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The Journal of Pharmacology and... Jun 2024Constitutive androstane receptor (CAR) and peroxisome proliferator-activated receptor (PPAR) are members of the nuclear receptor superfamily, which regulates various...
Constitutive androstane receptor (CAR) and peroxisome proliferator-activated receptor (PPAR) are members of the nuclear receptor superfamily, which regulates various physiologic and pathologic processes. Phase separation is a dynamic biophysical process in which biomacromolecules form liquid-like condensates, which have been identified as contributors to many cellular functions, such as signal transduction and transcription regulation. However, the possibility of phase separation for CAR and PPAR remains unknown. This study explored the potential phase separation of CAR and PPAR The computational analysis utilizing algorithm tools examining the intrinsically disordered regions of CAR and PPAR suggested a limited likelihood of undergoing phase separation. Experimental assays under varying conditions of hyperosmotic stress and agonist treatments confirmed the absence of phase separation for these receptors. Additionally, the optoDroplets assay, which utilizes blue light stimulation to induce condensate formation, showed that there was no condensate formation of the fusion protein of Cry2 with CAR or PPAR Furthermore, phase separation of CAR or PPAR did not occur despite reduced target expression under hyperosmotic stress. In conclusion, these findings revealed that neither the activation of CAR and PPAR nor hyperosmotic stress induces phase separation of CAR and PPAR in cells. SIGNIFICANCE STATEMENT: Constitutive androstane receptor (CAR) and peroxisome proliferator-activated receptor (PPAR) are key regulators of various functions in the body. This study showed that CAR and PPARα do not exhibit phase separation under hyperosmotic stress or after agonist-induced activation. These findings provide new insights into the CAR and PPARα biology and physiology.
Topics: Constitutive Androstane Receptor; PPAR alpha; Humans; Receptors, Cytoplasmic and Nuclear; Animals; Osmotic Pressure; Phase Separation
PubMed: 38719477
DOI: 10.1124/jpet.124.002174 -
Cell Metabolism Jun 2024The role and molecular mechanisms of intermittent fasting (IF) in non-alcoholic steatohepatitis (NASH) and its transition to hepatocellular carcinoma (HCC) are unknown....
The role and molecular mechanisms of intermittent fasting (IF) in non-alcoholic steatohepatitis (NASH) and its transition to hepatocellular carcinoma (HCC) are unknown. Here, we identified that an IF 5:2 regimen prevents NASH development as well as ameliorates established NASH and fibrosis without affecting total calorie intake. Furthermore, the IF 5:2 regimen blunted NASH-HCC transition when applied therapeutically. The timing, length, and number of fasting cycles as well as the type of NASH diet were critical parameters determining the benefits of fasting. Combined proteome, transcriptome, and metabolome analyses identified that peroxisome-proliferator-activated receptor alpha (PPARα) and glucocorticoid-signaling-induced PCK1 act co-operatively as hepatic executors of the fasting response. In line with this, PPARα targets and PCK1 were reduced in human NASH. Notably, only fasting initiated during the active phase of mice robustly induced glucocorticoid signaling and free-fatty-acid-induced PPARα signaling. However, hepatocyte-specific glucocorticoid receptor deletion only partially abrogated the hepatic fasting response. In contrast, the combined knockdown of Ppara and Pck1 in vivo abolished the beneficial outcomes of fasting against inflammation and fibrosis. Moreover, overexpression of Pck1 alone or together with Ppara in vivo lowered hepatic triglycerides and steatosis. Our data support the notion that the IF 5:2 regimen is a promising intervention against NASH and subsequent liver cancer.
Topics: PPAR alpha; Animals; Fasting; Carcinoma, Hepatocellular; Non-alcoholic Fatty Liver Disease; Humans; Mice; Liver Neoplasms; Mice, Inbred C57BL; Male; Phosphoenolpyruvate Carboxykinase (GTP); Intracellular Signaling Peptides and Proteins; Liver; Liver Cirrhosis; Signal Transduction; Intermittent Fasting
PubMed: 38718791
DOI: 10.1016/j.cmet.2024.04.015 -
Cardiovascular Diabetology May 2024Diabetic cardiomyopathy (DCM) is a crucial complication of long-term chronic diabetes that can lead to myocardial hypertrophy, myocardial fibrosis, and heart failure....
