as the indispensable part in the immune response, realize the change of function and state through metabolic reprogramming. And endothelial cells exhibit similar metabolic reprogramming. This review explores the interaction between endothelial cells and T cells to reveal the mechanism of the former as non-professional antigen presenting cells to recruit and activate the latter and the specific mechanism of cytokines produced by the latter in inflammatory response to regulate the function and state of the former, aiming to find the potential therapeutic targets for chronic inflammation and provide new ideas for the treatment.
  89. Semin Immunopathol. 2021 Nov 25.
    Circadian rhythms in adaptive immunity and vaccination.
    Nicolas Cermakian, Sophia K Stegeman, Kimaya Tekade, Nathalie Labrecque.
      Adaptive immunity allows an organism to respond in a specific manner to pathogens and other non-self-agents. Also, cells of the adaptive immune system, such as T and B lymphocytes, can mediate a memory of an encounter with a pathogen, allowing a more efficient response to a future infection. As for other aspects of physiology and of the immune system, the adaptive immune system is regulated by circadian clocks. Consequently, the development, differentiation, and trafficking between tissues of adaptive immune cells have been shown to display daily rhythms. Also, the response of T cells to stimuli (e.g., antigen presentation to T cells by dendritic cells) varies according to a circadian rhythm, due to T cell-intrinsic mechanisms as well as cues from other tissues. The circadian control of adaptive immune response has implications for our understanding of the fight against pathogens as well as auto-immune diseases, but also for vaccination, a preventive measure based on the development of immune memory.
    Keywords:  Antigen presentation; B lymphocyte; Circadian clock; Dendritic cell; T lymphocyte; Trafficking; Vaccination
    DOI:  https://doi.org/10.1007/s00281-021-00903-7
  90. Viruses. 2021 Nov 13. pii: 2273. [Epub ahead of print]13(11):
    In Vivo Bioluminescence Imaging of HBV Replicating Hepatocytes Allows for the Monitoring of Anti-Viral Immunity.
    Katrin Manske, Annika Schneider, Chunkyu Ko, Percy A Knolle, Katja Steiger, Ulrike Protzer, Dirk Wohlleber.
      Immunity against hepatitis B virus (HBV) infection is complex and not entirely understood so far, including the decisive factors leading to the development of chronic hepatitis B. This lack of a mechanistic understanding of HBV-specific immunity is also caused by a limited number of suitable animal models. Here, we describe the generation of a recombinant adenovirus expressing an HBV 1.3-overlength genome linked to luciferase (Ad-HBV-Luc) allowing for precise analysis of the quantity of infected hepatocytes. This enables sensitive and close-meshed monitoring of HBV-specific CD8 T cells and the onset of anti-viral immunity in mice. A high dose of Ad-HBV-Luc developed into chronic hepatitis B accompanied by dysfunctional CD8 T cells characterized by high expression of PD1 and TOX and low expression of KLRG1 and GzmB. In contrast, a low dose of Ad-HBV-Luc infection resulted in acute hepatitis with CD8 T cell-mediated elimination of HBV-replicating hepatocytes associated with elevated sALT levels and increased numbers of cytotoxic HBV-specific CD8 T cells. Thus, the infectious dose was a critical factor to induce either acute self-limited or chronic HBV infection in mice. Taken together, the new Ad-HBV-Luc vector will allow for highly sensitive and time-resolved analysis of HBV-specific immune responses during acute and chronic infection.
    Keywords:  CD8 T cells; HBV; T cell dysfunction; bioluminescence imaging (BLI); immunity; liver immunology
    DOI:  https://doi.org/10.3390/v13112273
  91. Cells. 2021 Oct 20. pii: 2806. [Epub ahead of print]10(11):
    Bile Acid Receptors and the Gut-Liver Axis in Nonalcoholic Fatty Liver Disease.
    Rui Xue, Lianyong Su, Shengyi Lai, Yanyan Wang, Derrick Zhao, Jiangao Fan, Weidong Chen, Phillip B Hylemon, Huiping Zhou.
      The prevalence of nonalcoholic fatty liver disease (NAFLD) has been significantly increased due to the global epidemic of obesity. The disease progression from simple steatosis (NAFL) to nonalcoholic steatohepatitis (NASH) is closely linked to inflammation, insulin resistance, and dysbiosis. Although extensive efforts have been aimed at elucidating the pathological mechanisms of NAFLD disease progression, current understanding remains incomplete, and no effective therapy is available. Bile acids (BAs) are not only important physiological detergents for the absorption of lipid-soluble nutrients in the intestine but also metabolic regulators. During the last two decades, BAs have been identified as important signaling molecules involved in lipid, glucose, and energy metabolism. Dysregulation of BA homeostasis has been associated with NAFLD disease severity. Identification of nuclear receptors and G-protein-coupled receptors activated by different BAs not only significantly expanded the current understanding of NAFLD/NASH disease progression but also provided the opportunity to develop potential therapeutics for NAFLD/NASH. In this review, we will summarize the recent studies with a focus on BA-mediated signaling pathways in NAFLD/NASH. Furthermore, the therapeutic implications of targeting BA-mediated signaling pathways for NAFLD will also be discussed.
    Keywords:  FXR; NAFLD; S1PR2; TGR5; bile acid receptor; bile acids; gut–liver axis
    DOI:  https://doi.org/10.3390/cells10112806
  92. Biomedicines. 2021 Nov 06. pii: 1631. [Epub ahead of print]9(11):
    Innate Immune Mechanisms and Immunotherapy of Myeloid Malignancies.
    Sara Small, Yazan Numan, Leonidas C Platanias.
      Similar to other cancers, myeloid malignancies are thought to subvert the immune system during their development. This subversion occurs via both malignant cell-autonomous and non-autonomous mechanisms and involves manipulation of the innate and adaptive immune systems. Multiple strategies are being studied to rejuvenate, redirect, or re-enforce the immune system in order to fight off myeloid malignancies. So far, the most successful strategies include interferon treatment and antibody-based therapies, though chimeric antigen receptor (CAR) cells and immune checkpoint inhibitors are also promising therapies. In this review, we discuss the inherent immune mechanisms of defense against myeloid malignancies, currently-approved agents, and agents under investigation. Overall, we evaluate the efficacy and potential of immuno-oncology in the treatment of myeloid malignancies.
    Keywords:  AML; CAR-T; antibodies; immunotherapy; interferon; myeloid malignancies
    DOI:  https://doi.org/10.3390/biomedicines9111631
  93. Cells. 2021 Nov 19. pii: 3231. [Epub ahead of print]10(11):
    From Bench to Bedside: How the Tumor Microenvironment Is Impacting the Future of Immunotherapy for Renal Cell Carcinoma.
    Jonathan Anker, Justin Miller, Nicole Taylor, Natasha Kyprianou, Che-Kai Tsao.
      Immunotherapy has revolutionized the treatment landscape for many cancer types. The treatment for renal cell carcinoma (RCC) has especially evolved in recent years, from cytokine-based immunotherapies to immune checkpoint inhibitors. Although clinical benefit from immunotherapy is limited to a subset of patients, many combination-based approaches have led to improved outcomes. The success of such approaches is a direct result of the tumor immunology knowledge accrued regarding the RCC microenvironment, which, while highly immunogenic, demonstrates many unique characteristics. Ongoing translational work has elucidated some of the mechanisms of response, as well as primary and secondary resistance, to immunotherapy. Here, we provide a comprehensive review of the RCC immunophenotype with a specific focus on how preclinical and clinical data are shaping the future of immunotherapy.
    Keywords:  immunology; immunotherapy; renal cell carcinoma; tumor microenvironment
    DOI:  https://doi.org/10.3390/cells10113231
  94. Nat Commun. 2021 Nov 25. 12(1): 6850
    Hematopoiesis under telomere attrition at the single-cell resolution.
    Natthakan Thongon, Feiyang Ma, Andrea Santoni, Matteo Marchesini, Elena Fiorini, Ashley Rose, Vera Adema, Irene Ganan-Gomez, Emma M Groarke, Fernanda Gutierrez-Rodrigues, Shuaitong Chen, Pamela Lockyer, Sarah Schneider, Carlos Bueso-Ramos, Guillermo Montalban-Bravo, Caleb A Class, Kelly A Soltysiak, Matteo Pellegrini, Ergun Sahin, Alison A Bertuch, Courtney D DiNardo, Guillermo Garcia-Manero, Neal S Young, Karen Dwyer, Simona Colla.
      The molecular mechanisms that drive hematopoietic stem cell functional decline under conditions of telomere shortening are not completely understood. In light of recent advances in single-cell technologies, we sought to redefine the transcriptional and epigenetic landscape of mouse and human hematopoietic stem cells under telomere attrition, as induced by pathogenic germline variants in telomerase complex genes. Here, we show that telomere attrition maintains hematopoietic stem cells under persistent metabolic activation and differentiation towards the megakaryocytic lineage through the cell-intrinsic upregulation of the innate immune signaling response, which directly compromises hematopoietic stem cells' self-renewal capabilities and eventually leads to their exhaustion. Mechanistically, we demonstrate that targeting members of the Ifi20x/IFI16 family of cytosolic DNA sensors using the oligodeoxynucleotide A151, which comprises four repeats of the TTAGGG motif of the telomeric DNA, overcomes interferon signaling activation in telomere-dysfunctional hematopoietic stem cells and these cells' skewed differentiation towards the megakaryocytic lineage. This study challenges the historical hypothesis that telomere attrition limits the proliferative potential of hematopoietic stem cells by inducing apoptosis, autophagy, or senescence, and suggests that targeting IFI16 signaling axis might prevent hematopoietic stem cell functional decline in conditions affecting telomere maintenance.
    DOI:  https://doi.org/10.1038/s41467-021-27206-7
  95. J Exp Med. 2021 Dec 06. pii: e20210639. [Epub ahead of print]218(12):
    ACC1-expressing pathogenic T helper 2 cell populations facilitate lung and skin inflammation in mice.
    Takahiro Nakajima, Toshio Kanno, Satoru Yokoyama, Shigemi Sasamoto, Hikari K Asou, Damon J Tumes, Osamu Ohara, Toshinori Nakayama, Yusuke Endo.
      T cells possess distinguishing effector functions and drive inflammatory disorders. We have previously identified IL-5-producing Th2 cells as the pathogenic population predominantly involved in the pathology of allergic inflammation. However, the cell-intrinsic signaling pathways that control the pathogenic Th2 cell function are still unclear. We herein report the high expression of acetyl-CoA carboxylase 1 (ACC1) in the pathogenic CD4+ T cell population in the lung and skin. The genetic deletion of CD4+ T cell-intrinsic ACC1 dampened eosinophilic and basophilic inflammation in the lung and skin by constraining IL-5 or IL-3 production. Mechanistically, ACC1-dependent fatty acid biosynthesis induces the pathogenic cytokine production of CD4+ T cells via metabolic reprogramming and the availability of acetyl-CoA for epigenetic regulation. We thus identified a distinct phenotype of the pathogenic T cell population in the lung and skin, and ACC1 was shown to be an essential regulator controlling the pathogenic function of these populations to promote type 2 inflammation.
    DOI:  https://doi.org/10.1084/jem.20210639
  96. Diagnostics (Basel). 2021 Oct 26. pii: 1982. [Epub ahead of print]11(11):
    From Immune Dysregulations to Therapeutic Perspectives in Myelodysplastic Syndromes: A Review.
    Thibault Comont, Emmanuel Treiner, François Vergez.
      The pathophysiology of myelodysplastic syndromes (MDSs) is complex and often includes immune dysregulation of both the innate and adaptive immune systems. Whereas clonal selection mainly involves smoldering inflammation, a cellular immunity dysfunction leads to increased apoptosis and blast proliferation. Addressing immune dysregulations in MDS is a recent concept that has allowed the identification of new therapeutic targets. Several approaches targeting the different actors of the immune system have therefore been developed. However, the results are very heterogeneous, indicating the need to improve our understanding of the disease and interactions between chronic inflammation, adaptive dysfunction, and somatic mutations. This review highlights current knowledge of the role of immune dysregulation in MDS pathophysiology and the field of new drugs.
    Keywords:  T-cell; immune; inflammation; myelodysplastic syndromes
    DOI:  https://doi.org/10.3390/diagnostics11111982
  97. Proteins. 2021 Nov 25.
    In Memoriam of Narayanaswamy Srinivasan (1962-2021).
    Frank Eisenhaber, Chandra Verma, Tom Blundell.
      
