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Background and Purpose: Depression is closely linked with microglial activation and neuro‐inflammation. Peroxisome proliferator‐activated receptor‐γ (PPAR‐γ) plays an important role in M2 activation of microglia. Forkhead box (FOX) O3a has been implicated in the regulation of mood‐relevant behaviour. However, little is known about the inflammatory mechanisms of in the microglia of the brain. Here, we have investigated the role of microglial FOXO3a/PPAR‐γ in the development of depression. Experimental Approach: The effect of FOXO3a on microglia inflammation was analysed in vitro and in lipopolysaccharide (LPS)‐induced depression‐like behaviours in vivo. ChIP‐seq and Dual‐luciferase reporter assays were used to confirm the interaction between FOXO3a and PPAR‐γ. Behavioural changes were measured, while inflammatory cytokines, microglial phenotype and morphological properties were determined by ELISA, qRT‐PCR, western blotting and immunostaining. Key Results: Overexpression of FOXO3a significantly attenuated expression of PPAR‐γ and enhanced the microglial polarization towards the M1 phenotype, while knockdown of FOXO3a had the opposite effect. FOXO3a binds to the promoters of PPAR‐γ and decreases its transcription activity. Importantly, deacetylation and activation of FOXO3a regulate LPS‐induced neuro‐inflammation by inhibiting the expression of PPAR‐γ in microglia cells, supporting the antidepressant potential of histone deacetylase inhibitors. Microglial FOXO3a deficiency in mice alleviated LPS‐induced neuro‐inflammation and depression‐like behaviours but failed to reduce anxiety behaviour, whereas pharmacological inhibition of PPAR‐γ by GW9662 restored LPS‐induced microglial activation and depressive‐like behaviours in microglial FOXO3a‐deficient mice. Conclusion and Implications: FOXO3a/PPAR‐γ axis plays an important role in microglial activation and depression, identifying a new therapeutic avenue for the treatment of major depression. [ABSTRACT FROM AUTHOR]

The PPARγ gene encodes a member of a nuclear receptor superfamily known as peroxisome proliferator-activated gamma (PPARγ). PPARγ plays an essential role in adipogenesis, stimulating the differentiation of preadipocytes into adipocytes. Loss-of-function pathogenic variants in PPARγ reduce the activity of the PPARγ receptor and can lead to severe metabolic consequences associated with familial partial lipodystrophy type 3 (FPLD3). This review focuses on recent scientific data related to FPLD3, including the role of PPARγ in adipose tissue metabolism and the phenotypic and clinical consequences of loss-of-function variants in the PPARγ gene. The clinical features of 41 PPARγ pathogenic variants associated with FPLD3 patients were reviewed, highlighting the genetic and clinical heterogeneity observed among 91 patients. Most of them were female, and the average age at the onset and diagnosis of lipoatrophy was 21 years and 33 years, respectively. Considering the metabolic profile, hypertriglyceridemia (91.9% of cases), diabetes (77%), hypertension (59.5%), polycystic ovary syndrome (58.2% of women), and metabolic-dysfunction-associated fatty liver disease (87,5%). We also discuss the current treatment for FPLD3. This review provides new data concerning the genetic and clinical heterogeneity in FPLD3 and highlights the importance of further understanding the genetics of this rare disease. [ABSTRACT FROM AUTHOR]

Peritoneal inflammation and fibrosis remain major challenges to the long-term maintenance of peritoneal dialysis. Pemafibrate, a selective peroxisome proliferator-activated receptor α (PPARα) modulator, has been implicated in the management of fibrosis-related disorders. We investigated whether pemafibrate ameliorates peritoneal inflammation and fibrosis and explored the underlying mechanisms in mice with methylglyoxal (MGO)-induced peritoneal fibrosis (MGO mice). MGO mice exhibited peritoneal fibrosis with increased expression of mesenchymal markers, transforming growth factor-β1 (TGF-β1), and substantial deposition of extracellular matrix (ECM) proteins. Additionally, MGO mice exhibited peritoneal inflammation as indicated by elevated tumor necrosis factor-α expression and macrophage infiltration in peritoneal tissue. These effects were mitigated by pemafibrate treatment, which also restored peritoneal membrane function. Furthermore, pemafibrate promoted anti-inflammatory macrophage polarization in both mice and THP-1 cells. In human peritoneal mesothelial cells (HPMCs), pemafibrate effectively inhibited interferon-γ-induced production of TGF-β1 and ECM while suppressing the proinflammatory cytokines nuclear factor-κB (NF-κB) and activator protein 1. The NF-κB inhibitory effect of pemafibrate involved stabilization of the NF-κB inhibitory protein IkBα. Notably, pemafibrate hindered activation of the NLR family pyrin domain containing 3/caspase-1 axis in interferon-γ-stimulated THP-1 cells. These findings suggest that pemafibrate ameliorates peritoneal inflammation and fibrosis, making it a promising candidate for peritoneal fibrosis therapy. [ABSTRACT FROM AUTHOR]

Background: Aging-related strength decline contributes to physiological deterioration and is a good predictor of poor prognosis. However, the mechanisms underlying neuromuscular junction disorders affecting contraction in aging are not well described. We hypothesized that the autocrine effect of interleukin (IL)-6 secreted by skeletal muscle inhibits acetylcholine receptor (AChR) expression, potentially causing aging-related strength decline. Therefore, we investigated IL-6 and AChR β-subunit (AChR-β) expression in the muscles and sera of aging C57BL/6J mice and verified the effect of IL-6 on AChR-β expression. Methods: Animal experiments, in vitro studies, bioinformatics, gene manipulation, dual luciferase reporter gene assays, and chromatin immunoprecipitation experiments were used to explore the role of the transcription cofactor peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC1α) and its interacting transcription factors in the IL-6-mediated regulation of AChR-β expression. Results: IL-6 expression gradually increased during aging, inhibiting AChR-β expression, which was reversed by tocilizumab. Both tocilizumab and the PGC1α agonist reversed the inhibiting effect of IL-6 expression on AChR-β. Compared to inhibition of signal transducer and activator of transcription 3, extracellular signal-regulated kinases 1/2 (ERK1/2) inhibition suppressed the effects of IL-6 on AChR-β and PGC1α. In aging mouse muscles and myotubes, myocyte enhancer factor 2 C (MEF2C) was recruited by PGC1α, which directly binds to the AChR-β promoter to regulate its expression. Conclusions: This study verifies AChR-β regulation by the IL-6/IL-6R-ERK1/2-PGC1α/MEF2C pathway. Hence, evaluating muscle secretion, myokines, and AChRs at an earlier stage to determine pathological progression is important. Moreover, developing intervention strategies for monitoring, maintaining, and improving muscle structure and function is necessary. [ABSTRACT FROM AUTHOR]

Background: The burden of nonalcoholic fatty liver disease is increasing, and limited therapeutic drugs are available for its treatment. Serotonin binds to approximately 14 serotonin receptors (HTR) and plays diverse roles in obesity and metabolic complications. In this study, we focused on the function of HTR4 on nonalcoholic fatty liver disease using GR113808, a selective HTR4 antagonist. Methods: Male C57BL/6J mice were fed high-fat diet for 12 weeks with intraperitoneal GR113808 injection, and HTR expression, weight changes, glucose and lipid metabolism, hepatic fat accumulation, changes in adipose tissue, the changes in transcriptional factors of signaling pathways, and inflammations were assessed. Hep3B cells and 3T3-L1 cells were treated with siRNA targeting HTR4 to downregulate its expression and then cultured with palmitate to mimic a high-fat diet. The changes in transcriptional factors of signaling pathways, and inflammations were assessed in those cells. Results: After feeding a high-fat diet to male C57BL/6J mice, HTR4 expression in the liver and adipose tissues decreased. GR113808 suppressed body weight gain and improved glucose intolerance. Furthermore, GR113808 not only decreased fatty liver formation but also reduced adipose tissue size. Additionally, GR113808 reduced inflammatory cytokine serum levels and inflammasome complex formation in both tissues. Palmitate treatment in HTR4-downregulated Hep3B cells, also reduced peroxisome proliferator-activated receptor γ and sterol regulatory element-binding protein-1 pathway induction as well as inflammasome complex formation, thus decreasing inflammatory cytokine levels. HTR4 downregulation in 3T3-L1 cells also reduced palmitate-induced inflammasome complex formation and inflammatory cytokine production. Palmitate-induced insulin resistance in Hep3B cells, but not in 3T3-L1 cells, was improved by HTR4 downregulation. Conclusions: In summary, GR113808 protected against fatty liver formation and improved inflammation in the liver and adipose tissue. Downregulation of HTR4 ameliorated insulin resistance in the liver. These results suggest that HTR4 could serve as a promising therapeutic target for metabolic diseases. [ABSTRACT FROM AUTHOR]

