bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2022–04–17
eighty-one papers selected by
Yasmin Elkabani, Egyptian Foundation for Research and Community Development
  1. Progress in Metabolic Studies of Gastric Cancer and Therapeutic Implications.
  2. The Interplay between Autophagy and Redox Signaling in Cardiovascular Diseases.
  3. Interplays between drugs and the gut microbiome.
  4. Treatment against glucose-dependent cancers through metabolic PFKFB3 targeting of glycolytic flux.
  5. Pharmacokinetic, Metabolism, and Metabolomic Strategies Provide Deep Insight Into the Underlying Mechanism of Ginkgo biloba Flavonoids in the Treatment of Cardiovascular Disease.
  6. Dysmetabolism and Neurodegeneration: Trick or Treat?
  7. Modulation of Notch Signaling Pathway by Bioactive Dietary Agents.
  8. Integrating metabolomics and network pharmacology to reveal the mechanisms of Delphinium brunonianum extract against nonalcoholic steatohepatitis.
  9. Amino Acid-Related Metabolic Signature in Obese Children and Adolescents.
  10. Er-Chen Decoction Alleviates High-Fat Diet-Induced Nonalcoholic Fatty Liver Disease in Rats through Remodeling Gut Microbiota and Regulating the Serum Metabolism.
  11. Mitochondrial Dysfunction and Acute Fatty Liver of Pregnancy.
  12. Impact of Lipid Metabolism on Antitumor Immune Response.
  13. Nutrition, metabolism, and epigenetics: pathways of circadian reprogramming.
  14. Lysosomes in Stem Cell Quiescence: A Potential Therapeutic Target in Acute Myeloid Leukemia.
  15. Iron metabolism: State of the art in hypoxic cancer cell biology.
  16. 'Reverse Warburg effect' of cancer‑associated fibroblasts (Review).
  17. Effects of Exogenous ATP on Melanoma Growth and Tumor Metabolism in C57BL/6 Mice.
  18. Multi-Omics Approach Reveals Dysregulation of Protein Phosphorylation Correlated with Lipid Metabolism in Mouse Non-Alcoholic Fatty Liver.
  19. Disruption of Iron Homeostasis and Mitochondrial Metabolism Are Promising Targets to Inhibit Candida auris.
  20. The role of AMPK-dependent pathways in cellular and molecular mechanisms of metformin: a new perspective for treatment and prevention of diseases.
  21. Pinpointing Cancer Sub-Type Specific Metabolic Tasks Facilitates Identification of Anti-cancer Targets.
  22. NSAIDs Induce Proline Dehydrogenase/Proline Oxidase-Dependent and Independent Apoptosis in MCF7 Breast Cancer Cells.
  23. Oxidative stress in the pathophysiology of type 2 diabetes and related complications: Current therapeutics strategies and future perspectives.
  24. Diet-gut microbiota interactions on cardiovascular disease.
  25. An Overlooked Prebiotic: Beneficial Effect of Dietary Nucleotide Supplementation on Gut Microbiota and Metabolites in Senescence-Accelerated Mouse Prone-8 Mice.
  26. Estrogens and Progestins Cooperatively Shift Breast Cancer Cell Metabolism.
  27. The Critical Role of the Branched Chain Amino Acids (BCAAs) Catabolism-Regulating Enzymes, Branched-Chain Aminotransferase (BCAT) and Branched-Chain α-Keto Acid Dehydrogenase (BCKD), in Human Pathophysiology.
  28. Pectic polysaccharides: Targeting gut microbiota in obesity and intestinal health.
  29. The Role of Palmitoleic Acid in Regulating Hepatic Gluconeogenesis through SIRT3 in Obese Mice.
  30. Synapses: The Brain's Energy-Demanding Sites.
  31. Obesity and gut-microbiota-brain axis: A narrative review.
  32. The Growth, Lipid Accumulation and Fatty Acid Profile Analysis by Abscisic Acid and Indol-3-Acetic Acid Induced in Chlorella sp. FACHB-8.
  33. How Does Immunomodulatory Nanoceria Work? ROS and Immunometabolism.
  34. Flazin as a Lipid Droplet Regulator against Lipid Disorders.
  35. The potential of dandelion in the fight against gastrointestinal diseases: A review.
  36. Astaxanthin Bioactivity Is Determined by Stereoisomer Composition and Extraction Method.
  37. Robust Validation and Comprehensive Analysis of a Novel Signature Derived from Crucial Metabolic Pathways of Pancreatic Ductal Adenocarcinoma.
  38. Retinoids in the Pathogenesis and Treatment of Liver Diseases.
  39. Aptamer‑based therapy for targeting key mediators of cancer metastasis (Review).
  40. High fructose diet: A risk factor for immune system dysregulation.
  41. Targeting signaling pathway by curcumin in osteosarcoma.
  42. Aging Microbiota-Gut-Brain Axis in Stroke Risk and Outcome.
  43. L-theanine prevents progression of nonalcoholic hepatic steatosis by regulating hepatocyte lipid metabolic pathways via the CaMKKβ-AMPK signaling pathway.
  44. PI3K/Akt/mTOR Pathway and Its Role in Cancer Therapeutics: Are We Making Headway?
  45. Oral-Gut Microbiome Axis in the Pathogenesis of Cancer Treatment-Induced Oral Mucositis.
  46. FGF21: A Novel Regulator of Glucose and Lipid Metabolism and Whole-Body Energy Balance.
  47. Nutritional programming by maternal diet alters offspring lipid metabolism in a marine teleost.
  48. Nuts as a Part of Dietary Strategy to Improve Metabolic Biomarkers: A Narrative Review.
  49. Murine Gut Microbiome Meta-analysis Reveals Alterations in Carbohydrate Metabolism in Response to Aging.
  50. A Rational Foundation for Micheliolide-based Combination Strategy by Targeting Redox and Metabolic Circuit in Cancer Cells.
  51. Curcumin as a Potential Therapeutic Agent in Certain Cancer Types.
  52. Cholesterol metabolism and its implication in glioblastoma therapy.
  53. Histamine Causes Pyroptosis of Liver by Regulating Gut-Liver Axis in Mice.
  54. Metabolic Syndrome and β-Oxidation of Long-Chain Fatty Acids in the Brain, Heart, and Kidney Mitochondria.
  55. Characteristics and molecular mechanisms through which SGLT2 inhibitors improve metabolic diseases: A mechanism review.
  56. Insulin-Degrading Enzyme, an Under-Estimated Potential Target to Treat Cancer?
  57. PyMiner: A method for metabolic pathway design based on the uniform similarity of substrate-product pairs and conditional search.
  58. Double-activation of mitochondrial permeability transition pore opening via calcium overload and reactive oxygen species for cancer therapy.
  59. Flavonoids in Treatment of Chronic Kidney Disease.
  60. A novel anticancer property of Lycium barbarum polysaccharide in triggering ferroptosis of breast cancer cells.
  61. Recent advances in the microbial production of squalene.
  62. Biochemical Functions and Clinical Characterizations of the Sirtuins in Diabetes-Induced Retinal Pathologies.
  63. Biochemical profiling of lead-intoxicated impaired lipid metabolism and its amelioration using plant-based bioactive compound.
  64. PM2.5 Exposure and Asthma Development: The Key Role of Oxidative Stress.
  65. Gut dysbiosis and homocysteine: a couple for boosting neurotoxicity in Huntington disease.
  66. Diet-Induced Metabolic Dysfunction of Hypothalamic Nutrient Sensing in Rodents.
  67. Fighting Carcinogenesis with Plant Metabolites by Weakening Proliferative Signaling and Disabling Replicative Immortality Networks of Rapidly Dividing and Invading Cancerous Cells.
  68. Schisandrin B mitigates hepatic steatosis and promotes fatty acid oxidation by inducing autophagy through AMPK/mTOR signaling pathway.
  69. Role of dietary iron revisited: in metabolism, ferroptosis and pathophysiology of cancer.
  70. Combined Levo-tetrahydropalmatine and diphenyleneiodonium chloride enhances antitumor activity in hepatocellular carcinoma.
  71. Zinc in Cancer Therapy Revisited.
  72. Sodium butyrate reduces endoplasmic reticulum stress by modulating CHOP and empowers favorable anti-inflammatory adipose tissue immune-metabolism in HFD fed mice model of obesity.
  73. Hepatic PTEN Signaling Regulates Systemic Metabolic Homeostasis through Hepatokines-Mediated Liver-to-Peripheral Organs Crosstalk.
  74. Overarching roles of diacylglycerol signaling in cancer development and antitumor immunity.
  75. Resistant starches and gut microbiota.
  76. Lipids and diastolic dysfunction: Recent evidence and findings.
  77. Traditional Chinese Medicine Ginseng Dingzhi Decoction Ameliorates Myocardial Fibrosis and High Glucose-Induced Cardiomyocyte Injury by Regulating Intestinal Flora and Mitochondrial Dysfunction.
  78. Kaempferol Can Reverse the 5-Fu Resistance of Colorectal Cancer Cells by Inhibiting PKM2-Mediated Glycolysis.
  79. Effects of dietary supplementation of different levels of vitamin B12 on the liver metabolism of laying hens.
  80. Targeting NLRP3 Inflammasome With Nrf2 Inducers in Central Nervous System Disorders.
  81. Melatonin Positively Regulates Both Dark- and Age-Induced Leaf Senescence by Reducing ROS Accumulation and Modulating Abscisic Acid and Auxin Biosynthesis in Cucumber Plants.
  1. Curr Cancer Drug Targets. 2022 Apr 13.
    Progress in Metabolic Studies of Gastric Cancer and Therapeutic Implications.
    Adriana Romo-Perez, Guadalupe Dominguez-Gomez, Alma Chavez-Blanco, Lucia Taja-Chayeb, Aurora Gonzalez-Fierro, Consuelo Diaz-Romero, Horacio Noe Lopez-Basave, Alfonso Duenas-Gonzalez.
       BACKGROUND: Worldwide, gastric cancer is ranked the fifth malignancy in incidence and the third malignancy in mortality. Gastric cancer causes an altered metabolism that can be therapeutically exploited.
    OBJECTIVE: To provide an overview of the significant metabolic alterations caused by gastric cancer and propose a blockade.
    METHODS: A comprehensive and up-to-date review of descriptive and experimental publications on the metabolic alterations caused by gastric cancer and their blockade. This is not a systematic review.
    RESULTS: Gastric cancer causes high rates of glycolysis and glutaminolysis. There are increased rates of de novo fatty acid synthesis and cholesterol synthesis. Moreover, gastric cancer causes high rates of lipid turnover via fatty acid -oxidation. Preclinical data indicate that the individual blockade of these pathways via enzyme targeting leads to antitumor effects in vitro and in vivo. Nevertheless, there is no data on the simultaneous blockade of these five pathways, which is critical, as tumors show metabolic flexibility in response to the availability of nutrients. This means tumors may activate alternate routes when one or more are inhibited. We hypothesize there is a need to simultaneously blockade them to avoid or decrease the metabolic flexibility that may lead to treatment resistance.
    CONCLUSIONS: There is a need to explore the preclinical efficacy and feasibility of combined metabolic therapy targeting the pathways of glucose, glutamine, fatty acid synthesis, cholesterol synthesis, and fatty acid oxidation. This may have therapeutical implications because we have clinically available drugs that target these pathways in gastric cancer.
    Keywords:  Gastric cancer; glutaminolysis; glycolysis; lipidic; metabolic blockade; metabolism
    DOI:  https://doi.org/10.2174/1568009622666220413083534
  2. Cells. 2022 Apr 02. pii: 1203. [Epub ahead of print]11(7):
    The Interplay between Autophagy and Redox Signaling in Cardiovascular Diseases.
    Barbora Boťanská, Ima Dovinová, Miroslav Barančík.
      Reactive oxygen and nitrogen species produced at low levels under normal cellular metabolism act as important signal molecules. However, at increased production, they cause damage associated with oxidative stress, which can lead to the development of many diseases, such as cardiovascular, metabolic, neurodegenerative, diabetes, and cancer. The defense systems used to maintain normal redox homeostasis plays an important role in cellular responses to oxidative stress. The key players here are Nrf2-regulated redox signaling and autophagy. A tight interface has been described between these two processes under stress conditions and their role in oxidative stress-induced diseases progression. In this review, we focus on the role of Nrf2 as a key player in redox regulation in cell response to oxidative stress. We also summarize the current knowledge about the autophagy regulation and the role of redox signaling in this process. In line with the focus of our review, we describe in more detail information about the interplay between Nrf2 and autophagy pathways in myocardium and the role of these processes in cardiovascular disease development.
    Keywords:  Nrf2; autophagy; cardiovascular disease; heart; redox signaling
    DOI:  https://doi.org/10.3390/cells11071203
  3. Gastroenterol Rep (Oxf). 2022 ;10 goac009
    Interplays between drugs and the gut microbiome.
    Yating Wan, Tao Zuo.
      The gut microbiota is considered a key 'metabolic organ'. Its metabolic activities play essential roles complementary to the host metabolic functions. The interplays between gut microbes and commonly used non-antibiotic drugs have garnered substantial attention over the years. Drugs can reshape the gut microorganism communities and, vice versa, the diverse gut microbes can affect drug efficacy by altering the bioavailability and bioactivity of drugs. The metabolism of drugs by gut microbial action or by microbiota-host cometabolism can transform the drugs into various metabolites. Secondary metabolites produced from the gut microbial metabolism of drugs contribute to both the therapeutic benefits and the side effects. In view of the significant effect of the gut microbiota on drug efficiency and clinical outcomes, it is pivotal to explore the interactions between drugs and gut microbiota underlying medical treatments. In this review, we describe and summarize the complex bidirectional interplays between gut microbes and drugs. We also illustrate the gut-microbiota profile altered by non-antibiotic drugs, the impacts and consequences of microbial alteration, and the biochemical mechanism of microbes impacting drug effectiveness. Understanding how the gut microbes interact with drugs and influence the therapeutic efficacy will help in discovering diverse novel avenues of regulating the gut microbes to improve the therapeutic effects and clinical outcomes of a drug in precision.
    Keywords:  drug; efficacy; gut microbiota; metabolism; microbiome
    DOI:  https://doi.org/10.1093/gastro/goac009
  4. Cancer Metastasis Rev. 2022 Apr 14.
    Treatment against glucose-dependent cancers through metabolic PFKFB3 targeting of glycolytic flux.
    Brandon C Jones, Paula R Pohlmann, Robert Clarke, Surojeet Sengupta.
      Reprogrammed metabolism and high energy demand are well-established properties of cancer cells that enable tumor growth. Glycolysis is a primary metabolic pathway that supplies this increased energy demand, leading to a high rate of glycolytic flux and a greater dependence on glucose in tumor cells. Finding safe and effective means to control glycolytic flux and curb cancer cell proliferation has gained increasing interest in recent years. A critical step in glycolysis is controlled by the enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), which converts fructose 6-phosphate (F6P) to fructose 2,6-bisphosphate (F2,6BP). F2,6BP allosterically activates the rate-limiting step of glycolysis catalyzed by PFK1 enzyme. PFKFB3 is often overexpressed in many human cancers including pancreatic, colon, prostate, and breast cancer. Hence, PFKFB3 has gained increased interest as a compelling therapeutic target. In this review, we summarize and discuss the current knowledge of PFKFB3 functions, its role in cellular pathways and cancer development, its transcriptional and post-translational activity regulation, and the multiple pharmacologic inhibitors that have been used to block PFKFB3 activity in cancer cells. While much remains to be learned, PFKFB3 continues to hold great promise as an important therapeutic target either as a single agent or in combination with current interventions for breast and other cancers.
    Keywords:  Aerobic glycolysis; Cancer; Glucose metabolism; PFKFB3; Phosphofructo-2-kinase/fructose-2,6-biphosphatase
    DOI:  https://doi.org/10.1007/s10555-022-10027-5
  5. Front Nutr. 2022 ;9 857370
    Pharmacokinetic, Metabolism, and Metabolomic Strategies Provide Deep Insight Into the Underlying Mechanism of Ginkgo biloba Flavonoids in the Treatment of Cardiovascular Disease.
    Yi Tao, Fei Zhu, Meiling Pan, Qing Liu, Ping Wang.
      Ginkgo biloba, known as the "living fossil," has a long history of being used as botanical drug for treating cardiovascular diseases and the content of flavonoids as high as 24%. More than 110 different kinds of flavonoids and their derivatives have been separated from G. biloba, including flavones, flavonols, biflavonoids, catechins, and their glycosides, etc., all of which display the ability to dilate blood vessels, regulate blood lipids, and antagonize platelet activating factor, and protect against ischemic damage. At present, many types of preparations based on G. biloba extract or the bioactive flavonoids of it have been developed, which are mostly used for the treatment of cardiovascular diseases. We herein review recent progress in understanding the metabolic regulatory processes and gene regulation of cellular metabolism in cardiovascular diseases of G. biloba flavonoids. First, we present the cardioprotective flavonoids of G. biloba and their possible pharmacological mechanism. Then, it is the pharmacokinetic and liver and gut microbial metabolism pathways that enable the flavonoids to reach the target organ to exert effect that is analyzed. In the end, we review the possible endogenous pathways toward restoring lipid metabolism and energy metabolism as well as detail novel metabolomic methods for probing the cardioprotective effect of flavonoids of G. biloba.
    Keywords:  Ginkgo biloba; cardiovascular disease; flavonoids; gut microbiota; metabolism; metabolomics; pharmacokinetics
    DOI:  https://doi.org/10.3389/fnut.2022.857370
  6. Nutrients. 2022 Mar 29. pii: 1425. [Epub ahead of print]14(7):
    Dysmetabolism and Neurodegeneration: Trick or Treat?
    Adriana M Capucho, Ana Chegão, Fátima O Martins, Hugo Vicente Miranda, Sílvia V Conde.
      Accumulating evidence suggests the existence of a strong link between metabolic syndrome and neurodegeneration. Indeed, epidemiologic studies have described solid associations between metabolic syndrome and neurodegeneration, whereas animal models contributed for the clarification of the mechanistic underlying the complex relationships between these conditions, having the development of an insulin resistance state a pivotal role in this relationship. Herein, we review in a concise manner the association between metabolic syndrome and neurodegeneration. We start by providing concepts regarding the role of insulin and insulin signaling pathways as well as the pathophysiological mechanisms that are in the genesis of metabolic diseases. Then, we focus on the role of insulin in the brain, with special attention to its function in the regulation of brain glucose metabolism, feeding, and cognition. Moreover, we extensively report on the association between neurodegeneration and metabolic diseases, with a particular emphasis on the evidence observed in animal models of dysmetabolism induced by hypercaloric diets. We also debate on strategies to prevent and/or delay neurodegeneration through the normalization of whole-body glucose homeostasis, particularly via the modulation of the carotid bodies, organs known to be key in connecting the periphery with the brain.
    Keywords:  hypercaloric diets; insulin signaling; metabolic disorders; neurodegeneration
    DOI:  https://doi.org/10.3390/nu14071425
  7. Int J Mol Sci. 2022 Mar 24. pii: 3532. [Epub ahead of print]23(7):
    Modulation of Notch Signaling Pathway by Bioactive Dietary Agents.
    Violet A Kiesel, Silvia D Stan.