    DOI:  https://doi.org/10.1002/prot.26287
  98. Br J Pharmacol. 2021 Nov 24.
    CORTISTATIN REGULATES FIBROSIS AND MYOFIBROBLAST ACTIVATION IN EXPERIMENTAL HEPATOTOXIC- AND CHOLESTATIC-INDUCED LIVER INJURY.
    Raquel Benitez, Marta Caro, Eduardo Andres-Leon, Francisco O'Valle, Mario Delgado.
       BACKGROUND AND PURPOSE: Liver fibrosis induced by chronic hepatic injury remains as a major cause of morbidity and mortality worldwide. Identification of susceptibility/prognosis factors and new therapeutic tools for treating hepatic fibrotic disorders are urgent medical needs. Cortistatin is a neuropeptide with potent anti-inflammatory and anti-fibrotic activities in lung that binds to receptors that are expressed in liver fibroblasts and hepatic stellate cells. We evaluated the capacity of cortistatin to regulate liver fibrosis.
    EXPERIMENTAL APPROACH: We experimentally induced liver fibrosis in mice by chronic CCl4 exposition and bile duct ligation and evaluated the histopathological signs and fibrotic markers.
    KEY RESULTS: Hepatic expression of cortistatin inversely correlated with liver fibrosis grade in mice and humans with hepatic disorders. Cortistatin-deficient mice showed exacerbated signs of liver damage and fibrosis and increased mortality rates when challenged to hepatotoxic and cholestatic injury. Compared to wild-type mice, non-parenchymal liver cells isolated from cortistatin-deficient mice showed increased presence of cells with activated myofibroblast phenotypes and a differential genetic signature that is indicative of activated hepatic stellate cells and periportal fibroblasts and of myofibroblasts with active contractile apparatus. Cortistatin treatment reversed in vivo and in vitro these exaggerated fibrogenic phenotypes and protected from progression to severe liver fibrosis in response to hepatic injury.
    CONCLUSION AND IMPLICATIONS: We identify cortistatin as an endogenous molecular break of liver fibrosis and its deficiency as a potential poor-prognosis marker for chronic hepatic disorders that course with fibrosis. Cortistatin-based therapies emerge as attractive strategies for ameliorating severe hepatic fibrosis of various etiologies.
    Keywords:  Kupffer cells; bile duct ligation; contractile fibers; hepatic stellate cell; neuropeptide; periportal fibroblast
    DOI:  https://doi.org/10.1111/bph.15752
  99. Metabolites. 2021 Oct 25. pii: 729. [Epub ahead of print]11(11):
    Single-Cell Multiomics Analysis for Drug Discovery.
    Sam F Nassar, Khadir Raddassi, Terence Wu.
      Given the heterogeneity seen in cell populations within biological systems, analysis of single cells is necessary for studying mechanisms that cannot be identified on a bulk population level. There are significant variations in the biological and physiological function of cell populations due to the functional differences within, as well as between, single species as a result of the specific proteome, transcriptome, and metabolome that are unique to each individual cell. Single-cell analysis proves crucial in providing a comprehensive understanding of the biological and physiological properties underlying human health and disease. Omics technologies can help to examine proteins (proteomics), RNA molecules (transcriptomics), and the chemical processes involving metabolites (metabolomics) in cells, in addition to genomes. In this review, we discuss the value of multiomics in drug discovery and the importance of single-cell multiomics measurements. We will provide examples of the benefits of applying single-cell omics technologies in drug discovery and development. Moreover, we intend to show how multiomics offers the opportunity to understand the detailed events which produce or prevent disease, and ways in which the separate omics disciplines complement each other to build a broader, deeper knowledge base.
    Keywords:  COVID-19; IsoLight; genomics; mass spectrometry; metabolomics; multiomics; proteomics; single-cell; transcriptomics
    DOI:  https://doi.org/10.3390/metabo11110729
  100. Elife. 2021 Nov 22. pii: e73808. [Epub ahead of print]10
    A coarse-grained NADH redox model enables inference of subcellular metabolic fluxes from fluorescence lifetime imaging.
    Xingbo Yang, Gloria Ha, Dan Needleman.
      Mitochondrial metabolism is of central importance to diverse aspects of cell and developmental biology. Defects in mitochondria are associated with many diseases, including cancer, neuropathology, and infertility. Our understanding of mitochondrial metabolism in situ and dysfunction in diseases are limited by the lack of techniques to measure mitochondrial metabolic fluxes with sufficient spatiotemporal resolution. Herein, we developed a new method to infer mitochondrial metabolic fluxes in living cells with subcellular resolution from fluorescence lifetime imaging of NADH. This result is based on the use of a generic coarse-grained NADH redox model. We tested the model in mouse oocytes and human tissue culture cells subject to a wide variety of perturbations by comparing predicted fluxes through the electron transport chain (ETC) to direct measurements of oxygen consumption rate. Interpreting the FLIM measurements of NADH using this model, we discovered a homeostasis of ETC flux in mouse oocytes: perturbations of nutrient supply and energy demand of the cell do not change ETC flux despite significantly impacting NADH metabolic state. Furthermore, we observed a subcellular spatial gradient of ETC flux in mouse oocytes and found that this gradient is primarily a result of a spatially heterogeneous mitochondrial proton leak. We concluded from these observations that ETC flux in mouse oocytes is not controlled by energy demand or supply, but by the intrinsic rates of mitochondrial respiration.
    Keywords:  biochemistry; chemical biology; human; mouse; physics of living systems
    DOI:  https://doi.org/10.7554/eLife.73808
  101. Proc Biol Sci. 2021 Nov 24. 288(1963): 20211787
    Fitness benefits of dietary restriction.
    Zahida Sultanova, Edward R Ivimey-Cook, Tracey Chapman, Alexei A Maklakov.
      Dietary restriction (DR) improves survival across a wide range of taxa yet remains poorly understood. The key unresolved question is whether this evolutionarily conserved response to temporary lack of food is adaptive. Recent work suggests that early-life DR reduces survival and reproduction when nutrients subsequently become plentiful, thereby challenging adaptive explanations. A new hypothesis maintains that increased survival under DR results from reduced costs of overfeeding. We tested the adaptive value of DR response in an outbred population of Drosophila melanogaster fruit flies. We found that DR females did not suffer from reduced survival upon subsequent re-feeding and had increased reproduction and mating success compared to their continuously fully fed (FF) counterparts. The increase in post-DR reproductive performance was of sufficient magnitude that females experiencing early-life DR had the same total fecundity as continuously FF individuals. Our results suggest that the DR response is adaptive and increases fitness when temporary food shortages cease.
    Keywords:  ageing; dietary restriction; lifespan extension; senescence
    DOI:  https://doi.org/10.1098/rspb.2021.1787
  102. PLoS One. 2021 ;16(11): e0260313
    Assessment of non-alcoholic fatty liver disease (NAFLD) severity with novel serum-based markers: A pilot study.
    Atul Goyale, Anjly Jain, Colette Smith, Margarita Papatheodoridi, Marta Guerrero Misas, Davide Roccarina, Laura Iogna Prat, Dimitri P Mikhailidis, Devaki Nair, Emmanuel Tsochatzis.
       BACKGROUND/AIMS: Non-alcoholic fatty liver disease (NAFLD) represents a significant public health issue. Identifying patients with simple steatosis from those with non-alcoholic steatohepatitis (NASH) is crucial since NASH is correlated with increased morbidity and mortality. Serum-based markers, including adipokines and cytokines, are important in the pathogenesis and progression of NAFLD. Here we assessed the usefulness of such markers in patients with NAFLD.
    METHODS: This prospective, cross-sectional study included 105 adult patients with varying severity of NAFLD. Twelve serum-based markers were measured by 3 biochip platforms and 2 enzyme-linked immunosorbent assay (ELISA) methods. We also developed a NAFLD individual fibrosis index (NIFI) using the serum-based markers mostly correlated with fibrosis severity.
    RESULTS: Sixty-one out of 105 patients were male (58.1%) with mean age was 53.5 years. Higher Interleukin-6 (IL-6) increased (p = 0.0321) and lower Matrix Metalloproteinase-9 (MMP-9) serum levels (p = 0.0031) were associated with higher fibrosis as measured by Fibroscan® in multivariable regression analysis. Using receiver-operating characteristic (ROC) curve analysis for the NIFI, area under the curve for predicting Fibroscan values ≥ 7.2 kPa was 0.77 (95%CI: 0.67, 0.88, p<0.001), with sensitivity of 89.3%, specificity of 57.9% and a positive likelihood ratio of 2.8.
    CONCLUSIONS: Increasing fibrosis severity in NAFLD is associated with differential expression of IL-6 and MMP-9. NIFI could be valuable for the prediction of advanced NAFLD fibrosis and potentially help avoid unnecessary interventions such as liver biopsy in low-risk patients.
    DOI:  https://doi.org/10.1371/journal.pone.0260313
  103. Front Immunol. 2021 ;12 751138
    Generation of an NFκB-Driven Alpharetroviral "All-in-One" Vector Construct as a Potent Tool for CAR NK Cell Therapy.
    Loreen Sophie Rudek, Katharina Zimmermann, Melanie Galla, Johann Meyer, Johannes Kuehle, Andriana Stamopoulou, Daniel Brand, I Erol Sandalcioglu, Belal Neyazi, Thomas Moritz, Claudia Rossig, Bianca Altvater, Christine S Falk, Hinrich Abken, Michael Alexander Morgan, Axel Schambach.
      Immune cell therapeutics are increasingly applied in oncology. Especially chimeric antigen receptor (CAR) T cells are successfully used to treat several B cell malignancies. Efforts to engineer CAR T cells for improved activity against solid tumors include co-delivery of pro-inflammatory cytokines in addition to CARs, via either constitutive cytokine expression or inducible cytokine expression triggered by CAR recognition of its target antigen-so-called "T cells redirected for universal cytokine-mediated killing" (TRUCKs) or fourth-generation CARs. Here, we tested the hypothesis that TRUCK principles could be expanded to improve anticancer functions of NK cells. A comparison of the functionality of inducible promoters responsive to NFAT or NFκB in NK cells showed that, in contrast to T cells, the inclusion of NFκB-responsive elements within the inducible promoter construct was essential for CAR-inducible expression of the transgene. We demonstrated that GD2CAR-specific activation induced a tight NFκB-promoter-driven cytokine release in NK-92 and primary NK cells together with an enhanced cytotoxic capacity against GD2+ target cells, also shown by increased secretion of cytolytic cytokines. The data demonstrate biologically relevant differences between T and NK cells that are important when clinically translating the TRUCK concept to NK cells for the treatment of solid malignancies.
    Keywords:  NFκB; NK cells; alpharetroviral vectors; chimeric antigen receptor (CAR); immunomodulatory cytokines; immunotherapy; tumor microenvironment; “all-in-one” TRUCK
    DOI:  https://doi.org/10.3389/fimmu.2021.751138
  104. Adv Wound Care (New Rochelle). 2021 Nov 22.
    Behind the scenes of extracellular vesicle therapy for skin injuries and disorders.
    Bibi Sheleeza Subhan, Michelle Ki, Alexandra Verzella, Shruthi Shankar, Piul Rabbani.
       SIGNIFICANCE: Skin wounds and disorders compromise the protective functions of skin and patient quality of life. Though accessible on the surface, they are challenging to address due to paucity of effective therapies. Exogenous extracellular vesicles (EVs), cell-free derivatives of adult multipotent stromal cells (MSCs), are developing as a treatment modality. Knowledge of origin MSCs, EV processing and mode of action is necessary for directed use of EVs in preclinical studies and methodical translation. Recent advances: Nano to microscale EVs, though from non-skin cells, induce functional responses in cutaneous wound cellular milieu. EVs allow a shift from cell-based to cell-free/derived modalities by carrying the MSC beneficial factors but eliminating risks associated with MSC transplantation. EVs have demonstrated striking efficacy in resolution of preclinical wound models, specifically within the complexity of skin structure and wound pathology.
    CRITICAL ISSUES: To facilitate comparison across studies, tissue sources and processing of MSCs, culture conditions, isolation and preparations of EVs, and vesicle sizes require standardization as these criteria influence EV types and contents, and potentially determine the induced biological responses. Procedural parameters for all steps preceding the actual therapeutic administration may be the key to generating EVs that demonstrate consistent efficacy through known mechanisms. We provide a comprehensive review of such parameters and the subsequent tissue, cellular and molecular impact of the derived EVs in different skin wounds/disorders.
    FUTURE DIRECTIONS: We will gain more complete knowledge of EV-induced effects in skin, and specificity for different wounds/conditions. The safety and efficacy of current preclinical xenogenic applications will favor translation into allogenic clinical applications of EVs as a biologic.
    DOI:  https://doi.org/10.1089/wound.2021.0066
  105. Pathogens. 2021 Oct 29. pii: 1401. [Epub ahead of print]10(11):
    Analysis of Schistosoma mansoni Extracellular Vesicles Surface Glycans Reveals Potential Immune Evasion Mechanism and New Insights on Their Origins of Biogenesis.
    Maude Dagenais, Jared Q Gerlach, George R Wendt, James J Collins, Louise E Atkinson, Angela Mousley, Timothy G Geary, Thavy Long.
      Parasitic helminths are master manipulators of host immunity. Their strategy is complex and involves the release of excreted/secreted products, including extracellular vesicles (EVs). The protein and miRNA contents of EVs have been characterised for many parasitic helminths but, despite reports suggesting the importance of EV surface carbohydrate structures (glycans) in the interactions with target cells and thus subsequent effector functions, little is known about parasite EV glycomics. Using lectin microarrays, we identified several lectins that exhibit strong adhesion to Schistosoma mansoni EVs, suggesting the presence of multiple glycan structures on these vesicles. Interestingly, SNA-I, a lectin that recognises structures with terminal sialic acid, displayed strong affinity for S. mansoni EVs, which was completely abolished by neuraminidase treatment, suggesting sialylation in the EV sample. This finding is of interest, as sialic acids play important roles in the context of infection by aiding immune evasion, affecting target recognition, cell entry, etc., but are not thought to be synthesised by helminths. These data were validated by quantitative analysis of free sialic acid released from EVs following treatment with neuraminidase. Lectin histochemistry and fluorescence in situ hybridisation analyses on whole adult worms suggest the involvement of sub-tegumental cell bodies, as well as the digestive and excretory systems, in the release of EVs. These results support previous reports of EV biogenesis diversity in trematodes and potentially highlight new means of immune modulation and evasion employed by schistosomes.
    Keywords:  exosomes; extracellular vesicles; glycans; helminths; lectin histochemistry; lectin microarray; schistosomes; secretome; sialic acid
    DOI:  https://doi.org/10.3390/pathogens10111401
  106. Pathologica. 2021 Oct;113(5): 339-353
    Multicentric Castleman disease and the evolution of the concept.
    Ting Zhou, Hao-Wei Wang, Stefania Pittaluga, Elaine S Jaffe.
      The term multicentric Castleman disease (MCD) encompasses a spectrum of conditions that share some overlapping clinicopathological manifestations. The fundamental pathogenetic mechanism involves dysregulated cytokine activity, causing systemic inflammatory symptoms as well as lymphadenopathy. Some of the histological changes in lymph nodes resemble the histology of unicentric Castleman disease (UCD). However, based on current knowledge, the use of this shared nomenclature is unfortunate, since these disorders differ in pathogenesis and prognosis. In Kaposi sarcoma-associated herpesvirus (KSHV)-associated MCD, cytokine overactivity is caused by viral products, which can also lead to atypical lymphoproliferations and potential progression to lymphoma. In idiopathic MCD, the hypercytokinemia can result from various mechanisms, which ultimately lead to different constellations of clinical presentations and varied pathology in lymphoid tissues. The authors review the evolving concepts and definitions of the various conditions under the eponym of multicentric Castleman disease.
    Keywords:  Castleman disease; Kaposi sarcoma-associated herpesvirus; TAFRO syndrome; human herpesvirus type 8; interleukin-6
    DOI:  https://doi.org/10.32074/1591-951X-351
  107. Saudi J Gastroenterol. 2021 Nov 02.
    Nonalcoholic fatty liver disease: The role of quercetin and its therapeutic implications.
    Maria Sotiropoulou, Ioannis Katsaros, Michail Vailas, Irene Lidoriki, George V Papatheodoridis, Nikolaos G Kostomitsopoulos, Georgia Valsami, Alexandra Tsaroucha, Dimitrios Schizas.
      Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease, affecting almost one-third of the general population and 75% of obese patients with type 2 diabetes. The aim of this article is to review the current evidence concerning the role of quercetin, a natural compound and flavonoid, and its possible therapeutic effects on this modern-day disease. Despite the fact that the exact pathophysiological mechanisms through which quercetin has a hepatoprotective effect on NAFLD are still not fully elucidated, this review clearly demonstrates that this flavonoid has potent antioxidative stress action and inhibitory effects on hepatocyte apoptosis, inflammation, and generation of reactive oxygen species, factors which are linked to the development of the disease. NAFLD is closely associated with increased dietary fat consumption, especially in Western countries. The hepatoprotective effect of quercetin against NAFLD merits serious consideration and further validation by future studies.
    Keywords:  Flavonoids; liver; nonalcoholic fatty liver disease; nonalcoholic steatohepatitis; quercetin
    DOI:  https://doi.org/10.4103/sjg.sjg_249_21
  108. Zootaxa. 2021 Jul 26. 5005(2): 218-226
    New species of the genus Gynaecoserica Brenske, 1896 from Indochina (Coleoptera: Scarabaeidae: Sericini).
    Dirk Ahrens.
      Here I describe five additional new species of Gynaecoserica Brenske, 1896 from Indochina: Gynaecoserica bihtanensis Ahrens, new species (from Myanmar), G. fallaciosa Ahrens, new species , G. feresimplex Ahrens, new species, G. pseudocymosa Ahrens, new species (all from Thailand), G. ottoi Ahrens, new species (from Laos). The male genitalia of the new species are illustrated.
    DOI:  https://doi.org/10.11646/zootaxa.5005.2.7
  109. Front Immunol. 2021 ;12 768966
    Expression of Immune Related Genes and Possible Regulatory Mechanisms in Alzheimer's Disease.
    Yanjun Lu, Ke Li, Yu Hu, Xiong Wang.
      Immune infiltration of peripheral natural killer (NK) cells in the brain has been observed in Alzheimer's disease (AD). Immunity-related genes (IRGs) play an essential role in immune infiltration; however, the expression of IRGs and possible regulatory mechanisms involved in AD remain unclear. The peripheral blood mononuclear cells (PBMCs) single-cell RNA (scRNA) sequencing data from patients with AD were analyzed and PBMCs obtained from the ImmPort database were screened for cluster marker genes. IRG activity was calculated using the AUCell package. A bulk sequencing dataset of AD brain tissues was analyzed to explore common IRGs between PBMCs and the brain. Relevant regulatory transcription factors (TFs) were identified from the Human TFDB database. The protein-protein interaction network of key TFs were generated using the STRING database. Eight clusters were identified, including memory CD4 T, NKT, NK, B, DC, CD8 T cells, and platelets. NK cells were significantly decreased in patients with AD, while CD4 T cells were increased. NK and DC cells exhibited the highest IRG activity. GO and KEGG analyses of the scRNA and bulk sequencing data showed that the DEGs focused on the immune response. Seventy common IRGs were found in both peripheral NK cells and the brain. Seventeen TFs were associated with IRG expression, and the PPI network indicated that STAT3, IRF1, and REL were the hub TFs. In conclusion, we propose that peripheral NK cells may infiltrate the brain and contribute to neuroinflammatory changes in AD through bioinformatic analysis of scRNA and bulk sequencing data. Moreover, STAT3 may be involved in the transcriptional regulation of IRGs in NK cells.
    Keywords:  Alzheimer’s disease; NK cells; immune infiltration; immunity related genes; single-cell sequencing
    DOI:  https://doi.org/10.3389/fimmu.2021.768966
  110. Nat Rev Endocrinol. 2021 Nov 24.
    MC3R controls growth and puberty onset.
    Olivia Tysoe.
      
