bims-metalz Biomed News
on Metabolic causes of Alzheimer’s disease
Issue of 2023–02–12
137 papers selected by
Mikaila Chetty, Goa University
  1. Oxidative Stress and Aging as Risk Factors for Alzheimer's Disease and Parkinson's Disease: The Role of the Antioxidant Melatonin.
  2. Adult neurogenesis in Alzheimer's disease.
  3. Computer-Aided Screening and Revealing Action Mechanism of Green Tea Polyphenols Intervention in Alzheimer's Disease.
  4. Potential Roles of mtDNA Mutations in PCOS-IR: A Review.
  5. Role of ceramides and sphingolipidsin Parkinson's disease.
  6. Mitochondrial calcium cycling in neuronal function and neurodegeneration.
  7. Methyl Donors, Epigenetic Alterations, and Brain Health: Understanding the Connection.
  8. lncRNA NEAT1: Key player in neurodegenerative diseases.
  9. Microglial Activation in Metal Neurotoxicity: Impact in Neurodegenerative Diseases.
  10. The Pursuit of the "Inside" of the Amyloid Hypothesis-Is C99 a Promising Therapeutic Target for Alzheimer's Disease?
  11. The Role of the Gut Microbiome and Trimethylamine Oxide in Atherosclerosis and Age-Related Disease.
  12. Gut microbes and host behavior: The forgotten members of the gut-microbiome.
  13. The dynamic interplay between cardiac mitochondrial health and myocardial structural remodeling in metabolic heart disease, aging, and heart failure.
  14. Roles of Microglia in AD Pathology.
  15. Acridine: A Scaffold for the development of drugs for Alzheimer's disease.
  16. Emerging Links between Nonalcoholic Fatty Liver Disease and Neurodegeneration.
  17. The Evolving Landscape of Fecal Microbial Transplantation.
  18. Genetic correlation and gene-based pleiotropy analysis for four major neurodegenerative diseases with summary statistics.
  19. Apolipoprotein E ε4 modulates astrocyte neuronal support functions in the presence of amyloid-β.
  20. New Perspectives of Taxifolin in neurodegenerative diseases.
  21. Free complement and complement containing extracellular vesicles as potential biomarkers for neuroinflammatory and neurodegenerative disorders.
  22. In silico analysis of TUBA4A mutations in Amyotrophic Lateral Sclerosis to define mechanisms of microtubule disintegration.
  23. Endothelial Dysfunction in Neurodegenerative Diseases.
  24. Virus-Like Cytosolic and Cell-Free Oxidatively Damaged Nucleic Acids Likely Drive Inflammation, Synapse Degeneration, and Neuron Death in Alzheimer's Disease.
  25. Analysis of Non-Amyloidogenic Mutations in APP Supports Loss of Function Hypothesis of Alzheimer's Disease.
  26. The Crosstalk between Microbiome and Mitochondrial Homeostasis in Neurodegeneration.
  27. [The glymphatic system - an overview].
  28. Activation of aryl hydrocarbon receptor (AhR) in Alzheimer's disease: role of tryptophan metabolites generated by gut host-microbiota.
  29. Association between oxidative stress, mitochondrial function of peripheral blood mononuclear cells and gastrointestinal cancers.
  30. Gut Microbiota in Colorectal Cancer: Biological Role and Therapeutic Opportunities.
  31. Mitochondrial cargo export in exosomes: Possible pathways and implication in disease biology.
  32. Employing nanoparticle tracking analysis of salivary neuronal exosomes for early detection of neurodegenerative diseases.
  33. The genetic basis of multiple system atrophy.
  34. Neurons, Nose, and Neurodegenerative Diseases: Olfactory Function and Cognitive Impairment.
  35. Metal-induced oxidative stress and human plasma protein oxidation after SARS-CoV-2 infection.
  36. Congo Red-Derived Carbon Dots: Simultaneously as Fluorescence Probe for Protein Aggregates, Inhibitor for Protein Aggregation, and Scavenger of Free Radicals.
  37. Connecting clinical, environmental, and genetic factors point to an essential role for vitamin A signaling in the pathogenesis of congenital diaphragmatic hernia.
  38. Defining the Role of the Gut Microbiome in the Pathogenesis and Treatment of Lymphoid Malignancies.
  39. Targeting the gut-microbiota-brain axis in irritable bowel disease to improve cognitive function - recent knowledge and emerging therapeutic opportunities.
  40. A Review of Fibraurea tinctoria and Its Component, Berberine, as an Antidiabetic and Antioxidant.
  41. Lactobacillus gasseri NK109 and Its Supplement Alleviate Cognitive Impairment in Mice by Modulating NF-κB Activation, BDNF Expression, and Gut Microbiota Composition.
  42. The Role of the Stress Response in Metabolic Dysfunction-Associated Fatty Liver Disease: A Psychoneuroendocrineimmunology-Based Perspective.
  43. Beta-Amyloid Peptide in Tears: An Early Diagnostic Marker of Alzheimer's Disease Correlated with Choroidal Thickness.
  44. Why does understanding the biology of fibroblasts in immunity really matter?
  45. Understanding the role of the gut microbiome in gastrointestinal cancer: A review.
  46. Lipoprotein Metabolism, Protein Aggregation, and Alzheimer's Disease: A Literature Review.
  47. Chemistry of CS2 and CS3 Bridged Decaborane Analogues: Regular Coordination Versus Cluster Expansion.
  48. Circulating Microbial Cell-Free DNA in Health and Disease.
  49. Melatonin Can Modulate Neurodegenerative Diseases by Regulating Endoplasmic Reticulum Stress.
  50. Genetic Background and Molecular Mechanisms of Juvenile Idiopathic Arthritis.
  51. Neuronal SIRT3 deletion predisposes to female-specific alterations in cellular metabolism, memory, and network excitability.
  52. Any Role for Microbiota in Cholangiocarcinoma? A Comprehensive Review.
  53. Inflammatory Response: A Crucial Way for Gut Microbes to Regulate Cardiovascular Diseases.
  54. Metal manipulators and regulators in human pathogens: A comprehensive review on microbial redox copper metalloenzymes "multicopper oxidases and superoxide dismutases".
  55. Global ambient particulate matter pollution and neurodegenerative disorders: a systematic review of literature and meta-analysis.
  56. Emerging Roles of Microglia in Blood-brain Barrier Integrity in Aging and Neurodegeneration.
  57. Development of membrane-active peptide therapeutics in oncology.
  58. Gut microbiome diversity and composition is associated with exploratory behavior in a wild-caught songbird.
  59. Molecular Physiology of TRPV Channels: Controversies and Future Challenges.
  60. Protein Diffusion Along Protein and DNA Lattices: Role of Electrostatics and Disordered Regions.
  61. Selected Aspects of the Intricate Background of Immune-Related Cholangiopathies-A Critical Overview.
  62. The role of mitochondrial energy metabolism in neuroprotection and axonal regeneration after spinal cord injury.
  63. Editorial: Beta-Amyloid oligomer specific treatments for Alzheimer's disease.
  64. Natural Bioactive Compounds Targeting NADPH Oxidase Pathway in Cardiovascular Diseases.
  65. Adjuvant Injections Altered the Ileal and Fecal Microbiota Differently with Changes in Immunoglobulin Isotypes and Antimycobacterial Antibody Responses.
  66. Hereditary Hyperferritinemia.
  67. Neuroimaging Studies of the Neural Correlates of Heart Rate Variability: A Systematic Review.
  68. Traversing through the cell signaling pathways of neuroprotection by betanin: therapeutic relevance to Alzheimer's Disease and Parkinson's Disease.
  69. The Black Box Orchestra of Gut Bacteria and Bile Acids: Who Is the Conductor?
  70. Molecular Mechanisms Underlying Neuroinflammation Elicited by Occupational Injuries and Toxicants.
  71. Interactions of reactive sulfur species with metalloproteins.
  72. Biological Activity of Selenium and Its Impact on Human Health.
  73. Osteochondritis dissecans of the knee: Epidemiology, etiology, and natural history.
  74. The Role of Pyruvate Metabolism in Mitochondrial Quality Control and Inflammation.
  75. From neurons to the neuro-glio-vascular unit: Seizures and brain homeostasis in networks.
  76. Role of Pel and Psl polysaccharides in the response of Pseudomonas aeruginosa to environmental challenges: oxidative stress agents (UVA, H2O2, sodium hypochlorite) and its competitor Staphylococcus aureus.
  77. Pesticide exposure and Alzheimer's disease: A case-control study.
  78. Procyanidins extracted from the lotus seedpod ameliorate cognitive impairment through CREB-BDNF pathway mediated LTP in APP/PS1 transgenic mice.
  79. Role of gut-brain axis in neurodevelopmental impairment of necrotizing enterocolitis.
  80. Apolipoprotein E4 targets mitochondria and the mitochondria-associated membrane complex in neuropathology, including Alzheimer's disease.
  81. Gut microbiome lipid metabolism and its impact on host physiology.
  82. Associated long-term effects of decabromodiphenyl ethane on the gut microbial profiles and metabolic homeostasis in Sprague-Dawley rat offspring.
  83. In vivo visualization of enantioselective targeting of amyloid and improvement of cognitive function by clickable chiral metallohelices.
  84. Role of Nutrition in Pediatric Patients with Cancer.
  85. Dietary Habit Modifications in Paediatric Patients after One Year of Treatment with the Crohn's Disease Exclusion Diet.
  86. Aza-Residue Modulation of Cyclic d,l-α-Peptide Nanotube Assembly with Enhanced Anti-Amyloidogenic Activity.
  87. Caloric restriction for the management of malignant tumors from animal studies towards clinical translation.
  88. Erythropoietin in Glaucoma: From Mechanism to Therapy.
  89. The Molecular Mechanisms of Systemic Sclerosis-Associated Lung Fibrosis.
  90. Cellular Labeling of Phosphatidylserine Using Clickable Serine Probes.
  91. Structural Proteomic Profiling of Cerebrospinal Fluids to Reveal Novel Conformational Biomarkers for Alzheimer's Disease.
  92. The Role of Platelets in the Pathogenesis and Pathophysiology of Adenomyosis.
  93. Therapeutic Use and Molecular Aspects of Ivabradine in Cardiac Remodeling: A Review.
  94. Retinal pathological features and proteome signatures of Alzheimer's disease.
  95. Oxidation State in Peritoneal Dialysis in Patients with Type 2 Diabetes Mellitus.
  96. Insights into the Peritumoural Brain Zone of Glioblastoma: CDK4 and EXT2 May Be Potential Drivers of Malignancy.
  97. The Alzheimer's risk gene APOE modulates the gut-brain axis.
  98. Mitochondrial Transplantation in Mitochondrial Medicine: Current Challenges and Future Perspectives.
  99. Gpr35 shapes gut microbial ecology to modulate hepatic steatosis.
  100. Revisiting the intersection of microglial activation and neuroinflammation in Alzheimer's disease from the perspective of ferroptosis.
  101. The Ubiquitin Proteasome System as a Therapeutic Area in Parkinson's Disease.
  102. PIKFYVE inhibition mitigates disease in models of diverse forms of ALS.
  103. Gut microbiota of Parkinson's disease in an appendectomy cohort: a preliminary study.
  104. Review of the correlation between Chinese medicine and intestinal microbiota on the efficacy of diabetes mellitus.
  105. Deciphering strontium sulfate precipitation via Ostwald's rule of stages: From prenucleation clusters to solution-mediated phase tranformation.
  106. Analysis of the mechanism of action of quercetin in the treatment of hyperlipidemia based on metabolomics and intestinal flora.
  107. Regional White Matter Hyperintensities and Alzheimer's Disease Biomarkers Among Older Adults with Normal Cognition and Mild Cognitive Impairment.
  108. Risk Factors for Descemet Membrane Endothelial Keratoplasty Rejection: Current Perspectives- Systematic Review.
  109. Gut-lung crosstalk during critical illness.
  110. Longevity, Centenarians and Modified Cellular Proteodynamics.
  111. Association of metals with expanded polystyrene in the marine environment.
  112. Sustainable organic waste management using vermicomposting: a critical review on the prevailing research gaps and opportunities.
  113. miRNAs and Alzheimer's Disease: Exploring the Role of Inflammation and Vitamin E in an Old-Age Population.
  114. In Silico Drug Design and Analysis of Dual Amyloid-Beta and Tau Protein-Aggregation Inhibitors for Alzheimer's Disease Treatment.
  115. Revealing gut microbiome associations with CFS.
  116. Toward attention-based learning to predict the risk of brain degeneration with multimodal medical data.
  117. Somatostatin slows Aβ plaque deposition in aged APPNL-F/NL-F mice by blocking Aβ aggregation.
  118. Anti-Amyloidogenic Effects of Metasequoia glyptostroboides Fruits and Its Active Constituents.
  119. Maitake Medicinal Mushroom, Grifola frondosa (Agaricomycetes), and Its Neurotrophic Properties: A Mini-Review.
  120. Salicylic acid interacts with other plant growth regulators and signal molecules in response to stressful environments in plants.
  121. Comparing therapeutic modulators of the SOD1 G93A Amyotrophic Lateral Sclerosis mouse pathophysiology.
  122. Isoniazid improves cognitive performance, clears Aβ plaques, and protects dendritic synapses in APP/PS1 transgenic mice.
  123. The Role of Nutrition in Chronic Disease.
  124. Role of selective attention in fatigue in neurological disorders.
  125. Therapeutic Potential and Limitation of Serotonin Type 7 Receptor Modulation.
  126. Advances in methods to analyse cardiolipin and their clinical applications.
  127. Revisiting the Psychobiological Inhibition Model: a conceptual framework for understanding and treating insomnia using cognitive and behavioural therapeutics (CBTx).
  128. Metabolomics as a Tool to Understand Nano-Plant Interactions: The Case Study of Metal-Based Nanoparticles.
  129. Gestational Diabetes Mellitus and Its Implications across the Life Span.
  130. S-(-)-Oleocanthal Ex Vivo Modulatory Effects on Gut Microbiota.
  131. Aqueous extract of Ceratonia siliqua L. leaves elicits antioxidant, anti-inflammatory, and AChE inhibiting effects in amyloid-β42-induced cognitive deficit mice: Role of α7-nAChR in modulating Jak2/PI3K/Akt/GSK-3β/β-catenin cascade.
  132. Soluble ST2 as a New Oxidative Stress and Inflammation Marker in Metabolic Syndrome.
  133. Dermoscopy of subclinical nail involvement in diabetes mellitus patients: A case-control study.
  134. Lost in space(s): multimodal neuroimaging of disorientation along the Alzheimer's disease continuum.
  135. TRPV4 regulates mitochondrial Ca2+-status and physiology in primary murine T cells based on their immunological state.
  136. Soluble TREM2, Alzheimer's Disease Pathology, and Risk for Progression of Cerebral Small Vessel Disease: A Longitudinal Study.
  137. Neuroprotective Actions of Different Exogenous Nucleotides in H2O2-Induced Cell Death in PC-12 Cells.
  1. Int J Mol Sci. 2023 Feb 03. pii: 3022. [Epub ahead of print]24(3):
    Oxidative Stress and Aging as Risk Factors for Alzheimer's Disease and Parkinson's Disease: The Role of the Antioxidant Melatonin.
    Jana Tchekalarova, Rumiana Tzoneva.
      Aging and neurodegenerative diseases share common hallmarks, including mitochondrial dysfunction and protein aggregation. Moreover, one of the major issues of the demographic crisis today is related to the progressive rise in costs for care and maintenance of the standard living condition of aged patients with neurodegenerative diseases. There is a divergence in the etiology of neurodegenerative diseases. Still, a disturbed endogenous pro-oxidants/antioxidants balance is considered the crucial detrimental factor that makes the brain vulnerable to aging and progressive neurodegeneration. The present review focuses on the complex relationships between oxidative stress, autophagy, and the two of the most frequent neurodegenerative diseases associated with aging, Alzheimer's disease (AD) and Parkinson's disease (PD). Most of the available data support the hypothesis that a disturbed antioxidant defense system is a prerequisite for developing pathogenesis and clinical symptoms of ADs and PD. Furthermore, the release of the endogenous hormone melatonin from the pineal gland progressively diminishes with aging, and people's susceptibility to these diseases increases with age. Elucidation of the underlying mechanisms involved in deleterious conditions predisposing to neurodegeneration in aging, including the diminished role of melatonin, is important for elaborating precise treatment strategies for the pathogenesis of AD and PD.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; aging; melatonin; oxidative stress
    DOI:  https://doi.org/10.3390/ijms24033022
  2. Hippocampus. 2023 Feb 07.
    Adult neurogenesis in Alzheimer's disease.
    Se Hoon Choi, Rudolph E Tanzi.
      Alzheimer's disease (AD) is the most common form of age-related dementia, characterized by progressive memory loss and cognitive disturbances. The hippocampus, where adult hippocampal neurogenesis (AHN), a relatively novel form of brain plasticity that refers to the birth of new neurons, occurs, is one of the first brain regions to be affected in AD patients. Recent studies showed that AHN persists throughout life in humans, but it drops sharply in AD patients. Next questions to consider would be whether AHN impairment is a contributing factor to learning and memory impairment in AD and whether restoring AHN could ameliorate or delay cognitive dysfunction. Here, we outline and discuss the current knowledge about the state of AHN in AD patients, AHN impairment as a potentially relevant mechanism underlying memory deficits in AD, therapeutic potential of activating AHN in AD, and the mechanisms of AHN impairment in AD.
    Keywords:  Alzheimer's disease; adult hippocampal neurogenesis
    DOI:  https://doi.org/10.1002/hipo.23504
  3. Foods. 2023 Feb 02. pii: 635. [Epub ahead of print]12(3):
    Computer-Aided Screening and Revealing Action Mechanism of Green Tea Polyphenols Intervention in Alzheimer's Disease.
    Min Wang, Xiaotang Yang, Yilin Gao, Weiwei Han.
      The accumulation of cross-β-sheet amyloid fibrils is a hallmark of the neurodegenerative process of Alzheimer's disease (AD). Although it has been reported that green tea substances such as epicatechin (EC), epicatechin-3-gallate (ECG), epigallocatechin (EGC) and epigallocatechin-3-gallate (EGCG) could alleviate the symptoms of AD and other neurodegenerative diseases, the pharmacological mechanism remains largely unexplored. This study aimed to reveal the underlying mechanism of EC, ECG, EGC and EGCG in AD using a computer-aided screening strategy. Our results showed that the four tea polyphenols interfered with the signaling pathways of AD via calcium signaling channels, neurodegeneration-multiple disease signal pathways and others. We also identified the key residues of the interaction between VEGFA and the four active components, which included Glu64 and Phe36. Overall, we have provided valuable insights into the molecular mechanism of tea polyphenols, which could be used as a reference to improve therapeutic strategies against AD.
    Keywords:  Alzheimer’s disease; molecular docking; network pharmacology; quantum chemical calculation; tea polyphenols
    DOI:  https://doi.org/10.3390/foods12030635
  4. Diabetes Metab Syndr Obes. 2023 ;16 139-149
    Potential Roles of mtDNA Mutations in PCOS-IR: A Review.
    Xiao-Chao Dong, Chang Liu, Guang-Chao Zhuo, Yu Ding.
      Polycystic ovary syndrome (PCOS) is the most common heterogeneous endocrine disease that affecting females in reproductive age. Insulin resistance (IR), an important molecular basis for PCOS, accounts for at least 75% of women carrying this syndrome. Although there have been many studies on PCOS-IR, the detailed mechanisms are not fully understood. As essential hub for energy generation, mitochondria are critical to insulin secretion and normal function, whereas mutations in mitochondrial DNA (mtDNA) result in mitochondrial dysfunctions contributing to the pathophysiology of PCOS-IR via the regulation of balance of oxidative stress (OS), energy deficiency, or hormone metabolism. In the current review, we summarize the clinical and molecular features of PCOS-IR and discuss molecular mechanisms related to mtDNA mutations.
    Keywords:  PCOS-IR; mitochondrial dysfunction; mtDNA mutations
    DOI:  https://doi.org/10.2147/DMSO.S393960
  5. J Mol Biol. 2023 Feb 08. pii: S0022-2836(23)00056-6. [Epub ahead of print] 168000
    Role of ceramides and sphingolipidsin Parkinson's disease.
    Melissa Vos, Christine Klein, Andrew A Hicks.
      Sphingolipids, including the basic ceramide, are a subset of bioactive lipids that consist of many different species. Sphingolipids are indispensable for proper neuronal function, and an increasing number of studies have emerged on the complexity and importance of these lipids in (almost) all biological processes. These include regulation of mitochondrial function, autophagy, and endosomal trafficking, which are affected in Parkinson's disease (PD). PD is the second most common neurodegenerative disorder and is characterized by the loss of dopaminergic neurons. Currently, PD cannot be cured due to the lack of knowledge of the exact pathogenesis. Nonetheless, important advances have identified molecular changes in mitochondrial function, autophagy, and endosomal function. Furthermore, recent studies have identified ceramide alterations in patients suffering from PD, and in PD models, suggesting a critical interaction between sphingolipids and related cellular processes in PD. For instance, autosomal recessive forms of PD cause mitochondrial dysfunction, including energy production or mitochondrial clearance, that is directly influenced by manipulating sphingolipids. Additionally, endo-lysosomal recycling is affected by genes that cause autosomal dominant forms of the disease, such as VPS35 and SNCA. Furthermore, endo-lysosomal recycling is crucial for transporting sphingolipids to different cellular compartments where they will execute their functions. This review will discuss mitochondrial dysfunction, defects in autophagy, and abnormal endosomal activity in PD and the role sphingolipids play in these vital molecular processes.
    Keywords:  Parkinson’s disease; Sphingolipids; autophagy; ceramide; endosome; mitochondria
    DOI:  https://doi.org/10.1016/j.jmb.2023.168000
  6. Front Cell Dev Biol. 2023 ;11 1094356
    Mitochondrial calcium cycling in neuronal function and neurodegeneration.
    Grant C Walters, Yuriy M Usachev.
      Mitochondria are essential for proper cellular function through their critical roles in ATP synthesis, reactive oxygen species production, calcium (Ca2+) buffering, and apoptotic signaling. In neurons, Ca2+ buffering is particularly important as it helps to shape Ca2+ signals and to regulate numerous Ca2+-dependent functions including neuronal excitability, synaptic transmission, gene expression, and neuronal toxicity. Over the past decade, identification of the mitochondrial Ca2+ uniporter (MCU) and other molecular components of mitochondrial Ca2+ transport has provided insight into the roles that mitochondrial Ca2+ regulation plays in neuronal function in health and disease. In this review, we discuss the many roles of mitochondrial Ca2+ uptake and release mechanisms in normal neuronal function and highlight new insights into the Ca2+-dependent mechanisms that drive mitochondrial dysfunction in neurologic diseases including epilepsy, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. We also consider how targeting Ca2+ uptake and release mechanisms could facilitate the development of novel therapeutic strategies for neurological diseases.
    Keywords:  MCU; calcium; mitochondria; neurodegeneration; neuronal calcium homeostasis
    DOI:  https://doi.org/10.3389/fcell.2023.1094356
  7. Int J Mol Sci. 2023 Jan 25. pii: 2346. [Epub ahead of print]24(3):
    Methyl Donors, Epigenetic Alterations, and Brain Health: Understanding the Connection.
    Rola A Bekdash.
      Methyl donors such as choline, betaine, folic acid, methionine, and vitamins B6 and B12 are critical players in the one-carbon metabolism and have neuroprotective functions. The one-carbon metabolism comprises a series of interconnected chemical pathways that are important for normal cellular functions. Among these pathways are those of the methionine and folate cycles, which contribute to the formation of S-adenosylmethionine (SAM). SAM is the universal methyl donor of methylation reactions such as histone and DNA methylation, two epigenetic mechanisms that regulate gene expression and play roles in human health and disease. Epigenetic mechanisms have been considered a bridge between the effects of environmental factors, such as nutrition, and phenotype. Studies in human and animal models have indicated the importance of the optimal levels of methyl donors on brain health and behavior across the lifespan. Imbalances in the levels of these micronutrients during critical periods of brain development have been linked to epigenetic alterations in the expression of genes that regulate normal brain function. We present studies that support the link between imbalances in the levels of methyl donors, epigenetic alterations, and stress-related disorders. Appropriate levels of these micronutrients should then be monitored at all stages of development for a healthier brain.
    Keywords:  SAM; brain; epigenetics; methyl donors; stress
    DOI:  https://doi.org/10.3390/ijms24032346
  8. Ageing Res Rev. 2023 Feb 03. pii: S1568-1637(23)00037-5. [Epub ahead of print]86 101878
    lncRNA NEAT1: Key player in neurodegenerative diseases.
    Kun Li, Ziqiang Wang.
      Neurodegenerative diseases are the most common causes of disability worldwide. Given their high prevalence, devastating symptoms, and lack of definitive diagnostic tests, there is an urgent need to identify potential biomarkers and new therapeutic targets. Long non-coding RNAs (lncRNAs) have recently emerged as powerful regulatory molecules in neurodegenerative diseases. Among them, lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) has been reported to be upregulated in Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). However, whether this is part of a protective or harmful mechanism is still unclear. This review summarizes our current knowledge of the role of NEAT1 in neurodegenerative diseases and its association with the characteristic aggregation of misfolded proteins: amyloid-β and tau in AD, α-synuclein in PD, mutant huntingtin in HD, and TAR DNA-binding protein-43 fused in sarcoma/translocated in liposarcoma in ALS. The aim of this review is to stimulate further research on more precise and effective treatments for neurodegenerative diseases.
    Keywords:  Gene regulation; NEAT1; Neurodegenerative disease; Therapeutic target; lncRNA
    DOI:  https://doi.org/10.1016/j.arr.2023.101878
  9. Biomed Res Int. 2023 ;2023 7389508
    Microglial Activation in Metal Neurotoxicity: Impact in Neurodegenerative Diseases.
    María I Martínez-Hernández, Leonor C Acosta-Saavedra, Luisa C Hernández-Kelly, Jaqueline Loaeza-Loaeza, Arturo Ortega.
      Neurodegenerative processes encompass a large variety of diseases with different pathological patterns and clinical features, such as Alzheimer's and Parkinson's diseases. Exposure to metals has been hypothesized to increase oxidative stress in brain cells leading to cell death and neurodegeneration. Neurotoxicity of metals has been demonstrated by several in vitro and in vivo experimental studies, and most probably, each metal has its specific pathway to trigger cell death. As a result, exposure to essential metals, such as manganese, iron, copper, zinc, and cobalt, and nonessential metals, including lead, aluminum, and cadmium, perturbs metal homeostasis at the cellular and organism levels leading to neurodegeneration. In this contribution, a comprehensive review of the molecular mechanisms by which metals affect microglia physiology and signaling properties is presented. Furthermore, studies that validate the disruption of microglia activation pathways as an essential mechanism of metal toxicity that can contribute to neurodegenerative disease are also presented and discussed.
    DOI:  https://doi.org/10.1155/2023/7389508
  10. Cells. 2023 Jan 31. pii: 454. [Epub ahead of print]12(3):
    The Pursuit of the "Inside" of the Amyloid Hypothesis-Is C99 a Promising Therapeutic Target for Alzheimer's Disease?
    Nobumasa Takasugi, Masato Komai, Nanaka Kaneshiro, Atsuya Ikeda, Yuji Kamikubo, Takashi Uehara.
      Aducanumab, co-developed by Eisai (Japan) and Biogen (U.S.), has received Food and Drug Administration approval for treating Alzheimer's disease (AD). In addition, its successor antibody, lecanemab, has been approved. These antibodies target the aggregated form of the small peptide, amyloid-β (Aβ), which accumulates in the patient brain. The "amyloid hypothesis" based therapy that places the aggregation and toxicity of Aβ at the center of the etiology is about to be realized. However, the effects of immunotherapy are still limited, suggesting the need to reconsider this hypothesis. Aβ is produced from a type-I transmembrane protein, Aβ precursor protein (APP). One of the APP metabolites, the 99-amino acids C-terminal fragment (C99, also called βCTF), is a direct precursor of Aβ and accumulates in the AD patient's brain to demonstrate toxicity independent of Aβ. Conventional drug discovery strategies have focused on Aβ toxicity on the "outside" of the neuron, but C99 accumulation might explain the toxicity on the "inside" of the neuron, which was overlooked in the hypothesis. Furthermore, the common region of C99 and Aβ is a promising target for multifunctional AD drugs. This review aimed to outline the nature, metabolism, and impact of C99 on AD pathogenesis and discuss whether it could be a therapeutic target complementing the amyloid hypothesis.
    Keywords:  Alzheimer’s disease; BACE1; C99; amyloid beta precursor protein; amyloid-β; autolysosome; endolysosome; vesicular trafficking
    DOI:  https://doi.org/10.3390/cells12030454
  11. Int J Mol Sci. 2023 Jan 25. pii: 2399. [Epub ahead of print]24(3):
    The Role of the Gut Microbiome and Trimethylamine Oxide in Atherosclerosis and Age-Related Disease.
    Racha El Hage, Nada Al-Arawe, Irene Hinterseher.
      The gut microbiome plays a major role in human health, and gut microbial imbalance or dysbiosis is associated with disease development. Modulation in the gut microbiome can be used to treat or prevent different diseases. Gut dysbiosis increases with aging, and it has been associated with the impairment of gut barrier function leading to the leakage of harmful metabolites such as trimethylamine (TMA). TMA is a gut metabolite resulting from dietary amines that originate from animal-based foods. TMA enters the portal circulation and is oxidized by the hepatic enzyme into trimethylamine oxide (TMAO). Increased TMAO levels have been reported in elderly people. High TMAO levels are linked to peripheral artery disease (PAD), endothelial senescence, and vascular aging. Emerging evidence showed the beneficial role of probiotics and prebiotics in the management of several atherogenic risk factors through the remodeling of the gut microbiota, thus leading to a reduction in TMAO levels and atherosclerotic lesions. Despite the promising outcomes in different studies, the definite mechanisms of gut dysbiosis and microbiota-derived TMAO involved in atherosclerosis remain not fully understood. More studies are still required to focus on the molecular mechanisms and precise treatments targeting gut microbiota and leading to atheroprotective effects.