      Notch signaling is often aberrantly activated in solid and hematological cancers and regulates cell fate decisions and the maintenance of cancer stem cells. In addition, increased expression of Notch pathway components is clinically associated with poorer prognosis in several types of cancer. Targeting Notch may have chemopreventive and anti-cancer effects, leading to reduced disease incidence and improved survival. While therapeutic agents are currently in development to achieve this goal, several researchers have turned their attention to dietary and natural agents for targeting Notch signaling. Given their natural abundance from food sources, the use of diet-derived agents to target Notch signaling offers the potential advantage of low toxicity to normal tissue. In this review, we discuss several dietary agents including curcumin, EGCG, resveratrol, and isothiocyanates, which modulate Notch pathway components in a context-dependent manner. Dietary agents modulate Notch signaling in several types of cancer and concurrently decrease in vitro cell viability and in vivo tumor growth, suggesting a potential role for their clinical use to target Notch pathway components, either alone or in combination with current therapeutic agents.
    Keywords:  Notch signaling; cancer stem cells; chemoprevention; dietary agents
    DOI:  https://doi.org/10.3390/ijms23073532
  8. J Ethnopharmacol. 2022 Apr 07. pii: S0378-8741(22)00307-5. [Epub ahead of print] 115268
    Integrating metabolomics and network pharmacology to reveal the mechanisms of Delphinium brunonianum extract against nonalcoholic steatohepatitis.
    Kaihui Zhang, Yue Yuan, Zeren Dawa, Fangle Liu, Yufeng Yao, Meiqi Wang, Chenchen Zhu, Chaozhan Lin.
       ETHNOPHARMACOLOGICAL RELEVANCE: Herba Delphinii Brunoniani, a Tibetan Material Medica, derived from the aerial parts of Delphinium brunonianum Royle, possesses efficacy of cooling blood to remove apthogentic heat, and dispelling wind to arrest itching, and has been used for the treatment for liver disease according to Tibetan Medicine Theories in Shel Gong Shel Phreng. However, the mechanisms of action remain unclear.
    AIM OF THE STUDY: This work aimed to investigate the efficacy mechanism of Delphinium brunonianum extract (DBE) on nonalcoholic steatohepatitis (NASH), a kind of liver disease by integrating serum metabolomics and network pharmacology analysis.
    MATERIALS AND METHODS: In this study, NASH model mice were established by a high-fat diet. The indexes of lipid accumulation, insulin resistance, and inflammatory reaction were used to evaluate the efficacy of DBE. A combination of UHPLC-QTOF-MS based metabolomics and network pharmacology was established to illustrate the serum biomarkers of NASH mice and to demonstrate the anti-NASH mechanisms of DBE. Serum metabolomics demonstrated potential metabolites and the corresponding metabolic pathways in the efficacy of DBE. Network pharmacology screened the targets of DBE against NASH. Finally, the mechanisms of DBE against NASH were verified by in-vivo pharmacology.
    RESULTS: Metabolomics revealed that DBE significantly regulated the abnormal levels of twenty-two metabolites, which involved the biosynthesis of unsaturated fatty acids and steroid hormone, linoleic acid metabolism, arachidonic acid metabolism, and alpha-Linolenic acid metabolism pathways. Network pharmacology showed that DBE exhibited anti-NASH effects through regulating the targets of PTGS2, PLA2, ALOX5, ALOX15, FASN, and CYP450. Finally, united pharmacological verification result, we found that the mechanisms of DBE against NASH may be related to the regulation of the unsaturated fatty acids biosynthesis and the arachidonic acid metabolism pathway.
    CONCLUSIONS: Integrating serum metabolomic and network analysis, we found that DBE might inhibit the pathological process of NASH by regulating the relative targets and the metabolic pathways, which may be a potential mechanism for the anti-NASH efficacy of DBE. This integrated strategy also provided a rational way for revealing the pharmacodynamic mechanisms of multi-components, multi-targets, and multi-pathways in Traditional Chinese Medicine (TCM).
    Keywords:  Delphinium brunonianum Royle; Metabolomics; Network pharmacology; Nonalcoholic steatohepatitis
    DOI:  https://doi.org/10.1016/j.jep.2022.115268
  9. Nutrients. 2022 Mar 30. pii: 1454. [Epub ahead of print]14(7):
    Amino Acid-Related Metabolic Signature in Obese Children and Adolescents.
    Nella Polidori, Eleonora Agata Grasso, Francesco Chiarelli, Cosimo Giannini.
      The growing interest in metabolomics has spread to the search for suitable predictive biomarkers for complications related to the emerging issue of pediatric obesity and its related cardiovascular risk and metabolic alteration. Indeed, several studies have investigated the association between metabolic disorders and amino acids, in particular branched-chain amino acids (BCAAs). We have performed a revision of the literature to assess the role of BCAAs in children and adolescents' metabolism, focusing on the molecular pathways involved. We searched on Pubmed/Medline, including articles published until February 2022. The results have shown that plasmatic levels of BCAAs are impaired already in obese children and adolescents. The relationship between BCAAs, obesity and the related metabolic disorders is explained on one side by the activation of the mTORC1 complex-that may promote insulin resistance-and on the other, by the accumulation of toxic metabolites, which may lead to mitochondrial dysfunction, stress kinase activation and damage of pancreatic cells. These compounds may help in the precocious identification of many complications of pediatric obesity. However, further studies are still needed to better assess if BCAAs may be used to screen these conditions and if any other metabolomic compound may be useful to achieve this goal.
    Keywords:  BCAAs; NAFLD; insulin resistance; obesity; pediatrics
    DOI:  https://doi.org/10.3390/nu14071454
  10. Evid Based Complement Alternat Med. 2022 ;2022 6221340
    Er-Chen Decoction Alleviates High-Fat Diet-Induced Nonalcoholic Fatty Liver Disease in Rats through Remodeling Gut Microbiota and Regulating the Serum Metabolism.
    Jing Miao, Liying Guo, Huantian Cui, Li Wang, Bo Zhu, Jinyan Lei, Peng Li, Jianwei Jia, Zhaiyi Zhang.
      Many studies have found that the dysfunction in gut microbiota and the metabolic dysfunction can promote nonalcoholic fatty liver disease (NAFLD) development. Er-Chen decoction (EC) can be used in the treatment of NAFLD. However, the mechanism of this hepatoprotection is still unknown. In this study, we constructed a rat model with NAFLD fed with high-fat chow and administered EC treatment. The therapeutic effects of EC on NAFLD were evaluated by measuring transaminases, blood lipid levels, and pathological changes in the liver. In addition, we measured the effects of EC on liver inflammatory response and oxidative stress. The changes in gut microbiota after EC treatment were studied using 16S rRNA sequencing. Serum untargeted metabolomics analysis was also used to study the metabolic regulatory mechanisms of EC on NAFLD. The results showed that EC decreased the serum transaminases and lipid levels and improved the pathological changes in NAFLD rats. Furthermore, EC enhanced the activities of SOD and GSH-Px and decreased MDA level in the liver. EC treatment also decreased the gene and protein levels of IL-6, IL-1β, and TNF-α in the liver and serum. The 16S rRNA sequencing and untargeted metabolomics indicated that EC treatment affected the gut microbiota and regulated serum metabolism. Correlation analysis showed that the effects of EC on taurine and hypotaurine metabolism, cysteine and methionine metabolism, and vitamin B6 metabolism pathways were associated with affecting in the abundance of Lactobacillus, Dubosiella, Lachnospiraceae, Desulfovibri, Romboutsia, Akkermansia, Intestinimonas, and Candidatus_saccharimonas in the gut. In conclusion, our study confirmed the protective effect of EC on NAFLD. EC could treat NAFLD by inhibiting oxidative stress, reducing inflammatory responses, and improving the dysbiosis of gut microbiota and the modulation of the taurine and hypotaurine metabolism, cysteine and methionine metabolism, and vitamin B6 metabolism pathways in serum.
    DOI:  https://doi.org/10.1155/2022/6221340
  11. Int J Mol Sci. 2022 Mar 25. pii: 3595. [Epub ahead of print]23(7):
    Mitochondrial Dysfunction and Acute Fatty Liver of Pregnancy.
    Raghu Ramanathan, Jamal A Ibdah.
      The liver is one of the richest organs in mitochondria, serving as a hub for key metabolic pathways such as β-oxidation, the tricarboxylic acid (TCA) cycle, ketogenesis, respiratory activity, and adenosine triphosphate (ATP) synthesis, all of which provide metabolic energy for the entire body. Mitochondrial dysfunction has been linked to subcellular organelle dysfunction in liver diseases, particularly fatty liver disease. Acute fatty liver of pregnancy (AFLP) is a life-threatening liver disorder unique to pregnancy, which can result in serious maternal and fetal complications, including death. Pregnant mothers with this disease require early detection, prompt delivery, and supportive maternal care. AFLP was considered a mysterious illness and though its pathogenesis has not been fully elucidated, molecular research over the past two decades has linked AFLP to mitochondrial dysfunction and defects in fetal fatty-acid oxidation (FAO). Due to deficient placental and fetal FAO, harmful 3-hydroxy fatty acid metabolites accumulate in the maternal circulation, causing oxidative stress and microvesicular fatty infiltration of the liver, resulting in AFLP. In this review, we provide an overview of AFLP and mitochondrial FAO followed by discussion of how altered mitochondrial function plays an important role in the pathogenesis of AFLP.
    Keywords:  acute fatty liver of pregnancy; liver; long chain 3-hydroxyacyl Co-A; mitochondrial dysfunction; mitochondrial trifunctional protein; β-oxidation
    DOI:  https://doi.org/10.3390/ijms23073595
  12. Cancers (Basel). 2022 Apr 06. pii: 1850. [Epub ahead of print]14(7):
    Impact of Lipid Metabolism on Antitumor Immune Response.
    Nesrine Mabrouk, Baptiste Lecoeur, Ali Bettaieb, Catherine Paul, Frédérique Végran.
      Over the past decade, metabolic reprogramming has been defined as a hallmark of cancer. More recently, a large number of studies have demonstrated that metabolic reprogramming can modulate the differentiation and functions of immune cells, and thus modify the antitumor response. Increasing evidence suggests that modified energy metabolism could be responsible for the failure of antitumor immunity. Indeed, tumor-infiltrating immune cells play a key role in cancer, and metabolic switching in these cells has been shown to help determine their phenotype: tumor suppressive or immune suppressive. Recent studies in the field of immunometabolism focus on metabolic reprogramming in the tumor microenvironment (TME) by targeting innate and adaptive immune cells and their associated anti- or protumor phenotypes. In this review, we discuss the lipid metabolism of immune cells in the TME as well as the effects of lipids; finally, we expose the link between therapies and lipid metabolism.
    Keywords:  cancer therapy; immune cells; immunosuppression; lipid metabolism
    DOI:  https://doi.org/10.3390/cancers14071850
  13. EMBO Rep. 2022 Apr 12. e52412
    Nutrition, metabolism, and epigenetics: pathways of circadian reprogramming.
    Tomoki Sato, Paolo Sassone-Corsi.
      Food intake profoundly affects systemic physiology. A large body of evidence has indicated a link between food intake and circadian rhythms, and ~24-h cycles are deemed essential for adapting internal homeostasis to the external environment. Circadian rhythms are controlled by the biological clock, a molecular system remarkably conserved throughout evolution. The circadian clock controls the cyclic expression of numerous genes, a regulatory program common to all mammalian cells, which may lead to various metabolic and physiological disturbances if hindered. Although the circadian clock regulates multiple metabolic pathways, metabolic states also provide feedback on the molecular clock. Therefore, a remarkable feature is reprogramming by nutritional challenges, such as a high-fat diet, fasting, ketogenic diet, and caloric restriction. In addition, various factors such as energy balance, histone modifications, and nuclear receptor activity are involved in the remodeling of the clock. Herein, we review the interaction of dietary components with the circadian system and illustrate the relationships linking the molecular clock to metabolism and critical roles in the remodeling process.
    Keywords:  circadian clock; energy metabolism; epigenetics; nutrition
    DOI:  https://doi.org/10.15252/embr.202152412
  14. Cancers (Basel). 2022 Mar 23. pii: 1618. [Epub ahead of print]14(7):
    Lysosomes in Stem Cell Quiescence: A Potential Therapeutic Target in Acute Myeloid Leukemia.
    Vaibhav Jain, Swaroop Bose, Awadhesh K Arya, Tasleem Arif.
      Lysosomes are cellular organelles that regulate essential biological processes such as cellular homeostasis, development, and aging. They are primarily connected to the degradation/recycling of cellular macromolecules and participate in cellular trafficking, nutritional signaling, energy metabolism, and immune regulation. Therefore, lysosomes connect cellular metabolism and signaling pathways. Lysosome's involvement in the critical biological processes has rekindled clinical interest towards this organelle for treating various diseases, including cancer. Recent research advancements have demonstrated that lysosomes also regulate the maintenance and hemostasis of hematopoietic stem cells (HSCs), which play a critical role in the progression of acute myeloid leukemia (AML) and other types of cancer. Lysosomes regulate both HSCs' metabolic networks and identity transition. AML is a lethal type of blood cancer with a poor prognosis that is particularly associated with aging. Although the genetic landscape of AML has been extensively described, only a few targeted therapies have been produced, warranting the need for further research. This review summarizes the functions and importance of targeting lysosomes in AML, while highlighting the significance of lysosomes in HSCs maintenance.
    Keywords:  AML; HSCs; NSCs; apoptosis; lysosomes; mitochondria
    DOI:  https://doi.org/10.3390/cancers14071618
  15. Arch Biochem Biophys. 2022 Apr 07. pii: S0003-9861(22)00084-4. [Epub ahead of print] 109199
    Iron metabolism: State of the art in hypoxic cancer cell biology.
    Sai Liu, Xiongfeng Cao, Dongqing Wang, Haitao Zhu.
      The tumor microenvironment (TME) promotes the malignant transformation of cancer cells, mainly through metabolic reprogramming. As one of the most prominent features of the TME, hypoxia contributes to cancer cell death resistance, invasion, metastasis, and therapy-resistant phenotypes. As an important cofactor for various enzymes, iron is essential for ATP generation, antioxidant protein function, and DNA-damage repair in hypoxic cancer cells. Iron metabolism, as a promoter of aggressive hypoxic cancer cell biology, has attracted an increasing amount of attention. Iron utilization, storage, and efflux are enhanced in hypoxic cancer cells, which further contributes to cancer cell proliferation, metastasis, ferroptosis resistance, and immune escape. This review describes the relationship between iron metabolism and proliferation, metastasis, and ferroptosis of hypoxic cancer cells, as well as several iron-targeted cancer therapy strategies. Understanding the hypoxia-specific regulatory mechanism of iron metabolism could aid the development of targeted therapy against refractory hypoxic cancer cells.
    Keywords:  Ferroptosis; Hypoxia; Iron metabolism; Metabolic reprogramming; The tumor microenvironment
    DOI:  https://doi.org/10.1016/j.abb.2022.109199
  16. Int J Oncol. 2022 Jun;pii: 67. [Epub ahead of print]60(6):
    'Reverse Warburg effect' of cancer‑associated fibroblasts (Review).
    Lin Liang, Wentao Li, Xin Li, Xi Jin, Qianjin Liao, Yanling Li, Yanhong Zhou.
      Metabolic reprogramming is one of the main characteristics of malignant tumors. The metabolic reprogramming of tumors is not only related to the characteristics of cancer cells, but also closely related to the tumor microenvironment (TME). 'Aerobic glycolysis' is considered to be the classic metabolic mode of tumor cells. However, recent experiments have shown that the TME plays a key role in carcinogenesis and epithelial‑mesenchymal transition. Cancer‑associated fibroblasts (CAFs) dominate in the microenvironment and affect the homeostasis of the TME. The interaction between cancer cells and the surrounding CAFs markedly affects the growth, metabolism, metastasis, and progression of cancer. Based on this, a 'dual‑chamber' model, also known as the 'Reverse Warburg effect', is proposed. Specifically, cancer cells secrete hydrogen peroxide into the TME to induce oxidative stress in neighboring stromal cells. CAFs undergo aerobic glycolysis and produce high levels of energy‑rich 'fuels' (such as pyruvate, ketone bodies, fatty acids, and lactic acid). In turn, these energy‑rich 'fuels' then 'feed' cancer cells. The mitochondrial oxidative phosphorylation system produces a large quantity of ATP, such that tumor cells have a higher proliferation ability. The proposed 'Reverse Warburg effect' redefines the tumor cell microenvironment and tumor metabolic reprogramming. Therefore, understanding the 'Reverse Warburg effect' of CAFs and its related mechanisms will help us to understand the association between the microenvironment, the matrix, and cancer cells, and may lead to new treatment strategies and targets.
    Keywords:  Reverse Warburg effect; cancer‑associated fibroblasts; interleukin‑6; reactive oxygen species; signal transduction pathway; transforming growth factor‑β
    DOI:  https://doi.org/10.3892/ijo.2022.5357
  17. Comp Med. 2022 Apr 11.
    Effects of Exogenous ATP on Melanoma Growth and Tumor Metabolism in C57BL/6 Mice.
    Yali Lei, Xu Zhou, Yang Zhao, Jianfa Zhang.
      Altered energy metabolism (glucose, lipid, amino acid) is a hallmark of cancer growth that provides the theoretical basis for the development of metabolic therapies as cancer treatments. ATP is one of the major biochemical constituents of the tumor microenvironment. ATP promotes tumor progression or suppression depending on various factors, including concentration and tumor type. Here we evaluated the antitumor effect of extracellular ATP on melanoma and the potential underlying mechanisms. A subcutaneous tumor model in mice was used to investigate the antitumor effects of ATP. Major lymphocyte cell changes and intratumoral metabolic changes were assessed. Metabolomic analysis (1H nuclear magnetic resonance spectroscopy) was performed on tumor samples. We measured the activities of lactate dehydrogenase A (LDHA) and LDHB in the excised tumors and serum and found that ATP and its metabolites affected the proliferation of and LDHA activity in B16F10 cells, a murine melanoma cell line. In addition, treatment with ATP dose-dependently reduced tumor size in melanoma-bearing mice. Moreover, flow cytometry analysis demonstrated that the antitumor effect of ATP was not achieved through changes in T-cell or B-cell subsets. Metabolomics analysis revealed that ATP treatment simultaneously reduced multiple intratumoral metabolites related to energy metabolism as well as serum and tumor LDHA activities. Furthermore, both ATP and its metabolites significantly suppressed both tumor cell proliferation and LDHA activity in the melanoma cell line. Our results in vivo and in vitro indicate that exogenous ATP inhibits melanoma growth in association with altered intratumoral metabolism.
    DOI:  https://doi.org/10.30802/AALAS-CM-21-000099
  18. Cells. 2022 Mar 30. pii: 1172. [Epub ahead of print]11(7):
    Multi-Omics Approach Reveals Dysregulation of Protein Phosphorylation Correlated with Lipid Metabolism in Mouse Non-Alcoholic Fatty Liver.
    Sora Q Kim, Rodrigo Mohallem, Jackeline Franco, Kimberly K Buhman, Kee-Hong Kim, Uma K Aryal.