    DOI:  https://doi.org/10.1038/s41574-021-00602-1
  111. Life (Basel). 2021 Oct 26. pii: 1141. [Epub ahead of print]11(11):
    Physiological Roles of Apoptotic Cell Clearance: Beyond Immune Functions.
    Minjoo Han, Gyoungah Ryu, Seong-Ah Shin, Jangeun An, Huiji Kim, Daeho Park, Dae-Hee Lee, Chang Sup Lee.
      The clearance of apoptotic cells is known to be a critical step in maintaining tissue and organism homeostasis. This process is rapidly/promptly mediated by recruited or resident phagocytes. Phagocytes that engulf apoptotic cells have been closely linked to the release of anti-inflammatory cytokines to eliminate inflammatory responses. Defective clearance of apoptotic cells can cause severe inflammation and autoimmune responses due to secondary necrosis of apoptotic cells. Recently accumulated evidence indicates that apoptotic cells and their clearance have important physiological roles in addition to immune-related functions. Herein, we review the current understanding of the mechanisms and fundamental roles of apoptotic cell clearance and the beneficial roles of apoptotic cells in physiological processes such as differentiation and development.
    Keywords:  apoptosis; apoptotic cell clearance; development; differentiation; inflammation; phagocyte
    DOI:  https://doi.org/10.3390/life11111141
  112. Cancers (Basel). 2021 Nov 22. pii: 5856. [Epub ahead of print]13(22):
    Updates on Immunotherapy and Immune Landscape in Renal Clear Cell Carcinoma.
    Myung-Chul Kim, Zeng Jin, Ryan Kolb, Nicholas Borcherding, Jonathan Alexander Chatzkel, Sara Moscovita Falzarano, Weizhou Zhang.
      Several clinicopathological features of clear cell renal cell carcinomas (ccRCC) contribute to make an "atypical" cancer, including resistance to chemotherapy, sensitivity to anti-angiogenesis therapy and ICIs despite a low mutational burden, and CD8+ T cell infiltration being the predictor for poor prognosis-normally CD8+ T cell infiltration is a good prognostic factor in cancer patients. These "atypical" features have brought researchers to investigate the molecular and immunological mechanisms that lead to the increased T cell infiltrates despite relatively low molecular burdens, as well as to decipher the immune landscape that leads to better response to ICIs. In the present study, we summarize the past and ongoing pivotal clinical trials of immunotherapies for ccRCC, emphasizing the potential molecular and cellular mechanisms that lead to the success or failure of ICI therapy. Single-cell analysis of ccRCC has provided a more thorough and detailed understanding of the tumor immune microenvironment and has facilitated the discovery of molecular biomarkers from the tumor-infiltrating immune cells. We herein will focus on the discussion of some major immune cells, including T cells and tumor-associated macrophages (TAM) in ccRCC. We will further provide some perspectives of using molecular and cellular biomarkers derived from these immune cell types to potentially improve the response rate to ICIs in ccRCC patients.
    Keywords:  cancer immunotherapy; clear cell renal cell carcinoma; immune landscape; single-cell RNA sequencing
    DOI:  https://doi.org/10.3390/cancers13225856
  113. Eur J Med Chem. 2021 Nov 16. pii: S0223-5234(21)00831-X. [Epub ahead of print] 113982
    Identification of indole-based activators of insulin degrading enzyme.
    Nicolas Kraupner, Chau Phi Dinh, Xiaoan Wen, Valérie Landry, Adrien Herledan, Florence Leroux, Damien Bosc, Julie Charton, Clara Maillard, Sandrine Warenghem, Isabelle Duplan, Catherine Piveteau, Nathalie Hennuyer, Bart Staels, Benoit Deprez, Rebecca Deprez-Poulain.
      Insulin degrading enzyme (IDE) is a zinc metalloprotease that cleaves numerous substrates among which amyloid-β and insulin. It has been linked through genetic studies to the risk of type-2 diabetes (T2D) or Alzheimer's disease (AD). Pharmacological activation of IDE is an attractive therapeutic strategy in AD. While IDE inhibition gave paradoxal activity in glucose homeostasis, recent studies, in particular in the liver suggest that IDE activators could be also of interest in diabetes. Here we describe the discovery of an original series of IDE activators by screening and structure-activity relationships. Early cellular studies show that hit 1 decreases glucose-stimulating insulin secretion. Docking studies revealed it has an unprecedented extended binding to the polyanion-binding site of IDE. These indole-based pharmacological tools are activators of both Aβ and insulin hydrolysis by IDE and could be helpful to explore the multiple roles of IDE.
    Keywords:  Activators; Insulin-degrading enzyme; Metalloenzymes; Screening
    DOI:  https://doi.org/10.1016/j.ejmech.2021.113982
  114. Nat Rev Immunol. 2021 Nov 23.
    Immune ageing at single-cell resolution.
    Denis A Mogilenko, Irina Shchukina, Maxim N Artyomov.
      Ageing leads to profound alterations in the immune system and increases susceptibility to some chronic, infectious and autoimmune diseases. In recent years, widespread application of single-cell techniques has enabled substantial progress in our understanding of the ageing immune system. These comprehensive approaches have expanded and detailed the current views of ageing and immunity. Here we review a body of recent studies that explored how the immune system ages using unbiased profiling techniques at single-cell resolution. Specifically, we discuss an emergent understanding of age-related alterations in innate and adaptive immune cell populations, antigen receptor repertoires and immune cell-supporting microenvironments of the peripheral tissues. Focusing on the results obtained in mice and humans, we describe the multidimensional data that align with established concepts of immune ageing as well as novel insights emerging from these studies. We further discuss outstanding questions in the field and highlight techniques that will advance our understanding of immune ageing in the future.
    DOI:  https://doi.org/10.1038/s41577-021-00646-4
  115. Arch Argent Pediatr. 2021 12;119(6): 427-430
    [Obesity-fatty liver: the role of the pediatrician].
    Mirta Ciocca, Fernando Álvarez.
      Pediatric nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in children and adolescents that cannot be attributed to other genetic, infectious, toxic or nutritional causes. It can evolve from simple steatosis to nonalcoholic steatohepatitis, and can progress to advanced fibrosis, cirrhosis, and an increased risk of hepatocellular carcinoma. Its treatment consists of a change in lifestyle, promoting weight loss with the incorporation of a healthy diet and increased physical activity. To achieve this goal, family support is essential. These measures will benefit the physical, mental and social quality of life of these children. The objective of this communication is to sensitize the pediatric community about the importance of managing these patients and their family environment, committing to modifying socioeconomic risk factors, to achieve a better quality of life for future generations.
    Keywords:  non-alcoholic fatty liver disease; pediatric obesity
    DOI:  https://doi.org/10.5546/aap.2021.427
  116. Gut. 2021 Nov 22. pii: gutjnl-2021-326284. [Epub ahead of print]
    The FODMAP diet: more than just a symptomatic therapy?
    Peter R Gibson, Emma P Halmos.
      
    Keywords:  diet; irritable bowel syndrome
    DOI:  https://doi.org/10.1136/gutjnl-2021-326284
  117. JHEP Rep. 2021 Dec;3(6): 100370
    Quality of life and unmet needs in patients with chronic liver disease: A mixed-method systematic review.
    Lea Ladegaard Grønkjær, Mette Munk Lauridsen.
       Background & Aims: In an attempt to uncover unmet patient needs, this review aims to synthesise quantitative and qualitative studies on patients' quality of life and their experience of having liver disease.
    Methods: Three databases (CINAHL, Embase, and PubMed) were searched from January 2000 to October 2020. The methodological quality and data extraction of both quantitative and qualitative studies were screened and appraised using Joanna Briggs Institute instruments for mixed-method systematic reviews and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A convergent, integrated approach to synthesis and integration was used. Studies including patients with autoimmune and cholestatic liver disease, chronic hepatitis B and C, non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma were considered.
    Results: The searches produced 5,601 articles, of which 95 (79 quantitative and 16 qualitative) were included in the review. These represented studies from 26 countries and a sample of 37,283 patients. The studies showed that patients´ quality of life was reduced. Unmet needs for information and support and perceived stigmatisation severely affected patients' quality of life.
    Conclusions: Our study suggests changes to improve quality of life. According to patients, this could be achieved by providing better education and information, being aware of patients' need for support, and raising awareness of liver disease among the general population to reduce misconceptions and stigmatisation.
    Registration number: PROSPERO CRD42020173501.
    Lay summary: Regardless of aetiology, patients with liver diseases have impaired quality of life. This is associated with disease progression, the presence of symptoms, treatment response, and mental, physical, and social factors such as anxiety, confusion, comorbidities, and fatigue, as well as limitations in daily living, including loneliness, low income, stigmatisation, and treatment costs. Patients highlighted the need for information to understand and manage liver disease, and awareness and support from healthcare professionals to better cope with the disease. In addition, there is a need to raise awareness of liver diseases in the general population to reduce negative preconceptions and stigmatisation.
    Keywords:  CLDQ, Chronic Liver Disease Questionnaire; EQ-5D, European Quality of Life; FACT-Hep, Functional Assessment of Cancer Therapy Hepatobiliary Carcinoma; HBQOL, Hepatitis B Quality of Life; HCC, hepatocellular carcinoma; JBI, Joanna Briggs Institute; LC-PROM, Liver Cirrhosis Patient Reported Outcome Measure; LDQOL, Liver Disease Quality of Life; Liver disease; MELD, model for end-stage liver disease; Mixed method; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; PBC, Primary Biliary Cholangitis Questionnaire; Patient experience; Patient reported outcomes; PedsQL, Pediatric Quality of Life Inventory; Quality of life; SF, Short Form; SIP, Sickness Impact Profile; Systematic review; Unmet needs; VAS, visual analogue scale; WHOQOL-BREF, WHO Quality of Life
    DOI:  https://doi.org/10.1016/j.jhepr.2021.100370
  118. Int J Mol Sci. 2021 Nov 17. pii: 12413. [Epub ahead of print]22(22):
    MyD88 in Macrophages Enhances Liver Fibrosis by Activation of NLRP3 Inflammasome in HSCs.
    Shuang Ge, Wei Yang, Haiqiang Chen, Qi Yuan, Shi Liu, Yongxiang Zhao, Jinhua Zhang.
      Chronic liver disease mediated by the activation of hepatic stellate cells (HSCs) leads to liver fibrosis. The signal adaptor MyD88 of Toll-like receptor (TLR) signaling is involved during the progression of liver fibrosis. However, the specific role of MyD88 in myeloid cells in liver fibrosis has not been thoroughly investigated. In this study, we used a carbon tetrachloride (CCl4)-induced mouse fibrosis model in which MyD88 was selectively depleted in myeloid cells. MyD88 deficiency in myeloid cells attenuated liver fibrosis in mice and decreased inflammatory cell infiltration. Furthermore, deficiency of MyD88 in macrophages inhibits the secretion of CXC motif chemokine 2 (CXCL2), which restrains the activation of HSCs characterized by NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome activation. Moreover, targeting CXCL2 by CXCR2 inhibitors attenuated the activation of HSCs and reduced liver fibrosis. Thus, MyD88 may represent a potential candidate target for the prevention and treatment of liver fibrosis.
    Keywords:  HSC; MyD88; NLRP3; liver fibrosis; macrophage
    DOI:  https://doi.org/10.3390/ijms222212413
  119. Methods Mol Biol. 2022 ;2380 77-84
    Identification of Non-classical Follicular T Cells.
    Alan Courey-Ghaouzi, Mauro Gaya.
      Nonclassical T cells are a heterogeneous group of T lymphocytes that are activated during the early stages of infection and act as a bridge between the innate and adaptive immune system. Among them, Natural Killer T (NKT) cells have been extensively studied in the last two decades due to their unique ability to recognize foreign/self-lipid antigens in the context of CD1d, a nonclassical major histocompatibility complex molecule. In this chapter, we describe our protocols to track murine NKT cells in lymph nodes by flow cytometry and confocal microscopy.
    Keywords:  CD1d-tetramer; Confocal microscopy; Flow cytometry; Influenza virus; Lymph node; Natural Killer T (NKT) cells
    DOI:  https://doi.org/10.1007/978-1-0716-1736-6_7
  120. Cureus. 2021 Oct;13(10): e18841
    Cannabis and Its Potential Protective Role Against Inflammatory Bowel Disease: A Scoping Review.
    Nso Nso, Akwe Nyabera, Mahmoud Nassar, Mohsen S Alshamam, Vikram Sumbly, Mallorie Vest, Nehal Patel, Gilbert Ojong, Vincent Rizzo.
      Globally, around 15%-40% of patients suffering from inflammatory bowel disease (IBD) use Cannabis for pain reduction, increased appetite, and reduced need for other medications. Although many patients report having benefited by using Cannabis in IBD, there is still a lack of consensus regarding the use of Cannabis in IBD. The aim is to identify, explore and map literature on the potential protective role of Cannabis against IBD through this scoping review. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed during the search to answer the focal question: (1) Does Cannabis play a protective role against IBD as assessed by clinical remission; (2) If yes, what is the mechanism of action for this protective role. There were only three randomized controlled trials (RCTs) and three observational studies that satisfied the selection criteria of this scoping review. Although promising results including the improvement in general well-being/ Harvey-Bradshaw Index, health perception enhancement [4.1±1.43 to 7±1.42 (p = 0.0002)], weight gain, Crohn's Disease Activity Index (CDAI) score<150, Mayo scores (4-10), and reduction in clinical complications have been found in some studies, its medical use in IBD is still questionable due to the lack of high-quality evidence. Future RCTs studies should determine the cannabis treatment parameters and validate its safety and effectiveness in the IBD setting. The highlights include: the current literature provides inconclusive evidence concerning the protective role of cannabis for IBD patients; limited research evidence regarding the therapeutic use of cannabinoids for IBD warrants future investigation via RCTs; cannabis provides some benefits to IBD patients by improving their general well-being perceptions, Harvey-Bradshaw Index, Mayo scores, and minimizing their clinical complications.
    Keywords:  cannabis science; ibd; internal medicine; pain management; preventative medicine
    DOI:  https://doi.org/10.7759/cureus.18841
  121. J Immunol. 2021 Nov 24. pii: ji2100503. [Epub ahead of print]
    Stereotypic Expansion of T Regulatory and Th17 Cells during Infancy Is Disrupted by HIV Exposure and Gut Epithelial Damage.
    Sonwabile Dzanibe, Katie Lennard, Agano Kiravu, Melanie S S Seabrook, Berenice Alinde, Susan P Holmes, Catherine A Blish, Heather B Jaspan, Clive M Gray.
      Few studies have investigated immune cell ontogeny throughout the neonatal and early pediatric period, when there is often increased vulnerability to infections. In this study, we evaluated the dynamics of two critical T cell populations, T regulatory (Treg) cells and Th17 cells, over the first 36 wk of human life. First, we observed distinct CD4+ T cells phenotypes between cord blood and peripheral blood, collected within 12 h of birth, showing that cord blood is not a surrogate for newborn blood. Second, both Treg and Th17 cells expanded in a synchronous fashion over 36 wk of life. However, comparing infants exposed to HIV in utero, but remaining uninfected, with HIV-unexposed uninfected control infants, there was a lower frequency of peripheral blood Treg cells at birth, resulting in a delayed expansion, and then declining again at 36 wk. Focusing on birth events, we found that Treg cells coexpressing CCR4 and α4β7 inversely correlated with plasma concentrations of CCL17 (the ligand for CCR4) and intestinal fatty acid binding protein, IL-7, and CCL20. This was in contrast with Th17 cells, which showed a positive association with these plasma analytes. Thus, despite the stereotypic expansion of both cell subsets over the first few months of life, there was a disruption in the balance of Th17 to Treg cells at birth likely being a result of gut damage and homing of newborn Treg cells from the blood circulation to the gut.
    DOI:  https://doi.org/10.4049/jimmunol.2100503
  122. Nat Commun. 2021 Nov 24. 12(1): 6831
    LSD1 inhibition sustains T cell invigoration with a durable response to PD-1 blockade.
    Yi Liu, Brian Debo, Mingfeng Li, Zhennan Shi, Wanqiang Sheng, Yang Shi.
      Exhausted CD8+ T cells are key targets of immune checkpoint blockade therapy and their ineffective reinvigoration limits the durable benefit in some cancer patients. Here, we demonstrate that histone demethylase LSD1 acts to enforce an epigenetic program in progenitor exhausted CD8+ T cells to antagonize the TCF1-mediated progenitor maintenance and to promote terminal differentiation. Consequently, genetic perturbation or small molecules targeting LSD1 increases the persistence of the progenitor exhausted CD8+ T cells, which provide a sustained source for the proliferative conversion to numerically larger terminally exhausted T cells with tumor-killing cytotoxicity, thereby leading to effective and durable responses to anti-PD1 therapy. Collectively, our findings provide important insights into epigenetic mechanisms that regulate T cell exhaustion and have important implications for durable immunotherapy.
    DOI:  https://doi.org/10.1038/s41467-021-27179-7
  123. Nutrients. 2021 Nov 17. pii: 4127. [Epub ahead of print]13(11):
    The Interplay of Vitamin D Deficiency and Cellular Senescence in The Pathogenesis of Obesity-Related Co-Morbidities.
    Abdulhadi Bima, Basmah Eldakhakhny, Dina Nuwaylati, Abrar Alnami, Mohammed Ajabnoor, Ayman Elsamanoudy.
      This scoping review aims to clarify the interplay between obesity, vitamin D deficiency, cellular senescence, and obesity-related metabolic consequences, mainly subclinical atherosclerosis, and non-alcoholic fatty liver disease (NAFLD). Obesity is a significant global health problem that involves cellular, environmental, behavioral, and genetic elements. The fundamental cause of obesity throughout all life stages is an energy imbalance, and its consequences are countless and, foremost, very common. Obesity has been comprehensively studied in the literature given its association with low serum vitamin D, with many proposed mechanisms linking the two conditions. Moreover, markers of exaggerated cellular senescence have been proven to accumulate in obese individuals. Subclinical atherosclerosis initiates an early stage that ends in serious cardiac events, and obesity, low vitamin D, and senescent cells largely contribute to its associated chronic low-grade inflammation. Furthermore, NAFLD signifies the hepatic manifestation of metabolic syndrome, and studies have highlighted the important role of obesity, vitamin D deficiency, and cellular senescence in its development. Therefore, we outlined the most important mechanisms tying these conditions to one another.
    Keywords:  cellular senescence; non-alcoholic fatty liver disease; obesity; subclinical atherosclerosis; vitamin D deficiency
    DOI:  https://doi.org/10.3390/nu13114127
  124. Hernia. 2021 Nov 22.
    Randomized controlled trials in surgery for inguinal hernias.
    S Huerta.
      