Background: Abnormalities in biochemical parameters and changes in eating habits are considered complications of obesity. Oleoylethanolamide (OEA), an endocannabinoid-like compound, has been shown to have protective effects on many metabolic disorders. Given this evidence, the present study aimed to assess the effects of OEA on lipid profile parameters, fasting blood sugar (FBS), and dietary habits in healthy obese people. Methods: In this randomized, double-blind, placebo-controlled clinical trial, which was carried out in 2016 in Tabriz, Iran, 60 obese people were enrolled in the study based on inclusion criteria. The intervention group consumed 125 mg of OEA capsules, and the placebo group received the same amount of starch twice for 8 weeks. Blood samples (5 mL) were taken at baseline and the end of the study in a fasting state. Serum concentrations of FBS, triglycerides (TGs), high-density lipoprotein cholesterol (HDL-C), and total cholesterol (TC) were measured by enzymatic methods using commercial kits. The low-density lipoprotein cholesterol (LDL-C) concentration was obtained using the Friede-Wald formula. To assess dietary habits, a food frequency questionnaire (147 items) was used at baseline and the end of the study. A value less than < 0.05 was considered to indicate statistical significance. Results: The TG concentration decreased significantly in the intervention group (mean (SD): 166.29 (70.01) mg/dL to 142.22 (48.05) mg/dL, p = 0.047). Changes in the placebo group were not significant (p > 0.05). After adjusting for baseline values and demographic characteristics, the difference in TG between groups remained significant (p = 0.044). Changes in other biochemical parameters were not significant. There was no significant difference between or within groups in terms of food groups. Conclusion: OEA, as a complementary agent, plays a protective role in TG regulation. However, future studies with longer durations are needed to explore the impact of OEA on regulating dietary habits and to identify the mechanisms related to metabolic abnormalities in obese people. Trial Registration: The study was registered in the Iranian Registry of Clinical Trials (IRCT) center as IRCT201607132017N30 with URL. www.IRCT.IR in date 03/10/2016. [ABSTRACT FROM AUTHOR]

Owing to its tyrosinase inhibitory activity, α-arbutin has been added to several skin care products as a skin-lightening agent. However, the protective effect of α-arbutin against ultraviolet A (UVA)-induced photoaging has not been well investigated. The present study was designed to investigate the photoprotective effect and mechanism of α-arbutin against UVA-induced photoaging. In vitro experiments, HaCaT cells were treated with UVA at a dose of 3 J/cm2 to evaluate the anti-photoaging effect of α-arbutin. α-Arbutin was found to exhibit a strong antioxidant effect by increasing glutathione (GSH) level and inhibiting reactive oxygen species (ROS) production. Meanwhile, α-arbutin markedly improved the expression of sirtuin 3 (SIRT3) and peroxisome proliferator-activated receptor γ coactivator 1 α (PGC-1α) proteins, initiating downstream signaling to increase mitochondrial membrane potential and mediate mitochondrial biogenesis, and improve mitochondrial structure significantly. In vivo analysis, the mice with shaved back hair were irradiated with a cumulative UVA dose of 10 J/cm2 and a cumulative ultraviolet B (UVB) dose of 0.63 J/cm2. The animal experiments demonstrated that α-arbutin increased the expression of SIRT3 and PGC-1α proteins in the back skin of mice, thereby reducing UV-induced skin damage. In conclusion, α-arbutin protects HaCaT cells and mice from UVA damage by regulating SIRT3/PGC-1α signaling pathway. [ABSTRACT FROM AUTHOR]

Resistance training activates mammalian target of rapamycin (mTOR) pathway of hypertrophy for strength gain, while endurance training increases peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) pathway of mitochondrial biogenesis benefiting oxidative phosphorylation. The conventional view suggests that resistance training-induced hypertrophy signaling interferes with endurance training-induced mitochondrial remodeling. However, this idea has been challenged because acute leg press and knee extension in humans enhance both muscle hypertrophy and mitochondrial remodeling signals. Thus, we first examined the muscle mitochondrial remodeling and hypertrophy signals with endurance training and resistance training, respectively. In addition, we discussed the influence of resistance training on muscle mitochondria, demonstrating that the PGC-1α-mediated muscle mitochondrial adaptation and hypertrophy occur simultaneously. The second aim was to discuss the integrative effects of concurrent training, which consists of endurance and resistance training sessions on mitochondrial remodeling. The study found that the resistance training component does not reduce muscle mitochondrial remodeling signals in concurrent training. On the contrary, concurrent training has the potential to amplify skeletal muscle mitochondrial biogenesis compared to a single exercise model. Concurrent training involving differential sequences of resistance and endurance training may result in varied mitochondrial biogenesis signals, which should be linked to the pre-activation of mTOR or PGC-1α signaling. Our review proposed a mechanism for mTOR signaling that promotes PGC-1α signaling through unidentified pathways. This mechanism may be account for the superior muscle mitochondrial remodeling change following the concurrent training. Our review suggested an interaction between resistance training and endurance training in skeletal muscle mitochondrial adaptation. [ABSTRACT FROM AUTHOR]

Fermented red ginseng (FRG) enhances the bioactivity and bioavailability of ginsenosides, which possess various immunomodulatory, antiaging, anti-obesity, and antidiabetic properties. However, the effects of FRG extract on muscle atrophy and the underlying molecular mechanisms remain unclear. This study aimed to elucidate the effects of FRG extract on muscle atrophy using both in vitro and in vivo models. In vitro experiments used dexamethasone (DEX)-induced C2C12 myotubes to assess cell viability, myotube diameter, and fusion index. In vivo experiments were conducted on hind limb immobilization (HI)-induced mice to evaluate grip strength, muscle mass, and fiber cross-sectional area (CSA) of the gastrocnemius (GAS), quadriceps (QUA), and soleus (SOL) muscles. Molecular mechanisms were investigated through the analysis of key signaling pathways associated with muscle protein synthesis, energy metabolism, and protein degradation. FRG extract treatment enhanced viability of DEX-induced C2C12 myotubes and restored myotube diameter and fusion index. In HI-induced mice, FRG extract improved grip strength, increased muscle mass and CSA of GAS, QUA, and SOL muscles. Mechanistic studies revealed that FRG extract activated the insulin-like growth factor 1/protein kinase B (Akt)/mammalian target of rapamycin signaling pathway, promoted muscle energy metabolism via the sirtuin 1/peroxisome proliferator-activated receptor gamma-coactivator-1α pathway, and inhibited muscle protein degradation by suppressing the forkhead box O3a, muscle ring-finger 1, and F-box protein (Fbx32) signaling pathways. FRG extract shows promise for ameliorating muscle atrophy by modulating key molecular pathways associated with muscle protein synthesis, energy metabolism, and protein degradation, offering insights for future drug development. [ABSTRACT FROM AUTHOR]

This study investigated the antiobesity effects of black ginger extract (BGE) in high-fat diet (HFD)-induced obese mice. Mice were divided into six groups: normal diet control (NC, AIN-93G normal diet), 60% HFD control (HFD), HFD containing metformin at 250 mg/kg b.w. (Met, positive control), and HFD containing BGE at 5, 10, or 20 mg/kg b.w. for 15 weeks. BGE administration significantly prevented HFD-induced increases in weight gain, organ weight, and adipose tissue mass. Furthermore, it resulted in decreased adipogenesis and lipogenesis-related factors, including phosphorylated mitogen-activated protein kinase, peroxisome proliferator-activated receptor gamma, CCAAT/enhancer-binding proteins, sterol regulatory element-binding protein 1, phosphorylated cAMP response element-binding protein, glucose-6-phosphate dehydrogenase, fatty acid synthase, dephosphorylated ATP-citrate lyase, dephosphorylated acetyl-CoA carboxylase, and lipoprotein lipase, in white adipose tissues. Moreover, BGE administration enhanced lipolysis in white adipose tissue, as evidenced by elevated levels of adipose triglyceride lipase, phosphorylated hormone-sensitive lipase, and protein kinase A, along with reduced levels of perilipin and phosphodiesterase 3B. BGE induced thermogenesis in brown adipose tissues, as reflected by the increased expression of AMP-activated protein kinase, uncoupling protein 1, and carnitine palmitoyltransferase 1 and decreased levels of fatty acid-binding protein 4. In conclusion, this study provides comprehensive evidence supporting the antiobesity effects of BGE, elucidating the underlying molecular mechanisms involved in preventing weight gain, suppressing adipogenesis, promoting lipolysis, and stimulating thermogenesis. These findings suggest the potential therapeutic utility of BGE in combating obesity and associated metabolic disorders (KHGASP-2023-034). [ABSTRACT FROM AUTHOR]

[Display omitted] • TBN exerts neuroprotection in different PD models. • TBN alleviates oxidative damage and mitochondrial dysfunction. • The therapeutic effect of TBN is associated with activation of PGC-1α/Nrf2 pathway. • TBN is safe in Phase I study and could be a disease-modifying treatment for PD. Parkinson's disease (PD) is common neurodegenerative disease where oxidative stress and mitochondrial dysfunction play important roles in its progression. Tetramethylpyrazine nitrone (TBN), a potent free radical scavenger, has shown protective effects in various neurological conditions. However, the neuroprotective mechanisms of TBN in PD models remain unclear. We aimed to investigate TBN's neuroprotective effects and mechanisms in PD models. TBN's neuroprotection was initially measured in MPP+/MPTP-induced PD models. Subsequently, a luciferase reporter assay was used to detect peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) promoter activity. Effects of TBN on antioxidant damage and the PGC-1α/Nuclear factor erythroid-2-related factor 2 (Nrf2) pathway were thoroughly investigated. In MPP+-induced cell model, TBN (30–300 μM) increased cell survival by 9.95 % (P < 0.05), 16.63 % (P < 0.001), and 24.09 % (P < 0.001), respectively. TBN enhanced oxidative phosphorylation (P < 0.05) and restored PGC-1α transcriptional activity suppressed by MPP+ (84.30 % vs 59.03 %, P < 0.01). In MPTP-treated mice, TBN (30 mg/kg) ameliorated motor impairment, increased striatal dopamine levels (16.75 %, P < 0.001), dopaminergic neurons survival (27.12 %, P < 0.001), and tyrosine hydroxylase expression (28.07 %, P < 0.01). Selegiline, a positive control, increased dopamine levels (15.35 %, P < 0.001) and dopaminergic neurons survival (25.34 %, P < 0.001). Additionally, TBN reduced oxidative products and activated the PGC-1α/Nrf2 pathway. PGC-1α knockdown diminished TBN's neuroprotective effects, decreasing cell viability from 73.65 % to 56.87 % (P < 0.001). TBN has demonstrated consistent effectiveness in MPP+-induced midbrain neurons and MPTP-induced mice. Notably, the therapeutic effect of TBN in mitigating motor deficits and neurodegeneration is superior to selegiline. The neuroprotective mechanisms of TBN are associated with activation of the PGC-1α/Nrf2 pathway, thereby reducing oxidative stress and maintaining mitochondrial function. These findings suggest that TBN may be a promising therapeutic candidate for PD, warranting further development and investigation. [ABSTRACT FROM AUTHOR]