      Obesity caused by overnutrition is a major risk factor for non-alcoholic fatty liver disease (NAFLD). Several lipid intermediates such as fatty acids, glycerophospholipids and sphingolipids are implicated in NAFLD, but detailed characterization of lipids and their functional links to proteome and phosphoproteome remain to be elucidated. To characterize this complex molecular relationship, we used a multi-omics approach by conducting comparative proteomic, phoshoproteomic and lipidomic analyses of high fat (HFD) and low fat (LFD) diet fed mice livers. We quantified 2447 proteins and 1339 phosphoproteins containing 1650 class I phosphosites, of which 669 phosphosites were significantly different between HFD and LFD mice livers. We detected alterations of proteins associated with cellular metabolic processes such as small molecule catabolic process, monocarboxylic acid, long- and medium-chain fatty acid, and ketone body metabolic processes, and peroxisome organization. We observed a significant downregulation of protein phosphorylation in HFD fed mice liver in general. Untargeted lipidomics identified upregulation of triacylglycerols, glycerolipids and ether glycerophosphocholines and downregulation of glycerophospholipids, such as lysoglycerophospholipids, as well as ceramides and acylcarnitines. Analysis of differentially regulated phosphosites revealed phosphorylation dependent deregulation of insulin signaling as well as lipogenic and lipolytic pathways during HFD induced obesity. Thus, this study reveals a molecular connection between decreased protein phosphorylation and lipolysis, as well as lipid-mediated signaling in diet-induced obesity.
    Keywords:  HFD; NAFLD; fatty liver; lipidomics; mass spectrometry; proteomics
    DOI:  https://doi.org/10.3390/cells11071172
  19. Microbiol Spectr. 2022 Apr 12. e0010022
    Disruption of Iron Homeostasis and Mitochondrial Metabolism Are Promising Targets to Inhibit Candida auris.
    Claudia Simm, Harshini Weerasinghe, David R Thomas, Paul F Harrison, Hayley J Newton, Traude H Beilharz, Ana Traven.
      Fungal infections are a global threat, but treatments are limited due to a paucity in antifungal drug targets and the emergence of drug-resistant fungi such as Candida auris. Metabolic adaptations enable microbial growth in nutrient-scarce host niches, and they further control immune responses to pathogens, thereby offering opportunities for therapeutic targeting. Because it is a relatively new pathogen, little is known about the metabolic requirements for C. auris growth and its adaptations to counter host defenses. Here, we establish that triggering metabolic dysfunction is a promising strategy against C. auris. Treatment with pyrvinium pamoate (PP) induced metabolic reprogramming and mitochondrial dysfunction evident in disrupted mitochondrial morphology and reduced tricarboxylic acid (TCA) cycle enzyme activity. PP also induced changes consistent with disrupted iron homeostasis. Nutrient supplementation experiments support the proposition that PP-induced metabolic dysfunction is driven by disrupted iron homeostasis, which compromises carbon and lipid metabolism and mitochondria. PP inhibited C. auris replication in macrophages, which is a relevant host niche for this yeast pathogen. We propose that PP causes a multipronged metabolic hit to C. auris: it restricts the micronutrient iron to potentiate nutritional immunity imposed by immune cells, and it further causes metabolic dysfunction that compromises the utilization of macronutrients, thereby curbing the metabolic plasticity needed for growth in host environments. Our study offers a new avenue for therapeutic development against drug-resistant C. auris, shows how complex metabolic dysfunction can be caused by a single compound triggering antifungal inhibition, and provides insights into the metabolic needs of C. auris in immune cell environments. IMPORTANCE Over the last decade, Candida auris has emerged as a human pathogen around the world causing life-threatening infections with wide-spread antifungal drug resistance, including pandrug resistance in some cases. In this study, we addressed the mechanism of action of the antiparasitic drug pyrvinium pamoate against C. auris and show how metabolism could be inhibited to curb C. auris proliferation. We show that pyrvinium pamoate triggers sweeping metabolic and mitochondrial changes and disrupts iron homeostasis. PP-induced metabolic dysfunction compromises the utilization of both micro- and macronutrients by C. auris and reduces its growth in vitro and in immune phagocytes. Our findings provide insights into the metabolic requirements for C. auris growth and define the mechanisms of action of pyrvinium pamoate against C. auris, demonstrating how this compound works by inhibiting the metabolic flexibility of the pathogen. As such, our study characterizes credible avenues for new antifungal approaches against C. auris.
    Keywords:  Candida auris; antifungal agents; fungal pathogens; iron; metabolism; mitochondrial metabolism
    DOI:  https://doi.org/10.1128/spectrum.00100-22
  20. Inflammopharmacology. 2022 Apr 13.
    The role of AMPK-dependent pathways in cellular and molecular mechanisms of metformin: a new perspective for treatment and prevention of diseases.
    Amin Hasanvand.
      Metformin can suppress gluconeogenesis and reduce blood sugar by activating adenosine monophosphate-activated protein kinase (AMPK) and inducing small heterodimer partner (SHP) expression in the liver cells. The main mechanism of metformin's action is related to its activation of the AMPK enzyme and regulation of the energy balance. AMPK is a heterothermic serine/threonine kinase made of a catalytic alpha subunit and two subunits of beta and a gamma regulator. This enzyme can measure the intracellular ratio of AMP/ATP. If this ratio is high, the amino acid threonine 172 available in its alpha chain would be activated by the phosphorylated liver kinase B1 (LKB1), leading to AMPK activation. Several studies have indicated that apart from its significant role in the reduction of blood glucose level, metformin activates the AMPK enzyme that in turn has various efficient impacts on the regulation of various processes, including controlling inflammatory conditions, altering the differentiation pathway of immune and non-immune cell pathways, and the amelioration of various cancers, liver diseases, inflammatory bowel disease (IBD), kidney diseases, neurological disorders, etc. Metformin's activation of AMPK enables it to control inflammatory conditions, improve oxidative status, regulate the differentiation pathways of various cells, change the pathological process in various diseases, and finally have positive therapeutic effects on them. Due to the activation of AMPK and its role in regulating several subcellular signalling pathways, metformin can be effective in altering the cells' proliferation and differentiation pathways and eventually in the prevention and treatment of certain diseases.
    Keywords:  AMPK; Diseases; Metformin
    DOI:  https://doi.org/10.1007/s10787-022-00980-6
  21. Front Med (Lausanne). 2022 ;9 872024
    Pinpointing Cancer Sub-Type Specific Metabolic Tasks Facilitates Identification of Anti-cancer Targets.
    Shuaishi Gao, Ziwei Dai, Hanyu Xu, Luhua Lai.
      Metabolic reprogramming is one of the hallmarks of tumorigenesis. Understanding the metabolic changes in cancer cells may provide attractive therapeutic targets and new strategies for cancer therapy. The metabolic states are not the same in different cancer types or subtypes, even within the same sample of solid tumors. In order to understand the heterogeneity of cancer cells, we used the Pareto tasks inference method to analyze the metabolic tasks of different cancers, including breast cancer, lung cancer, digestive organ cancer, digestive tract cancer, and reproductive cancer. We found that cancer subtypes haves different propensities toward metabolic tasks, and the biological significance of these metabolic tasks also varies greatly. Normal cells treat metabolic tasks uniformly, while different cancer cells focus on different pathways. We then integrated the metabolic tasks into the multi-objective genome-scale metabolic network model, which shows higher accuracy in the in silico prediction of cell states after gene knockout than the conventional biomass maximization model. The predicted potential single drug targets could potentially turn into biomarkers or drug design targets. We further implemented the multi-objective genome-scale metabolic network model to predict synthetic lethal target pairs of the Basal and Luminal B subtypes of breast cancer. By analyzing the predicted synthetic lethal targets, we found that mitochondrial enzymes are potential targets for drug combinations. Our study quantitatively analyzes the metabolic tasks of cancer and establishes cancer type-specific metabolic models, which opens a new window for the development of specific anti-cancer drugs and provides promising treatment plans for specific cancer subtypes.
    Keywords:  cancer metabolism; metabolic network; metabolic task; multi-objective; synthetic lethality
    DOI:  https://doi.org/10.3389/fmed.2022.872024
  22. Int J Mol Sci. 2022 Mar 30. pii: 3813. [Epub ahead of print]23(7):
    NSAIDs Induce Proline Dehydrogenase/Proline Oxidase-Dependent and Independent Apoptosis in MCF7 Breast Cancer Cells.
    Adam Kazberuk, Magda Chalecka, Jerzy Palka, Katarzyna Bielawska, Arkadiusz Surazynski.
      Non-steroidal anti-inflammatory drugs (NSAIDs) are considered in cancer therapy for their inhibitory effect on cyclooxygenase-2 (COX-2), which is overexpressed in most cancers. However, we found that NSAIDs as ligands of peroxisome proliferator-activated receptor-γ (PPARγ)-induced apoptosis independent of the COX-2 inhibition, and the process was mediated through activation of proline dehydrogenase/proline oxidase (PRODH/POX)-dependent generation of reactive oxygen species (ROS). This mitochondrial enzyme converts proline to ∆1-pyrroline-5-carboxylate (P5C) during which ATP or ROS is generated. To confirm the role of PRODH/POX in the mechanism of NSAID-induced apoptosis we obtained an MCF7 CRISPR/Cas9 PRODH/POX knockout breast cancer cell model (MCF7POK-KO). Interestingly, the studied NSAIDs (indomethacin and diclofenac) in MCF7POK-KO cells contributed to a more pronounced pro-apoptotic phenotype of the cells than in PRODH/POX-expressing MCF7 cells. The observed effect was independent of ROS generation, but it was related to the energetic disturbances in the cells as shown by an increase in the expression of AMPKα (sensor of cell energy status), GLUD1/2 (proline producing enzyme from glutamate), prolidase (proline releasing enzyme), PPARδ (growth supporting transcription factor) and a decrease in the expression of proline cycle enzymes (PYCR1, PYCRL), mammalian target of rapamycin (mTOR), and collagen biosynthesis (the main proline utilizing process). The data provide evidence that the studied NSAIDs induce PRODH/POX-dependent and independent apoptosis in MCF7 breast cancer cells.
    Keywords:  COX; NSAIDs; PPAR; apoptosis; breast cancer; mitochondria; oxidative stress; proline dehydrogenase; proline metabolism; proline oxidase
    DOI:  https://doi.org/10.3390/ijms23073813
  23. Free Radic Biol Med. 2022 Apr 07. pii: S0891-5849(22)00122-8. [Epub ahead of print]184 114-134
    Oxidative stress in the pathophysiology of type 2 diabetes and related complications: Current therapeutics strategies and future perspectives.
    Jasvinder Singh Bhatti, Abhishek Sehrawat, Jayapriya Mishra, Inderpal Singh Sidhu, Umashanker Navik, Naina Khullar, Shashank Kumar, Gurjit Kaur Bhatti, P Hemachandra Reddy.
      Type 2 diabetes (T2DM) is a persistent metabolic disorder rising rapidly worldwide. It is characterized by pancreatic insulin resistance and β-cell dysfunction. Hyperglycemia induced reactive oxygen species (ROS) production and oxidative stress are correlated with the pathogenesis and progression of this metabolic disease. To counteract the harmful effects of ROS, endogenous antioxidants of the body or exogenous antioxidants neutralise it and maintain bodily homeostasis. Under hyperglycemic conditions, the imbalance between the cellular antioxidant system and ROS production results in oxidative stress, which subsequently results in the development of diabetes. These ROS are produced in the endoplasmic reticulum, phagocytic cells and peroxisomes, with the mitochondrial electron transport chain (ETC) playing a pivotal role. The exacerbated ROS production can directly cause structural and functional modifications in proteins, lipids and nucleic acids. It also modulates several intracellular signaling pathways that lead to insulin resistance and impairment of β-cell function. In addition, the hyperglycemia-induced ROS production contributes to micro- and macro-vascular diabetic complications. Various in-vivo and in-vitro studies have demonstrated the anti-oxidative effects of natural products and their derived bioactive compounds. However, there is conflicting clinical evidence on the beneficial effects of these antioxidant therapies in diabetes prevention. This review article focused on the multifaceted role of oxidative stress caused by ROS overproduction in diabetes and related complications and possible antioxidative therapeutic strategies targeting ROS in this disease.
    Keywords:  Antioxidant enzymes; Electron transport system; Hyperglycemia; Insulin resistance; Oxidative stress; Pancreatic β-cells; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.03.019
  24. Comput Struct Biotechnol J. 2022 ;20 1528-1540
    Diet-gut microbiota interactions on cardiovascular disease.
    Xufei Zhang, Philippe Gérard.
      Cardiovascular diseases (CVD) are a group of disorders of the heart and blood vessels and remain the leading cause of morbidity and mortality worldwide. Over the past decades, accumulating studies indicated that the gut microbiota, an indispensable "invisible organ", plays a vital role in human metabolism and disease states including CVD. Among many endogenous and exogenous factors that can impact gut microbial communities, the dietary nutrients emerge as an essential component of host-microbiota relationships that can be involved in CVD susceptibility. In this review, we summarize the major concepts of dietary modulation of the gut microbiota and the chief principles of the involvement of this microbiota in CVD development. We also discuss the mechanisms of diet-microbiota crosstalk that regulate CVD progression, including endotoxemia, inflammation, gut barrier dysfunction and lipid metabolism dysfunction. In addition, we describe how metabolites produced by the microbiota, including trimethylamine-N-oxide (TMAO), secondary bile acids (BAs), short chain fatty acids (SCFAs) as well as aromatic amino acids (AAAs) derived metabolites play a role in CVD pathogenesis. Finally, we present the potential dietary interventions which interacted with gut microbiota as novel preventive and therapeutic strategies for CVD management.
    Keywords:  Cardiovascular disease; Dietary nutrients; Gut microbiota; Lipid metabolism; Microbial metabolites; Therapeutic strategies
    DOI:  https://doi.org/10.1016/j.csbj.2022.03.028
  25. Front Nutr. 2022 ;9 820799
    An Overlooked Prebiotic: Beneficial Effect of Dietary Nucleotide Supplementation on Gut Microbiota and Metabolites in Senescence-Accelerated Mouse Prone-8 Mice.
    Ting Ding, Meihong Xu, Yong Li.
      Nucleotides (NTs) are regulatory factors in many biological processes and play important roles in the growth, development, and metabolism of living organisms. We used senescence-accelerated mouse prone-8 (SAMP8) to investigate the effects of NTs on the gut microbiota and metabolites. And the promoting effect of NTs on the growth of a probiotic (Lactobacillus casei) was explored through in vitro experiments. The results showed that the sequencing depth of 16S rDNA covered all microbial species in the feces of SAMP8. Supplementation with exogenous NTs to the diet enhanced the diversity of the gut microbiota, reduced the abundance of bacteria with negative effects on the body (such as Verrucomicrobia, Ruminococcaceae, Akkermansia and Helicobacter), and increased the abundance of the microbiota, which had beneficial effects on the mice (such as Lactobacillus, Candidatus saccharimonas and Lachnospiraceae_NK4A136_group). Metabonomic analysis showed that NT deficiency in the diet significantly affected metabolites in the mouse feces. The metabolites in mice supplemented with NTs tended to be normal (SAMR1). The differentially expressed metabolites caused by NT addition are involved in various pathways in the body, including linoleic acid metabolism, vitamin B6 metabolism, and histidine metabolism. Correlation analysis revealed a significant correlation between the gut microbiota and differentially expressed metabolites caused by the addition of NTs. In vitro experiments showed that NTs significantly promoted the growth, secretion of biofilm and extracellular polymeric substance of L. casei. NTs also promoted the ability of the crude extract of L. casei to resist the secretion of Shigella biofilm. Thus, NTs can regulate the abundance of the gut microbiota and alter the metabolic expression of the intestinal microbiome.
    Keywords:  SAMP8 mice; dietary nucleotide; gut microbiota; metabonomic; prebiotic
    DOI:  https://doi.org/10.3389/fnut.2022.820799
  26. Cancers (Basel). 2022 Mar 31. pii: 1776. [Epub ahead of print]14(7):
    Estrogens and Progestins Cooperatively Shift Breast Cancer Cell Metabolism.
    Ashley V Ward, Shawna B Matthews, Lynsey M Fettig, Duncan Riley, Jessica Finlay-Schultz, Kiran V Paul, Matthew Jackman, Peter Kabos, Paul S MacLean, Carol A Sartorius.
      Metabolic reprogramming remains largely understudied in relation to hormones in estrogen receptor (ER) and progesterone receptor (PR) positive breast cancer. In this study, we investigated how estrogens, progestins, or the combination, impact metabolism in three ER and PR positive breast cancer cell lines. We measured metabolites in the treated cells using ultra-performance liquid chromatography coupled with mass spectrometry (UPLC-MS). Top metabolic processes upregulated with each treatment involved glucose metabolism, including Warburg effect/glycolysis, gluconeogenesis, and the pentose phosphate pathway. RNA-sequencing and pathway analysis on two of the cell lines treated with the same hormones, found estrogens target oncogenes, such as MYC and PI3K/AKT/mTOR that control tumor metabolism, while progestins increased genes associated with fatty acid metabolism, and the estrogen/progestin combination additionally increased glycolysis. Phenotypic analysis of cell energy metabolism found that glycolysis was the primary hormonal target, particularly for the progestin and estrogen-progestin combination. Transmission electron microscopy found that, compared to vehicle, estrogens elongated mitochondria, which was reversed by co-treatment with progestins. Progestins promoted lipid storage both alone and in combination with estrogen. These findings highlight the shift in breast cancer cell metabolism to a more glycolytic and lipogenic phenotype in response to combination hormone treatment, which may contribute to a more metabolically adaptive state for cell survival.
    Keywords:  breast cancer; estrogen receptor; estrogens; glycolysis; metabolism; progesterone receptor; progestins
    DOI:  https://doi.org/10.3390/cancers14071776
  27. Int J Mol Sci. 2022 Apr 05. pii: 4022. [Epub ahead of print]23(7):
    The Critical Role of the Branched Chain Amino Acids (BCAAs) Catabolism-Regulating Enzymes, Branched-Chain Aminotransferase (BCAT) and Branched-Chain α-Keto Acid Dehydrogenase (BCKD), in Human Pathophysiology.
    Aikaterini Dimou, Vasilis Tsimihodimos, Eleni Bairaktari.
      Branched chain amino acids (BCAAs), leucine, isoleucine and valine, are essential amino acids widely studied for their crucial role in the regulation of protein synthesis mainly through the activation of the mTOR signaling pathway and their emerging recognition as players in the regulation of various physiological and metabolic processes, such as glucose homeostasis. BCAA supplementation is primarily used as a beneficial nutritional intervention in chronic liver and kidney disease as well as in muscle wasting disorders. However, downregulated/upregulated plasma BCAAs and their defective catabolism in various tissues, mainly due to altered enzymatic activity of the first two enzymes in their catabolic pathway, BCAA aminotransferase (BCAT) and branched-chain α-keto acid dehydrogenase (BCKD), have been investigated in many nutritional and disease states. The current review focused on the underlying mechanisms of altered BCAA catabolism and its contribution to the pathogenesis of a numerous pathological conditions such as diabetes, heart failure and cancer. In addition, we summarize findings that indicate that the recovery of the dysregulated BCAA catabolism may be associated with an improved outcome and the prevention of serious disease complications.
    Keywords:  BCKAs; T2DM; cancer; catabolic enzymes; catabolism; heart failure; isoleucine; leucine; valine
    DOI:  https://doi.org/10.3390/ijms23074022
  28. Carbohydr Polym. 2022 Jul 01. pii: S0144-8617(22)00267-3. [Epub ahead of print]287 119363
    Pectic polysaccharides: Targeting gut microbiota in obesity and intestinal health.