    Keywords:  Meta-analysis; Publication bias; Systematic review
    DOI:  https://doi.org/10.1007/s10029-021-02541-2
  125. Nat Commun. 2021 Nov 26. 12(1): 6931
    CRISPR-enhanced human adipocyte browning as cell therapy for metabolic disease.
    Emmanouela Tsagkaraki, Sarah M Nicoloro, Tiffany DeSouza, Javier Solivan-Rivera, Anand Desai, Lawrence M Lifshitz, Yuefei Shen, Mark Kelly, Adilson Guilherme, Felipe Henriques, Nadia Amrani, Raed Ibraheim, Tomas C Rodriguez, Kevin Luk, Stacy Maitland, Randall H Friedline, Lauren Tauer, Xiaodi Hu, Jason K Kim, Scot A Wolfe, Erik J Sontheimer, Silvia Corvera, Michael P Czech.
      Obesity and type 2 diabetes are associated with disturbances in insulin-regulated glucose and lipid fluxes and severe comorbidities including cardiovascular disease and steatohepatitis. Whole body metabolism is regulated by lipid-storing white adipocytes as well as "brown" and "brite/beige" adipocytes that express thermogenic uncoupling protein 1 (UCP1) and secrete factors favorable to metabolic health. Implantation of brown fat into obese mice improves glucose tolerance, but translation to humans has been stymied by low abundance of primary human beige adipocytes. Here we apply methods to greatly expand human adipocyte progenitors from small samples of human subcutaneous adipose tissue and then disrupt the thermogenic suppressor gene NRIP1 by CRISPR. Ribonucleoprotein consisting of Cas9 and sgRNA delivered ex vivo are fully degraded by the human cells following high efficiency NRIP1 depletion without detectable off-target editing. Implantation of such CRISPR-enhanced human or mouse brown-like adipocytes into high fat diet fed mice decreases adiposity and liver triglycerides while enhancing glucose tolerance compared to implantation with unmodified adipocytes. These findings advance a therapeutic strategy to improve metabolic homeostasis through CRISPR-based genetic enhancement of human adipocytes without exposing the recipient to immunogenic Cas9 or delivery vectors.
    DOI:  https://doi.org/10.1038/s41467-021-27190-y
  126. Front Aging Neurosci. 2021 ;13 769506
    Alpha-Synuclein Induced Immune Cells Activation and Associated Therapy in Parkinson's Disease.
    Ruichen Su, Tian Zhou.
      Parkinson's disease (PD) is a neurodegenerative disorder closely related to immunity. An important aspect of the pathogenesis of PD is the interaction between α-synuclein and a series of immune cells. Studies have shown that accumulation of α-synuclein can induce an autoimmune response that accelerates the progression of PD. This study discusses the mechanisms underlying the interaction between α-synuclein and the immune system. During the development of PD, abnormally accumulated α-synuclein becomes an autoimmune antigen that binds to Toll-like receptors (TLRs) that activate microglia, which differentiate into the microglia type 1 (M1) subtype. The microglia activate intracellular inflammatory pathways, induce the release of proinflammatory cytokines, and promote the differentiation of cluster of differentiation 4 + (CD4 +) T cells into proinflammatory T helper type 1 (Th1) and T helper type 17 (Th17) subtypes. Given the important role of α-synuclein in the immune system of the patients with PD, identifying potential targets of immunotherapy related to α-synuclein is critical for slowing disease progression. An enhanced understanding of immune-associated mechanisms in PD can guide the development of associated therapeutic strategies in the future.
    Keywords:  Parkinson’s disease (PD); T cells; microglia; therapeutics; α-synuclein
    DOI:  https://doi.org/10.3389/fnagi.2021.769506
  127. Nat Rev Endocrinol. 2021 Nov 24.
    Time-restricted feeding and circadian autophagy for long life.
    Hong Long, Satchidananda Panda.
      
    DOI:  https://doi.org/10.1038/s41574-021-00600-3
  128. Zootaxa. 2021 Nov 05. 5061(3): 451-475
    Two new species of Petalophthalmus and Ipirophthalmus (Crustacea: Mysida: Petalophthalmidae), from New Zealand.
    Jeffrey S Forman, Kareen E Schnabel.
      Two new deep-water mysids from the subfamily Petalophthalminae (Crustacea: Mysida: Petalophthalmidae) are described from specimens collected from Challenger Plateau, Chatham Rise, and off the east coast of the North Island of New Zealand. These new species raise the number of species of both genera to five. Petalophthalmus lobatus sp. nov. differs from its congeners by the structure of an elongated ventilation lobe on the seventh oostegites, laterally flattened eyes, and the armature of the telson. Ipirophthalmus crusulus sp. nov. can easily be distinguished by the rudimentary sixth to eighth thoracic endopods. Both species were found to be the prey of several fishes, including commercially caught species, providing insight into their ecology. An identification key to the subfamily is provided.
    DOI:  https://doi.org/10.11646/zootaxa.5061.3.3
  129. Front Genet. 2021 ;12 763263
    Hybrid Clustering of Single-Cell Gene Expression and Spatial Information via Integrated NMF and K-Means.
    Sooyoun Oh, Haesun Park, Xiuwei Zhang.
      Advances in single cell transcriptomics have allowed us to study the identity of single cells. This has led to the discovery of new cell types and high resolution tissue maps of them. Technologies that measure multiple modalities of such data add more detail, but they also complicate data integration. We offer an integrated analysis of the spatial location and gene expression profiles of cells to determine their identity. We propose scHybridNMF (single-cell Hybrid Nonnegative Matrix Factorization), which performs cell type identification by combining sparse nonnegative matrix factorization (sparse NMF) with k-means clustering to cluster high-dimensional gene expression and low-dimensional location data. We show that, under multiple scenarios, including the cases where there is a small number of genes profiled and the location data is noisy, scHybridNMF outperforms sparse NMF, k-means, and an existing method that uses a hidden Markov random field to encode cell location and gene expression data for cell type identification.
    Keywords:  cell identity; data integration; non-negative matrix factorization; single cell transcriptomics; spatial locations
    DOI:  https://doi.org/10.3389/fgene.2021.763263
  130. Nat Rev Gastroenterol Hepatol. 2021 Nov 23.
    Mycobiota-host immune interactions in IBD: coming out of the shadows.
    Iliyan D Iliev.
      
    DOI:  https://doi.org/10.1038/s41575-021-00541-2
  131. EBioMedicine. 2021 Nov 17. pii: S2352-3964(21)00505-3. [Epub ahead of print]74 103711
    Cancer surveillance in non-alcoholic fatty liver disease: A potential role for lipidomics.
    Jan Best, Lars P Bechmann.
      
    DOI:  https://doi.org/10.1016/j.ebiom.2021.103711
  132. J Clin Aesthet Dermatol. 2021 Jun;14(6): 55-59
    Comparison of Guidelines for the Use of Interleukin-17 Inhibitors for Psoriasis in the United States, Britain, and Europe: A Critical Appraisal and Comprehensive Review.
    Donovan G Kearns, Shelley Uppal, Vipawee S Chat, Jashin J Wu.
       Background: Interleukin (IL)-17 inhibitors are a newer class of biologic used to treat patients with moderate-to-severe plaque psoriasis and psoriatic arthritis.
    Objective: We compared evidence-based clinical practice guidelines (CPGs) from leading dermatological organizations for the use of IL-17 inhibitors in psoriasis.
    Methods: Guidelines from the Joint American Academy of Dermatology-National Psoriasis Foundation (AAD-NFP) Guidelines, British Association of Dermatologists guidelines (BAD), and European S3 group (ES3) were all reviewed and compared.
    Results: This analysis revealed significant overlap in the recommendations made by experts from each CPG. However, our review highlights differences in routine laboratory recommendations and the relative and absolute contraindications to use with IL-17 inhibitors.
    Conclusion: IL-17 inhibitors are an effective treatment option for psoriasis. This analysis and review of guidelines for IL-17 inhibitor use highlights the consensus in treatment protocols and areas of disagreement between CPGs.
    Keywords:  IL-17 inhibitors; Psoriasis; brodalumab; ixekizumab; practice guidelines; secukinumab
  133. iScience. 2021 Nov 19. 24(11): 103347
    Myeloid cell subsets that express latency-associated peptide promote cancer growth by modulating T cells.
    Galina Gabriely, Duanduan Ma, Shafiuddin Siddiqui, Linqing Sun, Nathaniel P Skillin, Hadi Abou-El-Hassan, Thais G Moreira, Dustin Donnelly, Andre P da Cunha, Mai Fujiwara, Lena R Walton, Amee Patel, Rajesh Krishnan, Stuart S Levine, Brian C Healy, Rafael M Rezende, Gopal Murugaiyan, Howard L Weiner.
      Myeloid suppressor cells promote tumor growth by a variety of mechanisms which are not fully characterized. We identified myeloid cells (MCs) expressing the latency-associated peptide (LAP) of TGF-β on their surface and LAPHi MCs that stimulate Foxp3+ Tregs while inhibiting effector T cell proliferation and function. Blocking TGF-β inhibits the tolerogenic ability of LAPHi MCs. Furthermore, adoptive transfer of LAPHi MCs promotes Treg accumulation and tumor growth in vivo. Conversely, anti-LAP antibody, which reduces LAPHi MCs, slows cancer progression. Single-cell RNA-Seq analysis on tumor-derived immune cells revealed LAPHi dominated cell subsets with distinct immunosuppressive signatures, including those with high levels of MHCII and PD-L1 genes. Analogous to mice, LAP is expressed on myeloid suppressor cells in humans, and these cells are increased in glioma patients. Thus, our results identify a previously unknown function by which LAPHi MCs promote tumor growth and offer therapeutic intervention to target these cells in cancer.
    Keywords:  Cancer; Immunology
    DOI:  https://doi.org/10.1016/j.isci.2021.103347
  134. J Pers Med. 2021 Nov 14. pii: 1201. [Epub ahead of print]11(11):
    Innate-Immunity Genes in Obesity.
    Svetlana V Mikhailova, Dinara E Ivanoshchuk.
      The main functions of adipose tissue are thought to be storage and mobilization of the body's energy reserves, active and passive thermoregulation, participation in the spatial organization of internal organs, protection of the body from lipotoxicity, and ectopic lipid deposition. After the discovery of adipokines, the endocrine function was added to the above list, and after the identification of crosstalk between adipocytes and immune cells, an immune function was suggested. Nonetheless, it turned out that the mechanisms underlying mutual regulatory relations of adipocytes, preadipocytes, immune cells, and their microenvironment are complex and redundant at many levels. One possible way to elucidate the picture of adipose-tissue regulation is to determine genetic variants correlating with obesity. In this review, we examine various aspects of adipose-tissue involvement in innate immune responses as well as variants of immune-response genes associated with obesity.
    Keywords:  adipose tissue; gene knockout; genetic predisposition; innate immunity; microbiome; obesity; polymorphism
    DOI:  https://doi.org/10.3390/jpm11111201
  135. Nat Commun. 2021 Nov 25. 12(1): 6843
    Single-cell analysis identifies dynamic gene expression networks that govern B cell development and transformation.
    Robin D Lee, Sarah A Munro, Todd P Knutson, Rebecca S LaRue, Lynn M Heltemes-Harris, Michael A Farrar.
      Integration of external signals and B-lymphoid transcription factor activities organise B cell lineage commitment through alternating cycles of proliferation and differentiation, producing a diverse repertoire of mature B cells. We use single-cell transcriptomics/proteomics to identify differentially expressed gene networks across B cell development and correlate these networks with subtypes of B cell leukemia. Here we show unique transcriptional signatures that refine the pre-B cell expansion stages into pre-BCR-dependent and pre-BCR-independent proliferative phases. These changes correlate with reciprocal changes in expression of the transcription factor EBF1 and the RNA binding protein YBX3, that are defining features of the pre-BCR-dependent stage. Using pseudotime analysis, we further characterize the expression kinetics of different biological modalities across B cell development, including transcription factors, cytokines, chemokines, and their associated receptors. Our findings demonstrate the underlying heterogeneity of developing B cells and characterise developmental nodes linked to B cell transformation.
    DOI:  https://doi.org/10.1038/s41467-021-27232-5
  136. Viruses. 2021 Nov 03. pii: 2212. [Epub ahead of print]13(11):
    Single-Cell RNAseq Profiling of Human γδ T Lymphocytes in Virus-Related Cancers and COVID-19 Disease.
    Juan Pablo Cerapio, Marion Perrier, Fréderic Pont, Marie Tosolini, Camille Laurent, Stéphane Bertani, Jean-Jacques Fournie.
      The detailed characterization of human γδ T lymphocyte differentiation at the single-cell transcriptomic (scRNAseq) level in tumors and patients with coronavirus disease 2019 (COVID-19) requires both a reference differentiation trajectory of γδ T cells and a robust mapping method for additional γδ T lymphocytes. Here, we incepted such a method to characterize thousands of γδ T lymphocytes from (n = 95) patients with cancer or adult and pediatric COVID-19 disease. We found that cancer patients with human papillomavirus-positive head and neck squamous cell carcinoma and Epstein-Barr virus-positive Hodgkin's lymphoma have γδ tumor-infiltrating T lymphocytes that are more prone to recirculate from the tumor and avoid exhaustion. In COVID-19, both TCRVγ9 and TCRVγnon9 subsets of γδ T lymphocytes relocalize from peripheral blood mononuclear cells (PBMC) to the infected lung tissue, where their advanced differentiation, tissue residency, and exhaustion reflect T cell activation. Although severe COVID-19 disease increases both recruitment and exhaustion of γδ T lymphocytes in infected lung lesions but not blood, the anti-IL6R therapy with Tocilizumab promotes γδ T lymphocyte differentiation in patients with COVID-19. PBMC from pediatric patients with acute COVID-19 disease display similar γδ T cell lymphopenia to that seen in adult patients. However, blood γδ T cells from children with the COVID-19-related multisystem inflammatory syndrome are not lymphodepleted, but they are differentiated as in healthy PBMC. These findings suggest that some virus-induced memory γδ T lymphocytes durably persist in the blood of adults and could subsequently infiltrate and recirculate in tumors.
    Keywords:  COVID-19; differentiation; gammadelta; human; lymphocyte; single cell; trajectory; transcriptome; tumor
    DOI:  https://doi.org/10.3390/v13112212
  137. J Invest Dermatol. 2021 Nov 19. pii: S0022-202X(21)02487-8. [Epub ahead of print]
    Skin fibrosis and recovery is dependent on Wnt activation via DPP4.
    Anna R Jussila, Brian Zhang, Elizabeth Caves, Sakin Kirti, Miarasa Steele, Emily Hamburg-Shields, John Lydon, Yan Ying, Robert Lafyatis, Sanjay Rajagopalan, Valerie Horsley, Radhika P Atit.
      Fibrosis is the life-threatening, excessive accumulation of extracellular matrix (ECM) and is sometimes associated with a loss of lipid-filled cells in skin and other organs. Understanding the mechanisms of fibrosis and associated lipodystrophy and their reversal may reveal new targets for therapeutic intervention. In vivo genetic models are needed to identify key targets that induce recovery from established fibrosis. Wnt signaling is activated in animal and human fibrotic diseases across organs. Here, we developed a genetically inducible and reversible Wnt activation model and show it is sufficient to cause fibrotic dermal remodeling, including ECM expansion and shrinking of dermal adipocytes. Upon withdrawal from Wnt activation, Wnt-induced fibrotic remodeling was reversed in mouse skin -- fully restoring skin architecture. Next, we demonstrated CD26/Dipeptidyl peptidase 4 (DPP4) is a Wnt/β-catenin-responsive gene and a functional mediator of fibrotic transformation. We provide genetic evidence that the Wnt/DPP4 axis is required to drive fibrotic dermal remodeling and associated with human skin fibrosis severity. Remarkably, DPP4 inhibitors can be repurposed to accelerate recovery from established Wnt-induced fibrosis. Collectively, this study identifies Wnt/DPP4 axis as a key driver of ECM homeostasis and dermal fat loss, providing therapeutic avenues to manipulate the onset and reversal of tissue-fibrosis.
    Keywords:  Adipocytes; Cell Biology; Matrix Biology; Scleroderma; Wnt Signaling
    DOI:  https://doi.org/10.1016/j.jid.2021.10.025
  138. Sci Total Environ. 2021 Nov 22. pii: S0048-9697(21)06891-1. [Epub ahead of print] 151815
    Assessing microplastic exposure of large marine filter-feeders.
    L J Zantis, T Bosker, F Lawler, S E Nelms, R O'Rorke, R Constantine, M Sewell, E L Carroll.
      Large filter-feeding animals are potential sentinels for understanding the extent of microplastic pollution, as their mode of foraging and prey mean they are continuously sampling the environment. However, there is considerable uncertainty about the total and mode of exposure (environmental vs trophic). Here, we explore microplastic exposure and ingestion by baleen whales feeding year-round in coastal Auckland waters, New Zealand. Plastic and DNA were extracted concurrently from whale scat, with 32 ± 24 (mean ± SD, n = 21) microplastics per 6 g scat sample detected. Using a novel stochastic simulation modeling incorporating new and previously published DNA diet information, we extrapolate this to total microplastic exposure levels of 24,028 (95% CI: 2119, 69,270) microplastics per mouthful of prey, or 3,408,002 microplastics (95% CI: 295,810, 10,031,370) per day, substantially higher than previous estimates for large filter-feeding animals. Critically, we find that the total exposure is four orders of magnitude more than expected from microplastic measurements of local coastal surface waters. This suggests that trophic transfer, rather than environmental exposure, is the predominant mode of exposure of large filter feeders for microplastic pollution. Measuring plastic concentration from the environment alone significantly underestimates exposure levels, an important consideration for future risk assessment studies.
    Keywords:  Baleen whale; Dietary analysis; Metabarcoding; Microplastic; Trophic transfer
    DOI:  https://doi.org/10.1016/j.scitotenv.2021.151815
  139. Nat Rev Microbiol. 2021 Nov 25.
    Diet underlying autism-microbiome association.
    Ursula Hofer.
      