    Keywords:  TMAO; aging; atherosclerosis; gut dysbiosis; gut microbiome; probiotics; short chain fatty acids
    DOI:  https://doi.org/10.3390/ijms24032399
  12. Neuropharmacology. 2023 Feb 02. pii: S0028-3908(23)00043-6. [Epub ahead of print] 109453
    Gut microbes and host behavior: The forgotten members of the gut-microbiome.
    Ariel Weiner, Sondra Turjeman, Omry Koren.
      The gut microbiota refers to an entire population of microorganisms that colonize the gut. This community includes viruses, prokaryotes (bacteria and archaea), and eukaryotes (fungi and parasites). Multiple studies in the last decades described the significant involvement of gut bacteria in gut-brain axis communication; however, the involvement of other members of the gut microbiota has been neglected. Recent studies found that these 'forgotten' members of the gut microbiota may also have a role in gut-brain communication, although it is still unclear whether they have a direct effect on the brain or if their effects are mediated by gut bacteria. Here, we provide concrete suggestions for future research to tease out mechanisms of the microbiota-gut-brain axis.
    Keywords:  Archaeome; Bacteriome; Gut-brain axis; Microbiome; Mycobiome; Parasitome; Virome
    DOI:  https://doi.org/10.1016/j.neuropharm.2023.109453
  13. J Cardiovasc Aging. 2023 Jan;pii: 9. [Epub ahead of print]3(1):
    The dynamic interplay between cardiac mitochondrial health and myocardial structural remodeling in metabolic heart disease, aging, and heart failure.
    Benjamin Werbner, Omid Mohammad Tavakoli-Rouzbehani, Amir Nima Fatahian, Sihem Boudina.
      This review provides a holistic perspective on the bi-directional relationship between cardiac mitochondrial dysfunction and myocardial structural remodeling in the context of metabolic heart disease, natural cardiac aging, and heart failure. First, a review of the physiologic and molecular drivers of cardiac mitochondrial dysfunction across a range of increasingly prevalent conditions such as metabolic syndrome and cardiac aging is presented, followed by a general review of the mechanisms of mitochondrial quality control (QC) in the heart. Several important mechanisms by which cardiac mitochondrial dysfunction triggers or contributes to structural remodeling of the heart are discussed: accumulated metabolic byproducts, oxidative damage, impaired mitochondrial QC, and mitochondrial-mediated cell death identified as substantial mechanistic contributors to cardiac structural remodeling such as hypertrophy and myocardial fibrosis. Subsequently, the less studied but nevertheless important reverse relationship is explored: the mechanisms by which cardiac structural remodeling feeds back to further alter mitochondrial bioenergetic function. We then provide a condensed pathogenesis of several increasingly important clinical conditions in which these relationships are central: diabetic cardiomyopathy, age-associated declines in cardiac function, and the progression to heart failure, with or without preserved ejection fraction. Finally, we identify promising therapeutic opportunities targeting mitochondrial function in these conditions.
    Keywords:  Mitochondria; cardiac; fibroblasts; fibrosis; mitophagy; remodeling
    DOI:  https://doi.org/10.20517/jca.2022.42
  14. Curr Alzheimer Res. 2023 Feb 03.
    Roles of Microglia in AD Pathology.
    Gao Rong, Wu Hongrong, Li Qingqi, Zhao Jianfeng.
      Amyloid plaques and neurofibrillary tangles are two main characteristics of Alzheimer's disease (AD). As cerebral resident phagocytes, microglia have different roles in Aβ pathology and tau pathology. In this review, we discuss microglial functions in the formation, clearance, and spread of Aβ and tau. Many receptors and enzymes, which are related to microglia, participate in AD pathologies and thus are thought to be potential targets of AD. So, making use of microglia can be beneficial to confine AD pathologies. To sum up, we review the roles of microglia in AD pathology and possible corresponding treatments.
    Keywords:  Alzheimer ’s disease; Amyloid β; Microglia; Neurofibrillary tangles; Tau
    DOI:  https://doi.org/10.2174/1567205020666230203112351
  15. Curr Top Med Chem. 2023 Feb 03.
    Acridine: A Scaffold for the development of drugs for Alzheimer's disease.
    Anuradha Sharma, Poonam Piplani.
      Alzheimer's disease (AD) is drawing scientists' consideration, being one of the gravest diseases mankind will have to battle against in the near future. The number of people with AD is expected to triple in the next 40 years. It is a most common age-related multifactorial neurodegenerative disease and characterized by two histopathological hallmarks; the formation of senile plaques composed of the amyloid-β (Aβ) peptide and neurofibrillary tangles composed of hyperphosphorylated tau protein. Discovery and development of rationally designed multi-targeted ligands for the management of AD could be more beneficial than classical single targeted molecules. Acridine, a heterocyclic nucleus is a sole moiety in various existing drug molecules such as quinacrine (antimalarial), acriflavine and proflavine (antiseptics), ethacridine (abortifacient), amsacrine and nitracine (anticancer) and tacrine (anti-Alzheimer). It is proposed that acridine may combat the AD by acting on several targets like acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), dual specificity tyrosine kinase 1A (Dyrk 1A), amyloid and prion protein (PrPC) etc. involved in its pathogenesis. The main aim of this compilation is to review the most promising therapeutic developments within the vast research area dealing with acridine derivatives. Further research is required to evaluate the effectiveness of the acridine derivatives with various substitutions in the treatment of AD. In conclusion, our review will suggest the potentiality of the versatile acridine framework for drug designing and developing novel multi-target inhibitors for the Alzheimer's disease.
    Keywords:  Acetylcholinesterase; Acridine; Alzheimer's disease; Amyloid; Drug designing; Dual specificity tyrosine kinase; Prion protein.
    DOI:  https://doi.org/10.2174/1568026623666230203141543
  16. Semin Liver Dis. 2023 Feb 10.
    Emerging Links between Nonalcoholic Fatty Liver Disease and Neurodegeneration.
    Taylor J Kelty, Ryan J Dashek, W David Arnold, R Scott Rector.
      The association between liver and brain health has gained attention as biomarkers of liver function have been revealed to predict neurodegeneration. The liver is a central regulator in metabolic homeostasis. However, in nonalcoholic fatty liver disease (NAFLD), homeostasis is disrupted which can result in extrahepatic organ pathologies. Emerging literature provides insight into the mechanisms behind the liver-brain health axis. These include the increased production of liver-derived factors that promote insulin resistance and loss of neuroprotective factors under conditions of NAFLD that increase insulin resistance in the central nervous system. In addition, elevated proinflammatory cytokines linked to NAFLD negatively impact the blood-brain barrier and increase neuroinflammation. Furthermore, exacerbated dyslipidemia associated with NAFLD and hepatic dysfunction can promote altered brain bioenergetics and oxidative stress. In this review, we summarize the current knowledge of the crosstalk between liver and brain as it relates to the pathophysiology between NAFLD and neurodegeneration, with an emphasis on Alzheimer's disease. We also highlight knowledge gaps and future areas for investigation to strengthen the potential link between NAFLD and neurodegeneration.
    DOI:  https://doi.org/10.1055/s-0043-1762585
  17. Clin Rev Allergy Immunol. 2023 Feb 09.
    The Evolving Landscape of Fecal Microbial Transplantation.
    Tihong Shao, Ronald Hsu, Camelia Hacein-Bey, Weici Zhang, Lixia Gao, Mark J Kurth, Huanhuan Zhao, Zongwen Shuai, Patrick S C Leung.
      The human gastrointestinal tract houses an enormous microbial ecosystem. Recent studies have shown that the gut microbiota plays significant physiological roles and maintains immune homeostasis in the human body. Dysbiosis, an imbalanced gut microbiome, can be associated with various disease states, as observed in infectious diseases, inflammatory diseases, autoimmune diseases, and cancer. Modulation of the gut microbiome has become a therapeutic target in treating these disorders. Fecal microbiota transplantation (FMT) from a healthy donor restores the normal gut microbiota homeostasis in the diseased host. Ample evidence has demonstrated the efficacy of FMT in recurrent Clostridioides difficile infection (rCDI). The application of FMT in other human diseases is gaining attention. This review aims to increase our understanding of the mechanisms of FMT and its efficacies in human diseases. We discuss the application, route of administration, limitations, safety, efficacies, and suggested mechanisms of FMT in rCDI, autoimmune diseases, and cancer. Finally, we address the future perspectives of FMT in human medicine.
    Keywords:  Autoimmune diseases; Cancer; Clostridium infections; Dysbiosis; Fecal microbiota transplantation (FMT); Gut microbiota
    DOI:  https://doi.org/10.1007/s12016-023-08958-0
  18. Neurobiol Aging. 2022 Dec 31. pii: S0197-4580(22)00275-5. [Epub ahead of print]
    Genetic correlation and gene-based pleiotropy analysis for four major neurodegenerative diseases with summary statistics.
    Jiahao Qiao, Ting Wang, Zhonghe Shao, Yiyang Zhu, Meng Zhang, Shuiping Huang, Ping Zeng.
      Recent genome-wide association studies suggested shared genetic components between neurodegenerative diseases. However, pleiotropic association patterns among them remain poorly understood. We here analyzed 4 major neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), and found suggestively positive genetic correlation. We next implemented a gene-centric pleiotropy analysis with a powerful method called PLACO and detected 280 pleiotropic associations (226 unique genes) with these diseases. Functional analyses demonstrated that these genes were enriched in the pancreas, liver, heart, blood, brain, and muscle tissues; and that 42 pleiotropic genes exhibited drug-gene interactions with 341 drugs. Using Mendelian randomization, we discovered that AD and PD can increase the risk of developing ALS, and that AD and ALS can also increase the risk of developing FTD, respectively. Overall, this study provides in-depth insights into shared genetic components and causal relationship among the 4 major neurodegenerative diseases, indicating genetic overlap and causality commonly drive their co-occurrence. It also has important implications on the etiology understanding, drug development and therapeutic targets for neurodegenerative diseases.
    Keywords:  Causal inference; Gene-centric association analysis; Genetic correlation; Genome-wide association study; Neurodegenerative disease; Pleiotropy; Summary statistics
    DOI:  https://doi.org/10.1016/j.neurobiolaging.2022.12.012
  19. J Neurochem. 2023 Feb 10.
    Apolipoprotein E ε4 modulates astrocyte neuronal support functions in the presence of amyloid-β.
    Rebecca M Fleeman, Madison K Kuhn, Dennis C Chan, Elizabeth A Proctor.
      Apolipoprotein E (APOE) is a lipid transporter produced predominantly by astrocytes in the brain. The ε4 variant of APOE (APOE4) is the strongest and most common genetic risk factor for Alzheimer's disease (AD). Although the molecular mechanisms of this increased risk are unclear, APOE4 is known to alter immune signaling and lipid and glucose metabolism. Astrocytes provide various forms of support to neurons, including regulating neuronal metabolism and immune responses through cytokine signaling. Changes in astrocyte function due to APOE4 may therefore decrease neuronal support, leaving neurons more vulnerable to stress and disease insults. To determine whether APOE4 alters astrocyte neuronal support functions, we measured glycolytic and oxidative metabolism of neurons treated with conditioned media from APOE4 or APOE3 (the common, risk-neutral variant) primary astrocyte cultures. We found that APOE4 neurons treated with conditioned media from resting APOE4 astrocytes had similar metabolism to APOE3 neurons treated with media from resting APOE3 astrocytes, but treatment with astrocytic conditioned media from astrocytes challenged with amyloid-β (Aβ), a key pathological protein in AD, caused APOE4 neurons to increase their basal mitochondrial and glycolytic metabolic rates more than APOE3 neurons. These changes were not due to differences in astrocytic lactate production or glucose utilization, but instead correlated with increased glycolytic ATP production and a lack of cytokine secretion in response to Aβ. Additionally, we identified that astrocytic cytokine signatures could predict basal metabolism on neurons treated with the astrocytic conditioned media. Together, these findings suggest that in the presence of Aβ, APOE4 astrocytes alter immune and metabolic functions that result in a compensatory increase in neuronal metabolic stress.
    Keywords:  ATP; Astrocytes; amyloid-β; cytokines; glucose; glycolysis; immunometabolism
    DOI:  https://doi.org/10.1111/jnc.15781
  20. Curr Neuropharmacol. 2023 Feb 03.
    New Perspectives of Taxifolin in neurodegenerative diseases.
    Rong Yang, Xinxing Yang, Feng Zhang.
      Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Cerebral amyloid angiopathy (CAA) and Huntington's disease (HD), are characterized by cognitive and motor dysfunctions and neurodegeneration. These diseases become more severe over time and cannot be cured currently. Until now, most treatments for these diseases are only used to relieve the symptoms. Taxifolin (TAX), 3, 5, 7, 3, 4-pentahydroxy flavanone, also named dihydroquercetin, is a compound derived primarily from Douglas fir and Larix gemelini. TAX has been confirmed to present various pharmacological activities, including anti-inflammation, anti-cancer, anti-virus and regulation of oxidative stress effects. In central nervous system, TAX is demonstrated to inhibit Aβ fibril formation, protect neurons and improve cerebral blood flow, cognitive ability and dyskinesia. At present, TAX is only applied as a health additive in clinical practice. This review aimed to summarize the application of TAX in neurodegenerative diseases and the underlying neuroprotective mechanisms, such as suppressing inflammation, attenuating oxidative stress, preventing Aβ protein formation, maintaining dopamine levels and thus reducing neuronal loss.
    Keywords:  Alzheimer ’s disease.; Neurodegenerative disease; Neuroinflammation; Neuroprotection; Oxidative Stress; Parkinson ’s disease; Taxifolin
    DOI:  https://doi.org/10.2174/1570159X21666230203101107
  21. Front Immunol. 2022 ;13 1055050
    Free complement and complement containing extracellular vesicles as potential biomarkers for neuroinflammatory and neurodegenerative disorders.
    Marlies Burgelman, Pieter Dujardin, Charysse Vandendriessche, Roosmarijn E Vandenbroucke.
      The complement system is implicated in a broad range of neuroinflammatory disorders such as Alzheimer's disease (AD) and multiple sclerosis (MS). Consequently, measuring complement levels in biofluids could serve as a potential biomarker for these diseases. Indeed, complement levels are shown to be altered in patients compared to controls, and some studies reported a correlation between the level of free complement in biofluids and disease progression, severity or the response to therapeutics. Overall, they are not (yet) suitable as a diagnostic tool due to heterogeneity of reported results. Moreover, measurement of free complement proteins has the disadvantage that information on their origin is lost, which might be of value in a multi-parameter approach for disease prediction and stratification. In light of this, extracellular vesicles (EVs) could provide a platform to improve the diagnostic power of complement proteins. EVs are nanosized double membrane particles that are secreted by essentially every cell type and resemble the (status of the) cell of origin. Interestingly, EVs can contain complement proteins, while the cellular origin can still be determined by the presence of EV surface markers. In this review, we summarize the current knowledge and future opportunities on the use of free and EV-associated complement proteins as biomarkers for neuroinflammatory and neurodegenerative disorders.
    Keywords:  Alzheimer’s disease; biomarker; complement; extracellular vesicle (EV); multiple sclerosis; neuroinflammation
    DOI:  https://doi.org/10.3389/fimmu.2022.1055050
  22. Sci Rep. 2023 Feb 06. 13(1): 2096
    In silico analysis of TUBA4A mutations in Amyotrophic Lateral Sclerosis to define mechanisms of microtubule disintegration.
    Akshatha Ganne, Meenakshisundaram Balasubramaniam, Haarika Ayyadevara, Lily Kiaei, Robert J Shmookler Reis, Kottayil I Varughese, Mahmoud Kiaei.
      Amyotrophic lateral sclerosis (ALS) is an inexorably progressive and degenerative disorder of motor neurons with no currently-known cure. Studies to determine the mechanism of neurotoxicity and the impact of ALS-linked mutations (SOD1, FUS, TARDP, C9ORF72, PFN1, TUBA4A and others) have greatly expanded our knowledge of ALS disease mechanisms and have helped to identify potential targets for ALS therapy. Cellular pathologies (e.g., aggregation of mutant forms of SOD1, TDP43, FUS, Ubiqulin2, PFN1, and C9ORF72), mitochondrial dysfunction, neuroinflammation, and oxidative damage are major pathways implicated in ALS. Nevertheless, the selective vulnerability of motor neurons remains unexplained. The importance of tubulins for long-axon infrastructure, and the special morphology and function of motor neurons, underscore the central role of the cytoskeleton. The recent linkage of mutations to the tubulin α chain, TUBA4A, to familial and sporadic cases of ALS provides a new investigative opportunity to shed light on both mechanisms of ALS and the vulnerability of motor neurons. In the current study we investigate TUBA4A, a structural microtubule protein with mutations causal to familial ALS, using molecular-dynamic (MD) modeling of protein structure to predict the effects of each mutation and its overall impact on GTP binding, chain stability, tubulin assembly, and aggregation propensity. These studies predict that each of the reported mutations will cause notable structural changes to the TUBA4A (α chain) tertiary protein structure, adversely affecting its physical properties and functions. Molecular docking and MD simulations indicate certain α chain mutations (e.g. K430N, R215C, and W407X) may cause structural deviations that impair GTP binding, and plausibly prevent or destabilize tubulin polymerization. Furthermore, several mutations (including R320C and K430N) confer a significant increase in predicted aggregation propensity of TUBA4A mutants relative to wild-type. Taken together, these in silico modeling studies predict structural perturbations and disruption of GTP binding, culminating in failure to form a stable tubulin heterocomplex, which may furnish an important pathogenic mechanism to trigger motor neuron degeneration in ALS.
    DOI:  https://doi.org/10.1038/s41598-023-28381-x
  23. Int J Mol Sci. 2023 Feb 02. pii: 2909. [Epub ahead of print]24(3):
    Endothelial Dysfunction in Neurodegenerative Diseases.
    Yao-Ching Fang, Yi-Chen Hsieh, Chaur-Jong Hu, Yong-Kwang Tu.
      The cerebral vascular system stringently regulates cerebral blood flow (CBF). The components of the blood-brain barrier (BBB) protect the brain from pathogenic infections and harmful substances, efflux waste, and exchange substances; however, diseases develop in cases of blood vessel injuries and BBB dysregulation. Vascular pathology is concurrent with the mechanisms underlying aging, Alzheimer's disease (AD), and vascular dementia (VaD), which suggests its involvement in these mechanisms. Therefore, in the present study, we reviewed the role of vascular dysfunction in aging and neurodegenerative diseases, particularly AD and VaD. During the development of the aforementioned diseases, changes occur in the cerebral blood vessel morphology and local cells, which, in turn, alter CBF, fluid dynamics, and vascular integrity. Chronic vascular inflammation and blood vessel dysregulation further exacerbate vascular dysfunction. Multitudinous pathogenic processes affect the cerebrovascular system, whose dysfunction causes cognitive impairment. Knowledge regarding the pathophysiology of vascular dysfunction in neurodegenerative diseases and the underlying molecular mechanisms may lead to the discovery of clinically relevant vascular biomarkers, which may facilitate vascular imaging for disease prevention and treatment.
    Keywords:  Alzheimer’s disease (AD); blood–brain barrier (BBB); cerebral blood flow (CBF); vascular dementia (VaD)
    DOI:  https://doi.org/10.3390/ijms24032909
  24. J Alzheimers Dis Rep. 2023 ;7(1): 1-19
    Virus-Like Cytosolic and Cell-Free Oxidatively Damaged Nucleic Acids Likely Drive Inflammation, Synapse Degeneration, and Neuron Death in Alzheimer's Disease.
    Owen Davis Sanders.
      Oxidative stress, inflammation, and amyloid-β are Alzheimer's disease (AD) hallmarks that cause each other and other AD hallmarks. Most amyloid-β-lowering, antioxidant, anti-inflammatory, and antimicrobial AD clinical trials failed; none stopped or reversed AD. Although signs suggest an infectious etiology, no pathogen accumulated consistently in AD patients. Neuropathology, neuronal cell culture, rodent, genome-wide association, epidemiological, biomarker, and clinical studies, plus analysis using Hill causality criteria and revised Koch's postulates, indicate that the virus-like oxidative damage-associated molecular-pattern (DAMP) cytosolic and cell-free nucleic acids accumulated in AD patients' brains likely drive neuroinflammation, synaptotoxicity, and neurotoxicity. Cytosolic oxidatively-damaged mitochondrial DNA accumulated outside mitochondria dose-dependently in preclinical AD and AD patients' hippocampal neurons, and in AD patients' neocortical neurons but not cerebellar neurons or glia. In oxidatively-stressed neural cells and rodents' brains, cytosolic oxidatively-damaged mitochondrial DNA accumulated and increased antiviral and inflammatory proteins, including cleaved caspase-1, interleukin-1β, and interferon-β. Cytosolic double-stranded RNA and DNA are DAMPs that induce antiviral interferons and/or inflammatory proteins by oligomerizing with various innate-immune pattern-recognition receptors, e.g., cyclic GMP-AMP synthase and the nucleotide-binding-oligomerization-domain-like-receptor-pyrin-domain-containing-3 inflammasome. In oxidatively-stressed neural cells, cytosolic oxidatively-damaged mitochondrial DNA caused synaptotoxicity and neurotoxicity. Depleting mitochondrial DNA prevented these effects. Additionally, cell-free nucleic acids accumulated in AD patients' blood, extracellular vesicles, and senile plaques. Injecting cell-free nucleic acids bound to albumin oligomers into wild-type mice's hippocampi triggered antiviral interferon-β secretion; interferon-β injection caused synapse degeneration. Deoxyribonuclease-I treatment appeared to improve a severe-AD patient's Mini-Mental Status Exam by 15 points. Preclinical and clinical studies of deoxyribonuclease-I and a ribonuclease for AD should be prioritized.
    Keywords:  Cell-free nucleic acids; deoxyribonuclease I; mitochondrial DNA; neuroinflammatory diseases; oxidative stress; ribonucleases; wounds and injuries
    DOI:  https://doi.org/10.3233/ADR-220047
  25. Int J Mol Sci. 2023 Jan 20. pii: 2092. [Epub ahead of print]24(3):
    Analysis of Non-Amyloidogenic Mutations in APP Supports Loss of Function Hypothesis of Alzheimer's Disease.
    Meewhi Kim, Ilya Bezprozvanny.
      Proteolytic processing of amyloid precursor protein (APP) plays a critical role in pathogenesis of Azheimer's disease (AD). Sequential cleavage of APP by β- and γ-secretases leads to generation of Aβ40 (non-amyloidogenic) and Aβ42 (amyloidogenic) peptides. Presenilin-1 (PS1) or presenilin-2 (PS2) act as catalytic subunits of γ-secretase. Multiple familial AD (FAD) mutations in APP, PS1, or PS2 affect APP proteolysis by γ-secretase and influence levels of generated Aβ40 and Aβ42 peptides. The predominant idea in the field is the "amyloid hypothesis" that states that the resulting increase in Aβ42:Aβ40 ratio leads to "toxic gain of function" due to the accumulation of toxic Aβ42 plaques and oligomers. An alternative hypothesis based on analysis of PS1 conditional knockout mice is that "loss of function" of γ-secretase plays an important role in AD pathogenesis. In the present paper, we propose a mechanistic hypothesis that may potentially reconcile these divergent ideas and observations. We propose that the presence of soluble Aβ peptides in endosomal lumen (and secreted to the extracellular space) is essential for synaptic and neuronal function. Based on structural modeling of Aβ peptides, we concluded that Aβ42 peptides and Aβ40 peptides containing non-amyloidogenic FAD mutations in APP have increased the energy of association with the membranes, resulting in reduced levels of soluble Aβ in endosomal compartments. Analysis of PS1-FAD mutations also revealed that all of these mutations lead to significant reduction in both total levels of Aβ produced and in the Aβ40/Aβ42 ratio, suggesting that the concentration of soluble Aβ in the endosomal compartments is reduced as a result of these mutations. We further reasoned that similar changes in Aβ production may also occur as a result of age-related accumulation of cholesterol and lipid oxidation products in postsynaptic spines. Our analysis more easily reconciled with the "loss of γ-secretase function" hypothesis than with the "toxic gain of Aβ42 function" idea. These results may also explain why inhibitors of β- and γ- secretase failed in clinical trials, as these compounds are also expected to significantly reduce soluble Aβ levels in the endosomal compartments.
    Keywords:  APP; Alzheimer’s disease; gamma-secretase; modeling; presenilins
    DOI:  https://doi.org/10.3390/ijms24032092
  26. Cells. 2023 Jan 28. pii: 429. [Epub ahead of print]12(3):
    The Crosstalk between Microbiome and Mitochondrial Homeostasis in Neurodegeneration.
    Fivos Borbolis, Eirini Mytilinaiou, Konstantinos Palikaras.
      Mitochondria are highly dynamic organelles that serve as the primary cellular energy-generating system. Apart from ATP production, they are essential for many biological processes, including calcium homeostasis, lipid biogenesis, ROS regulation and programmed cell death, which collectively render them invaluable for neuronal integrity and function. Emerging evidence indicates that mitochondrial dysfunction and altered mitochondrial dynamics are crucial hallmarks of a wide variety of neurodevelopmental and neurodegenerative conditions. At the same time, the gut microbiome has been implicated in the pathogenesis of several neurodegenerative disorders due to the bidirectional communication between the gut and the central nervous system, known as the gut-brain axis. Here we summarize new insights into the complex interplay between mitochondria, gut microbiota and neurodegeneration, and we refer to animal models that could elucidate the underlying mechanisms, as well as novel interventions to tackle age-related neurodegenerative conditions, based on this intricate network.
    Keywords:  Alzheimer’s disease; Amyotrophic Lateral Sclerosis; Huntington’s disease; ageing; gut–brain axis; microbiome; mitochondria; neurodegeneration
    DOI:  https://doi.org/10.3390/cells12030429
  27. Lakartidningen. 2023 Feb 08. pii: 22124. [Epub ahead of print]120
    [The glymphatic system - an overview].
    Alba Corell, Asgeir S Jakola, Thomas Skoglund.
      The glymphatic system as a concept was introduced a decade ago and the knowledge regarding the circulation of the cerebrospinal fluid has since been revised. The research of the glymphatic system is extensive today, but there are many knowledge gaps. The glymphatic system was first investigated in animal experiments, but with the MR techniques available today the glymphatic system has also been shown to exist in humans. Studies suggest that the glymphatic system may be involved in the pathophysiological processes of neurological pathologies, such as degenerative brain disorders and normal pressure hydrocephalus (NPH), but also in the aftermath of ischemic stroke, subarachnoidal hemorrhage and traumatic brain injury. It is believed that the glymphatic system with its cleansing capabilities is upregulated during sleep, and interestingly studies show association between lack of sleep and neurodegenerative diseases. In this article, we present an overview of the glymphatic system and its possible role in intracranial pathologies.
  28. J Mol Med (Berl). 2023 Feb 09.
    Activation of aryl hydrocarbon receptor (AhR) in Alzheimer's disease: role of tryptophan metabolites generated by gut host-microbiota.
    Antero Salminen.
      Gut microbiota in interaction with intestinal host tissues influences many brain functions and microbial dysbiosis has been linked with brain disorders, such as neuropsychiatric conditions and Alzheimer's disease (AD). L-tryptophan metabolites and short-chained fatty acids (SCFA) are major messengers in the microbiota-brain axis. Aryl hydrocarbon receptors (AhR) are main targets of tryptophan metabolites in brain microvessels which possess an enriched expression of AhR protein. The Ah receptor is an evolutionarily conserved, ligand-activated transcription factor which is not only a sensor of xenobiotic toxins but also a pleiotropic regulator of both developmental processes and age-related tissue degeneration. Major microbiota-produced tryptophan metabolites involve indole derivatives, e.g., indole 3-pyruvic acid, indole 3-acetaldehyde, and indoxyl sulfate, whereas indoleamine and tryptophan 2,3-dioxygenases (IDO/TDO) of intestine host cells activate the kynurenine (KYN) pathway generating KYN metabolites, many of which are activators of AhR signaling. Chronic kidney disease (CKD) increases the serum level of indoxyl sulfate which promotes AD pathogenesis, e.g., it disrupts integrity of blood-brain barrier (BBB) and impairs cognitive functions. Activation of AhR signaling disturbs vascular homeostasis in brain; (i) it controls blood flow via the renin-angiotensin system, (ii) it inactivates endothelial nitric oxide synthase (eNOS), thus impairing NO production and vasodilatation, and (iii) it induces oxidative stress, stimulates inflammation, promotes cellular senescence, and enhances calcification of vascular walls. All these alterations are evident in cerebral amyloid angiopathy (CAA) in AD pathology. Moreover, AhR signaling can disturb circadian regulation and probably affect glymphatic flow. It seems plausible that dysbiosis of gut microbiota impairs the integrity of BBB via the activation of AhR signaling and thus aggravates AD pathology. KEY MESSAGES: Dysbiosis of gut microbiota is associated with dementia and Alzheimer's disease. Tryptophan metabolites are major messengers from the gut host-microbiota to brain. Tryptophan metabolites activate aryl hydrocarbon receptor (AhR) signaling in brain. The expression of AhR protein is enriched in brain microvessels and blood-brain barrier. Tryptophan metabolites disturb brain vascular integrity via AhR signaling. Dysbiosis of gut microbiota promotes inflammation and AD pathology via AhR signaling.
    Keywords:  Aging; Hypoperfusion; Immunosuppression; Microbiome; Microflora; Uremic toxin
    DOI:  https://doi.org/10.1007/s00109-023-02289-5
  29. J Transl Med. 2023 Feb 10. 21(1): 107
    Association between oxidative stress, mitochondrial function of peripheral blood mononuclear cells and gastrointestinal cancers.
    Weili Liu, Yuan Gao, Hua Li, Xinxing Wang, Min Jin, Zhiqiang Shen, Dong Yang, Xuelian Zhang, Zilin Wei, Zhaoli Chen, Junwen Li.
       BACKGROUND: The incidence and mortality rate of gastrointestinal cancers are high worldwide. Increasing studies have illustrated that the occurrence, progression, metastasis and prognosis of cancers are intimately linked to the immune system. Mitochondria, as the main source of cellular energy, play an important role in maintaining the physiological function of immune cells. However, the relationship between mitochondrial function of immune cells and tumorigenesis has not yet been systematically investigated.