    Hye-Bin Lee, Young-Soo Kim, Ho-Young Park.
      The gut microbiome is a complex ecosystem of the host body that maintains a balance with its host. In this context, dysbiosis can lead to inflammatory response, immune dysregulation, and various metabolic disorders. Dietary polysaccharides mediate gut microbiota and its metabolites related to host health. In this review, we describe the structural characteristics of pectic polysaccharides and the functional correlation between their structure-specific characteristics and the modulatory activity of gut microbiota. We also discuss the health benefits of pectic polysaccharides on diet-induced obesity and intestinal health based on their source and structure. By regulating gut microbiota, pectic polysaccharides exert a wide range of biological effects, including the inhibition of obesity, fatty liver disease, and inflammation, and the increase in gut barrier function and immune-enhancing activity. This review expected to serve as a valuable resource to further clarity the relationship between pectic polysaccharides and gut microbiota.
    Keywords:  Galacturonan; Gut microbiota; Intestinal health; Obesity; Pectic polysaccharides
    DOI:  https://doi.org/10.1016/j.carbpol.2022.119363
  29. Nutrients. 2022 Apr 01. pii: 1482. [Epub ahead of print]14(7):
    The Role of Palmitoleic Acid in Regulating Hepatic Gluconeogenesis through SIRT3 in Obese Mice.
    Xin Guo, Xiaofan Jiang, Keyun Chen, Qijian Liang, Shixiu Zhang, Juan Zheng, Xiaomin Ma, Hongmei Jiang, Hao Wu, Qiang Tong.
      Hepatic gluconeogenesis is a crucial process to maintain glucose level during starvation. However, unabated glucose production in diabetic patients is a major contributor to hyperglycemia. Palmitoleic acid is a monounsaturated fatty acid (16:1n7) that is available from dietary sources. Palmitoleic acid exhibits health beneficial effects on diabetes, insulin resistance, inflammation, and metabolic syndrome. However, the mechanism by which palmitoleate reduces blood glucose is still unclear. SIRT3 is a key metabolism-regulating NAD+-dependent protein deacetylase. It is known that fasting elevates the expression of SIRT3 in the liver and it regulates many aspects of liver's response to nutrient deprivation, such as fatty acid oxidation and ketone body formation. However, it is unknown whether SIRT3 also regulates gluconeogenesis. Our study revealed that palmitoleic acid reduced hepatic gluconeogenesis and the expression of SIRT3 under high-fat diet conditions. Overexpression of SIRT3 in the liver and hepatocytes enhanced gluconeogenesis. Further study revealed that SIRT3 played a role in enhancing the activities of gluconeogenic enzymes, such as PEPCK, PC, and MDH2. Therefore, our study indicated that under a high-fat diet, palmitoleic acid decreased gluconeogenesis by reducing enzymatic activities of PEPCK, PC, and MDH2 by down-regulating the expression of SIRT3.
    Keywords:  SIRT3; gluconeogenesis; high-fat diet; palmitoleic acid
    DOI:  https://doi.org/10.3390/nu14071482
  30. Int J Mol Sci. 2022 Mar 26. pii: 3627. [Epub ahead of print]23(7):
    Synapses: The Brain's Energy-Demanding Sites.
    Andreia Faria-Pereira, Vanessa A Morais.
      The brain is one of the most energy-consuming organs in the mammalian body, and synaptic transmission is one of the major contributors. To meet these energetic requirements, the brain primarily uses glucose, which can be metabolized through glycolysis and/or mitochondrial oxidative phosphorylation. The relevance of these two energy production pathways in fulfilling energy at presynaptic terminals has been the subject of recent studies. In this review, we dissect the balance of glycolysis and oxidative phosphorylation to meet synaptic energy demands in both resting and stimulation conditions. Besides ATP output needs, mitochondria at synapse are also important for calcium buffering and regulation of reactive oxygen species. These two mitochondrial-associated pathways, once hampered, impact negatively on neuronal homeostasis and synaptic activity. Therefore, as mitochondria assume a critical role in synaptic homeostasis, it is becoming evident that the synaptic mitochondria population possesses a distinct functional fingerprint compared to other brain mitochondria. Ultimately, dysregulation of synaptic bioenergetics through glycolytic and mitochondrial dysfunctions is increasingly implicated in neurodegenerative disorders, as one of the first hallmarks in several of these diseases are synaptic energy deficits, followed by synapse degeneration.
    Keywords:  brain energy metabolism; glycolysis; mitochondria; synapses
    DOI:  https://doi.org/10.3390/ijms23073627
  31. J Clin Lab Anal. 2022 Apr 14. e24420
    Obesity and gut-microbiota-brain axis: A narrative review.
    Arezoo Asadi, Negar Shadab Mehr, Mohamad Hosein Mohamadi, Fazlollah Shokri, Mohsen Heidary, Nourkhoda Sadeghifard, Saeed Khoshnood.
       INTRODUCTION: Obesity is a major health problem that is associated with many physiological and mental disorders, such as diabetes, stroke, and depression. Gut microbiota has been affirmed to interact with various organs, including the brain. Intestinal microbiota and their metabolites might target the brain directly via vagal stimulation or indirectly through immune-neuroendocrine mechanisms, and they can regulate metabolism, adiposity, homoeostasis and energy balance, and central appetite and food reward signaling, which together have crucial roles in obesity. Studies support the concept of bidirectional signaling within the gut-brain axis (GBA) in the pathophysiology of obesity, mediated by metabolic, endocrine, neural, and immune system mechanisms.
    MATERIALS AND METHODS: Scopus, PubMed, Google Scholar, and Web of Science databases were searched to find relevant studies.
    RESULTS: The gut-brain axis (GBA), a bidirectional connection between the gut microbiota and brain, influences physiological function and behavior through three different pathways. Neural pathway mainly consists of the enteric nervous system (ENS) and vagus nerve. Endocrine pathway, however, affects the neuroendocrine system of the brain, particularly the hypothalamus-pituitary-adrenal (HPA) axis and immunological pathway. Several alterations in the gut microbiome can lead to obesity, by modulating metabolic pathways and eating behaviors of the host through GBA. Therefore, novel therapies targeting the gut microbiome, i.e., fecal microbiota transplantation and supplementation with probiotics and prebiotics, can be a potential treatment for obesity.
    CONCLUSION: This study corroborates the effect of gut microbiome on physiological function and body weight. The results show that the gut microbiota is becoming a target for new antiobesity therapies.
    Keywords:  gut-brain axis; obesity; prebiotic; probiotic; review
    DOI:  https://doi.org/10.1002/jcla.24420
  32. Int J Mol Sci. 2022 Apr 06. pii: 4064. [Epub ahead of print]23(7):
    The Growth, Lipid Accumulation and Fatty Acid Profile Analysis by Abscisic Acid and Indol-3-Acetic Acid Induced in Chlorella sp. FACHB-8.
    Yihua Lin, Yue Dai, Weinan Xu, Xiaobin Wu, Yanyan Li, Hongmei Zhu, Hantao Zhou.
      Microalgae are considered a promising source for biodiesel. The addition of plant hormone can exert a significant impact on the production of microalgae biomass and lipid accumulation. Nevertheless, the response of microalgae cells to hormones is species- or strain-dependent. It remains controversial which genes involved in strong increase of fatty acids production in response to abscisic acid (ABA) in Chlorella sp. FACHB-8 strain. We investigated cell growth, lipid accumulation, and fatty acid composition when ABA and indol-3-acetic acid (IAA) were used in the growth medium of Chlorella sp. FACHB-8. The four treatments, including 5 mg/L IAA (E1), 10 mg/L IAA (E2), 10 mg/L ABA (E3), the combination of 5 mg/L IAA and 5 mg/L ABA (E4), were found to increase cell growth, but only 10 mg/L ABA treatment could enhance the lipid accumulation. The fatty acid profile was changed by the addition of ABA, making fatty acids afflux from polyunsaturated fatty acids to monounsaturated and saturated fatty acids, which were suitable for diesel application. Furthermore, a transcriptome analysis was conducted, unraveling the differentially expressed genes enriched in fatty acid biosynthesis, fatty acid metabolism, and biosynthesis of the unsaturated fatty acid pathway in response to ABA. Our results clarified the correlation of fatty acid synthesis-related genes and fatty acid profiles, helping understand the potential response mechanism of Chlorella sp. FACHB-8 strain respond to ABA treatment.
    Keywords:  fatty acid; microalgae; plant hormones; transcriptome
    DOI:  https://doi.org/10.3390/ijms23074064
  33. Front Immunol. 2022 ;13 750175
    How Does Immunomodulatory Nanoceria Work? ROS and Immunometabolism.
    Lena M Ernst, Victor Puntes.
      Dysregulation of the immune system is associated with an overproduction of metabolic reactive oxygen species (ROS) and consequent oxidative stress. By buffering excess ROS, cerium oxide (CeO2) nanoparticles (NPs) (nanoceria) not only protect from oxidative stress consequence of inflammation but also modulate the immune response towards inflammation resolution. Immunomodulation is the modulation (regulatory adjustment) of the immune system. It has natural and human-induced forms, and it is part of immunotherapy, in which immune responses are induced, amplified, attenuated, or prevented according to therapeutic goals. For decades, it has been observed that immune cells transform from relative metabolic quiescence to a highly active metabolic state during activation(1). These changes in metabolism affect fate and function over a broad range of timescales and cell types, always correlated to metabolic changes closely associated with mitochondria number and morphology. The question is how to control the immunochemical potential, thereby regulating the immune response, by administering cellular power supply. In this regard, immune cells show different general catabolic modes relative to their activation status, linked to their specific functions (maintenance, scavenging, defense, resolution, and repair) that can be correlated to different ROS requirements and production. Properly formulated, nanoceria is highly soluble, safe, and potentially biodegradable, and it may overcome current antioxidant substances limitations and thus open a new era for human health management.
    Keywords:  ROS - reactive oxygen species; entropy; immunemetabolism; inflammation; macrophages; metabolism; nanoceria; nanoparticles
    DOI:  https://doi.org/10.3389/fimmu.2022.750175
  34. Nutrients. 2022 Apr 03. pii: 1501. [Epub ahead of print]14(7):
    Flazin as a Lipid Droplet Regulator against Lipid Disorders.
    Xunzhi Wu, Zhen Chen, Yue Wu, Yifan Chen, Jiaping Jia, Nianqiu Shen, Hitoshi Chiba, Shu-Ping Hui.
      Lipid disorders are closely related to numerous metabolic diseases, and lipid droplets (LDs) have been considered as a new target for regulating lipid metabolism. Dietary intervention and nutraceuticals provide safe and long-term beneficial effects for treating metabolic diseases. Flazin is a diet-derived bioactive constituent mainly existing in fermented foods, of which the lipid metabolism improvement function has not been studied. In this study, the effect of flazin on lipid regulation at both cell level and organelle level was investigated. Lipidomic profiling showed that flazin significantly decreased cellular triglyceride (TG) by 12.0-22.4% compared with modeling groups and improved the TG and free fatty acid profile. LD staining revealed that flazin efficiently reduced both cellular neutral lipid content by 17.4-53.9% and LD size by 10.0-35.3%. Furthermore, nanoelectrospray ionization mass spectrometry analysis proved that flazin exhibited a preferential suppression of LD TG and regulated LD morphology, including a size decrease and surface property improvement. An evaluation of related gene expression suggested the mechanism to be lipolysis promotion and lipogenesis inhibition. These findings indicated that flazin might be an LD regulator for reversing lipid metabolism disturbance. Moreover, the strategy proposed in this study may contribute to developing other nutraceuticals for treating lipid disorder-related metabolic diseases.
    Keywords:  diabetic nephropathy; functional foods; lipid metabolism; lipid-storage disorders; lipidomics; mass spectrometry; metabolic diseases; nutraceuticals; triglyceride
    DOI:  https://doi.org/10.3390/nu14071501
  35. J Ethnopharmacol. 2022 Apr 08. pii: S0378-8741(22)00311-7. [Epub ahead of print] 115272
    The potential of dandelion in the fight against gastrointestinal diseases: A review.
    Yanni Li, Yilun Chen, Dongxiao Sun-Waterhouse.
       ETHNOPHARMACOLOGICAL RELEVANCE: Dandelion (Taraxacum officinale Weber ex F. H. Wigg.), as a garden weed grown globally, has long been consumed as a therapeutic herb. Its folkloric uses include treatments of digestive disorders (dyspepsia, anorexia, stomach disorders, gastritis and enteritis) and associate complex ailments involving uterine, liver and lung disorders.
    AIM OF THE STUDY: The present study aims to critically assess the current state of research and summarize the potential roles of dandelion and its constituents in gastrointestinal (GI) -protective actions. A focus is placed on the reported bioactive components, pharmacological activities and modes of action (including molecular mechanisms and interactions among bioactive substances) of dandelion products/preparations and derived active constituents related to GI protection.
    MATERIALS AND METHODS: The available information published prior to August 2021 was reviewed via SciFinder, Web of Science, Google Scholar, PubMed, Elsevier, Wiley On-line Library, and The Plant List. The search was based on the ethnomedical remedies, pharmacological activities, bioactive compounds of dandelion for GI protection, as well as the interactions of the components in dandelion with the gut microbiota or biological regulators, and with other ingested bioactive compounds. The key search words were "Taraxacum" and "dandelion".
    RESULTS: T. coreanum Nakai, T. mongolicum and T. officinale are the most commonly used species for folkloric uses, with the whole plant, leaves and root of dandelion being used more frequently. GI-protective substances of dandelion include taraxasterol, taraxerol, caffeic acid, chicoric acid, chlorogenic acid, luteolin and its glucosides, polysaccharides, inulin, and β-sitosterol. Dandelion products and derived constituents exhibit pharmacological effects against GI disorders, mainly including dyspepsia, gastroesophageal reflux disease, gastritis, small intestinal ulcer, ulcerative colitis, liver diseases, gallstones, acute pancreatitis, and GI malignancy. The underlying molecular mechanisms may include immuno-inflammatory mechanisms, apoptosis mechanism, autophagy mechanism, and cholinergic mechanism, although interactions of dandelion's constituents with GI health-related biological entities (e.g., GI microbiota and associated biological modulators) or other ingested bioactive compounds shouldn't be ignored.
    CONCLUSION: The review reveals some in vivo and in vitro studies on the potential of dandelion derived products as complementary and alternative medicines/therapeutics against GI disorders. The whole herb may alleviate some symptoms related GI immuno-inflammatory basing on the abundant anti-inflammatory and anti-oxide active substances. Dandelion root could be a nontoxic and effective anticancer alternative, owing to its abundant terpenoids and polysaccharides. However, research related to GI protective dandelion-derived products remains limited. Besides the need of identifying bioactive compounds/complexes in various dandelion species, more clinical studies are also required on the metabolism, bioavailability and safety of these substances to support their applications in food, medicine and pharmaceuticals.
    Keywords:  Biologically active substances; Dandelion; Gastrointestinal diseases; Interactions; Microbiota; Pharmacological activities
    DOI:  https://doi.org/10.1016/j.jep.2022.115272
  36. Nutrients. 2022 Apr 06. pii: 1522. [Epub ahead of print]14(7):
    Astaxanthin Bioactivity Is Determined by Stereoisomer Composition and Extraction Method.
    Terry W Snell, John Carberry.
      Astaxanthin (ASX) is a natural product and one of the most powerful antioxidants known. It has significant effects on the metabolism of many animals, increasing fecundity, egg yolk volume, growth rates, immune responses, and disease resistance. A large part of the bioactivity of ASX is due to its targeting of mitochondria, where it inserts itself into cell membranes. Here, ASX stabilizes membranes and acts as a powerful antioxidant, protecting mitochondria from damage by reactive oxygen species (ROS). ROS are ubiquitous by-products of energy metabolism that must be tightly regulated by cells, lest they bind to and inactivate proteins, DNA and RNA, lipids, and signaling molecules. Most animals cannot synthesize ASX, so they need to acquire it in their diet. ASX is easily thermally denatured during extraction, and its high hydrophobicity limits its bioavailability. Our focus in this review is to contrast the bioactivity of different ASX stereoisomers and how extraction methods can denature ASX, compromising its bioavailability and bioactivity. We discuss the commercial sources of astaxanthin, structure of stereoisomers, relative bioavailability and bioactivity of ASX stereoisomers, mechanisms of ASX bioactivity, evolution of carotenoids, and why mitochondrial targeting makes ASX such an effective antioxidant.
    Keywords:  astaxanthin; bioactivity; bioavailability; metabolic effects; micronutrient; mitochondrial targeting; stereoisomers
    DOI:  https://doi.org/10.3390/nu14071522
  37. Cancers (Basel). 2022 Apr 04. pii: 1825. [Epub ahead of print]14(7):
    Robust Validation and Comprehensive Analysis of a Novel Signature Derived from Crucial Metabolic Pathways of Pancreatic Ductal Adenocarcinoma.
    Wenchao Gu, Shaocong Mo, Yulin Wang, Reika Kawabata-Iwakawa, Wei Zhang, Zongcheng Yang, Chenyu Sun, Yoshito Tsushima, Huaxiang Xu, Takahito Nakajima.
      Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor with a dismal prognosis. PDAC have extensively reprogrammed metabolic characteristics influenced by interactions with normal cells, the effects of the tumor microenvironment and oncogene-mediated cell-autonomous pathways. In this study, we found that among all cancer hallmarks, metabolism played an important role in PDAC. Subsequently, a 16-gene prognostic signature was established with genes derived from crucial metabolic pathways, including glycolysis, bile acid metabolism, cholesterol homeostasis and xenobiotic metabolism (gbcx). The signature was used to distinguish overall survival in multiple cohorts from public datasets as well as a validation cohort followed up by us at Shanghai Cancer Center. Notably, the gbcx-related risk score (gbcxMRS) also accurately predicted poor PDAC subtypes, such as pure-basal-like and squamous types. At the same time, it also predicted PDAC recurrence. The gbcxMRS was also associated with immune cells, especially CD8 T cells, Treg cells. Furthermore, a high gbcxMRS may indicate high drug sensitivity to irinotecan and docetaxel and CTLA4 inhibitor immunotherapy. Taken together, these results indicate a robust and reproducible metabolic-related signature based on analysis of the overall pathogenesis of pancreatic cancer, which may have excellent prognostic and therapeutic implications for PDAC.
    Keywords:  drug sensitivity; metabolic pathways; pancreatic ductal adenocarcinoma; prognosis; recurrence
    DOI:  https://doi.org/10.3390/cancers14071825
  38. Nutrients. 2022 Mar 31. pii: 1456. [Epub ahead of print]14(7):
    Retinoids in the Pathogenesis and Treatment of Liver Diseases.
    Marta Melis, Xiao-Han Tang, Steven E Trasino, Lorraine J Gudas.
      Vitamin A (VA), all-trans-retinol (ROL), and its analogs are collectively called retinoids. Acting through the retinoic acid receptors RARα, RARβ, and RARγ, all-trans-retinoic acid, an active metabolite of VA, is a potent regulator of numerous biological pathways, including embryonic and somatic cellular differentiation, immune functions, and energy metabolism. The liver is the primary organ for retinoid storage and metabolism in humans. For reasons that remain incompletely understood, a body of evidence shows that reductions in liver retinoids, aberrant retinoid metabolism, and reductions in RAR signaling are implicated in numerous diseases of the liver, including hepatocellular carcinoma, non-alcohol-associated fatty liver diseases, and alcohol-associated liver diseases. Conversely, restoration of retinoid signaling, pharmacological treatments with natural and synthetic retinoids, and newer agonists for specific RARs show promising benefits for treatment of a number of these liver diseases. Here we provide a comprehensive review of the literature demonstrating a role for retinoids in limiting the pathogenesis of these diseases and in the treatment of liver diseases.