    DOI:  https://doi.org/10.1038/s41579-021-00670-0
  140. iScience. 2021 Nov 19. 24(11): 103337
    Stabilin receptors clear LPS and control systemic inflammation.
    Fatima Cabral, Mustafa Al-Rahem, John Skaggs, Thushara A Thomas, Naresh Kumar, Qian Wu, Paolo Fadda, Lianbo Yu, John M Robinson, Jonghan Kim, Ekta Pandey, Xinghui Sun, Wael N Jarjour, Murugesan V S Rajaram, Edward N Harris, Latha P Ganesan.
      Lipopolysaccharides (LPSs) cause lethal endotoxemia if not rapidly cleared from blood circulation. Liver sinusoidal endothelial cells (LSEC) systemically clear LPS by unknown mechanisms. We discovered that LPS clearance through LSEC involves endocytosis and lysosomal inactivation via Stabilin-1 and 2 (Stab1 and Stab2) but does not involve TLR4. Cytokine production was inversely related to clearance/endocytosis of LPS by LSEC. When exposed to LPS, Stabilin double knockout mice (Stab DK) and Stab1 KO, but not Stab2 KO, showed significantly enhanced systemic inflammatory cytokine production and early death compared with WT mice. Stab1 KO is not significantly different from Stab DK in circulatory LPS clearance, LPS uptake and endocytosis by LSEC, and cytokine production. These data indicate that (1) Stab1 receptor primarily facilitates the proactive clearance of LPS and limits TLR4-mediated inflammation and (2) TLR4 and Stab1 are functionally opposing LPS receptors. These findings suggest that endotoxemia can be controlled by optimizing LPS clearance by Stab1.
    Keywords:  Biological sciences; Immune response; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2021.103337
  141. J Trace Elem Med Biol. 2021 Nov 15. pii: S0946-672X(21)00191-7. [Epub ahead of print]69 126901
    Diversity of effects induced by boron-containing compounds on immune response cells and on antibodies in basal state.
    Ivonne M Arciniega-Martínez, Karla S Romero-Aguilar, Eunice D Farfán-García, Jazmín García-Machorro, Aldo A Reséndiz-Albor, Marvin A Soriano-Ursúa.
       BACKGROUND: It has been reported that boron induces changes in the immune response, including in inflammatory processes. Recently, the effect of boric acid has been documented on the differentiation of lymphocyte clusters in mice and rats. However, the differences among boron-containing compounds (BCC) have been poorly explored.
    METHODS: In this study, we analyzed the effects after oral administration of boric acid (BOR), methylboronic (MET), 3-thyenylboronic (3TB), 4-hydroxymethyl-phenylboronic (4MP) and 4-methanesulfonyl-phenylboronic (4SP) acids on the populations of lymphocytes from spleen and Peyer's patch (PP) as well as on antibodies. Groups of six male BALB/c were orally treated with 4.6 mg/kg of body weight with BOR, MET, 3TB, 4MP, and 4SP/daily for 10 days or vehicle (VEH) as a control group. After euthanasia, the spleen and small intestine were dissected. We conducted flow cytometry assays to assess B, CD3+ T, CD4+ T, and CD8+ T cells. Levels of IgG and IgM in serum, and IgA in intestinal fluid samples were analyzed by enzyme immunoassay.
    RESULTS: In particular, we observed the effects of the administration of boronic acids on the number of lymphocytes; these changes were more notable in spleen than in PP. We found different profiles for each boron-containing compound, that is BOR induced an increase in the percentage of CD8+ T and CD19+/IgA+ cells in spleen, but a decrease in CD8+ T and B220+/CD19+ cells in PP. Meanwhile MET induced a decrease of CD4+ T in spleen, but induced an increase of CD4+ T cells and a decrease in the number of CD8+ T cells in PP. Boronic acids with an aromatic ring moiety induced changes in serum immunoglobulins levels, while 3TB acid induced a notable increase in S-IgA.
    CONCLUSIONS: Effects in lymphocyte populations and antibodies are different for each tested compound. These results highlight the establishment of the necessary structure-activity relationship for BCC as immunomodulatory drugs. This is relevant in the biomedical field due to their attractiveness for selecting compounds to develop therapeutic tools.
    Keywords:  Antibodies; Boron; Local and systemic immune response; Lymphocyte; Oral administration; Structure-activity relationship
    DOI:  https://doi.org/10.1016/j.jtemb.2021.126901
  142. Front Cell Dev Biol. 2021 ;9 735001
    A Comparative Proteomic Analysis of Extracellular Vesicles Associated With Lipotoxicity.
    Yasuhiko Nakao, Masanori Fukushima, Amy S Mauer, Chieh-Yu Liao, Anya Ferris, Debanjali Dasgupta, Carrie Jo Heppelmann, Patrick M Vanderboom, Mayank Saraswat, Akhilesh Pandey, K Sreekumaran Nair, Alina M Allen, Kazuhiko Nakao, Harmeet Malhi.
      Extracellular vesicles (EVs) are emerging mediators of intercellular communication in nonalcoholic steatohepatitis (NASH). Palmitate, a lipotoxic saturated fatty acid, activates hepatocellular endoplasmic reticulum stress, which has been demonstrated to be important in NASH pathogenesis, including in the release of EVs. We have previously demonstrated that the release of palmitate-stimulated EVs is dependent on the de novo synthesis of ceramide, which is trafficked by the ceramide transport protein, STARD11. The trafficking of ceramide is a critical step in the release of lipotoxic EVs, as cells deficient in STARD11 do not release palmitate-stimulated EVs. Here, we examined the hypothesis that protein cargoes are trafficked to lipotoxic EVs in a ceramide-dependent manner. We performed quantitative proteomic analysis of palmitate-stimulated EVs in control and STARD11 knockout hepatocyte cell lines. Proteomics was performed on EVs isolated by size exclusion chromatography, ultracentrifugation, and density gradient separation, and EV proteins were measured by mass spectrometry. We also performed human EV proteomics from a control and a NASH plasma sample, for comparative analyses with hepatocyte-derived lipotoxic EVs. Size exclusion chromatography yielded most unique EV proteins. Ceramide-dependent lipotoxic EVs contain damage-associated molecular patterns and adhesion molecules. Haptoglobin, vascular non-inflammatory molecule-1, and insulin-like growth factor-binding protein complex acid labile subunit were commonly detected in NASH and hepatocyte-derived ceramide-dependent EVs. Lipotoxic EV proteomics provides novel candidate proteins to investigate in NASH pathogenesis and as diagnostic biomarkers for hepatocyte-derived EVs in NASH patients.
    Keywords:  DAMP; StAR-related lipid transfer domain 11; exosome; hepatocyte; microvesicle
    DOI:  https://doi.org/10.3389/fcell.2021.735001
  143. Nat Rev Nephrol. 2021 Nov 25.
    More from ASN high-impact trials.
    Susan J Allison.
      
