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Frontiers in Pharmacology 2024Gentiopicroside (GPS) is a highly water-soluble small-molecule drug and the main bioactive secoiridoid glycoside of Gentiana scabra that has been shown to have...
Gentiopicroside (GPS) is a highly water-soluble small-molecule drug and the main bioactive secoiridoid glycoside of Gentiana scabra that has been shown to have hepatoprotective effects against non-alcoholic steatohepatitis (NASH), a form of non-alcoholic fatty liver disease (NAFLD) that can progress to cirrhosis and hepatocellular carcinoma. However, the effects of GPS on NASH and the underlying mechanisms remain obscure. Firstly, a high-fat, high-cholesterol (HFHC) diet and a high-sugar solution containing d-fructose and d-glucose were used to establish a non-alcoholic steatohepatitis (NASH) mice model. Secondly, we confirmed GPS supplementation improve metabolic abnormalities and reduce inflammation in NASH mice induced by HFHC and high-sugar solution. Then we used metabolomics to investigate the mechanisms of GPS in NASH mice. Metabolomics analysis showed GPS may work through the Peroxisome Proliferator-Activated Receptor (PPAR) signaling pathway and glycine, serine, and threonine metabolism. Functional metabolites restored by GPS included serine, glycine, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Western blot and qRT-PCR analysis confirmed GPS improve NASH by regulating PPARα and Hypoxia-Inducible Factor-1α (HIF-1α) signaling pathways. , studies further demonstrated EPA and DHA enhance fatty acid oxidation through the PPARα pathway, while serine and glycine inhibit oxidative stress through the HIF-1α pathway in palmitic acid-stimulated HepG2 cells. Our results suggest GPS's anti-inflammatory and anti-steatosis effects in NASH progression are related to the suppression of HIF-1α through the restoration of L-serine and glycine and the activation of PPARα through increased EPA and DHA.
PubMed: 38515850
DOI: 10.3389/fphar.2024.1335814 -
Clinical and Translational Science Mar 2024Persea americana fruit (PAF) is a favorable nutraceutical resource that comprises diverse unsaturated fatty acids (UFAs). UFAs are significant dietary supplementation,...
Persea americana fruit (PAF) is a favorable nutraceutical resource that comprises diverse unsaturated fatty acids (UFAs). UFAs are significant dietary supplementation, as they relieve metabolic disorders, including obesity (OB). In another aspect, this study was focused on the anti-OB efficacy of the non-fatty acids (NFAs) in PAF through network pharmacology (NP). Natural product activity & species source (NPASS), SwissADME, similarity ensemble approach (SEA), Swiss target prediction (STP), DisGeNET, and online Mendelian inheritance in man (OMIM) were utilized to gather significant molecules and its targets. The crucial targets were adopted to construct certain networks: protein-protein interaction (PPI), PAF-signaling pathways-targets-compounds (PSTC) networks, a bubble chart, molecular docking assay (MDA), and density function theory (DFT). Finally, the toxicities of the key compounds were validated by ADMETlab 2.0 platform. All 41 compounds in PAF conformed to Lipinski's rule, and the key 31 targets were identified between OB and PAF. On the bubble chart, PPAR signaling pathway had the highest rich factor, suggesting that the pathway might be an agonism for anti-OB. Conversely, estrogen signaling pathway had the lowest rich factor, indicating that the mechanism might be antagonism against OB. Likewise, the PSTC network represented that AKT1 had the greatest degree value. The MDA results showed that AKT1-gamma-tocopherol, PPARA-fucosterol, PPARD-stigmasterol, (PPARG)-fucosterol, (NR1H3)-campesterol, and ILK-alpha-tocopherol formed the most stable conformers. The DFT represented that the five molecules might be promising agents via multicomponent targeting. Overall, this study suggests that the NFAs in PAF might play important roles against OB.
Topics: Humans; Fruit; Molecular Docking Simulation; Persea; Biological Assay; Fatty Acids; Obesity
PubMed: 38515346
DOI: 10.1111/cts.13778 -
Brazilian Journal of Medical and... 2024The imbalance between pro-inflammatory M1 and anti-inflammatory M2 macrophages plays a critical role in the pathogenesis of sepsis-induced acute lung injury (ALI)....
