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Objective: In this study, we performed RNA sequencing (RNA-seq) on the abdominal aorta tissue of New Zealand rabbits and investigated the potential association of lncRNA TCONS_02443383 with the development of AS through bioinformatics analysis of the sequencing data. The obtained results were further validated using quantitative real-time polymerase chain reaction (qRT-PCR)., Method: We induced an AS model in New Zealand rabbits by causing balloon injury to the abdominal aorta vascular wall and administering a high-fat diet. We then upregulated the expression level of the lncRNA TCONS_02443383 by injecting lentiviral plasmids through the ear vein. RNA sequencing (RNA-seq) was performed on the abdominal aorta tissues. We conducted Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway and Gene Ontology (GO) analyses., Result: The overexpression of the lncRNA TCONS_02443383 led to an upregulation of peroxisome proliferator-activated receptor (PPAR) signaling pathways as well as genes related to cell adhesion., Conclusion: The overexpression of the lncRNA TCONS_02443383 can inhibit the occurrence and development of AS by upregulating peroxisome proliferator-activated receptor (PPAR) signaling pathways and genes related to cell adhesion., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide; however, effective intervention strategies for NAFLD are still unavailable. The present study sought to investigate the efficacy of chiglitazar, a pan-PPAR agonist, in protecting against NAFLD in mice and its underlying molecular mechanism. Male C57BL/6 J mice were fed a high-fat diet (HFD) for 8 weeks to generate NAFLD and the HFD was continued for an additional 10 weeks in the absence or presence of 5 mg/kg/d or 10 mg/kg/d chiglitazar by gavage. Chiglitazar significantly improved dyslipidemia and insulin resistance, ameliorated hepatic steatosis and reduced liver inflammation and oxidative stress in NAFLD mice. RNA-seq revealed that chiglitazar alleviated HFD-induced NAFLD in mice through multiple pathways, including fatty acid metabolism regulation, insulin signaling pathway, and AMPK signaling pathway. This study demonstrated the potential therapeutic effect of chiglitazar on NAFLD. Chiglitazar ameliorated NAFLD by modulating multiple pathways., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Phthalates are a class of known endocrine-disrupting chemicals that are found in common everyday products. Several studies associate phthalate exposure with detrimental effects on ovarian function, including growth and development of the follicle and production of steroid hormones. We hypothesized that dysregulation of the ovary by phthalates may be mediated by phthalate toxicity towards granulosa cells, a major cell type in ovarian follicles responsible for key steps of hormone production and nourishing the developing oocyte. To test the hypothesis that phthalates target granulosa cells, we harvested granulosa cells from adult CD-1 mouse ovaries and cultured them for 96 h in vehicle control, a phthalate mixture, or a phthalate metabolite mixture (0.1 to 100 μg/ml). After culture, we measured metabolism of the phthalate mixture into monoester metabolites by the granulosa cells, finding that granulosa cells do not significantly contribute to ovarian metabolism of phthalates. Immunohistochemistry of phthalate metabolizing enzymes in whole ovaries confirmed that these enzymes are not strongly expressed in granulosa cells of antral follicles and that ovarian metabolism of phthalates likely occurs primarily in the stroma. RNA sequencing of treated granulosa cells identified 407 differentially expressed genes, with overrepresentation of genes from lipid metabolic processes, cholesterol metabolism, and peroxisome proliferator-activated receptor (PPAR) signaling pathways. Expression of significantly differentially expressed genes related to these pathways was confirmed using qPCR. Our results agree with previous findings that phthalates and phthalate metabolites have different effects on the ovary, but both interfere with PPAR signaling in granulosa cells., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Obesity and type 2 diabetes (T2D) are widespread metabolic disorders that significantly impact global health today, affecting approximately 17% of adults worldwide with obesity and 9.3% with T2D. Both conditions are closely linked to disruptions in lipid metabolism, where peroxisomes play a pivotal role. Mitochondria and peroxisomes are vital organelles responsible for lipid and energy regulation, including the β-oxidation and oxidation of very long-chain fatty acids (VLCFAs), cholesterol biosynthesis, and bile acid metabolism. These processes are significantly influenced by estrogens, highlighting the interplay between these organelles' function and hormonal regulation in the development and progression of metabolic diseases, such as obesity, metabolic dysfunction-associated fatty liver disease (MAFLD), and T2D. Estrogens modulate lipid metabolism through interactions with nuclear receptors, like peroxisome proliferator-activated receptors (PPARs), which are crucial for maintaining metabolic balance. Estrogen deficiency, such as in postmenopausal women, impairs PPAR regulation, leading to lipid accumulation and increased risk of metabolic disorders. The disruption of peroxisomal-mitochondrial function and estrogen regulation exacerbates lipid imbalances, contributing to insulin resistance and ROS accumulation. This review emphasizes the critical role of these organelles and estrogens in lipid metabolism and their implications for metabolic health, suggesting that therapeutic strategies, including hormone replacement therapy, may offer potential benefits in treating and preventing metabolic diseases.

Background: Organophosphate esters (OPEs) exposure could affect offspring health. However, the underlying mechanisms are not well documented., Objectives: Based on a birth cohort study, we aimed to investigate the associations among gestational OPEs exposure, placental DNA methylation levels of peroxisome proliferator-activated receptor (PPAR) signaling pathway-related genes, and fetal growth., Methods: We measured the concentrations of eight OPE metabolites in maternal urine samples and neonatal anthropometric measurements in 733 mother-child pairs. In 327 placental samples, we assessed the DNA methylation levels of 14 genes which were involved in the PPARs signaling pathway and expressed in placenta. Multiple linear regression models were used to examine the associations of OPEs exposure with placental DNA methylation, and of OPEs and placental DNA methylation with neonatal anthropometric measurements. Causal mediation analyses were conducted to examine the potential mediating role of placental DNA methylation in the pathway between OPEs exposure and fetal growth., Results: We observed a general pattern of OPEs exposure being associated with hypermethylation of candidate genes, with statistically significant associations identified for several OPEs with RXRA, ACAA1, ACADL, ACADM, PLTP, and NR1H3 methylation. Further, gestational exposure to BCIPP, DPP, BBOEP, ∑NCl-OPEs, and ∑OPEs tended to be associated with lower anthropometric measurements, with more significant associations observed on arm circumference, and abdominal and back skinfold thickness. Notably, RXRA, ACAA1, ACOX1, CPT2, ACADM, and NR1H3 methylation tended to be associated with lower neonatal anthropometric measurements, especially for abdominal and back skinfold thickness. Moreover, mediation analyses showed that 19.42 % of the total effect of DPP on the back skinfold thickness was mediated by changes in RXRA methylation, and there was a significant indirect effect of RXRA methylation., Conclusions: Gestational OPEs exposure could disrupt the placental DNA methylation levels of PPAR signaling pathway-related genes, which might contribute to the effect of OPEs on fetal growth., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that sense lipophilic molecules and act as transcription factors to regulate target genes. PPARs have been implicated in the regulation of innate immunity, glucose and lipid metabolism, cell proliferation, wound healing, and fibrotic processes. Some synthetic PPAR ligands are promising molecules for the treatment of inflammatory and fibrotic processes in immune-mediated intestinal diseases. Some of these are currently undergoing or have previously undergone clinical trials. Dietary PPAR ligands and changes in microbiota composition could modulate PPARs' activation to reduce inflammatory responses in these immune-mediated diseases, based on animal models and clinical trials. This narrative review aims to summarize the role of PPARs in immune-mediated bowel diseases and their potential therapeutic use.