    DOI:  https://doi.org/10.1038/s41581-021-00516-1
  144. Front Immunol. 2021 ;12 755995
    Delivery of IL-2 to the T Cell Surface Through Phosphatidylserine Permits Robust Expansion of CD8 T Cells.
    Alana MacDonald, Brandon Lam, John Lin, Louise Ferrall, Yu Jui Kung, Ya Chea Tsai, T-C Wu, Chien-Fu Hung.
      The phospholipid phosphatidylserine (PS) is naturally maintained on the cytoplasmic side of the plasma membrane. Independent of apoptosis, PS is redistributed to the surface of CD8 T cells in response to TCR-mediated activation. Annexin V (AnnV) is a protein known to bind PS with high affinity and has been effectively utilized to anchor antigen to the surface of CD8 T cells. To expand these studies, we aimed to exploit TCR activation driven PS exposure as a target to deliver cytokine, namely interleukin-2 (IL-2), to the surface of CD8 T cells. This was accomplished using a novel chimeric fusion protein of annexin V and interleukin 2 (AnnV-IL2). In vitro analysis revealed that AnnV-IL2 is able to specifically bind PS on the T cell surface following TCR stimulation. Consequently, AnnV-IL2 proved to be significantly more effective at enhancing T cell activation compared to recombinant IL-2. In vivo, AnnV-IL2 promotes robust expansion of antigen-specific cells capable of interferon gamma (IFNγ) production when administered following peptide vaccination. Importantly, upon antigen rechallenge, AnnV-IL2 treatment mice demonstrated a stronger secondary expansion, indicating durability of AnnV-IL2 mediated responses. Our data supports the use of AnnV-IL2 to modulate antigen-specific T cell immunity and demonstrates that the PS-AnnV axis is a feasible mechanism to target diverse cargo to CD8 T cells.
    Keywords:  CD8 T cells; activation; annexin V; interleukin 2 (IL 2); phosphatidylserine (PS)
    DOI:  https://doi.org/10.3389/fimmu.2021.755995
  145. Obesity (Silver Spring). 2021 Nov 25.
    Combining a β3 adrenergic receptor agonist with alpha-lipoic acid reduces inflammation in male mice with diet-induced obesity.
    Zahraa Abdul Sater, Cheryl Cero, Anne E Pierce, Hannah J Lea, Houssein Abdul Sater, Kenneth Y Zhu, Naili Liu, Yinyan Ma, Oksana Gavrilova, Aaron M Cypess.
       OBJECTIVES: Beta-3 adrenergic receptors (β3-AR) stimulate lipolysis and thermogenesis in white and brown adipose tissue (WAT and BAT). Obesity increases oxidative stress and inflammation that attenuate AT β3-AR signaling. The objective of this study was to test the hypothesis that the combination of the β3-AR agonist CL-316,243 (CL) and the antioxidant alpha-lipoic acid (ALA) would lower inflammation in diet-induced obesity (DIO) and improve β3-AR function.
    METHODS: A total of 40 DIO mice were separated into four groups: Control (per os and intraperitoneal [IP] vehicle); CL alone (0.01 mg/kg IP daily); ALA alone (250 mg/kg in drinking water); or ALA+CL combination, all for 5 weeks.
    RESULTS: Food intake was similar in all groups; however, mice receiving ALA+CL showed improved body composition and inflammation as well as lower body weight (+1.7 g Control vs. -2.5 g ALA+CL [-7%]; p < 0.01) and percentage of body fat (-9%, p < 0.001). Systemic and epididymal WAT inflammation was lower with ALA+CL than all other groups, with enhanced recruitment of epididymal WAT anti-inflammatory CD206+ M2 macrophages. β3-AR signaling in WAT was enhanced in the combination-treatment group, with higher mRNA and protein levels of thermogenic uncoupling protein 1 and AT lipases.
    CONCLUSIONS: Chronic treatment with ALA and a β3-AR agonist reduces DIO-induced inflammation. AT immune modulation could be a therapeutic target in patients with obesity.
    DOI:  https://doi.org/10.1002/oby.23309
  146. Pharmaceutics. 2021 Nov 15. pii: 1931. [Epub ahead of print]13(11):
    Thinking Quantitatively of RNA-Based Information Transfer via Extracellular Vesicles: Lessons to Learn for the Design of RNA-Loaded EVs.
    Max Piffoux, Jeanne Volatron, Amanda K A Silva, Florence Gazeau.
      Extracellular vesicles (EVs) are 50-1000 nm vesicles secreted by virtually any cell type in the body. They are expected to transfer information from one cell or tissue to another in a short- or long-distance way. RNA-based transfer of information via EVs at long distances is an interesting well-worn hypothesis which is ~15 years old. We review from a quantitative point of view the different facets of this hypothesis, ranging from natural RNA loading in EVs, EV pharmacokinetic modeling, EV targeting, endosomal escape and RNA delivery efficiency. Despite the unique intracellular delivery properties endowed by EVs, we show that the transfer of RNA naturally present in EVs might be limited in a physiological context and discuss the lessons we can learn from this example to design efficient RNA-loaded engineered EVs for biotherapies. We also discuss other potential EV mediated information transfer mechanisms, among which are ligand-receptor mechanisms.
    Keywords:  RNA; engineering; exosome; extracellular vesicles; loading; mechanism of action; miRNA; targeting
    DOI:  https://doi.org/10.3390/pharmaceutics13111931
  147. Nutrients. 2021 Oct 28. pii: 3846. [Epub ahead of print]13(11):
    Time-Restricted Feeding in Mice Prevents the Disruption of the Peripheral Circadian Clocks and Its Metabolic Impact during Chronic Jetlag.
    Louis Desmet, Theo Thijs, Rosalie Mas, Kristin Verbeke, Inge Depoortere.
      We used time-restricted feeding (TRF) to investigate whether microbial metabolites and the hunger hormone ghrelin can become the dominant entraining factor during chronic jetlag to prevent disruption of the master and peripheral clocks, in order to promote health. Therefore, hypothalamic clock gene and Agrp/Npy mRNA expression were measured in mice that were either chronically jetlagged and fed ad libitum, jetlagged and fed a TRF diet, or not jetlagged and fed a TRF diet. Fecal short-chain fatty acid (SCFA) concentrations, plasma ghrelin and corticosterone levels, and colonic clock gene mRNA expression were measured. Preventing the disruption of the food intake pattern during chronic jetlag using TRF restored the rhythmicity in hypothalamic clock gene mRNA expression of Reverbα but not of Arntl. TRF countered the changes in plasma ghrelin levels and in hypothalamic Npy mRNA expression induced by chronic jetlag, thereby reestablishing the food intake pattern. Increase in body mass induced by chronic jetlag was prevented. Alterations in diurnal fluctuations in fecal SCFAs during chronic jetlag were prevented thereby re-entraining the rhythmic expression of peripheral clock genes. In conclusion, TRF during chronodisruption re-entrains the rhythms in clock gene expression and signals from the gut that regulate food intake to normalize body homeostasis.
    Keywords:  chronic jetlag; circadian clock; ghrelin; short-chain fatty acids; time-restricted feeding
    DOI:  https://doi.org/10.3390/nu13113846
  148. Metabolites. 2021 Oct 29. pii: 751. [Epub ahead of print]11(11):
    Non-Invasive Analysis of Human Liver Metabolism by Magnetic Resonance Spectroscopy.
    John G Jones.
      The liver is a key node of whole-body nutrient and fuel metabolism and is also the principal site for detoxification of xenobiotic compounds. As such, hepatic metabolite concentrations and/or turnover rates inform on the status of both hepatic and systemic metabolic diseases as well as the disposition of medications. As a tool to better understand liver metabolism in these settings, in vivo magnetic resonance spectroscopy (MRS) offers a non-invasive means of monitoring hepatic metabolic activity in real time both by direct observation of concentrations and dynamics of specific metabolites as well as by observation of their enrichment by stable isotope tracers. This review summarizes the applications and advances in human liver metabolic studies by in vivo MRS over the past 35 years and discusses future directions and opportunities that will be opened by the development of ultra-high field MR systems and by hyperpolarized stable isotope tracers.
    Keywords:  hyperpolarization; in vivo magnetic resonance; liver metabolism; stable isotopes
    DOI:  https://doi.org/10.3390/metabo11110751
  149. J Immunol. 2021 Nov 22. pii: ji2100535. [Epub ahead of print]
    Identification and Characterization of Antigen-Specific CD8+ T Cells Using Surface-Trapped TNF-α and Single-Cell Sequencing.
    Shaheed Abdulhaqq, Abigail B Ventura, Jason S Reed, Arman A Bashirova, Katherine B Bateman, Eric McDonald, Helen L Wu, Justin M Greene, John B Schell, David Morrow, Karin Wisskirchen, Jeffrey N Martin, Steven G Deeks, Mary Carrington, Ulrike Protzer, Klaus Früh, Scott G Hansen, Louis J Picker, Jonah B Sacha, Benjamin N Bimber.
      CD8+ T cells are key mediators of antiviral and antitumor immunity. The isolation and study of Ag-specific CD8+ T cells, as well as mapping of their MHC restriction, has practical importance to the study of disease and the development of therapeutics. Unfortunately, most experimental approaches are cumbersome, owing to the highly variable and donor-specific nature of MHC-bound peptide/TCR interactions. Here we present a novel system for rapid identification and characterization of Ag-specific CD8+ T cells, particularly well suited for samples with limited primary cells. Cells are stimulated ex vivo with Ag of interest, followed by live cell sorting based on surface-trapped TNF-α. We take advantage of major advances in single-cell sequencing to generate full-length sequence data from the paired TCR α- and β-chains from these Ag-specific cells. The paired TCR chains are cloned into retroviral vectors and used to transduce donor CD8+ T cells. These TCR transductants provide a virtually unlimited experimental reagent, which can be used for further characterization, such as minimal epitope mapping or identification of MHC restriction, without depleting primary cells. We validated this system using CMV-specific CD8+ T cells from rhesus macaques, characterizing an immunodominant Mamu-A1*002:01-restricted epitope. We further demonstrated the utility of this system by mapping a novel HLA-A*68:02-restricted HIV Gag epitope from an HIV-infected donor. Collectively, these data validate a new strategy to rapidly identify novel Ags and characterize Ag-specific CD8+ T cells, with applications ranging from the study of infectious disease to immunotherapeutics and precision medicine.
    DOI:  https://doi.org/10.4049/jimmunol.2100535
  150. Int J Mol Sci. 2021 Nov 10. pii: 12149. [Epub ahead of print]22(22):
    Immune Tolerance in the Oral Mucosa.
    Hector F Pelaez-Prestel, Jose L Sanchez-Trincado, Esther M Lafuente, Pedro A Reche.
      The oral mucosa is a site of intense immune activity, where a large variety of immune cells meet to provide a first line of defense against pathogenic organisms. Interestingly, the oral mucosa is exposed to a plethora of antigens from food and commensal bacteria that must be tolerated. The mechanisms that enable this tolerance are not yet fully defined. Many works have focused on active immune mechanisms involving dendritic and regulatory T cells. However, epithelial cells also make a major contribution to tolerance by influencing both innate and adaptive immunity. Therefore, the tolerogenic mechanisms concurring in the oral mucosa are intertwined. Here, we review them systematically, paying special attention to the role of oral epithelial cells.
    Keywords:  T cell; dendritic cell; epithelial cell; mucosa; oral; tolerance
    DOI:  https://doi.org/10.3390/ijms222212149
  151. Front Immunol. 2021 ;12 739918
    Metallothionein 1: A New Spotlight on Inflammatory Diseases.
    Hanying Dai, Lu Wang, Lingyun Li, Zhong Huang, Liang Ye.
      MT1 has been demonstrated to be an essential stress protein in maintaining physiological balance and regulating immune homeostasis. While the immunological involvement of MT1 in central nervous system disorders and cancer has been extensively investigated, mounting evidence suggests that MT1 has a broader role in inflammatory diseases and can shape innate and adaptive immunity. In this review, we will first summarize the biological features of MT1 and the regulators that influence MT1 expression, emphasizing metal, inflammation, and immunosuppressive factors. We will then focus on the immunoregulatory function of MT1 on diverse immune cells and the signaling pathways regulated by MT1. Finally, we will discuss recent advances in our knowledge of the biological role of MT1 in several inflammatory diseases to develop novel therapeutic strategies.
    Keywords:  cytokine; immunoregulation; inflammatory disease; metal; metallothionein 1; signaling
    DOI:  https://doi.org/10.3389/fimmu.2021.739918
  152. Front Cell Dev Biol. 2021 ;9 738731
    Leptin Signaling in the Ovary of Diet-Induced Obese Mice Regulates Activation of NOD-Like Receptor Protein 3 Inflammasome.
    Marek Adamowski, Karolina Wołodko, Joana Oliveira, Juan Castillo-Fernandez, Daniel Murta, Gavin Kelsey, António M Galvão.
      Obesity leads to ovarian dysfunction and the establishment of local leptin resistance. The aim of our study was to characterize the levels of NOD-like receptor protein 3 (NLRP3) inflammasome activation in ovaries and liver of mice during obesity progression. Furthermore, we tested the putative role of leptin on NLRP3 regulation in those organs. C57BL/6J female mice were treated with equine chorionic gonadotropin (eCG) or human chorionic gonadotropin (hCG) for estrous cycle synchronization and ovary collection. In diet-induced obesity (DIO) protocol, mice were fed chow diet (CD) or high-fat diet (HFD) for 4 or 16 weeks, whereas in the hyperleptinemic model (LEPT), mice were injected with leptin for 16 days (16 L) or saline (16 C). Finally, the genetic obese leptin-deficient ob/ob (+/? and -/-) mice were fed CD for 4 week. Either ovaries and liver were collected, as well as cumulus cells (CCs) after superovulation from DIO and LEPT. The estrus cycle synchronization protocol showed increased protein levels of NLRP3 and interleukin (IL)-18 in diestrus, with this stage used for further sample collections. In DIO, protein expression of NLRP3 inflammasome components was increased in 4 week HFD, but decreased in 16 week HFD. Moreover, NLRP3 and IL-1β were upregulated in 16 L and downregulated in ob/ob. Transcriptome analysis of CC showed common genes between LEPT and 4 week HFD modulating NLRP3 inflammasome. Liver analysis showed NLRP3 protein upregulation after 16 week HFD in DIO, but also its downregulation in ob/ob-/-. We showed the link between leptin signaling and NLRP3 inflammasome activation in the ovary throughout obesity progression in mice, elucidating the molecular mechanisms underpinning ovarian failure in maternal obesity.
    Keywords:  NLRP3 inflammasome; inflammation; leptin; obesity; ovary
    DOI:  https://doi.org/10.3389/fcell.2021.738731
  153. J Physiol. 2021 Nov 22.
    Consumption of dietary fat causes loss of olfactory sensory neurons and associated circuitry that is not mitigated by voluntary exercise in mice.
    Brandon M Chelette, Ashley M Loeven, Destinee N Gatlin, Daniel R Landi Conde, Carley M Huffstetler, Meizhu Qi, Debra Ann Fadool.
       KEY POINTS: Obesity can disrupt the structure and function of organ systems, including the olfactory system that is important for food selection and satiety. We designed dietary treatments in mice such that mice received fat, but the total calories provided were the same as in control diets so that they would not gain weight or increase adipose tissue. Mice that were not obese but consumed isocaloric fatty diets still lost olfactory neuronal circuits, had fewer numbers of olfactory neurons, had an elevation in inflammatory signals, and an intermediate ability to clear glucose (prediabetes). Mice were allowed access to running wheels while consuming fatty diets, yet still lost olfactory structures. We conclude that a long-term imbalance in nutrition that favors fat in the diet disrupts the olfactory system of mice in the absence of obesity.
    ABSTRACT: Excess nutrition causes loss of olfactory sensory neurons (OSNs) and reduces odor discrimination and odor perception in mice. To separate diet-induced obesity from the consumption of dietary fat, we designed pair-feeding experiments whereby mice were maintained on isocaloric diets for 5 months that prevented increased fat storage. To test our hypothesis that adiposity was not a prerequisite for loss of OSNs and bulbar projections, we used male and female mice with an odorant receptor-linked genetic reporter (M72tauLacZ; Olfr160) to visualize neural circuitry changes resulting from fat in the diet. Simultaneously we monitored glucose clearance (diagnostic for prediabetes), body fat deposition, ingestive behaviors, select inflammatory markers, and energy metabolism. Axonal projections to defined olfactory glomeruli were visualized in whole-mount brains and the number of OSNs were manually counted across whole olfactory epithelia. After being pair fed a moderately high-fat (MHF) diet, mice of both sexes had body weight, adipose deposits, energy expenditure, respiratory exchange ratios, and locomotor activity that were unchanged from control-fed mice. Despite this, they were still found to lose OSNs and associated bulbar projections. Even with unchanged adipocyte storage, pair-fed animals had an elevation in TNF cytokines and an intermediate ability for glucose clearance. Albeit improving health metrics, access to voluntary running while consuming an ad libitum fatty diet, still precipitated a loss of OSNs and associated axonal projections for male mice. Our results support that long-term macronutrient imbalance can drive anatomical loss in the olfactory system regardless of total energy expenditure. This article is protected by copyright. All rights reserved.
    Keywords:   
    DOI:  https://doi.org/10.1113/JP282112
  154. Nutrients. 2021 Nov 15. pii: 4079. [Epub ahead of print]13(11):
    Coix Seed Consumption Affects the Gut Microbiota and the Peripheral Lymphocyte Subset Profiles of Healthy Male Adults.
    Minami Jinnouchi, Taisei Miyahara, Yoshio Suzuki.
      A systematic examination of the effects of traditional herbal medicines including their mechanisms could allow for their effective use and provide opportunities to develop new medicines. Coix seed has been suggested to promote spontaneous regression of viral skin infection. Purified oil from coix seed has also been suggested to increase the peripheral CD4+ lymphocytes. We, herein, attempt to shed more light on the way through which coix seed affects the human systemic immune function by hypothesizing that a central role to these changes could be played through changes in the gut microbiota. To that end, healthy adult males (n = 19) were divided into two groups; 11 of them consumed cooked coix seed (160 g per day) for 7 days (intervention), while the other eight were given no intervention. One week of coix seed consumption lead to an increase of the intestinal Faecalibacterium abundance and of the abundance (as % presence of overall peripheral lymphocytes) of CD3+CD8+ cells, CD4+ cells, CD4+CD25+ cells, and naïve/memory T cell ratio. As the relationship of microbiota and skin infection has not been clarified, our findings could provide a clue to a mechanism through which coix seed could promote the spontaneous regression of viral skin infections.
    Keywords:  adlay; gut microbiota; herbal medicine; immune system; pearl barley
    DOI:  https://doi.org/10.3390/nu13114079
  155. Bioorg Med Chem Lett. 2021 Nov 19. pii: S0960-894X(21)00691-0. [Epub ahead of print] 128464
    Design, synthesis and activity evaluation of prodrug form JBP485 and Vitamin E for alleviation of NASH.
    Bin Wu, Xu Zheng, Xing Li, Changyuan Wang, Lei Li, Zeyao Tang, Hongxia Cui, Zhen Li, Lixue Chen, Xiaodong Ma.
      Non-alcoholic steatohepatitis (NASH) is a serious form of non-alcoholic fatty liver disease (NAFLD) characterized by liver steatosis with lobular inflammation, hepatocyte injury and pericellular fibrosis. JBP485 is a hydrophilic dipeptide with protective effects on liver through alleviation of oxidative stress and inhibition of hepatocyte apoptosis and ICAM-1 expression. Vitamin E (VE), as a powerful biological antioxidant, exerts a certain protective effect on cell membranes and lipoproteins from lipid peroxidation. In this study, combining the structural characteristics of two agents, target in prodrug form of JBP485 and VE (JBP485-VE) was designed and synthesized via succinic acid linker. The synthesized compound significantly reduced the degree of inflammation and fibrosis according to hematoxylin-eosin (H&E) and sirius red staining assay for the liver tissue in the CCl4-induced NASH mouse model. The clear reduction of TG, T-CHO and ALT, AST content also demonstrated its efficacy in the treatment of NASH. In addition, JBP485-VE also reduced the expression of the inflammatory markers IL-2, IL-17A and malondialdehyde (MDA) in liver tissue, which indicated its higher anti-inflammatory and anti-oxidative stress activity. All these evaluated biological properties suggest that the strategy of prodrug design provided an effective method for the treatment of NASH.
    Keywords:  JBP485; NASH; Prodrug; Vitamin E
    DOI:  https://doi.org/10.1016/j.bmcl.2021.128464
  156. Zhonghua Gan Zang Bing Za Zhi. 2021 Oct 20. 29(10): 1006-1013
    [Study of abnormal lipid metabolism analysis and significance of fatty acid binding protein expression in patients with hepatocellular carcinoma].
    Y X Lin, K Chen, F M An, Y F Wang, X B Wu, Q Zhan, G Q Zhang.
      Objective: Hepatocellular carcinoma (HCC) is the fourth most dominant cancer in the world and the second leading cause of cancer-related deaths in the China. With the increase in the incidence of metabolic syndrome (MS) in the population, the correlation between MS and HCC has gradually been recognized. MS manifests as non-alcoholic fatty liver disease (shortly known as NAFLD) in the liver. A large number of research results has shown that the development of fatty liver is closely related to the occurrence of HCC, in which lipid metabolism plays a key regulatory role, and lipid metabolism is regulated by fatty acid binding protein (FABP). This study signifies the lipid metabolism analysis and the key FABP expression conditions in HCC. Methods: Data of patients who were first diagnosed with primary HCC between January 2016 to July 2019 were collected, and were divided into two groups according to the etiology, namely the viral and non-viral hepatitis-related HCC group. The relationship between MS-related factors and HCC was analyzed by t-test and chi square test. The expressions of FABP1, FABP4 and FABP5 were detected in cancer and adjacent tissues by immunohistochemistry, and the expressions of FABP1, FABP4 and FABP5 in HCC with fatty liver were detected by immunofluorescence. Finally, the expressional characteristics of the above-mentioned FABPs in HCC patients were analyzed with different clinicopathological features. Results: There were statistically significant differences in the rate of abnormal lipid metabolism and the number of abnormalities in MS-related factors between the viral and non-viral hepatitis-related HCC group. FABP1, FABP4, and FABP5 expression in HCC tissues were lower than the corresponding adjacent tumor tissues. Compared with simple HCC, FABP1, FABP4, FABP5 expression were increased in HCC tissues with steatosis, and the expression of FABP was closely related to the clinical characteristics of patients. Conclusion: Abnormal lipid metabolism is closely related to non-viral hepatitis-related HCC. The expression of lipid metabolism regulatory proteins FABP1, FABP4, and FABP5 are down-regulated in HCC tissues, but up-regulated in HCC with fatty liver, suggesting that the relationship between MS, especially dyslipidemia, and HCC should be paid attention to in clinical practice for early intervention. FABP1, FABP4, FABP5 may regulate HCC occurrence and development.
    Keywords:  Hepatocellular carcinoma; Metabolic syndrome; Non-alcoholic fatty liver disease
    DOI:  https://doi.org/10.3760/cma.j.cn501113-20200416-00189
  157. Hepatol Commun. 2021 Nov 23.
    Lipidomics and Redox Lipidomics Indicate Early Stage Alcohol-Induced Liver Damage.
    Jeremy P Koelmel, Wan Y Tan, Yang Li, John A Bowden, Atiye Ahmadireskety, Andrew C Patt, David J Orlicky, Ewy Mathé, Nicholas M Kroeger, David C Thompson, Jason A Cochran, Jaya Prakash Golla, Aikaterini Kandyliari, Ying Chen, Georgia Charkoftaki, Joy D Guingab-Cagmat, Hiroshi Tsugawa, Anmol Arora, Kirill Veselkov, Shunji Kato, Yurika Otoki, Kiyotaka Nakagawa, Richard A Yost, Timothy J Garrett, Vasilis Vasilou.
      Alcoholic fatty liver disease (AFLD) is characterized by lipid accumulation and inflammation and can progress to cirrhosis and cancer in the liver. AFLD diagnosis currently relies on histological analysis of liver biopsies. Early detection permits interventions that would prevent progression to cirrhosis or later stages of the disease. Herein, we have conducted the first comprehensive time-course study of lipids using novel state-of-the art lipidomics methods in plasma and liver in the early stages of a mouse model of AFLD, i.e., Lieber-DeCarli diet model. In ethanol-treated mice, changes in liver tissue included up-regulation of triglycerides (TGs) and oxidized TGs and down-regulation of phosphatidylcholine, lysophosphatidylcholine, and 20-22-carbon-containing lipid-mediator precursors. An increase in oxidized TGs preceded histological signs of early AFLD, i.e., steatosis, with these changes observed in both the liver and plasma. The major lipid classes dysregulated by ethanol play important roles in hepatic inflammation, steatosis, and oxidative damage. Conclusion: Alcohol consumption alters the liver lipidome before overt histological markers of early AFLD. This introduces the exciting possibility that specific lipids may serve as earlier biomarkers of AFLD than those currently being used.
    DOI:  https://doi.org/10.1002/hep4.1825
  158. J Vet Dent. 2021 Jun;38(2): 113-115
    Abstracts From Other Journals.
      