The imbalance between pro-inflammatory M1 and anti-inflammatory M2 macrophages plays a critical role in the pathogenesis of sepsis-induced acute lung injury (ALI). Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) may modulate macrophage polarization toward the M2 phenotype by altering mitochondrial activity. This study aimed to investigate the role of the PGC-1α agonist pioglitazone (PGZ) in modulating sepsis-induced ALI. A mouse model of sepsis-induced ALI was established using cecal ligation and puncture (CLP). An in vitro model was created by stimulating MH-S cells with lipopolysaccharide (LPS). qRT-PCR was used to measure mRNA levels of M1 markers iNOS and MHC-II and M2 markers Arg1 and CD206 to evaluate macrophage polarization. Western blotting detected expression of peroxisome proliferator-activated receptor gamma (PPARγ) PGC-1α, and mitochondrial biogenesis proteins NRF1, NRF2, and mtTFA. To assess mitochondrial content and function, reactive oxygen species levels were detected by dihydroethidium staining, and mitochondrial DNA copy number was measured by qRT-PCR. In the CLP-induced ALI mouse model, lung tissues exhibited reduced PGC-1α expression. PGZ treatment rescued PGC-1α expression and alleviated lung injury, as evidenced by decreased lung wet-to-dry weight ratio, pro-inflammatory cytokine secretion (tumor necrosis factor-α, interleukin-1β, interleukin-6), and enhanced M2 macrophage polarization. Mechanistic investigations revealed that PGZ activated the PPARγ/PGC-1α/mitochondrial protection pathway to prevent sepsis-induced ALI by inhibiting M1 macrophage polarization. These results may provide new insights and evidence for developing PGZ as a potential ALI therapy.
Topics: Mice; Animals; Pioglitazone; Up-Regulation; PPAR gamma; Acute Lung Injury; Sepsis; Lipopolysaccharides; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
PubMed: 38511769
DOI: 10.1590/1414-431X2024e13235 -
Scientific Reports Mar 2024The feed-forward loop between the transcription factors Ppar-gamma and C/ebp-alpha is critical for lineage commitment during adipocytic differentiation. Ppar-gamma...
The feed-forward loop between the transcription factors Ppar-gamma and C/ebp-alpha is critical for lineage commitment during adipocytic differentiation. Ppar-gamma interacts with epigenetic cofactors to activate C/ebp-alpha and the downstream adipocytic gene expression program. Therefore, knowledge of the epigenetic cofactors associated with Ppar-gamma, is central to understanding adipocyte differentiation in normal differentiation and disease. We found that Prmt6 is present with Ppar-gamma on the Ppar-gamma and C/ebp-alpha promoter. It contributes to the repression of C/ebp-alpha expression, in part through its ability to induce H3R2me2a. During adipocyte differentiation, Prmt6 expression is reduced and the methyltransferase leaves the promoters. As a result, the expression of Ppar-gamma and C/ebp-alpha is upregulated and the adipocytic gene expression program is established. Inhibition of Prmt6 by a small molecule enhances adipogenesis, opening up the possibility of epigenetic manipulation of differentiation. Our data provide detailed information on the molecular mechanism controlling the Ppar-gamma-C/ebp-alpha feed-forward loop. Thus, they advance our understanding of adipogenesis in normal and aberrant adipogenesis.
Topics: Mice; Animals; Transcription Factors; Adipogenesis; PPAR alpha; Gene Expression Regulation; Adipocytes; CCAAT-Enhancer-Binding Protein-alpha; Cell Differentiation; PPAR gamma; 3T3-L1 Cells
PubMed: 38509237
DOI: 10.1038/s41598-024-57310-9 -
Journal of Applied Biomedicine Mar 2024We have extracted and characterized Phasa fish (Setipinna phasa) oil for the first time to evaluate the anti-obesity and related anti-inflammatory effects on obese mice....