Introduction: "Peroxisome Proliferator-Activated Receptors" (PPARs) belong to the class of transcription factors (TF) identified as Nuclear Receptors (NR). Upon activation by peroxisome proliferators (PPs), PPARs modulate a diverse range of genes, consequently regulating intra-cellular lipid metabolism, glucose uptake, apoptosis, and cell proliferation. Subsequent to the heterodimerization of Retinoid X Receptors (RXR) with PPARs induced by the binding of activators to PPARs, facilitates the binding of the resulting complex to Peroxisome Proliferator-Activated Receptors Response Elements (PPRE), with a consensus sequence 5'AGGTCANAGGTCA-3', and regulate the transcription of the targeted genes., Methods: A comprehensive screening of PPRE within the whole human genome was performed using the Genome Workbench and UCSC Genome Browser to find the associated genes. Subsequently, the kinase subset was isolated from the extracted list of PPRE-related genes. Functional enrichment of the kinases was performed using FunRich, ToppGene, and ShinyGO. Network analysis and enrichment studies were then further performed using NDEx to elucidate these identified kinases' connections and significance. Additionally, the disease association of the PPRE kinases was analyzed using DisGeNET data in R studio and the COSMIC dataset., Results: A comprehensive analysis of 1002 PPRE sequences within the human genome (T2T), yielded the identification of 660 associated genes, including 29 kinases. The engagement of these kinases in various biological pathways, such as apoptosis, platelet activation, and cytokine pathways, revealed from the functional enrichment analysis, illuminates the multifaceted role of PPAR in the regulation of cellular homeostasis and biological processes. Network analysis reveals the kinases interact with approximately 5.56% of the Human Integrated Protein-Protein Interaction rEference (HIPPIE) network. Disease association analysis using DisGeNET and COSMIC datasets revealed the significant roles of these kinases in cellular processes and disease modulation., Discussion: This study elucidates the regulatory role of PPAR-associated genes and their association with numerous biological pathways. The involvement of the kinases with disease-related pathways highlights new potential for the development of therapeutic strategies designed for disease management and intervention., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Saha and Talwar.)

With the increase of cadmium content in the environment, the losses caused by cadmium-induced intestinal diseases to animal husbandry are increasing year by year. However, most of the on-going research activities focus on zoonotic diseases rather than exploring the mechanisms of animal disease occurrence from an anthropogenic environmental perspective. In this study, stressed Hu sheep under cadmium environmental exposure were selected to explore the mechanism of inflammatory bowel disease development. 16 s, untargeted metabolomics and transcriptomic multiomics were used to analyze the changes of their intestinal tract and intestinal contents. The results showed that the beneficial microorganisms (s_Ruminococcus_sp) in the Cd group were significantly decreased and the potentially harmful microorganisms were significantly enriched, and the changes of these microorganisms affected the changes of metabolites (caprylic acid) to a certain extent, resulting in a decrease in fatty acids in the intestine. Due to the combined effect of cadmium ion and fatty acid reduction, the PPAR signaling pathway was inhibited, and the fatty acid transport and binding were further reduced, causing very serious damage to the intestine. We revealed for the first time the mechanism of intestinal injury in Hu sheeps under cadmium environmental exposure and provided new prevention and treatment methods of intestinal diseases under the environmental exposure to trace metals., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The synthetic phenolic antioxidant 2,4-di-tert-butylphenol (2,4-DTBP) is an emergent contaminant and can disrupt the delicate balance of aquatic ecosystems. This study aimed to investigate 2,4-DTBP-induced hepatotoxicity in common carp and the underlying mechanisms involved. Sixty common carp were divided into four groups and exposed to 0 mg/L, 0.01 mg/L, 0.1 mg/L or 1 mg/L 2,4-DTBP for 30 days. Here, we first demonstrated that 2,4-DTBP exposure caused liver damage, manifested as hepatocyte nuclear pyknosis, inflammatory cell infiltration and apoptosis. Moreover, 2,4-DTBP exposure induced hepatic reactive oxygen species (ROS) overload and disrupted antioxidant capacity, as indicated by the reduced activity of the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px). In addition, transmission electron microscopy revealed that 2,4-DTBP exposure induced autophagosome accumulation in the liver of common carp. Western blot analysis further revealed that 2,4-DTBP exposure significantly decreased the protein levels of mTOR and increased the LC3II/LC3I ratio. Furthermore, 2,4-DTBP exposure inhibited lysozyme (LZM) and alkaline phosphatase (AKP) activity; decreased immunoglobulin M (IgM), complement 3 (C3), and complement 4 (C4) levels in the serum; increased the mRNA levels of proinflammatory cytokines (NF-κB, TNF-α, IL-1β and IL-6); and increased the mRNA levels of three types of proliferator-activated receptors (PPARs) (α, β/δ and γ). Molecular docking revealed that 2,4-DTBP directly binds to the internal active pocket of PPARs. Overall, we concluded that 2,4-DTBP exposure in aquatic systems could induce hepatotoxicity in common carp by regulating autophagy and controlling inflammatory responses. The present study provides new insights into the hepatotoxicity mechanism induced by 2,4-DTBP in aquatic organisms and furthers our understanding of the effects of 2,4-DTBP on public health and ecotoxicology., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (© 2024. The Author(s).)

Perfluorooctanoic acid (PFOA), a persistent organic pollutant known for its chemical stability, is widely dispersed in the environment, posing significant health risks to mammals through various exposure routes such as ingestion, inhalation, and dermal contact. In this study, mice were exposed to PFOA (0, 0.2, 2 mg/L) through drinking water for 180 days to investigate its toxic effects on the colon. We identified differentially expressed genes through RNA sequencing and validated the impact of PFOA on the expression of these genes in colon tissue. Our findings revealed that long-term exposure to PFOA caused inflammatory bowel disease (IBD)-like damage to the mouse colon. We found PFOA could induce damage to the intestinal barrier. Inhibition of the Wnt signaling pathway following PFOA exposure results in impaired stem cell function in the colon of mice. Furthermore, PFOA activated the PPAR signaling pathway, disrupting cellular lipid metabolism in colon tissues. Additionally, PFOA induced inflammatory responses in colon tissue, facilitating NLR family, pyrin domain containing 3 (NLRP3) inflammasome activation and cell apoptosis. This study offers a thorough understanding of the mechanisms responsible for the damage to mouse colon tissue resulting from long-term exposure to PFOA., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Acupuncture combined with nucleos(t)ide analogues (NAs) has shown promise in treating chronic hepatitis B (CHB), though mechanisms remain unclear. This study evaluates the antiviral effects of combining acupuncture with NAs against hepatitis B virus (HBV) and explores underlying mechanisms., Methods: The HBV-infected mouse model, established using the high-pressure hydrodynamic method, was divided into three groups: normal saline (NS), tenofovir disoproxil fumarate (TF), and electroacupuncture combined with TF (E_T), n = 6. Antiviral effects were assessed by monitoring HBV DNA, HBsAg, and HBeAg levels weekly. Mechanistic insights were gained via transcriptomics, metabolomics, and 16S rDNA sequencing, validated by WB, PCR, and flow cytometry., Results: Serum HBV DNA levels decreased by 1.98 log 10 IU/mL in TF and 2.2 log 10 IU/mL in E_T groups compared to NS. Serum HBeAg decreased by 10.61 % in TF and 35.75 % in E_T, while HBsAg decreased by 7.38 % and 37.58 %, respectively. Multi-omics indicated E_T modulates the PPAR pathway, upregulates taurine and all-trans-retinoic acid, and increases gut microbiota like Bacteroides and Blautia. E_T also enhanced tight junction proteins (ZO-1, Occludin, Claudin-4), improving intestinal barrier integrity. Mechanistically, E_T inhibited the PGC-1α/PPAR-α/SIRT1 pathway, reducing PGC-1α, PPAR-α, SIRT1, RXRα, and HNF4α, while promoting JAK/STAT signaling via IFN-γ, p-JAK1, p-JAK2, p-STAT1, IRF8, and suppressing SOCS-1., Conclusion: E_T more effectively inhibited HBV replication, showing superior antigen inhibition, particularly HBsAg, than TF alone. This may be due to PPAR-JAK/STAT pathway regulation, suggesting E_T as a potential adjuvant therapy for CHB, especially in achieving a functional cure., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Aim: This study sought to evaluate the effects of LDT409, a pan-PPAR partial agonist obtained from the main industrial waste from cashew nut processing, on hepatic remodeling, highlighting energy metabolism and endoplasmic reticulum (ER) stress in high-fructose-fed mice., Methods: Male C57BL/6 mice received a control diet (C) or a high-fructose diet (HFRU) for ten weeks. Then, a five-week treatment started: C, C-LDT409, HFRU, and HFRU-LDT409. The LDT409 (40 mg/kg of body weight) was mixed with the diets., Results: The HFRU diet caused insulin resistance and endoplasmic reticulum (ER) stress. High Pparg and decreased Ppara expression increased steatosis and pro-fibrogenic gene expression in livers of HFRU-fed mice. Suppressed lipogenic factors, orchestrated by PPAR-gamma, and mitigated ER stress concomitant with the increase in beta-oxidation driven by PPAR-alpha mediated the LDT409 beneficial effects., Conclusions: LDT409 may represent a potential low-cost approach to treat metabolic dysfunction-associated steatotic liver disease, which does not currently have a specific treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Low or insufficient testosterone levels caused by caponization promote fat deposition in animals. However, the molecular mechanism of fat deposition in caponized animals remains unclear. This study aimed to investigate the metabolomics and transcriptomic profiles of adipose tissues and study the effect of testosterone and leptin on the proliferation of adipocytes. We observed a significant enlargement in the areas of adipocytes in the abdominal fat tissues in capon, as well as increased luciferase activity of the serum leptin and a sharp decrease in the serum testosterone in caponized gander. Metabolomics and transcriptomic results revealed differentially expressed genes and differentially expressed metabolites with enhanced PARR signal pathway. The mRNA levels of peroxisome proliferators-activated receptor γ, fatty acid synthase, and suppressor of cytokine signaling 3 in goose primary pre-adipocytes were significantly upregulated with high leptin treatment and decreased significantly with increasing testosterone dose. Hence, reduced testosterone and increased leptin levels after caponization possibly promoted adipocytes proliferation and abdominal fat deposition by altering the expression of PPAR pathway related genes in caponized ganders. This study provides a new direction for the mechanism through which testosterone regulates the biological function of leptin and fat deposition in male animals.