    DOI:  https://doi.org/10.1177/08987564211048659
  159. Nat Commun. 2021 Nov 26. 12(1): 6938
    Neoadjuvant PD-1 blockade induces T cell and cDC1 activation but fails to overcome the immunosuppressive tumor associated macrophages in recurrent glioblastoma.
    Alexander H Lee, Lu Sun, Aaron Y Mochizuki, Jeremy G Reynoso, Joey Orpilla, Frances Chow, Jenny C Kienzler, Richard G Everson, David A Nathanson, Steven J Bensinger, Linda M Liau, Timothy Cloughesy, Willy Hugo, Robert M Prins.
      Primary brain tumors, such as glioblastoma (GBM), are remarkably resistant to immunotherapy, even though pre-clinical models suggest effectiveness. To understand this better in patients, here we take advantage of our recent neoadjuvant treatment paradigm to map the infiltrating immune cell landscape of GBM and how this is altered following PD-1 checkpoint blockade using high dimensional proteomics, single cell transcriptomics, and quantitative multiplex immunofluorescence. Neoadjuvant PD-1 blockade increases T cell infiltration and the proportion of a progenitor exhausted population of T cells found within the tumor. We identify an early activated and clonally expanded CD8+ T cell cluster whose TCR overlaps with a CD8+ PBMC population. Distinct changes are also observed in conventional type 1 dendritic cells that may facilitate T cell recruitment. Macrophages and monocytes still constitute the majority of infiltrating immune cells, even after anti-PD-1 therapy. Interferon-mediated changes in the myeloid population are consistently observed following PD-1 blockade; these also mediate an increase in chemotactic factors that recruit T cells. However, sustained high expression of T-cell-suppressive checkpoints in these myeloid cells continue to prevent the optimal activation of the tumor infiltrating T cells. Therefore, future immunotherapeutic strategies may need to incorporate the targeting of these cells for clinical benefit.
    DOI:  https://doi.org/10.1038/s41467-021-26940-2
  160. Anaesthesiol Intensive Ther. 2021 Nov 24. pii: 44991. [Epub ahead of print]
    Why is it worth remembering the lung microbiome in ICU patients?
    Dorota Siwicka-Gieroba, Malgorzata Barud, Wojciech Dabrowski.
      In recent years commensal microorganisms are not just "passive occupants", but important element of homeostasis. There are numerous reports documenting the composition and role of the gut, skin or vagina microbiome but the role of commensal orga-nisms living in the lungs is relatively unknown. Pulmonary microbiome impact on the immune response of the host organism and may indicate new therapeutic directions. Lung microbiome, by modulating the expression of innate immunity genes, causes an increase in the concentration of interleukin (IL)-5, IL-10, interferon γ and C-C motif chemokine ligand 11, affects the toll-like receptor-4-dependent response of pulmonary macrophages and modulate the production of antibacterial peptides contained in the mucus. It is documented that disorders of the lung microbiome contribute to asthma or chronic obstructive pulmonary disease. However it is known that pulmonary dysbiosis also occurs in critically ill patients. It is possible, therefore, that microbiota-targeted therapy may constitute the future therapeutic direction in ICU.
    Keywords:   lung microbiome; lung-gut interaction.; ICU
    DOI:  https://doi.org/10.5114/ait.2021.108646
  161. Front Immunol. 2021 ;12 771279
    Hsa-miR-31 Governs T-Cell Homeostasis in HIV Protection via IFN-γ-Stat1-T-Bet Axis.
    Lingyan Zhu, Chao Qiu, Lili Dai, Linxia Zhang, Meiqi Feng, Yu Yang, Chenli Qiu, Anli Zhang, Jun Huang, Ying Wang, Ying Wan, Chen Zhao, Hao Wu, Jianxin Lyu, Xiaoyan Zhang, Jianqing Xu.
      It remains poorly defined whether any human miRNAs play protective roles during HIV infection. Here, focusing on a unique cohort of HIV-infected former blood donors, we identified miR-31 (hsa-miR-31) by comparative miRNA profiling as the only miRNA inversely correlating with disease progression. We further validated this association in two prospective cohort studies. Despite conservation during evolution, hsa-miR-31, unlike its mouse counterpart (mmu-miR-31), was downregulated in human T cell upon activation. Our ex vivo studies showed that inhibiting miR-31 in naïve CD4+ T cells promoted a transcriptional profile with activation signature. Consistent with this skewing effect, miR-31 inhibition led to remarkably increased susceptibility to HIV infection. The suppressive nature of miR-31 in CD4+ T cell activation was pinpointed to its ability to decrease T-bet, the key molecule governing IFN-γ production and activation of CD4+ T cells, by directly targeting the upstream STAT1 transcriptional factor for downregulation, thus blunting Th1 response. Our results implicated miR-31 as a useful biomarker for tracking HIV disease progression and, by demonstrating its importance in tuning the activation of CD4+ T cells, suggested that miR-31 may play critical roles in other physiological contexts where the CD4+ T cell homeostasis needs to be deliberately controlled.
    Keywords:  CD4+ T cell; HIV-1; STAT1; T-bet; disease progression; miR-31
    DOI:  https://doi.org/10.3389/fimmu.2021.771279
  162. Zootaxa. 2021 Sep 09. 5032(4): 533-548
    Seven new Otacilia Thorell, 1897 species from China (Araneae: Phrurolithidae).
    Yannan Mu, Feng Zhang.
      Seven new species of Otacilia Thorell, 1897 from China are described and illustrated, all from both sexes: O. ensifera sp. nov. and O. arcuata sp. nov. from Hunan Province; O. spiralis sp. nov. from Hunan Province and Chongqing City; O. lubrica sp. nov. and O. wuli sp. nov. from Chongqing City; O. dentigera sp. nov. from Sichuan Province; and O. shanxi sp. nov. from Shanxi Province. Based on Jin et al. (2016), the seven new species described here belong to two species groups: O. ensifera sp. nov., O. shanxi sp. nov., O. spiralis sp. nov. and O. lubrica sp. nov. belong to the armatissima-group, while O. wuli sp. nov., O. dentigera sp. nov. and O. arcuata sp. nov. belong to the longituba-group.
    DOI:  https://doi.org/10.11646/zootaxa.5032.4.4
  163. Cells. 2021 Oct 21. pii: 2833. [Epub ahead of print]10(11):
    A Role for the Bone Marrow Microenvironment in Drug Resistance of Acute Myeloid Leukemia.
    Seyed Mohammadreza Bolandi, Mahdi Pakjoo, Peyman Beigi, Mohammad Kiani, Ali Allahgholipour, Negar Goudarzi, Jamshid S Khorashad, Anna M Eiring.
      Acute myeloid leukemia (AML) is a heterogeneous disease with a poor prognosis and remarkable resistance to chemotherapeutic agents. Understanding resistance mechanisms against currently available drugs helps to recognize the therapeutic obstacles. Various mechanisms of resistance to chemotherapy or targeted inhibitors have been described for AML cells, including a role for the bone marrow niche in both the initiation and persistence of the disease, and in drug resistance of the leukemic stem cell (LSC) population. The BM niche supports LSC survival through direct and indirect interactions among the stromal cells, hematopoietic stem/progenitor cells, and leukemic cells. Additionally, the BM niche mediates changes in metabolic and signal pathway activation due to the acquisition of new mutations or selection and expansion of a minor clone. This review briefly discusses the role of the BM microenvironment and metabolic pathways in resistance to therapy, as discovered through AML clinical studies or cell line and animal models.
    Keywords:  acute myeloid leukemia; bone marrow microenvironment; drug resistance; leukemic stem cell
    DOI:  https://doi.org/10.3390/cells10112833
  164. Surg Obes Relat Dis. 2021 Oct 19. pii: S1550-7289(21)00493-7. [Epub ahead of print]
    Comment on: Assurance of surgical quality within multicenter randomized, controlled trials for bariatric and metabolic surgery: a systematic review.
    John Morton.
      
    DOI:  https://doi.org/10.1016/j.soard.2021.10.010
  165. J Am Geriatr Soc. 2021 Nov 26.
    Cicero's "On Old Age".
    Jeffrey M Levine.
      
    DOI:  https://doi.org/10.1111/jgs.17584
  166. Pharmaceuticals (Basel). 2021 Nov 17. pii: 1172. [Epub ahead of print]14(11):
    T Cell Bispecific Antibodies: An Antibody-Based Delivery System for Inducing Antitumor Immunity.
    Daisuke Kamakura, Ryutaro Asano, Masahiro Yasunaga.
      As a breakthrough immunotherapy, T cell bispecific antibodies (T-BsAbs) are a promising antibody therapy for various kinds of cancer. In general, T-BsAbs have dual-binding specificity to a tumor-associated antigen and a CD3 subunit forming a complex with the TCR. This enables T-BsAbs to crosslink tumor cells and T cells, inducing T cell activation and subsequent tumor cell death. Unlike immune checkpoint inhibitors, which release the brake of the immune system, T-BsAbs serve as an accelerator of T cells by stimulating their immune response via CD3 engagement. Therefore, they can actively redirect host immunity toward tumors, including T cell recruitment from the periphery to the tumor site and immunological synapse formation between tumor cells and T cells. Although the low immunogenicity of solid tumors increases the challenge of cancer immunotherapy, T-BsAbs capable of immune redirection can greatly benefit patients with such tumors. To investigate the detailed relationship between T-BsAbs delivery and their T cell redirection activity, it is necessary to determine how T-BsAbs deliver antitumor immunity to the tumor site and bring about tumor cell death. This review article discusses T-BsAb properties, specifically their pharmacokinetics, redirection of anticancer immunity, and local mechanism of action within tumor tissues, and discuss further challenges to expediting T-BsAb development.
    Keywords:  T cell bispecific antibody; T cell redirection; T-BsAb; drug development; mechanism of action; pharmacokinetics
    DOI:  https://doi.org/10.3390/ph14111172
  167. J Transl Med. 2021 Nov 22. 19(1): 473
    Ibrutinib protects T cells in patients with CLL from proliferation-induced senescence.
    Joanne E Davis, Chia Sharpe, Kylie Mason, Constantine S Tam, Rachel M Koldej, David S Ritchie.
       BACKGROUND: The development of Bruton's tyrosine kinase inhibitors (BTKi) for the treatment of chronic lymphocytic leukaemia (CLL) has provided a highly effective and relatively non-toxic alternative to conventional chemotherapy. Some studies have shown that BTKi can also lead to improvements in T cell immunity in patients despite in vitro analyses suggesting an immunosuppressive effect of BTKi on T cell function.
    METHODS: In this study, we examined both the in vitro effect and long-term in vivo effect of two clinically available BTKi, ibrutinib and zanubrutinib. Additional in vitro assessments were undertaken for a third BTKi, acalabrutinib. Immune subset phenotyping, cytokine secretion, T cell degranulation and proliferation assays were performed on peripheral blood mononuclear cells isolated from untreated CLL patients, and CLL patients on long-term (> 12 months) BTKi treatment.
    RESULTS: Similar to prior studies we observed that long-term BTKi treatment normalises lymphocyte subset frequency and reduces PD-1 expression on T cells. We also observed that T cells from patients taken prior to BTKi therapy showed an abnormal hyper-proliferation pattern typical of senescent T cells, which was normalised by long-term BTKi treatment. Furthermore, BTKi therapy resulted in reduced expression of the T cell exhaustion markers PD-1, TIM3 and LAG3 in late generations of T cells undergoing proliferation.
    CONCLUSIONS: Collectively, these findings indicate that there are critical differences between the in vitro effects of BTKi on T cell function and the effects derived from long-term BTKi exposure in vivo. Overall long-term exposure to BTKi, and particularly ibrutinib, resulted in improved T cell fitness in part due to suppressing the abnormal hyper-proliferation of CLL T cells and the associated development of T cell senescence.
    Keywords:  Bruton’s tyrosine kinase inhibitors; Chronic Lymphocytic Leukaemia; Proliferation; Senescence; T cells
    DOI:  https://doi.org/10.1186/s12967-021-03136-2
  168. Int Immunopharmacol. 2021 Nov 22. pii: S1567-5769(21)01010-9. [Epub ahead of print] 108374
    Crosstalk between macrophages and natural killer cells in the tumor microenvironment.
    Jingping Zhou, Shaolong Zhang, Changying Guo.
      The tumor microenvironment (TME) is jointly constructed by a variety of cell types, including tumor cells, immune cells, fibroblasts, and epithelial cells, among others. The cells within the TME interact with each other and with tumor cells to influence tumor development and progression. As the most abundant immune cells in the TME, macrophages regulate the immune network by not only secreting a large amount of versatile cytokines but also expressing a series of ligands or receptors on the surface to interact with other cells directly. Due to their strong plasticity, they exert both immunostimulatory and immunosuppressive effects in the complex TME. The major effector cells of the immune system that directly target cancer cells include but are not limited to natural killer cells (NKs), dendritic cells (DCs), macrophages, polymorphonuclear leukocytes, mast cells, and cytotoxic T lymphocytes (CTLs). Among them, NK cells are the predominant innate lymphocyte subsets that mediate antitumor and antiviral responses. The activation and inhibition of NK cells are regulated by cytokines and the balance between activating and inhibitory receptors. There is an inextricable regulatory relationship between macrophages and NK cells. Herein, we systematically elaborate on the regulatory network between macrophages and NK cells through soluble mediator crosstalk and cell-to-cell interactions. We believe that a better understanding of the crosstalk between macrophages and NKs in the TME will benefit the development of novel macrophage- or NK cell-focused therapeutic strategies with superior efficacies in cancer therapy.
    Keywords:  Crosstalk; Immunotherapy; Macrophages; NK cells; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.intimp.2021.108374
  169. Kidney Int Rep. 2021 Nov;6(11): 2935
    Response to Letter to the Editor.
    Adnan Sharif.
      
    DOI:  https://doi.org/10.1016/j.ekir.2021.09.015
  170. J Clin Invest. 2021 Nov 23. pii: e150535. [Epub ahead of print]
    Neoantigen-reactive CD8+ T cells affect clinical outcome of adoptive transfer with tumor-infiltrating lymphocytes in melanoma.
    Nikolaj Pagh Kristensen, Christina Heeke, Siri A Tvingsholm, Annie Borch, Arianna Draghi, Michael D Crowther, Ibel Carri, Kamilla K Munk, Jeppe Sejerø Holm, Anne-Mette Bjerregaard, Amalie Kai Bentzen, Andrea M Marquard, Zoltan Szallasi, Nicholas McGranahan, Rikke Andersen, Morten Nielsen, Göran B Jönsson, Marco Donia, Inge Marie Svane, Sine Reker Hadrup.
       BACKGROUND: Neoantigen-driven recognition and T cell-mediated killing contribute to tumor clearance following adoptive cell therapy (ACT) with Tumor-Infiltrating Lymphocytes (TILs). Yet, how diversity, frequency, and persistence of expanded neoepitope-specific CD8+ T cells derived from TIL infusion products affect patient outcome is not fully determined.
    METHODS: Using barcoded pMHC multimers, we provide a comprehensive mapping of CD8+ T cells recognizing neoepitopes in TIL infusion products and blood samples from 26 metastatic mela-noma patients who received ACT.
    RESULTS: We identified 106 neoepitopes within TIL infusion products corresponding to 1.8% of all predicted neoepitopes. We observed neoepitope-specific recognition to be virtually devoid in TIL infusion products given to patients with progressive disease outcome. Moreover, we found that the frequency of neoepitope-specific CD8+ T cells in TIL infusion products correlated with in-creased survival, and that detection of engrafted CD8+ T cells in post-treatment (i.e. originating from the TIL infusion product) were unique to responders of TIL-ACT. Finally, we found that a transcriptional signature for lymphocyte activity within the tumor microenvironment was associated with a higher frequency of neoepitope-specific CD8+ T cells in the infusion product.
    CONCLUSIONS: These data support previous case studies of neoepitope-specific CD8+ T cells in melanoma, and indicate that successful TIL-ACT is associated with an expansion of neoepitope-specific CD8+ T cells.
    FUNDING: NEYE Foundation; European Research Council; Lundbeck Foundation Fellowship; Carlsberg Foundation.
    Keywords:  Cancer immunotherapy; Immunology; Melanoma; T cells; Therapeutics
    DOI:  https://doi.org/10.1172/JCI150535
  171. Nutrients. 2021 Oct 28. pii: 3839. [Epub ahead of print]13(11):
    Intestinal Microbiota as a Contributor to Chronic Inflammation and Its Potential Modifications.
    Marta Potrykus, Sylwia Czaja-Stolc, Marta Stankiewicz, Łukasz Kaska, Sylwia Małgorzewicz.
      The gut microbiota is a crucial factor in maintaining homeostasis. The presence of commensal microorganisms leads to the stimulation of the immune system and its maturation. In turn, dysbiosis with an impaired intestinal barrier leads to accelerated contact of microbiota with the host's immune cells. Microbial structural parts, i.e., pathogen-associated molecular patterns (PAMPs), such as flagellin (FLG), peptidoglycan (PGN), lipoteichoic acid (LTA), and lipopolysaccharide (LPS), induce inflammation via activation of pattern recognition receptors. Microbial metabolites can also develop chronic low-grade inflammation, which is the cause of many metabolic diseases. This article aims to systematize information on the influence of microbiota on chronic inflammation and the benefits of microbiota modification through dietary changes, prebiotics, and probiotic intake. Scientific research indicates that the modification of the microbiota in various disease states can reduce inflammation and improve the metabolic profile. However, since there is no pattern for a healthy microbiota, there is no optimal way to modify it. The methods of influencing microbiota should be adapted to the type of dysbiosis. Although there are studies on the microbiota and its effects on inflammation, this subject is still relatively unknown, and more research is needed in this area.
    Keywords:  diet; inflammation; intestinal epithelial barrier; microbiome; prebiotic; probiotic
    DOI:  https://doi.org/10.3390/nu13113839
  172. Nat Commun. 2021 Nov 25. 12(1): 6838
    Epigenetic interaction between UTX and DNMT1 regulates diet-induced myogenic remodeling in brown fat.
    Fenfen Li, Jia Jing, Miranda Movahed, Xin Cui, Qiang Cao, Rui Wu, Ziyue Chen, Liqing Yu, Yi Pan, Huidong Shi, Hang Shi, Bingzhong Xue.
      Brown adipocytes share the same developmental origin with skeletal muscle. Here we find that a brown adipocyte-to-myocyte remodeling also exists in mature brown adipocytes, and is induced by prolonged high fat diet (HFD) feeding, leading to brown fat dysfunction. This process is regulated by the interaction of epigenetic pathways involving histone and DNA methylation. In mature brown adipocytes, the histone demethylase UTX maintains persistent demethylation of the repressive mark H3K27me3 at Prdm16 promoter, leading to high Prdm16 expression. PRDM16 then recruits DNA methyltransferase DNMT1 to Myod1 promoter, causing Myod1 promoter hypermethylation and suppressing its expression. The interaction between PRDM16 and DNMT1 coordinately serves to maintain brown adipocyte identity while repressing myogenic remodeling in mature brown adipocytes, thus promoting their active brown adipocyte thermogenic function. Suppressing this interaction by HFD feeding induces brown adipocyte-to-myocyte remodeling, which limits brown adipocyte thermogenic capacity and compromises diet-induced thermogenesis, leading to the development of obesity.
    DOI:  https://doi.org/10.1038/s41467-021-27141-7
  173. Nature. 2021 Nov;599(7886): 553-554
    How dogs became humans' best friends: from Neanderthals to now.
    Josie Glausiusz.
      
    Keywords:  Evolution; History; Zoology
    DOI:  https://doi.org/10.1038/d41586-021-03497-0
  174. Cells. 2021 Nov 21. pii: 3257. [Epub ahead of print]10(11):
    Accumulation of Genetic and Epigenetic Alterations in the Background Liver and Emergence of Hepatocellular Carcinoma in Patients with Non-Alcoholic Fatty Liver Disease.
    Satoru Hagiwara, Naoshi Nishida, Kazuomi Ueshima, Yasunori Minami, Yoriaki Komeda, Tomoko Aoki, Masahiro Takita, Masahiro Morita, Hirokazu Chishina, Akihiro Yoshida, Hiroshi Ida, Masatoshi Kudo.
      The incidence of hepatocellular carcinoma (HCC) related to non-alcoholic fatty liver disease (NAFLD) is increasing worldwide. We analyzed 16 surgically resected HCC cases in which the background liver was pathologically diagnosed as NAFLD. Specimens with Brunt classification grade 3 or higher were assigned as the fibrotic progression group (n = 8), and those with grade 1 or lower were classified as the non-fibrosis progression group (n = 8). Comprehensive mutational and methylome analysis was performed in cancerous and noncancerous tissues. The target gene mutation analysis with deep sequencing revealed that CTNNB1 and TP53 mutation was observed in 37.5% and TERT promoter mutation was detected in 50% of cancerous samples. Furthermore, somatic mutations in non-cancerous samples were less frequent, but were observed regardless of the progression of fibrosis. Similarly, on cluster analysis of methylome data, status for methylation events involving non-cancerous liver was similar regardless of the progression of fibrosis. It was found that, even in cases of non-progressive fibrosis, accumulation of gene mutations and abnormal methylation within non-cancerous areas were observed. Patients with NAFLD require a rigorous liver cancer surveillance due to the high risk of HCC emergence based on the accumulation of genetic and epigenetic abnormalities, even when fibrosis is not advanced.
    Keywords:  genome; liver cancer; methylation; mutation; non-alcoholic fatty liver disease
    DOI:  https://doi.org/10.3390/cells10113257
  175. J Hepatol. 2021 Nov 20. pii: S0168-8278(21)02218-2. [Epub ahead of print]
    Assessing causal relationships between COVID-19 and non-alcoholic fatty liver disease.
    Dong Liu, Qianlong Zhang, Pinqing Bai, Jian Zhao.
      