We have extracted and characterized Phasa fish (Setipinna phasa) oil for the first time to evaluate the anti-obesity and related anti-inflammatory effects on obese mice. Inbred male albino BALB/c mice were segregated into three categories: control (C), Obese control group (OC), and Phasa fish oil treated group (TX). To establish the potentiality of Setipinna phasa oil for its anti-obesity and anti-inflammatory properties, it was extracted and characterized using GC-MS method. To evaluate the anti-obesity effect, different parameters were considered, such as body weight, lipid composition, obesity, and obesity associated inflammation. The physicochemical characteristics of Phasa fish oil revealed that the oil quality was good because acid value, peroxide value, p-anisidine value, Totox value, refractive index, and saponification value were within the standard value range. The GC-MS study explored the presence of fatty acids beneficial to health such as Hexadec-9-enoic acid; Octadec-11-enoic acid; EPA, DHA, Methyl Linolenate, etc. The application of Setipinna phasa oil on the treated mice group acutely lowered body weight and serum lipid profile compared to the obese group. In connection with this, leptin, FAS, and pro-inflammatory cytokines TNF-α genes expression were downregulated in the treated group compared to the obese group. The Phasa oil treated group had an elevated expression of PPAR-α, adiponectin, LPL gene, and anti-inflammatory markers IL-10 and IL-1Ra compared to the obese group. This study suggests that Phasa fish oil, enriched with essential fatty acid, might be used as an anti-obesity and anti-inflammatory supplement.
Topics: Male; Mice; Animals; Diet, High-Fat; Mice, Inbred BALB C; Obesity; Fish Oils; Body Weight; Inflammation; Anti-Inflammatory Agents
PubMed: 38505970
DOI: 10.32725/jab.2024.003 -
Ecotoxicology and Environmental Safety Apr 2024Phthalic acid esters (PAEs) are widely used as plasticizers and have been suggested to engender adverse effects on glucose metabolism. However, epidemiological data...
Phthalic acid esters (PAEs) are widely used as plasticizers and have been suggested to engender adverse effects on glucose metabolism. However, epidemiological data regarding the PAE mixture on type 2 diabetes (T2DM), as well as the mediating role of oxidative stress are scarce. This case-control study enrolled 206 T2DM cases and 206 matched controls in Guangdong Province, southern China. The concentrations of eleven phthalate metabolites (mPAEs) and the oxidative stress biomarker 8-hydroxy-2'-deoxyguanosine (8-OHdG) in urine were determined. Additionally, biomarkers of T2DM in paired serum were measured to assess glycemic status and levels of insulin resistance. Significantly positive associations were observed for mono-(2-ethylhexyl) phthalate (MEHP) and Mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) with T2DM (P < 0.001). Restricted cubic spline modeling revealed a non-linear dose-response relationship between MEHHP and T2DM (P = 0.001). The Bayesian kernel machine regression and quantile g-computation analyses demonstrated a significant positive joint effect of PAE exposure on T2DM risk, with MEHHP being the most significant contributor. The mediation analysis revealed marginal evidence that oxidative stress mediated the association between the mPAEs mixture and T2DM, while 8-OHdG respectively mediated 26.88 % and 12.24 % of MEHP and MEHHP on T2DM risk individually (P < 0.05). Di(2-ethylhexyl) phthalate (DEHP, the parent compound for MEHP and MEHHP) was used to further examine the potential molecular mechanisms by in silico analysis. Oxidative stress may be crucial in the link between DEHP and T2DM, particularly in the reactive oxygen species metabolic process and glucose import/metabolism. Molecular simulation docking experiments further demonstrated the core role of Peroxisome Proliferator Activated Receptor alpha (PPARα) among the DEHP-induced T2DM. These findings suggest that PAE exposure can alter oxidative stress via PPARα, thereby increasing T2DM risk.
Topics: Humans; Diethylhexyl Phthalate; Diabetes Mellitus, Type 2; Case-Control Studies; Bayes Theorem; PPAR alpha; Phthalic Acids; 8-Hydroxy-2'-Deoxyguanosine; Oxidative Stress; Biomarkers; Environmental Exposure
PubMed: 38503103
DOI: 10.1016/j.ecoenv.2024.116216 -
Nan Fang Yi Ke Da Xue Xue Bao = Journal... Feb 2024To explore the role of the PPARα/HOXA10 signaling pathway in mediating the effect of adiponectin (APN) for improving endometrial receptivity in a rat model of...