    METHODS: A total of 150 cases, including 60 healthy donors and 90 primary gastrointestinal cancer patients without anti-tumor treatments (30 with gastric cancer, 30 with liver cancer and 30 with colorectal cancer) were involved in our study. The oxidant/antioxidant and cytokine levels in plasma, the ROS level, mitochondrial function and apoptosis ratio of peripheral blood mononuclear cells (PBMCs) were evaluated.
    RESULTS: The imbalance between oxidant and antioxidant in plasma was discovered in the primary gastrointestinal cancer patients. The levels of cell reactive oxygen species (ROS) and mitochondrial ROS in PBMCs of primary gastrointestinal cancers were significantly increased compared with that in healthy donors. Meanwhile, the ATP content, the mtDNA copy number and the mitochondrial membrane potential (MMP) in PBMCs of patients with primary gastrointestinal cancers were lower than those in control group. The decreased MMP also occurred in immune cells of gastrointestinal cancers, including T cell, B cell, NK cell and monocyte. Furthermore, the PBMCs apoptosis ratio of primary gastrointestinal cancer patients was significantly higher than that of control group. Importantly, an increase of IL-2 and IL-6 and a decrease of IgG in plasma were found in the patients with primary gastrointestinal cancers. These changes of mitochondrial function in immune cells were consistent among primary gastrointestinal cancers without anti-tumor treatments, such as liver cancer, gastric cancer and colorectal cancer.
    CONCLUSION: Our study demonstrated that the imbalance of oxidation/antioxidation in primary gastrointestinal cancer patients without anti-tumor treatments results in excessive ROS. The oxidative stress was associated to the mitochondrial dysfunction, the apoptosis of immune cells and eventually the abnormal immune function in primary gastrointestinal cancers. The application of immune cell mitochondrial dysfunction into clinical evaluation is anticipated.
    Keywords:  Gastrointestinal cancers; Mitochondrial dysfunction; PBMCs
    DOI:  https://doi.org/10.1186/s12967-023-03952-8
  30. Cancers (Basel). 2023 Jan 30. pii: 866. [Epub ahead of print]15(3):
    Gut Microbiota in Colorectal Cancer: Biological Role and Therapeutic Opportunities.
    Himani Pandey, Daryl W T Tang, Sunny H Wong, Devi Lal.
      Colorectal cancer (CRC) is the second-leading cause of cancer-related deaths worldwide. While CRC is thought to be an interplay between genetic and environmental factors, several lines of evidence suggest the involvement of gut microbiota in promoting inflammation and tumor progression. Gut microbiota refer to the ~40 trillion microorganisms that inhabit the human gut. Advances in next-generation sequencing technologies and metagenomics have provided new insights into the gut microbial ecology and have helped in linking gut microbiota to CRC. Many studies carried out in humans and animal models have emphasized the role of certain gut bacteria, such as Fusobacterium nucleatum, enterotoxigenic Bacteroides fragilis, and colibactin-producing Escherichia coli, in the onset and progression of CRC. Metagenomic studies have opened up new avenues for the application of gut microbiota in the diagnosis, prevention, and treatment of CRC. This review article summarizes the role of gut microbiota in CRC development and its use as a biomarker to predict the disease and its potential therapeutic applications.
    Keywords:  chemotherapy; colorectal cancer; dysbiosis; immunotherapy; microbiota; probiotics
    DOI:  https://doi.org/10.3390/cancers15030866
  31. J Cell Physiol. 2023 Feb 06.
    Mitochondrial cargo export in exosomes: Possible pathways and implication in disease biology.
    Aman Sharma.
      Exosome biogenesis occurs parallel to multiple endocytic traffic routes. These coexisting routes drive cargo loading in exosomes via overlapping of exosome biogenesis with endosomal pathways. One such pathway is autophagy which captures damaged intracellular organelles or their components in an autophagosome vesicle and route them for lysosomal degradation. However, in case of a noncanonical fusion event between autophagosome and maturing multivesicular body (MVB)-a site for exosome biogenesis, the autophagic cargo is putatively loaded in exosomes and subsequent released out of the cell via formation of an "amphisome" like structure. Similarly, during "mitophagy" or mitochondrial (mt) autophagy, amphisome formation routes mitophagy cargo to exosomes. These mt-cargo enriched exosomes or mt-enREXO are often positive for LC3 protein-an autophagic flux marker, and potent regulators of paracrine signaling with both homeostatic and pathological roles. Here, I review this emerging concept and discuss how intracellular autophagic routes helps in generation of mt-enREXO and utility of these vesicles in paracrine cellular signaling and diagnostic areas.
    Keywords:  cancer; exosomes; heart disease; mitochondria cargo
    DOI:  https://doi.org/10.1002/jcp.30967
  32. Transl Neurodegener. 2023 Feb 07. 12(1): 7
    Employing nanoparticle tracking analysis of salivary neuronal exosomes for early detection of neurodegenerative diseases.
    Vaibhav Sharma, Fredrik Nikolajeff, Saroj Kumar.
      Neurodegenerative diseases are a set of progressive and currently incurable diseases that are primarily caused by neuron degeneration. Neurodegenerative diseases often lead to cognitive impairment and dyskinesias. It is now well recognized that molecular events precede the onset of clinical symptoms by years. Over the past decade, intensive research attempts have been aimed at the early diagnosis of these diseases. Recently, exosomes have been shown to play a pivotal role in the occurrence and progression of many diseases including cancer and neurodegenerative diseases. Additionally, because exosomes can cross the blood-brain barrier, they may serve as a diagnostic tool for neural dysfunction. In this review, we detail the mechanisms and current challenges of these diseases, briefly review the role of exosomes in the progression of neurodegenerative diseases, and propose a novel strategy based on salivary neuronal exosomes and nanoparticle tracking analysis that could be employed for screening the early onset of neurodegenerative diseases.
    Keywords:  Alzheimer’s disease; Diagnosis; Exosomes; Extracellular vesicles; Nanoparticle tracking analysis; Neurodegenerative disease; Parkinson’s disease; Prognosis
    DOI:  https://doi.org/10.1186/s40035-023-00339-z
  33. J Transl Med. 2023 Feb 10. 21(1): 104
    The genetic basis of multiple system atrophy.
    Fan Shuen Tseng, Joel Qi Xuan Foo, Aaron Shengting Mai, Eng-King Tan.
      Multiple system atrophy (MSA) is a heterogenous, uniformly fatal neurodegenerative ɑ-synucleinopathy. Patients present with varying degrees of dysautonomia, parkinsonism, cerebellar dysfunction, and corticospinal degeneration. The underlying pathophysiology is postulated to arise from aberrant ɑ-synuclein deposition, mitochondrial dysfunction, oxidative stress and neuroinflammation. Although MSA is regarded as a primarily sporadic disease, there is a possible genetic component that is poorly understood. This review summarizes current literature on genetic risk factors and potential pathogenic genes and loci linked to both sporadic and familial MSA, and underlines the biological mechanisms that support the role of genetics in MSA. We discuss a broad range of genes that have been associated with MSA including genes related to Parkinson's disease (PD), oxidative stress, inflammation, and tandem gene repeat expansions, among several others. Furthermore, we highlight various genetic polymorphisms that modulate MSA risk, including complex gene-gene and gene-environment interactions, which influence the disease phenotype and have clinical significance in both presentation and prognosis. Deciphering the exact mechanism of how MSA can result from genetic aberrations in both experimental and clinical models will facilitate the identification of novel pathophysiologic clues, and pave the way for translational research into the development of disease-modifying therapeutic targets.
    Keywords:  Genetics; Movement disorders; Multiple system atrophy; Mutations; Neurodegeneration; Polymorphisms
    DOI:  https://doi.org/10.1186/s12967-023-03905-1
  34. Int J Mol Sci. 2023 Jan 20. pii: 2117. [Epub ahead of print]24(3):
    Neurons, Nose, and Neurodegenerative Diseases: Olfactory Function and Cognitive Impairment.
    Irene Fatuzzo, Giovanni Francesco Niccolini, Federica Zoccali, Luca Cavalcanti, Mario Giuseppe Bellizzi, Gabriele Riccardi, Marco de Vincentiis, Marco Fiore, Carla Petrella, Antonio Minni, Christian Barbato.
      Olfactory capacity declines with aging, but increasing evidence shows that smell dysfunction is one of the early signs of prodromal neurodegenerative diseases such as Alzheimer's and Parkinson's disease. The study of olfactory ability and its role in neurodegenerative diseases arouses much interest in the scientific community. In neurology, olfactory impairment is a potential early marker for the onset of neurodegenerative diseases, but the underlying mechanism is poorly understood. The loss of smell is considered a clinical sign of early-stage disease and a marker of the disease's progression and cognitive impairment. Highlighting the importance of biological bases of smell and molecular pathways could be fundamental to improve neuroprotective and therapeutic strategies. We focused on the review articles and meta-analyses on olfactory and cognitive impairment. We depicted the neurobiology of olfaction and the most common olfactory tests in neurodegenerative diseases. In addition, we underlined the close relationship between the olfactory and cognitive deficit due to nasal neuroepithelium, which is a direct extension of the CNS in communication with the external environment. Neurons, Nose, and Neurodegenerative diseases highlights the role of olfactory dysfunction as a clinical marker for early stages of neurodegenerative diseases when it is associated with molecular, clinical, and neuropathological correlations.
    Keywords:  anosmia; cognitive dysfunction; nasal neuroepithelium; neurodegenerative disease; neurons; nose; olfactory biomarkers
    DOI:  https://doi.org/10.3390/ijms24032117
  35. Sci Rep. 2023 Feb 10. 13(1): 2441
    Metal-induced oxidative stress and human plasma protein oxidation after SARS-CoV-2 infection.
    Baikuntha Aryal, Joseph Tillotson, Kiwon Ok, Andrew T Stoltzfus, Sarah L J Michel, V Ashutosh Rao.
      Pathogenesis of COVID-19 by SARS-CoV-2 resulted in a global pandemic and public health emergency in 2020. Viral infection can induce oxidative stress through reactive oxygen species (ROS). Inflammation and environmental stress are major sources of oxidative stress after infection. Micronutrients such as iron, copper, zinc, and manganese play various roles in human tissues and their imbalance in blood can impact immune responses against pathogens including SARS CoV-2. We hypothesized that alteration of free metal ions during infection and metal-catalyzed oxidation plays a critical role towards pathogenesis after infection. We analyzed convalescent and hospitalized COVID-19 patient plasma using orthogonal analytical techniques to determine redox active metal concentrations, overall protein oxidation, oxidative modifications, and protein levels via proteomics to understand the consequences of metal-induced oxidative stress in COVID-19 plasma proteins. Metal analysis using ICP-MS showed significantly greater concentrations of copper in COVID-19 plasma compared to healthy controls. We demonstrate significantly greater total protein carbonylation, other oxidative modifications, and deamidation of plasma proteins in COVID-19 plasma compared to healthy controls. Proteomics analysis showed that levels of redox active proteins including hemoglobulin were elevated in COVID-19 plasma. Molecular modeling concurred with potential interactions between iron binding proteins and SARS CoV-2 surface proteins. Overall, increased levels of redox active metals and protein oxidation indicate that oxidative stress-induced protein oxidation in COVID-19 may be a consequence of the interactions of SARS-CoV-2 proteins with host cell metal binding proteins resulting in altered cellular homeostasis.
    DOI:  https://doi.org/10.1038/s41598-023-29119-5
  36. Small. 2023 Feb 07. e2205634
    Congo Red-Derived Carbon Dots: Simultaneously as Fluorescence Probe for Protein Aggregates, Inhibitor for Protein Aggregation, and Scavenger of Free Radicals.
    Qin-Ying Li, Xu Yu, Xi Li, Li-Na Bao, Yu Zhang, Shi-Lin Wang, Ming Jiang, Kun Huang, Li Xu.
      The pathological aggregation of some proteins is claimed to be highly related to several human diseases, such as β-amyloid 1-42 (Aβ42 ) to Alzheimer's disease (AD), islet amyloid polypeptide, and insulin to type 2 diabetes mellitus. Therefore, it is in desperate need to develop effective methods for detection of protein aggregates and inhibition of abnormal aggregation. Herein, to construct all-in-one probe with both diagnosis and treatment potentials for protein aggregation diseases, Congo red (CR), a classical staining reagent with red fluorescence signal output for protein aggregates, is deliberately adopted to react with three different reductive carbon sources and ammonium persulfate to generate three CR-derived carbon dots (CDs). The obtained CDs exhibit the capabilities of turn-on red fluorescence imaging of protein aggregates, and/or inhibition of protein aggregation as well as scavenging of free radicals. Among them, CA-CDs, using citric acid as the reductive carbon source, demonstrate the superiority to the other two studied CDs in integrating all of these functions, and particularly exert excellent cytoprotection effect against toxic Aβ42 species, possessing tremendous potential in diagnosis and treatment of AD for future study. The present study paves a new way to develop all-in-one CDs for the protein disease research.
    Keywords:  carbon dots; fluorescence probe; free radical scavenger; inhibitor; protein aggregation
    DOI:  https://doi.org/10.1002/smll.202205634
  37. Am J Physiol Lung Cell Mol Physiol. 2023 Feb 07.
    Connecting clinical, environmental, and genetic factors point to an essential role for vitamin A signaling in the pathogenesis of congenital diaphragmatic hernia.
    Rachel M Gilbert, Jason P Gleghorn.
      Congenital diaphragmatic hernia (CDH) is a developmental disorder that results in incomplete diaphragm formation, pulmonary hypoplasia, and pulmonary hypertension. Although a variety of genes have been linked to its etiology, CDH is not a monogenetic disease, and the cause of the condition is still unclear in the vast majority of clinical cases. By comparing human clinical data and experimental rodent data from the literature, we present clear support demonstrating the importance of vitamin A (vitA) during the early window of pregnancy when the diaphragm and lung are forming. Alteration of vitA signaling via dietary and genetic perturbations can create diaphragmatic defects. Unfortunately, vitA deficiency is chronic amongst people of child-bearing age, and this early window of diaphragm development occurs before many might be aware of pregnancy. Further, there is an increased demand for vitA during this critical period, which exacerbates the likelihood of deficiency. It would be beneficial for the field to further investigate the connections between maternal vitA and CDH incidence, with the goal of determining vitA status as a CDH risk factor. Regular clinical monitoring of vitA levels in child-bearing years is a tractable method by which CDH outcomes could be prevented or improved.
    Keywords:  development; maternal fetal health; pregnancy; pulmonary hypoplasia; retinol
    DOI:  https://doi.org/10.1152/ajplung.00349.2022
  38. Int J Mol Sci. 2023 Jan 24. pii: 2309. [Epub ahead of print]24(3):
    Defining the Role of the Gut Microbiome in the Pathogenesis and Treatment of Lymphoid Malignancies.
    Shristi Upadhyay Banskota, Sydney A Skupa, Dalia El-Gamal, Christopher R D'Angelo.
      The gut microbiome is increasingly being recognized as an important immunologic environment, with direct links to the host immune system. The scale of the gut microbiome's genomic repertoire extends the capacity of its host's genome by providing additional metabolic output, and the close communication between gut microbiota and mucosal immune cells provides a continued opportunity for immune education. The relationship between the gut microbiome and the host immune system has important implications for oncologic disease, including lymphoma, a malignancy derived from within the immune system itself. In this review, we explore past and recent discoveries describing the role that bacterial populations play in lymphomagenesis, diagnosis, and therapy. We highlight key relationships within the gut microbiome-immune-oncology axis that present exciting opportunities for directed interventions intended to shape the microbiome for therapeutic effect. We conclude with a limited summary of active clinical trials targeting the microbiome in hematologic malignancies, along with future directions on gut microbiome investigations within lymphoid malignancies.
    Keywords:  gut microbiome; gut microbiome and lymphomagenesis; lymphoma; lymphoma and gut microbiome; microbial interventions in lymphoma
    DOI:  https://doi.org/10.3390/ijms24032309
  39. Rev Neurosci. 2023 Feb 10.
    Targeting the gut-microbiota-brain axis in irritable bowel disease to improve cognitive function - recent knowledge and emerging therapeutic opportunities.
    Heyong Tang, Xiaoqi Chen, Shun Huang, Gang Yin, Xiyang Wang, Guoming Shen.
      The brain-gut axis forms a bidirectional communication system between the gastrointestinal (GI) tract and cognitive brain areas. Disturbances to this system in disease states such as inflammatory bowel disease have consequences for neuronal activity and subsequent cognitive function. The gut-microbiota-brain axis refers to the communication between gut-resident bacteria and the brain. This circuits exists to detect gut microorganisms and relay information to specific areas of the central nervous system (CNS) that in turn, regulate gut physiology. Changes in both the stability and diversity of the gut microbiota have been implicated in several neuronal disorders, including depression, autism spectrum disorder Parkinson's disease, Alzheimer's disease and multiple sclerosis. Correcting this imbalance with medicinal herbs, the metabolic products of dysregulated bacteria and probiotics have shown hope for the treatment of these neuronal disorders. In this review, we focus on recent advances in our understanding of the intricate connections between the gut-microbiota and the brain. We discuss the contribution of gut microbiota to neuronal disorders and the tangible links between diseases of the GI tract with cognitive function and behaviour. In this regard, we focus on irritable bowel syndrome (IBS) given its strong links to brain function and anxiety disorders. This adds to the growing body of evidence supporting targeted therapeutic strategies to modulate the gut microbiota for the treatment of brain/mental-health-related disease.
    Keywords:  brain gut-axis; cognition; gastrointestinal tract; inflammatory bowel disease; microbiota; neurodegeneration
    DOI:  https://doi.org/10.1515/revneuro-2022-0155
  40. Molecules. 2023 Jan 29. pii: 1294. [Epub ahead of print]28(3):
    A Review of Fibraurea tinctoria and Its Component, Berberine, as an Antidiabetic and Antioxidant.
    Indah Purwaningsih, Iman Permana Maksum, Dadan Sumiarsa, Sriwidodo Sriwidodo.
      Diabetes mellitus is a group of metabolic disorders characterized by hyperglycemia caused by resistance to insulin action, inadequate insulin secretion, or excessive glucagon production. Numerous studies have linked diabetes mellitus and oxidative stress. People with diabetes usually exhibit high oxidative stress due to persistent and chronic hyperglycemia, which impairs the activity of the antioxidant defense system and promotes the formation of free radicals. Recently, several studies have focused on exploring natural antioxidants to improve diabetes mellitus. Fibraurea tinctoria has long been known as the native Borneo used in traditional medicine to treat diabetes. Taxonomically, this plant is part of the Menispermaceae family, widely known for producing various alkaloids. Among them are protoberberine alkaloids such as berberine. Berberine is an isoquinoline alkaloid with many pharmacological activities. Berberine is receiving considerable interest because of its antidiabetic and antioxidant activities, which are based on many biochemical pathways. Therefore, this review explores the pharmacological effects of Fibraurea tinctoria and its active constituent, berberine, against oxidative stress and diabetes, emphasizing its mechanistic aspects. This review also summarizes the pharmacokinetics and toxicity of berberine and in silico studies of berberine in several diseases and its protein targets.
    Keywords:  Fibraurea tinctoria; antidiabetes; antioxidant; berberine; in silico
    DOI:  https://doi.org/10.3390/molecules28031294
  41. Nutrients. 2023 Feb 03. pii: 790. [Epub ahead of print]15(3):
    Lactobacillus gasseri NK109 and Its Supplement Alleviate Cognitive Impairment in Mice by Modulating NF-κB Activation, BDNF Expression, and Gut Microbiota Composition.
    Soo-Won Yun, Hee-Seo Park, Yoon-Jung Shin, Xiaoyang Ma, Myung Joo Han, Dong-Hyun Kim.
      Aging-related gut microbiota dysbiosis initiates gut inflammation and microbiota dysbiosis, which induce the occurrence of psychiatric disorders including dementia. The alleviation of gut microbiota dysbiosis by probiotics is suggested to be able to alleviate psychiatric disorders including cognitive impairment (CI). Therefore, to understand how probiotics could alleviate CI, we examined the effects of anti-inflammatory Lactobacillus gasseri NK109 and its supplement (NS, mixture of NK109 and soybean embryo ethanol extract) on cognitive function in aged (Ag), 5XFAD transgenic (Tg), or mildly cognition-impaired adult fecal microbiota (MCF)-transplanted mice. Oral administration of NK109 or NS decreased CI-like behaviors in Ag mice. Their treatments suppressed TNF-α and p16 expression and NF-κB-activated cell populations in the hippocampus and colon, while BDNF expression was induced. Moreover, they partially shifted the β-diversity of gut microbiota in Ag mice to those of young mice: they decreased Bifidobacteriaceae, Lactobacillaceae, and Helicobacteriaceae populations and increased Rikenellaceae and Prevotellaceae populations. Oral administration of NK109 or NS also reduced CI-like behaviors in Tg mice. Their treatments induced BDNF expression in the hippocampus, decreased hippocampal TNF-α and Aβ expression and hippocampal and colonic NF-κB-activated cell populations. NK109 and NS partially shifted the β-diversity of gut microbiota in Tg mice: they decreased Muribaculaceae and Rhodospiraceae populations and increased Helicobacteriaceae population. Oral administration of NK109 or NS decreased MCF transplantation-induced CI-like behaviors in mice. NK109 and NS increased hippocampal BDNF expression, while hippocampal and colonic TNF-α expression and NF-κB-activated cell populations decreased. These findings suggest that dementia can fluctuate the gut microbiota composition and NK109 and its supplement NS can alleviate CI with systemic inflammation by inducing BDNF expression and suppressing NF-κB activation and gut microbiota dysbiosis.
    Keywords:  Lactobacillus gasseri; aging; dementia; fecal microbiota transplantation; gut inflammation; gut microbiota dysbiosis
    DOI:  https://doi.org/10.3390/nu15030790
  42. Nutrients. 2023 Feb 03. pii: 795. [Epub ahead of print]15(3):
    The Role of the Stress Response in Metabolic Dysfunction-Associated Fatty Liver Disease: A Psychoneuroendocrineimmunology-Based Perspective.
    Ilaria Demori, Elena Grasselli.
      The novel term metabolic dysfunction-associated fatty liver disease (MAFLD), which has been proposed to describe the major cause of hepatic disease, pinpoints the coexistence of multiple metabolic disturbances and liver steatosis, giving rise to different phenotypic manifestations. Within the psychoneuroendocrineimmunological (PNEI) network that regulates body-mind interactions, the stress response plays a pervasive role by affecting metabolic, hormonal, immune, and behavioral balance. In this perspective, we focus on chronic psychosocial stress and high levels of cortisol to highlight their role in MAFLD pathogenesis and worsening. From a PNEI perspective, considering the stress response as a therapeutic target in MAFLD allows for simultaneously influencing multiple pathways in the development of MAFLD, including dysmetabolism, inflammation, feeding behaviors, gut-liver axis, and dysbiosis, with the hope of better outcomes.
    Keywords:  MAFLD; cortisol; eating behaviors; gut microbiota; gut–liver axis; inflammation; insulin resistance; liver steatosis; psychoneuroendocrineimmunology; stress response
    DOI:  https://doi.org/10.3390/nu15030795
  43. Int J Mol Sci. 2023 Jan 30. pii: 2590. [Epub ahead of print]24(3):
    Beta-Amyloid Peptide in Tears: An Early Diagnostic Marker of Alzheimer's Disease Correlated with Choroidal Thickness.
    Magda Gharbiya, Giacomo Visioli, Alessandro Trebbastoni, Giuseppe Maria Albanese, Mayra Colardo, Fabrizia D'Antonio, Marco Segatto, Alessandro Lambiase.
      We aimed to evaluate the diagnostic role of Alzheimer's disease (AD) biomarkers in tears as well as their association with retinal and choroidal microstructures. In a cross-sectional study, 35 subjects (age 71.7 ± 6.9 years) were included: 11 with prodromal AD (MCI), 10 with mild-to-moderate AD, and 14 healthy controls. The diagnosis of AD and MCI was confirmed according to a complete neuropsychological evaluation and PET or MRI imaging. After tear sample collection, β-amyloid peptide Aβ1-42 concentration was analyzed using ELISA, whereas C-terminal fragments of the amyloid precursor protein (APP-CTF) and phosphorylated tau (p-tau) were assessed by Western blot. Retinal layers and choroidal thickness (CT) were acquired by spectral-domain optical coherence tomography (SD-OCT). Aβ1-42 levels in tears were able to detect both MCI and AD patients with a specificity of 93% and a sensitivity of 81% (AUC = 0.91). Tear levels of Aβ1-42 were lower, both in the MCI (p < 0.01) and in the AD group (p < 0.001) when compared to healthy controls. Further, Aβ1-42 was correlated with psychometric scores (p < 0.001) and CT (p < 0.01). CT was thinner in the affected patients (p = 0.035). No differences were observed for APP-CTF and p-tau relative abundance in tears. Testing Aβ1-42 levels in tears seems to be a minimally invasive, cost-saving method for early detection and diagnosis of AD.
    Keywords:  APP; Alzheimer’s disease; beta-amyloid; biomarkers; choroidal thickness; p-tau; tears
    DOI:  https://doi.org/10.3390/ijms24032590
  44. PLoS Biol. 2023 Feb;21(2): e3001954
    Why does understanding the biology of fibroblasts in immunity really matter?
    Zhi Yi Wong, Eloise Nee, Mark Coles, Christopher D Buckley.
      Fibroblasts are known for their ability to make and modify the extracellular matrix. However, there is more to them than meets the eye. It is now clear that they help define tissue microenvironments and support immune responses in organs. As technology advances, we have started to uncover the secrets of fibroblasts. In this Essay, we present fibroblasts as not only the builders and renovators of tissue environments but also the rheostat cells for immune circuits. Although they perform location-specific functions, they do not have badges of fixed identity. Instead, they display a spectrum of functional states and can swing between these states depending on the needs of the organ. As fibroblasts participate in a range of activities both in health and disease, finding the key factors that alter their development and functional states will be an important goal to restore homeostasis in maladapted tissues.
    DOI:  https://doi.org/10.1371/journal.pbio.3001954
  45. Front Pharmacol. 2023 ;14 1130562
    Understanding the role of the gut microbiome in gastrointestinal cancer: A review.
    Duygu Ağagündüz, Ermelinda Cocozza, Özge Cemali, Ayşe Derya Bayazıt, Maria Francesca Nanì, Ida Cerqua, Floriana Morgillo, Suna Karadeniz Saygılı, Roberto Berni Canani, Paola Amero, Raffaele Capasso.
      Gastrointestinal cancer represents one of the most diagnosed types of cancer. Cancer is a genetic and multifactorial disease, influenced by the host and environmental factors. It has been stated that 20% of cancer is caused by microorganisms such as Helicobacter pylori, hepatitis B and C virus, and human papillomavirus. In addition to these well-known microorganisms associated with cancer, it has been shown differences in the composition of the microbiota between healthy individuals and cancer patients. Some studies have suggested the existence of the selected microorganisms and their metabolites that can promote or inhibit tumorigenesis via some mechanisms. Recent findings have shown that gut microbiome and their metabolites can act as cancer promotors or inhibitors. It has been shown that gastrointestinal cancer can be caused by a dysregulation of the expression of non-coding RNA (ncRNA) through the gut microbiome. This review will summarize the latest reports regarding the relationship among gut microbiome, ncRNAs, and gastrointestinal cancer. The potential applications of diagnosing and cancer treatments will be discussed.
    Keywords:  diagnosis; gastrointestinal cancer; microbiome; non-coding RNAs; therapeutics
    DOI:  https://doi.org/10.3389/fphar.2023.1130562
  46. Int J Mol Sci. 2023 Feb 02. pii: 2944. [Epub ahead of print]24(3):
    Lipoprotein Metabolism, Protein Aggregation, and Alzheimer's Disease: A Literature Review.
    Elena Grao-Cruces, Carmen M Claro-Cala, Sergio Montserrat-de la Paz, Clevio Nobrega.
      Alzheimer's disease (AD) is the most common form of dementia. The physiopathology of AD is well described by the presence of two neuropathological features: amyloid plaques and tau neurofibrillary tangles. In the last decade, neuroinflammation and cellular stress have gained importance as key factors in the development and pathology of AD. Chronic cellular stress occurs in degenerating neurons. Stress Granules (SGs) are nonmembranous organelles formed as a response to stress, with a protective role; however, SGs have been noted to turn into pathological and neurotoxic features when stress is chronic, and they are related to an increased tau aggregation. On the other hand, correct lipid metabolism is essential to good function of the brain; apolipoproteins are highly associated with risk of AD, and impaired cholesterol efflux and lipid transport are associated with an increased risk of AD. In this review, we provide an insight into the relationship between cellular stress, SGs, protein aggregation, and lipid metabolism in AD.
    Keywords:  amyloid; apolipoprotein; lipid metabolism; lipoprotein; stress granules; tau
    DOI:  https://doi.org/10.3390/ijms24032944
  47. Molecules. 2023 Jan 19. pii: 998. [Epub ahead of print]28(3):
    Chemistry of CS2 and CS3 Bridged Decaborane Analogues: Regular Coordination Versus Cluster Expansion.
    Ketaki Kar, Suvam Saha, Rahul Maganbhai Parmar, Arindam Roy, Marie Cordier, Thierry Roisnel, Sundargopal Ghosh.