    DOI:  https://doi.org/10.1016/j.jhep.2021.11.014
  176. Biomedicines. 2021 Nov 16. pii: 1697. [Epub ahead of print]9(11):
    Non-Alcoholic Fatty Liver Disease (NAFLD) and Potential Links to Depression, Anxiety, and Chronic Stress.
    Sue Shea, Christos Lionis, Chris Kite, Lou Atkinson, Surinderjeet S Chaggar, Harpal S Randeva, Ioannis Kyrou.
      Non-alcoholic fatty liver disease (NAFLD) constitutes the most common liver disease worldwide, and is frequently linked to the metabolic syndrome. The latter represents a clustering of related cardio-metabolic components, which are often observed in patients with NAFLD and increase the risk of cardiovascular disease. Furthermore, growing evidence suggests a positive association between metabolic syndrome and certain mental health problems (e.g., depression, anxiety, and chronic stress). Given the strong overlap between metabolic syndrome and NAFLD, and the common underlying mechanisms that link the two conditions, it is probable that potentially bidirectional associations are also present between NAFLD and mental health comorbidity. The identification of such links is worthy of further investigation, as this can inform more targeted interventions for patients with NAFLD. Therefore, the present review discusses published evidence in relation to associations of depression, anxiety, stress, and impaired health-related quality of life with NAFLD and metabolic syndrome. Attention is also drawn to the complex nature of affective disorders and potential overlapping symptoms between such conditions and NAFLD, while a focus is also placed on the postulated mechanisms mediating associations between mental health and both NAFLD and metabolic syndrome. Relevant gaps/weaknesses of the available literature are also highlighted, together with future research directions that need to be further explored.
    Keywords:  NAFLD; NASH; anxiety; depression; health related quality of life; insulin resistance; metabolic syndrome; non-alcoholic fatty liver disease; obesity; stress
    DOI:  https://doi.org/10.3390/biomedicines9111697
  177. J Gen Intern Med. 2021 Nov 23.
    Nonalcoholic Fatty Liver Disease Underdiagnosis in Primary Care: What Are We Missing?
    Ellen M Nielsen, Kathryn P Anderson, Justin Marsden, Jingwen Zhang, Andrew D Schreiner.
      
    DOI:  https://doi.org/10.1007/s11606-021-07197-3
  178. Mol Ther. 2021 Nov 19. pii: S1525-0016(21)00586-4. [Epub ahead of print]
    Spatial distribution and functional analysis define the action pathway of Tim-3/Tim-3 ligands in tumor development.
    Tixiao Wang, Jie Zhang, Na Li, Mengzhen Li, Shuaiya Ma, Siyu Tan, Xiaowei Guo, Zehua Wang, Zhuanchang Wu, Lifen Gao, Chunhong Ma, Xiaohong Liang.
      The spatial organization of immune cells within the tumor microenvironment (TME) largely determines the anti-tumor immunity and also highly predicts tumor progression and therapeutic response. Tim-3 is a well-accepted immune checkpoint and plays multifaceted immunoregulatory roles via interaction with distinct Tim-3 ligands (Tim-3L), showing great potential as an immunotherapy target. However, the cell sociology mediated by Tim-3/Tim-3L and their contribution to tumor development remains elusive. Here we analyzed the spatial distribution of Tim-3/Tim-3L in TME using multiplex fluorescence staining and revealed that in spite of the increased Tim-3 expression in various tumor-infiltrated lymphocytes, Tim-3+CD4+ cells were more accumulated in parenchymal/tumor region compared with stromal region and exhibited more closely association with patient survival. Strikingly, CD4 T cells surrounding Tim-3L+ cells expressed higher Tim-3 than other cells in cancerous tissues. In vivo studies confirmed that depletion of CD4 T cells completely abrogated the inhibition of tumor growth and metastasis, as well as the functional improvement of CD8 T and NK, mediated by Tim-3 blockade, which was further validated in peripheral lymphocytes from patients with hepatocellular carcinoma. In conclusion, our findings unravel the importance of CD4 T cells in Tim-3/Tim-3L mediated immunosuppression and provide new thoughts for Tim-3 targeted cancer immunotherapy.
    DOI:  https://doi.org/10.1016/j.ymthe.2021.11.015
  179. Mol Imaging Biol. 2021 Nov 23.
    Whole-Body Imaging to Assess Cell-Based Immunotherapy: Preclinical Studies with an Update on Clinical Translation.
    Noriko Sato, Peter L Choyke.
      In the past decades, immunotherapies against cancers made impressive progress. Immunotherapy includes a broad range of interventions that can be separated into two major groups: cell-based immunotherapies, such as adoptive T cell therapies and stem cell therapies, and immunomodulatory molecular therapies such as checkpoint inhibitors and cytokine therapies. Genetic engineering techniques that transduce T cells with a cancer-antigen-specific T cell receptor or chimeric antigen receptor have expanded to other cell types, and further modulation of the cells to enhance cancer targeting properties has been explored. Because cell-based immunotherapies rely on cells migrating to target organs or tissues, there is a growing interest in imaging technologies that non-invasively monitor transferred cells in vivo. Here, we review whole-body imaging methods to assess cell-based immunotherapy using a variety of examples. Following a review of preclinically used cell tracking technologies, we consider the status of their clinical translation.
    Keywords:  Cell-based immunotherapy; Fluorine-19 perfluorocarbon; Imaging; Immune cell; Magnetic resonance imaging; Positron emission tomography; Reporter gene imaging; Superparamagnetic iron oxide nanoparticles; Zirconium-89 oxine
    DOI:  https://doi.org/10.1007/s11307-021-01669-y
  180. Neuroimmunomodulation. 2021 Nov 25. 1-11
    Distinct Immunological Features of Inflammatory Demyelinating Diseases of the Central Nervous System.
    Bo Chen, Meng-Cui Gui, Su-Qiong Ji, Yi Xie, Dai-Shi Tian, Bi-Tao Bu.
       OBJECTIVE: The immunological features between neuromyelitis optica spectrum disorder (NMOSD), multiple sclerosis (MS), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), lacked systemic comparisons. Accordingly, we aimed to investigate immunological differences between NMOSD, MS, and MOGAD.
    METHODS: Patients with MOGAD, MS, and NMOSD who received immunological tests including cytokine profiles and cytometry analysis of the lymphocyte subgroups were retrospectively reviewed and divided into training and validation sets. Discriminatory models based on immunological data were established to identify optimal classifiers using orthogonal partial least square discriminant analysis (OPLS-DA). Constructed models were tested in another independent cohort.
    RESULTS: OPLS-DA of the immunological data from 50 patients (26 NMOSD, 14 MS, and 10 MOGAD) demonstrated the discriminatory values of a relatively low level of T-lymphocyte subsets, especially the CD4+ T cells, in MOGAD; a decreased NK cell, eosinophil, and lymphocyte level; an elevated neutrophil-to-lymphocyte ratio in NMOSD; and a declined IFN-γ-producing CD4+ T cells/Th with an increased IL-8 concentration in MS. All the models (NMOSD vs. MS, NMOSD vs. MOGAD, and MS vs. MOGAD) exhibited a significant predictive value and accuracy (>85%).
    CONCLUSIONS: NMOSD, MS, and MOGAD may be different in pathogenesis, and several immunological biomarkers can serve as potential classifiers clinically.
    Keywords:  Immunological features; Multiple sclerosis; Myelin oligodendrocyte glycoprotein antibody-associated disease; Neuromyelitis optica spectrum disorder; Orthogonal partial least square discriminant analysis
    DOI:  https://doi.org/10.1159/000519835
  181. Zootaxa. 2021 Sep 08. 5032(3): 357-378
    Additions to the Neoserica calva group from continental South East Asia (Coleoptera: Scarabaeidae: Melolonthinae: Sericini).
    Dirk Ahrens, Phu VAN Pham.
      In this paper we revise the species of the Neoserica calva group from continental South East Asia, which was so far known only from China. Here we describe 11 new species from Laos, Thailand, and Vietnam: Neoserica allosigillata Ahrens Pham, new species, N. axelkalliesi Ahrens Pham, new species, N. chetaoensis Ahrens Pham, new species, N. diplospinosa Ahrens Pham, new species, N. fragilis Ahrens Pham, new species, N. ihlei Ahrens Pham, new species, N. judsoni Ahrens Pham, new species, N. peregovitsi Ahrens Pham, new species, N. rufoplagiatoides Ahrens Pham, new species, N. sharkeyi Ahrens Pham, new species, and N. tramton Ahrens Pham, new species.
    DOI:  https://doi.org/10.11646/zootaxa.5032.3.3
  182. Ocul Surf. 2021 Nov 19. pii: S1542-0124(21)00133-6. [Epub ahead of print]
    High fat diet induced gut dysbiosis alters corneal epithelial injury response in mice.
    Kai Kang, Qiang Zhou, Lander McGinn, Tara Nguyen, Yuncin Luo, Ali Djalilian, Mark Rosenblatt.
       PURPOSE: Commensal microbiome secretes various metabolites that can exert important effects on the host immunity and inflammation and can alter cellular functions. However, little is known regarding the effect of microbiome on corneal immunity and genetic expression. The purpose of this study is to describe the effect of diet-induced gut dysbiosis on corneal immunity and corneal gene expression after wounding.
    METHODS: This study is approved by the Animal Care and Use of the University of Illinois. Six-week-old female C57BL6 mice were fed on a normal chow diet (ND), isocaloric low-fat control diet (LFD), or a 21% milk high-fat diet (HFD) for six weeks. 2mm corneal epithelial debridement was performed (n = 10). Fecal samples from mice were used for microbial diversity analysis (n > 3). Immunofluorescence staining of corneal wholemount tissue post-debridement was used to visualize immune cell distribution. RNA Seq was performed on tissue samples from corneas following debridement.
    RESULTS: Mice fed differing diets had significant alterations in gut microbial diversities. After corneal debridement, HFD mice experienced delayed wound healing in comparison to LFD mice and ND mice groups. However, fecal transplantation led to normalization of wound closure rates. Increased γδTCR staining was observed in the LFD group, and decreased LY6G was observed in HFD group (p < 0.05). Gene Ontology terms of differentially expressed genes included response to external stimulus, cell proliferation, migration, adhesion, defense response and leukocyte migration. Top over-represented pathways included ECM-receptor interaction, Cytokine-cytokine receptor interaction, Focal adhesion and Leukocyte trans-endothelial migration.
    CONCLUSIONS: Gut microbial dysbiosis alters corneal immune cell distribution, corneal response to injury, and genes related to epithelial function and corneal immunity.
    Keywords:  Corneal healing; Gut dysbiosis; Microbiome
    DOI:  https://doi.org/10.1016/j.jtos.2021.11.006
  183. J Vasc Surg. 2021 Dec;pii: S0741-5214(21)00834-X. [Epub ahead of print]74(6): 2086
    To walk or not to walk: That is the question.
    Anahita Dua.
      
    DOI:  https://doi.org/10.1016/j.jvs.2021.05.024
  184. J Biol Chem. 2021 Nov 18. pii: S0021-9258(21)01245-X. [Epub ahead of print] 101436
    Metabolic adaptation to the chronic loss of Ca2+ signaling induced by knockout of IP3 receptors or the mitochondrial Ca2+ uniporter.
    Michael P Young, Zachary T Schug, David M Booth, David I Yule, Katsuhiko Mikoshiba, György Hajnóczky, Suresh K Joseph.
      Calcium signaling is essential for regulating many biological processes. Endoplasmic reticulum (ER) inositol trisphosphate receptors (IP3R) and the mitochondrial Ca2+ uniporter (MCU) are key proteins that regulate intracellular Ca2+ concentration. Mitochondrial Ca2+ accumulation activates Ca2+-sensitive dehydrogenases of the tricarboxylic acid (TCA) cycle that maintain the biosynthetic and bioenergetics needs of both normal and cancer cells. However, the interplay between calcium signaling and metabolism is not well understood. In this study, we used human cancer cell lines (HEK293, HeLa) with stable knockouts of all three IP3R isoforms (TKO) or MCU to examine metabolic and bioenergetic responses to the chronic loss of cytosolic and/or mitochondrial Ca2+ signaling. Our results show that TKO cells (exhibiting total loss of Ca2+ signaling) are viable, displaying a lower proliferation and oxygen consumption rate, with no significant changes in ATP levels, even when made to rely solely on the TCA cycle for energy production. MCU KO cells also maintained normal ATP levels, but showed increased proliferation, oxygen consumption, and metabolism of both glucose and glutamine. However, MCU KO cells were unable to maintain ATP levels and died when relying solely on the TCA cycle for energy. We conclude that constitutive Ca2+ signaling is dispensable for the bioenergetic needs of both IP3R TKO and MCU KO human cancer cells, likely due to adequate basal glycolytic and TCA cycle flux. However, in MCU KO cells, the higher energy expenditure associated with increased proliferation and oxygen consumption makes these cells more prone to bioenergetic failure under conditions of metabolic stress.
    Keywords:  IP(3) receptor; TCA cycle; bioenergetics; calcium signaling; glycolysis; mitochondrial calcium uniporter; mitochondrial metabolism
    DOI:  https://doi.org/10.1016/j.jbc.2021.101436
  185. Cancers (Basel). 2021 Nov 21. pii: 5844. [Epub ahead of print]13(22):
    Hepatocellular Carcinoma in Non-Alcoholic Fatty Liver Disease: From Epidemiology to Diagnostic Approach.
    Ivica Grgurevic, Tonci Bozin, Mislav Mikus, Michal Kukla, James O'Beirne.
      Non-alcoholic fatty liver disease (NAFLD) is becoming the leading cause of liver morbidity worldwide and, as such, represents the pathogenic background for the increasing incidence of hepatocellular carcinoma (HCC). The annual incidence of NAFLD-related HCC is expected to increase by 45-130% by 2030. Diabetes mellitus is the most important risk factor for HCC development in NAFLD, with the risk further increased when associated with other metabolic traits, such as obesity, arterial hypertension and dyslipidemia. The highest risk of HCC exists in patients with advanced fibrosis or cirrhosis, although 20-50% of HCC cases arise in NAFLD patients with an absence of cirrhosis. This calls for further investigation of the pathogenic mechanisms that are involved in hepatocarcinogenesis, including genetics, metabolomics, the influence of the gut microbiota and immunological responses. Early identification of patients with or at risk of NAFLD is of utmost importance to improve outcomes. As NAFLD is highly prevalent in the community, the identification of cases should rely upon simple demographic and clinical characteristics. Once identified, these patients should then be evaluated for the presence of advanced fibrosis or cirrhosis and subsequently enter HCC surveillance programs if appropriate. A significant problem is the early recognition of non-cirrhotic NAFLD patients who will develop HCC, where new biomarkers and scores are potential solutions to tackle this issue.
    Keywords:  biomarkers; diabetes mellitus; hepatocellular carcinoma; metabolic syndrome; non-alcoholic fatty liver disease; screening programs; ultrasound
    DOI:  https://doi.org/10.3390/cancers13225844
  186. Cells. 2021 Oct 26. pii: 2896. [Epub ahead of print]10(11):
    Metabolic Changes in Tumor Microenvironment: How Could They Affect γδ T Cells Functions?
    Anna Maria Corsale, Marta Di Simone, Elena Lo Presti, Carmela Picone, Francesco Dieli, Serena Meraviglia.
      The metabolic changes that occur in tumor microenvironment (TME) can influence not only the biological activity of tumor cells, which become more aggressive and auto sustained, but also the immune response against tumor cells, either producing ineffective responses or polarizing the response toward protumor activity. γδ T cells are a subset of T cells characterized by a plasticity that confers them the ability to differentiate towards different cell subsets according to the microenvironment conditions. On this basis, we here review the more recent studies focused on altered tumor metabolism and γδ T cells, considering their already known antitumor role and the possibility of manipulating their effector functions by in vitro and in vivo approaches. γδ T cells, thanks to their unique features, are themselves a valid alternative to overcome the limits associated with the use of conventional T cells, such as major histocompatibility complex (MHC) restriction, costimulatory signal and specific tumor-associated antigen recognition. Lipids, amino acids, hypoxia, prostaglandins and other metabolic changes inside the tumor microenvironment could reduce the efficacy of this important immune population and polarize γδ T cells toward IL17 producing cells that play a pro tumoral role. A deeper knowledge of this phenomenon could be helpful to formulate new immunotherapeutic approaches that target tumor metabolisms.
    Keywords:  tumor microenvironment; tumoral metabolism; γδ T cells
    DOI:  https://doi.org/10.3390/cells10112896
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