BACKGROUND
Diabetic cardiomyopathy (DCM) is a crucial complication of long-term chronic diabetes that can lead to myocardial hypertrophy, myocardial fibrosis, and heart failure. There is increasing evidence that DCM is associated with pyroptosis, a form of inflammation-related programmed cell death. Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor β superfamily, which regulates oxidative stress, inflammation, and cell survival to mitigate myocardial hypertrophy, myocardial infarction, and vascular injury. However, the role of GDF11 in regulating pyroptosis in DCM remains to be elucidated. This research aims to investigate the role of GDF11 in regulating pyroptosis in DCM and the related mechanism.
METHODS AND RESULTS
Mice were injected with streptozotocin (STZ) to induce a diabetes model. H9c2 cardiomyocytes were cultured in high glucose (50 mM) to establish an in vitro model of diabetes. C57BL/6J mice were preinjected with adeno-associated virus 9 (AAV9) intravenously via the tail vein to specifically overexpress myocardial GDF11. GDF11 attenuated pyroptosis in H9c2 cardiomyocytes after high-glucose treatment. In diabetic mice, GDF11 alleviated cardiomyocyte pyroptosis, reduced myocardial fibrosis, and improved cardiac function. Mechanistically, GDF11 inhibited pyroptosis by preventing inflammasome activation. GDF11 achieved this by specifically binding to apoptosis-associated speck-like protein containing a CARD (ASC) and preventing the assembly and activation of the inflammasome. Additionally, the expression of GDF11 during pyroptosis was regulated by peroxisome proliferator-activated receptor α (PPARα).
CONCLUSION
These findings demonstrate that GDF11 can treat diabetic cardiomyopathy by alleviating pyroptosis and reveal the role of the PPARα-GDF11-ASC pathway in DCM, providing ideas for new strategies for cardioprotection.
Topics: Animals; Pyroptosis; Diabetic Cardiomyopathies; Myocytes, Cardiac; Mice, Inbred C57BL; Diabetes Mellitus, Experimental; Cell Line; Inflammasomes; Male; Fibrosis; Signal Transduction; Growth Differentiation Factors; Rats; Blood Glucose; Mice; Glucose; Bone Morphogenetic Proteins; PPAR alpha
PubMed: 38715043
DOI: 10.1186/s12933-024-02258-3 -
Experimental Biology and Medicine... 2024Liver fibrosis has become a serious public health problem that can develop into liver cirrhosis and hepatocellular carcinoma and even lead to death. Cannabidiol (CBD),...
Liver fibrosis has become a serious public health problem that can develop into liver cirrhosis and hepatocellular carcinoma and even lead to death. Cannabidiol (CBD), which is an abundant nonpsychoactive component in the cannabis plant, exerts cytoprotective effects in many diseases and under pathological conditions. In our previous studies, CBD significantly attenuated liver injury induced by chronic and binge alcohol in a mouse model and oxidative bursts in human neutrophils. However, the effects of CBD on liver fibrosis and the underlying mechanisms still need to be further explored. A mouse liver fibrosis model was induced by carbon tetrachloride (CCl) for 10 weeks and used to explore the protective properties of CBD and related molecular mechanisms. After the injection protocol, serum samples and livers were used for molecular biology, biochemical and pathological analyses. The results showed that CBD could effectively improve liver function and reduce liver damage and liver fibrosis progression in mice; the expression levels of transaminase and fibrotic markers were reduced, and histopathological characteristics were improved. Moreover, CBD inhibited the levels of inflammatory cytokines and reduced the protein expression levels of p-NF-κB, NF-κB, p-IκBα, p-p38 MAPK, and COX-2 but increased the expression level of PPAR-α. We found that CBD-mediated protection involves inhibiting NF-κB and activating PPAR-α. In conclusion, these results suggest that the hepatoprotective effects of CBD may be due to suppressing the inflammatory response in CCl-induced mice and that the NF-κB and PPAR-α signaling pathways might be involved in this process.