      In an effort to synthesize metallaheteroborane clusters of higher nuclearity, the reactivity of metallaheteroboranes, nido-[(Cp*M)2B6S2H4(CS3)] (Cp* = C5Me5) (1: M = Co; 2: M = Rh) with various metal carbonyls have been investigated. Photolysis of nido-1 and nido-2 with group 6 metal carbonyls, M'(CO)5.THF (M' = Mo or W) were performed that led to the formation of a series of adducts [(Cp*M)2B6S2H4(CS3){M'(CO)5}] (3: M = Co, M' = Mo; 4: M = Co, M' = W; 5: M = Rh, M' = Mo; 6: M = Rh, M' = W) instead of cluster expansion reactions. In these adducts, the S atom of C=S group of di(thioboralane)thione {B2CS3} moiety is coordinated to M'(CO)5 (M = Mo or W) in η1-fashion. On the other hand, thermolysis of nido-1 with Ru3(CO)12 yielded one fused metallaheteroborane cluster [{Ru(CO)3}3S{Ru(CO)}{Ru(CO)2}Co2B6SH4(CH2S2){Ru(CO)3}2S], 7. This 20-vertex-fused cluster is composed of two tetrahedral {Ru3S} and {Ru2B2}, a flat butterfly {Ru3S} and one octadecahedron {Co2RuB7S} core with one missing vertex, coordinated to {Ru2SCH2S2} through two boron and one ruthenium atom. On the other hand, the room temperature reaction of nido-2 with Co2(CO)8 produced one 19-vertex fused metallaheteroborane cluster [(Cp*Rh)2B6H4S4{Co(CO)}2{Co(CO)2}2(μ-CO)S{Co(CO)3}2], 8. Cluster 8 contains one nido-decaborane {Rh2B6S2}, one butterfly {Co2S2} and one bicapped square pyramidal {Co6S} unit that exhibits an intercluster fusion with two sulfur atoms in common. Clusters 3-6 have been characterized by multinuclear NMR and IR spectroscopy, mass spectrometry and structurally determined by XRD analyses. Furthermore, the DFT calculations have been carried out to gain insight into electronic, structural and bonding patterns of the synthesized clusters.
    Keywords:  cluster; coordination; expansion; fusion; metallaheteroborane
    DOI:  https://doi.org/10.3390/molecules28030998
  48. Int J Mol Sci. 2023 Feb 03. pii: 3051. [Epub ahead of print]24(3):
    Circulating Microbial Cell-Free DNA in Health and Disease.
    Bernadeta Pietrzak, Iwona Kawacka, Agnieszka Olejnik-Schmidt, Marcin Schmidt.
      Human blood contains low biomass of circulating microbial cell-free DNA (cfmDNA) that predominantly originates from bacteria. Numerous studies have detected circulating cfmDNA in patients with infectious and non-infectious diseases, and in healthy individuals. Remarkable differences were found in the microbial composition of healthy subjects and patients compared to cohorts with various diseases or even patients with diversified prognoses, implying that these alterations may be associated with disease development. Although the function of circulating cfmDNA needs to be elucidated (whether it acts as a bystander of dysbiosis or a key player in disease development), several studies have demonstrated its potential as a non-invasive biomarker that may improve diagnosis and treatment efficacy. The origin of circulating cfmDNA is still the subject of much deliberation, but studies have identified members of various microbiome niches, including the gut, oral cavity, airways, and skin. Further studies investigating the origin and function of circulating cfmDNA are needed. Moreover, low-biomass microbiome studies are prone to contamination, therefore stringent negative experimental control reactions and decontamination frameworks are advised in order to detect genuine circulating cfmDNA.
    Keywords:  circulating microbial cell-free DNA; microbial translocation; non-invasive biomarker
    DOI:  https://doi.org/10.3390/ijms24033051
  49. Int J Mol Sci. 2023 Jan 25. pii: 2381. [Epub ahead of print]24(3):
    Melatonin Can Modulate Neurodegenerative Diseases by Regulating Endoplasmic Reticulum Stress.
    Yeong-Min Yoo, Seong Soo Joo.
      As people age, their risks of developing degenerative diseases such as cancer, diabetes, Parkinson's Disease (PD), Alzheimer's Disease (AD), rheumatoid arthritis, and osteoporosis are generally increasing. Millions of people worldwide suffer from these diseases as they age. In most countries, neurodegenerative diseases are generally recognized as the number one cause afflicting the elderly. Endoplasmic reticulum (ER) stress has been suggested to be associated with some human neurological diseases, such as PD and AD. Melatonin, a neuroendocrine hormone mainly synthesized in the pineal gland, is involved in pleiotropically biological functions, including the control of the circadian rhythm, immune enhancement, and antioxidant, anti-aging, and anti-tumor effects. Although there are many papers on the prevention or suppression of diseases by melatonin, there are very few papers about the effects of melatonin on ER stress in neurons and neurodegenerative diseases. This paper aims to summarize and present the effects of melatonin reported so far, focusing on its effects on neurons and neurodegenerative diseases related to ER stress. Studies have shown that the primary target molecule of ER stress for melatonin is CHOP, and PERK and GRP78/BiP are the secondary target molecules. Therefore, melatonin is crucial in protecting neurons and treating neurodegeneration against ER stress.
    Keywords:  endoplasmic reticulum stress; melatonin; neurodegenerative diseases; neurons
    DOI:  https://doi.org/10.3390/ijms24032381
  50. Int J Mol Sci. 2023 Jan 17. pii: 1846. [Epub ahead of print]24(3):
    Genetic Background and Molecular Mechanisms of Juvenile Idiopathic Arthritis.
    Saverio La Bella, Marta Rinaldi, Armando Di Ludovico, Giulia Di Donato, Giulio Di Donato, Vincenzo Salpietro, Francesco Chiarelli, Luciana Breda.
      Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in the paediatric population. JIA comprises a heterogeneous group of disorders with different onset patterns and clinical presentations with the only element in common being chronic joint inflammation. This review sought to evaluate the most relevant and up-to-date evidence on current knowledge regarding the pathogenesis of JIA subtypes to provide a better understanding of these disorders. Despite significant improvements over the past decade, the aetiology and molecular mechanisms of JIA remain unclear. It has been suggested that the immunopathogenesis is characterised by complex interactions between genetic background and environmental factors that may differ between JIA subtypes. Human leukocyte antigen (HLA) haplotypes and non-HLA genes play a crucial role in the abnormal activation of both innate and adaptive immune cells that cooperate in causing the inflammatory process. This results in the involvement of proinflammatory cytokines, including tumour necrosis factor (TNF)α, interleukin (IL)-1, IL-6, IL-10, IL-17, IL-21, IL-23, and others. These mediators, interacting with the surrounding tissue, cause cartilage stress and bone damage, including irreversible erosions. The purpose of this review is to provide a comprehensive overview of the genetic background and molecular mechanisms of JIA.
    Keywords:  JIA; juvenile idiopathic arthritis; molecular mechanisms; paediatric rheumatology
    DOI:  https://doi.org/10.3390/ijms24031846
  51. J Neurosci. 2023 Feb 08. pii: JN-RM-1259-22. [Epub ahead of print]
    Neuronal SIRT3 deletion predisposes to female-specific alterations in cellular metabolism, memory, and network excitability.
    Jennifer N Pearson-Smith, Ruth Fulton, Christopher Q Huynh, Anna G Figueroa, Gia B Huynh, Li-Ping Liang, Lindsey B Gano, Cole R Michel, Nichole Reisdorph, Richard Reisdorph, Kristofer S Fritz, Eric Verdin, Manisha Patel.
      Mitochondrial dysfunction is an early event in the pathogenesis of neurological disorders and aging. Sirtuin 3 (SIRT3) regulates mitochondrial function in response to the cellular environment through the reversible deacetylation of proteins involved in metabolism and reactive oxygen species detoxification. As the primary mitochondrial deacetylase, germline, or peripheral tissue-specific deletion of SIRT3 produces mitochondrial hyperacetylation and the accelerated development of age-related diseases. Given the unique metabolic demands of neurons, the role of SIRT3 in the brain is only beginning to emerge. Using mass-spectrometry based acetylomics, high-resolution respirometry, video-EEG, and cognition testing, we report targeted deletion of SIRT3 from select neurons in the cortex and hippocampus produces altered neuronal excitability and metabolic dysfunction in female mice. Targeted deletion of SIRT3 from neuronal helix-loop-helix 1 (NEX)-expressing neurons resulted in mitochondrial hyperacetylation, female-specific superoxide dismutase-2 (SOD2) modification, increased steady-state superoxide levels, metabolic reprogramming, altered neuronal excitability and working spatial memory deficits. Inducible neuronal deletion of SIRT3 likewise produced female-specific deficits in spatial working memory. Together, the data demonstrate that deletion of SIRT3 from forebrain neurons selectively predisposes female mice to deficits in mitochondrial and cognitive function.SIGNIFICANCE STATEMENT:Mitochondrial SIRT3 is an enzyme shown to regulate energy metabolism and antioxidant function, by direct deacetylation of proteins. In this study, we show that neuronal SIRT3 deficiency renders female mice selectively vulnerable to impairment in redox and metabolic function, spatial memory, and neuronal excitability. The observed sex-specific effects on cognition and neuronal excitability in female SIRT3 deficient mice suggest that mitochondrial dysfunction may be one factor underlying comorbid neuronal diseases such as Alzheimer's disease and epilepsy. Furthermore, the data suggest that SIRT3 dysfunction may predispose females to age-related metabolic and cognitive impairment.
    DOI:  https://doi.org/10.1523/JNEUROSCI.1259-22.2023
  52. Cells. 2023 Jan 19. pii: 370. [Epub ahead of print]12(3):
    Any Role for Microbiota in Cholangiocarcinoma? A Comprehensive Review.
    Alessandra Elvevi, Alice Laffusa, Camilla Gallo, Pietro Invernizzi, Sara Massironi.
      Alterations in the human microbiota have been linked to carcinogenesis in several cancers. To date, few studies have addressed the role of the microbiota in cholangiocarcinoma (CCA). Our work aims to update the knowledge about the role of the microbiota in the CCA microenvironment, and to highlight possible novel insights for the development of new diagnostic, prognostic, or even therapeutic strategies. We thus conducted a review of the literature. In recent years, great progress has been made in understanding the pathogenesis, the clinical and histological behavior, and the molecular profile of CCA. Much evidence suggests that the bile microbiota plays an essential role in biliary diseases, including CCA. Some studies have demonstrated that alterations in the qualitative and quantitative composition of the intestinal commensal bacteria lead to overall cancer susceptibility through various pathways. Other studies suggest that the gut microbiota plays a role in the pathogenesis and/or progression of CCA. The clinical implications are far-reaching, and the role of the microbiota in the CCA microenvironment may lead to considering the exciting implications of implementing therapeutic strategies that target the microbiota-immune system axis.
    Keywords:  biliary tract cancer; cholangiocarcinoma; gut-liver axis; microbiota
    DOI:  https://doi.org/10.3390/cells12030370
  53. Nutrients. 2023 Jan 24. pii: 607. [Epub ahead of print]15(3):
    Inflammatory Response: A Crucial Way for Gut Microbes to Regulate Cardiovascular Diseases.
    Wen Wang, Luo-Jiang Zhu, Yue-Qi Leng, Yu-Wan Wang, Te Shi, Wei-Zhong Wang, Jia-Cen Sun.
      Gut microbiota is the largest and most complex microflora in the human body, which plays a crucial role in human health and disease. Over the past 20 years, the bidirectional communication between gut microbiota and extra-intestinal organs has been extensively studied. A better comprehension of the alternative mechanisms for physiological and pathophysiological processes could pave the way for health. Cardiovascular disease (CVD) is one of the most common diseases that seriously threatens human health. Although previous studies have shown that cardiovascular diseases, such as heart failure, hypertension, and coronary atherosclerosis, are closely related to gut microbiota, limited understanding of the complex pathogenesis leads to poor effectiveness of clinical treatment. Dysregulation of inflammation always accounts for the damaged gastrointestinal function and deranged interaction with the cardiovascular system. This review focuses on the characteristics of gut microbiota in CVD and the significance of inflammation regulation during the whole process. In addition, strategies to prevent and treat CVD through proper regulation of gut microbiota and its metabolites are also discussed.
    Keywords:  cardiovascular disease; gut microbiota; inflammatory response; metabolite; prebiotics and probiotics
    DOI:  https://doi.org/10.3390/nu15030607
  54. Int J Biol Macromol. 2023 Feb 03. pii: S0141-8130(23)00427-0. [Epub ahead of print] 123534
    Metal manipulators and regulators in human pathogens: A comprehensive review on microbial redox copper metalloenzymes "multicopper oxidases and superoxide dismutases".
    Krishna Kant Sharma, Deepti Singh, Shreya Vishwas Mohite, Peter R Williamson, John F Kennedy.
      The chemistry of metal ions with human pathogens is essential for their survival, energy generation, redox signaling, and niche dominance. To regulate and manipulate the metal ions, various enzymes and metal chelators are present in pathogenic bacteria. Metalloenzymes incorporate transition metal such as iron, zinc, cobalt, and copper in their reaction centers to perform essential metabolic functions; however, iron and copper have gained more importance. Multicopper oxidases have the ability to perform redox reaction on phenolic substrates with the help of copper ions. They have been reported from Enterobacteriaceae, namely Salmonella enterica, Escherichia coli, and Yersinia enterocolitica, but their role in virulence is still poorly understood. Similarly, superoxide dismutases participate in reducing oxidative stress and allow the survival of pathogens. Their role in virulence and survival is well established in Salmonella typhimurium and Mycobacterium tuberculosis. Further, to ensure survival against stress, like metal starvation or metal toxicity, redox metalloenzymes and metal transportation systems of pathogens actively participates in metal homeostasis. Recently, the omics studies have helped to suggest new targets for regulating the colonization potential of the pathogenic strains. The current review is focused on the major roles of redox metalloenzymes, especially MCOs and SODs of human pathogenic bacteria.
    Keywords:  Gut microbiota; Laccase; Metalloenzymes; Multicopper oxidase; Redox reaction; Superoxide dismutase
    DOI:  https://doi.org/10.1016/j.ijbiomac.2023.123534
  55. Environ Sci Pollut Res Int. 2023 Feb 10.
    Global ambient particulate matter pollution and neurodegenerative disorders: a systematic review of literature and meta-analysis.
    Yuting Gong, Xiaoan Zhang, Xin Zhao, Hui Chang, Junxi Zhang, Zhan Gao, Yang Mi, Yao Chen, Huanhuan Zhang, Cunrui Huang, Zengli Yu.
      Previous studies on particulate matter (PM) exposure and neurodegenerative disorders showed inconsistent results, and few studies systematically examined the long-term effect of PM on neurodegenerative diseases, including all-cause dementia, Alzheimer's disease, Parkinson's disease, vascular dementia, amyotrophic lateral sclerosis, and cognitive function decline. We systematically searched for published studies in PubMed, Embase, Cochrane Library, and Web of Science up to October 31, 2022. To facilitate a comparison of effect sizes from different studies, we standardized units across studies to a 10 μg/m3 increase for PM. Heterogeneity was assessed by Cochran's Q test and I2 statistic. Publication bias was evaluated using funnel plots and Egger's tests. Subgroup analysis, meta-regression, and sensitivity analysis were performed. The protocol for this review was registered with PROSPERO (CRD42021277112). Of the 3403 originally identified studies, a meta-analysis was finally performed in 49 studies. The results showed that there was a significant positive association between long-term PM2.5 exposure and all-cause dementia, Alzheimer's disease as well as Parkinson's disease, with pooled OR of 1.30 (95%CI: 1.14, 1.47, I2 = 99.3%), 1.65 (95%CI: 1.37, 1.94, I2 = 98.2%), and 1.17 (95%CI: 1.00, 1.33, I2 = 91.8%). A positive association between PM10 and vascular dementia was observed (OR = 1.12, 95%CI: 1.04, 1.21, I2 = 0.0%). Association between PM exposure and decreased cognitive function score was found. Our results highlight the important role of PM pollution, particularly PM2.5, in the risk of age-related neurodegenerative diseases and cognitive function decline.
    Keywords:  Cognitive function; Meta-analysis; Neurodegenerative disease; Particulate matter
    DOI:  https://doi.org/10.1007/s11356-023-25731-0
  56. Curr Neuropharmacol. 2023 Feb 03.
    Emerging Roles of Microglia in Blood-brain Barrier Integrity in Aging and Neurodegeneration.
    Simeng Zhang, Rui Meng, Muzhou Jiang, Hong Qing, Junjun Ni.
      The blood-brain barrier (BBB) is a highly selective interface between the blood and the brain parenchyma. It plays an essential role in maintaining a specialized environment for central nervous system function and homeostasis. The BBB disrupts with age, which contributes to the development of many age-related disorders due to central and peripheral toxic factors or BBB dysfunction. Microglia, the resident innate immune cells of the brain, have recently been explored for their ability to directly and indirectly regulate the integrity of the BBB. This review will focus on the current understanding of the molecular mechanisms utilized by microglia to regulate BBB integrity and how this becomes disrupted in aging and age-associated diseases. We will also discuss the rational to consider microglia as a therapeutic target to prevent or slow down the neurodegeneration.
    Keywords:  Aging; Blood-brain barrier; Microglia; Neurodegeneration; Neuroinflammation; Neurovascular unit
    DOI:  https://doi.org/10.2174/1570159X21666230203103910
  57. J Pept Sci. 2023 Feb 05. e3482
    Development of membrane-active peptide therapeutics in oncology.
    Charles H Chen, Bing Zan, Jakob P Ulmschneider, William C Wimley, Timothy K Lu, Martin B Ulmschneider, Liping Zhou.
      Membrane-active peptides play an essential role in many living organisms and their immune systems and counter many infectious diseases. Many have dual or multiple mechanisms and can synergize with other molecules, like peptides, proteins, and small molecules. Although membrane-active peptides have been intensively studied in the past decades and more than 3500 sequences have been identified, only a few received approvals from the US Food and Drug Administration. In this review, we investigated all the peptide therapeutics that have entered the market or were subjected to preclinical and clinical studies to understand how they succeeded. With technological advancement (e.g., chemical modifications and pharmaceutical formulations) and a better understanding of the mechanism of action and the potential targets, we found at least five membrane-active peptide drugs that have entered preclinical/clinical phases and show promising results for cancer treatment. We summarized our findings in this review and provided insights into membrane-active anticancer peptide therapeutics.
    Keywords:  membrane-active drug; oncology; oncolytic peptide; peptide therapeutics
    DOI:  https://doi.org/10.1002/psc.3482
  58. Anim Microbiome. 2023 Feb 04. 5(1): 8
    Gut microbiome diversity and composition is associated with exploratory behavior in a wild-caught songbird.
    Melanie R Florkowski, Jessica L Yorzinski.
       BACKGROUND: The gut microbiome influences its host in a myriad of ways, from immune system development to nutrient utilization. However, our understanding of the relationship between the gut microbiome and behavior, especially in wild species, is still poor. One behavior that potentially interacts with the gut microbiome is exploratory behavior, which animals use to acquire new information from the environment. We hypothesized that diversity of the gut microbiome will be correlated with exploratory behavior in a wild-caught bird species. To test this hypothesis, we captured wild house sparrows (Passer domesticus) and collected fecal samples to measure the diversity of their gut microbiomes. We then introduced individuals to a novel environment and measured their exploratory behavior.
    RESULTS: We found that birds with higher alpha diversity of the gut microbiome exhibited higher exploratory behavior. These results suggest that high exploratory birds encounter more types of environmental microbes that contribute to their diverse gut microbiome compared with less exploratory birds. Alternatively, increased gut microbiome diversity may contribute to increased exploratory behavior. We also found differences in beta diversity when comparing high and low exploring birds, indicating differences in microbiome community structure. When comparing predicted functional pathways of the birds' microbiomes, we found that the microbiomes of high explorers contained more pathways involved in biofilm formation and xenobiotic degradation than those of low explorers.
    CONCLUSIONS: Overall, we found that the alpha and beta diversity of the gut microbiome is correlated with exploratory behavior of house sparrows. The predicted functions of the gut microbiome from high explorers differs from that of low explorers. Our study highlights the importance of considering the gut microbiome when investigating animal behavior.
    Keywords:  16S rRNA gene; Biofilm formation; Exploratory behavior; Gut microbiome; House sparrow; Passer domesticus; Xenobiotic degradation
    DOI:  https://doi.org/10.1186/s42523-023-00227-x
  59. Annu Rev Physiol. 2023 Feb 10. 85 293-316
    Molecular Physiology of TRPV Channels: Controversies and Future Challenges.
    Tamara Rosenbaum, León D Islas.
      The ability to detect stimuli from the environment plays a pivotal role in our survival. The molecules that allow the detection of such signals include ion channels, which are proteins expressed in different cells and organs. Among these ion channels, the transient receptor potential (TRP) family responds to the presence of diverse chemicals, temperature, and osmotic changes, among others. This family of ion channels includes the TRPV or vanilloid subfamily whose members serve several physiological functions. Although these proteins have been studied intensively for the last two decades, owing to their structural and functional complexities, a number of controversies regarding their function still remain. Here, we discuss some salient features of their regulation in light of these controversies and outline some of the efforts pushing the field forward.
    Keywords:  TRP channels; function; ion channels; pain; physiology; structure
    DOI:  https://doi.org/10.1146/annurev-physiol-030222-012349
  60. Annu Rev Biophys. 2022 Feb 07.
    Protein Diffusion Along Protein and DNA Lattices: Role of Electrostatics and Disordered Regions.
    Lavi S Bigman, Yaakov Levy.
      Diffusion is a pervasive process present in a broad spectrum of cellular reactions. Its mathematical description has existed for nearly two centuries and permits the construction of simple rules for evaluating the characteristic timescales of diffusive processes and some of their determinants. Although the term diffusion originally referred to random motions in three-dimensional (3D) media, several biological diffusion processes in lower dimensions have been reported. One-dimensional (1D) diffusions have been reported, for example, for translocations of various proteins along DNA or protein (e.g., microtubule) lattices and translation of helical peptides along the coil-coiled interface. Two-dimensional (2D) diffusion has been shown for dynamics of proteins along membranes. The microscopic mechanisms of these 1-3D diffusions may vary significantly depending on the nature of the diffusing molecules, the substrate, and the interactions between them. In this review, we highlight some key examples of 1-3D biomolecular diffusion processes and illustrate the roles that electrostatic interactions and intrinsic disorder may play in modulating these processes. Expected final online publication date for the Annual Review of Biophysics, Volume 52 is May 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-biophys-111622-091220
  61. Nutrients. 2023 Feb 02. pii: 760. [Epub ahead of print]15(3):
    Selected Aspects of the Intricate Background of Immune-Related Cholangiopathies-A Critical Overview.
    Beata Kasztelan-Szczerbinska, Anna Rycyk-Bojarzynska, Agnieszka Szczerbinska, Halina Cichoz-Lach.
      Primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) are rare immune-related cholangiopathies with still poorly explained pathogenesis. Although triggers of chronic inflammation with subsequent fibrosis that affect cholangiocytes leading to obliteration of bile ducts and conversion to liver cirrhosis are unclear, both disorders are regarded to be multifactorial. Different factors can contribute to the development of hepatocellular injury in the course of progressive cholestasis, including (1) body accumulation of bile acids and their toxicity, (2) decreased food intake and nutrient absorption, (3) gut microbiota transformation, and (4) reorganized host metabolism. Growing evidence suggests that intestinal microbiome composition not only can be altered by liver dysfunction, but in turn, it actively impacts hepatic conditions. In this review, we highlight the role of key factors such as the gut-liver axis, intestinal barrier integrity, bile acid synthesis and circulation, and microbiome composition, which seem to be strongly related to PBC and PSC outcome. Emerging treatments and future therapeutic strategies are also presented.
    Keywords:  agonist of farnesoid X receptor (FXR); bile acids (BAs); gut microbiome (GM); obeticholic acid (OCA); primary biliary cholangitis (PBC); primary sclerosing cholangitis (PSC); ursodeoxycholic acid (UDCA)
    DOI:  https://doi.org/10.3390/nu15030760
  62. Mitochondrion. 2023 Feb 04. pii: S1567-7249(23)00009-0. [Epub ahead of print]69 57-63
    The role of mitochondrial energy metabolism in neuroprotection and axonal regeneration after spinal cord injury.
    Li Cheng, Bin Cai, Dezhi Lu, Hong Zeng.
      Mitochondrial dysfunction occurs in the early stage of axonal degeneration after spinal cord injury and involves oxidative stress, energy deficiency, imbalance of mitochondrial dynamics, etc., which play a key role in axonal degeneration and regeneration under physiological and pathological conditions. Failure of axonal regeneration can lead to long-term structural and functional damage. Several recent studies have shown that improved mitochondrial energy metabolism provides conditions for axonal regeneration and central nervous system repair. Here, we describe the role of mitochondrial energy metabolism in neuroprotection and axonal regeneration after spinal cord injury and review recent advances in targeted mitochondrial therapy.
    Keywords:  Axon regeneration; Energy metabolism; Mitochondria; Mitochondrial dysfunction; Spinal cord injury
    DOI:  https://doi.org/10.1016/j.mito.2023.01.009
  63. Front Neurosci. 2023 ;17 1034158
    Editorial: Beta-Amyloid oligomer specific treatments for Alzheimer's disease.
    Heinz Hillen.
      
    Keywords:  Alzheimer's disease; beta amyloid (Aβ); homeostasis; oligomer; therapy
    DOI:  https://doi.org/10.3389/fnins.2023.1034158
  64. Molecules. 2023 Jan 20. pii: 1047. [Epub ahead of print]28(3):
    Natural Bioactive Compounds Targeting NADPH Oxidase Pathway in Cardiovascular Diseases.
    Siti Sarah M Sofiullah, Dharmani Devi Murugan, Suhaila Abd Muid, Wu Yuan Seng, Sharifah Zamiah Syed Abdul Kadir, Razif Abas, Nurul Raudzah Adib Ridzuan, Nor Hisam Zamakshshari, Choy Ker Woon.
      Cardiovascular disease (CVD) is the leading cause of death worldwide, in both developed and developing countries. According to the WHO report, the morbidity and mortality caused by CVD will continue to rise with the estimation of death going up to 22.2 million in 2030. NADPH oxidase (NOX)-derived reactive oxygen species (ROS) production induces endothelial nitric oxide synthase (eNOS) uncoupling and mitochondrial dysfunction, resulting in sustained oxidative stress and the development of cardiovascular diseases. Seven distinct members of the family have been identified of which four (namely, NOX1, 2, 4 and 5) may have cardiovascular functions. Currently, the treatment and management plan for patients with CVDs mainly depends on the drugs. However, prolonged use of prescribed drugs may cause adverse drug reactions. Therefore, it is crucial to find alternative treatment options with lesser adverse effects. Natural products have been gaining interest as complementary therapy for CVDs over the past decade due to their wide range of medicinal properties, including antioxidants. These might be due to their potent active ingredients, such as flavonoid and phenolic compounds. Numerous natural compounds have been demonstrated to have advantageous effects on cardiovascular disease via NADPH cascade. This review highlights the potential of natural products targeting NOX-derived ROS generation in treating CVDs. Emphasis is put on the activation of the oxidases, including upstream or downstream signalling events.
    Keywords:  NADPH signalling pathway; cardiovascular diseases; natural products; oxidative stress
    DOI:  https://doi.org/10.3390/molecules28031047
  65. Int J Mol Sci. 2023 Feb 01. pii: 2818. [Epub ahead of print]24(3):
    Adjuvant Injections Altered the Ileal and Fecal Microbiota Differently with Changes in Immunoglobulin Isotypes and Antimycobacterial Antibody Responses.
    Sundar Khadka, Seiichi Omura, Fumitaka Sato, Ikuo Tsunoda.
      Alterations in the gut microbiota, "dysbiosis," have been reported in autoimmune diseases, including multiple sclerosis (MS), and their animal models. Although the animal models were induced by injections of autoantigens with adjuvants, including complete Freund's adjuvant (CFA) and pertussis toxin (PT), the effects of adjuvant injections on the microbiota are largely unknown. We aimed to clarify whether adjuvant injections could affect the microbiota in the ileum and feces. Using 16S rRNA sequencing, we found decreased alpha diversities of the gut microbiota in mice injected with CFA and PT, compared with naïve mice. Overall, microbial profiles visualized by principal component analysis demonstrated dysbiosis in feces, but not in the ileum, of adjuvant-injected mice, where the genera Lachnospiraceae NK4A136 group and Alistipes contributed to dysbiosis. When we compared the relative abundances of individual bacteria, we found changes in 16 bacterial genera in feces and seven genera in the ileum of adjuvant-injected mice, in which increased serum levels of antibody against mycobacteria (a component of CFA) and total IgG2c were correlated with the genus Facklamia. On the other hand, increased IgG1 and IgA concentrations were correlated with the genus Atopostipes. Therefore, adjuvant injections alone could alter the overall microbial profiles (i.e., microbiota) and individual bacterial abundances with altered antibody responses; dysbiosis in animal models could be partly due to adjuvant injections.
    Keywords:  Mycobacterium tuberculosis; adjuvant; animal model; antibody isotype; bioinformatics; experimental autoimmune encephalomyelitis; pattern matching
    DOI:  https://doi.org/10.3390/ijms24032818
  66. Int J Mol Sci. 2023 Jan 29. pii: 2560. [Epub ahead of print]24(3):
    Hereditary Hyperferritinemia.
    Alberto Piperno, Sara Pelucchi, Raffaella Mariani.
      Ferritin is a ubiquitous protein that is present in most tissues as a cytosolic protein. The major and common role of ferritin is to bind Fe2+, oxidize it and sequester it in a safe form in the cell, and to release iron according to cellular needs. Ferritin is also present at a considerably low proportion in normal mammalian sera and is relatively iron poor compared to tissues. Serum ferritin might provide a useful and convenient method of assessing the status of iron storage, and its measurement has become a routine laboratory test. However, many additional factors, including inflammation, infection, metabolic abnormalities, and malignancy-all of which may elevate serum ferritin-complicate interpretation of this value. Despite this long history of clinical use, fundamental aspects of the biology of serum ferritin are still unclear. According to the high number of factors involved in regulation of ferritin synthesis, secretion, and uptake, and in its central role in iron metabolism, hyperferritinemia is a relatively common finding in clinical practice and is found in a large spectrum of conditions, both genetic and acquired, associated or not with iron overload. The diagnostic strategy to reveal the cause of hyperferritinemia includes family and personal medical history, biochemical and genetic tests, and evaluation of liver iron by direct or indirect methods. This review is focused on the forms of inherited hyperferritinemia with or without iron overload presenting with normal transferrin saturation, as well as a step-by-step approach to distinguish these forms to the acquired forms, common and rare, of isolated hyperferritinemia.