Respirable metal oxide nanoparticles in welding fumes pose significant health risks upon inhalation, potentially leading to neurodegenerative diseases. While the exact mechanisms remain unclear, it is evident that metal oxide nanoparticles can disrupt cellular functions, including metabolism and inflammatory responses after crossing the blood-brain barrier (BBB). Our study investigates the impact of manual metal arc welding fumes on hormone receptor transcription in an in vivo mouse model. After collecting samples from six different brain regions at 24 and 96 h upon exposure, we focused on expression levels of estrogen receptors (ERs), thyroid hormone receptors (TRs), and peroxisome proliferator-activated receptors (PPARs) due to their roles in modulating neuroprotective responses and neuroinflammatory processes. Analysis revealed differential susceptibility of brain regions to hormonal disruption induced by welding fumes, with the hypothalamus (HT) and olfactory bulb (OB) showing prominent changes in receptor expression. Considering ERs, 24 h sampling showed an elevation in OB, with later increases in both ERα and ERβ. HT showed significant ERβ change only by 96 h. TRs mirrored ER patterns, with notable changes in OB and less in HT. PPARγ followed TR trends, with early upregulation in HT and downregulation elsewhere. These findings suggest a compensatory response within the CNS aimed at mitigating neuroinflammatory effects, as evidenced by the upregulation of ERβ, TRα, and PPARγ. The coordinated increase in ERs, TRs, and PPARs in the hypothalamus and olfactory bulb also highlights their potential neuroprotective roles in response to welding fume exposure. Our results also support the theory of metal oxide penetration to the CNS via the lungs-blood-BBB pathway, making HT and OB more vulnerable to welding fume exposure., (© 2024. The Author(s).)

Permethrin (Per) is a widely used and frequently detected pyrethroid pesticide in agricultural products and the environment. It may pose potential toxicity to non-target organisms. Per has been reported to affect lipid homeostasis, although the mechanism is undefined. This study aims to explore the characteristic transcriptomic profiles and clarify the underlying signaling pathways of Per-induced lipid metabolism disorder in zebrafish liver. The results showed that environmental exposure to Per caused changes in the liver index, histopathology, and oxidative stress in zebrafish. Moreover, transcriptome results showed that Per heavily altered the pathways involved in metabolism, the immune system, and the endocrine system. We conducted a more in-depth analysis of the genes associated with lipid metabolism. Our findings revealed that exposure to Per led to a disruption in lipid metabolism by activating the KRAS-PPAR-GLUT signaling pathways through oxidative stress. The disruption of lipid homeostasis caused by exposure to Per may also contribute to obesity, hepatitis, and other diseases. The results may provide new insights for the risk of Permethrin to aquatic organisms and new horizons for the pathogenesis of hepatotoxicity., Competing Interests: Declaration of competing interest No potential conflict of interest was reported by the authors., (Copyright © 2024. Published by Elsevier B.V.)

Cholestatic liver diseases, including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), result from an impairment of bile flow that leads to the hepatic retention of bile acids, causing liver injury. Until recently, the only approved treatments for PBC were ursodeoxycholic acid (UDCA) and obeticholic acid (OCA). While these therapies slow the progression of PBC in the early stage of the disease, approximately 40% of patients respond incompletely to UDCA, and advanced cases do not respond. UDCA does not improve survival in patients with PSC, and patients often have dose-limiting pruritus reactions to OCA. Left untreated, these diseases can progress to fibrosis and cirrhosis, resulting in liver failure and the need for transplantation. These shortcomings emphasize the urgent need for alternative treatment strategies. Recently, nuclear hormone receptors have been explored as pharmacological targets for adjunct therapy because they regulate enzymes involved in bile acid metabolism and detoxification. In particular, the peroxisome proliferator-activated receptor (PPAR) has emerged as a therapeutic target for patients with PBC or PSC who experience an incomplete response to UDCA. PPARα is predominantly expressed in the liver, and it plays an essential role in the regulation of cytochrome P450 (CYP) and uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes, both of which are critical enzyme families involved in the regulation of bile acid metabolism and glucuronidation, respectively. Importantly, PPARα agonists, e.g., fenofibrate, have shown therapeutic benefits in reducing elevated markers of cholestasis in patients with PBC and PSC, and elafibranor, the first PPAR (dual α, β/δ) agonist, has been FDA-approved for the second-line treatment of PBC. Additionally, newer PPAR agonists that target various PPAR isoforms (β/δ, γ) are under development as an adjunct therapy for PBC or PSC, although their impact on glucuronidation pathways are less characterized. This review will focus on PPAR-mediated bile acid glucuronidation as a therapeutic pathway to improve outcomes for patients with PBC and PSC.

Rationale: Peroxisome proliferator-activated receptors (PPARs) are transcription factors that regulate various physiological processes such as inflammation, lipid metabolism, and glucose homeostasis. Recent studies suggest that targeting PPARs could be beneficial in treating neuropsychiatric disorders by modulating neuronal function and signaling pathways in the brain. PPAR-α, PPAR-δ, and PPAR-γ have been found to play important roles in cognitive function, neuroinflammation, and neuroprotection. Dysregulation of PPARs has been associated with neuropsychiatric disorders like bipolar disorder, schizophrenia, major depression disorder, and autism spectrum disorder. The limitations and side effects of current treatments have prompted research to target PPARs as a promising novel therapeutic strategy. Preclinical and clinical studies have shown the potential of PPAR agonists and antagonists to improve symptoms associated with these disorders., Objective: This review aims to provide an overview of the current understanding of PPARs in neuropsychiatric disorders, their potential as therapeutic targets, and the challenges and future directions for developing PPAR-based therapies., Methods: An extensive literature review of various search engines like PubMed, Medline, Bentham, Scopus, and EMBASE (Elsevier) databases was carried out with the keywords "PPAR, Neuropsychiatric disorders, Oxidative stress, Inflammation, Bipolar Disorder, Schizophrenia, Major depression disorder, Autism spectrum disorder, molecular pathway"., Result & Conclusion: Although PPARs present a hopeful direction for innovative therapeutic approaches in neuropsychiatric conditions, additional research is required to address obstacles and convert this potential into clinically viable and individualized treatments., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Diabetic nephropathy (DN) is one of the most important comorbidities for diabetic patients, which is the main factor leading to end-stage renal disease. Heparin analogs can delay the progression of DN, but the mechanism is not fully understood. In this study, we found that low molecular weight heparin therapy significantly upregulated some downstream proteins of the peroxisome proliferator-activated receptor (PPAR) signaling pathway by label-free quantification of the mouse kidney proteome. Through cell model verification, low molecular weight heparin can protect the heparan sulfate of renal tubular epithelial cells from being degraded by heparanase that is highly expressed in a high-glucose environment, enhance the endocytic recruitment of fatty acid-binding protein 1, a coactivator of the PPAR pathway, and then regulate the activation level of intracellular PPAR. In addition, we have elucidated for the first time the molecular mechanism of heparan sulfate and fatty acid-binding protein 1 interaction. These findings provide new insights into understanding the role of heparin in the pathogenesis of DN and developing corresponding treatments., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Obesity is a common public health issue and is currently deemed a disease. Research has shown that the risk of gallstones in individuals with obesity is elevated. This study aimed to explore the bile proteomics differences between cholelithiasis patients with obesity and normal body weight., Methods: Bile samples from 20 patients (10 with obesity and 10 with normal body weight) who underwent laparoscopic cholecystectomy at our center were subjected to tandem mass tag labeling (TMT) and liquid chromatography-tandem mass spectrometry (LC-MS/MS), followed by further bioinformatic analysis., Results: Among the differentially expressed proteins, 23 were upregulated and 67 were downregulated. Bioinformatic analysis indicated that these differentially expressed proteins were mainly involved in cell development, inflammatory responses, glycerolipid metabolic processes, and protein activation cascades. In addition, the activity of the peroxisome proliferator-activated receptor (PPAR, a subfamily of nuclear receptors) signaling pathway was decreased in the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Two downregulated proteins in the PPAR signaling pathway, APO A-I and APO A-II, were confirmed using enzyme-linked immunosorbent assay., Conclusions: The PPAR signaling pathway may play a crucial role in the development of cholelithiasis among patients with obesity. Furthermore, biliary proteomics profiling of gallstones patients with obesity is revealed, providing a reference for future research., (Copyright © 2023 First Affiliated Hospital, Zhejiang University School of Medicine in China. Published by Elsevier B.V. All rights reserved.)