Topics: Animals; Cannabidiol; NF-kappa B; PPAR alpha; Liver Cirrhosis; Mice; Carbon Tetrachloride; Male; Signal Transduction; Disease Models, Animal; Mice, Inbred C57BL; Liver
PubMed: 38711461
DOI: 10.3389/ebm.2024.10141 -
The Journal of Biological Chemistry Jun 2024Triclosan (TCS) is an antimicrobial toxicant found in a myriad of consumer products and has been detected in human tissues, including breastmilk. We have evaluated the...
Triclosan (TCS) is an antimicrobial toxicant found in a myriad of consumer products and has been detected in human tissues, including breastmilk. We have evaluated the impact of lactational TCS on UDP-glucuronosyltransferase 1A1 (UGT1A1) expression and bilirubin metabolism in humanized UGT1 (hUGT1) neonatal mice. In hUGT1 mice, expression of the hepatic UGT1A1 gene is developmentally delayed resulting in elevated total serum bilirubin (TSB) levels. We found that newborn hUGT1 mice breastfed or orally treated with TCS presented lower TSB levels along with induction of hepatic UGT1A1. Lactational and oral treatment by gavage with TCS leads to the activation of hepatic nuclear receptors constitutive androstane receptor (CAR), peroxisome proliferator-activated receptor alpha (PPARα), and stress sensor, activating transcription factor 4 (ATF4). When CAR-deficient hUGT1 mice (hUGT1/Car) were treated with TCS, TSB levels were reduced with a robust induction of hepatic UGT1A1, leaving us to conclude that CAR is not tied to UGT1A1 induction. Alternatively, when PPARα-deficient hUGT1 mice (hUGT1/Pparα) were treated with TCS, hepatic UGT1A1 was not induced. Additionally, we had previously demonstrated that TCS is a potent inducer of ATF4, a transcriptional factor linked to the integrated stress response. When ATF4 was deleted in liver of hUGT1 mice (hUGT1/Atf4) and these mice treated with TCS, we observed superinduction of hepatic UGT1A1. Oxidative stress genes in livers of hUGT1/Atf4 treated with TCS were increased, suggesting that ATF4 protects liver from excessive oxidative stress. The increase oxidative stress may be associated with superinduction of UGT1A1. The expression of ATF4 in neonatal hUGT1 hepatic tissue may play a role in the developmental repression of UGT1A1.
Topics: Animals; Glucuronosyltransferase; PPAR alpha; Mice; Activating Transcription Factor 4; Triclosan; Humans; Animals, Newborn; Bilirubin; Liver; Mice, Knockout; Female; Constitutive Androstane Receptor; Receptors, Cytoplasmic and Nuclear
PubMed: 38705390
DOI: 10.1016/j.jbc.2024.107340 -
Animal Science Journal = Nihon Chikusan... 2024Intramuscular fat (IMF) is a crucial determinant of meat quality and is influenced by various regulatory factors. Despite the growing recognition of the important role...
Intramuscular fat (IMF) is a crucial determinant of meat quality and is influenced by various regulatory factors. Despite the growing recognition of the important role of long noncoding RNAs (lncRNAs) in IMF deposition, the mechanisms underlying buffalo IMF deposition remain poorly understood. In this study, we identified and characterized a lncRNA, lncFABP4, which is transcribed from the antisense strand of fatty acid-binding protein 4 (FABP4). lncFABP4 inhibited cell proliferation in buffalo intramuscular preadipocytes. Moreover, lncFABP4 significantly increased intramuscular preadipocyte differentiation, as indicated by an increase in the expression of the adipogenic markers peroxisome proliferator-activated receptor gamma (PPARG), CCAAT enhancer binding protein alpha (C/EBPα), and FABP4. Mechanistically, lncFABP4 was found to have the potential to regulate downstream gene expression by participating in protein-protein interaction pathways. These findings contribute to further understanding of the intricate mechanisms through which lncRNAs modulate intramuscular adipogenesis in buffaloes.
Topics: Animals; Buffaloes; Adipogenesis; Adipocytes; Fatty Acid-Binding Proteins; RNA, Long Noncoding; Cell Differentiation; PPAR gamma; Cell Proliferation; Gene Expression; Cells, Cultured; CCAAT-Enhancer-Binding Protein-alpha; Food Quality
PubMed: 38703069
DOI: 10.1111/asj.13951 -
Journal of Ethnopharmacology Sep 2024The Sang Yu granule (SY), a traditional Chinese medicine prescription of Xijing Hospital, was developed based on the Guanyin powder in the classical prescription "Hong's...