    Keywords:  ferritin; hereditary; hyperferritinemia; iron
    DOI:  https://doi.org/10.3390/ijms24032560
  67. J Clin Med. 2023 Jan 28. pii: 1016. [Epub ahead of print]12(3):
    Neuroimaging Studies of the Neural Correlates of Heart Rate Variability: A Systematic Review.
    Patrycja S Matusik, Chuwen Zhong, Paweł T Matusik, Omar Alomar, Phyllis K Stein.
      Direct and indirect links between brain regions and cardiac function have been reported. We performed a systematic literature review to summarize current knowledge regarding the associations of heart rate variability (HRV) and brain region morphology, activity and connectivity involved in autonomic control at rest in healthy subjects. Both positive and negative correlations of cortical thickness and gray matter volumes of brain structures with HRV were observed. The strongest were found for a cluster located within the cingulate cortex. A decline in HRV, as well as cortical thickness with increasing age, especially in the orbitofrontal cortex were noted. When associations of region-specific brain activity with HRV were examined, HRV correlated most strongly with activity in the insula, cingulate cortex, frontal and prefrontal cortices, hippocampus, thalamus, striatum and amygdala. Furthermore, significant correlations, largely positive, between HRV and brain region connectivity (in the amygdala, cingulate cortex and prefrontal cortex) were observed. Notably, right-sided neural structures may be preferentially involved in heart rate and HRV control. However, the evidence for left hemispheric control of cardiac vagal function has also been reported. Our findings provide support for the premise that the brain and the heart are interconnected by both structural and functional networks and indicate complex multi-level interactions. Further studies of brain-heart associations promise to yield insights into their relationship to health and disease.
    Keywords:  brain activity; brain structures; heart rate variability; heart–brain connections; magnetic resonance imaging; neuroimaging; resting state
    DOI:  https://doi.org/10.3390/jcm12031016
  68. Metab Brain Dis. 2023 Feb 06.
    Traversing through the cell signaling pathways of neuroprotection by betanin: therapeutic relevance to Alzheimer's Disease and Parkinson's Disease.
    Banashree Chetia Phukan, Rubina Roy, Rajib Paul, Muhammed Khairujjaman Mazumder, Joyobrato Nath, Pallab Bhattacharya, Anupom Borah.
      Modulation of cell signaling pathways is the key area of research towards the treatment of neurodegenerative disorders. Altered Nrf2-Keap1-ARE (Nuclear factor erythroid-2-related factor 2-Kelch-like ECH-associated protein 1-Antioxidant responsive element) and SIRT1 (Sirtuin 1) cell signaling pathways are considered to play major role in the etiology and pathogenesis of Alzheimer's disease (AD) and Parkinson's disease (PD). Strikingly, betanin, a betanidin 5-O-β-D-glucoside compound is reported to show commendable anti-oxidative, anti-inflammatory and anti-apoptotic effects in several disease studies including AD and PD. The present review discusses the pre-clinical studies demonstrating the neuroprotective effects of betanin by virtue of its potential to ameliorate oxidative stress, neuroinflammation, abnormal protein aggregation and cell death. It highlights the direct linkage between the neuroprotective abilities of betanin and upregulation of the Nrf2-Keap1-ARE and SIRT1 signaling pathways. The review further hypothesizes the involvement of the betanin-Nrf2-ARE route in the inhibition of beta-amyloid aggregation through beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), one of the pivotal hallmarks of AD. The present review hereby for the first time elaborately discusses the reported neuroprotective abilities of betanin and decodes the Nrf2 and SIRT1 modulating potential of betanin as a primary mechanism of action behind, hence highlighting it as a novel drug candidate for the treatment of neurodegenerative diseases in the near future.
    Keywords:  Apoptosis; Beta-amyloid; Betalain; Neurodegenerative disorder; Neuroinflammation; Oxidative stress
    DOI:  https://doi.org/10.1007/s11011-023-01177-8
  69. Int J Mol Sci. 2023 Jan 17. pii: 1816. [Epub ahead of print]24(3):
    The Black Box Orchestra of Gut Bacteria and Bile Acids: Who Is the Conductor?
    Soumia Majait, Max Nieuwdorp, Marleen Kemper, Maarten Soeters.
      Over the past decades the potential role of the gut microbiome and bile acids in type 2 diabetes mellitus (T2DM) has been revealed, with a special reference to low bacterial alpha diversity. Certain bile acid effects on gut bacteria concern cytotoxicity, or in the case of the microbiome, bacteriotoxicity. Reciprocally, the gut microbiome plays a key role in regulating the bile acid pool by influencing the conversion and (de)conjugation of primary bile acids into secondary bile acids. Three main groups of bacterial enzymes responsible for the conversion of bile acids are bile salt hydrolases (BSHs), hydroxysteroid dehydrogenases (HSDHs) and enzymes encoded in the bile acid inducible (Bai) operon genes. Interventions such as probiotics, antibiotics and fecal microbiome transplantation can impact bile acids levels. Further evidence of the reciprocal interaction between gut microbiota and bile acids comes from a multitude of nutritional interventions including macronutrients, fibers, prebiotics, specific individual products or diets. Finally, anatomical changes after bariatric surgery are important because of their metabolic effects. The heterogeneity of studies, diseases, bacterial species and (epi)genetic influences such as nutrition may challenge establishing specific and detailed interventions that aim to tackle the gut microbiome and bile acids.
    Keywords:  bile acids; enterohepatic circulation; gut microbiome; nutrition; prebiotics; probiotics; type 2 diabetes mellitus
    DOI:  https://doi.org/10.3390/ijms24031816
  70. Int J Mol Sci. 2023 Jan 23. pii: 2272. [Epub ahead of print]24(3):
    Molecular Mechanisms Underlying Neuroinflammation Elicited by Occupational Injuries and Toxicants.
    Dhruba Pathak, Krishnan Sriram.
      Occupational injuries and toxicant exposures lead to the development of neuroinflammation by activating distinct mechanistic signaling cascades that ultimately culminate in the disruption of neuronal function leading to neurological and neurodegenerative disorders. The entry of toxicants into the brain causes the subsequent activation of glial cells, a response known as 'reactive gliosis'. Reactive glial cells secrete a wide variety of signaling molecules in response to neuronal perturbations and thus play a crucial role in the progression and regulation of central nervous system (CNS) injury. In parallel, the roles of protein phosphorylation and cell signaling in eliciting neuroinflammation are evolving. However, there is limited understanding of the molecular underpinnings associated with toxicant- or occupational injury-mediated neuroinflammation, gliosis, and neurological outcomes. The activation of signaling molecules has biological significance, including the promotion or inhibition of disease mechanisms. Nevertheless, the regulatory mechanisms of synergism or antagonism among intracellular signaling pathways remain elusive. This review highlights the research focusing on the direct interaction between the immune system and the toxicant- or occupational injury-induced gliosis. Specifically, the role of occupational injuries, e.g., trips, slips, and falls resulting in traumatic brain injury, and occupational toxicants, e.g., volatile organic compounds, metals, and nanoparticles/nanomaterials in the development of neuroinflammation and neurological or neurodegenerative diseases are highlighted. Further, this review recapitulates the recent advancement related to the characterization of the molecular mechanisms comprising protein phosphorylation and cell signaling, culminating in neuroinflammation.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; astrocytes; cell signaling; gliosis; hydrocarbons; immune response; inflammation; metals; microglia; multiple sclerosis; nanoparticles; neurodegenerative diseases; neuroinflammation; neurological disorders; occupational injury; traumatic brain injury; workplace toxicants
    DOI:  https://doi.org/10.3390/ijms24032272
  71. Redox Biol. 2023 Jan 27. pii: S2213-2317(23)00018-6. [Epub ahead of print]60 102617
    Interactions of reactive sulfur species with metalloproteins.
    Andrea Domán, Éva Dóka, Dorottya Garai, Virág Bogdándi, György Balla, József Balla, Péter Nagy.
      Reactive sulfur species (RSS) entail a diverse family of sulfur derivatives that have emerged as important effector molecules in H2S-mediated biological events. RSS (including H2S) can exert their biological roles via widespread interactions with metalloproteins. Metalloproteins are essential components along the metabolic route of oxygen in the body, from the transport and storage of O2, through cellular respiration, to the maintenance of redox homeostasis by elimination of reactive oxygen species (ROS). Moreover, heme peroxidases contribute to immune defense by killing pathogens using oxygen-derived H2O2 as a precursor for stronger oxidants. Coordination and redox reactions with metal centers are primary means of RSS to alter fundamental cellular functions. In addition to RSS-mediated metalloprotein functions, the reduction of high-valent metal centers by RSS results in radical formation and opens the way for subsequent per- and polysulfide formation, which may have implications in cellular protection against oxidative stress and in redox signaling. Furthermore, recent findings pointed out the potential role of RSS as substrates for mitochondrial energy production and their cytoprotective capacity, with the involvement of metalloproteins. The current review summarizes the interactions of RSS with protein metal centers and their biological implications with special emphasis on mechanistic aspects, sulfide-mediated signaling, and pathophysiological consequences. A deeper understanding of the biological actions of reactive sulfur species on a molecular level is primordial in H2S-related drug development and the advancement of redox medicine.
    Keywords:  Heme; Hydrogen sulfide; Metalloprotein; Oxidative stress; Reactive sulfur species
    DOI:  https://doi.org/10.1016/j.redox.2023.102617
  72. Int J Mol Sci. 2023 Jan 30. pii: 2633. [Epub ahead of print]24(3):
    Biological Activity of Selenium and Its Impact on Human Health.
    Giuseppe Genchi, Graziantonio Lauria, Alessia Catalano, Maria Stefania Sinicropi, Alessia Carocci.
      Selenium (Se) is a naturally occurring metalloid element essential to human and animal health in trace amounts but it is harmful in excess. Se plays a substantial role in the functioning of the human organism. It is incorporated into selenoproteins, thus supporting antioxidant defense systems. Selenoproteins participate in the metabolism of thyroid hormones, control reproductive functions and exert neuroprotective effects. Among the elements, Se has one of the narrowest ranges between dietary deficiency and toxic levels. Its level of toxicity may depend on chemical form, as inorganic and organic species have distinct biological properties. Over the last decades, optimization of population Se intake for the prevention of diseases related to Se deficiency or excess has been recognized as a pressing issue in modern healthcare worldwide. Low selenium status has been associated with an increased risk of mortality, poor immune function, cognitive decline, and thyroid dysfunction. On the other hand, Se concentrations slightly above its nutritional levels have been shown to have adverse effects on a broad spectrum of neurological functions and to increase the risk of type-2 diabetes. Comprehension of the selenium biochemical pathways under normal physiological conditions is therefore an important issue to elucidate its effect on human diseases. This review gives an overview of the role of Se in human health highlighting the effects of its deficiency and excess in the body. The biological activity of Se, mainly performed through selenoproteins, and its epigenetic effect is discussed. Moreover, a brief overview of selenium phytoremediation and rhizofiltration approaches is reported.
    Keywords:  epigenetics; human diseases; phytoremediation; rhizofiltration; selenium; selenium deficiency; selenoproteins
    DOI:  https://doi.org/10.3390/ijms24032633
  73. J Child Orthop. 2023 Feb;17(1): 40-46
    Osteochondritis dissecans of the knee: Epidemiology, etiology, and natural history.
    Marco Turati, Filippo Maria Anghilieri, Marco Bigoni, Luca Rigamonti, Stephane Tercier, Nicolas Nicolaou, Franck Accadbled.
      Osteochondritis dissecans of the knee is a disease that typically affects skeletally immature patients. Clinically manifested with knee pain, limping, and joint disfunction, this condition has remained misunderstood and undervalued for a long period. Although being a rare condition, its awareness is of utmost clinical interest because of the possible severe consequences it can bring when misrecognized or inadequately treated. Its etiology remains unclear and is still debated. Many theories have been proposed, including inflammation, local ischemia, subchondral ossification abnormalities, genetic factors, and repetitive mechanical microtrauma, with a likely interplay of the same. This review article aims to deliver and discuss current and up-to-date concepts on epidemiology, etiology, and natural history of this pediatric condition. Level of evidence: level V.
    Keywords:  Osteochondritis dissecans; children; epidemiology; etiology; knee
    DOI:  https://doi.org/10.1177/18632521221149063
  74. Mol Cells. 2023 Feb 09.
    The Role of Pyruvate Metabolism in Mitochondrial Quality Control and Inflammation.
    Min-Ji Kim, Hoyul Lee, Dipanjan Chanda, Themis Thoudam, Hyeon-Ji Kang, Robert A Harris, In-Kyu Lee.
      Pyruvate metabolism, a key pathway in glycolysis and oxidative phosphorylation, is crucial for energy homeostasis and mitochondrial quality control (MQC), including fusion/fission dynamics and mitophagy. Alterations in pyruvate flux and MQC are associated with reactive oxygen species accumulation and Ca2+ flux into the mitochondria, which can induce mitochondrial ultrastructural changes, mitochondrial dysfunction and metabolic dysregulation. Perturbations in MQC are emerging as a central mechanism for the pathogenesis of various metabolic diseases, such as neurodegenerative diseases, diabetes and insulin resistance-related diseases. Mitochondrial Ca2+ regulates the pyruvate dehydrogenase complex (PDC), which is central to pyruvate metabolism, by promoting its dephosphorylation. Increase of pyruvate dehydrogenase kinase (PDK) is associated with perturbation of mitochondria-associated membranes (MAMs) function and Ca2+ flux. Pyruvate metabolism also plays an important role in immune cell activation and function, dysregulation of which also leads to insulin resistance and inflammatory disease. Pyruvate metabolism affects macrophage polarization, mitochondrial dynamics and MAM formation, which are critical in determining macrophage function and immune response. MAMs and MQCs have also been intensively studied in macrophage and T cell immunity. Metabolic reprogramming connected with pyruvate metabolism, mitochondrial dynamics and MAM formation are important to macrophages polarization (M1/M2) and function. T cell differentiation is also directly linked to pyruvate metabolism, with inhibition of pyruvate oxidation by PDKs promoting proinflammatory T cell polarization. This article provides a brief review on the emerging role of pyruvate metabolism in MQC and MAM function, and how dysfunction in these processes leads to metabolic and inflammatory diseases.
    Keywords:  T cell; macrophage; mitochondria quality control; mitochondria-associated membranes; pyruvate dehydrogenase complex; pyruvate dehydrogenase kinase
    DOI:  https://doi.org/10.14348/molcells.2023.2128
  75. Rev Neurol (Paris). 2023 Feb 07. pii: S0035-3787(23)00748-8. [Epub ahead of print]
    From neurons to the neuro-glio-vascular unit: Seizures and brain homeostasis in networks.
    N Cresto, A Janvier, N Marchi.
      While seizures are undoubtedly neuronal events, an ensemble of auxiliary brain cells profoundly shapes synaptic transmission in health and disease conditions. Endothelial-astrocyte-pericyte assemblies at the blood-brain barrier (BBB) and neuroglia within the neuro-glio-vascular unit (NGVU) finely tune brain parenchymal homeostasis, safeguarding the ionic and molecular compositions of the interstitial fluid. BBB permeability with neuroinflammation and the resulting loss of brain homeostatic control are unifying mechanisms sustaining aberrant neuronal discharges, with temporal specificities linked to acute (head trauma, stroke, infections) and pre-existent (genetic) or chronic ( dysplasia, tumors, neurodegenerative disorders) pathological conditions. Within this research template, one hypothesis is that the topography of BBB damage and neuroinflammation could associate with symptoms, e.g., limbic structures for seizures or pre-frontal for psychiatric episodes. Another uncharted matter is whether seizure activity, without tissue lesions or sclerosis, is sufficient to promote stable cellular-level maladaptations in networks. Contingent to localization and duration, BBB damage and inflammation forecast pathological trajectories, and the concept of an epileptic NGVU could enable time-sensitive biomarkers to predict disease progression. The coherence between electrographic, imaging and molecular NGVU biomarkers could be established from the epileptogenic to the propagating zones. This paradigm shift could lead to new diagnostic and therapeutic modalities germane to specific epilepsies or when seizure activity represents a comorbidity.
    Keywords:  Astrocytes; Biomarkers; Blood–brain barrier; Epileptogenic; Homeostasis; Immunity; Inflammation; Microglia; Pericytes; Seizure propagation
    DOI:  https://doi.org/10.1016/j.neurol.2022.12.005
  76. Microbiology (Reading). 2023 Feb;169(2):
    Role of Pel and Psl polysaccharides in the response of Pseudomonas aeruginosa to environmental challenges: oxidative stress agents (UVA, H2O2, sodium hypochlorite) and its competitor Staphylococcus aureus.
    Romina Grossich, Martín Lemos Vilches, Cristina S Costa, Magdalena Pezzoni.
      Pseudomonas aeruginosa is a versatile bacterium capable of adapting to a wide range of stress factors, including solar UVA radiation (400-315 nm). High UVA doses produce lethal effects due to the action of reactive oxygen species. Sublethal UVA doses also induces oxidative damage, but, in addition, it triggers a variety of adaptive responses, including the overexpression of pelA and pslA genes in P. aeruginosa. These genes encode the synthesis of Pel and Psl, which are essential polysaccharides in biofilm formation. The present study analysed the role of Pel and Psl in the adaptive responses generated by exposure to low UVA doses, and their importance in the response to lethal doses of UVA, hydrogen peroxide (H2O2), and sodium hypochlorite, in both planktonic cells and submerged and air-liquid interface (ALI) biofilms. It also studied the roles of Pel and Psl in P. aeruginosa-Staphylococcus aureus interaction. The results demonstrate that the capacity of sublethal UVA exposure to increase cell hydrophobicity and cell attachment and generate cross-protection phenomena in P. aeruginosa depends on the presence of Pel and Psl. The study also shows that Pel and Psl have a key role in the tolerance to lethal doses of UVA radiation, sodium hypochlorite and H2O2, in both biofilms and planktonic cells. Finally, co-culture assays showed total inhibition of S. aureus growth in presence of P. aeruginosa. This phenomenon depends, at least in part, on the simultaneous presence of Pel and Psl in planktonic cells and biofilms, suggesting a relevant role of these polysaccharides in the interaction between these species.
    Keywords:  H2O2; Pel/Psl; Pseudomonas aeruginosa; UVA; sodium hypochlorite
    DOI:  https://doi.org/10.1099/mic.0.001301
  77. Curr Alzheimer Res. 2023 Feb 06.
    Pesticide exposure and Alzheimer's disease: A case-control study.
    Zohreh Kiani, Gholamreza Asadikaram, Sanaz Faramarz, Fouzieh Salimi, Hosseinali Ebrahimi.
       PURPOSE: This study aimed to investigate the levels of organochlorine pesticides (OCPs) in the serum of Alzheimer's disease (AD) patients.
    METHODS: 63 AD patients and 50 healthy individuals participated, and the levels of some OCPs derivatives (including; α-HCH, β-HCH, γ-HCH, 2,4-DDT, 4,4-DDT, 2,4-DDE, and 4,4-DDE), total antioxidant capacity (TAC), protein carbonyl (PC), malondialdehyde (MDA), Nitric oxide (NO) along with the activity of superoxide dismutase (SOD), glutathione peroxidase (GPx), paraoxonase 1(PON1), and acetylcholinesterase (AChE) were measured.
    RESULTS: The mean OCP level of OCPs in AD patients was significantly higher than in the control group. However, the patients' mean levels of TAC, PC, MDA and activity of SOD, GPx, PON1 and AChE were significantly lower than controls. A significant positive correlation was also observed between 2,4-DDE and MDA and between γ-HCH and PC in AD patients. These findings showed that pesticide exposure is associated with an increased risk of AD. Furthermore, the mean levels of oxidative stress markers, which may result from pesticide exposure, were significantly lower in AD patients compared to healthy individuals.
    CONCLUSION: Therefore, it may conclude that pesticides, at least in part, contribute to AD development through several mechanisms, including the induction of oxidative stress.
    Keywords:  Alzheimer's disease.; Organochlorine pesticides; Organophosphorus pesticides
    DOI:  https://doi.org/10.2174/1567205020666230206142738
  78. Curr Pharm Biotechnol. 2023 Feb 09.
    Procyanidins extracted from the lotus seedpod ameliorate cognitive impairment through CREB-BDNF pathway mediated LTP in APP/PS1 transgenic mice.
    Ziping Wang, Xiaotong Ren, Xiaolong Li, Siqi Zhao, Wenwen Chen, Cheng Fan, Yangliu Xu, Xuejiao Pi, Yidan Zhang, Ting Wang, Shuang Rong.
       BACKGROUND: Alzheimer's disease (AD) is an age-related neurodegenerative disease and featured by cognitive impairment. Procyanidins have been shown to have a potential protective effect against neurodegenerative diseases, but the underlying mechanism is not comprehensive enough.
    OBJECTIVE: To further investigate the effects of procyanidins from lotus seedpod (LSPC) on cognition in AD.
    METHODS: The APP/PS1 transgenic mice were administered with LSPC (100 mg/kg body weight) for five months. The Morris water maze test was used to assess learning and memory function, the long-term potentiation (LTP) was measured and the expression of Aβ, pCREB/CREB and BDNF were quantified by western blot.
    RESULTS: LSPC significantly ameliorated cognitive dysfunction, reduced Aβ deposition and reversed remarkable reduction of the phosphorylation of CREB and the expression of BDNF, and then enhanced the effect of LTP in APP/PS1 mice.
    CONCLUSION: These results revealed that LSPC could ameliorate cognitive impairment through CREB-BDNF pathway mediated the enhancement of LTP in APP/PS1 transgenic mice.
    Keywords:  APP/PS1; Alzheimer’s disease; Amyloid β; Cognitive impairment; Long-term potentiation; Procyanidins from lotus seedpod; transgenic mice
    DOI:  https://doi.org/10.2174/1389201024666230209142145
  79. Front Neurosci. 2023 ;17 1059552
    Role of gut-brain axis in neurodevelopmental impairment of necrotizing enterocolitis.
    Yu Wang, Chengcheng Hang, Jun Hu, Chen Li, Canyang Zhan, Jiarong Pan, Tianming Yuan.
      Necrotizing enterocolitis (NEC) is a common gastrointestinal disease of preterm infants with high morbidity and mortality. In survivors of NEC, one of the leading causes of long-term morbidity is the development of severe neurocognitive injury. The exact pathogenesis of neurodevelopmental delay in NEC remains unknown, but microbiota is considered to have dramatic effects on the development and function of the host brain via the gut-brain axis. In this review, we discuss the characteristics of microbiota of NEC, the impaired neurological outcomes, and the role of the complex interplay between the intestinal microbiota and brain to influence neurodevelopment in NEC. The increasing knowledge of microbial-host interactions has the potential to generate novel therapies for manipulating brain development in the future.
    Keywords:  gut-brain axis; microbiota; necrotizing enterocolitis; neurodevelopmental impairment; neurodevelopmental outcomes
    DOI:  https://doi.org/10.3389/fnins.2023.1059552
  80. Curr Opin Neurobiol. 2023 Feb 06. pii: S0959-4388(23)00009-0. [Epub ahead of print]79 102684
    Apolipoprotein E4 targets mitochondria and the mitochondria-associated membrane complex in neuropathology, including Alzheimer's disease.
    Robert W Mahley.
      Apolipoprotein (apo) E4 sets the stage for neuropathology in Alzheimer's disease (AD) by causing mitochondrial dysfunction and altering mitochondria-associated membranes. Contact and apposition of mitochondrial-endoplasmic reticulum membranes are enhanced in brain cells in AD and associated with increases in tethering and spacing proteins that modulate many cellular processes. Contact site protein levels are higher in apoE4 cells. In apoE4 neurons, the NAD+/NADH ratio is lowered, reactive oxygen species are increased, and NAD/NADH pathway components and redox proteins are decreased. Oxidative phosphorylation is impaired and reserve ATP generation capacity is lacking. ApoE4 neurons have ∼50% fewer respiratory complex subunits (e.g., ATP synthase) and may increase translocase levels of the outer and inner mitochondrial membranes to facilitate delivery of nucleus-encoded complex subunits. Respiratory complex assembly relies on mitochondrial cristae organizing system subunits that are altered in apoE4 cells, and apoE4 increases mitochondrial proteases that control respiratory subunit composition for complex assembly.
    DOI:  https://doi.org/10.1016/j.conb.2023.102684
  81. Cell Host Microbe. 2023 Feb 08. pii: S1931-3128(23)00034-3. [Epub ahead of print]31(2): 173-186
    Gut microbiome lipid metabolism and its impact on host physiology.
    Eric M Brown, Jon Clardy, Ramnik J Xavier.
      Metabolites produced by commensal gut microbes impact host health through their recognition by the immune system and their influence on numerous metabolic pathways. Notably, the gut microbiota can both transform and synthesize lipids as well as break down dietary lipids to generate secondary metabolites with host modulatory properties. Although lipids have largely been consigned to structural roles, particularly in cell membranes, recent research has led to an increased appreciation of their signaling activities, with potential impacts on host health and physiology. This review focuses on studies that highlight the functions of bioactive lipids in mammalian physiology, with a special emphasis on immunity and metabolism.
    Keywords:  PUFAs; autoimmune disease; bacteria; cholesterol; diet; inflammation; innate immunity; lipids; metabolism; microbiome; phospholipids; sphingolipids
    DOI:  https://doi.org/10.1016/j.chom.2023.01.009
  82. Environ Int. 2023 Feb 04. pii: S0160-4120(23)00075-2. [Epub ahead of print]172 107802
    Associated long-term effects of decabromodiphenyl ethane on the gut microbial profiles and metabolic homeostasis in Sprague-Dawley rat offspring.
    Guoxia Zhang, Fengmin Ma, Ziwei Zhang, Zenghua Qi, Meiqiong Luo, Yingxin Yu.
      Decabromodiphenyl ethane (DBDPE) as a widely used brominated flame retardant is harmful to human health due to its toxicity, including cardiovascular toxicity, reproductive toxicity, and hepatotoxicity. However, the knowledge of the long-term effects and structural and metabolic function influence on gut microbiota from DBDPE exposure remains limited. This study was mainly aimed at the gut microbiome and fecal metabolome of female rats and their offspring exposed to DBDPE in early life. 16S rRNA gene sequencing demonstrated that maternal DBDPE exposure could increase the α-diversity of gut microbiota in immature offspring while decreasing the abundance of Bifidobacterium, Clostridium, Muribaculum, Escherichia, and Lactobacillus in adult offspring. The nonmetric multidimensional scaling showed a consistency in the alternation of β-diversity between pregnant rats and their adult offspring. Furthermore, the short-chain fatty acids produced by gut microbiota dramatically increased in adult offspring after maternal DBDPE exposure, revealing that DBDPE treatment disrupted the gut microbial compositions and altered the gut community's metabolic functions. Untargeted metabolomics identified 41 differential metabolites and seven metabolic pathways between adult offspring from various groups. Targeted metabolomic showed that maternal high dose DBDPE exposure obviously decreased the level of glutathione, taurine, and l-carnitine in their adult offspring, which verified the correlation between weight loss and amino acid metabolites. An interesting link between some gut bacteria (especially the Firmicutes) and fecal metabolites demonstrated the shifts in gut microbiota may drive the metabolic process of fecal metabolites. The current findings provide new insight into long-term effects on human health.
    Keywords:  Decabromodiphenyl ethane; Gut microbiota; Short-chain fatty acids; Untargeted metabolomics
    DOI:  https://doi.org/10.1016/j.envint.2023.107802
  83. Chem Sci. 2023 Jan 18. 14(3): 506-513
    In vivo visualization of enantioselective targeting of amyloid and improvement of cognitive function by clickable chiral metallohelices.
    Zhi Du, Chun Liu, Zhenqi Liu, Hualong Song, Peter Scott, Xiubo Du, Jinsong Ren, Xiaogang Qu.
      The pathogenesis of Alzheimer's disease (AD) is closely related to several contributing factors, especially amyloid-β (Aβ) aggregation. Bioorthogonal reactions provide a general, facile, and robust route for the localization and derivatization of Aβ-targeted agents. Herein, a pair of chiral alkyne-containing metallohelices (ΛA and ΔA) were demonstrated to enantioselectively target and modulate Aβ aggregation, which has been monitored in triple-transgenic AD model mice and proved to improve cognitive function. Compared with its enantiomer ΔA, ΛA performed better in blocking Aβ fibrillation, relieving Aβ-triggered toxicity, and recovering memory deficits in vivo. Moreover, clickable ΛA could act as a functional module for subsequent visualization and versatile modification of amyloid via bioorthogonal reaction. As a proof-of-concept, thioflavin T, tacrine, and magnetic nanoparticles were conjugated with ΛA to realize Aβ photo-oxygenation, acetylcholinesterase inhibition, and Aβ clearance, respectively. This proof-of-principle work provided new insights into the biolabeling and bioconjugation of multifunctional metallosupramolecules through click reactions for AD therapy.
    DOI:  https://doi.org/10.1039/d2sc05897a
  84. Nutrients. 2023 Jan 30. pii: 710. [Epub ahead of print]15(3):
    Role of Nutrition in Pediatric Patients with Cancer.
    Laura Pedretti, Serena Massa, Davide Leardini, Edoardo Muratore, Sofia Rahman, Andrea Pession, Susanna Esposito, Riccardo Masetti.
      Children with cancer are at high risk for developing short-term and long-term nutritional problems related to their underlying disease and side effects of multimodal treatments. Nutritional status (NS) can influence several clinical outcomes, such as overall survival (OS) and event-free survival (EFS), treatment tolerance, risk of developing infections and quality of life (QoL). However, the importance of nutrition in children with cancer is still underestimated. This review focuses on alterations of NS that occurs in children during cancer treatment. In particular, we reviewed the pathogenesis of undernutrition in oncological children, as well as how NS affects treatment tolerance and response, the immune system and the risk of infections of children with cancer. Thanks to recent advances in all types of supportive therapy and to the progress of knowledge on this topic, it has been realized that NS is a modifiable prognostic factor that can be intervened upon to improve the outcome of these patients. Currently, there is a lack of a systematic approach and standard recommendations for nutritional care in the pediatric cancer population. Literature analysis showed that it is essential to define the NS and treat any alterations in a timely manner ensuring proper growth and development. Nutritional follow-up should become an integral part of the care pathway. Regular nutritional monitoring should be performed at diagnosis, during treatment and during follow-up. A close collaboration and sharing of expertise between pediatric oncologists and nutrition specialists, combined with careful and participatory sharing of the feeding experience with the family and the child (after age 6 years), is strongly required.