The long noncoding RNA growth arrest-specific 5 (lncRNA Gas5) is implicated in various kidney diseases. In this study, we investigated the lncRNA Gas5 expression profile and its critical role as a potential biomarker in the progression of chronic kidney disease. Subsequently, we assessed the effect of lncRNA Gas5 deletion on renal fibrosis induced by unilateral ureteral obstruction (UUO). The results indicated that loss of lncRNA Gas5 exacerbates UUO-induced renal injury and extracellular matrix deposition. Notably, the deletion of lncRNA Gas5 had a similar effect on control mice. The fibrogenic phenotype observed in mice lacking lncRNA Gas5 correlates with peroxisome proliferator-activated receptor (PPAR) signaling pathway activation and aberrant cytokine and chemokine reprogramming. Single-cell RNA sequencing analysis revealed key transcriptomic features of fibroblasts after Gas5 deletion, revealing heterogeneous cellular states suggestive of a propensity for renal fibrosis. Our findings indicate that lncRNA Gas5 regulates the differentiation and activation of immune cells and the transcription of key genes in the PPAR signaling pathway. These data offer novel insights into the involvement of lncRNA Gas5 in renal fibrosis, potentially paving the way for innovative diagnostic and therapeutic targets., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Hepatocellular carcinoma (HCC) holds a prominent position among global cancer types. Classically, HCC manifests in individuals with a genetic predisposition when they encounter risk elements, particularly in the context of liver cirrhosis. Peroxisome proliferator-activated receptors (PPARs), which are transcription factors activated by fatty acids, belong to the nuclear hormone receptor superfamily and play a pivotal role in the regulation of energy homeostasis. At present, three distinct subtypes of PPARs have been recognized: PPARα, PPARγ, and PPARβ/δ. They regulate the transcription of genes responsible for cellular development, energy metabolism, inflammation, and differentiation. In recent years, with the rising incidence of HCC, there has been an increasing focus on the mechanisms and roles of PPARs in HCC. PPARα primarily mediates the occurrence and development of HCC by regulating glucose and lipid metabolism, inflammatory responses, and oxidative stress. PPARβ/δ is closely related to the self-renewal ability of liver cancer stem cells (LCSCs) and the formation of the tumor microenvironment. PPARγ not only influences tumor growth by regulating the glucose and lipid metabolism of HCC, but its agonists also have significant clinical significance for the treatment of HCC. Therefore, this review offers an exhaustive examination of the role of the three PPAR subtypes in HCC progression, focusing on their mediation of critical cellular processes such as glucose and lipid metabolism, inflammation, oxidative stress, and other pivotal signaling pathways. At the end of the review, we discuss the merits and drawbacks of existing PPAR-targeted therapeutic strategies and suggest a few alternative combinatorial therapeutic approaches that diverge from conventional methods., Competing Interests: Declaration of Competing Interest We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Chronic obstructive pulmonary disease (COPD), an inflammatory lung disease, causes approximately 3 million deaths each year; however, its pathological mechanisms are not fully understood. In this study, we examined whether HX110B, a mixture of Taraxacum officinale, Dioscorea batatas, and Schizonepeta tenuifolia extracts, could suppress porcine pancreatic elastase (PPE)-induced emphysema in mice and its mechanism of action. The therapeutic efficacy of HX110B was tested using a PPE-induced emphysema mouse model and human bronchial epithelial cell line BEAS-2B. In vivo data showed that the alveolar wall and air space expansion damaged by PPE were improved by HX110B administration. HX110B also effectively suppresses the expression levels of pro-inflammatory mediators including IL-6, IL-1β, MIP-2, and iNOS, while stimulating the expression of lung protective factors such as IL-10, CC16, SP-D, and sRAGE. Moreover, HX110B improved the impaired OXPHOS subunit gene expression. In vitro analysis revealed that HX110B exerted its effects by activating the PPAR-RXR signaling pathways. Overall, our data demonstrated that HX110B could be a promising therapeutic option for COPD treatment., Competing Interests: All authors are the employees of Helixmith Co., Ltd. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Lee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: The study of cardiotoxicity of drugs has become an important part of clinical safety evaluation of drugs. It is commonly known that podophyllotoxin (PPT) and its many derivatives and congeners are broad-spectrum pharmacologically active substances. Clinical cardiotoxicity of PPT and its derivatives has been raised, basic research on the mechanism of cardiotoxicity remains insufficient., Purpose: In present study, our group's innovative concept of toxicological evidence chain (TEC) was applied to reveal the cardiac toxicity mechanism of PPT by targeted metabolomics, TMT-based quantitative proteomics and western blot., Methods: The injury phenotype evidence (IPE) acquired from the toxicity manifestations, such as weight and behavior observation of Sprague-Dawley rat. The damage to rat hearts were assessed through histopathological examination and myocardial enzymes levels, which were defined as Adverse Outcomes Evidence (AOE). The damage to rat hearts was assessed through histopathological examination and myocardial enzyme levels, which were defined as evidence of adverse outcomes.Overall measurements of targeted metabolomics based on energy metabolism and TMT-based quantitative proteomics were obtained after exposure to PPT to acquire the Toxic Event Evidence (TEE). The mechanism of cardiac toxicity was speculated based on the integrated analysis of targeted metabolomics and TMT-based quantitative proteomics, which was verified by western blot., Results: The results indicated that exposure to PPT could result in significant elevation of myocardial enzymes and pathological alterations in rat hearts. In addition, we found that PPT caused disorders in cardiac energy metabolism, characterized by a decrease in energy metabolism fuels. TMT-based quantitative proteomics revealed that the PPAR (Peroxisome proliferators-activated receptor) signaling pathway needs further study. It is worth noting that PPT may suppress the expression of SIRT1, subsequently inhibiting AMPK, decreasing the expression of PGC-1α, PPARα and PPARγ. This results in disorders of glucose oxidation, glycolysis and ketone body metabolism. Additionally, the increase in the expression of p-IKK and p-IκBα, leads to the nuclear translocation of NF-κB p65 from the cytosol, thus triggering inflammation., Conclusion: This study comprehensively evaluated cardiac toxicity of PPT and initially revealed the mechanism of cardiotoxicity,suggesting that PPT induced disorders of energy metabolism and inflammation via SIRT1/PPAR/NF-κB axis, potentially contributing to cardiac injury., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier GmbH.)