Endoplasmic reticulum (ER) stress is a major cause of hepatic steatosis through increasing de novo lipogenesis. Forkhead box O6 (FoxO6) is a transcription factor mediating insulin signaling to glucose and lipid metabolism. Therefore, dysregulated FoxO6 is involved in hepatic lipogenesis. This study elucidated the role of FoxO6 in ER stress–induced hepatic steatosis in vivo and in vitro. Hepatic ER stress responses and β-oxidation were monitored in mice overexpressed with constitutively active FoxO6 allele and FoxO6-null mice. For the in vitro study, liver cells overexpressing constitutively active FoxO6 and FoxO6-siRNA were treated with high glucose, and lipid metabolism alterations were measured. ER stress–induced FoxO6 activation suppressed hepatic β-oxidation in vivo. The expression and transcriptional activity of peroxisome proliferator-activated receptor α (PPARα) were significantly decreased in the constitutively active FoxO6 allele. Otherwise, inhibiting β-oxidation genes were reduced in the FoxO6-siRNA and FoxO6-KO mice. Our data showed that the FoxO6-induced hepatic lipid accumulation was negatively regulated by insulin signaling. High glucose treatment as a hyperglycemia condition caused the expression of ER stress–inducible genes, which was deteriorated by FoxO6 activation in liver cells. However, high glucose-mediated ER stress suppressed β-oxidation gene expression through interactions between PPARα and FoxO6 corresponding to findings in the in vivo study—lipid catabolism is also regulated by FoxO6. Furthermore, insulin resistance suppressed b-oxidation through the interaction between FoxO6 and PPARα promotes hepatic steatosis, which, due to hyperglycemia-induced ER stress, impairs insulin signaling. Key messages: Our original aims were to delineate the interrelation between the regulation of PPARα and the transcription factor FoxO6 pathway in relation to lipid metabolism at molecular levels. Evidence on high glucose promoted FoxO6 activation induced lipid accumulation in liver cells. The effect of PPARα activation of the insulin signaling. FoxO6 plays a pivotal role in hepatic lipid accumulation through inactivation of PPARα in FoxO6-overexpression mice. [ABSTRACT FROM AUTHOR]

The current understanding of the role of non-coding RNAs in the regulation of signaling pathways that control lipid accumulation and the development of inflammation in non-alcoholic fatty liver disease (NAFLD) is outlined. The contribution of peroxisome proliferator-activated receptors (PPARs) to changes in lipid metabolism and the formation of lipotoxicity as trigger mechanisms of NAFLD is considered. The role of TGFβ, TNFα/NF-κb, IL-6/JAK/STAT3 signaling pathways in the activation of stellate cells, liver fibrogenesis and the progression of NAFLD has been demonstrated. Analysis of literature data has revealed a number of microRNAs and long non-coding RNAs (lncRNAs) presumably associated with the regulation of these signaling pathways in this disease. They may probably have prognostic significance for differentiating clinical forms and severity of NAFLD. [ABSTRACT FROM AUTHOR]

Adriamycin is an anticancer anthracycline drug that inhibits the progression of topoisomerase II activity and causes apoptosis. The effective clinical application of the drug is very much limited by its adverse drug reactions on various tissues. Most importantly, Adriamycin causes cardiomyopathy, one of the life‐threatening complications of the drug. Altered expression of PPARγ in adipocytes inhibited the glucose and fatty acids uptake by down regulating GLUT4 and CD36 expression and causes cardiotoxicity. Therefore, the influence of Adriamycin in cardiac ailments was investigated in vivo and in vitro. Adriamycin treated rats showed altered ECG profile, arrhythmic heartbeat with the elevated levels of CRP and LDH. Dysregulated lipid profiles with elevated levels of cholesterol and triglycerides were also observed. Possibilities of cardiac problems due to cardiomyopathy were analyzed through histopathology. Adriamycin treated rats showed no signs for atheromatous plaque formation in aorta but disorganized cardiomyocytes with myofibrillar loss and inflammation in heart tissue, indicative of cardiomyopathy. Reduced levels of antioxidant enzymes confirmed the incidence of oxidative stress. Adriamycin treatment significantly reduced glucose and insulin levels, creating energy demand due to decreased glucose and insulin levels with increased fatty acid accumulation, ultimately resulting in oxidative stress mediated cardiomyopathy. Since PPARs play a vital role in regulating oxidative stress, the effect of Adriamycin on PPARγ was analyzed by western blot. Adriamycin downregulated PPARγ in a dose‐dependent manner in H9C2 cells in vitro. Overall, our study suggests that Adriamycin alters glucose and lipid metabolism via PPARγ inhibition that leads to oxidative stress and cardiomyopathy that necessitates a different therapeutic approach. [ABSTRACT FROM AUTHOR]

Background: Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant lung epithelial phenotypes, fibroblast activation, and increased extracellular matrix deposition. Transforming growth factor-beta (TGF-β)1-induced Smad signaling and downregulation of peroxisomal genes are involved in the pathogenesis and can be inhibited by peroxisome proliferator-activated receptor (PPAR)-α activation. However, the three PPARs, that is PPAR-α, PPAR-β/δ, and PPAR-γ, are known to interact in a complex crosstalk. Methods: To mimic the pathogenesis of lung fibrosis, primary lung fibroblasts from control and IPF patients with comparable levels of all three PPARs were treated with TGF-β1 for 24 h, followed by the addition of PPAR ligands either alone or in combination for another 24 h. Fibrosis markers (intra- and extracellular collagen levels, expression and activity of matrix metalloproteinases) and peroxisomal biogenesis and metabolism (gene expression of peroxisomal biogenesis and matrix proteins, protein levels of PEX13 and catalase, targeted and untargeted lipidomic profiles) were analyzed after TGF-β1 treatment and the effects of the PPAR ligands were investigated. Results: TGF-β1 induced the expected phenotype; e.g. it increased the intra- and extracellular collagen levels and decreased peroxisomal biogenesis and metabolism. Agonists of different PPARs reversed TGF-β1-induced fibrosis even when given 24 h after TGF-β1. The effects included the reversals of (1) the increase in collagen production by repressing COL1A2 promoter activity (through PPAR-β/δ activation); (2) the reduced activity of matrix metalloproteinases (through PPAR-β/δ activation); (3) the decrease in peroxisomal biogenesis and lipid metabolism (through PPAR-γ activation); and (4) the decrease in catalase protein levels in control (through PPAR-γ activation) and IPF (through a combined activation of PPAR-β/δ and PPAR-γ) fibroblasts. Further experiments to explore the role of catalase showed that an overexpression of catalase protein reduced collagen production. Additionally, the beneficial effect of PPAR-γ but not of PPAR-β/δ activation on collagen synthesis depended on catalase activity and was thus redox-sensitive. Conclusion: Our data provide evidence that IPF patients may benefit from a combined activation of PPAR-β/δ and PPAR-γ. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is increasingly recognized as being intertwined with the dysregulation of lipid metabolism. Lipids are a significant class of nutrients vital to all organisms, playing crucial roles in cellular structure, energy storage, and signaling. Alterations in the levels of various lipids in AD brains and dysregulation of lipid pathways and transportation have been implicated in AD pathogenesis. Clinically, evidence for a high-fat diet firmly links disrupted lipid metabolism to the pathogenesis and progression of AD, although contradictory findings warrant further exploration. In view of the significance of various lipids in brain physiology, the discovery of complex and diverse mechanisms that connect lipid metabolism with AD-related pathophysiology will bring new hope for patients with AD, underscoring the importance of lipid metabolism in AD pathophysiology, and promising targets for therapeutic intervention. Specifically, cholesterol, sphingolipids, and fatty acids have been shown to influence amyloid-beta (Ab) accumulation and tau hyperphosphorylation, which are hallmarks of AD pathology. Recent studies have highlighted the potential therapeutic targets within lipid metabolism, such as enhancing apolipoprotein E lipidation, activating liver X receptors and retinoid X receptors, and modulating peroxisome proliferator-activated receptors. Ongoing clinical trials are investigating the efficacy of these strategies, including the use of ketogenic diets, statin therapy, and novel compounds like NE3107. The implications of these findings suggest that targeting lipid metabolism could offer new avenues for the treatment and management of AD. By concentrating on alterations in lipid metabolism within the central nervous system and their contribution to AD development, this review aims to shed light on novel research directions and treatment approaches for combating AD, offering hope for the development of more effective management strategies. [ABSTRACT FROM AUTHOR]