    Keywords:  cancer; enteral nutrition; gut microbiome; malnutrition; nutrition; parenteral nutrition
    DOI:  https://doi.org/10.3390/nu15030710
  85. Nutrients. 2023 Jan 20. pii: 554. [Epub ahead of print]15(3):
    Dietary Habit Modifications in Paediatric Patients after One Year of Treatment with the Crohn's Disease Exclusion Diet.
    Rafael Martín-Masot, Marta Herrador-López, Víctor Manuel Navas-López.
      Gut microbiota alterations play a key role in the pathogenesis of inflammatory bowel disease (IBD), and its modification through specific diets is an emerging line of treatment that is currently being researched. The aim of this study was to assess changes in the dietary habits of patients with Crohn's disease (CD) and their long-term adherence to dietary therapy with the Crohn's disease exclusion diet (CDED) after one year. To analyse the modification of dietary habits and adherence to the Mediterranean diet (DM), the KIDMED questionnaire, a food consumption frequency questionnaire, was used. Twenty-four hour recalls at two timepoints, namely prior to the start of the dietary therapy and one year later, were also carried out. The processing degrees of the foods consumed by the patients were analysed at both timepoints using the NOVA classification system. Data from 24 patients (15 boys), with a mean age of 12.7 ± 2.9 years at the start of the dietary therapy, were analysed. All patients showed an improvement in their dietary pattern in the form of a reduction in the intake of ultra-processed foods (UPFs); a higher adherence to the MD; a decrease in the intake of cold meats, seafood, pasta, precooked foods, soft drinks, and pastries; an increase in the intake of eggs, legumes, dairy products, and nuts (p < 0.05); and adequate adherence, even in the long-term, to foods allowed during the different phases of the dietary regimen. Although more factors have an impact on the course of the disease in these patients, improving their dietary habits is essential.
    Keywords:  Crohn’s disease; Crohn’s disease exclusion diet; children; dietary habits
    DOI:  https://doi.org/10.3390/nu15030554
  86. J Med Chem. 2023 Feb 10.
    Aza-Residue Modulation of Cyclic d,l-α-Peptide Nanotube Assembly with Enhanced Anti-Amyloidogenic Activity.
    Maram Habashi, Pradeep S Chauhan, Suresh Vutla, Sudipta Senapati, Mykhailo Diachkov, Ali El-Husseini, Brigitte Guérin, William D Lubell, Shai Rahimipour.
      Transient soluble oligomers of amyloid-β (Aβ) are considered among the most toxic species in Alzheimer's disease (AD). Soluble Aβ oligomers accumulate early prior to insoluble plaque formation and cognitive impairment. The cyclic d,l-α-peptide CP-2 (1) self-assembles into nanotubes and demonstrates promising anti-amyloidogenic activity likely by a mechanism involving engagement of soluble oligomers. Systematic replacement of the residues in peptide 1 with aza-amino acid counterparts was performed to explore the effects of hydrogen bonding on propensity to mitigate Aβ aggregation and toxicity. Certain azapeptides exhibited improved ability to engage, alter the secondary structure, and inhibit aggregation of Aβ. Moreover, certain azapeptides disassembled preformed Aβ fibrils and protected cells from Aβ-mediated toxicity. Substitution of the l-norleucine3 and d-serine6 residues in peptide 1 with aza-norleucine and aza-homoserine provided, respectively, nontoxic [azaNle3]-1 (4) and [azaHse6]-1 (7), that significantly abated symptoms in a transgenic Caenorhabditis elegans AD model by decreasing Aβ oligomer levels.
    DOI:  https://doi.org/10.1021/acs.jmedchem.2c02049
  87. Int J Vitam Nutr Res. 2023 Feb 09.
    Caloric restriction for the management of malignant tumors from animal studies towards clinical translation.
    Aggelos T Margetis.
       In the last few years, numerous studies have demonstrated that dietary modifications in the form of calories restriction exert beneficial effects in several clinical entities, including aging-related pathologies, autoimmune diseases and cancer. Both as preventive but also as therapeutic modalities, these dietary regimens can impact systemic metabolism, immune and hormonal responses, redox balance and gut microbiota, among others. In the field of oncology, the vast majority of experimental work has explored the role of restricted diets in the prevention of malignant tumors, mostly in carcinogenesis-induced models, with at least encouraging results; on the contrary, less research has been performed in the management of full-blown cancer with ketogenic diet or caloric restriction protocols. Herein, we are aiming to review the relevant preclinical and clinical studies to date which investigate the role of caloric restriction in the treatment of established cancer.
    Keywords:  caloric restriction; cancer; diet; fasting
    DOI:  https://doi.org/10.1024/0300-9831/a000779
  88. Int J Mol Sci. 2023 Feb 03. pii: 2985. [Epub ahead of print]24(3):
    Erythropoietin in Glaucoma: From Mechanism to Therapy.
    Yi-Fen Lai, Ting-Yi Lin, Yi-Hao Chen, Da-Wen Lu.
      Glaucoma can cause irreversible vision loss and is the second leading cause of blindness worldwide. The disease mechanism is complex and various factors have been implicated in its pathogenesis, including ischemia, excessive oxidative stress, neurotropic factor deprivation, and neuron excitotoxicity. Erythropoietin (EPO) is a hormone that induces erythropoiesis in response to hypoxia. However, studies have shown that EPO also has neuroprotective effects and may be useful for rescuing apoptotic retinal ganglion cells in glaucoma. This article explores the relationship between EPO and glaucoma and summarizes preclinical experiments that have used EPO to treat glaucoma, with an aim to provide a different perspective from the current view that glaucoma is incurable.
    Keywords:  erythropoietin; glaucoma; neuroprotection; retinal ganglion cell
    DOI:  https://doi.org/10.3390/ijms24032985
  89. Int J Mol Sci. 2023 Feb 03. pii: 2963. [Epub ahead of print]24(3):
    The Molecular Mechanisms of Systemic Sclerosis-Associated Lung Fibrosis.
    Joe E Mouawad, Carol Feghali-Bostwick.
      Systemic sclerosis (SSc), also known as scleroderma, is an autoimmune disorder that affects the connective tissues and has the highest mortality rate among the rheumatic diseases. One of the hallmarks of SSc is fibrosis, which may develop systemically, affecting the skin and virtually any visceral organ in the body. Fibrosis of the lungs leads to interstitial lung disease (ILD), which is currently the leading cause of death in SSc. The identification of effective treatments to stop or reverse lung fibrosis has been the main challenge in reducing SSc mortality and improving patient outcomes and quality of life. Thus, understanding the molecular mechanisms, altered pathways, and their potential interactions in SSc lung fibrosis is key to developing potential therapies. In this review, we discuss the diverse molecular mechanisms involved in SSc-related lung fibrosis to provide insights into the altered homeostasis state inherent to this fatal disease complication.
    Keywords:  fibroblast; fibrosis; interstitial lung disease; lung; molecular mechanisms; pulmonary; scleroderma; systemic sclerosis
    DOI:  https://doi.org/10.3390/ijms24032963
  90. ACS Chem Biol. 2023 Feb 06.
    Cellular Labeling of Phosphatidylserine Using Clickable Serine Probes.
    Christelle F Ancajas, Shahrina Alam, Daiane S Alves, Yue Zhou, Nicholas M Wadsworth, Chelsi D Cassilly, Tanei J Ricks, Adam J Carr, Todd B Reynolds, Francisco N Barrera, Michael D Best.
      Phosphatidylserine (PS) is a key lipid that plays important roles in disease-related biological processes, and therefore, the means to track PS in live cells are invaluable. Herein, we describe the metabolic labeling of PS in Saccharomyces cerevisiae cells using analogues of serine, a PS precursor, derivatized with azide moieties at either the amino (N-l-SerN3) or carbonyl (C-l-SerN3) groups. The conservative click tag modification enabled these compounds to infiltrate normal lipid biosynthetic pathways, thereby producing tagged PS molecules as supported by mass spectrometry studies, thin-layer chromatography (TLC) analysis, and further derivatization with fluorescent reporters via click chemistry to enable imaging in yeast cells. This approach shows strong prospects for elucidating the complex biosynthetic and trafficking pathways involving PS.
    DOI:  https://doi.org/10.1021/acschembio.2c00813
  91. J Am Soc Mass Spectrom. 2023 Feb 06.
    Structural Proteomic Profiling of Cerebrospinal Fluids to Reveal Novel Conformational Biomarkers for Alzheimer's Disease.
    Bin Wang, Xiaofang Zhong, Lauren Fields, Haiyan Lu, Zexin Zhu, Lingjun Li.
      Alzheimer's disease (AD) is the most common representation of dementia, with brain pathological hallmarks of protein abnormal aggregation, such as with amyloid beta and tau protein. It is well established that posttranslational modifications on tau protein, particularly phosphorylation, increase the likelihood of its aggregation and subsequent formation of neurofibrillary tangles, another hallmark of AD. As additional misfolded proteins presumably exist distinctly in AD disease states, which would serve as potential source of AD biomarkers, we used limited proteolysis-coupled with mass spectrometry (LiP-MS) to probe protein structural changes. After optimizing the LiP-MS conditions, we further applied this method to human cerebrospinal fluid specimens collected from healthy control, mild cognitive impairment (MCI), and AD subject groups to characterize proteome-wide misfolding tendencies as a result of disease progression. The fully tryptic peptides embedding LiP sites were compared with the half-tryptic peptides generated from internal cleavage of the same region to determine any structural unfolding or misfolding. We discovered hundreds of significantly up- and down-regulated peptides associated with MCI and AD indicating their potential structural changes in AD progression. Moreover, we detected 53 structurally changed regions in 12 proteins with high confidence between the healthy control and disease groups, illustrating the functional relevance of these proteins with AD progression. These newly discovered conformational biomarker candidates establish valuable future directions for exploring the molecular mechanism of designing therapeutic targets for AD.
    Keywords:  Alzheimer’s disease; LiP-MS; conformational biomarker; limited proteolysis; proteomics; structural mass spectrometry
    DOI:  https://doi.org/10.1021/jasms.2c00332
  92. J Clin Med. 2023 Jan 20. pii: 842. [Epub ahead of print]12(3):
    The Role of Platelets in the Pathogenesis and Pathophysiology of Adenomyosis.
    Sun-Wei Guo.
      Widely viewed as an enigmatic disease, adenomyosis is a common gynecological disease with bewildering pathogenesis and pathophysiology. One defining hallmark of adenomyotic lesions is cyclic bleeding as in eutopic endometrium, yet bleeding is a quintessential trademark of tissue injury, which is invariably followed by tissue repair. Consequently, adenomyotic lesions resemble wounds. Following each bleeding episode, adenomyotic lesions undergo tissue repair, and, as such, platelets are the first responder that heralds the subsequent tissue repair. This repeated tissue injury and repair (ReTIAR) would elicit several key molecular events crucial for lesional progression, eventually leading to lesional fibrosis. Platelets interact with adenomyotic cells and actively participate in these events, promoting the lesional progression and fibrogenesis. Lesional fibrosis may also be propagated into their neighboring endometrial-myometrial interface and then to eutopic endometrium, impairing endometrial repair and causing heavy menstrual bleeding. Moreover, lesional progression may result in hyperinnervation and an enlarged uterus. In this review, the role of platelets in the pathogenesis, progression, and pathophysiology is reviewed, along with the therapeutic implication. In addition, I shall demonstrate how the notion of ReTIAR provides a much needed framework to tether to and piece together many seemingly unrelated findings and how it helps to make useful predictions.
    Keywords:  adenomyosis; coagulation; dysmenorrhea; fibrogenesis; heavy menstrual bleeding; repeated tissue injury and repair
    DOI:  https://doi.org/10.3390/jcm12030842
  93. Int J Mol Sci. 2023 Feb 01. pii: 2801. [Epub ahead of print]24(3):
    Therapeutic Use and Molecular Aspects of Ivabradine in Cardiac Remodeling: A Review.
    Yusof Kamisah, Hamat H Che Hassan.
      Cardiac remodeling can cause ventricular dysfunction and progress to heart failure, a cardiovascular disease that claims many lives globally. Ivabradine, a funny channel (If) inhibitor, is used in patients with chronic heart failure as an adjunct to other heart failure medications. This review aims to gather updated information regarding the therapeutic use and mechanism of action of ivabradine in heart failure. The drug reduces elevated resting heart rate, which is linked to increased morbidity and mortality in patients with heart failure. Its use is associated with improved cardiac function, structure, and quality of life in the patients. Ivabradine exerts several pleiotropic effects, including an antiremodeling property, which are independent of its principal heart-rate-reducing effects. Its suppressive effects on cardiac remodeling have been demonstrated in animal models of cardiac remodeling and heart failure. It reduces myocardial fibrosis, apoptosis, inflammation, and oxidative stress as well as increases autophagy in the animals. It also modulates myocardial calcium homeostasis, neurohumoral systems, and energy metabolism. However, its role in improving heart failure remains unclear. Therefore, elucidating its molecular mechanisms is imperative and would aid in the design of future studies.
    Keywords:  cardiac function; cardiac structure; heart failure; left ventricular dysfunction; myocardial fibrosis
    DOI:  https://doi.org/10.3390/ijms24032801
  94. Acta Neuropathol. 2023 Feb 11.
    Retinal pathological features and proteome signatures of Alzheimer's disease.
    Yosef Koronyo, Altan Rentsendorj, Nazanin Mirzaei, Giovanna C Regis, Julia Sheyn, Haoshen Shi, Ernesto Barron, Galen Cook-Wiens, Anthony R Rodriguez, Rodrigo Medeiros, Joao A Paulo, Veer B Gupta, Andrei A Kramerov, Alexander V Ljubimov, Jennifer E Van Eyk, Stuart L Graham, Vivek K Gupta, John M Ringman, David R Hinton, Carol A Miller, Keith L Black, Antonino Cattaneo, Giovanni Meli, Mehdi Mirzaei, Dieu-Trang Fuchs, Maya Koronyo-Hamaoui.
      Alzheimer's disease (AD) pathologies were discovered in the accessible neurosensory retina. However, their exact nature and topographical distribution, particularly in the early stages of functional impairment, and how they relate to disease progression in the brain remain largely unknown. To better understand the pathological features of AD in the retina, we conducted an extensive histopathological and biochemical investigation of postmortem retina and brain tissues from 86 human donors. Quantitative examination of superior and inferior temporal retinas from mild cognitive impairment (MCI) and AD patients compared to those with normal cognition (NC) revealed significant increases in amyloid β-protein (Aβ42) forms and novel intraneuronal Aβ oligomers (AβOi), which were closely associated with exacerbated retinal macrogliosis, microgliosis, and tissue atrophy. These pathologies were unevenly distributed across retinal layers and geometrical areas, with the inner layers and peripheral subregions exhibiting most pronounced accumulations in the MCI and AD versus NC retinas. While microgliosis was increased in the retina of these patients, the proportion of microglial cells engaging in Aβ uptake was reduced. Female AD patients exhibited higher levels of retinal microgliosis than males. Notably, retinal Aβ42, S100 calcium-binding protein B+ macrogliosis, and atrophy correlated with severity of brain Aβ pathology, tauopathy, and atrophy, and most retinal pathologies reflected Braak staging. All retinal biomarkers correlated with the cognitive scores, with retinal Aβ42, far-peripheral AβOi and microgliosis displaying the strongest correlations. Proteomic analysis of AD retinas revealed activation of specific inflammatory and neurodegenerative processes and inhibition of oxidative phosphorylation/mitochondrial, and photoreceptor-related pathways. This study identifies and maps retinopathy in MCI and AD patients, demonstrating the quantitative relationship with brain pathology and cognition, and may lead to reliable retinal biomarkers for noninvasive retinal screening and monitoring of AD.
    Keywords:  Eye; GFAP; IBA1; Immune responses; Neurodegenerative disorders; Ocular abnormalities; S100β; scFvA13-intraneuronal oligomers
    DOI:  https://doi.org/10.1007/s00401-023-02548-2
  95. Int J Mol Sci. 2023 Jan 31. pii: 2669. [Epub ahead of print]24(3):
    Oxidation State in Peritoneal Dialysis in Patients with Type 2 Diabetes Mellitus.
    Leonardo Pazarín-Villaseñor, Yessica García-Salas, Francisco Gerardo Yanowsky-Escatell, Fermín Paul Pacheco-Moisés, Jorge Andrade-Sierra, Tannia Isabel Campos-Bayardo, Daniel Román-Rojas, Andrés García-Sánchez, Alejandra Guillermina Miranda-Díaz.
      End-stage renal disease (ESRD) progression is closely related to oxidative stress (OS). The study objective was to determine the oxidant and antioxidant status in peritoneal dialysis (PD) patients with type 2 diabetes mellitus (DM). An analytical cross-sectional study from the PD program was carried out with 62 patients, 22 with and 40 without DM. Lipoperoxides (LPO) levels in patients with DM, 3.74 ± 1.09 mM/L, and without DM, 3.87 ± 0.84 mM/L were found to increase compared to healthy controls (HC) 3.05 ± 0.58 mM/L (p = 0.006). The levels of the oxidative DNA damage marker (8-OH-dG) were found to be significantly increased in patients with DM, 1.71 ng/mL (0.19-71.92) and without DM, 1.05 ng/mL (0.16-68.80) front to 0.15 ng/mL (0.15-0.1624) of HC (p = 0.001). The antioxidant enzyme superoxide dismutase (SOD) activity was found to be significantly increased in patients with DM, 0.37 ± 0.15 U/mL, and without DM, 0.37 ± 0.17 compared to HC, 0.23 ± 0.05 U/mL (p = 0.038). The activity of the enzyme glutathione peroxidase (GPx) showed a significant increase (p < 0.001) in patients with DM, 3.56 ± 2.18 nmol/min/mL, and without DM, 3.28 ± 1.46 nmol/min/mL, contrary to the activity obtained in HC, 1.55 ± 0.34 nmol/min/mL. In conclusion, we found an imbalance of oxidative status in patients undergoing PD with and without DM through the significant increase in LPO oxidants and the marker of oxidative damage in DNA. The activity of the antioxidant enzymes SOD and GPx were significantly increased in patients with and without DM undergoing PD, possibly in an attempt to compensate for the deregulation of oxidants. Antioxidant enzymes could be promising therapeutic strategies as a complement to the management of chronic kidney diseases.
    Keywords:  ESRD; antioxidants; diabetes mellitus; oxidants; oxidative stress; peritoneal dialysis
    DOI:  https://doi.org/10.3390/ijms24032669
  96. Int J Mol Sci. 2023 Feb 02. pii: 2835. [Epub ahead of print]24(3):
    Insights into the Peritumoural Brain Zone of Glioblastoma: CDK4 and EXT2 May Be Potential Drivers of Malignancy.
    Martina Giambra, Andrea Di Cristofori, Donatella Conconi, Matilde Marzorati, Serena Redaelli, Melissa Zambuto, Alessandra Rocca, Louis Roumy, Giorgio Carrabba, Marialuisa Lavitrano, Gaia Roversi, Carlo Giussani, Angela Bentivegna.
      Despite the efforts made in recent decades, glioblastoma is still the deadliest primary brain cancer without cure. The potential role in tumour maintenance and progression of the peritumoural brain zone (PBZ), the apparently normal area surrounding the tumour, has emerged. Little is known about this area due to a lack of common definition and due to difficult sampling related to the functional role of peritumoural healthy brain. The aim of this work was to better characterize the PBZ and to identify genes that may have role in its malignant transformation. Starting from our previous study on the comparison of the genomic profiles of matched tumour core and PBZ biopsies, we selected CDK4 and EXT2 as putative malignant drivers of PBZ. The gene expression analysis confirmed their over-expression in PBZ, similarly to what happens in low-grade glioma and glioblastoma, and CDK4 high levels seem to negatively influence patient overall survival. The prognostic role of CDK4 and EXT2 was further confirmed by analysing the TCGA cohort and bioinformatics prediction on their gene networks and protein-protein interactions. These preliminary data constitute a good premise for future investigations on the possible role of CDK4 and EXT2 in the malignant transformation of PBZ.
    Keywords:  CDK4; EXT2; glioblastoma; malignant transformation; peritumoural brain zone
    DOI:  https://doi.org/10.3390/ijms24032835
  97. Nature. 2023 Feb 06.
    The Alzheimer's risk gene APOE modulates the gut-brain axis.
    Alfonso Martín-Peña, Malú Gámez Tansey.
      
    Keywords:  Alzheimer's disease; Immunology; Microbiology; Neurodegeneration
    DOI:  https://doi.org/10.1038/d41586-023-00261-4
  98. Int J Mol Sci. 2023 Jan 19. pii: 1969. [Epub ahead of print]24(3):
    Mitochondrial Transplantation in Mitochondrial Medicine: Current Challenges and Future Perspectives.
    Marco D'Amato, Francesca Morra, Ivano Di Meo, Valeria Tiranti.
      Mitochondrial diseases (MDs) are inherited genetic conditions characterized by pathogenic mutations in nuclear DNA (nDNA) or mitochondrial DNA (mtDNA). Current therapies are still far from being fully effective and from covering the broad spectrum of mutations in mtDNA. For example, unlike heteroplasmic conditions, MDs caused by homoplasmic mtDNA mutations do not yet benefit from advances in molecular approaches. An attractive method of providing dysfunctional cells and/or tissues with healthy mitochondria is mitochondrial transplantation. In this review, we discuss what is known about intercellular transfer of mitochondria and the methods used to transfer mitochondria both in vitro and in vivo, and we provide an outlook on future therapeutic applications. Overall, the transfer of healthy mitochondria containing wild-type mtDNA copies could induce a heteroplasmic shift even when homoplasmic mtDNA variants are present, with the aim of attenuating or preventing the progression of pathological clinical phenotypes. In summary, mitochondrial transplantation is a challenging but potentially ground-breaking option for the treatment of various mitochondrial pathologies, although several questions remain to be addressed before its application in mitochondrial medicine.
    Keywords:  mitochondria; mitochondrial diseases; mitochondrial dysfunction; mitochondrial medicine; mitochondrial transplantation
    DOI:  https://doi.org/10.3390/ijms24031969
  99. Pharmacol Res. 2023 Feb 07. pii: S1043-6618(23)00046-4. [Epub ahead of print] 106690
    Gpr35 shapes gut microbial ecology to modulate hepatic steatosis.
    Xin Wu, Shuobing Chen, Qingyuan Yan, Feng Yu, Hua Shao, Xiao Zheng, Xueli Zhang.
      The gut microbiome is closely shaped by host genetic and dietary factors to regulate metabolic health and disease. However, the signaling mechanisms underlying such interactions have been largely unclear. Here we identify G protein-coupled receptor 35 (Gpr35) as a regulator of gut microbial ecology and the susceptibility to obesity and hepatic steatosis in mice. Both global and intestinal epithelia specific ablation of Gpr35 aggravated high-fat diet (HFD)-induced metabolic disturbance and hepatic steatosis in mice. Gpr35 deficiency induced a marked loss of goblet cells and an extensive remodeling of the gut microbiome, featuring enrichment of the Bacteroides and Ruminococcus genera. Antibiotics treatment and co-housing alleviated the metabolic disturbance markers in Gpr35 deficient mice. Spatiotemporal profiling and mono-colonization screening revealed that Ruminococcus gnavus synergized with HFD to promote hepatic steatosis possibly via tryptophan and phenylalanine pathway metabolites. Our results provide mechanistic insights into a genetic-diet-microbe interplay that dictates susceptibility to metabolic disorder.
    Keywords:  Goblet cells; Gpr35; Gut dysbiosis; Gut-liver axis; Liver steatosis; Ruminococcus gnavus
    DOI:  https://doi.org/10.1016/j.phrs.2023.106690
  100. Chem Biol Interact. 2023 Feb 07. pii: S0009-2797(23)00054-6. [Epub ahead of print] 110387
    Revisiting the intersection of microglial activation and neuroinflammation in Alzheimer's disease from the perspective of ferroptosis.
    Miaomiao Wang, Gan Tang, Congfa Zhou, Hongmin Guo, Zihui Hu, Qixing Hu, Guilin Li.
      Alzheimer's disease (AD) is a neurodegenerative disorder characterized by chronic neuroinflammation with amyloid beta-protein deposition and hyperphosphorylated tau protein. The typical clinical manifestation of AD is progressive memory impairment, and AD is considered a multifactorial disease with various etiologies (genetic factors, aging, lifestyle, etc.) and complicated pathophysiological processes. Previous research identified that neuroinflammation and typical microglial activation are significant mechanisms underlying AD, resulting in dysfunction of the nervous system and progression of the disease. Ferroptosis is a novel modality involved in this process. As an iron-dependent form of cell death, ferroptosis, characterized by iron accumulation, lipid peroxidation, and irreversible plasma membrane disruption, promotes AD by accelerating neuronal dysfunction and abnormal microglial activation. In this case, disturbances in brain iron homeostasis and neuronal ferroptosis aggravate neuroinflammation and lead to the abnormal activation of microglia. Abnormally activated microglia release various pro-inflammatory factors that aggravate the dysregulation of iron homeostasis and neuroinflammation, forming a vicious cycle. In this review, we first introduce ferroptosis, microglia, AD, and their relationship. Second, we discuss the nonnegligible role of ferroptosis in the abnormal microglial activation involved in the chronic neuroinflammation of AD to provide new ideas for the identification of potential therapeutic targets for AD.
    Keywords:  Alzheimer's disease; Ferroptosis; Iron metabolism; Microglia; Neuroinflammation
    DOI:  https://doi.org/10.1016/j.cbi.2023.110387
  101. Neuromolecular Med. 2023 Feb 05.
    The Ubiquitin Proteasome System as a Therapeutic Area in Parkinson's Disease.
    Kumar Suresh, Michael Mattern, Matthew S Goldberg, Tauseef R Butt.
      Parkinson's disease (PD) is the most common neurodegenerative movement disorder. There are no available therapeutics that slow or halt the progressive loss of dopamine-producing neurons, which underlies the primary clinical symptoms. Currently approved PD drugs can provide symptomatic relief by increasing brain dopamine content or activity; however, the alleviation is temporary, and the effectiveness diminishes with the inevitable progression of neurodegeneration. Discovery and development of disease-modifying neuroprotective therapies has been hampered by insufficient understanding of the root cause of PD-related neurodegeneration. The etiology of PD involves a combination of genetic and environmental factors. Although a single cause has yet to emerge, genetic, cell biological and neuropathological evidence implicates mitochondrial dysfunction and protein aggregation. Postmortem PD brains show pathognomonic Lewy body intraneuronal inclusions composed of aggregated α-synuclein, indicative of failure to degrade misfolded protein. Mutations in the genes that code for α-synuclein, as well as the E3 ubiquitin ligase Parkin, cause rare inherited forms of PD. While many ubiquitin ligases label proteins with ubiquitin chains to mark proteins for degradation by the proteasome, Parkin has been shown to mark dysfunctional mitochondria for degradation by mitophagy. The ubiquitin proteasome system participates in several aspects of the cell's response to mitochondrial damage, affording numerous therapeutic opportunities to augment mitophagy and potentially stop PD progression. This review examines the role and therapeutic potential of such UPS modulators, exemplified by both ubiquitinating and deubiquitinating enzymes.
    Keywords:  Mitochondria; Mitophagy; Neurodegeneration; Parkin; Parkinson’s disease; Ubiquitin
    DOI:  https://doi.org/10.1007/s12017-023-08738-1
  102. Cell. 2023 Feb 02. pii: S0092-8674(23)00005-3. [Epub ahead of print]
    PIKFYVE inhibition mitigates disease in models of diverse forms of ALS.
    Shu-Ting Hung, Gabriel R Linares, Wen-Hsuan Chang, Yunsun Eoh, Gopinath Krishnan, Stacee Mendonca, Sarah Hong, Yingxiao Shi, Manuel Santana, Chuol Kueth, Samantha Macklin-Isquierdo, Sarah Perry, Sarah Duhaime, Claudia Maios, Jonathan Chang, Joscany Perez, Alexander Couto, Jesse Lai, Yichen Li, Samuel V Alworth, Eric Hendricks, Yaoming Wang, Berislav V Zlokovic, Dion K Dickman, J Alex Parker, Daniela C Zarnescu, Fen-Biao Gao, Justin K Ichida.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that results from many diverse genetic causes. Although therapeutics specifically targeting known causal mutations may rescue individual types of ALS, these approaches cannot treat most cases since they have unknown genetic etiology. Thus, there is a pressing need for therapeutic strategies that rescue multiple forms of ALS. Here, we show that pharmacological inhibition of PIKFYVE kinase activates an unconventional protein clearance mechanism involving exocytosis of aggregation-prone proteins. Reducing PIKFYVE activity ameliorates ALS pathology and extends survival of animal models and patient-derived motor neurons representing diverse forms of ALS including C9ORF72, TARDBP, FUS, and sporadic. These findings highlight a potential approach for mitigating ALS pathogenesis that does not require stimulating macroautophagy or the ubiquitin-proteosome system.
    Keywords:  ALS; PIKFYVE; neurodegeneration
    DOI:  https://doi.org/10.1016/j.cell.2023.01.005
  103. Sci Rep. 2023 Feb 07. 13(1): 2210
    Gut microbiota of Parkinson's disease in an appendectomy cohort: a preliminary study.
    Keiichi Nakahara, Shunya Nakane, Kazuo Ishii, Tokunori Ikeda, Yukio Ando.
      In patients with Parkinson's disease (PD), α-synuclein pathology is thought to spread to the brain via the dorsal motor nucleus of the vagus nerve. The link between the gut microbiome and PD has been explored in various studies. The appendix might play an important role in immunity by maintaining the microbiota as a reservoir. In recent times, appendectomy has been linked to a lower risk of PD, possibly owing to the role of the appendix in altering the gut microbiome. We aimed to elucidate whether the gut microbiota affects PD development in the appendectomy cohort. We analyzed the fecal microbial composition in patients with PD and healthy controls with and without a history of appendectomy. The abundance of microbes from the family Enterobacteriaceae was higher in feces samples from patients with Parkinson's disease compared to that in samples collected from healthy controls. Furthermore, there was a significant phylogenetic difference between patients with PD and healthy controls who had undergone appendectomy. There was a significant phylogenetic difference between patients with PD and HCs who had undergone APP. These results suggest the correlation between gut microbiota and PD in patients who have undergone APP.