ETHNOPHARMACOLOGICAL RELEVANCE
The Sang Yu granule (SY), a traditional Chinese medicine prescription of Xijing Hospital, was developed based on the Guanyin powder in the classical prescription "Hong's Collection of Proven Prescriptions" and the new theory of modern Chinese medicine. It has been proved to have a certain therapeutic effect on drug-induced liver injury (DILI), but the specific mechanism of action is still unclear.
AIM OF STUDY
Aim of the study was to explore the effect of SangYu granule on treating drug-induced liver injury induced by acetaminophen in mice.
MATERIALS AND METHODS
The chemical composition of SY, serum, and liver tissue was analyzed using ultrahigh-performance liquid chromatography quadrupole time-of-flight mass spectrometry. To assess hepatic function, measurements were taken using kits for total bile acids, as well as serum AST, ALT, and ALP activity. Concentrations of IL-1β and TNF-α in serum were quantified using ELISA kits. Transcriptome Sequencing Analysis and 2bRAD-M microbial diversity analysis were employed to evaluate gene expression variance in liver tissue and fecal microbiota diversity among different groups, respectively. Western blotting was performed to observe differences in the activation levels of FXR, SHP, CYP7A1 and PPARα in the liver, and the levels of FXR and FGF-15 genes and proteins in the ileum of mice. Additionally, fecal microbiota transplantation (FMT) experiments were conducted to investigate the potential therapeutic effect of administering the intestinal microbial suspension from mice treated with SY on drug-induced liver injury.
RESULTS
SY treatment exhibited significant hepatoprotective effects in mice, effectively ameliorating drug-induced liver injury while concurrently restoring intestinal microbial dysbiosis. Furthermore, SY administration demonstrated a reduction in the concentration of total bile acids, the expression of FXR and SHP proteins in the liver was up-regulated, CYP7A1 protein was down-regulated, and the expressions of FXR and FGF-15 proteins in the ileum were up-regulated. However, no notable impact on PPARα was observed. Furthermore, results from FMT experiments indicated that the administration of fecal suspensions derived from mice treated with SY did not yield any therapeutic benefits in the context of drug-induced liver injury.
CONCLUSION
The aforementioned findings strongly suggest that SY exerts a pronounced ameliorative effect on drug-induced liver injury through its ability to modulate the expression of key proteins involved in bile acid secretion, thereby preserving hepato-enteric circulation homeostasis.
Topics: Animals; Acetaminophen; Chemical and Drug Induced Liver Injury; Drugs, Chinese Herbal; Male; Liver; Mice; PPAR alpha; Gastrointestinal Microbiome; Fibroblast Growth Factors; Cholesterol 7-alpha-Hydroxylase; Receptors, Cytoplasmic and Nuclear; Tumor Necrosis Factor-alpha; Bile Acids and Salts; Interleukin-1beta
PubMed: 38701935
DOI: 10.1016/j.jep.2024.118282 -
Diabetes Research and Clinical Practice Jun 2024Type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD), mainly related to nutrition and lack of physical activity, are both very... (Review)
Review
Type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD), mainly related to nutrition and lack of physical activity, are both very common conditions, share several disease pathways and clinical manifestations, and increasingly co-occur with disease progression. Insulin resistance is an upstream node in the biology of both conditions and triggers liver parenchymal injury, inflammation and fibrosis. Peroxisome proliferator-activated receptor (PPAR) nuclear transcription factors are master regulators of energy homeostasis - insulin signaling in liver, adipose and skeletal muscle tissue - and affect immune and fibrogenesis pathways. Among distinct yet overlapping effects, PPARα regulates lipid metabolism and energy expenditure, PPARβ/δ has anti-inflammatory effects and increases glucose uptake by skeletal muscle, while PPARγ improves insulin sensitivity and exerts direct antifibrotic effects on hepatic stellate cells. Together PPARs thus represent pharmacological targets across the entire biology of MASH. Single PPAR agonists are approved for hypertriglyceridemia (PPARα) and T2D (PPARγ), but these, as well as dual PPAR agonists, have shown mixed results as anti-MASH treatments in clinical trials. Agonists of all three PPAR isoforms have the potential to improve the full disease spectrum from insulin resistance to fibrosis, and correspondingly to improve cardiometabolic and hepatic health, as has been shown (phase II data) with the pan-PPAR agonist lanifibranor.