AbstractObjectivesMethodsResultsConclusionsMetabolic disorders, as multifactorial disorders, are induced by genetic susceptibility and exposure to environmental chemicals. Di (2-ethyl hexyl) phthalate (DEHP), a ubiquitous plasticizer, is well known as an endocrine-disrupting chemical in living organisms. In recent decades, researchers have focused on the potential of DEHP and its main metabolite (Mono (2-ethylhexyl) phthalate) (MEHP) to induce metabolic disorders. In the present review, we aimed to summarize studies regarding DEHP and MEHP-induced Metabolic syndrome (MetS) as well as address the involved mechanisms.A search has been carried out in Google Scholar, PubMed, Scopus, and Web of Science databases using appropriate keywords including ‘Metabolic syndrome’ or ‘Metabolic disorder’ or ‘Obesity’ or ‘Hyperglycemia’ or ‘Hyperlipidemia’ or ‘Hypertension’ or ‘Non-alcoholic fatty liver disease’ and ‘DEHP’ or ‘Di (2-ethyl hexyl) phthalate’ or ‘Bis(2-ethylhexyl) phthalate’ or ‘MEHP’ or ‘Mono (2-ethylhexyl) phthalate’. Studies were chosen based on inclusion and exclusion criteria. Inclusion criteria are in vitro, in vivo, epidemiological studies, and English-written studies. Exclusion criteria are lack of access to the full text of studies, editorial articles, review articles, and conference articles.Animal studies indicate that DEHP and MEHP disrupt insulin hemostasis, increase glucose content, and induce hyperlipidemia and hypertension as well as obesity, which could lead to type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). DEHP and its metabolite induce such effects directly through influence on nuclear receptors such as peroxisome proliferator-activated receptors (PPARs) or indirectly through reactive oxygen species (ROS) production. Both events led to the disruption of several molecular signaling pathways and subsequently metabolic syndrome (MetS). Furthermore, epidemiological studies showed that there was a correlation between DEHP metabolites levels and obesity, hyperglycemia, and hypertension.According to studies, DEHP and its main metabolite have the potential to induce MetS by involving various molecular mechanisms. Epidemiological studies concerning the association of DEHP and MetS in humans are not sufficient. Therefore, more studies are needed in this regard. [ABSTRACT FROM AUTHOR]

The role of astroglial and microglial cells in the pathogenesis of epilepsy is currently under active investigation. It has been proposed that the activity of these cells may be regulated by the agonists of peroxisome proliferator-activated nuclear receptors (PPARs). This study investigated the effects of a seven-day treatment with the PPAR β/δ agonist GW0742 (Fitorine, 5 mg/kg/day) on the behavior and gene expression of the astroglial and microglial proteins involved in the regulation of epileptogenesis in the rat brain within a lithium–pilocarpine model of temporal lobe epilepsy (TLE). TLE resulted in decreased social and increased locomotor activity in the rats, increased expression of astro- and microglial activation marker genes (Gfap, Aif1), pro- and anti-inflammatory cytokine genes (Tnfa, Il1b, Il1rn), and altered expression of other microglial (Nlrp3, Arg1) and astroglial (Lcn2, S100a10) genes in the dorsal hippocampus and cerebral cortex. GW0742 attenuated, but did not completely block, some of these impairments. Specifically, the treatment affected Gfap gene expression in the dorsal hippocampus and Aif1 gene expression in the cortex. The GW0742 injections attenuated the TLE-specific enhancement of Nlrp3 and Il1rn gene expression in the cortex. These results suggest that GW0742 may affect the expression of some genes involved in the regulation of epileptogenesis. [ABSTRACT FROM AUTHOR]

Background: Heart failure (HF) is a serious and common condition affecting millions of people worldwide, with obesity being a major cause of metabolic disorders such as diabetes and cardiovascular disease. This study aimed to investigate the effects of fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARα) agonist, on the obese- and diabetes-related cardiomyopathy. Methods and results: We used db/db mice and high fat diet-streptozotocin induced diabetic mice to investigate the underlying mechanisms of fenofibrate's beneficial effects on heart function. Fenofibrate reduced fibrosis, and lipid accumulation, and suppressed inflammatory and immunological responses in the heart via TNF signaling. In addition, we investigated the beneficial effects of fenofibrate on HF hospitalization. The Korean National Health Insurance database was used to identify 427,154 fenofibrate users and 427,154 non-users for comparison. During the 4.22-year follow-up, fenofibrate use significantly reduced the risk of HF hospitalization (hazard ratio, 0.907; 95% CI 0.824–0.998). Conclusions: The findings suggest that fenofibrate may be a useful therapeutic agent for obesity- and diabetes-related cardiomyopathy. [ABSTRACT FROM AUTHOR]

Inflammation in the reproductive tract has become a serious threat to animal fertility. Recently, the role of peroxisome proliferator-activated receptor gamma (PPARγ) in the context of reproduction and the inflammatory response has been highlighted, but the role of PPARβ/δ has not been fully elucidated. The aim of the present study was to investigate the in vitro effect of PPARβ/δ ligands (agonist: L-165,041 and antagonist: GSK 3787) on the transcriptome profile of porcine endometrium during LPS-induced inflammation in the mid-luteal and follicular phases of the oestrous cycle (days 10–12 and 18–20, respectively) using the RNA-Seq method. During the mid-luteal phase of the oestrous cycle, the current study identified 145 and 143 differentially expressed genes (DEGs) after treatment with an agonist or antagonist, respectively. During the follicular phase of the oestrous cycle, 55 and 207 DEGs were detected after treatment with an agonist or antagonist, respectively. The detected DEGs are engaged in the regulation of various processes, such as the complement and coagulation cascade, NF-κB signalling pathway, or the pathway of 15-eicosatetraenoic acid derivatives synthesis. The results of the current study indicate that PPARβ/δ ligands are involved in the control of the endometrial inflammatory response. • PPARβ/δ ligands are involved in the control of the inflammatory response in the porcine endometrium. • PPARβ/δ ligands may regulate the endometrial inflammatory response by engaging multiple intracellular mechanisms. • Effects of PPARβ/δ ligands on the transcriptome of LPS-stimulated endometrium depends on the phase of the oestrous cycle. [ABSTRACT FROM AUTHOR]

Age-related macular degeneration (AMD) is a major cause of blindness that affects people over 60. While aging is the prominent factor in AMD, studies have reported a higher prevalence of AMD in women compared to age-matched men. Higher levels of the innate immune response's effector proteins complement factor B and factor I were also found in females compared to males in intermediate AMD. However, the mechanisms underlying these differences remain elusive. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) is a key regulator of mitochondrial biogenesis and metabolic pathways. Previously, we showed that Pgc-1α repression and high-fat diet induce drastic AMD-like phenotypes in mice. Our recent data revealed that Pgc-1α repression alone can also induce retinal pigment epithelium (RPE) and retinal dysfunction in mice, and its inhibition in vitro results in lipid droplet accumulation in human RPE. Whether sex is a contributing factor in these phenotypes remains to be elucidated. Using electroretinography, we demonstrate that sex could influence RPE function during aging independent of Pgc-1α in wild-type (WT) mice. We further show that Pgc-1α repression exacerbates RPE and retinal dysfunction in females compared to aged-match male mice. Gene expression analyses revealed that Pgc-1α differentially regulates genes related to antioxidant enzymes and mitochondrial dynamics in males and females. RPE flat mounts immunolabeled with TOMM20 and DRP1 indicated a sex-dependent role for Pgc-1α in regulating mitochondrial fission. Analyses of mitochondrial network morphology suggested sex-dependent effects of Pgc-1α repression on mitochondrial dynamics. Together, our study demonstrates that inhibition of Pgc-1α induces a sex-dependent decline in RPE and retinal function in mice. These observations on the sex-dependent regulation of RPE and retinal function could offer novel insights into targeted therapeutic approaches for age-related RPE and retinal degeneration. [ABSTRACT FROM AUTHOR]

Background: Breast cancer is the most diagnosed cancer in women. Its pathogenesis includes several pathways in cancer proliferation, apoptosis, and metastasis. Some clinical data have indicated the association between coffee consumption and decreased cancer risk. However, little data is available on the effect of coffee on breast cancer cells in vitro and in vivo. Methods: In our study, we assessed the effect of Turkish coffee and Fridamycin-H on different pathways in breast cancer, including apoptosis, proliferation, and oxidative stress. A human breast cancer cell line (MCF-7) was treated for 48 h with either coffee extract (5% or 10 v/v) or Fridamycin-H (10 ng/ml). Ehrlich solid tumors were induced in mice for in vivo modeling of breast cancer. Mice with Ehrlich solid tumors were treated orally with coffee extract in drinking water at a final concentration (v/v) of either 3%, 5%, or 10% daily for 21 days. Protein expression levels of Caspase-8 were determined in both in vitro and in vivo models using ELISA assay. Moreover, P-glycoprotein and peroxisome proliferator-activated receptor gamma (PPAR-γ) protein expression levels were analyzed in the in vitro model. β-catenin protein expression was analyzed in tumor sections using immunohistochemical analysis. In addition, malondialdehyde (MDA) serum levels were analyzed using colorimetry. Results: Both coffee extract and Fridamycin-H significantly increased Caspase-8, P-glycoprotein, and PPAR-γ protein levels in MCF-7 cells. Consistently, all doses of in vivo coffee treatment induced a significant increase in Caspase-8 and necrotic zones and a significant decrease in β- catenin, MDA, tumor volume, tumor weight, and viable tumor cell density. Conclusion: These findings suggest that coffee extract and Fridamycin-H warrant further exploration as potential therapies for breast cancer. [ABSTRACT FROM AUTHOR]

Adipose tissue is mainly composed by adipocytes. Moreover, mesenchymal stromal/stem cells (MSCs), macrophages, endothelial cells, and extracellular matrix components are present. The variety of molecules as cytokines and growth factors of its structure very rich in blood vessel makes it also similar to a true endocrine organ that however needs still to be fully investigated. In our study, we used human lipoaspirate to obtain mechanically microfragmented fat (MiFAT) which was washed and then devitalized by freezing–thawing cycles. In our experiments, thawed MiFAT was used to stimulate cultures of MSCs from two different sources (adipose tissue and gingiva papilla) in comparison with a traditional stimulation in vitro obtained by culturing MSCs with adipogenic medium. MSCs stimulated with MiFAT showed a very early production of lipid droplets, after only 3 days, that correlated with an increased expression of adipokines. Furthermore, a significant upregulation of PPAR gamma 1 alpha coactivator (PPARGC1A) was observed with an overexpression of uncoupling protein 1 (UCP1) that suggest a pattern of differentiation compatible with the beige–brown fat. [ABSTRACT FROM AUTHOR]