    DOI:  https://doi.org/10.1038/s41598-023-29219-2
  104. Front Endocrinol (Lausanne). 2022 ;13 1085092
    Review of the correlation between Chinese medicine and intestinal microbiota on the efficacy of diabetes mellitus.
    Min Su, Rao Hu, Ting Tang, Weiwei Tang, Chunxia Huang.
      Diabetes mellitus is a serious metabolic disorder that can lead to a number of life-threatening complications. Studies have shown that intestinal microbiota is closely related to the development of diabetes, making it a potential target for the treatment of diabetes. In recent years, research on the active ingredients of traditional Chinese medicine (TCM), TCM compounds, and prepared Chinese medicines to regulate intestinal microbiota and improve the symptoms of diabetes mellitus is very extensive. We focus on the research progress of TCM active ingredients, herbal compounds, and prepared Chinese medicines in the treatment of diabetes mellitus in this paper. When diabetes occurs, changes in the abundance and function of the intestinal microbiota disrupt the intestinal environment by disrupting the intestinal barrier and fermentation. TCM and its components can increase the abundance of beneficial bacteria while decreasing the abundance of harmful bacteria, regulate the concentration of microbial metabolites, improve insulin sensitivity, regulate lipid metabolism and blood glucose, and reduce inflammation. TCM can be converted into active substances with pharmacological effects by intestinal microbiota, and these active substances can reverse intestinal microecological disorders and improve diabetes symptoms. This can be used as a reference for diabetes prevention and treatment.
    Keywords:  active ingredients; diabetes; intestinal microbiota; metabolism; traditional Chinese medicine
    DOI:  https://doi.org/10.3389/fendo.2022.1085092
  105. J Chem Phys. 2023 Feb 07. 158(5): 054501
    Deciphering strontium sulfate precipitation via Ostwald's rule of stages: From prenucleation clusters to solution-mediated phase tranformation.
    A R Lauer, R Hellmann, G Montes-Hernandez, N Findling, W L Ling, T Epicier, A Fernandez-Martinez, A E S Van Driessche.
      Multiple-step nucleation pathways have been observed during mineral formation in both inorganic and biomineral systems. These pathways can involve precursor aqueous species, amorphous intermediates, or metastable phases. Despite the widespread occurrence of these processes, elucidating the precise nucleation steps and the transformation mechanisms between each step remains a challenging task. Using a suite of potentiometric, microscopic, and spectroscopic tools, we studied the nucleation pathway of SrSO4 as a function of the physico-chemical solution parameters. Our observations reveal that below a threshold supersaturation, nucleation is driven by bound species, akin to the prenucleation cluster model, which directly leads to the formation of the stable phase celestine, SrSO4. At higher supersaturations, this situation is altered, with nucleation dominated by the consumption of free ions. Importantly, this change in nucleation mechanism is coupled to the formation of a hemihydrate metastable phase, SrSO4 · 1/2H2O, which eventually transforms into celestine, adhering to Ostwald's rule of stages. This transformation is a solution-mediated process, also occurring in the presence of a fluid film and is controlled by the physico-chemical parameters of the surrounding environment. It proceeds through the dissolution of the metastable phase and the de novo crystallization of the final phase. Overall, our results reveal that ion association taking place during the prenucleation stage dictates whether the nucleation pathway goes through an intermediate phase or not. This also underlines that although Ostwald's rule of stages is a common process, it is not a prerequisite for mineral formation-even in systems where it can occur.
    DOI:  https://doi.org/10.1063/5.0136870
  106. Food Funct. 2023 Feb 06.
    Analysis of the mechanism of action of quercetin in the treatment of hyperlipidemia based on metabolomics and intestinal flora.
    Tongtong Wang, Ling Liu, Jun Deng, Yu Jiang, Xiao Yan, Wen Liu.
      Hyperlipidemia (HLP) is one of the main factors leading to cardiovascular diseases. Quercetin (QUE) is a naturally occurring polyhydroxy flavonoid compound that has a wide range of pharmacological effects. However, the potential mechanism for treating HLP remains unclear. Thus, the study aimed to investigate the role of QUE in HLP development and its underlying mechanisms in HLP rats based on the analysis of gut microbiota and plasma metabolomics. Following the establishment of an HLP model in rats, QUE was orally administered. Plasma samples and fecal samples were collected from HLP rats for microbiome 16S rDNA sequencing and metabolic UPLC-Q-Exactive-MS analysis. The results suggested that QUE could regulate dyslipidemia and inhibit the levels of TC, TG, and LDL-c. Additionally, histopathological findings revealed that QUE could reduce lipid deposition, ameliorate hepatic injury and steatosis in HFD-induced rats, and have a protective effect on the liver. The analysis and identification of plasma metabolomics showed that the intervention effect of QUE on HLP rats was related to 60 differential metabolites and signal pathways such as lactosamine, 11b-hydroxyprogesterone, arachidonic acid, glycerophospholipid, sphingolipid, glycerolipid, and linoleic acid metabolism. Combined with fecal microbiological analysis, it was found that QUE could significantly change the composition of intestinal flora in HLP rats, increase beneficial bacteria, and reduce the composition of harmful bacteria, attenuating the Firmicutes/Bacteroidetes ratio. The results of correlation analysis showed that the relative abundance level of Firmicutes, Deironobacterium, Fusobacterium, Bacteroides, and Escherichia coli was closely related to the change of differential metabolites. In summary, combined with metabolomics and gut microbiota studies, it is found that QUE can reduce lipid levels and improve liver function. The potential mechanism may be the regulation of metabolism and intestinal flora that play a role in reducing lipid levels, to achieve the purpose of treatment of HLP.
    DOI:  https://doi.org/10.1039/d2fo03509j
  107. J Alzheimers Dis. 2023 Jan 28.
    Regional White Matter Hyperintensities and Alzheimer's Disease Biomarkers Among Older Adults with Normal Cognition and Mild Cognitive Impairment.
    BIOCARD Research Team
       BACKGROUND: Alzheimer's disease (AD) frequently co-occurs with other brain pathologies. Recent studies suggest there may be a mechanistic link between AD and small vessel cerebrovascular disease (CVD), as opposed to simply the overlap of two disorders.
    OBJECTIVE: We investigated the cross-sectional relationship between white matter hyperintensity (WMH) volumes (markers of CVD) and cerebrospinal fluid (CSF) biomarkers of AD.
    METHODS: WMH volumes were assessed globally and regionally (i.e., frontal, parietal, temporal, occipital, and limbic). CSF AD biomarkers (i.e., Aβ 40, Aβ 42, Aβ 42/Aβ 40 ratio, phosphorylated tau-181 [p-tau181], and total tau [t-tau]) were measured among 152 non-demented individuals (134 cognitively unimpaired and 18 with mild cognitive impairment (MCI)).
    RESULTS: Linear regression models showed that among all subjects, higher temporal WHM volumes were associated with AD biomarkers (higher levels of p-tau181, t-tau, and Aβ 40), particularly among APOE ɛ 4 carriers (independent of Aβ 42 levels). Higher vascular risk scores were associated with greater parietal and frontal WMH volumes (independent of CSF AD biomarker levels). Among subjects with MCI only, parietal WMH volumes were associated with a lower level of Aβ 42/Aβ 40. In addition, there was an association between higher global WMH volumes and higher CSF t-tau levels among younger participants versus older ones (∼<65 versus 65+ years), independent of Aβ 42/Aβ 40 and p-tau181.
    CONCLUSION: These findings suggest that although WMH are primarily related to systemic vascular risk and neurodegeneration (i.e., t-tau), AD-specific pathways may contribute to the formation of WMH in a regionally-specific manner, with neurofibrillary tangles (i.e., p-tau) playing a role in temporal WMHs and amyloid (i.e., Aβ 42/Aβ 40) in parietal WMHs.
    Keywords:  APOE; Alzheimer’s disease; amyloid; cerebrospinal fluid; magnetic resonance imaging; tau; vascular risk; white matter hyperintensity volumes
    DOI:  https://doi.org/10.3233/JAD-220846
  108. Clin Ophthalmol. 2023 ;17 421-440
    Risk Factors for Descemet Membrane Endothelial Keratoplasty Rejection: Current Perspectives- Systematic Review.
    Bharat Gurnani, Kirandeep Kaur, Vaitheeswaran Ganesan Lalgudi, Koushik Tripathy.
      Descemet membrane endothelial keratoplasty (DMEK) is a corneal endothelial transplantation procedure with selective removal of a patient's defective Descemet membrane and endothelium. It is replaced with a healthy donor Descemet membrane and endothelium without a stromal component. Corneal graft rejection can be at the level of epithelium, stroma as well endothelium. DMEK graft rejection is relatively less common than rejection with DSAEK or penetrating keratoplasty, and a good outcome may be achieved with prompt management. The clinical picture of DMEK rejection is usually similar to endothelial rejection in Descemet Stripping Endothelial Keratoplasty (DSEK/DSAEK), which generally manifests as pain, redness, reduction in visual acuity, stromal edema, endothelial rejection line, keratic precipitates at the back of the cornea and corneal neovascularization. However, more subtle forms of rejection or immune reactions are more common in DMEK compared to DSAEK eyes. Early clinical diagnosis, prompt intervention, and meticulous management safeguard visual acuity and graft survival in these cases. Intensive topical steroids form the mainstay in the management of DMEK rejection. Sometimes, oral or intravenous steroids or other systemic immunomodulators may be required. DMEK graft failure can be primary or secondary, and failure usually requires a second procedure in the form of repeat DMEK or DSEK or penetrating keratoplasty (PKP). A detailed literature search was performed using search engines such as Google Scholar, PubMed, and Google books, and a comprehensive review on DMEK rejection was found to be lacking. This review is a comprehensive update on the risk factors, pathophysiology, primary and secondary graft failure, recent advances in diagnosis, prevention of rejection, and updates in the management of DMEK rejection. The review also discusses the differential diagnosis of DMEK failure and rejection, prognosis, and future perspectives considering DMEK failure and rejection.
    Keywords:  DMEK rejection; descemet membrane endothelial keratoplasty; primary graft failure; rebubbling; secondary graft failure
    DOI:  https://doi.org/10.2147/OPTH.S398418
  109. Curr Opin Crit Care. 2023 Jan 25.
    Gut-lung crosstalk during critical illness.
    Sridesh Nath, Georgios D Kitsios, Lieuwe D J Bos.
       PURPOSE OF REVIEW: Study of organ crosstalk in critical illness has uncovered complex biological communication between different organ systems, but the role of microbiota in organ crosstalk has received limited attention. We highlight the emerging understanding of the gut-lung axis, and how the largest biomass of the human body in the gut may affect lung physiology in critical illness.
    RECENT FINDINGS: Disruption of healthy gut microbial communities and replacement by disease-promoting pathogens (pathobiome) generates a maladaptive transmitter of messages from the gut to the lungs, connected via the portal venous and the mesenteric lymphatic systems. Gut barrier impairment allows for microbial translocation (living organisms or cellular fragments) to the lungs. Host-microbiota interactions in the gut mucosa can also impact lung physiology through microbial metabolite secretion or host-derived messengers (hormones, cytokines or immune cells). Clinical examples like the prevention of ventilator-associated pneumonia by selective decontamination of the digestive tract show that the gut-lung axis can be manipulated therapeutically.
    SUMMARY: A growing body of evidence supports the pathophysiological relevance of the gut-lung axis, yet we are only at the brink of understanding the therapeutic and prognostic relevance of the gut microbiome, metabolites and host-microbe interactions in critical illness.
    DOI:  https://doi.org/10.1097/MCC.0000000000001015
  110. Int J Mol Sci. 2023 Feb 02. pii: 2888. [Epub ahead of print]24(3):
    Longevity, Centenarians and Modified Cellular Proteodynamics.
    Natalia Frankowska, Ewa Bryl, Tamas Fulop, Jacek M Witkowski.
      We have shown before that at least one intracellular proteolytic system seems to be at least as abundant in the peripheral blood lymphocytes of centenarians as in the same cells of young individuals (with the cells of the elderly population showing a significant dip compared to both young and centenarian cohorts). Despite scarce published data, in this review, we tried to answer the question how do different types of cells of longevous people-nonagenarians to (semi)supercentenarians-maintain the quality and quantity of their structural and functional proteins? Specifically, we asked if more robust proteodynamics participate in longevity. We hypothesized that at least some factors controlling the maintenance of cellular proteomes in centenarians will remain at the "young" level (just performing better than in the average elderly). In our quest, we considered multiple aspects of cellular protein maintenance (proteodynamics), including the quality of transcribed DNA, its epigenetic changes, fidelity and quantitative features of transcription of both mRNA and noncoding RNAs, the process of translation, posttranslational modifications leading to maturation and functionalization of nascent proteins, and, finally, multiple facets of the process of elimination of misfolded, aggregated, and otherwise dysfunctional proteins (autophagy). We also included the status of mitochondria, especially production of ATP necessary for protein synthesis and maintenance. We found that with the exception of the latter and of chaperone function, practically all of the considered aspects did show better performance in centenarians than in the average elderly, and most of them approached the levels/activities seen in the cells of young individuals.
    Keywords:  autophagy; centenarians; geroproteome; longevity; proteodynamics; proteostasis
    DOI:  https://doi.org/10.3390/ijms24032888
  111. Sci Total Environ. 2023 Feb 06. pii: S0048-9697(23)00535-1. [Epub ahead of print] 161920
    Association of metals with expanded polystyrene in the marine environment.
    Sophie Irene Twyford, Andrew Turner.
      Expanded polystyrene (EPS) has characteristics distinctive from many thermoplastics that strongly influence its behaviour in the marine environment. However, the extent and nature of its interactions with metals are poorly understood. In the present study, fragments of beached EPS have been retrieved from an urban harbour and an open sandy beach in southwest England and the concentrations, locations and availabilities of various metals (and metalloids) of geochemical importance and anthropogenic significance determined. Total (aqua regia-digestible) metal concentrations at the surface (normalised to a depth of 0.5 cm) were considerably greater than surface concentrations reported for polyolefins retrieved from the same region and, with the exception of Cd, Sb and Zn, were significantly greater than those in unweathered EPS packaging material. Median surface concentrations of Al, As, Co, Fe, Mn, Ni and Sb were significantly greater at the open beach than the harbour, but concentrations of Cu and Pb were significantly greater at the latter. Where measured, concentrations of all metals were similar at the surface and subsurface (0.5 to 1 cm), and availability to 0.7 M HCl ranged from <20 % for Al and Fe to >60 % for Mn and Pb. These results, coupled with visible characteristics, suggest that aqueous and particulate metals are able to interact with the EPS surface via a number of mechanisms (adsorption, precipitation, entrapment) and migrate through the weathered, porous structure to within the polymer matrix. Enrichment factors normalised to Al as a granulometric proxy and relative to a regional baseline indicate "moderately severe" contamination with respect to Cd, Cu, Pb, Sb and Zn in at least one of the environments studied, suggesting that EPS might be a significant carrier and means of exposure for these metals in the marine environment.
    Keywords:  Adsorption; Bioavailability; Enrichment; ICP-MS; Marine plastics; Weathering
    DOI:  https://doi.org/10.1016/j.scitotenv.2023.161920
  112. Environ Sci Process Impacts. 2023 Feb 06.
    Sustainable organic waste management using vermicomposting: a critical review on the prevailing research gaps and opportunities.
    Arunachalam Thirunavukkarasu, Raja Sivashankar, Rajarathinam Nithya, Arunachalam Bose Sathya, Venkatachalam Priyadharshini, Balakrishnan Prem Kumar, Murugan Muthuveni, Sakthishobana Krishnamoorthy.
      Logistic growth of human population, exponential rate in agronomic industries and feeble waste management practices have resulted in the massive generation of organic wastes. Vermicomposting is one of the eco-biotechnological practices to efficiently transform them into stable and nutrient-rich organic manure with the synergetic actions of earthworms and soil microbiota. Vermicompost, a derivative product has the desirable physicochemical traits such as excellent porosity, buffering actions, aeration and water holding capacity. Also the presences of enzymic and microbial secretions contribute to growth and disease resistance of the crops. Owing to the benefits of soil nutrients restoration and effective organic waste management, vermicomposting has gained much attention among the scientific researchers and organic farmers. The present review is intended to provide comprehensive information on the site selection, screening of earthworms, different modes of operation and their desirable micro-environmental conditions. Also, the review has critically identified the prevailing research gaps viz. limited studies on the substrate formulation or optimization designs, poor control on the operational variables, lack of field-level investigations, technological feasibility of scale-up process, economic viability and cost-benefit analysis. Prospective researches can be made on these hotspots to identify the vermicomposting as a successful and profitable business model in the circular economy.
    DOI:  https://doi.org/10.1039/d2em00324d
  113. Nutrients. 2023 Jan 26. pii: 634. [Epub ahead of print]15(3):
    miRNAs and Alzheimer's Disease: Exploring the Role of Inflammation and Vitamin E in an Old-Age Population.
    Virginia Boccardi, Giulia Poli, Roberta Cecchetti, Patrizia Bastiani, Michela Scamosci, Marta Febo, Emanuela Mazzon, Stefano Bruscoli, Stefano Brancorsini, Patrizia Mecocci.
      Alzheimer's disease (AD) is the most frequent cause of dementia worldwide and represents one of the leading factors for severe disability in older persons. Although its etiology is not fully known yet, AD may develop due to multiple factors, including inflammation and oxidative stress, conditions where microRNAs (miRNAs) seem to play a pivotal role as a molecular switch. All these aspects may be modulated by nutritional factors. Among them, vitamin E has been widely studied in AD, given the plausibility of its various biological functions in influencing neurodegeneration. From a cohort of old-aged people, we measured eight vitamin E forms (tocopherols and tocotrienols), thirty cytokines/chemokines, and thirteen exosome-extracted miRNAs in plasma of subjects suffering from subjects affected by AD and age-matched healthy controls (HC). The sample population included 80 subjects (40 AD and 40 HC) with a mean age of 77.6 ± 3.8 years, mostly women (45; 56.2%). Of the vitamin E forms, only α-tocopherol differed between groups, with significantly lower levels in AD. Regarding the examined inflammatory molecules, G-CSF, GM-CSF, INF-α2, IL-3, and IL-8 were significantly higher and IL-17 lower in AD than HC. Among all miRNAs examined, AD showed downregulation of miR-9, miR-21, miR29-b, miR-122, and miR-132 compared to controls. MiR-122 positively and significantly correlated with some inflammatory molecules (GM-CSF, INF-α2, IL-1α, IL-8, and MIP-1β) as well as with α-tocopherol even after correction for age and gender. A final binary logistic regression analysis showed that α-tocopherol serum levels were associated with a higher AD probability and partially mediated by miR-122. Our results suggest an interplay between α-tocopherol, inflammatory molecules, and microRNAs in AD, where miR-122 may be a good candidate as modulating factor.
    Keywords:  aging; inflammation; miRNAs; oxidative stress; vitamin E
    DOI:  https://doi.org/10.3390/nu15030634
  114. Molecules. 2023 Feb 01. pii: 1388. [Epub ahead of print]28(3):
    In Silico Drug Design and Analysis of Dual Amyloid-Beta and Tau Protein-Aggregation Inhibitors for Alzheimer's Disease Treatment.
    Nisha Job, Venkatesan S Thimmakondu, Krishnan Thirumoorthy.
      Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder that gradually leads to the state of dementia. The main features of AD include the deposition of amyloid-beta peptides (Aβ), forming senile plaques, and the development of neurofibrillary tangles due to the accumulation of hyperphosphorylated Tau protein (p-tau) within the brain cells. In this report, seven dual-inhibitor molecules (L1-7) that can prevent the aggregation of both Aβ and p-tau are suggested. The drug-like features and identification of the target proteins are analyzed by the in silico method. L1-7 show positive results in both Blood-Brain Barrier (BBB) crossing and gastrointestinal absorption, rendering to the results of the permeation method. The molecular docking test performed for L1-7 shows binding energies in the range of -4.9 to -6.0 kcal/mol towards Aβ, and -4.6 to -5.6 kcal/mol for p-tau. The drug's effectiveness under physiological conditions is assessed by the use of solvation models on the investigated systems. Further, the photophysical properties of L1-3 are predicted using TD-DFT studies.
    Keywords:  Alzheimer’s disease; MD simulation; TD-DFT; amyloid beta; dual inhibitors; molecular docking; tau protein
    DOI:  https://doi.org/10.3390/molecules28031388
  115. Cell Host Microbe. 2023 Feb 08. pii: S1931-3128(23)00036-7. [Epub ahead of print]31(2): 171-172
    Revealing gut microbiome associations with CFS.
    Timothy R Sampson.
      The etiology of chronic fatigue syndrome (CFS) is largely unknown. In this issue of Cell Host and Microbe, Guo et al. and Xiong et al. report CFS-associated gut microbiome and metabolomic datasets-implicating dysregulation of immune modulating molecules. This may provide a framework for new therapeutic paradigms and disease origins.
    DOI:  https://doi.org/10.1016/j.chom.2023.01.011
  116. Front Neurosci. 2022 ;16 1043626
    Toward attention-based learning to predict the risk of brain degeneration with multimodal medical data.
    Xiaofei Sun, Weiwei Guo, Jing Shen.
       Introduction: Brain degeneration is commonly caused by some chronic diseases, such as Alzheimer's disease (AD) and diabetes mellitus (DM). The risk prediction of brain degeneration aims to forecast the situation of disease progression of patients in the near future based on their historical health records. It is beneficial for patients to make an accurate clinical diagnosis and early prevention of disease. Current risk predictions of brain degeneration mainly rely on single-modality medical data, such as Electronic Health Records (EHR) or magnetic resonance imaging (MRI). However, only leveraging EHR or MRI data for the pertinent and accurate prediction is insufficient because of single-modality information (e.g., pixel or volume information of image data or clinical context information of non-image data).
    Methods: Several deep learning-based methods have used multimodal data to predict the risks of specified diseases. However, most of them simply integrate different modalities in an early, intermediate, or late fusion structure and do not care about the intra-modal and intermodal dependencies. A lack of these dependencies would lead to sub-optimal prediction performance. Thus, we propose an encoder-decoder framework for better risk prediction of brain degeneration by using MRI and EHR. An encoder module is one of the key components and mainly focuses on feature extraction of input data. Specifically, we introduce an encoder module, which integrates intra-modal and inter-modal dependencies with the spatial-temporal attention and cross-attention mechanism. The corresponding decoder module is another key component and mainly parses the features from the encoder. In the decoder module, a disease-oriented module is used to extract the most relevant disease representation features. We take advantage of a multi-head attention module followed by a fully connected layer to produce the predicted results.
    Results: As different types of AD and DM influence the nature and severity of brain degeneration, we evaluate the proposed method for three-class prediction of AD and three-class prediction of DM. Our results show that the proposed method with integrated MRI and EHR data achieves an accuracy of 0.859 and 0.899 for the risk prediction of AD and DM, respectively.
    Discussion: The prediction performance is significantly better than the benchmarks, including MRI-only, EHR-only, and state-of-the-art multimodal fusion methods.
    Keywords:  cross-attention mechanism; multimodal learning; multimodal medical data; risk prediction of brain degeneration; self-attention mechanism
    DOI:  https://doi.org/10.3389/fnins.2022.1043626
  117. Sci Rep. 2023 Feb 09. 13(1): 2337
    Somatostatin slows Aβ plaque deposition in aged APPNL-F/NL-F mice by blocking Aβ aggregation.
    Declan Williams, Bei Qi Yan, Hansen Wang, Logine Negm, Christopher Sackmann, Claire Verkuyl, Vanessa Rezai-Stevens, Shehab Eid, Nimit Vediya, Christine Sato, Joel C Watts, Holger Wille, Gerold Schmitt-Ulms.
      The neuroendocrine peptide somatostatin (SST) has long been thought of as influencing the deposition of the amyloid β peptide (Aβ) in Alzheimer's disease (AD). Missing have been in vivo data in a relevant Aβ amyloidosis model. Here we crossed AppNL-F/NL-F mice with Sst-deficient mice to assess if and how the presence of Sst influences pathological hallmarks of Aβ amyloidosis. We found that Sst had no influence on whole brain neprilysin transcript, protein or activity levels, an observation that cannot be accounted for by a compensatory upregulation of the Sst paralog, cortistatin (Cort), that we observed in 15-month-old Sst-deficient mice. Sst-deficiency led to a subtle but significant increase in the density of cortical Aβ amyloid plaques. Follow-on western blot analyses of whole brain extracts indicated that Sst interferes with early steps of Aβ assembly that manifest in the appearance of SDS-stable smears of 55-150 kDa in Sst null brain samples. As expected, no effect of Sst on tau steady-state levels or its phosphorylation were observed. Results from this study are easier reconciled with an emerging body of data that point toward Sst affecting Aβ amyloid plaque formation through direct interference with Aβ aggregation rather than through its effects on neprilysin expression.
    DOI:  https://doi.org/10.1038/s41598-023-29559-z
  118. Molecules. 2023 Jan 19. pii: 1017. [Epub ahead of print]28(3):
    Anti-Amyloidogenic Effects of Metasequoia glyptostroboides Fruits and Its Active Constituents.
    Ji-Yun Yeo, Seul Lee, Min Sung Ko, Chung Hyun Lee, Jee Yeon Choi, Kwang Woo Hwang, So-Young Park.
      Alzheimer's disease (AD) is a serious neurodegenerative brain disease that interferes with daily life. The accumulation of beta-amyloid (Aβ), along with oxidative stress-inducing neurocellular apoptosis, has been considered one of the causes of AD. Thus, the purpose of this study is to find natural products that can reduce Aβ accumulation. The ethanol extract of Metasequoia glyptostroboides Hu & Cheng fruits (Cupressaceae) significantly reduced the aggregation of Aβ into oligomers and fibrils determined by Thioflavin T (ThT) assay. The solvent-partitioned ethyl acetate layer was further separated based on the bioassay-guided isolation method combined with the ThT assay. As a result, five compounds were isolated and elucidated as taxoquinone (1), sugiol (2), suginal (3), sandaracopimarinol (4), and sandaracopimaradien-19-ol (5) by comparing NMR data with references. All the compounds significantly reduced the aggregation of Aβ and enhanced the disaggregation of pre-formed Aβ aggregates in a dose-dependent manner. Furthermore, the inhibition of Aβ aggregation by the compounds protected PC12 cells from Aβ aggregate-induced toxicity. Among the five compounds, sandaracopimarinol (4) and sandaracopimaradien-19-ol (5) were the most effective. These results suggest that M. glyptostroboides and isolated five compounds have a potential for further study to be developed as anti-AD agents.
    Keywords:  Metasequoia glyptostroboides fruits; PC12 cells; Thioflavin T assay; beta-amyloid; sandaracopimaradien-19-ol; sandaracopimarinol
    DOI:  https://doi.org/10.3390/molecules28031017
  119. Int J Med Mushrooms. 2023 ;25(2): 11-22
    Maitake Medicinal Mushroom, Grifola frondosa (Agaricomycetes), and Its Neurotrophic Properties: A Mini-Review.
    Adrina Mohamad Naguib, Yasaaswini Apparoo, Chuan Xiong, Chia Wei Phan.
      Neurodegeneration is one of the most common manifestations in an aging population. The occurrence of oxidative stress and neuroinflammation are the main contributors to the phenomenon. Neurologic conditions such as Alzheimer's disease (AD) and Parkinson's disease (PD) are challenging to treat due to their irreversible manner as well as the lack of effective treatment. Grifola frondosa (Dicks.: Fr.) S.F. Gray, or maitake mushroom, is believed to be a potential choice as a therapeutic agent for neurodegenerative diseases. G. frondosa is known to be a functional food that has a wide variety of medicinal purposes. Thus, this review emphasizes the neuroprotective effects and the chemical composition of G. frondosa. Various studies have described that G. frondosa can protect and proliferate neuronal cells through neurogenesis, antioxidative, anti-inflammatory, and anti-β-amyloid activities. The mechanism of action behind these therapeutic findings in various in vitro and in vivo models has also been intensively studied. In this mini review, we also summarized the chemical composition of G. frondosa to provide a better understanding of the presence of nutritional compounds in G. frondosa.
    DOI:  https://doi.org/10.1615/IntJMedMushrooms.2022046849
  120. Plant Physiol Biochem. 2023 Feb 04. pii: S0981-9428(23)00080-3. [Epub ahead of print]196 431-443
    Salicylic acid interacts with other plant growth regulators and signal molecules in response to stressful environments in plants.
    Cengiz Kaya, Ferhat Ugurlar, Muhammed Ashraf, Parvaiz Ahmad.
      Salicylic acid (SA) is one of the potential plant growth regulators (PGRs) that regulate plant growth and development by triggering many physiological and metabolic processes. It is also known to be a crucial component of plant defense mechanisms against environmental stimuli. In stressed plants, it is documented that it can effectively modulate a myriad of metabolic processes including strengthening of oxidative defense system by directly or indirectly limiting the buildup of reactive nitrogen and oxygen radicals. Although it is well recognized that it performs a crucial role in plant tolerance to various stresses, it is not fully elucidated that whether low or high concentrations of this PGR is effective to achieve optimal growth of plants under stressful environments. It is also not fully understood that to what extent and in what manner it cross-talks with other potential growth regulators and signalling molecules within the plant body. Thus, this critical review discusses how far SA mediates crosstalk with other key PGRs and molecular components of signalling pathways mechanisms, particularly in plants exposed to environmental cues. Moreover, the function of SA exogenously applied in regulation of growth and development as well as reinforcement of oxidative defense system of plants under abiotic stresses is explicitly elucidated.
    Keywords:  Biosynthesis; Metabolism; Plant hormones; Salicylic acid; Signal molecules; Stress tolerance
    DOI:  https://doi.org/10.1016/j.plaphy.2023.02.006
  121. Front Neurosci. 2022 ;16 1111763
    Comparing therapeutic modulators of the SOD1 G93A Amyotrophic Lateral Sclerosis mouse pathophysiology.