Topics: Humans; Diabetes Mellitus, Type 2; Peroxisome Proliferator-Activated Receptors; Fatty Liver; Insulin Resistance; PPAR alpha; PPAR gamma; Animals
PubMed: 38697298
DOI: 10.1016/j.diabres.2024.111688 -
Heliyon May 2024The current study aimed to investigate the influence of taxifolin on depression symptoms alleviation in Male Sprague-Dawley rats by targeting underlying pathways of...
The current study aimed to investigate the influence of taxifolin on depression symptoms alleviation in Male Sprague-Dawley rats by targeting underlying pathways of depression. Molecular docking analyses were conducted to validate taxifolin's binding affinities against various targets. analysis of taxifolin revealed various aspects of post docking interactions with different protein targets. Depression was induced in rats via intraperitoneal injection of Lipopolysaccharide (LPS; 500 g/Kg) for 14 alternative days. Rats (n = 6/group) were randomly assigned to four groups: (i) Saline/Control, (ii) Disease (LPS 500 μg/kg), (iii) Standard (fluoxetine 20 mg/kg), and (iv) Treatment (taxifolin 20 mg/kg). At the end of the in vivo study, brain samples were used for biochemical and morphological analysis. Taxifolin exhibited neuroprotective effects, as evidenced by behavioral studies, antioxidant analysis, histopathological examination, immunohistochemistry, ELISA and RT PCR, indicating an increase number of surviving neurons, normalization of cell size and shape, and reduction in vacuolization. Taxifolin also decreased inflammatory markers such as TNF-α, NF-κb, IL-6 and COX-2, while significantly upregulating and activating the protective PPAR-γ pathway, through which it reduces the oxidative stress, neuroinflammation, neurodegeneration, thereby ameliorating depression symptoms in experimental rat model of depression. Our finding suggests that taxifolin act as neuroprotective agent partially mediated through PPAR-γ pathway.
PubMed: 38694040
DOI: 10.1016/j.heliyon.2024.e30467 -
Journal of Microbiology and... Jun 2024Citrus fruits offer a range of health benefits due to their rich nutritional profile, including vitamin C, flavonoids, carotenoids, and fiber. It is known that unripe...
Citrus fruits offer a range of health benefits due to their rich nutritional profile, including vitamin C, flavonoids, carotenoids, and fiber. It is known that unripe citrus has higher levels of vitamin C, dietary fiber, polyphenols, and flavonoids compared to mature fruits. In this study, we assessed the nutritional components of unripe citrus peel and pressed juices, as well as their anti-obesity potential through the modulation of adipocyte differentiation and the expression of adipogenesis-related genes, specifically PPARγ and C/EBPα, in 3T3-L1 preadipocytes. Our analysis revealed that unripe citrus peel exhibited elevated levels of fiber and protein compared to pressed juice, with markedly low levels of free sugar, particularly sucrose. The content of hesperidin, a representative flavonoid in citrus fruits, was 3,157.6 mg/kg in unripe citrus peel and 455.5 mg/kg in pressed juice, indicating that it was approximately seven times higher in unripe citrus peel compared to pressed juice. Moreover, we observed that the peel had a dose-dependently inhibitory effect on adipocyte differentiation, which was linked to a significant downregulation of adipogenesis-related gene expression. Thus, our findings suggest that unripe citrus possesses anti-obesity effects by impeding adipogenesis and adipocyte differentiation, with the peel demonstrating a more pronounced effect compared to pressed juice.
Topics: Citrus; Adipogenesis; Animals; Mice; Adipocytes; 3T3-L1 Cells; Cell Differentiation; PPAR gamma; Fruit; CCAAT-Enhancer-Binding Protein-alpha; Dietary Fiber; Flavonoids; Hesperidin; Anti-Obesity Agents; Plant Extracts; Fruit and Vegetable Juices; Ascorbic Acid
PubMed: 38693048
DOI: 10.4014/jmb.2403.03015