Grape seed proanthocyanidin extract (GSPE) is a natural polyphenolic compound, which plays an important role in anti-inflammatory and antioxidant. The present study aimed to investigate the effects of GSPE supplementation on the cholesterol metabolism and antioxidant status of finishing pigs. In longissimus dorse (LD) muscle, the data showed that GSPE significantly decreased the contents of total cholesterol (T-CHO) and triglyceride (TG), and decreased the mRNA expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoAR) and Fatty acid synthase (FAS), while increased the mRNA expression of carnitine palmitoyl transferase-1b (CPT1b), peroxisome proliferator-activated receptors (PPARα) and peroxisome proliferator activated receptor-γ coactivator-1α (PGC-1α). GSPE also reduced the enzyme activities of HMG-CoAR and FAS, and meanwhile amplified the activity of CPT1b in LD muscle of finishing pigs. Furthermore, dietary GSPE supplementation increased the serum catalase (CAT) and total antioxidant capacity (T-AOC), serum and liver total superoxide dismutase (T-SOD) and glutathione peroxidase (GSH-Px) levels, while reduced serum and liver malondialdehyde (MDA) level in finishing pigs. In the liver, Superoxide Dismutase 1 (SOD1), catalase (CAT), glutathione peroxidase 1 (GPX1), Nuclear Factor erythroid 2-Related Factor 2 (NRF2) mRNA levels were increased by GSPE. In conclusion, this study showed that GSPE might be an effective dietary supplement for improving cholesterol metabolism and antioxidant status in finishing pigs. [ABSTRACT FROM AUTHOR]

Aim: Hearing loss, affecting a significant portion of the global population, is prevented with peroxisome proliferator-activated receptor γ agonism. Understanding potential protective treatments is crucial for public health. We examine the effect of telmisartan, an antihypertensive drug and partial peroxisome proliferator-activated receptor γ agonist, on hearing loss in patients with hypertension. Method and results: This retrospective cohort analysis used data from the OMOP Common Data Model database, encompassing information from three tertiary institutions in South Korea. The study included a substantial sample size of 860,103 people diagnosed with hypertension. The study included individuals who had been medically diagnosed with hypertension and had been prescribed antihypertensive drugs, including telmisartan. The study design was established to evaluate the comparative effects of telmisartan and other hypertension medications on hearing loss. We used propensity score matching (PSM) to create a balanced cohort, reducing potential biases between the telmisartan and non-telmisartan groups. Fromthe initial 860,103 patients with hypertension, a propensity score matched cohort was derived from 20,010 patients, with 2,193 in the telmisartan group. After PSM, lower incidence of total hearing loss was observed in the telmisartan group compared to the non-telmisartan group during the 3-year follow-up (0.5% vs. 1.5%, log-rank p = 0.005). In subgroup analysis, this study showed consistent results that lower incidence of total hearing loss was higher in the telmisartan group than in the non-telmisartan group. Conclusion: Telmisartan was associated with reducing certain types of hearing loss in patients with hypertension. Further research is needed to confirm these findings and understand the mechanisms. [ABSTRACT FROM AUTHOR]

Aim Methods Results Conclusion Inflammation plays a critical role in the progression of diabetic nephropathy. Peroxisome proliferator‐activated receptor gamma (PPARγ) and its coactivator PPARγ coactivator‐1 alpha (PGC‐1α) enhance mitochondrial biogenesis and cellular energy metabolism but inhibit inflammation. However, the molecular mechanism through which these two proteins cooperate in the kidney remains unclear. The aim of the present study was to investigate this mechanism.HK‐2 human proximal tubular cells were stimulated by inflammatory factors, the expression of PPARγ and PGC‐1α were determined via reverse transcription‐quantitative polymerase chain reaction (PCR) and western blotting (WB), and DNA binding capacity was measured by an EMSA. Furthermore, db/db mice were used to establish a diabetic nephropathy model and were administered PPARγ and PGC‐1α activators. Kidney injury was evaluated microscopically, and the inflammatory response was assessed via WB, immunohistochemistry and immunofluorescence staining. Besides, HK‐2 cells were stimulated by high glucose and inflammatory factors with and without ZLN005 treatment, the expression of PPARγ, PGC‐1α, p‐p65 and p65 were determined via qPCR and WB.Our results revealed that both TNF‐α and IL‐1β significantly decreased PPARγ and PGC‐1 expression in vitro. Cytokines obviously decreased PPARγ DNA binding capacity. Moreover, we detected rapid activation of the NF‐κB pathway in the presence of TNF‐α or IL‐1β. PPARγ and PGC‐1α activators effectively protected against diabetic nephropathy and suppressed NF‐κB expression both in db/db mice and HK‐2 cells.PPARγ and its coactivator PGC‐1α actively participate in protecting against renal inflammation by regulating the NF‐κB pathway, which highlights their potential as therapeutic targets for renal diseases. [ABSTRACT FROM AUTHOR]

This review article explores the relationship between alpha-synuclein and mitochondrial dysfunction in Parkinson's disease (PD), focusing on the role of hypoxia as an intermediate factor. The interaction between alpha-synuclein and mitochondria, particularly through membranal lipids such as cardiolipins, is highlighted as a key factor in mitochondrial disruption and neurodegeneration. Hypoxia, caused by oxygen deprivation, is identified as a crucial link between alpha-synuclein and mitochondrial regulation, leading to neuronal death in PD. The article also discusses the involvement of other proteins, such as peroxisome proliferator-activated receptor gamma coactivator, Sirtuin-1, Sirtuin-3 and adenosine monophosphate-activated protein kinase, in maintaining mitochondrial biogenesis during hypoxia. The study emphasizes the need for further research to understand the complex molecular interactions causing Lewy body aggregation, improper mitochondrial functioning and neurodegeneration in PD, with a specific focus on the role of hypoxia. Alpha-synuclein aggregation disrupts mitochondrial respiration, leading to mitochondrial dysfunction and increased production of reactive oxygen species. Mitochondrial dysfunction, in turn, causes neurodegeneration in PD. Oligomeric alpha-synuclein results in mitochondrial dysfunction, lethal synaptic disruption and reduced adenosine triphosphate generation. Oligomeric alpha-synuclein also increases the accumulation of mitochondrial rho nucleotide guanosine triphosphate, leading to delayed mitophagy. Hypoxia, another factor in PD, alters both alpha-synuclein and mitochondria. Controlling hypoxia reduces the oligomerization of alpha-synuclein. The interaction between alpha-synuclein and mitochondria is complex, and determining the primary player in inducing the other is still debatable. [ABSTRACT FROM AUTHOR]

Objective：To study the protective effect of Eriodictyol preconditioning on cerebral ischemia/reperfusion (I/R) injury in rats and its mechanism. Methods：Ninety SD rats were randomly divided into sham operation group, model group, Eriodictyol low- dose group (17.5 mg/kg), Eriodictyol medium-dose group (35 mg/kg), Eriodictyol high-dose group (70 mg/kg) and high-dose group+ peroxisome proliferator-activated receptors δ (PPARδ) antagonist GSK3787 group (70 mg/kg Eriodictyol+300 μg/kg GSK3787), with 15 rats in each group. Rat model of cerebral I/R was established by bilateral common carotid artery occlusion combined with hypotension. Before modeling, different doses of Eriodictyol or GSK3787 were used to intervene rats. After 24 hours of I/R, the signs of neurological deficit were scored；the area of cerebral infarction in rats were observed by TTC staining；pathological changes of cerebral cortex was observed by HE staining；content of MDA and activity of SOD in cerebral cortex were detected by biochemical method；levels of IL-1β, IL-6 and TNF- α in cerebral cortex were detected by ELISA；protein expression levels of PPARδ, PPARγ coactivator-1α (PGC-1α) and NF-κB p65 in cerebral cortex were detected by Western blot. Results：Compared with sham operation group, pathological injury of brain tissue was serious, the sign score of neurological deficit, the area of cerebral infarction and contents of MDA, IL-1β, IL-6 and TNF-α in model group were increased significantly (P<0.05), while activity of SOD and protein expression levels of PPARδ and PGC-1α were decreased significantly (P<0.05), meanwhile, protein expression level of NF-κB p65 was increased significantly (P<0.05) . Compared with model group, pathological injury of brain tissue was reduced, the sign score of neurological deficit, cerebral infarcition area and contents of MDA, IL-1β, IL-6 and TNF-α in cerebral cortex of rats in different concentrations of Eriodictyol groups were decreased significantly (P<0.05), activity of SOD and protein expression levels of PPARδ and PGC-1α were increased significantly (P<0.05), meanwhile, protein expression level of NF-κB p65 was decreased significantly (P<0.05) . Compared with Eriodictyol high-dose group, GSK3787 combined intervention could significantly reduce the protective effect of Eriodictyol on cerebral I/R injury in rats (P<0.05) . Conclusion：Eriodictyol preconditioning has a good protective effect on cerebral I/R injury, and its mechanism may be related to the activation of PPARδ/PGC-1α signaling pathway [ABSTRACT FROM AUTHOR]