    Albert J B Lee, Tyler E Kittel, Renaid B Kim, Thao-Nguyen Bach, Tian Zhang, Cassie S Mitchell.
       Introduction: Amyotrophic Lateral Sclerosis (ALS) is a paralyzing, multifactorial neurodegenerative disease with limited therapeutics and no known cure. The study goal was to determine which pathophysiological treatment targets appear most beneficial.
    Methods: A big data approach was used to analyze high copy SOD1 G93A experimental data. The secondary data set comprised 227 published studies and 4,296 data points. Treatments were classified by pathophysiological target: apoptosis, axonal transport, cellular chemistry, energetics, neuron excitability, inflammation, oxidative stress, proteomics, or systemic function. Outcome assessment modalities included onset delay, health status (rotarod performance, body weight, grip strength), and survival duration. Pairwise statistical analysis (two-tailed t-test with Bonferroni correction) of normalized fold change (treatment/control) assessed significant differences in treatment efficacy. Cohen's d quantified pathophysiological treatment category effect size compared to "all" (e.g., all pathophysiological treatment categories combined).
    Results: Inflammation treatments were best at delaying onset (d = 0.42, p > 0.05). Oxidative stress treatments were significantly better for prolonging survival duration (d = 0.18, p < 0.05). Excitability treatments were significantly better for prolonging overall health status (d = 0.22, p < 0.05). However, the absolute best pathophysiological treatment category for prolonging health status varied with disease progression: oxidative stress was best for pre-onset health (d = 0.18, p > 0.05); excitability was best for prolonging function near onset (d = 0.34, p < 0.05); inflammation was best for prolonging post-onset function (d = 0.24, p > 0.05); and apoptosis was best for prolonging end-stage function (d = 0.49, p > 0.05). Finally, combination treatments simultaneously targeting multiple pathophysiological categories (e.g., polytherapy) performed significantly (p < 0.05) better than monotherapies at end-stage.
    Discussion: In summary, the most effective pathophysiological treatments change as function of assessment modality and disease progression. Shifting pathophysiological treatment category efficacy with disease progression supports the homeostatic instability theory of ALS disease progression.
    Keywords:  Amyotrophic Lateral Sclerosis (ALS); SOD1; SOD1 G93A mouse; motoneuron disease; mouse model; neuromuscular; pharmacology
    DOI:  https://doi.org/10.3389/fnins.2022.1111763
  122. Front Aging Neurosci. 2023 ;15 1105095
    Isoniazid improves cognitive performance, clears Aβ plaques, and protects dendritic synapses in APP/PS1 transgenic mice.
    Jiacheng Chen, Ning Guo, Yuting Ruan, Yingren Mai, Wang Liao, Yanqing Feng.
       Background and objective: Alzheimer's disease (AD) is characterized by amyloid β (Aβ) aggregation and neuroinflammation. This study aimed to investigate the therapeutic effect of isoniazid (INH) against AD.
    Methods: The APP/PS1 transgenic mouse model of AD was adopted. The APP/PS1 mice received oral INH (45 mg/kg/d) for 14 days. The cognitive capability was assessed by the Morris Water Maze test. Amyloid plaques and Aβ levels were determined by immunohistochemistry and ELISA assay. The dendritic spines were analyzed by DiOlistic labeling. Immunofluorescence staining was used to observe the microglia and astrocytes.
    Results: The Morris Water Maze test suggested that INH administration can effectively attenuate the reference memory deficit and improve the working memory of the APP/PS1 mice compared to the untreated mice (all p < 0.001). INH significantly decreased the Aβ plaques in the hippocampus and cortex and reduced the levels of Aβ1-40 and Aβ1-42 in the brain homogenates, cerebrospinal fluid, and serum (all p < 0.001). INH also inhibited enzyme activities of β-site amyloid precursor protein cleaving enzyme 1 (BACE1, p < 0.05) and monoamine oxidase B (Mao-b, p < 0.01). INH significantly increased the protrusion density in the hippocampus (p < 0.01). Immunofluorescence staining revealed that INH significantly reduced the number of activated microglia and astrocytes around the Aβ plaques (both p < 0.01).
    Conclusion: Isoniazid administration effectively improved cognitive performance, cleared Aβ plaques, protected dendritic synapses, and reduced innate immune cells around the Aβ plaques, suggesting that INH could be a potential drug for AD treatment.
    Keywords:  Alzheimer’s disease; amyloid β; dendritic synapse; isoniazid; neuroinflammation
    DOI:  https://doi.org/10.3389/fnagi.2023.1105095
  123. Nutrients. 2023 Jan 28. pii: 664. [Epub ahead of print]15(3):
    The Role of Nutrition in Chronic Disease.
    Sareen S Gropper.
      According to the Centers for Disease Control and Prevention, six out of every ten adults in the United States have at least one chronic disease, and about four in ten have two or more chronic diseases [...].
    DOI:  https://doi.org/10.3390/nu15030664
  124. Eur J Neurol. 2023 Feb 11.
    Role of selective attention in fatigue in neurological disorders.
    Annapoorna Kuppuswamy.
       BACKGROUND: Chronic fatigue is a significant symptom in several diseases including traumatic and degenerative neurological disorders. While several studies have investigated the correlates of chronic fatigue, there is as yet no unifying framework to explain chronic fatigue.
    METHODS: In this narrative review, I investigate the role of selective attention in the development of chronic fatigue, and discuss results within the framework of the sensory attenuation model of fatigue, which posits that fatigue is the phenomenological output of altered attention to sensory input. Following a short introduction of this framework, I present results from investigations that address attentional mechanisms in fatigue in multiple sclerosis, stroke, traumatic brain injury and parkinson's disease.
    RESULTS: Attention was quantified in all four disease models using a variety of outcome measures, including behavioural, neurophysiological, structural and functional brain connectivity. The range of measures precluded direct comparison of results across disease conditions, however, in all four disease models, there was evidence of poor selective attention that explained levels of chronic fatigue, supporting the sensory attenuation model of fatigue as a disease-independent mechanism of fatigue. Evidence was lacking to draw any conclusions about the direction of causality.
    CONCLUSION: The role of selective attention in development of fatigue is indicated. Future studies must focus on establishing causality and exploring attentional circuitry as a potential therapeutic target.
    Keywords:  Fatigue; attention; sensory attenuation
    DOI:  https://doi.org/10.1111/ene.15739
  125. Int J Mol Sci. 2023 Jan 20. pii: 2070. [Epub ahead of print]24(3):
    Therapeutic Potential and Limitation of Serotonin Type 7 Receptor Modulation.
    Kouji Fukuyama, Eishi Motomura, Motohiro Okada.
      Although a number of mood-stabilising atypical antipsychotics and antidepressants modulate serotonin type 7 receptor (5-HT7), the detailed contributions of 5-HT7 function to clinical efficacy and pathophysiology have not been fully understood. The mood-stabilising antipsychotic agent, lurasidone, and the serotonin partial agonist reuptake inhibitor, vortioxetine, exhibit higher binding affinity to 5-HT7 than other conventional antipsychotics and antidepressants. To date, the initially expected rapid onset of antidepressant effects-in comparison with conventional antidepressants or mood-stabilising antipsychotics-due to 5-HT7 inhibition has not been observed with lurasidone and vortioxetine; however, several clinical studies suggest that 5-HT7 inhibition likely contributes to quality of life of patients with schizophrenia and mood disorders via the improvement of cognition. Furthermore, recent preclinical studies reported that 5-HT7 inhibition might mitigate antipsychotic-induced weight gain and metabolic complication by blocking other monoamine receptors. Further preclinical studies for the development of 5-HT7 modulation against neurodevelopmental disorders and neurodegenerative diseases have been ongoing. To date, various findings from various preclinical studies indicate the possibility that 5-HT7 modifications can provide two independent strategies. The first is that 5-HT7 inhibition ameliorates the dysfunction of inter-neuronal transmission in mature networks. The other is that activation of 5-HT7 can improve transmission dysfunction due to microstructure abnormality in the neurotransmission network-which could be unaffected by conventional therapeutic agents-via modulating intracellular signalling during the neurodevelopmental stage or via loss of neural networks with aging. This review attempts to describe the current and novel clinical applications of 5-HT7 modulation based on preclinical findings.
    Keywords:  antidepressants; antipsychotics; cognition; lurasidone; mood stabilising; schizophrenia; serotonin type 7 receptor; vortioxetine
    DOI:  https://doi.org/10.3390/ijms24032070
  126. Trends Analyt Chem. 2022 Dec;157 116808
    Advances in methods to analyse cardiolipin and their clinical applications.
    Javier S Bautista, Micol Falabella, Padraig J Flannery, Michael G Hanna, Simon J R Heales, Simon A S Pope, Robert D S Pitceathly.
      Cardiolipin (CL) is a mitochondria-exclusive phospholipid, primarily localised within the inner mitochondrial membrane, that plays an essential role in mitochondrial architecture and function. Aberrant CL content, structure, and localisation have all been linked to impaired mitochondrial activity and are observed in the pathophysiology of cancer and neurological, cardiovascular, and metabolic disorders. The detection, quantification, and localisation of CL species is a valuable tool to investigate mitochondrial dysfunction and the pathophysiological mechanisms underpinning several human disorders. CL is measured using liquid chromatography, usually combined with mass spectrometry, mass spectrometry imaging, shotgun lipidomics, ion mobility spectrometry, fluorometry, and radiolabelling. This review summarises available methods to analyse CL, with a particular focus on modern mass spectrometry, and evaluates their advantages and limitations. We provide guidance aimed at selecting the most appropriate technique, or combination of techniques, when analysing CL in different model systems, and highlight the clinical contexts in which measuring CL is relevant.
    Keywords:  Cardiolipin; Clinical analysis; Lipids; Liquid chromatography; Mass spectrometry; Mitochondria
    DOI:  https://doi.org/10.1016/j.trac.2022.116808
  127. J Sleep Res. 2023 Feb 06. e13841
    Revisiting the Psychobiological Inhibition Model: a conceptual framework for understanding and treating insomnia using cognitive and behavioural therapeutics (CBTx).
    Colin A Espie.
      Sleep is a biological imperative, so one might wonder "what has psychology got to do with it?" A person's behaviours, thoughts, emotions and interactions with the environment inevitably serve for good, or for ill, as the "setting conditions" for the expression of sleep. Put simply, although sleep is not a psychological phenomenon, sleep has crucial behavioural dependencies. Consequently, the Psychobiological Inhibition Model can embrace numerous, potentially interacting, pathways to the persistence of this ubiquitous disorder, providing an overarching conceptual framework for why and how insomnia develops. The clinical guideline treatment for chronic insomnia is cognitive behavioural therapy. Although typically delivered as "talking therapy", cognitive behavioural therapy is not some form of "psychobabble". Rather, the Psychobiological Inhibition Model framework for insomnia articulates how specific techniques can correct the various ways in which the expression of normal sleep and circadian brain-behaviour relationships have become disrupted. Indeed, cognitive behavioural therapy is best conceived of as an approach to treatment rather than being one specific agent. A shift in emphasis towards a cognitive and behavioural therapeutics formulary would provide improved impetus to understanding of how insomnia develops, and of how it may best be treated in any given patient.
    Keywords:  aetiology; cognitive behavioural therapy; conceptual; insomnia; model; sleep; therapeutics
    DOI:  https://doi.org/10.1111/jsr.13841
  128. Plants (Basel). 2023 Jan 21. pii: 491. [Epub ahead of print]12(3):
    Metabolomics as a Tool to Understand Nano-Plant Interactions: The Case Study of Metal-Based Nanoparticles.
    Sónia Silva, Maria Celeste Dias, Diana C G A Pinto, Artur M S Silva.
      Metabolomics is a powerful tool in diverse research areas, enabling an understanding of the response of organisms, such as plants, to external factors, their resistance and tolerance mechanisms against stressors, the biochemical changes and signals during plant development, and the role of specialized metabolites. Despite its advantages, metabolomics is still underused in areas such as nano-plant interactions. Nanoparticles (NPs) are all around us and have a great potential to improve and revolutionize the agri-food sector and modernize agriculture. They can drive precision and sustainability in agriculture as they can act as fertilizers, improve plant performance, protect or defend, mitigate environmental stresses, and/or remediate soil contaminants. Given their high applicability, an in-depth understanding of NPs' impact on plants and their mechanistic action is crucial. Being aware that, in nano-plant interaction work, metabolomics is much less addressed than physiology, and that it is lacking a comprehensive review focusing on metabolomics, this review gathers the information available concerning the metabolomic tools used in studies focused on NP-plant interactions, highlighting the impact of metal-based NPs on plant metabolome, metabolite reconfiguration, and the reprogramming of metabolic pathways.
    Keywords:  impact on plants; metabolic pathways; metabolite content; metallic nanoparticles
    DOI:  https://doi.org/10.3390/plants12030491
  129. Diabetes Metab J. 2023 Feb 08.
    Gestational Diabetes Mellitus and Its Implications across the Life Span.
    Brandy Wicklow, Ravi Retnakaran.
      Gestational diabetes mellitus (GDM) has historically been perceived as a medical complication of pregnancy that also serves as a harbinger of maternal risk of developing type 2 diabetes mellitus (T2DM) in the future. In recent decades, a growing body of evidence has detailed additional lifelong implications that extend beyond T2DM, including an elevated risk of ultimately developing cardiovascular disease. Furthermore, the risk factors that mediate this lifetime cardiovascular risk are evident not only after delivery but are present even before the pregnancy in which GDM is first diagnosed. The concept thus emerging from these data is that the diagnosis of GDM enables the identification of women who are already on an enhanced track of cardiometabolic risk that starts early in life. Studies of the offspring of pregnancies complicated by diabetes now suggest that the earliest underpinnings of this cardiometabolic risk profile may be determined in utero and may first manifest clinically in childhood. Accordingly, from this perspective, GDM is now seen as a chronic metabolic disorder that holds implications across the life span of both mother and child.
    Keywords:  Cardiovascular diseases; Child; Diabetes, gestational; Life change events
    DOI:  https://doi.org/10.4093/dmj.2022.0348
  130. Nutrients. 2023 Jan 25. pii: 618. [Epub ahead of print]15(3):
    S-(-)-Oleocanthal Ex Vivo Modulatory Effects on Gut Microbiota.
    Mohammed H Qusa, Khaldoun S Abdelwahed, Ronald A Hill, Khalid A El Sayed.
      Compelling evidence points to the critical role of bioactive extra-virgin olive oil (EVOO) phenolics and gut microbiota (GM) interplay, but reliable models for studying the consequences thereof remain to be developed. Herein, we report an optimized ex vivo fecal anaerobic fermentation model to study the modulation of GM by the most bioactive EVOO phenolic S-(-)-oleocanthal (OC), and impacts therefrom, focusing on OC biotransformation in the gut. This model will also be applicable for characterization of GM interactions with other EVOO phenolics, and moreover, for a broadly diverse range of bioactive natural products. The fecal fermentation media and time, and mouse type and gender, were the major factors varied and optimized to provide better understanding of GM-OC interplay. A novel resin entrapment technique (solid-phase extraction) served to selectively entrap OC metabolites, degradation products, and any remaining fraction of OC while excluding interfering complex fecal medium constituents. The effects of OC on GM compositions were investigated via shallow shotgun DNA sequencing. Robust metabolome analyses identified GM bacterial species selectively altered (population numbers/fraction) by OC. Finally, the topmost OC-affected gut bacterial species of the studied mice were compared with those known to be extant in humans and distributions of these bacteria at different human body sites. OC intake caused significant quantitative and qualitative changes to mice GM, which was also comparable with human GM. Results clearly highlight the potential positive health outcomes of OC as a prospective nutraceutical.
    Keywords:  S-(−)-oleocanthal; extra-virgin olive oil; fecal fermentation; microbiota; shotgun analysis
    DOI:  https://doi.org/10.3390/nu15030618
  131. Phytother Res. 2023 Feb 09.
    Aqueous extract of Ceratonia siliqua L. leaves elicits antioxidant, anti-inflammatory, and AChE inhibiting effects in amyloid-β42-induced cognitive deficit mice: Role of α7-nAChR in modulating Jak2/PI3K/Akt/GSK-3β/β-catenin cascade.
    Nesrine S El Sayed, Sara Abidar, Mohamed Nhiri, Lucian Hritcu, Weam W Ibrahim.
      Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder attributed to several etiological factors including cholinergic dysregulation, neuroinflammation, oxidative stress, β-amyloidogenesis, and tauopathy. This demands the search for multitarget drugs, especially of natural sources owing to their pleiotropic activities and low adverse effects. The present study was conducted to investigate the cognitive-improving potential of Ceratonia siliqua L. (Cs) extract compared with donepezil, an acetylcholinesterase inhibitor, on AD-like pathological alterations induced by single intracerebroventricular amyloid-β42 (Aβ42) injection in mice. Aβ42-injected mice were treated with Cs (100 mg/kg/day, po) with or without methyllycaconitine (MLA; 1 mg/kg/day, ip), an α7-nAChR antagonist. Aβ42-injected animals demonstrated an elevation of hippocampal Aβ42, p-Tau, and acetylcholinesterase. They also showed a decline in phosphorylated levels of Jak2, PI3K, Akt, and GSK-3β, leading to induction of neuroinflammation and oxidative stress. Noteworthy, Cs improved the histopathological and behavioral variables in addition to mitigating AD hallmarks. It also exerted neuroprotection by reducing NF-κBp65 and TNF-α, while elevating Nrf2 and HO-1, along with stabilizing β-catenin under the impact of Jak2/PI3K/Akt/GSK-3β signaling. These beneficial effects of Cs were abrogated by MLA co-administration signifying the α7-nAChR involvement in Cs-mediated effects. Therefore, Cs can ameliorate Aβ42-induced neurodegeneration by modulating Jak2/PI3K/Akt/GSK-3β/β-catenin axis in an α7-nAChR-dependent manner.
    Keywords:  Ceratonia siliqua L.; PI3K/Akt/GSK-3β; amyloid-β; mice; α7-nAChR; β-catenin
    DOI:  https://doi.org/10.1002/ptr.7766
  132. Int J Environ Res Public Health. 2023 Jan 31. pii: 2579. [Epub ahead of print]20(3):
    Soluble ST2 as a New Oxidative Stress and Inflammation Marker in Metabolic Syndrome.
    Ignacio Roy, Eva Jover, Lara Matilla, Virginia Alvarez, Amaya Fernández-Celis, Maite Beunza, Elena Escribano, Alicia Gainza, Rafael Sádaba, Natalia López-Andrés.
       BACKGROUND: Metabolic syndrome (MS) is a complex and prevalent disorder. Oxidative stress and inflammation might contribute to the progression of MS. Soluble ST2 (sST2) is an attractive and druggable molecule that sits at the interface between inflammation, oxidative stress and fibrosis. This study aims to analyze the relationship among sST2, oxidative stress, inflammation and echocardiographic parameters in MS patients.
    METHODS: Fifty-eight patients with MS were recruited and underwent physical, laboratory and transthoracic echocardiography examinations. Commercial ELISA and appropriate colorimetric assays were used to quantify serum levels of oxidative stress and inflammation markers and sST2.
    RESULTS: Circulating sST2 was increased in MS patients and was significantly correlated with the oxidative stress markers nitrotyrosine and 8-hydroxy-2'-deoxyguanosine as well as with peroxide levels. The inflammatory parameters interleukin-6, intercellular adhesion molecule-1 and myeloperoxidase were positively correlated with sST2. Noteworthy, sST2 was positively correlated with left ventricular mass, filling pressures and pulmonary arterial pressures.
    CONCLUSION: Circulating levels of sST2 are associated with oxidative stress and inflammation burden and may underlie the pathological remodeling and dysfunction of the heart in MS patients. Our results suggest that sST2 elevation precedes diastolic dysfunction, emerging as an attractive biotarget in MS.
    Keywords:  inflammation; metabolic syndrome; oxidative stress; soluble ST2
    DOI:  https://doi.org/10.3390/ijerph20032579
  133. Clin Exp Dermatol. 2023 Jan 11. pii: llad010. [Epub ahead of print]
    Dermoscopy of subclinical nail involvement in diabetes mellitus patients: A case-control study.
    Eman R M Hofny, Yasmin M Tawfik, Mohamed S Hasan, Yasmin Salah, Mahmoud A Rageh.
       BACKGROUND: Diabetes mellitus (DM) is a chronic disease characterized by elevated blood glucose levels, which can lead to serious complications. Nails are a mirror for general health, so their changes can be an indicator of the disease progression in diabetic patients.
    OBJECTIVES: To detect subclinical nail changes in DM patients with dermoscopy.
    METHODS: One hundred participants from Dermatology, Venereology and, Andrology outpatient clinics were recruited. They were grouped into a diabetic group (50 patients) and an age and sex-matched healthy reference group (50 participants). All patients had clinically free nails. Dermoscopic examinations were conducted and compared between both groups.
    RESULTS: It was found that 33 patients of DM group (66%) had dermoscopic nail findings in the form of microhemorrhage (26%), longitudinal striations (24%), distal subungual onychomycosis (24%), superficial pitting (20%) distal onycholysis (18%), splinter hemorrhage (14%), subungual hyperkeratosis (12%), dilated vessels (10%) and distal yellowish discoloration (8%).
    CONCLUSIONS: Nail examination can be accomplished with the help of dermoscopy to detect subclinical nail changes in patients diagnosed with DM and, therefore, can give us an idea about the disease progression and help with disease control and treatment plans.
    DOI:  https://doi.org/10.1093/ced/llad010
  134. bioRxiv. 2023 Jan 26. pii: 2023.01.25.525587. [Epub ahead of print]
    Lost in space(s): multimodal neuroimaging of disorientation along the Alzheimer's disease continuum.
    Gregory Peters-Founshtein, Lidor Gazit, Tahel Naveh, Liran Domachevsky, Amos Korczyn, Hanna Bernstine, David Groshar, Gad A Marshall, Shahar Arzy.
      Orientation is a fundamental cognitive faculty, allowing the behaving self to link his/her current state to their internal representations of the external world. Once exclusively linked to knowledge of the current place and present time, in recent years, the concept of orientation has evolved to include processing of social, temporal, and abstract relations. Concordantly with the growing focus on orientation, spatial disorientation has been increasingly recognized as a hallmark symptom of Alzheimer's disease (AD). However, few studies have sought to explore disorientation along the AD continuum beyond the spatial domain. 51 participants along the AD continuum performed an orientation task in the spatial, temporal and social domains. Under functional magnetic resonance imaging (fMRI), participants determined which of two familiar places/events/people is geographically/chronologically/socially closer to them, respectively. A series of analyses revealed disorientation along the AD-continuum to follow a three-way association between (1) orientation domain, (2) brain region, and (3) disease stage. Specifically, participants with MCI exhibited impaired spatio-temporal orientation and reduced task-evoked activity in temporoparietal regions, while participants with AD dementia exhibited impaired social orientation and reduced task-evoked activity in frontoparietal regions. Furthermore, these patterns of hypoactivation coincided with Default Mode Network (DMN) sub-networks, with spatio-temporal orientation activation overlapping DMN-C and social orientation with DMN-A. Finally, these patterns of disorientation-associated hypoactivations coincided with patterns of fluorodeoxyglucose (FDG) hypometabolism and cortical atrophy characteristic to AD-dementia. Taken together, our results suggest that AD may constitute a disorder of orientation, characterized by a biphasic process as (1) early spatio-temporal and (2) late social disorientation, concurrently manifesting in task-evoked and neurodegenerative changes in temporoparietal and parieto-frontal brain networks, respectively. We propose that a profile of disorientation across multiple domains offers a unique window into the progression of AD.
    DOI:  https://doi.org/10.1101/2023.01.25.525587
  135. Life Sci. 2023 Feb 08. pii: S0024-3205(23)00127-3. [Epub ahead of print] 121493
    TRPV4 regulates mitochondrial Ca2+-status and physiology in primary murine T cells based on their immunological state.
    Tusar Kanta Acharya, Shamit Kumar, Tejas Pravin Rokade, Young-Tae Chang, Chandan Goswami.
      T cell activation process is critically affected by temperature and intracellular Ca2+-signalling. Yet, the nature and the key molecules involved in such complex Ca2+-signalling is poorly understood. It is mostly assumed that ion channels present in the plasma membrane primarily regulate the cytosolic Ca2+-levels exclusively. TRPV4 is a non-selective Ca2+ channel which can be activated at physiological temperature. TRPV4 is involved in several physiological, pathophysiological process as well as different forms of pain. Here we demonstrate that TRPV4 is endogenously expressed in T cell and is present in the mitochondria of T cells. TRPV4 activation increases mitochondrial Ca2+-levels, and alters mitochondrial temperature as well as specific metabolisms. The TRPV4-dependent increment in the mitochondrial Ca2+ is context-dependent and not just passively due to the increment in the cytosolic Ca2+. Our work also indicates that mitochondrial Ca2+-level correlates positively with a series of essential factors, such as mitochondrial membrane potential, mitochondrial ATP production and negatively correlates with certain factors such as mitochondrial temperature. We propose that TRPV4-mediated mitochondrial Ca2+-signalling and other metabolisms has implications in the immune activation process including immune synapse formation. Our data also endorse the re-evaluation of Ca2+-signalling in T cell, especially in the light of mitochondrial Ca2+-buffering and in higher body temperature, such as in case of fever. Presence of TRPV4 in the mitochondria of T cell is relevant for proper and optimum immune response and may provide evolutionary adaptive benefit. These findings may also have broad implications in different pathophysiological process, neuro-immune cross-talks, and channelopathies involving TRPV4.
    Keywords:  ATP; Ca2+; Cardiolipin; ER-mito contact sites; Membrane potential; Mitochondria; Pain; T cell; TCR activation; TRPV4; Temperature
    DOI:  https://doi.org/10.1016/j.lfs.2023.121493
  136. J Alzheimers Dis. 2023 Jan 28.
    Soluble TREM2, Alzheimer's Disease Pathology, and Risk for Progression of Cerebral Small Vessel Disease: A Longitudinal Study.
    Alzheimer’s Disease Neuroimaging Initiative
      BackgroundUntil recently, studies on associations between neuroinflammation in vivo and cerebral small vessel disease (CSVD) are scarce. Cerebrospinal fluid (CSF) levels of soluble triggering receptor expressed on myeloid cells 2 (sTREM2), a candidate biomarker of microglial activation and neuroinflammation, were found elevated in Alzheimer's disease (AD), but they have not been fully explored in CSVD.ObjectiveTo determine whether CSF sTREM2 levels are associated with the increased risk of CSVD progression.MethodsA total of 426 individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database were included in this study. All participants underwent measurements of CSF sTREM2 and AD pathology (Aβ 1 - 42, P-tau181P). The progression of CSVD burden and imaging markers, including cerebral microbleeds (CMBs), white matter hyperintensities and lacunes, were estimated based on neuroimaging changes. Logistic regression and moderation effect models were applied to explore associations of sTREM2 with CSVD progression and AD pathology.Results Higher CSF sTREM2 levels at baseline were associated with increased CSVD burden (OR = 1.28 [95% CI, 1.01-1.62]) and CMBs counts (OR = 1.32 [95% CI, 1.03-1.68]). Similarly, increased change rates of CSF sTREM2 might predict elevated CMBs counts (OR = 1.44 [95% CI, 1.05-1.98]). Participants with AD pathology (Aβ 1 - 42 and P-tau181P) showed a stronger association between CSF sTREM2 and CSVD progression.ConclusionThis longitudinal study found a positive association between CSF sTREM2 and CSVD progression, suggesting that neuroinflammation might promote CSVD. Furthermore, neuroinflammation could be a shared pathogenesis of CSVD and AD at the early stage. Targeting neuroinflammation to intervene the progression of CSVD and AD warrants further investigation.
    Keywords:  Alzheimer’s disease; amyloid-β; cerebral small vessel disease; microglia; neuroinflammation; sTREM2
    DOI:  https://doi.org/10.3233/JAD-220731
  137. Molecules. 2023 Jan 26. pii: 1226. [Epub ahead of print]28(3):
    Neuroprotective Actions of Different Exogenous Nucleotides in H2O2-Induced Cell Death in PC-12 Cells.
    Na Zhu, Riu Liu, Mei-Hong Xu, Yong Li.
      Exogenous nucleotides (NTs) are considered conditionally essential nutrients, and the brain cannot synthesize NTs de novo. Therefore, the external supplementation of exogenous NTs is of great significance for maintaining normal neuronal metabolism and function under certain conditions, such as brain aging. This study, therefore, sets out to assess the neuroprotective effect of four kinds of single exogenous NTs and a mixture of the NTs, and to elucidate the potential mechanism. A rat pheochromocytoma cell line PC-12 was treated with different concentrations of exogenous NTs after 4 h of exposure to 200 µM H2O2. We found that the exogenous NTs exerted significant neuroprotection through decreasing neuron apoptosis and DNA damage, ameliorating inflammation and mitochondrial dysfunction, promoting cell viability, and augmenting antioxidant activity, and that they tended to up-regulate the NAD+/SIRTI/PGC-1α pathway involved in mitochondrial biogenesis. Among the different NTs, the neuroprotective effect of AMP seemed to be more prominent, followed by the NT mixture, NMN, and CMP. AMP also exhibited the strongest antioxidant activity in H2O2-treated PC-12 cells. UMP was excellent at inhibiting neuronal inflammation and improving mitochondrial function, while GMP offered major advantages in stabilizing mitochondrial membrane potential. The mixture of NTs had a slightly better performance than NMN, especially in up-modulating the NAD+/SIRTI/PGC-1α pathway, which regulates mitochondrial biogenesis. These results suggest that antioxidant activity, anti-inflammatory activity, and protection of mitochondrial function are possible mechanisms of the neuroprotective actions of exogenous NTs, and that the optimization of the mixture ratio and the concentration of NTs may achieve a better outcome.
    Keywords:  exogenous nucleotides; inflammation; mitochondrial function; neurodegenerative; neuroprotective; oxidative stress
    DOI:  https://doi.org/10.3390/molecules28031226
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