Podophyllotoxin (PPT) is a lignan derived from the roots and stems of the Podophyllum plant. However, its enterotoxicity restricts its clinical application. The underlying mechanisms by which PPT exerts its action remain largely elusive. This study aimed to evaluate the molecular mechanisms underlying PPT-induced enterotoxicity utilizing the concept of toxicological evidence chain. Changes in body weight, behavior, and histopathological and biochemical markers in rats were observed. Additionally, microbiome, metabolome, and transcriptome analyses were integrated to identify potential microorganisms, metabolic markers, and major pathways using a co-occurrence network. Our findings suggested that PPT induced pathological changes in rats, including weight loss, diarrhea, and inflammation accompanied by increased levels of IFN-γ, IL-5, IL-6, GRO/KC, and IL-12p70. The decrease in butyrate levels in the PPT group may be related to the enrichment of Firmicutes. The reduction of butyrate levels may impair the expression of PPARγ, subsequently promoting Escherichia-Shigella proliferation. Additionally, the suppression of PPARs pathway may result in the increased production of inflammatory factors, contributing to enterotoxicity. This study offers a novel understanding of the molecular mechanisms underlying PPT-induced enterotoxicity, making a significant contribution to developing strategies to mitigate PPT toxicity and prevent associated diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Xiaozhi formula (XZF) is a practical Chinese herbal formula for the treatment of non-alcoholic fatty liver disease (NAFLD), which possesses an authorized patent certificate issued by the State Intellectual Property Office of China (ZL202211392355.0). However, the underlying mechanism by which XZF treats NAFLD remains unclear., Purpose: This study aimed to explore the main component of XZF and its mechanism of action in NAFLD treatment., Methods: UHPLC-Q-Orbitrap HRMS was used to identify the components of the XZF. A high-fat diet (HFD)-induced NAFLD mouse model was used to demonstrate the effectiveness of XZF. Body weight, liver weight, and white fat weight were recorded to evaluate the therapeutic efficacy of XZF. H&E and Oil Red O staining were applied to observe the extent of hepatic steatosis. Liver damage, lipid metabolism, and glucose metabolism were detected by relevant assay kits. Moreover, the intraperitoneal insulin tolerance test and the intraperitoneal glucose tolerance test were employed to evaluate the efficacy of XZF in insulin homeostasis. Hepatocyte oxidative damage markers were detected to assess the efficacy of XZF in preventing oxidative stress. Label-free proteomics was used to investigate the underlying mechanism of XZF in NAFLD. RT-qPCR was used to calculate the expression levels of lipid metabolism genes. Western blot analysis was applied to detect the hepatic protein expression of AMPK, p-AMPK, PPARɑ, CPT1, and PPARγ., Results: 120 compounds were preliminarily identified from XZF by UHPLC-Q-Orbitrap HRMS. XZF could alleviate HFD-induced obesity, white adipocyte size, lipid accumulation, and hepatic steatosis in mice. Additionally, XZF could normalize glucose levels, improve glucolipid metabolism disorders, and prevent oxidative stress damage induced by HFD. Furthermore, the proteomic analysis showed that the major pathways in fatty acid metabolism and the PPAR signaling pathway were significantly impacted by XZF treatment. The expression levels of several lipolytic and β-oxidation genes were up-regulated, while the expression of fatty acid synthesis genes declined in the HFD + XZF group. Mechanically, XZF treatment enhanced the expression of p-AMPK, PPARɑ, and CPT-1 and suppressed the expression of PPARγ in the livers of NAFLD mice, indicating that XZF could activate the AMPK and PPAR pathways to attenuate NALFD progression., Conclusion: XZF could attenuate NAFLD by moderating lipid metabolism by activating AMPK and PPAR signaling pathways., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Evodiae Fructus (EF), an herbal medicine, possesses remarkable anti-inflammatory and analgesic properties. It exhibits insecticidal activity as a potent insecticide candidate. However, the toxic characteristics of EF and the underlying mechanisms have not been comprehensively elucidated comprehensively. Thus, we comprehensively explored the toxic components of EF and established the relationship between the therapeutic and toxic effects of EF, encouraging its therapeutic use. We found that evodiamine (EVO), one of the main ingredients of EF, can truly reflect its analgesic properties. In phenotype observation trials, low doses of EVO (< 35 ng/mL) exhibited distinct analgesic activity without any adverse effects in zebrafish. However, EVO dose-dependently led to gross morphological abnormalities in the liver, followed by pericardial edema, and increased myocardial concentrations. Furthermore, the toxic effects of EVO decreased after processing in liver microsomes but increased after administering CYP450 inhibitors in zebrafish, highlighting the prominent effect of CYP450s in EVO-mediated hepatotoxicity. EVO significantly changed the expression of genes enriched in multiple pathways and biological processes, including lipid metabolism, inflammatory response, tight junction damage, and cell apoptosis. Importantly, the PPAR/PI3K/AKT/NF-кB/tight junction-mediated apoptosis pathway was confirmed as a critical functional signaling pathway inducing EVO-mediated hepatotoxicity. This study provided a typical example of the overall systematic evaluation of traditional Chinese medicine (TCM) and its active ingredients with significant therapeutic effects and simultaneous toxicities, especially metabolic toxicities., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

This year marks the 35th anniversary of Professor Walter Wahli's discovery of the PPARs (Peroxisome Proliferator-Activated Receptors) family of nuclear hormone receptors. To mark the occasion, the editors of the scientific periodical Biomolecules decided to publish a special issue in his honor. This paper summarizes what is known about PPARs and shows how trends have changed and how research on PPARs has evolved. The article also highlights the importance of PPARs and what role they play in various diseases and ailments. The paper is in a mixed form; essentially it is a review article, but it has been enriched with the results of our experiments. The selection of works was subjective, as there are more than 200,000 publications in the PubMed database alone. First, all papers done on an animal model were discarded at the outset. What remained was still far too large to describe directly. Therefore, only papers that were outstanding, groundbreaking, or simply interesting were described and briefly commented on.

Objective: The prevalence of metabolic diseases is increasing globally at an alarming rate; thus, it is essential that effective, accessible, low-cost therapeutics are developed. Peroxisome proliferator-activated receptors (PPARs) are transcription factors that tightly regulate glucose homeostasis and lipid metabolism and are important drug targets for the treatment of type 2 diabetes and dyslipidemia. We previously identified LDT409, a fatty acid-like compound derived from cashew nut shell liquid, as a novel pan-active PPARα/γ/δ compound. Herein, we aimed to assess the efficacy of LDT409 in vivo and investigate the molecular mechanisms governing the actions of the fatty acid mimetic LDT409 in diet-induced obese mice., Methods: C57Bl/6 mice (6-11-month-old) were fed a chow or high fat diet (HFD) for 4 weeks; mice thereafter received once daily intraperitoneal injections of vehicle, 10 mg/kg Rosiglitazone, 40 mg/kg WY14643, or 40 mg/kg LDT409 for 18 days while continuing the HFD. During treatments, body weight, food intake, glucose and insulin tolerance, energy expenditure, and intestinal lipid absorption were measured. On day 18 of treatment, tissues and plasma were collected for histological, molecular, and biochemical analysis., Results: We found that treatment with LDT409 was effective at reversing HFD-induced obesity and associated metabolic abnormalities in mice. LDT409 lowered food intake and hyperlipidemia, while improving insulin tolerance. Despite being a substrate of both PPARα and PPARγ, LDT409 was crucial for promoting hepatic fatty acid oxidation and reducing hepatic steatosis in HFD-fed mice. We also highlighted a role for LDT409 in white and brown adipocytes in vitro and in vivo where it decreased fat accumulation, increased lipolysis, induced browning of WAT, and upregulated thermogenic gene Ucp1. Remarkably, LDT409 reversed HFD-induced weight gain back to chow-fed control levels. We determined that the LDT409-induced weight-loss was associated with a combination of increased energy expenditure (detectable before weight loss was apparent), decreased food intake, increased systemic fat utilization, and increased fecal lipid excretion in HFD-fed mice., Conclusions: Collectively, LDT409 represents a fatty acid mimetic that generates a uniquely favorable metabolic response for the treatment of multiple abnormalities including obesity, dyslipidemia, metabolic dysfunction-associated steatotic liver disease, and diabetes. LDT409 is derived from a highly abundant natural product-based starting material and its development could be pursued as a therapeutic solution to the global metabolic health crisis., Competing Interests: Declaration of competing interest CLC, LASR, and LM are co-authors on a patent related to this work. They wish to pursue collaborations to further develop LDT409 as an orally bioavailable low-cost therapy to treat obesity-related metabolic disease., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