With aging populations in many countries, including Japan, efforts to mitigate the aging-related decline in physical function have gained importance not only for improving individual quality of life but also for mitigating the effects of this loss of function on society. Impaired glucose tolerance, muscle weakness, and cognitive decline are well-known effects of aging. These interrelated factors can create a vicious cycle because impaired glucose tolerance can accelerate muscle weakness and cognitive decline. Unmodulated 40 Hz (u40Hz) stimulation is imperceptible to the human ear and has been reported to improve cognitive function in humans and mice. However, research on the effects of u40Hz stimulation is still limited. This study aimed to report the effects of u40Hz stimulation on glucose tolerance and muscle strength in senescence-accelerated prone (SAMP)-10 mice, a model of accelerated aging. SAMP-10 mice underwent five weeks of u40Hz stimulation followed by glucose-tolerance tests, cognitive and behavioral assessments, and frailty evaluations. In comparison with the control group, the u40Hz-stimulation group showed mitigation of age-related decline in glucose tolerance, a better frailty index (FI), and notably preserved muscle strength. Microarray analysis of stimulated muscle tissue revealed significant upregulation of β-oxidation genes and genes functioning downstream of peroxisome proliferator-activated receptor gamma, and significant downregulation of clock genes. These findings indicate the beneficial effects of u40Hz stimulation on glucose tolerance, muscle strength, and cognitive function, warranting further research in this area. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the differentially expressed genes associated with intramuscular fat deposition in the longissimus dorsi muscle of Xinjiang Brown Bulls. The longissimus dorsi muscles of 10 Xinjiang Brown Bulls were selected under the same feeding conditions. The intramuscular fat content of muscle samples was determined by the Soxhlet extraction method, for which 5 samples with high intramuscular fat content (HIMF group) and 5 samples with low intramuscular fat content (LIMF group) were selected. It was found that the intramuscular fat content of the HIMF group was 46.054% higher than that of the LIMF group. Muscle samples produced by paraffin sectioning were selected for morphological observation. It was found that the fat richness of the HIMF group was better than that of the LIMF group. Transcriptome sequencing technology was used to analyze the gene expression differences of longissimus dorsi muscle. Through in-depth analysis of the longissimus dorsi muscle by transcriptome sequencing technology, we screened a total of 165 differentially expressed genes. The results of Gene Ontology (GO) enrichment analysis showed that the differentially expressed genes in the two groups were mainly clustered in biological pathways related to carbohydrate metabolic processes, redox processes and oxidoreductase activities. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that the differentially expressed genes were significantly clustered in 15 metabolic pathways, which mainly covered fatty acid metabolism (related to lipid metabolism and glucose metabolism), the pentose phosphate pathway, the Peroxisome Proliferator-Activated Receptor (PPAR) signaling pathway and other important metabolic processes. The three genes that were predominantly enriched in the glycolipid metabolic pathway by analysis were SCD5, CPT1C and FBP2, all of which directly or indirectly affect intramuscular fat deposition. In summary, the present study investigated the differences in gene expression between high and low intramuscular fat content in the longissimus dorsi muscle of Xinjiang Brown Bulls by transcriptome sequencing technology and revealed the related signaling pathways. Therefore, we hypothesized that SCD5, CPT1C and FBP2 were the key genes responsible for the significant differences in intramuscular fat content of the longissimus dorsi muscles in a population of Xinjiang Brown Bulls. We expect that these findings will provide fundamental support for subsequent studies exploring key genes affecting fat deposition characteristics in Xinjiang Brown Bulls. [ABSTRACT FROM AUTHOR]

Elafibranor (IQIRVO®) is a first-in-class peroxisome proliferator-activated receptor (PPAR) agonist being developed by Ipsen, under license from Genfit, for the treatment of primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). On 10 June 2024, elafibranor received accelerated approval based on reduction of alkaline phosphatase (ALP) in the USA for the treatment of PBC in combination with ursodeoxycholic acid (UDCA) in adults who have an inadequate response to UDCA, or as monotherapy in patients unable to tolerate UDCA. Elafibranor has also received a positive opinion in the EU. This article summarizes the milestones in the development of elafibranor leading to this first approval for PBC. [ABSTRACT FROM AUTHOR]

Aims As the interactions of alcohol and HIV/SIV infection and their impact on liver metabolic homeostasis remain to be fully elucidated, this study aimed to determine alcohol-mediated hepatic adaptations of metabolic pathways in SIV/ART-treated female rhesus macaques fed a nutritionally balanced diet. Methods Macaques were administered chronic binge alcohol (CBA; 13–14 g ethanol/kg/week for 14.5 months; n = 7) or vehicle (VEH; n = 8) for 14.5 months. Livers were excised following an overnight fast. Gene and protein expression, enzymatic activity, and lipid content were determined using frozen tissue and histological staining was performed using paraffin-embedded tissue. Results CBA/SIV macaques showed increased hepatic protein expression of electron transport Complex III and increased gene expression of glycolytic (phosphofructokinase and aldolase) and gluconeogenic (pyruvate carboxylase) enzymes and of genes involved in lipid turnover homeostasis (perilipin 1, peroxisome proliferator-activated receptor gamma, carbohydrate responsive binding protein, and acetyl-CoA carboxylase B) as compared to that of livers from the VEH/SIV group. Plasma triglyceride concentration had a significant positive association with liver triglyceride content in the CBA/SIV group. Conclusions These results reflect CBA-associated alterations in expression of proteins and genes involved in glucose and lipid metabolism homeostasis without significant evidence of steatosis or dysglycemia. Whether these changes predispose to greater liver pathology upon consumption of a high fat/high sugar diet that is more aligned with dietary intake of PWH and/or exposure to additional environmental factors warrants further investigation. [ABSTRACT FROM AUTHOR]

Significance: Mitochondria are recognized as a central metabolic hub with bioenergetic, biosynthetic, and signaling functions that tightly control key cellular processes. As a crucial component of mitochondrial biogenesis, peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) is involved in regulating various metabolic pathways, including energy metabolism and reactive oxygen species homeostasis. Recent Advances: Recent studies have highlighted the significant role of PGC-1α in tumorigenesis, cancer progression, and treatment resistance. However, PGC-1α exhibits pleiotropic effects in different cancer types, necessitating a more comprehensive and thorough understanding. Critical Issues: In this review, we discuss the structure and regulatory mechanisms of PGC-1α, analyze its cellular and metabolic functions, explore its impact on tumorigenesis, and propose potential strategies for targeting PGC-1α. Future Directions: The targeted adjustment of PGC-1α based on the metabolic preferences of different cancer types could offer a hopeful therapeutic approach for both preventing and treating tumors. Antioxid. Redox Signal. 41, 557–572. [ABSTRACT FROM AUTHOR]

Excessive fat deposition leads to obesity and cardiovascular diseases with abnormal metabolism. Pantothenic acid (PA) is a major B vitamin required for energy metabolism. However, the effect of PA on lipid metabolism and obesity has not been explored. We investigated the effects and molecular mechanism of PA on fat accumulation as well as the influence of adipogenic marker genes in both adult male mice and primary adipocytes. First, we demonstrated that PA attenuates weight gain in mice fed high-fat diet (HFD). Besides, PA supplementation substantially improved glucose tolerance and lipid metabolic disorder in obese mice. Furthermore, PA significantly inhibited white adipose tissue (WAT) deposition as well as fat droplets visualized by magnification in both chow and HFD group. More importantly, PA obviously suppressed the mRNA levels of CD36, IL-6, and TNF-α to alleviate inflammation and reduced the levels of PPARγ, aP2, and C/EBPα genes that are related to lipid metabolism in inguinal white adipose tissue (ing-WAT) and epididymal white adipose tissue (ei-WAT). In vitro, PA supplementation showed a lower lipid droplet aggregation as well as reduced expression levels of adipogentic genes. Finally, we identified that PA inhibits the phosphorylation levels of p38 and JNK in murine primary adipocytes. Collectively, our data demonstrated for the first time that PA attenuates lipid metabolic disorder as well as fat deposition by JNK/p38 MAPK signaling pathway. [ABSTRACT FROM AUTHOR]

Hypertriglyceridemia therapy is essential for preventing cardiovascular diseases. Fibrates belong to an important class of lipid-lowering drugs useful for the management of dyslipidaemia. By acting on the peroxisome proliferator-activated receptor (PPAR)-α, these drugs lower serum triglyceride levels and raise high-density lipoprotein cholesterol. Fibrate monotherapy is associated with a risk of myopathy and this risk is enhanced when these agents are administered together with statins. However, whereas gemfibrozil can increase plasma concentrations of statins, fenofibrate has less influence on the pharmacokinetics of statins. Pemafibrate is a new PPAR-α-selective drug considered for therapy, and clinical trials are ongoing. Apart from this class of drugs, new therapies have emerged with different mechanisms of action to reduce triglycerides and the risk of cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Simple Summary: In recent years, cancer has gradually become a terrible killer of human health. Due to various factors such as tumor heterogeneity and the complexity of the microenvironment, completely conquering cancer has always been a major problem in the scientific research community. Therefore, more detailed research and individualized treatment are essential. Everyone knows that tumor cells in the process of rapid proliferation need replenishing nutrients to sustain their energy supply. Intervention of tumor cell metabolism is gradually becoming a way to treat cancer. As an important transporter of glutamine, ASCT2 can uptake glutamine from the tumor microenvironment to support the growth and metabolism of cancer cells. Deficiency of ASCT2 can significantly inhibit tumor progression. However, not all patients benefit from this treatment. Our study aims to explore the metabolic heterogeneity of breast cancer and its related mechanisms, as well as to find metabolic-sensitive populations for further precision treatment. As a crucial amino acid, glutamine can provide the nitrogen and carbon sources needed to support cancer cell proliferation, invasion, and metastasis. Interestingly, different types of breast cancer have different dependences on glutamine. This research shows that basal-like breast cancer depends on glutamine, while the other types of breast cancer may be more dependent on glucose. Glutamine transporter ASCT2 is highly expressed in various cancers and significantly promotes the growth of breast cancer. However, the key regulatory mechanism of ASCT2 in promoting basal-like breast cancer progression remains unclear. Our research demonstrates the significant change in fatty acid levels caused by ASCT2, which may be a key factor in glutamine sensitivity. This phenomenon results from the mutual activation between ASCT2-mediated glutamine transport and lipid metabolism via the nuclear receptor PPARα. ASCT2 cooperatively promoted PPARα expression, leading to the upregulation of lipid metabolism. Moreover, we also found that C118P could inhibit lipid metabolism by targeting ASCT2. More importantly, this research identifies a potential avenue of evidence for the prevention and early intervention of basal-like breast cancer by blocking the glutamine–lipid feedback loop. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases remain the leading cause of death in the world, and that is why finding an effective and multi-functional treatment alternative to combat these diseases has become more important. Fibrates and thiazolidinediones, peroxisome proliferator-activated receptors alpha and gamma are the pharmacological therapies used to treat dyslipidemia and type 2 diabetes, respectively. New mechanisms of action of these drugs have been found, demonstrating their pleiotropic effects, which contribute to preserving the heart by reducing or even preventing myocardial damage. Here, we review the mechanisms underlying the cardioprotective effects of PPAR agonists and regulating morphological and physiological heart alterations (metabolic flexibility, mitochondrial damage, apoptosis, structural remodeling, and inflammation). Moreover, clinical evidence regarding the cardioprotective effect of PPAR agonists is also addressed. [ABSTRACT FROM AUTHOR]