OBJECTIVE
To explore the role of the PPARα/HOXA10 signaling pathway in mediating the effect of adiponectin (APN) for improving endometrial receptivity in a rat model of polycystic ovary syndrome (PCOS).
METHODS
Forty female SD rat models with letrozole-induced PCOS were randomized, with 10 normal rats as the control, into 4 equal groups for treatment with APN alone, APN combined with GW6471 (a specific PPARα inhibitor) or the vehicle for 20 days, or no further treatment (PCOS model group). GW6471 treatment (daily dose of 1 mg/kg) and vehicle treatment were initiated on the 11th day following the start of APN treatment, all administered via intraperitoneal injection. The rats were observed for changes in estrous cycle, body weight, ovarian index and morphology, uterine index and morphology, serum hormone levels and lipid metabolism parameters. Endometrial expressions of PPARα and HOXA10 were detected with immunohistochemistry and Western blotting. The development of endometrial pinopodes was observed under electron microscope, and pregnancies of the rats were recorded.
RESULTS
The rat models of PCOS exhibited obvious estrous cycle disorders with significantly prolonged estrous interval, increased body weight and ovarian index, decreased uterine index, disordered serum hormones and lipid metabolism ( < 0.05), and polycystic ovarian changes, and these changes were significantly improved by APN treatment. Endometrial expressions of PPARα and HOXA10 were significantly lowered in PCOS rats and effectively up-regulated after APN treatment, but GW6471 treatment obviously blocked the effect of APN ( < 0.05). APN showed strong protective effect against PCOS-induced impairment of endometrial pinopode development, and this effect was obviously attenuated by GW6471. APN also significantly increased the pregnancy rate and embryo number in PCOS rats, while GW6471 obviously reduced the embryo number and caused developmental retardation of the embryos.
CONCLUSION
APN can improve endometrial receptivity in PCOS rats by upregulating the PARα/HOXA10 pathway.
Topics: Humans; Rats; Animals; Female; Polycystic Ovary Syndrome; Adiponectin; PPAR alpha; Rats, Sprague-Dawley; Body Weight; Homeobox A10 Proteins
PubMed: 38501415
DOI: 10.12122/j.issn.1673-4254.2024.02.12 -
International Immunopharmacology Apr 2024We recently found that butyrate could ameliorate inflammation of alcoholic liver disease (ALD) in mice. However, the exact mechanism remains incompletely comprehended....
BACKGROUND
We recently found that butyrate could ameliorate inflammation of alcoholic liver disease (ALD) in mice. However, the exact mechanism remains incompletely comprehended. Here, we examined the role of butyrate on ALD-associated inflammation through macrophage (Mψ) regulation and polarization using in vivo and in vitro experiments.
METHODS
For in vivo experiments, C57BL/6J mice were fed modified Lieber-DeCarli liquid diets supplemented with or without ethanol and sodium butyrate (NaB). After 6 weeks of treatment, mice were euthanized and associated indicators were analyzed. For in vitro experiments, lipopolysaccharide (LPS)-induced inflammatory murine RAW264.7 cells were treated with NaB or miR-155 inhibitor/mimic to verify the anti-inflammatory effect and underlying mechanism.
RESULTS
The administration of NaB alleviated pathological damage and associated inflammation, including LPS, tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1β levels in ALD mice. NaB intervention restored the imbalance of macrophage polarization by inhibiting inducible nitric oxide synthase (iNOS) and elevating arginase-1 (Arg-1). Moreover, NaB reduced histone deacetylase-1 (HDAC1), nuclear factor kappa-B (NF-κB), NOD-like receptor thermal protein domain associated protein 3 (NLRP3), and miR-155 expression in ALD mice, but also increased peroxisome proliferator-activated receptor-γ (PPAR-γ). Thus, MiR-155 was identified as a strong regulator of ALD. To further penetrate the role of miR-155, LPS-stimulated RAW264.7 cells co-cultured with NaB were treated with the specific inhibitor or mimic. Intriguingly, miR-155 was capable of negatively regulated inflammation with NaB intervention by targeting SOCS1, SHIP1, and IRAK-M genes.
CONCLUSION
Butyrate suppresses the inflammation in mice with ALD by regulating macrophage polarization via the HDAC1/miR-155 axis, which may potentially contribute to the novel therapeutic treatment for the disease.