We have previously reported the total synthesis and structure-activity relationships (SAR) of 2-prenylated benzopyrans with PPAR agonist activity. Herein, we have described the synthesis and PPAR activity of 2-prenylated benzopyrans and 2-prenylated quinolines. The benzopyran nucleus was generated via enamine-catalyzed Kabbe condensation, and the quinoline nucleus via Friedländer condensation. Results demonstrated that both benzopyran (5a) and quinoline (4b) derivatives bearing a γ,δ-unsaturated ester displayed a pan-PPAR agonism. They were full PPARα agonists, but showed different preferences for PPARγ and PPARβ/δ activation. It was noteworthy that quinoline 4b displayed full hPPARα activation (2-fold than WY-14,643), weak PPARβ/δ and partial PPARγ activation. In addition, quinoline 4b showed anti-inflammatory effects on macrophages by reducing LPS-induced expression of both MCP-1 and IL-6. Therefore, 4b emerges as a first-in-class promising hit compound for the development of potential therapeutics aimed at treating metabolic syndrome, metabolic dysfunction-associated fatty liver disease (MAFLD), and its associated cardiovascular comorbidities., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Aim: This study explores the efficacy of electroacupuncture (EA) in treating cerebral palsy (CP) in Sprague-Dawley (SD) pups, specifically CP animal models, and its molecular mechanisms., Methods: Gait analysis and Y-maze were used to detect the improvement of motor ability and cognitive function of CP rats after EA treatment. Transcription sequencing was used to determine the key pathway for EA to improve the symptoms of CP. PPAR agonists were used to verify the causal relationship between the pathway and the improvement of CP phenotype., Results: The motor ability and cognitive function of CP pups were improved after EA treatment. The results of transcriptome sequencing suggest that the improvement of CP phenotype may be caused by the activation of PPAR pathway. PPAR pathway is widely activated in the epithelium of CP pups treated with EA, which is verified by qPCR. Rosiglitazone (Ros), a PPAR agonist, can improve CP phenotype while activating PPAR pathway, which proves the causal relationship between PPAR pathway activation and CP phenotype improvement., Conclusion: Our study demonstrated behavioral improvements and enhanced cognitive functions in CP models after EA treatment by activating PPAR pathway, suggesting new perspectives for CP rehabilitation, and providing theoretical support for acupuncture treatment of CP., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Endometritis is a common disease in postpartum cows, characterized by delayed uterine recovery due to endometrial inflammation. Although antibiotics and hormones are commonly used, they have certain limitations. One potential alternative is using motherwort extract, specifically leonurine, which exhibits anti-inflammatory properties. However, leonurine's exact molecular mechanism of action remains unclear. In this study, 40 mice were randomly divided into four groups: a control group, endometritis model group, LPS + leonurine group (30 mg/kg), and LPS + dexamethasone group (5 mg/kg). Transcriptomic analysis revealed that leonurine modulates multiple signaling pathways, including JAK-STAT/PI3K-Akt, and influences the expression of key genes, such as Prlr , Socs2 , Col1a1 , and Akt1 . Furthermore, leonurine effectively reduces levels of inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and IL-1β ( p < 0.01), which play a crucial role in regulating acute endometritis. Additionally, leonurine helps maintain cholesterol homeostasis and attenuates inflammation through the peroxisome proliferator-activated receptor (PPAR) signaling pathway by modulating genes such as Cyp27a1 , Hmgcs1 , and Scd2 . These findings suggest that leonurine has a protective effect against LPS-induced endometritis and that its anti-inflammatory properties involve multiple pathways and targets, which are potentially mediated by regulating signaling pathways such as JAK-STAT/PI3K-Akt and PPAR.

The cornea is an avascular tissue in the eye that has multiple functions in the eye to maintain clear vision which can significantly impair one's vision when subjected to damage. Peroxisome proliferator-activated receptors (PPARs), a family of nuclear receptor proteins comprising three different peroxisome proliferator-activated receptor (PPAR) isoforms, namely, PPAR alpha (α), PPAR gamma (γ), and PPAR delta (δ), have emerged as potential therapeutic targets for treating corneal diseases. In this review, we summarised the current literature on the therapeutic effects of PPAR agents on corneal diseases. We discussed the role of PPARs in the modulation of corneal wound healing, suppression of corneal inflammation, neovascularisation, fibrosis, stimulation of corneal nerve regeneration, and amelioration of dry eye by inhibiting oxidative stress within the cornea. We also discussed the underlying mechanisms of these therapeutic effects. Future clinical trials are warranted to further attest to the clinical therapeutic efficacy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chow, Lee, Liu and Liu.)

The ubiquitous presence of micro-and nanoplastics (MNPs) in the environment and everyday products has attracted attention due to their hazardous risks. However, the effects of MNPs on reproduction and the underlying mechanisms remain unclear. The present study investigated the impact of polystyrene (PS) nanoplastics of 80, 200 and 500 nm diameters on zebrafish reproduction at an environmentally relevant concentration of 0.5 mg/L. Exposure to PS delayed spermatogenesis and caused aberrant follicular growth, resulting in dysgenesis in F0 adults and impacting F1 embryo development. Notably, the reproductive toxicity exhibited size-dependency, with the 500 nm PS being the most detrimental. Combined analyses of transcriptomics and metabolomics in ovary tissue revealed that treatment with 500 nm PS affected the peroxisome proliferator-activated receptor (PPAR) signaling pathway, dysregulated lipid transport, binding and activity processes, and led to dysgenesis in zebrafish. Specifically, the ovulatory dysfunction induced by PS exposure resembled clinical manifestations of polycystic ovary syndrome (PCOS) and can be attributed to lipid metabolism disorder involving glycerophospholipid, sphingolipid, arachidonic acid, and alpha-linolenic acid. Collectively, our results provide new evidence revealing the molecular mechanisms of PS-induced reproductive toxicity, highlighting that MNPs may pose a risk to female reproductive health., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

PFOA is one of the most representative compounds in the family of perfluorinated organic compounds. Due to its varying toxicity, alternatives to PFOA are beginning to emerge. HFPO-TA is an alternative for PFOA. It is currently unclear whether HFPO-TA affects glucose and lipid metabolism. In this study, rats were used as an animal model to investigate the effects of HFPO-TA on liver glucose and lipid metabolism. We found that HFPO-TA can affect glucose tolerance. Through omics analysis and molecular detection, it was found that HFPO-TA mainly affects the PPAR signaling pathway in the liver of rats, inhibiting liver glycolysis while promoting glucose production. HFPO-TA not only promotes the synthesis of fatty acids in the liver, but also promotes the breakdown of fatty acids, which ultimately leads to the disruption of hepatic glucose and lipid metabolism. The effects of HFPO-TA on metabolism are discussed in this paper to provide a reference for the risk assessment of this PFOA substitute., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

The global prevalence of obesity-related systemic disorders, including non-alcoholic fatty liver disease (NAFLD), and cancers are rapidly rising. Several of these disorders involve peroxisome proliferator-activated receptors (PPARs) as one of the key cell signaling pathways. PPARs are nuclear receptors that play a central role in lipid metabolism and glucose homeostasis. They can activate or suppress the genes responsible for inflammation, adipogenesis, and energy balance, making them promising therapeutic targets for treating metabolic disorders. In this study, an attempt has been made to screen novel PPAR pan-agonists from the ZINC database targeting the three PPAR family of receptors (α, γ, β/δ), using molecular docking and molecular dynamics (MD) simulations. The top scoring five ligands with strong binding affinity against all the three PPAR isoforms were eprosartan, canagliflozin, pralatrexate, sacubitril, olaparib. The ADMET analysis was performed to assess the pharmacokinetic profile of the top 5 molecules. On the basis of ADMET analysis, the top ligand was subjected to MD simulations, and compared with lanifibranor (reference PPAR pan-agonist). Comparatively, the top-scoring ligand showed better protein-ligand complex (PLC) stability with all the PPARs (α, γ, β/δ). When experimentally tested in in vitro cell culture model of NAFLD, eprosartan showed dose dependent decrease in lipid accumulation and oxidative damage. These outcomes suggest potential PPAR pan-agonist molecules for further experimental validation and pharmacological development, towards treatment of PPAR-mediated metabolic disorders., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD), and more specifically steatohepatitis may be associated with fat infiltration of skeletal muscles which is known as myosteatosis. Pan-peroxisome proliferator-activated receptor (PPAR) agonists have been shown to promote metabolic dysfunction-associated steatohepatitis (MASH) remission. However, the effect of PPAR agonists on myosteatosis remains to be determined. The aim of this review is to evaluate the effect that PPAR agonists alone or in combination, have on myosteatosis in the context of MASLD., Methods: Original research reports concerning the impact of PPAR agonists on muscle fat in MASLD were screened from PUBMED and EMBASE databases following the PRISMA methodology., Results: Eleven original manuscripts were included in this review. Two preclinical studies assessed the impact of the PPARα agonist on fat content in the quadriceps muscle and the liver by extracting triglycerides in rats fed a high-fat diet and in insulin-resistant mice. Both models showed muscle and liver triglyceride content reduction using WY14643. Fenofibrate had no significant impact on soleus intramyocellular lipids or liver fat content in insulin-resistant subjects based on proton magnetic resonance spectroscopy. Treatment with PPARδ agonists increased the expression of genes involved in fatty acid oxidation in two studies on muscle cell culture. PPARγ agonists were investigated in two preclinical studies and one clinical study using spectroscopy and computed tomography respectively. In the first preclinical study in Zucker diabetic fatty rats, rosiglitazone reduced muscle lipids and hepatic steatosis. In a second preclinical study using the same animal model, pioglitazone reduced tibialis anterior intramyocellular lipids. In contrast, computed tomography analyses in patients with type 2 diabetes revealed a surface area increase of low-density muscles (suggesting an increase in muscle fat content) after a one-year treatment with rosiglitazone. Varying combinations of PPAR agonists (cevoglitazar, fenofibrate/pioglitazone and muraglitazar) were evaluated in two preclinical studies and one clinical study. In rats, these treatments showed variable results for muscle and liver depending on the combinations studied. In type 2 diabetic patients, treatment with muraglitazar (a PPARα/γ agonist) reduced the intramyocellular lipid content of tibialis anterior as well as liver fat content following spectroscopy assessment., Conclusion: The combination of different PPAR agonists could have a positive impact on reducing myosteatosis, in addition to their effect on the liver. Some discrepancies could be explained by the different techniques used to assess muscle lipid content, the muscles assessed and the possible adipogenic effect of PPARγ agonists. Further clinical research is needed to fully assess the efficacy of these treatments on both MASLD progression and associated myosteatosis.