    Keywords:  alcohol-associated liver disease; hepatocellular carcinoma; liver steatosis; nonalcoholic fatty liver disease; retinoic acid; retinoic acid receptor; vitamin A
    DOI:  https://doi.org/10.3390/nu14071456
  39. Int J Oncol. 2022 Jun;pii: 65. [Epub ahead of print]60(6):
    Aptamer‑based therapy for targeting key mediators of cancer metastasis (Review).
    Yahya Alhamhoom, Homood M As Sobeai, Sary Alsanea, Ali Alhoshani.
      Cancer‑related deaths remain a challenging and devastating obstacle to defeat despite the tremendous advances in cancer treatment. Cancer metastasis is the major cause of these cancer‑related deaths. Metastasis involves sequential steps during cancer cells' journey to a new site. These steps are coordinately regulated by specific intracellular regulators and cellular interactions between the cancer cells and the supporting microenvironment of the different organs. The development of aptamer‑based therapeutics is a promising strategy to fight cancer metastasis as it holds potential advantages. Oligonucleotide and peptide aptamers are short sequences of single‑stranded nucleic acids or amino acids, respectively, that target proteins, genetic materials, and cells. Antimetastatic aptamer‑based therapeutics exert their pharmacological effect by direct interaction with the signaling pathways inside the cancer cells or the communications between cancer cells and the tumor microenvironment. In addition, aptamers have been utilized as a guiding ligand to deliver a therapeutic moiety to cancer cells or the supporting microenvironment. The selected aptamer possesses high specificity since it is designed to recognize and interact with its target. This review summarizes recent advances in the development of aptamer‑based therapeutics targeting mediators of cancer metastasis. In addition, potential opportunities are discussed to inspire researchers in the field to develop novel aptamer‑based antimetastatic treatments.
    Keywords:  antimetastatic treatment; aptamer‑based therapeutics; cancer metastasis; drug delivery; targeted treatment
    DOI:  https://doi.org/10.3892/ijo.2022.5355
  40. Hum Immunol. 2022 Apr 09. pii: S0198-8859(22)00067-2. [Epub ahead of print]
    High fructose diet: A risk factor for immune system dysregulation.
    Hao Cheng, Jingyang Zhou, Yutong Sun, Qipeng Zhan, Dunfang Zhang.
      Excessive intake of sweets is a predisposing factor for metabolic disorders, and fructose, as one of the major dietary sugars in the diet, has been shown to be a major cause of obesity, diabetes, and metabolic syndrome. These disorders are usually associated with immune dysfunction. Therefore, exploring the effects of a high fructose diet on the immune system may provide insight into the underlying mechanisms of these diseases. We synthesized the available evidence to suggest that excessive fructose intake disrupts the body's immune homeostasis by promoting immune cell metabolic rearrangements, alterations in gut microbial community structure, and intestinal barrier permeability. Indeed, not only does fructose itself affect immune system homeostasis, but its metabolites also have a profound influence. The metabolites from fructolysis are mainly produced in the small intestine and liver and subsequently enter the systemic circulation. Elevated levels of fructose metabolites, such as uric acid, FFAs, and lactate, are closely associated with oxidative stress and local tissue and organ inflammatory responses. In this review, we will focus on the link between fructose and inflammatory responses. In the meanwhile, we will also briefly summarize the studies of cancer development and immune escape mediated by fructose, as it might be beneficial for cancer immunotherapy.
    Keywords:  Autoimmunity; Cancer; Fructose; Inflammation; Microbiota
    DOI:  https://doi.org/10.1016/j.humimm.2022.03.007
  41. Curr Mol Pharmacol. 2022 Apr 08.
    Targeting signaling pathway by curcumin in osteosarcoma.
    Parnia Rahnamay Farnood, Romina Danesh Pazhooh, Zatollah Asemi, Bahman Yousefi.
      The most prevalent primary bone malignancy among children and adolescents is osteosarcoma. The high mortality rate of osteosarcoma is due to lung metastasis. Despite the development of multi-agent chemotherapy and surgical resection, patients with osteosarcoma have a high metastasis rate and poor prognosis. Thus, it is necessary to identify novel therapeutic agents to improve the 5-year survival rate of these patients. Curcumin, a phytochemical compound derived from Curcuma longa, has been employed in treating several types of cancers through various mechanisms. Also, in vitro studies have demonstrated that curcumin could inhibit cell proliferation and induce apoptosis in osteosarcoma cells. Development in identifying signaling pathways involved in the pathogenesis of osteosarcoma has provided insight into finding new therapeutic targets for the treatment of this cancer. Targeting MAPK/ERK, PI3k/AKT, Wnt/β-catenin, Notch, and MircoRNA by curcumin has been evaluated to improve outcomes in patients with osteosarcoma. Although curcumin is a potent anti-cancer compound, it has rarely been studied in clinical settings due to its congenital properties such as hydrophobicity and poor bioavailability. In this review, we recapitulate and describe the effect of curcumin in regulating signaling pathways involved in osteosarcoma.
    Keywords:  Curcumin; Osteosarcoma; signaling pathway
    DOI:  https://doi.org/10.2174/1874467215666220408104341
  42. Circ Res. 2022 Apr 15. 130(8): 1112-1144
    Aging Microbiota-Gut-Brain Axis in Stroke Risk and Outcome.
    Pedram Honarpisheh, Robert M Bryan, Louise D McCullough.
      The microbiota-gut-brain-axis (MGBA) is a bidirectional communication network between gut microbes and their host. Many environmental and host-related factors affect the gut microbiota. Dysbiosis is defined as compositional and functional alterations of the gut microbiota that contribute to the pathogenesis, progression and treatment responses to disease. Dysbiosis occurs when perturbations of microbiota composition and function exceed the ability of microbiota and its host to restore a symbiotic state. Dysbiosis leads to dysfunctional signaling of the MGBA, which regulates the development and the function of the host's immune, metabolic, and nervous systems. Dysbiosis-induced dysfunction of the MGBA is seen with aging and stroke, and is linked to the development of common stroke risk factors such as obesity, diabetes, and atherosclerosis. Changes in the gut microbiota are also seen in response to stroke, and may impair recovery after injury. This review will begin with an overview of the tools used to study the MGBA with a discussion on limitations and potential experimental confounders. Relevant MGBA components are introduced and summarized for a better understanding of age-related changes in MGBA signaling and its dysfunction after stroke. We will then focus on the relationship between the MGBA and aging, highlighting that all components of the MGBA undergo age-related alterations that can be influenced by or even driven by the gut microbiota. In the final section, the current clinical and preclinical evidence for the role of MGBA signaling in the development of stroke risk factors such as obesity, diabetes, hypertension, and frailty are summarized, as well as microbiota changes with stroke in experimental and clinical populations. We conclude by describing the current understanding of microbiota-based therapies for stroke including the use of pre-/pro-biotics and supplementations with bacterial metabolites. Ongoing progress in this new frontier of biomedical sciences will lead to an improved understanding of the MGBA's impact on human health and disease.
    Keywords:  aging; brain-gut axis; dysbiosis; microbiota; risk factors; stroke
    DOI:  https://doi.org/10.1161/CIRCRESAHA.122.319983
  43. Nutr Metab (Lond). 2022 Apr 15. 19(1): 29
    L-theanine prevents progression of nonalcoholic hepatic steatosis by regulating hepatocyte lipid metabolic pathways via the CaMKKβ-AMPK signaling pathway.
    Juanjuan Liang, Lili Gu, Xianli Liu, Xintong Yan, Xiaowen Bi, Xirui Fan, Jinyi Zhou, Shuai Lu, Lan Luo, Zhimin Yin.
       BACKGROUND: L-theanine, a non-protein amino acid was found principally in the green tea, has been previously shown to exhibit potent anti-obesity property and hepatoprotective effect. Herein, we investigated the effects of L-theanine on alleviating nonalcoholic hepatic steatosis in vitro and in vivo, and explored the underlying molecular mechanism.
    METHODS: In vitro, HepG2 and AML12 cells were treated with 500 μM oleic acid (OA) or treated with OA accompanied by L-theanine. In vivo, C57BL/6J mice were fed with normal control diet (NCD), high-fat diet (HFD), or HFD along with L-theanine for 16 weeks. The levels of triglycerides (TG), accumulation of lipid droplets and the expression of genes related to hepatocyte lipid metabolic pathways were detected in vitro and in vivo.
    RESULTS: Our data indicated that, in vivo, L-theanine significantly reduced body weight, hepatic steatosis, serum levels of alanine transaminase (ALT), aspartate transaminase (AST), TG and LDL cholesterol (LDL-C) in HFD-induced nonalcoholic fatty liver disease (NAFLD) mice. In vitro, L-theanine also significantly alleviated OA induced hepatocytes steatosis. Mechanic studies showed that L-theanine significantly inhibited the nucleus translocation of sterol regulatory element binding protein 1c (SREBP-1c) through AMPK-mTOR signaling pathway, thereby contributing to the reduction of fatty acid synthesis. We also identified that L-theanine enhanced fatty acid β-oxidation by increasing the expression of peroxisome proliferator-activated receptor α (PPARα) and carnitine palmitoyltransferase-1 A (CPT1A) through AMP-activated protein kinase (AMPK). Furthermore, our study indicated that L-theanine can active AMPK through its upstream kinase Calmodulin-dependent protein kinase kinase-β (CaMKKβ).
    CONCLUSIONS: Taken together, our findings suggested that L-theanine alleviates nonalcoholic hepatic steatosis by regulating hepatocyte lipid metabolic pathways via the CaMKKβ-AMPK signaling pathway.
    Keywords:  CaMKKβ; Hepatic steatosis; L-theanine; Lipid accumulation; SREBP-1c
    DOI:  https://doi.org/10.1186/s12986-022-00664-6
  44. Front Oncol. 2022 ;12 819128
    PI3K/Akt/mTOR Pathway and Its Role in Cancer Therapeutics: Are We Making Headway?
    Yan Peng, Yuanyuan Wang, Cheng Zhou, Wuxuan Mei, Changchun Zeng.
      Cancer is a severe public health issue that is a leading cause of mortality globally. It is also an impediment to improving life expectancy worldwide. Furthermore, the global burden of cancer incidence and death is continuously growing. Current therapeutic options are insufficient for patients, and tumor complexity and heterogeneity necessitate customized medicine or targeted therapy. It is critical to identify potential cancer therapeutic targets. Aberrant activation of the PI3K/AKT/mTOR pathway has a significant role in carcinogenesis. This review summarized oncogenic PI3K/Akt/mTOR pathway alterations in cancer and various cancer hallmarks associated with the PI3K/AKT/mTOR pathway, such as cell proliferation, autophagy, apoptosis, angiogenesis, epithelial-to-mesenchymal transition (EMT), and chemoresistance. Importantly, this review provided recent advances in PI3K/AKT/mTOR inhibitor research. Overall, an in-depth understanding of the association between the PI3K/AKT/mTOR pathway and tumorigenesis and the development of therapies targeting the PI3K/AKT/mTOR pathway will help make clinical decisions.
    Keywords:  PI3K/Akt/mTOR pathway; cancer; oncogenic alterations; precision medicine; targeted therapy
    DOI:  https://doi.org/10.3389/fonc.2022.819128
  45. Front Oral Health. 2022 ;3 881949
    Oral-Gut Microbiome Axis in the Pathogenesis of Cancer Treatment-Induced Oral Mucositis.
    Ghanyah Al-Qadami, Ysabella Van Sebille, Joanne Bowen, Hannah Wardill.
      Oral mucositis (OM) is one of the most common and debilitating oral complications of cancer treatments including chemotherapy, radiotherapy, and hematopoietic stem cell transplantation. It is associated with severe pain and difficulties in chewing, swallowing, and speech. This leads to impairment of basic oral functions and could result in unplanned treatment interruption or modification. As such, OM negatively impacts both patients' quality of life as well as tumor prognostic outcomes. Understanding pathways underlying OM pathogenesis help identify new targets for intervention or prevention. The pathophysiology of OM has been widely studied over past decades with several pathways related to oxidative stress, inflammation, and molecular and cellular signaling being implicated. In this mini-review, we will discuss the emerging role of the oral-gut microbiome axis in the development of OM. Particularly, we will elaborate on how the alterations in the oral and gut microbiota as well as intestinal dysfunction caused by cancer treatments could contribute to the pathogenesis of OM. Further, we will briefly discuss the potential methods for targeting the oral-gut microbiome axis to improve OM outcomes.
    Keywords:  HSCT; chemotherapy; gut microbiota; oral microbiota; oral mucositis; oral-gut microbiome axis; radiotherapy
    DOI:  https://doi.org/10.3389/froh.2022.881949
  46. Horm Metab Res. 2022 Apr;54(4): 203-211
    FGF21: A Novel Regulator of Glucose and Lipid Metabolism and Whole-Body Energy Balance.
    Ewa Szczepańska, Małgorzata Gietka-Czernel.
      Fibroblast growth factor (FGF) 21 is a recently recognized metabolic regulator that evokes interest due to its beneficial action of maintaining whole-body energy balance and protecting the liver from excessive triglyceride production and storage. Together with FGF19 and FGF23, FGF21 belongs to the FGF family with hormone-like activity. Serum FGF21 is generated primarily in the liver under nutritional stress stimuli like prolonged fasting or the lipotoxic diet, but also during increased mitochondrial and endoplasmic reticulum stress. FGF21 exerts its endocrine action in the central nervous system and adipose tissue. Acting in the ventromedial hypothalamus, FGF21 diminishes simple sugar intake. In adipose tissue, FGF21 promotes glucose utilization and increases energy expenditure by enhancing adipose tissue insulin sensitivity and brown adipose tissue thermogenesis. Therefore, FGF21 favors glucose consumption for heat production instead of energy storage. Furthermore, FGF21 specifically acts in the liver, where it protects hepatocytes from metabolic stress caused by lipid overload. FGF21 stimulates hepatic fatty acid oxidation and reduces lipid flux into the liver by increasing peripheral lipoprotein catabolism and reducing adipocyte lipolysis. Paradoxically, and despite its beneficial action, FGF21 is elevated in insulin resistance states, that is, fatty liver, obesity, and type 2 diabetes.
    DOI:  https://doi.org/10.1055/a-1778-4159
  47. Fish Physiol Biochem. 2022 Apr 11.
    Nutritional programming by maternal diet alters offspring lipid metabolism in a marine teleost.
    Zhenxin Hou, Xiyuan Lu, Stefano Tiziani, Lee A Fuiman.
      Nutritional programming - the association between the early nutritional environment and long-term consequences for an animal - is an emerging area of research in fish biology. Previous studies reported correlations between maternal provisioning of essential fatty acids to eggs and the whole-body fatty acid composition of larvae reared under uniform conditions for red drum, Sciaenops ocellatus. This study aimed to further investigate the nutritional stimulus and the consequences of nutritional programming by feeding adult red drum several distinct diets and rearing larvae under uniform conditions until 21 days post-hatching when larval lipid and fatty acid compositions were assessed. Different maternal diets produced eggs with distinctive lipid and fatty acid compositions, and despite receiving the same larval diet for almost 3 weeks, larvae showed differences in total fatty acid accumulation and in retention of highly unsaturated fatty acids (HUFA). Specifically, larvae reared from a maternal diet of shrimp generally showed elevated levels of fatty acids in the initial steps of the n-3 and n-6 HUFA biosynthetic pathways and reduced levels of fatty acid products of the same pathways, especially in triglyceride. Furthermore, the variations in larval fatty acid accumulation induced by maternal diet varied among females. Lipid metabolism altered by parental diet may have consequences for larval physiological processes and behavioral performance, which may ultimately influence larval survival.
    Keywords:  Fatty acid; Larval fish; Lipid metabolism; Maternal nutrition; Nutritional programming
    DOI:  https://doi.org/10.1007/s10695-022-01069-1
  48. Front Nutr. 2022 ;9 881843
    Nuts as a Part of Dietary Strategy to Improve Metabolic Biomarkers: A Narrative Review.
    Leila Khalili, Thoraya Mohamed Elhassan A-Elgadir, Ayaz Khurram Mallick, Hesham Ali El Enshasy, R Z Sayyed.
       Background: Nuts are in the spotlight because of their association with improved health outcomes. We aimed to summarize the findings of previous studies to evaluate the impact of nuts consumption on glycaemic and lipid profile, inflammation, and oxidative stress.
    Methods: Electronic searches for observational and intervention studies were undertaken in PubMed, Embase, Web of Science, and Science Direct until 2022 for searching the studies aiming the application of different types of nuts and the beneficial effects of nuts in improving glycemia, dyslipidemia, inflammation, and oxidative stress.
    Results: Results from 56 interventional, 9 narrative and 3 systematic reviews, and 12 meta-analysis studies, aiming at the evaluating beneficial effects of different types of nuts on metabolic markers, showed that nut consumption could improve metabolic markers, including glycaemic factors, lipid profile, and inflammatory and oxidative stress parameters in both healthy and individuals with metabolic disorders in a type-, dose- and duration-dependent manner. According to their unique nutrient components, nuts can be known as a part of a healthy diet, resulting in improved metabolic biomarkers.
    Conclusion: Considering the efficacy of nuts in improving metabolic markers, incorporation of, incorporating nuts the effectiveness of nuts in improving metabolic markers, incorporating nuts in the diet may prevent the incidence or aggravation of chronic metabolic diseases. Considering the health benefits of the nuts' components, including essential micronutrients, if consumed in the appropriate dose and duration to provide the necessary amount of effective micronutrients to improve health, we will see an improvement in metabolic factors. At the same time, more research is required to determine the optimal type, dose, and duration of nut intervention with regards to metabolic control and reducing the risk of developing metabolic disorders.
    Keywords:  glycemic control (A1C); inflammation; lipid profile; metabolic biomarkers; oxidative stress
    DOI:  https://doi.org/10.3389/fnut.2022.881843
  49. mSystems. 2022 Apr 11. e0124821
    Murine Gut Microbiome Meta-analysis Reveals Alterations in Carbohydrate Metabolism in Response to Aging.
    Xiaomeng You, Ushashi C Dadwal, Marc E Lenburg, Melissa A Kacena, Julia F Charles.