Objectives Increasing studies demonstrated the importance of C5a and anti-neutrophil cytoplasmic antibody (ANCA)-induced neutrophil activation in the pathogenesis of ANCA-associated vasculitis (AAV). Sphingosine-1-phosphate (S1P) acts as a downstream effector molecule of C5a and enhances neutrophil activation induced by C5a and ANCA. The current study investigated the role of a S1P receptor modulator, FTY720, in experimental autoimmune vasculitis (EAV) and explored the immunometabolism-related mechanisms of FTY720 in modulating ANCA-induced neutrophil activation. Methods The effects of FTY720 in EAV were evaluated by quantifying haematuria, proteinuria, crescent formation, tubulointerstitial injury and pulmonary haemorrhage. RNA sequencing of renal cortex and gene enrichment analysis were performed. The proteins of key identified pathways were analysed in neutrophils isolated from peripheral blood of patients with active AAV and normal controls. We assessed the effects of FTY720 on ANCA-induced neutrophil respiratory burst and neutrophil extracellular traps formation (NETosis). Results FTY720 treatment significantly attenuated renal injury and pulmonary haemorrhage in EAV. RNA sequencing analyses of renal cortex demonstrated enhanced fatty acid oxidation (FAO) and peroxisome proliferator-activated receptor (PPAR) signalling in FTY720-treated rats. Compared with normal controls, patients with active AAV showed decreased FAO in neutrophils. FTY720-treated differentiated HL-60 cells showed increased expression of carnitine palmitoyltransferase 1a (CPT1a) and PPARα. Blocking or knockdown of CPT1a or PPARα in isolated human neutrophils and HL-60 cells reversed the inhibitory effects of FTY720 on ANCA-induced neutrophil respiratory burst and NETosis. Conclusion FTY720 attenuated renal injury in EAV through upregulating FAO via the PPARα–CPT1a pathway in neutrophils, offering potential immunometabolic targets in AAV treatment. [ABSTRACT FROM AUTHOR]

Non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, diclofenac, ibuprofen, or celecoxib have a well-established and unquestionable role in the human therapeutic arsenal, but still new perspectives are being discovered. This review presents new anti-inflammatory mechanisms of NSAIDs action, other than the classical one, i.e., the inhibition of cyclooxygenase (COX) isoforms leading to the prostanoids synthesis blockage. Literature data show that this group of drugs can activate anti-inflammatory peroxisome proliferator-activated receptor gamma (PPARγ), inhibit pro-inflammatory nuclear factor-κB (NF-κB) activation or modulate the components of the unfolded protein response (UPR) pathway. These alternative pathways induced by NSAIDs may not only enhance their basic anti-inflammatory mechanism of action but also promote other effects of the drugs such as anti-cancer. It was also proved that neuroinflammation, with the involvement of NF-κB, PPARγ and the components of the UPR pathway has an essential impact on the development of central nervous system (CNS) diseases. Thus, it seems possible that these new molecular targets may expand the use of NSAIDs, e.g., in the treatment of cancers and/or CNS disorders. [ABSTRACT FROM AUTHOR]

Presently, a major challenge is the search for new compounds that may exhibit an inhibitory effect on tumor progression. Recently, the 4-thiazolidinone (4-TZD) group has gained attention in this research field. The aim of the present study was to evaluate the anticancer effects of two new 4-TZD-based derivatives (Z)-5-[5-(2-hydroxyphenyl)- (Les- 4368) and (Z)-5-[5-(4-dimethylaminophenyl)-3-phenyl-4,5-dihydropyrazol-1-ylmethylene]-3-(3-acetoxyphenyl)-2-thioxothiazolidin-4-ones (Les-4370) on peroxisome proliferator-activated receptor gamma (PPARγ)-dependent cytotoxicity in human colorectal adenocarcinoma cells (CACO-2) and in normal human fibroblasts (BJ) in vitro. Les-4368 and Les-4370 exerted a toxic effect on both tested cell lines in high (micromolar) concentrations (10–100 µM). In addition, Les-4368 and Les-4370 applied in the BJ and CACO-2 cells in the concentration range of 10 µM to 100 µM increased the activity of caspase-3 and the production of reactive oxygen species (ROSs). The mRNA expression of PPARγ-related genes (PPARγ, AhR, PXR, and NF-κB) showed certain changes in these parameters, proving the engagement of this receptor in the induction of the biological effects of both tested 4-TZD derivatives. Moreover, the treatment of the BJ and CACO-2 cells with Les-4368, Les-4370, an antagonist (GW9662), or an agonist (rosiglitazone) of the PPARγ receptor also resulted in changes in the above-mentioned parameters. Unfortunately, the tested substances studied cell line work in a non-selective way at a relatively high concentration, which reduces their potential for clinical application. Our research is the preliminary study with the use of these compounds and requires further studies to elucidate the mechanisms of action of their anticancer potential. [ABSTRACT FROM AUTHOR]

Mitochondrial homeostasis is controlled by biogenesis, dynamics, and mitophagy. Mitochondrial dysfunction plays a central role in cardiovascular and renal disease and omega-3 fatty acids (FAs) are beneficial for cardiovascular disease. We investigated whether omega-3 fatty acids (FAs) regulate mitochondrial biogenesis, dynamics, and mitophagy in the kidney and heart of adenine-induced uremic rats. Eighteen male Sprague Dawley rats were divided into normal control, adenine control, and adenine with omega-3 FA groups. Using Western blot analysis, the kidney and heart expression of mitochondrial homeostasis-related molecules, including peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), dynamin-related protein 1 (Drp1), and phosphatase and tensin homolog-induced putative kinase 1 (PINK1) were investigated. Compared to normal, serum creatinine and heart weight/body weight in adenine control were increased and slightly improved in the omega-3 FA group. Compared to the normal controls, the expression of PGC-1α and PINK1 in the kidney and heart of the adenine group was downregulated, which was reversed after omega-3 FA supplementation. Drp1 was upregulated in the kidney but downregulated in the heart in the adenine group. Drp1 expression in the heart recovered in the omega-3 FA group. Mitochondrial DNA (mtDNA) was decreased in the kidney and heart of the adenine control group but the mtDNA of the heart was recovered in the omega-3 FA group. Drp1, which is related to mitochondrial fission, may function oppositely in the uremic kidney and heart. Omega-3 FAs may be beneficial for mitochondrial homeostasis by activating mitochondrial biogenesis and PINK1-dependent mitophagy in the kidney and heart of uremic rats. [ABSTRACT FROM AUTHOR]

Applying cold to a bone injury can aid healing, though its mechanisms are complex. This study investigates how cold therapy impacts bone repair to optimize healing. Cold was applied to a rodent bone model, with the physiological responses analyzed. Vasoconstriction was mediated by an increase in the transient receptor protein channels (TRPs), transient receptor potential ankyrin 1 (TRPA1; p = 0.012), and transient receptor potential melastatin 8 (TRPM8; p < 0.001), within cortical defects, enhancing the sensory response and blood flow regulation. Cold exposure also elevated hypoxia (p < 0.01) and vascular endothelial growth factor expression (VEGF; p < 0.001), promoting angiogenesis, vital for bone regeneration. The increased expression of osteogenic proteins peroxisome proliferator-activated receptor gamma coactivator (PGC-1α; p = 0.039) and RNA-binding motif protein 3 (RBM3; p < 0.008) suggests that the reparative processes have been stimulated. Enhanced osteoblast differentiation and the presence of alkaline phosphatase (ALP) at day 5 (three-fold, p = 0.021) and 10 (two-fold, p < 0.001) were observed, along with increased osteocalcin (OCN) at day 10 (two-fold, p = 0.019), indicating the presence of mature osteoblasts capable of mineralization. These findings highlight cold therapy's multifaceted effects on bone repair, offering insights for therapeutic strategies. [ABSTRACT FROM AUTHOR]