Type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD), mainly related to nutrition and lack of physical activity, are both very common conditions, share several disease pathways and clinical manifestations, and increasingly co-occur with disease progression. Insulin resistance is an upstream node in the biology of both conditions and triggers liver parenchymal injury, inflammation and fibrosis. Peroxisome proliferator-activated receptor (PPAR) nuclear transcription factors are master regulators of energy homeostasis - insulin signaling in liver, adipose and skeletal muscle tissue - and affect immune and fibrogenesis pathways. Among distinct yet overlapping effects, PPARα regulates lipid metabolism and energy expenditure, PPARβ/δ has anti-inflammatory effects and increases glucose uptake by skeletal muscle, while PPARγ improves insulin sensitivity and exerts direct antifibrotic effects on hepatic stellate cells. Together PPARs thus represent pharmacological targets across the entire biology of MASH. Single PPAR agonists are approved for hypertriglyceridemia (PPARα) and T2D (PPARγ), but these, as well as dual PPAR agonists, have shown mixed results as anti-MASH treatments in clinical trials. Agonists of all three PPAR isoforms have the potential to improve the full disease spectrum from insulin resistance to fibrosis, and correspondingly to improve cardiometabolic and hepatic health, as has been shown (phase II data) with the pan-PPAR agonist lanifibranor., Competing Interests: Declaration of competing interest MC is an employee and owns stock of Inventiva. SF has received grants and consultancy payments from several companies with drugs in development for NASH/MASH. LV has received consultancy payments from several companies with drugs in development for NASH/MASH., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The Actinopterygian and specifically the Teleostean peroxisome proliferator-activated receptors (PPARs) present an impressive variability and complexity in their structures, both at the gene and protein levels. These structural differences may also reflect functional divergence from their mammalian homologs, or even between fish species. This review, taking advantage of the data generated from the whole-genome sequencing of several fish species, highlights the differences in the primary structure of the receptors, while discussing results from the literature pertaining to the functions of fish PPARs and their activation by natural and synthetic compounds.

Hypertension is a complex disease with unknown causes. Therefore, it's crucial to deeply study its molecular mechanism. The hypertension dataset was obtained from Gene Expression Omnibus data base (GEO), and miRNA regulating central hub genes was screened via weighted gene co-expression network (DEGs) and gene set enrichment (GSEA). Cell experiments validated TSR2's role and the PPAR signaling pathway through western blotting. 500 DEGs were identified for hypertension, mainly enriched in actin cross-linking, insulin signaling, PPAR signaling, and protein localization. Eight hub genes (SEC61G, SRP14, Liy AR, NIP7, SDAD1, POLR1D, DYNLL2, TSR2) were identified. Four hub genes (LYAR, SDAD1, POLR1D, TSR2) exhibited high expression levels in the hypertensive tissue samples, while showing low expression levels in the normal tissue samples. This led us to speculate that they may have relevant regulatory effects on hypertension. When TSR2 was knocked down in the hypertension peripheral blood mononuclear cells (PBMC) model, the critical proteins in the PPAR signaling pathway (FABP, PPAR, PLTP, ME1, SCD1, CYP27, FABP1, OLR1, CPT-1, PGAR, CAP, ADIPO, MMP1, UCP1, ILK, PDK1 UBC AQP7) were downregulated. This also occurred in the hypertension peripheral blood mononuclear cells (PBMC) + TSR2&#95; OV model. TSR2 is highly expressed in individuals with hypertension and may play a significant role in the development of hypertension through the PPAR signaling pathway. TSR2 could serve as a molecular target for the early diagnosis and precise treatment of hypertension, providing a valuable direction for the mechanism research of this condition.

Ginsenoside Rk1, one kind of ginsenoside, is a minor ginsenoside found in Panax ginseng and used as traditional Chinese medicine for centuries. It exhibits anti-tumor and anti-aggregation effects. However, little research has been done on its effect on endothelial function. This study investigated whether ginsenoside Rk1 improved endothelial dysfunction in diabetes and the underlying mechanisms in vivo and in vitro . Male C57BL/6 mice were fed with a 12 week high-fat diet (60% kcal % fat), whereas treatment groups were orally administered with ginsenoside Rk1 (10 and 20 mg per kg per day) in the last 4 weeks. Aortas isolated from C57BL/6 mice were induced by high glucose (HG; 30 mM) and co-treated with or without ginsenoside Rk1 (1 and 10 μM) for 48 h ex vivo . Moreover, primary rat aortic endothelial cells (RAECs) were cultured and stimulated by HG (44 mM) to mimic hyperglycemia, with or without the co-treatment of ginsenoside Rk1 (10 μM) for 48 h. Endothelium-dependent relaxations of mouse aortas were damaged with elevated oxidative stress and downregulation of three isoforms of peroxisome proliferator-activated receptors (PPARs), PPAR-α, PPAR-β/δ, and PPAR-γ, as well as endothelial nitric oxide synthase (eNOS) phosphorylation due to HG or high-fat diet stimulation, which also existed in RAECs. However, after the treatment with ginsenoside Rk1, these impairments were all ameliorated significantly. Moreover, the vaso-protective and anti-oxidative effects of ginsenoside Rk1 were abolished by PPAR antagonists (GSK0660, GW9662 or GW6471). In conclusion, this study reveals that ginsenoside Rk1 ameliorates endothelial dysfunction and suppresses oxidative stress in diabetic vasculature through activating the PPAR/eNOS pathway.

Lanifibranor, a pan-PPAR agonist, improves liver histology in patients with metabolic dysfunction-associated steatohepatitis (MASH), who have poor cardiometabolic health (CMH) and cardiovascular events as major mortality cause. NATIVE trial secondary and exploratory outcomes (ClinicalTrials.gov NCT03008070) were analyzed for the effect of lanifibranor on IR, lipid and glucose metabolism, systemic inflammation, blood pressure (BP), hepatic steatosis (imaging and histological grading) for all patients of the original analysis. With lanifibranor, triglycerides, HDL-C, apolipoproteins, insulin, HOMA-IR, HbA1c, fasting glucose (FG), hs-CRP, ferritin, diastolic BP and steatosis improved significantly, independent of diabetes status: most patients with prediabetes returned to normal FG levels. Significant adiponectin increases correlated with hepatic and CMH marker improvement; patients had an average weight gain of 2.5 kg, with 49% gaining ≥2.5% weight. Therapeutic benefits were similar regardless of weight change. Here, we show that effects of lanifibranor on liver histology in MASH are accompanied with CMH improvement, indicative of potential cardiovascular clinical benefits., (© 2024. The Author(s).)