      Compositional and functional alterations to the gut microbiota during aging are hypothesized to potentially impact our health. Thus, determining aging-specific gut microbiome alterations is critical for developing microbiome-based strategies to improve health and promote longevity in the elderly. In this study, we performed a meta-analysis of publicly available 16S rRNA gene sequencing data from studies investigating the effect of aging on the gut microbiome in mice. Aging reproducibly increased gut microbial alpha diversity and shifted the microbial community structure in mice. We applied the bioinformatic tool PICRUSt2 to predict microbial metagenome function and established a random forest classifier to differentiate between microbial communities from young and old hosts and to identify aging-specific metabolic features. In independent validation data sets, this classifier achieved an area under the receiver operating characteristic curve (AUC) of 0.75 to 0.97 in differentiating microbiomes from young and old hosts. We found that 50% of the most important predicted aging-specific metabolic features were involved in carbohydrate metabolism. Furthermore, fecal short-chain fatty acid (SCFA) concentrations were significantly decreased in old mice, and the expression of the SCFA receptor Gpr41 in the colon was significantly correlated with the relative abundances of gut microbes and microbial carbohydrate metabolic pathways. In conclusion, this study identified aging-specific alterations in the composition and function of the gut microbiome and revealed a potential relationship between aging, microbial carbohydrate metabolism, fecal SCFA, and colonic Gpr41 expression. IMPORTANCE Aging-associated microbial alteration is hypothesized to play an important role in host health and longevity. However, investigations regarding specific gut microbes or microbial functional alterations associated with aging have had inconsistent results. We performed a meta-analysis across 5 independent studies to investigate the effect of aging on the gut microbiome in mice. Our analysis revealed that aging increased gut microbial alpha diversity and shifted the microbial community structure. To determine if we could reliably differentiate the gut microbiomes from young and old hosts, we established a random forest classifier based on predicted metagenome function and validated its performance against independent data sets. Alterations in microbial carbohydrate metabolism and decreased fecal short-chain fatty acid (SCFA) concentrations were key features of aging and correlated with host colonic expression of the SCFA receptor Gpr41. This study advances our understanding of the impact of aging on the gut microbiome and proposes a hypothesis that alterations in gut microbiota-derived SCFA-host GPR41 signaling are a feature of aging.
    Keywords:  aging; carbon metabolism; meta-analysis; murine gut microbiome
    DOI:  https://doi.org/10.1128/msystems.01248-21
  50. Biochem Pharmacol. 2022 Apr 12. pii: S0006-2952(22)00131-9. [Epub ahead of print] 115037
    A Rational Foundation for Micheliolide-based Combination Strategy by Targeting Redox and Metabolic Circuit in Cancer Cells.
    Jianshuang Guo, Kaihui Liu, Jiyan Wang, Hao Jiang, Mengyi Zhang, Yang Liu, Changliang Shan, Fangzhong Hu, Wenzheng Fu, Chunze Zhang, Jing Li, Yue Chen.
      Accumulating evidence has supported that targeting oxidative stress and metabolic alterations of cancer is an effective strategy to combat cancer. We previously reported that Dimethylaminomicheliolide (DMAMCL) and its active metabolite micheliolide (MCL) can cause oxidative stress and cell death in leukemia and glioblastoma. However, the detailed mechanism underlying MCL or DMAMCL triggered oxidative stress remains elusive. Herein, using leukemia HL60 cells and glioblastoma U118MG cells as models, we found that MCL-induced oxidative stress is mainly mediated by reduced glutathione (GSH). Overproduced reactive oxygen species (ROS) can lead to oxidative damage to mitochondrial, impairing the ability of the tricarboxylic acid (TCA) cycle and causing dysfunction of mitochondrial respiratory chain. On the other hand, the depletion of GSH activates GSH biosynthesis pathway and has possibility to give rise to more GSH to scavenge ROS in cancer cells. Targeting this redox and metabolic circuit, we identified L-buthionine sulfoximine (BSO), an inhibitor in GSH biosynthesis, as an agent that can enhance MCL regimen to inhibit GSH compensatory event and thereby further facilitate cancer cell oxidative stress. Together, these results illustrate that targeting redox and metabolic pathway by MCL/DMAMCL combination with BSO is a potent therapeutic intervention for the treatments of glioblastoma and acute-myelocytic leukemia.
    Keywords:  glioblastoma; glutathione metabolism; leukemia; micheliolide; mitochondrial dysfunction; oxidative stress
    DOI:  https://doi.org/10.1016/j.bcp.2022.115037
  51. Cureus. 2022 Mar;14(3): e22825
    Curcumin as a Potential Therapeutic Agent in Certain Cancer Types.
    Anish K Vadukoot, Shabna Mottemmal, Pratikkumar H Vekaria.
      Cancer is a devastating disease condition and is the second most common etiology of death globally. After decades of research in the field of hematological malignancies and cellular therapeutics, we are still looking for therapeutic agents with the most efficacies and least toxicities. Curcumin is one of the cancer therapeutic agents that is derived from the Curcuma longa (turmeric) plant, and still in vitro and in vivo research is going on to find its beneficial effects on various cancers. Due to its potency to affect multiple targets of different cellular pathways, it is considered a promising agent to tackle various cancers alone or in combination with the existing chemotherapies. This review covers basic properties, mechanism of action, potential targets (molecules and cell-signaling pathways) of curcumin, as well as its effect on various solid and hematological malignancies.
    Keywords:  cancer; cell-signaling pathways; curcumin; hematological malignancies; molecules
    DOI:  https://doi.org/10.7759/cureus.22825
  52. J Cancer. 2022 ;13(6): 1745-1757
    Cholesterol metabolism and its implication in glioblastoma therapy.
    Xuyang Guo, Shaolong Zhou, Zhuo Yang, Zi-An Li, Weihua Hu, Lirui Dai, Wulong Liang, Xinjun Wang.
      Glioblastoma (GBM) is the most lethal malignant tumor in the central nervous system, with a median survival of only 14 months. Cholesterol, which is the main component of cell membrane and the precursor of many hormones, is one of the most important lipid components in human body. Since reprogramming of the cholesterol metabolic profile has been discovered in many cancers including GBM, cholesterol metabolism becomes a promising potential target for therapy. Since GBM cells rely on external cholesterol to survive and accumulate lipid droplets to meet their rapid growth needs, targeting the metabolism of cholesterol by different strategies including inhibition of cholesterol uptake and promotion of cholesterol efflux by activating LXRs and disruption of cellular cholesterol trafficking, inhibition of SREBP signaling, inhibition of cholesterol esterification, could potentially oppose the growth of glial tumors. In this review, we discussed the above findings and describe cholesterol synthesis and homeostatic feedback pathways in normal brain tissues and brain tumors, statin use in GBM and the role of lipid rafts and cholesterol precursors and oxysterols in the treatment and pathogenesis of GBM are also summarized.
    DOI:  https://doi.org/10.7150/jca.63609
  53. Int J Mol Sci. 2022 Mar 28. pii: 3710. [Epub ahead of print]23(7):
    Histamine Causes Pyroptosis of Liver by Regulating Gut-Liver Axis in Mice.
    Qiaoqiao Luo, Ruoyu Shi, Yutong Liu, Libo Huang, Wei Chen, Chengtao Wang.
      Huangjiu usually caused rapid-drunkenness and components such as β-benzyl ethanol (β-be), isopentanol (Iso), histamine (His), and phenethylamine (PEA) have been reported linked with intoxication. However, the destructive effect of these components on gut microbiota and liver is unclear. In this study, we found oral treatment of these components, especially His, stimulated the level of oxidative stress and inflammatory cytokines in liver and serum of mice. The gut microbiota community was changed and the level of lipopolysaccharide (LPS) increased significantly. Additionally, cellular pyroptosis pathway has been assessed and correlation analysis revealed a possible relationship between gut microbiota and liver pyroptosis. We speculated oral His treatment caused the reprogramming of gut microbiota metabolism, and increased LPS modulated the gut-liver interaction, resulting in liver pyroptosis, which might cause health risks. This study provided a theoretical basis for the effect of Huangjiu, facilitating the development of therapeutic and preventive strategies for related inflammatory disorders.
    Keywords:  food ingredients; gut microbiota; health; metabolic disease; metabolism; molecular mechanism
    DOI:  https://doi.org/10.3390/ijms23073710
  54. Int J Mol Sci. 2022 Apr 06. pii: 4047. [Epub ahead of print]23(7):
    Metabolic Syndrome and β-Oxidation of Long-Chain Fatty Acids in the Brain, Heart, and Kidney Mitochondria.
    Alexander Panov, Vladimir I Mayorov, Sergey Dikalov.
      We present evidence that metabolic syndrome (MetS) represents the postreproductive stage of the human postembryonic ontogenesis. Accordingly, the genes governing this stage experience relatively weak evolutionary selection pressure, thus representing the metabolic phenotype of distant ancestors with β-oxidation of long-chain fatty acids (FAs) as the primary energy source. Mitochondria oxidize at high-rate FAs only when succinate, glutamate, or pyruvate are present. The heart and brain mitochondria work at a wide range of functional loads and possess an intrinsic inhibition of complex II to prevent oxidative stress at periods of low functional activity. Kidney mitochondria constantly work at a high rate and lack inhibition of complex II. We suggest that in people with MetS, oxidative stress is the central mechanism of the heart and brain pathologies. Oxidative stress is a secondary pathogenetic mechanism in the kidney, while the primary mechanisms are kidney hypoxia caused by persistent hyperglycemia and hypertension. Current evidence suggests that most of the nongenetic pathologies associated with MetS originate from the inconsistencies between the metabolic phenotype acquired after the transition to the postreproductive stage and excessive consumption of food rich in carbohydrates and a sedentary lifestyle.
    Keywords:  brain mitochondria; heart; human postembryonic ontogenesis; kidney; long-chain fatty acids; metabolic syndrome; oxidative stress; β-oxidation
    DOI:  https://doi.org/10.3390/ijms23074047
  55. Life Sci. 2022 Apr 11. pii: S0024-3205(22)00243-0. [Epub ahead of print] 120543
    Characteristics and molecular mechanisms through which SGLT2 inhibitors improve metabolic diseases: A mechanism review.
    Xie Lingli, Xia Wenfang.
      Metabolic diseases, such as diabetes, gout and hyperlipidemia are global health challenges. Among them, diabetes has been extensively investigated. Type 2 diabetes mellitus (T2DM), which is characterized by hyperglycemia, is a complex metabolic disease that is associated with various metabolic disorders. The newly developed oral hypoglycemic agent, sodium-glucose cotransporter 2 (SGLT2) inhibitor, has been associated with glucose-lowering effects and it affects metabolism in various ways. However, the potential mechanisms of SGLT2 inhibitors in metabolic diseases have not fully reviewed. Many of the effects beyond glycemic control must be considered off-target effects. Therefore, we reviewed the effects of SGLT2 inhibition on metabolic diseases such as obesity, hypertension, hyperlipidemia, hyperuricemia, fatty liver disease, insulin resistance, osteoporosis and fractures. Moreover, we elucidated their molecular mechanisms to provide a theoretical basis for metabolic disease treatment.
    Keywords:  Diabetes mellitus; Metabolic diseases; Molecular mechanism; Off-target effects; SGLT2 inhibitors
    DOI:  https://doi.org/10.1016/j.lfs.2022.120543
  56. Cells. 2022 Apr 05. pii: 1228. [Epub ahead of print]11(7):
    Insulin-Degrading Enzyme, an Under-Estimated Potential Target to Treat Cancer?
    Laetitia Lesire, Florence Leroux, Rebecca Deprez-Poulain, Benoit Deprez.
      Insulin-degrading enzyme (IDE) is a multifunctional protease due to the variety of its substrates, its various cellular locations, its conservation between species and its many non-proteolytic functions. Numerous studies have successfully demonstrated its implication in two main therapeutic areas: metabolic and neuronal diseases. In recent years, several reports have underlined the overexpression of this enzyme in different cancers. Still, the exact role of IDE in the physiopathology of cancer remains to be elucidated. Known as the main enzyme responsible for the degradation of insulin, an essential growth factor for healthy cells and cancer cells, IDE has also been shown to behave like a chaperone and interact with the proteasome. The pharmacological modulation of IDE (siRNA, chemical compounds, etc.) has demonstrated interesting results in cancer models. All these results point towards IDE as a potential target in cancer. In this review, we will discuss evidence of links between IDE and cancer development or resistance, IDE's functions, catalytic or non-catalytic, in the context of cell proliferation, cancer development and the impact of the pharmacomodulation of IDE via cancer therapeutics.
    Keywords:  cancer; insulin-degrading enzyme; target
    DOI:  https://doi.org/10.3390/cells11071228
  57. PLoS One. 2022 ;17(4): e0266783
    PyMiner: A method for metabolic pathway design based on the uniform similarity of substrate-product pairs and conditional search.
    Xinfang Song, Mingyu Dong, Min Liu.
      Metabolic pathway design is an essential step in the course of constructing an efficient microbial cell factory to produce high value-added chemicals. Meanwhile, the computational design of biologically meaningful metabolic pathways has been attracting much attention to produce natural and non-natural products. However, there has been a lack of effective methods to perform metabolic network reduction automatically. In addition, comprehensive evaluation indexes for metabolic pathway are still relatively scarce. Here, we define a novel uniform similarity to calculate the main substrate-product pairs of known biochemical reactions, and develop further an efficient metabolic pathway design tool named PyMiner. As a result, the redundant information of general metabolic network (GMN) is eliminated, and the number of substrate-product pairs is shown to decrease by 81.62% on average. Considering that the nodes in the extracted metabolic network (EMN) constructed in this work is large in scale but imbalanced in distribution, we establish a conditional search strategy (CSS) that cuts search time in 90.6% cases. Compared with state-of-the-art methods, PyMiner shows obvious advantages and demonstrates equivalent or better performance on 95% cases of experimentally verified pathways. Consequently, PyMiner is a practical and effective tool for metabolic pathway design.
    DOI:  https://doi.org/10.1371/journal.pone.0266783
  58. J Nanobiotechnology. 2022 Apr 12. 20(1): 188
    Double-activation of mitochondrial permeability transition pore opening via calcium overload and reactive oxygen species for cancer therapy.
    Ying Zhou, Shisong Jing, Sainan Liu, Xizhong Shen, Lihan Cai, Changfeng Zhu, Yicheng Zhao, Maolin Pang.
       BACKGROUND: Calcium ions (Ca2+) participates in various intracellular signal cascades and especially plays a key role in pathways relevant to cancer cells. Mitochondrial metabolism stimulated by calcium overload can trigger the opening of the mitochondrial permeability transition pore (MPTP), which leads to cancer cell death.
    METHODS: Herein, a mitochondrial pathway for tumour growth inhibition was built via the double-activation of MPTP channel. Fe2+ doped covalent organic frameworks (COF) was synthesised and applied as template to grow CaCO3 shell. Then O2 was storaged into Fe2+ doped COF, forming O2-FeCOF@CaCO3 nanocomposite. After modification with folic acid (FA), O2-FeCOF@CaCO3@FA (OFCCF) can target breast cancer cells and realize PDT/Ca2+ overload synergistic treatment.
    RESULTS: COF can induce the production of 1O2 under 650 nm irradiation for photodynamic therapy (PDT). Low pH and hypoxia in tumour microenvironment (TME) can activate the nanocomposite to release oxygen and Ca2+. The released O2 can alleviate hypoxia in TME, thus enhancing the efficiency of COF-mediated PDT. Abundant Ca2+ were released and accumulated in cancer cells, resulting in Ca2+ overload. Notably, the reactive oxygen species (ROS) and Ca2+ overload ensure the sustained opening of MPTP, which leads to the change of mitochondria transmembrane potential, the release of cytochrome c (Cyt c) and the activation of caspases 3 for cancer cell apoptosis.
    CONCLUSION: This multifunctional nanosystem with TME responded abilities provided a novel strategy for innovative clinical cancer therapy.
    Keywords:  Ca2+ overload; Covalent organic frameworks; Hypoxia; MPTP; Photodynamic therapy
    DOI:  https://doi.org/10.1186/s12951-022-01392-y
  59. Molecules. 2022 Apr 06. pii: 2365. [Epub ahead of print]27(7):
    Flavonoids in Treatment of Chronic Kidney Disease.
    Yi-Ling Cao, Ji-Hong Lin, Hans-Peter Hammes, Chun Zhang.
      Chronic kidney disease (CKD) is a progressive systemic disease, which changes the function and structure of the kidneys irreversibly over months or years. The final common pathological manifestation of chronic kidney disease is renal fibrosis and is characterized by glomerulosclerosis, tubular atrophy, and interstitial fibrosis. In recent years, numerous studies have reported the therapeutic benefits of natural products against modern diseases. Substantial attention has been focused on the biological role of polyphenols, in particular flavonoids, presenting broadly in plants and diets, referring to thousands of plant compounds with a common basic structure. Evidence-based pharmacological data have shown that flavonoids play an important role in preventing and managing CKD and renal fibrosis. These compounds can prevent renal dysfunction and improve renal function by blocking or suppressing deleterious pathways such as oxidative stress and inflammation. In this review, we summarize the function and beneficial properties of common flavonoids for the treatment of CKD and the relative risk factors of CKD.
    Keywords:  chronic kidney disease; flavonoids; inflammation; nephroprotection; oxidative stress
    DOI:  https://doi.org/10.3390/molecules27072365
  60. J Zhejiang Univ Sci B. 2022 Apr 15. pii: 1673-1581(2022)04-0286-14. [Epub ahead of print]23(4): 286-299
    A novel anticancer property of Lycium barbarum polysaccharide in triggering ferroptosis of breast cancer cells.
    Xing DU, Jingjing Zhang, Ling Liu, Bo Xu, Hang Han, Wenjie Dai, Xiuying Pei, Xufeng Fu, Shaozhang Hou.
      Breast cancer is one of the most malignant tumors and is associated with high mortality rates among women. Lycium barbarum polysaccharide (LBP) is an extract from the fruits of the traditional Chinese herb, L. barbarum. LBP is a promising anticancer drug, due to its high activity and low toxicity. Although it has anticancer properties, its mechanisms of action have not been fully established. Ferroptosis, which is a novel anticancer strategy, is a cell death mechanism that relies on iron-dependent lipid reactive oxygen species (ROS) accumulation. In this study, human breast cancer cells (Michigan Cancer Foundation-7 (MCF-7) and MD Anderson-Metastatic Breast-231 (MDA-MB-231)) were treated with LBP. LBP inhibited their viability and proliferation in association with high levels of ferroptosis. Therefore, we aimed to ascertain whether LBP reduced cell viability through ferroptosis. We found that the structure and function of mitochondria, lipid peroxidation, and expression of solute carrier family 7 member 11 (SLC7A11, also known as xCT, the light-chain subunit of cystine/glutamate antiporter system Xc-) and glutathione peroxidase 4 (GPX4) were altered by LBP. Moreover, the ferroptosis inhibitor, Ferrostatin-1 (Fer-1), rescued LBP-induced ferroptosis-associated events including reduced cell viability and glutathione (GSH) production, accumulation of intracellular free divalent iron ions and malondialdehyde (MDA), and down-regulation of the expression of xCT and GPX4. Erastin (xCT inhibitor) and RSL3 (GPX4 inhibitor) inhibited the expression of xCT and GPX4, respectively, which was lower after the co-treatment of LBP with Erastin and RSL3. These results suggest that LBP effectively prevents breast cancer cell proliferation and promotes ferroptosis via the xCT/GPX4 pathway. Therefore, LBP exhibits novel anticancer properties by triggering ferroptosis, and may be a potential therapeutic option for breast cancer.
    Keywords:  Breast cancer cells; Ferroptosis; Glutathione peroxidase 4 (GPX4); Lycium barbarum polysaccharide; xCT
    DOI:  https://doi.org/10.1631/jzus.B2100748
  61. World J Microbiol Biotechnol. 2022 Apr 15. 38(5): 91
    Recent advances in the microbial production of squalene.
    Kalaivani Paramasivan, Sarma Mutturi.