Topics: Mice; Animals; Lipopolysaccharides; Mice, Inbred C57BL; Liver Diseases, Alcoholic; Inflammation; Macrophages; Hepatitis, Alcoholic; Butyric Acid; NF-kappa B; Tumor Necrosis Factor-alpha; MicroRNAs
PubMed: 38492338
DOI: 10.1016/j.intimp.2024.111852 -
Frontiers in Pharmacology 2024Nobiletin (NOB) is a flavonoid derived from citrus peel that has potential as an alternative treatment for liver disease. Liver disease is a primary health concern... (Review)
Review
Nobiletin (NOB) is a flavonoid derived from citrus peel that has potential as an alternative treatment for liver disease. Liver disease is a primary health concern globally, and there is an urgent need for effective drugs. This review summarizes the pharmacological characteristics of NOB and current and studies investigating the preventive and therapeutic effects of NOB on liver diseases and its potential mechanisms. The findings suggest that NOB has promising therapeutic potential in liver diseases. It improves liver function, reduces inflammation and oxidative stress, remodels gut microflora, ameliorates hepatocellular necrosis, steatosis, and insulin resistance, and modulates biorhythms. Nuclear factor erythroid 2-related factor 2 (Nrf2), nuclear transcription factor kappa (NF-κB), AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor α(PPAR-α), extracellular signal-regulated kinase (ERK), protein kinase B (AKT), toll-like receptor 4 (TLR4) and transcription factor EB (TFEB) signaling pathways are important molecular targets for NOB to ameliorate liver diseases. In conclusion, NOB may be a promising drug candidate for treating liver disease and can accelerate its application from the laboratory to the clinic. However, more high-quality clinical trials are required to validate its efficacy and identify its molecular mechanisms and targets.
PubMed: 38487166
DOI: 10.3389/fphar.2024.1354809 -
BMC Endocrine Disorders Mar 2024A better understanding of adipose tissue (AT) dysfunction, which includes morphological and functional changes such as adipocyte hypertrophy as well as impaired...
BACKGROUND
A better understanding of adipose tissue (AT) dysfunction, which includes morphological and functional changes such as adipocyte hypertrophy as well as impaired adipogenesis, lipid storage/mobilization, endocrine and inflammatory responses, is needed in the context of obesity. One dimension of AT dysfunction, secretory adiposopathy, often assessed as a low plasma adiponectin (A)/leptin (L) ratio, is commonly observed in obesity. The aim of this study was to examine markers of AT development and metabolism in 67 women of varying age and adiposity (age: 40-62 years; body mass index, BMI: 17-41 kg/m) according to levels of adiponectinemia, leptinemia or the plasma A/L ratio.
METHODS
Body composition, regional AT distribution and circulating adipokines were determined. Lipolysis was measured from glycerol release in subcutaneous abdominal (SCABD) and omental (OME) adipocytes under basal, isoproterenol-, forskolin (FSK)- and dibutyryl-cyclic AMP (DcAMP)-stimulated conditions. Adipogenesis (C/EBP-α/β/δ, PPAR-γ2 and SREBP-1c) and lipid metabolism (β2-ARs, HSL, FABP4, LPL and GLUT4) gene expression (RT-qPCR) was assessed in both fat depots. Participants in the upper versus lower tertile of adiponectin, leptin or the A/L ratio were compared.
RESULTS
Basal lipolysis was similar between groups. Women with a low plasma A/L ratio were characterized by higher adiposity and larger SCABD and OME adipocytes (p<0.01) compared to those with a high ratio. In OME adipocytes, women in the low adiponectinemia tertile showed higher isoproterenol-stimulated lipolysis (0.01
CONCLUSIONS
Secretory adiposopathy assessed as the plasma A/L ratio, more so than adiponectin or leptin levels alone, discriminates low and elevated lipolysis in OME and SCABD adipocytes despite similar AT expression of selected genes involved in lipid metabolism.
Topics: Female; Humans; Adult; Middle Aged; Adiponectin; Leptin; Isoproterenol; Adipose Tissue; Obesity
PubMed: 38481206
DOI: 10.1186/s12902-024-01567-8