Ethnopharmacological Relevance: The Huanglian-Hongqu herb pair (HH) is a synergistic drug combination used to treat non-alcoholic fatty liver disease (NAFLD). However, the molecular mechanism underlying the therapeuticeffects of HH requires further elucidation., Aim of the Study: The present study explored the potential mechanism of HH in treating NAFLD., Materials and Methods: UPLC-Q-TOF-MS was employed to identify the drug constituents in HH. A NAFLD rat model was induced by a high-fat diet (HFD) and treated with different doses of HH. The functional mechanism of HH in NAFLD rats was predicted using network pharmacology, metabolomics and transcriptomics. Immunohistochemistry, real-time PCR, and Western blot were performed to validate the key mechanisms., Results: Pharmacodynamic assessment demonstrated that HH exhibited improvements in lipid deposition and reduced hepatic oxidative stress in NAFLD rats. Hepatic wide-target metabolomics revealed that HH primarily modulated amino acids and their metabolites, fatty acids, organic acids and their derivatives, bile acids, and other liver metabolites. The enriched pathways included metabolic pathways, primary bile acid biosynthesis, and bile secretion. Network pharmacology analysis indicated that HH regulated the key pathways in NAFLD, notably PPAR, AMPK, NF-κB and other signaling pathways. Furthermore, hepatic transcriptomics, based on Illumina RNA-Seq sequencing analyses, suggested that HH improved NAFLD through metabolic pathways, the PPAR signaling pathway, primary bile acid biosynthesis, and fatty acid metabolism. Further mechanistic studies indicated that HH could regulate the genes and proteins associated with the PPAR signaling pathway., Conclusion: Our findings demonstrated that the potential therapeutic benefits of HH in ameliorating NAFLD by targeting the PPAR signaling pathway, thereby facilitating a more extensive use of HH in NAFLD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Circular RNAs (circRNAs) are a novel kind of non-coding RNAs proved to play crucial roles in the development of multiple diabetic complications. However, their expression and function in diabetes mellitus (DM)-impaired salivary glands are unknown., Results: By using microarray technology, 663 upregulated and 999 downregulated circRNAs companied with 813 upregulated and 525 downregulated mRNAs were identified in the parotid glands (PGs) of type2 DM mice under a 2-fold change and P < 0.05 cutoff criteria. Gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) analysis of upregulated mRNAs showed enrichments in immune system process and peroxisome proliferator-activated receptor (PPAR) signaling pathway. Infiltration of inflammatory cells and increased inflammatory cytokines were observed in diabetic PGs. Seven differently expressed circRNAs validated by qRT-PCR were selected for coding-non-coding gene co-expression (CNC) and competing endogenous RNA (ceRNA) networks analysis. PPAR signaling pathway was primarily enriched through analysis of circRNA-mRNA networks. Moreover, the circRNA-miRNA-mRNA networks highlighted an enrichment in the regulation of actin cytoskeleton., Conclusion: The inflammatory response is elevated in diabetic PGs. The selected seven distinct circRNAs may attribute to the injury of diabetic PG by modulating inflammatory response through PPAR signaling pathway and actin cytoskeleton in diabetic PGs., (© 2024. The Author(s).)

We aimed to investigate the role of Synbiotic preparations on the interaction of gut microbiota with AD development. APP/PS1 mice were randomized into APP/PS1 and Synbiotics groups, and C57BL/6J mice were used as wild type (WT) control group. The mice in the Synbiotics group and the APP/PS1 group were given Synbiotics and xylo-oligosaccharides for 3 months, respectively. The mice in the WT group were given the same amount of normal saline. Cognitive function was measured. Positron emission computed tomography/magnetic resonance imaging (PET/MRI) was used to detect fasting blood glucose level. Immunohistochemical assay, ELISA, western blot and qRT-PCR were carried out to detect inflammatory factors. DNA extraction of fecal sample was performed to carry out sequencing. Bioinformatics analysis, metabolites sample preparation and Liquid Chromatograph Mass Spectrometer (LC/MS) analysis were also performed. Synbiotics treatment can significantly ameliorate learning and memory competence by inhibiting Aβ protein deposition. Different bacteria in the intestine were significantly improved and changes in gut microbiota can affect the intestinal metabolism to affect multiple potential pathways after Synbiotics treatment. Synbiotics treatment can activate peroxisome proliferator activated receptor (PPARs) signaling pathway and significantly reduce neuroinflammation in APP/PS1 mice brains. Synbiotics treatment can effectively reduce neuro-inflammatory response through the regulation of intestinal microflora to delay AD development.

Glioma is the most common type of primary intracranial malignant tumor, and because of its high invasiveness and recurrence, its prognosis remains poor. The present study investigated the biological function of piggyBac transportable element derived 5 (PGBD5) in glioma. Glioma and para-cancerous tissues were obtained from five patients. Reverse transcription-quantitative PCR and western blotting were used to detect the expression levels of PGBD5. Transwell assay and flow cytometry were used to evaluate cell migration, invasion, apoptosis and cell cycle distribution. In addition, a nude mouse tumor transplantation model was established to study the downstream pathways of PGBD5 and the molecular mechanism was analyzed using transcriptome sequencing. The mRNA and protein expression levels of PGBD5 were increased in glioma tissues and cells. Notably, knockdown of PGBD5 in vitro could inhibit the migration and invasion of glioma cells. In addition, the knockdown of PGBD5 expression promoted apoptosis and caused cell cycle arrest in the G 2 /M phase, thus inhibiting cell proliferation. Furthermore, in vivo experiments revealed that knockdown of PGBD5 expression could inhibit Ki67 expression and slow tumor growth. Changes in PGBD5 expression were also shown to be closely related to the peroxisome proliferator-activated receptor (PPAR) signaling pathway. In conclusion, interference with PGBD5 could inhibit the malignant progression of glioma through the PPAR pathway, suggesting that PGBD5 may be a potential molecular target of glioma.

The metabolic and immune systems are complex networks of organs, cells, and proteins that are involved in the extraction of energy from food; this is to run complex cellular processes and defend the body against infections while protecting its own tissues, respectively [...].

Background: Lactoferrin (LF) is an iron-binding multifunctional cationic glycoprotein. Previous studies have demonstrated that LF may be a potential drug for treating acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). In this study, we explored the anti-inflammatory effect and mechanism of bovine lactoferrin (bLF) in ALI using the RNA sequencing (RNA-seq) technology and transcriptome analysis., Methods and Results: Based on the differentially expressed genes (DEGs) obtained from RNA-seq of the Lung from mouse model, the bioinformatics workflow was implemented using the BGISEQ-500 platform. The protein-protein interaction (PPI) network was obtained using STRING, and the hub gene was screened using Cytoscape. To verify the results of transcriptome analysis, the effects of bLF on Lipopolysaccharide (LPS)-induced BEAS-2B cells and its anti-reactive oxygen species (ROS), anti-inflammatory, and antiapoptotic effects were studied via Cell Counting Kit-8 (CCK-8) test, active oxygen detection test, ELISA, and western blot assay. Transcriptome analysis revealed that two hub gene modules of DEGs were screened via PPI analysis using the STRING and MCODE plug-ins of Cytoscape. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that these core modules are enriched in the PPAR (peroxisome proliferator-activated receptor) and AMPK (AMP-activated protein kinase) signaling pathways. Through cell experiments, our study shows that bLF can inhibit ROS, inflammatory reaction, and LPS-induced BEAS-2B cell apoptosis, which are significantly antagonized by the PPAR-γ inhibitor GW9662., Conclusion: This study has suggested that the PPAR-γ pathway is the critical target of bLF in anti-inflammatory reactions and apoptosis of ALI, which provides a direction for further research., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Nonalcoholic fatty liver disease (NAFLD) is a common liver disorder affecting a quarter of the global residents. Progression of NAFL into nonalcoholic steatohepatitis (NASH) may cause cirrhosis, liver cancer, and failure. Gut microbiota imbalance causes microbial components translocation into the circulation, triggering liver inflammation and NASH-related fibrosis. MicroRNAs (miRNAs) regulate gene expression via repressing target genes. Exosomal miRNAs are diagnostic and prognostic biomarkers for NAFL and NASH liver damage. Our work investigated the role of the gut microbiota in NAFLD pathogenesis via the lipopolysaccharide/toll-like receptor 4/Forkhead box protein O3 (LPS/TLR-4/FoxO3) pathway and certain miRNAs as noninvasive biomarkers for NAFL or its development to NASH. miRNA expression levels were measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR) in 50 NAFL patients, 50 NASH patients, and 50 normal controls. Plasma LPS, TLR-4, adiponectin, peroxisome proliferator-activated receptor γ (PPAR-γ), and FoxO3 concentrations were measured using enzyme-linked immunosorbent assay (ELISA). In NAFL and NASH patients, miR-122, miR-128, FoxO3, TLR-4, LPS, and PPAR-γ were upregulated while miR-200, miR-298, miR-342, and adiponectin were downregulated compared with the normal control. The examined miRNAs might distinguish NAFL and NASH patients from the normal control using receiver operating characteristic analysis. Our study is the first to examine these miRNAs in NAFLD. Our findings imply that these are potentially promising biomarkers for noninvasive early NAFL diagnosis and NASH progression. Understanding the LPS/TLR-4/FoxO3 pathway involvement in NAFL/NASH pathogenesis may aid disease management., (© 2024 Deutsche Pharmazeutische Gesellschaft.)