      Squalene is a triterpene hydrocarbon, a biochemical precursor for all steroids in plants and animals. It is a principal component of human surface lipids, in particular of sebum. Squalene has several applications in the food, pharmaceutical, and medical sectors. It is essentially used as a dietary supplement, vaccine adjuvant, moisturizer, cardio-protective agent, anti-tumor agent and natural antioxidant. With the increased demand for squalene along with regulations on shark-derived squalene, there is a need to find alternatives for squalene production which are low-cost as well as sustainable. Microbial platforms are being considered as a potential option to meet such challenges. Considerable progress has been made using both wild-type and engineered microbial strains for improved productivity and yields of squalene. Native strains for squalene production are usually limited by low growth rates and lesser titers. Metabolic engineering, which is a rational strain engineering tool, has enabled the development of microbial strains such as Saccharomyces cerevisiae and Yarrowia lipolytica, to overproduce the squalene in high titers. This review focuses on key strain engineering strategies involving both in-silico and in-vitro techniques. Emphasis is made on gene manipulations for improved precursor pool, enzyme modifications, cofactor regeneration, up-regulation of limiting reactions, and downregulation of competing reactions during squalene production. Process strategies and challenges related to both upstream and downstream during mass cultivation are detailed.
    Keywords:  S. cerevisiae; Squalene; Strain engineering; Terpene
    DOI:  https://doi.org/10.1007/s11274-022-03273-w
  62. Int J Mol Sci. 2022 Apr 06. pii: 4048. [Epub ahead of print]23(7):
    Biochemical Functions and Clinical Characterizations of the Sirtuins in Diabetes-Induced Retinal Pathologies.
    Samanta Taurone, Chiara De Ponte, Dante Rotili, Elena De Santis, Antonello Mai, Francesco Fiorentino, Susanna Scarpa, Marco Artico, Alessandra Micera.
      Diabetic retinopathy (DR) is undoubtedly one of the most prominent causes of blindness worldwide. This pathology is the most frequent microvascular complication arising from diabetes, and its incidence is increasing at a constant pace. To date, the insurgence of DR is thought to be the consequence of the intricate complex of relations connecting inflammation, the generation of free oxygen species, and the consequent oxidative stress determined by protracted hyperglycemia. The sirtuin (SIRT) family comprises 7 histone and non-histone protein deacetylases and mono (ADP-ribosyl) transferases regulating different processes, including metabolism, senescence, DNA maintenance, and cell cycle regulation. These enzymes are involved in the development of various diseases such as neurodegeneration, cardiovascular pathologies, metabolic disorders, and cancer. SIRT1, 3, 5, and 6 are key enzymes in DR since they modulate glucose metabolism, insulin sensitivity, and inflammation. Currently, indirect and direct activators of SIRTs (such as antagomir, glycyrrhizin, and resveratrol) are being developed to modulate the inflammation response arising during DR. In this review, we aim to illustrate the most important inflammatory and metabolic pathways connecting SIRT activity to DR, and to describe the most relevant SIRT activators that might be proposed as new therapeutics to treat DR.
    Keywords:  anti-VEGF; antioxidants; diabetes mellitus; diabetic retinopathy; free radicals; neuroinflammation; oxidative stress; sirtuins
    DOI:  https://doi.org/10.3390/ijms23074048
  63. Environ Sci Pollut Res Int. 2022 Apr 14.
    Biochemical profiling of lead-intoxicated impaired lipid metabolism and its amelioration using plant-based bioactive compound.
    Abdul Qader, Kanwal Rehman, Muhammad Sajid Hamid Akash.
      The aim of this study was to investigate the lead (Pb)-induced lipid metabolism impairment and its amelioration using plant-based therapeutic interventions. Pb-induced hepatotoxicity can disturb the normal levels of natural antioxidant enzymes including glutathione (GSH) and superoxide dismutase (SOD) exerting a crucial impact on membrane unsaturated fatty acids (FA), hence leading to lipid peroxidation. Furthermore, Pb toxicity can also alter the regulation of various hormones involved in the synthesis of 3-hydroxy-methyl glutaryl CoA (HMG-CoA reductase), leading to an impairment in normal levels of serum cholesterol and other associated conjugated lipid molecules such HDL-cholesterol, LDL-cholesterol and VLDL-cholesterol. In this study, the lipoprotein fractions, cholesterol, triglyceride (TGs) and biomarkers of liver functions were estimated by employing respective assay kits. The levels of antioxidant enzymes, FFAs and HMG-CoA reductase were determined by employing sandwich ELISA method. The administration of PbAc in experimental rats induced a significant disturbance in lipid profile (P < 0.05) accompanying a significant reduction in natural antioxidant defence system (P < 0.05). The significant alteration in the levels of serum antioxidant enzymes can lead to membrane lipid peroxidation that is reflected by a significantly (P < 0.05) high level of serum MDA in PbAc-induced experimental rats. However, the administration of resveratrol proved therapeutically effective in the treatment of Pb toxicity. Overall, the results of this study accompanying histopathological examination had proved the ameliorating effect of resveratrol in Pb-induced lipid metabolism impairment by adopting vitamin C as a standard therapeutic intervention.
    Keywords:  Pb toxicity; antioxidant enzymes; hepatotoxicity; lipid peroxidation; lipid profile; therapeutic intervention
    DOI:  https://doi.org/10.1007/s11356-022-20069-5
  64. Oxid Med Cell Longev. 2022 ;2022 3618806
    PM2.5 Exposure and Asthma Development: The Key Role of Oxidative Stress.
    Kaimeng Liu, Shucheng Hua, Lei Song.
      Oxidative stress is defined as the imbalance between reactive oxygen species (ROS) production and the endogenous antioxidant defense system, leading to cellular damage. Asthma is a common chronic inflammatory airway disease. The presence of asthma tends to increase the production of reactive oxygen species (ROS), and the antioxidant system in the lungs is insufficient to mitigate it. Therefore, asthma can lead to an exacerbation of airway hyperresponsiveness and airway inflammation. PM2.5 exposure increases ROS levels. Meanwhile, the accumulation of ROS will further enhance the oxidative stress response, resulting in DNA, protein, lipid, and other cellular and molecular damage, leading to respiratory diseases. An in-depth study on the relationship between oxidative stress and PM2.5-related asthma is helpful to understand the pathogenesis and progression of the disease and provides a new direction for the treatment of the disease. This paper reviews the research progress of oxidative stress in PM2.5-induced asthma as well as highlights the therapeutic potentials of antioxidant approaches in treatment of asthma.
    DOI:  https://doi.org/10.1155/2022/3618806
  65. Rev Neurosci. 2022 Apr 12.
    Gut dysbiosis and homocysteine: a couple for boosting neurotoxicity in Huntington disease.
    Juan Carlos Martínez-Lazcano, Edith González-Guevara, Catherine Boll, Graciela Cárdenas.
      Huntington's disease (HD), a neurodegenerative disorder caused by an expansion of the huntingtin triplet (Htt), is clinically characterized by cognitive and neuropsychiatric alterations. Although these alterations appear to be related to mutant Htt (mHtt)-induced neurotoxicity, several other factors are involved. The gut microbiota is a known modulator of brain-gut communication and when altered (dysbiosis), several complaints can be developed including gastrointestinal dysfunction which may have a negative impact on cognition, behavior, and other mental functions in HD through several mechanisms, including increased levels of lipopolysaccharide, proinflammatory cytokines and immune cell response, as well as alterations in Ca2+ signaling, resulting in both increased intestinal and blood-brain barrier (BBB) permeability. Recently, the presence of dysbiosis has been described in both transgenic mouse models and HD patients. A bidirectional influence between host brain tissues and the gut microbiota has been observed. On the one hand, the host diet influences the composition and function of microbiota; and on the other hand, microbiota products can affect BBB permeability, synaptogenesis, and the regulation of neurotransmitters and neurotrophic factors, which has a direct effect on host metabolism and brain function. This review summarizes the available evidence on the pathogenic synergism of dysbiosis and homocysteine, and their role in the transgression of BBB integrity and their potential neurotoxicity of HD.
    Keywords:  Huntington’s disease; blood-brain-barrier; cognitive status; dysbiosis
    DOI:  https://doi.org/10.1515/revneuro-2021-0164
  66. Int J Mol Sci. 2022 Apr 02. pii: 3958. [Epub ahead of print]23(7):
    Diet-Induced Metabolic Dysfunction of Hypothalamic Nutrient Sensing in Rodents.
    Isabel Arrieta-Cruz, Blanca Samara Torres-Ávila, Hilda Martínez-Coria, Héctor Eduardo López-Valdés, Roger Gutiérrez-Juárez.
      A sedentary lifestyle and excessive nutrient intake resulting from the consumption of high-fat and calorie-rich diets are environmental factors contributing to the rapid growth of the current pandemic of type 2 diabetes mellitus (DM2). Fasting hyperglycemia, an established hallmark of DM2, is caused by excessive production of glucose by the liver, resulting in the inability of insulin to suppress endogenous glucose production. To prevent inappropriate elevations of circulating glucose resulting from changes in nutrient availability, mammals rely on complex mechanisms for continuously detecting these changes and to respond to them with metabolic adaptations designed to modulate glucose output. The mediobasal hypothalamus (MBH) is the key center where nutritional cues are detected and appropriate modulatory responses are integrated. However, certain environmental factors may have a negative impact on these adaptive responses. For example, consumption of a diet enriched in saturated fat in rodents resulted in the development of a metabolic defect that attenuated these nutrient sensing mechanisms, rendering the animals prone to developing hyperglycemia. Thus, high-fat feeding leads to a state of "metabolic disability" in which animals' glucoregulatory responses fail. We postulate that the chronic faltering of the hypothalamic glucoregulatory mechanisms contributes to the development of metabolic disease.
    Keywords:  amino acids; diabetes; glycemia; high-fat diet; liver; mediobasal hypothalamus; nutrients
    DOI:  https://doi.org/10.3390/ijms23073958
  67. Curr Drug Deliv. 2022 Apr 14.
    Fighting Carcinogenesis with Plant Metabolites by Weakening Proliferative Signaling and Disabling Replicative Immortality Networks of Rapidly Dividing and Invading Cancerous Cells.
    Atif Khurshid Wani, Nahid Akhtar, Arun Sharma, Sally A El-Zahaby.
       BACKGROUND: Cancer, an uncontrolled multistage process causing swift division of cells, is a leading disease with the highest mortality rate. Cellular heterogeneity, evading growth suppressors, resisting cell death, and replicative immortality drive the tumor progression by resisting therapeutic action of existing anticancer drugs through a series of intrinsic and extrinsic cellular interactions. The innate cellular mechanisms also regulate the replication process as a fence against proliferative signaling, enabling replicative immortality through telomere dysfunction.
    AREA COVERED: The conventional genotoxic drugs have several off-target and collateral side effects associated with them. Thus, the need for the therapies targeting cyclin-dependent kinases or P13K signaling pathway to expose cancer cells to immune destruction, deactivation of invasion and metastasis, and maintaining cellular energetics is imperative. Compounds with anticancer attributes isolated from plant and rich in alkaloids, terpenes, and polyphenols have proven to be less toxic and highly target-specific, making them biologically significant. This has opened a gateway for the exploration of more novel plant molecules by signifying their role as anticancer agents in synergy and alone making them effective than the existing cytotoxic regimens.
    EXPERT OPINION: In this context, the current review presented recent data on cancer cases around the globe along with discussing the fundamentals of proliferative signaling and replicative immortality of cancer cells. Recent findings were also highlighted including antiproliferative and antireplicative action of plant-derived compounds besides explaning the need for improving drug delivery systems.
    Keywords:  Cancer; Cancer therapy; Plant metabolites; Proliferative signaling; Replicative immortality; growth
    DOI:  https://doi.org/10.2174/1567201819666220414085606
  68. Metabolism. 2022 Apr 08. pii: S0026-0495(22)00078-6. [Epub ahead of print] 155200
    Schisandrin B mitigates hepatic steatosis and promotes fatty acid oxidation by inducing autophagy through AMPK/mTOR signaling pathway.
    Li-Shan Yan, Shuo-Feng Zhang, Gan Luo, Brian Chi-Yan Cheng, Chao Zhang, Yi-Wei Wang, Xin-Yu Qiu, Xiao-Hong Zhou, Qing-Gao Wang, Xue-Lan Song, Si-Yuan Pan, Yi Zhang.
       BACKGROUND: Schisandrin B (Sch B), which inhibits hepatic steatosis caused by non-alcoholic fatty liver disease (NAFLD), is one of the most active dibenzocyclooctadienes isolated from Schisandra chinensis (Turcz.) Baill with various pharmacological activities. In this study, the role of Sch B-induced autophagy in lipid-lowering activities of Sch B was examined and the underlying mechanisms were elucidated.
    METHODS: Free fatty acid (FFA)-stimulated HepG2 cells and mouse primary hepatocytes (MPHs) and high-fat diet (HFD)-fed mice were used as NAFLD models. The role of Sch B-induced autophagy in lipid-lowering effects of Sch B was assessed using ATG5/TFEB-deficient cells and 3-methyladenine (3-MA)-treated hepatocytes and mice.
    RESULTS: Sch B simultaneously active autophagy through AMPK/mTOR pathway and decreased the number of lipid droplets in FFA-treated HepG2 cells and MPHs. Additionally, siATG5/siTFEB transfection or 3-MA treatment mitigated Sch B-induced autophagy and activation of fatty acid oxidation (FAO) and ketogenesis in FFA-treated HepG2 cells and MPHs. Sch B markedly decreased hepatic lipid content and activated the autophagy through AMPK/mTOR pathway in HFD-fed mice. However, the activities of Sch B were suppressed upon 3-MA treatment. Sch B upregulated the expression of key enzymes involved in FAO and ketogenesis, which was mitigated upon 3-MA treatment. Moreover, changes in hepatic lipid components and amino acids may be related to the Sch B-induced autophagy pathway in vivo.
    CONCLUSION: These results suggested that Sch B inhibited hepatic steatosis by activation of autophagy through AMPK/mTOR pathway. Our study provided novel insights into the hepatic lipophagic activity of Sch B and its potential application in the management of NAFLD.
    Keywords:  Autophagy; Lipid metabolism; Non-alcoholic fatty liver disease; Schisandrin B
    DOI:  https://doi.org/10.1016/j.metabol.2022.155200
  69. Am J Cancer Res. 2022 ;12(3): 974-985
    Role of dietary iron revisited: in metabolism, ferroptosis and pathophysiology of cancer.
    Santhi Latha Pandrangi, Prasanthi Chittineedi, Rajasekhar Chikati, Joji Reddy Lingareddy, Meeravali Nagoor, Suresh Kumar Ponnada.
      Iron is the most abundant metal in the human body. No independent life forms on earth can survive without iron. However, excess iron is closely associated with carcinogenesis by increasing oxidative stress via its catalytic activity to generate hydroxyl radicals. Therefore, it is speculated that iron might play a dual role in cells, by both stimulating cell growth and causing cell death. Dietary iron is absorbed by the intestinal enterocytes in the form of ferrous ion which forms cLIP. Excess iron stored in the form of Ferritin serves as a reservoir under iron depletion conditions. Ferroptosis, is an iron-dependent non-mutational form of cell death process and is suppressed by iron-binding compounds such as deferoxamine. Blocking transferrin-mediated iron import or recycling of iron-containing storage proteins (i.e., ferritin) also attenuates ferroptosis, consistent with the iron-dependent nature of this process. Unsurprisingly, ferroptosis also plays a role in the development of cancer and maybe a beneficial strategy for anticancer treatment. Different lines of evidence suggest that ferroptosis plays a crucial role in the suppression of tumorigenesis. In this review, we have discussed the pros and cons of iron accumulation, utilization and, its role in cell proliferation, ferroptosis and pathophysiology of cancer.
    Keywords:  Iron; cancer; cytoplasmic labile iron pool (cLIP); ferroptosis; reactive oxygen species
  70. Pharmacol Res. 2022 Apr 10. pii: S1043-6618(22)00164-5. [Epub ahead of print]179 106219
    Combined Levo-tetrahydropalmatine and diphenyleneiodonium chloride enhances antitumor activity in hepatocellular carcinoma.
    Xunzhe Yin, Jiaxin Zhang, Wenjing Zhao, Zuojia Liu, Jin Wang.
      Metabolic dysregulation is a hallmark of hepatocellular carcinoma (HCC). AMPK is a crucial hub of metabolic regulation during cancer progression. We show that phytochemical Levo-tetrahydropalmatine (THP) activates AMPK-dependent autophagy to downregulate the mitochondrial respiration and glycolysis. Consequently, THP significantly decreased cell viability in two HCC cell lines, BEL-7402 and SMMC-7721. Similarly, NOX4 inhibitor diphenyleneiodonium chloride (DPI) induces concomitant downregulation of the mitochondrial and glycolytic metabolism. In contrast to THP, cells are less sensitive to proliferation inhibition induced by DPI treatment as compared to THP treatment did. Combined treatment of THP and DPI was found to be more efficacious in killing cancer cells than either of the agents treated individually. Indeed, the co-operative effect by the THP-DPI combination improves the pro-apoptotic activity in response to the energy depletion as outlined by a drastic decrease in ATP levels. Therapeutic regime significantly reduced the tumor growth in mice. Importantly, this is realized without causing systemic toxicity to other organs. Collectively, our work shows that the combinatorial therapy of autophagy activator THP and NOX4 inhibitor DPI may be considered as a therapeutic avenue against HCC.
    Keywords:  AMPK; Autophagy; Cancer metabolism; Chloroquine (PubChem CID: 2719); Dimethyl sulfoxide (PubChem CID: 679); Diphenyleneiodonium; Hepatocellular carcinoma; Levo-tetrahydropalmatine; Levo-tetrahydropalmatine (PubChem CID: 132535036); chloride (PubChem CID: 2733504)
    DOI:  https://doi.org/10.1016/j.phrs.2022.106219
  71. Isr Med Assoc J. 2022 Apr;24(4): 258-262
    Zinc in Cancer Therapy Revisited.
    Amos Gelbard.
       BACKGROUND: Zinc is a trace element, which is abundant in nature. It is also an essential and important micronutrient found in many foods. It has a role in multiple bodily processes including wound healing and boosting of the immune system. This review shows evidence of zinc deficiency in cancer patients of all types, a deficiency that correlates with disease severity and negatively correlates with survival rates. Lower zinc levels led to more severe and advanced disease symptoms and to lower survival rates. Zinc is a nanoparticle and acts as a photosensitizer in photodynamic therapy in various combinations with other substances. It also shows incredible cytotxicity and tumor suppressive ability in studies conducted both in vitro and in vivo as well as in studies conducted in humans. This result is shown in all types of cancer tested. Zinc shows incredible toxicity toward cancer cells without showing any side effects toward healthy cells. It is recommended that zinc be added to cancer treatment regimens to alleviate zinc deficiency in cancer patients and perhaps to treat cancer as a whole.
  72. Food Chem (Oxf). 2022 Jul 30. 4 100079
    Sodium butyrate reduces endoplasmic reticulum stress by modulating CHOP and empowers favorable anti-inflammatory adipose tissue immune-metabolism in HFD fed mice model of obesity.
    Vinita Kushwaha, Prashant Rai, Salil Varshney, Sanchita Gupta, Nilesh Khandelwal, Durgesh Kumar, Anil Nilkanth Gaikwad.