This study aimed to determine the effects of Myrtus communis L. fruit extract on the diabetes-related glycemic and lipid profile, some serum biochemical parameters, and mRNA expression of some endogenous substances in type 2 diabetes. A total of 54 healthy male Swiss albino mice were divided into 5 groups. Except for the mice in the healthy control group, the mice in the other group were fed high-fat diets, and streptozotocin (50 mg/kg) was administered. No medication was administered to the animals in the diabetes control group. Metformin (200 mg/kg), Myrtus communis L. fruit extract (2 g/kg), and metformin + Myrtus communis L. fruit extract were administered orally to D+ metformin, D + Myrtus communis L. fruit extract, and D + Myrtus communis L. fruit extract+ metformin groups for 14 days, respectively. In serum samples, glucose, triglyceride, cholesterol, aspartate aminotransferase, alanine aminotransferase, and blood urea nitrogen were measured with an autoanalyzer and hemoglobin A1C (Hb1Ac) was measured with an Hb1Ac analyzer. Adiponectin, insulin, leptin, and adenosine monop hosph ate-a ctiva ted protein kinase levels were analyzed in an ELISA reader in serum samples. The mRNA expressions of glucose transporter-1 (GLUT-1), glucose transporter-4 (GLUT-4), peroxisome proliferator-activated receptor-a (PPAR-a), and peroxisome proliferator-activated receptor-α (PPAR-γ) in the liver and striated muscles were determined with real-time polymerase chain reaction. Compared to the diabetic control group, Myrtus communis L. fruit extract significantly improved serum glucose, cholesterol, and triglyceride levels (p < .05) and significantly increased serum adiponectin, AMPK, and leptin levels (p < .05). The Myrtus communis L. fruit extract Myrtus communis significantly increased GLUT-1, PPAR-a, and PPAR-α mRNA expressions in striated muscle tissue (p < .05) but did not cause any changes in the liver. In conclusion, it may be stated that the Myrtus communis L. fruit extract had a significant positive impact on both glucose and lipid metabolism. Further studies are needed to elucidate the mechanisms of action of Myrtus communis L. fruit extract and its application in human diabetes treatment. [ABSTRACT FROM AUTHOR]

The most prevalent chronic liver disease, known as metabolic dysfunction-associated steatotic liver disease (MASLD), is characterized by an excessive accumulation of lipids and oxidative damage. Clinopodium gracile, a natural herbal medicine widely used by Chinese folk, has antioxidative, anti-inflammatory, and lipid metabolism-regulating effects. Here, we explored the effect of C. gracile extract (CGE) on MASLD using palmitic acid (PA)-induced hepatocytes and high-fat diet (HFD)-fed mice. In vitro, CGE could promote fatty acid oxidation and inhibit fatty acid synthesis and uptake to reduce lipid accumulation by regulating PPARα activation. Moreover, CGE could inhibit reactive oxygen species production and maintain mitochondrial homeostasis in PA-induced HepG2 cells. In vivo, animal study results indicated that CGE could effectively reduce lipid metabolism disorder, inhibit oxidative stress, and upregulate PPARα protein in the liver of HFD-fed mice. Molecular docking results also showed that active compounds isolated from CGE had low binding energy and highly stable binding with PPARα. In summary, these findings reveal that CGE may be a potential therapeutic candidate for MASLD and act by upregulating PPARα to reduce lipid accumulation and suppress mitochondrial oxidative damage. [ABSTRACT FROM AUTHOR]

Adipogenesis involves intricate molecular mechanisms regulated by various transcription factors and signaling pathways. In this study, we aimed to identify factors specifically induced during adipogenesis in the human preadipocyte cell line, SGBS, but not in the mouse preadipocyte cell line, 3T3-L1. Microarray analysis revealed distinct gene expression profiles, with 1460 genes induced in SGBS cells and 1297 genes induced in 3T3-L1 cells during adipogenesis, with only 297 genes commonly induced. Among the genes uniquely induced in SGBS cells, we focused on GALNT15, which encodes polypeptide N-acetylgalactosaminyltransferase-15. Its expression increased transiently during adipogenesis in SGBS cells but remained low in 3T3-L1 cells. Overexpression of GALNT15 increased mRNA levels of CCAAT-enhancer binding protein (C/EBPα) and leptin but had no significant impact on adipogenesis in SGBS cells. Conversely, knockdown of GALNT15 suppressed mRNA expression of adipocyte marker genes, reduced lipid accumulation, and decreased the percentage of cells with oil droplets. The induction of C/EBPα and peroxisome proliferator-activated receptor γ during adipogenesis was promoted or suppressed in SGBS cells subjected to overexpression or knockdown of GALNT15, respectively. These data suggest that polypeptide N-acetylgalactosaminyltransferase-15 is a novel regulatory molecule that enhances adipogenesis in SGBS cells. [ABSTRACT FROM AUTHOR]

Obesity has become a global issue that affects the emergence of various chronic diseases such as diabetes mellitus, dysplasia, heart disorders, and cancer. In this study, an integration method was developed between the metabolite profile of the active compound of Murraya paniculata and the exploration of the targeting mechanism of adipose tissue using network pharmacology, molecular docking, molecular dynamics simulation, and in vitro tests. Network pharmacology results obtained with the skyline query technique using a block-nested loop (BNL) showed that histone acetyltransferase p300 (EP300), peroxisome proliferator-activated receptor gamma (PPARG), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A) are potential targets for treating obesity. Enrichment analysis of these three proteins revealed their association with obesity, thermogenesis, energy metabolism, adipocytokines, fat cell differentiation, and glucose homeostasis. Metabolite profiling of M. paniculata leaves revealed sixteen active compounds, ten of which were selected for molecular docking based on drug-likeness and ADME results. Molecular docking results between PPARG and EP300 with the ten active compounds showed a binding affinity value of ≤ -5.0 kcal/mol in all dockings, indicating strong binding. The stability of the protein-ligand complex resulting from docking was examined using molecular dynamics simulations, and we observed the best average root mean square deviation (RMSD) of 0.99 Å for PPARG with trans-3-indoleacrylic acid, which was lower than with the native ligand BRL (2.02 Å). Furthermore, the RMSD was 2.70 Å for EP300 and the native ligand 99E, and the lowest RMSD with the ligand (1R,9S)-5-[(E)-2-(4-Chlorophenyl)vinyl]-11-(5-pyrimidinylcarbonyl)-7,11-diazatricyclo[7.3.1.02,7]trideca-2,4-dien-6-one was 3.33 Å. The in vitro tests to validate the potential of M. paniculata in treating obesity showed that there was a significant decrease in PPARG and EP300 gene expressions in 3T3-L1 mature adipocytes treated with M. paniculata ethanolic extract starting at concentrations 62.5 μg/ml and 15.625 μg/ml, respectively. These results indicate that M. paniculata can potentially treat obesity by disrupting adipocyte maturation and influencing intracellular lipid metabolism. [ABSTRACT FROM AUTHOR]

This study aimed to explore the protective mechanism of Banxia Xiexin Tang (BXXXT) on liver cell damage caused by high glucose (H-G) and to clarify its molecular regulatory pathways. First, the main components in BXXXT-containing serum were analyzed by high-performance liquid chromatography (HPLC) to provide basic data for subsequent experiments. Subsequently, the effect of BXXXT on high glucose (H-G)-induced hepatocyte activity was evaluated through screening of the optimal concentration of drug-containing serum. Experimental results showed that BXXXT significantly reduced the loss of cell activity caused by high glucose. Further research focuses on the regulatory effect of BXXXT on high glucose-induced hepatocyte apoptosis, especially its effect on the PGC-1α (peroxisome proliferator-activated receptor γ coactivator-1α) pathway. Experimental results showed that BXXXT reduced high-glucose-induced hepatocyte apoptosis and exerted its protective effect by upregulating the activity of the PGC-1α pathway. BXXXT significantly increased the expression level of IGFBP1 (insulin-like growth factor-binding proteins) in hepatocytes under a high-glucose environment. It cleared mitochondrial ROS (reactive oxygen species) by enhancing SOD2 (superoxide dismutase) enzyme activity and maintained the survival of hepatocytes under a high-glucose environment. Finally, the regulation of PGC-1α by BXXXT is indeed involved in the regulation of IGFBP1 expression in hepatocytes and its downstream SOD2 effector signaling. Taken together, this study provides an in-depth explanation of the protective mechanism of BXXXT on hepatocytes in a high-glucose environment, focusing on regulating the expression of the PGC-1α pathway and IGFBP1, and reducing cell damage by scavenging ROS. This provides an experimental basis for further exploring the potential of BXXXT in the treatment of diabetes-related liver injury. [ABSTRACT FROM AUTHOR]

Liver cancer is the 4th most lethal form of cancer with a poor prognosis for patients worldwide. Dysregulation of lipid metabolism is related to FA oxidation alternation which can be modified by peroxisome proliferator-activated receptor-α (PPARα). Therefore, it is important to identify the lipid metabolism-related genes regulated by PPARα in liver cancer. Hub genes related to the lipid metabolism pathway of HCC samples treated with PPARα agonist (WY-14,643) were identified through a weighted gene co-expression network analysis (WGCNA). Gene expression and clinical information were obtained from the Gene Expression Omnibus (GEO) database. The network of top main hub genes was visualized by the Cytoscape software using MCODE and CytoHubba plugins. Finally, the expression and clinical association of each hub gene were evaluated using enrichment analysis, TCGA data, GEPIA, GSCA, and q-PCR. Based on our results, the top 5 co-expressed genes including (CPT2, ACSL1, ACSL3, ACOX1, and SLC27A2) were selected as the main hub genes participating in fatty acid metabolism, fatty acid beta-oxidation, and PPAR signaling pathway. All association of higher ACSL3 expression with lower outcomes and survival rates was detected in HCC patients. Therefore, lipid metabolism-related Hub genes regulated by PPARα are potential biomarkers, and they may offer a therapeutical foundation for targeted therapy directed against the HCC antitumor strategy. [ABSTRACT FROM AUTHOR]