      Over the past decade, the gut microbiome has been linked to several diseases including gastrointestinal diseases, cancer, immune disorder and metabolic syndrome. Shifts in the gut bacterial population affect the overall metabolic health status leading towards obesity and Type II diabetes mellitus. Secondary metabolites secreted by the gut microbiome interact with various host-sensing signalling pathways and are responsible for functional modulation of immune resident cells in metabolic tissues (Blüher, 2019). Of these, short- chain fatty acids (SCFAs) i.e., acetate, propionate and butyrate have been significantly correlated with the disposition of diabetes and metabolic disorder. The altered gut microbial population depletes the intestinal barrier causing entry of LPS into circulation and towards metabolic tissues triggering pro-inflammatory responses. As butyrate has been known to maintain intestinal integrity, we aimed to assess the apparent effect of externally given sodium butyrate [NaB] on immuno-metabolic profiling of adipose tissue, and its association with metabolic and inflammatory status of adipose tissue. To assess this, we put groups of C57BL/6 mice i.e., Control fed with a regular chow diet and another group that was fed on a high fat diet (HFD, 60%) for 8 weeks. Following this, the HFD group were further subdivided into two groups one fed with HFD and the other with HFD + NaB (5%w/w) for another 8 weeks. Body composition, weight gain, body adiposity and biochemical parameters were assessed. NaB fed group showed an improved metabolic profile compared to HFD fed group. Administration of NaB also improved glucose tolerance capacity and insulin sensitivity as determined by IPGTT and ITT profiles. Earlier reports have shown gut leakage and increased LPS in circulation is the primary cause of setting up inflammation at the tissue level. Our studies exhibited that, NaB increased the expression of tight junction proteins of intestinal linings and thereby enhanced intestinal barrier integrity. The FITC dextran permeability assay further confirmed this enhanced intestinal barrier integrity. We assessed the quantitative and relative population of different types of resident immune cells from a stromal vascular fraction of adipose tissue. Flow cytometry studies revealed significantly increased M2 (CD206+ ) macrophages and Tregs (CD25+ ) relative to the M1 macrophage population and CD4+ T cells respectively in NaB treated mice, suggesting its potential role in alleviating the inflammatory profile. In a nutshell, taken together better glucose tolerance, better gut health, reduced inflammatory adipose tissue immune cells, suggest potential beneficial role of sodium butyrate in alleviating overall inflammation and metabolic dysfunction associated with obesity.
    Keywords:  Adipose tissue; ER stress; Immune cell population; Obesity; SCFA
    DOI:  https://doi.org/10.1016/j.fochms.2022.100079
  73. Int J Mol Sci. 2022 Apr 02. pii: 3959. [Epub ahead of print]23(7):
    Hepatic PTEN Signaling Regulates Systemic Metabolic Homeostasis through Hepatokines-Mediated Liver-to-Peripheral Organs Crosstalk.
    Flavien Berthou, Cyril Sobolewski, Daniel Abegg, Margot Fournier, Christine Maeder, Dobrochna Dolicka, Marta Correia de Sousa, Alexander Adibekian, Michelangelo Foti.
      Liver-derived circulating factors deeply affect the metabolism of distal organs. Herein, we took advantage of the hepatocyte-specific PTEN knockout mice (LPTENKO), a model of hepatic steatosis associated with increased muscle insulin sensitivity and decreased adiposity, to identify potential secreted hepatic factors improving metabolic homeostasis. Our results indicated that protein factors, rather than specific metabolites, released by PTEN-deficient hepatocytes trigger an improved muscle insulin sensitivity and a decreased adiposity in LPTENKO. In this regard, a proteomic analysis of conditioned media from PTEN-deficient primary hepatocytes identified seven hepatokines whose expression/secretion was deregulated. Distinct expression patterns of these hepatokines were observed in hepatic tissues from human/mouse with NAFLD. The expression of specific factors was regulated by the PTEN/PI3K, PPAR or AMPK signaling pathways and/or modulated by classical antidiabetic drugs. Finally, loss-of-function studies identified FGF21 and the triad AHSG, ANGPTL4 and LECT2 as key regulators of insulin sensitivity in muscle cells and in adipocytes biogenesis, respectively. These data indicate that hepatic PTEN deficiency and steatosis alter the expression/secretion of hepatokines regulating insulin sensitivity in muscles and the lipid metabolism in adipose tissue. These hepatokines could represent potential therapeutic targets to treat obesity and insulin resistance.
    Keywords:  FGF21; NAFLD; PTEN; hepatokines; insulin resistance; interorgan communication; liver; metabolites; obesity
    DOI:  https://doi.org/10.3390/ijms23073959
  74. Sci Signal. 2022 Apr 12. 15(729): eabo0264
    Overarching roles of diacylglycerol signaling in cancer development and antitumor immunity.
    Mariana Cooke, Marcelo G Kazanietz.
      Diacylglycerol (DAG) is a lipid second messenger that is generated in response to extracellular stimuli and channels intracellular signals that affect mammalian cell proliferation, survival, and motility. DAG exerts a myriad of biological functions through protein kinase C (PKC) and other effectors, such as protein kinase D (PKD) isozymes and small GTPase-regulating proteins (such as RasGRPs). Imbalances in the fine-tuned homeostasis between DAG generation by phospholipase C (PLC) enzymes and termination by DAG kinases (DGKs), as well as dysregulation in the activity or abundance of DAG effectors, have been widely associated with tumor initiation, progression, and metastasis. DAG is also a key orchestrator of T cell function and thus plays a major role in tumor immunosurveillance. In addition, DAG pathways shape the tumor ecosystem by arbitrating the complex, dynamic interaction between cancer cells and the immune landscape, hence representing powerful modifiers of immune checkpoint and adoptive T cell-directed immunotherapy. Exploiting the wide spectrum of DAG signals from an integrated perspective could underscore meaningful advances in targeted cancer therapy.
    DOI:  https://doi.org/10.1126/scisignal.abo0264
  75. Food Chem. 2022 Apr 05. pii: S0308-8146(22)00857-3. [Epub ahead of print]387 132895
    Resistant starches and gut microbiota.
    Jia-Jia Wen, Ming-Zhi Li, Jie-Lun Hu, Hui-Zi Tan, Shao-Ping Nie.
      Resistant starches (RS), which are considered as one of the dietary fibers, could exert widely beneficial impacts, reduce fat accumulation, show significant effects on regulating blood glucose metabolism and insulin levels, and have protective effects on the gut. Five types of RS have different responses to chronic disease by modulating gut microbiota. Short-chain fatty acids are the linkage between gut microbiota and RS, and RS could improve the metabolism of gut microbiota as well as increase the abundance of beneficial microbes in the gut. The composition of gut microbiota is associated with RS properties, which is reflected by the changes of butyrate-producing bacteria primarily influenced by consumption of RS with various fine structures and types of crystallinities. RS with different fine structures and properties is consumed to varying degrees by gut microbiota, which can be applied to produce functional foods for gut health in future.
    Keywords:  Functions; Gut microbiota; Resistant starches; Short-chain fatty acids
    DOI:  https://doi.org/10.1016/j.foodchem.2022.132895
  76. Nutr Metab Cardiovasc Dis. 2022 Mar 07. pii: S0939-4753(22)00123-5. [Epub ahead of print]
    Lipids and diastolic dysfunction: Recent evidence and findings.
    Padideh Daneii, Sina Neshat, Monir Sadat Mirnasiry, Zahra Moghimi, Fatemeh Dehghan Niri, Armita Farid, Masood Shekarchizadeh, Kiyan Heshmat-Ghahdarijani.
       AIM: Diastolic dysfunction is the decreased flexibility of the left ventricle due to the impaired ability of the myocardium to relax and plays an important role in the pathogenesis of heart failure. Lipid metabolism is a well-known contributor to cardiac conditions, including ventricular function. In this article, we aimed to review the literature addressing the connections between lipids, their storage, and metabolism with left ventricular diastolic dysfunction.
    DATA SYNTHESIS: We searched Google scholar, Pubmed, Embase and Researchgate for our keywords: "Diastolic function", "Fat" and "Lipid profile". Initially, 250 articles were selected by title and 84 of them were chosen as most relevant and directly reviewed.
    CONCLUSIONS: Alterations of lipid metabolism in cardiac muscle and cardiac lipid content can occur in many conditions, including consumption of a high-fat diet, obesity, metabolic syndrome, and non-alcoholic fatty liver disease (NAFLD). These conditions induce alterations in myocardial lipid metabolism, increase myocardial fat content and epicardial fat thickness and increase inflammation and oxidative stress which ultimately lead to cardiac lipotoxicity and diastolic dysfunction. The effects of lipids on diastolic function can differ based on gender. Lipid profile and metabolism are as important in the pathogenesis of diastolic dysfunction as they are in other cardiovascular disorders. A more careful look at cardiac lipid metabolism in molecular, histological and gross levels results in more precise understanding of its role in myocardial function and leads to development of potential treatments for diastolic dysfunction.
    Keywords:  Diastolic dysfunction; Dyslipidemia; Lipids; Review article
    DOI:  https://doi.org/10.1016/j.numecd.2022.03.003
  77. Oxid Med Cell Longev. 2022 ;2022 9205908
    Traditional Chinese Medicine Ginseng Dingzhi Decoction Ameliorates Myocardial Fibrosis and High Glucose-Induced Cardiomyocyte Injury by Regulating Intestinal Flora and Mitochondrial Dysfunction.
    Junyan Wang, Peiwen Chen, Qiuyu Cao, Wei Wang, Xing Chang.
      Myocardial fibrosis refers to the pathological changes of heart structure and morphology caused by various reasons of myocardial damage. It has become an important challenge in the later clinical treatment of acute myocardial infarction/ischemic cardiomyopathy or diabetes complicated with heart failure. Ginseng Dingzhi Decoction (GN), a Chinese herbal medicine, can reduce heart failure and protect cardiomyocytes. We infer that this may be related to the interaction with intestinal microbiota and mitochondrial homeostasis. The regulatory mechanism of GN on gut microbiota and mitochondria has not yet been elucidated. The intestinal microbiota was analyzed by the 16S rRNA gene; the fecal samples were sequenced and statistically analyzed to determine the changes of microbiota in the phenotype of heart failure rats. In addition, GN can regulate the microbial population that increases the proportion of short-chain fatty acids and anti-inflammatory bacteria and reduces the proportion of conditional pathogens to diabetic phenotype. The results suggest that GN may improve myocardial injury by regulating intestinal flora. Our data also show that stress-type heart failure caused by TAC (transverse aortic constriction) is accompanied by severe cardiac hypertrophy, reduced cardiac function, redox imbalance, and mitochondrial dysfunction. However, the use of GN intervention can significantly reduce heart failure and myocardial hypertrophy, improve heart function and improve myocardial damage, and maintain the mitochondrial homeostasis and redox of myocardial cells under high glucose stimulation. Interestingly, through in vitro experiments after TMBIM6 siRNA treatment, the improvement effect of GN on cell damage and the regulation of mitochondrial homeostasis were eliminated. TMBIM6 can indirectly regulate mitophagy and mitochondrial homeostasis to attenuate myocardial damage and confirms the regulatory effect of GN on mitophagy and mitochondrial homeostasis. We further intervened cardiomyocytes in high glucose through metformin (MET) and GN combination therapy. Research data show that MET and GN combination therapy can improve the level of mitophagy and protect cardiomyocytes. Our findings provide novel mechanistic insights for the treatment of diabetes combined with myocardial injury (myocardial fibrosis) and provide a pharmacological basis for the study of the combination of Chinese medicine and conventional diabetes treatment drugs.
    DOI:  https://doi.org/10.1155/2022/9205908
  78. Int J Mol Sci. 2022 Mar 24. pii: 3544. [Epub ahead of print]23(7):
    Kaempferol Can Reverse the 5-Fu Resistance of Colorectal Cancer Cells by Inhibiting PKM2-Mediated Glycolysis.
    Haili Wu, Jin'e Du, Chenglu Li, Hanqing Li, Huiqin Guo, Zhuoyu Li.
      Resistance to 5-Fluorouracil (5-Fu) chemotherapy is the main cause of treatment failure in the cure of colon cancer. Therefore, there is an urgent need to explore a safe and effective multidrug resistance reversal agent for colorectal cancer, which would be of great significance for improving clinical efficacy. The dietary flavonoid kaempferol plays a key role in the progression of colorectal cancer and 5-Fu resistance. However, the molecular mechanism of kaempferol in reversing 5-Fu resistance in human colorectal cancer cells is still unclear. We found that kaempferol could reverse the drug resistance of HCT8-R cells to 5-Fu, suggesting that kaempferol alone or in combination with 5-Fu has the potential to treat colorectal cancer. It is well known that aerobic glycolysis is related to tumor growth and chemotherapy resistance. Indeed, kaempferol treatment significantly reduced glucose uptake and lactic acid production in drug-resistant colorectal cancer cells. In terms of mechanism, kaempferol promotes the expression of microRNA-326 (miR-326) in colon cancer cells, and miR-326 could inhibit the process of glycolysis by directly targeting pyruvate kinase M2 isoform (PKM2) 3'-UTR (untranslated region) to inhibit the expression of PKM2 or indirectly block the alternative splicing factors of PKM mRNA, and then reverse the resistance of colorectal cancer cells to 5-Fu. Taken together, our data suggest that kaempferol may play an important role in overcoming resistance to 5-Fu therapy by regulating the miR-326-hnRNPA1/A2/PTBP1-PKM2 axis.
    Keywords:  5-Fu resistance; PKM2; aerobic glycolysis; colorectal cancer; kaempferol; miR-326
    DOI:  https://doi.org/10.3390/ijms23073544
  79. J Sci Food Agric. 2022 Apr 11.
    Effects of dietary supplementation of different levels of vitamin B12 on the liver metabolism of laying hens.
    Rui Wang, Yan Bai, Yu Yang.
       BACKGROUND: Vitamin B12 plays an important role in the lipid, protein, carbohydrate, and nucleic acid metabolism. We investigated the effect of supplementing layer's diets with different vitamin B12 levels on the the liver metabolism using a LC-MS-based metabolomic approach to observe and analyze wide-target metabolomics in the liver.
    RESULTS: We assigned hens into three groups, namely blank control group without vitamin B12 diet (BCG), normal control group with 25 μg/kg vitamin B12 (NCG), and vitamin B12 supplement group I with 100 μg/kg vitamin (VBSG I). The VBSG I group layers had higher (P < 0.05) vitamin B12 concentration than those from other groups. The egg yolk vitamin B12 concentration increased (P < 0.01) with the increasing vitamin B12 dietary supplemental level. Between the NCG versus (vs.) BCG, VBSG I vs. BCG, and VBSG I vs. NCG groups, eleven, twenty and eleven metabolites were significantly changed, respectively. The KEGG pathway of vitamin B6 metabolism was significantly impacted in the NCG layers than those from BCG; seven and five pathways were significantly impacted in the VBSG I layers than those from BCG and NCG，including pyrimidine metabolism, vitamin B6 metabolism, glycerophospholipid metabolism, etc. CONCLUSION: We concluded that 25 μg/kg of vitamin B12 supplementation in corn-soybean meal-based layer diet increased the egg yolk vitamin B12 concentration and impacted the vitamin B6 metabolic pathway, and 100 μg/kg of it increased the egg yolk and liver vitamin B12 concentrations and impacted vitamin B6 , lipid, nucleic acid, and amino acid metabolic pathways. This article is protected by copyright. All rights reserved.
    Keywords:  dietary supplementation of vitamin B12; laying hen; liver metabolism; metabolomics
    DOI:  https://doi.org/10.1002/jsfa.11928
  80. Front Immunol. 2022 ;13 865772
    Targeting NLRP3 Inflammasome With Nrf2 Inducers in Central Nervous System Disorders.
    Bora Tastan, Burak I Arioz, Sermin Genc.
      The NLRP3 inflammasome is an intracellular multiprotein complex that plays an essential role in the innate immune system by identifying and eliminating a plethora of endogenous and exogenous threats to the host. Upon activation of the NLRP3 complex, pro-inflammatory cytokines are processed and released. Furthermore, activation of the NLRP3 inflammasome complex can induce pyroptotic cell death, thereby propagating the inflammatory response. The aberrant activity and detrimental effects of NLRP3 inflammasome activation have been associated with cardiovascular, neurodegenerative, metabolic, and inflammatory diseases. Therefore, clinical strategies targeting the inhibition of the self-propelled NLRP3 inflammasome activation are required. The transcription factor Nrf2 regulates cellular stress response, controlling the redox equilibrium, metabolic programming, and inflammation. The Nrf2 pathway participates in anti-oxidative, cytoprotective, and anti-inflammatory activities. This prominent regulator, through pharmacologic activation, could provide a therapeutic strategy for the diseases to the etiology and pathogenesis of which NLRP3 inflammasome contributes. In this review, current knowledge on NLRP3 inflammasome activation and Nrf2 pathways is presented; the relationship between NLRP3 inflammasome signaling and Nrf2 pathway, as well as the pre/clinical use of Nrf2 activators against NLRP3 inflammasome activation in disorders of the central nervous system, are thoroughly described. Cumulative evidence points out therapeutic use of Nrf2 activators against NLRP3 inflammasome activation or diseases that NLRP3 inflammasome contributes to would be advantageous to prevent inflammatory conditions; however, the side effects of these molecules should be kept in mind before applying them to clinical practice.
    Keywords:  NLRP3 inflammasome; Nrf2; central nervous system; dimethyl fumarate; inflammation; sulforaphane
    DOI:  https://doi.org/10.3389/fimmu.2022.865772
  81. Int J Mol Sci. 2022 Mar 25. pii: 3576. [Epub ahead of print]23(7):
    Melatonin Positively Regulates Both Dark- and Age-Induced Leaf Senescence by Reducing ROS Accumulation and Modulating Abscisic Acid and Auxin Biosynthesis in Cucumber Plants.
    Tongtong Jing, Kun Liu, Yanan Wang, Xizhen Ai, Huangai Bi.
      Melatonin (MT), as a signaling molecule, plays a vital role in regulating leaf senescence in plants. This study aimed to verify the antioxidant roles of MT in delaying dark- or age-induced leaf senescence of cucumber plants. The results showed that endogenous MT responds to darkness and overexpression of CsASMT, the key gene of MT synthesis, and delays leaf senescence stimulated by darkness, as manifested by significantly lower malonaldehyde (MDA) and reactive oxygen species (ROS) contents as well as higher activities and gene expression of antioxidant enzymes compared to the control. Moreover, MT suppressed both age- or dark-induced leaf senescence of cucumber, as evidenced by a decrease in senescence-related gene SAG20 and cell-death-related gene PDCD expression and ROS content and an increase in antioxidant capacity and chlorophyll biosynthesis compared with the H2O-treated seedlings. Meanwhile, the suppression of age-induced leaf senescence by melatonin was also reflected by the reduction in abscisic acid (ABA) biosynthesis and signaling pathways as well as the promotion of auxin (IAA) biosynthesis and signaling pathways in cucumber plants in the solar greenhouse. Combining the results of the two separate experiments, we demonstrated that MT acts as a powerful antioxidant to alleviate leaf senescence by activating the antioxidant system and IAA synthesis and signaling while inhibiting ABA synthesis and signaling in cucumber plants.
    Keywords:  abscisic acid; antioxidant system; auxin; cucumber; leaf senescence; melatonin
    DOI:  https://doi.org/10.3390/ijms23073576
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