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The PPARG 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 PPARG 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 PPARG gene. The clinical features of 41 PPARG 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]

Background: Per- and polyfluoroalkyl substances (PFAS) are human-made chemicals that accumulate in the human body and the environment over time. Humans are primarily exposed to PFAS through drinking water, food, consumer products, and dust. These exposures can have many adverse health effects, including cardiovascular diseases (CVDs) and factors contributing to CVDs. This study identified the molecular mechanisms of CVDs caused by PFAS. Methods: For this purpose, various computational tools, such as the Comparative Toxicogenomic Database, ShinyGO, ChEA3, MIENTURNET, GeneMANIA, STRING, and Cytoscape, were used to conduct in silico analyses. Results: The results showed that 10 genes were common between PFAS and CVDs, and among these common genes, the PPAR signaling pathway, fatty acid metabolic processes, and lipid binding were the most significantly associated gene ontology terms. Among the top 10 transcription factors (TFs) related to these common genes, peroxisome proliferator-activated receptor gamma and androgen receptor were the most prominent. Additionally, hsa-miR-130b-3p, hsa-miR-130a-3p, and hsa-miR-129-5p were featured microRNAs involved in PFAS-induced CVDs. Finally, PPARA and PPARG were identified as core genes involved in PFAS-induced CVDs. Conclusion: These findings may contribute to a better understanding of the molecular mechanisms and reveal new potential targets in PFAS-induced CVDs. [ABSTRACT FROM AUTHOR]

The PPARG gene encodes a member of a nuclear receptor superfamily known as peroxisome proliferator-activated gamma (PPARg). PPARg plays an essential role in adipogenesis, stimulating the differentiation of preadipocytes into adipocytes. Loss-of-function pathogenic variants in PPARG reduce the activity of the PPARg 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 PPARg in adipose tissue metabolism and the phenotypic and clinical consequences of loss-of-function variants in the PPARG gene. The clinical features of 41 PPARG 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]

Background Diabetes-induced cardiac fibrosis is one of the main mechanisms of diabetic cardiomyopathy. As a common histone methyltransferase, enhancer of zeste homolog 2 (EZH2) has been implicated in fibrosis progression in multiple organs. However, the mechanism of EZH2 in diabetic myocardial fibrosis has not been clarified. Methods In the current study, rat and mouse diabetic model were established, the left ventricular function of rat and mouse were evaluated by echocardiography and the fibrosis of rat ventricle was evaluated by Masson staining. Primary rat ventricular fibroblasts were cultured and stimulated with high glucose (HG) in vitro. The expression of histone H3 lysine 27 (H3K27) trimethylation, EZH2, and myocardial fibrosis proteins were assayed. Results In STZ-induced diabetic ventricular tissues and HG-induced primary ventricular fibroblasts in vitro, H3K27 trimethylation was increased and the phosphorylation of EZH2 was reduced. Inhibition of EZH2 with GSK126 suppressed the activation, differentiation, and migration of cardiac fibroblasts as well as the overexpression of the fibrotic proteins induced by HG. Mechanical study demonstrated that HG reduced phosphorylation of EZH2 on Thr311 by inactivating AMP-activated protein kinase (AMPK), which transcriptionally inhibited peroxisome proliferator-activated receptor γ (PPAR-γ) expression to promote the fibroblasts activation and differentiation. Conclusion Our data revealed an AMPK/EZH2/PPAR-γ signal pathway is involved in HG-induced cardiac fibrosis.

Background: Diabetes-induced cardiac fibrosis is one of the main mechanisms of diabetic cardiomyopathy. As a common histone methyltransferase, enhancer of zeste homolog 2 (EZH2) has been implicated in fibrosis progression in multiple organs. However, the mechanism of EZH2 in diabetic myocardial fibrosis has not been clarified. Methods: In the current study, rat and mouse diabetic model were established, the left ventricular function of rat and mouse were evaluated by echocardiography and the fibrosis of rat ventricle was evaluated by Masson staining. Primary rat ventricular fibroblasts were cultured and stimulated with high glucose (HG) in vitro. The expression of histone H3 lysine 27 (H3K27) trimethylation, EZH2, and myocardial fibrosis proteins were assayed. Results: In STZ-induced diabetic ventricular tissues and HG-induced primary ventricular fibroblasts in vitro, H3K27 trimethylation was increased and the phosphorylation of EZH2 was reduced. Inhibition of EZH2 with GSK126 suppressed the activation, differentiation, and migration of cardiac fibroblasts as well as the overexpression of the fibrotic proteins induced by HG. Mechanical study demonstrated that HG reduced phosphorylation of EZH2 on Thr311 by inactivating AMP-activated protein kinase (AMPK), which transcriptionally inhibited peroxisome proliferator-activated receptor γ (PPAR-γ) expression to promote the fibroblasts activation and differentiation. Conclusion: Our data revealed an AMPK/EZH2/PPAR-γ signal pathway is involved in HG-induced cardiac fibrosis. [ABSTRACT FROM AUTHOR]

Obesity has become a pandemic, as currently more than half a billion people worldwide are obese. The etiology of obesity is multifactorial, and combines a contribution of hereditary and behavioral factors, such as nutritional inadequacy, along with the influences of environment and reduced physical activity. Two types of adipose tissue widely known are white and brown. While white adipose tissue functions predominantly as a key energy storage, brown adipose tissue has a greater mass of mitochondria and expresses the uncoupling protein 1 (UCP1) gene, which allows thermogenesis and rapid catabolism. Even though white and brown adipocytes are of different origin, activation of the brown adipocyte differentiation program in white adipose tissue cells forces them to transdifferentiate into "beige" adipocytes, characterized by thermogenesis and intensive lipolysis. Nowadays, researchers in the field of small molecule medicinal chemistry and gene therapy are making efforts to develop new drugs that effectively overcome insulin resistance and counteract obesity. Here, we discuss various aspects of white-to-beige conversion, adipose tissue catabolic re-activation, and non-shivering thermogenesis. [ABSTRACT FROM AUTHOR]

Purpose of Review: This review summarizes evidence on osteocyte support of extramedullary and bone marrow adipocyte development and discusses the role of endogenous osteocyte activities of nuclear receptors peroxisome proliferator-activated receptor gamma (PPARG) and alpha (PPARA) in this support. Recent Findings: PPARG and PPARA proteins, key regulators of glucose and fatty acid metabolism, are highly expressed in osteocytes. They play significant roles in the regulation of osteocyte secretome and osteocyte bioenergetics; both activities contributing to the levels of systemic energy metabolism in part through an effect on metabolic function of extramedullary and bone marrow adipocytes. The PPARs-controlled osteocyte endocrine/paracrine activities, including sclerostin expression, directly regulate adipocyte function, while the PPARs-controlled osteocyte fuel utilization and oxidative phosphorylation contribute to the skeletal demands for glucose and fatty acids, whose availability is under the control of adipocytes. Summary: Bone is an inherent element of systemic energy metabolism with PPAR nuclear receptors regulating osteocyte-adipocyte metabolic axes. [ABSTRACT FROM AUTHOR]

The PPARG 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 PPARG 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 PPARG gene. The clinical features of 41 PPARG 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 Interleukin-33 (IL-33), an emerging cytokine within the IL-1 family, assumes a pivotal function in the control of obesity. However, the specific mechanism of its regulation of obesity formation remains unclear. In this study, we found that the expression level of IL-33 increased in visceral adipose tissue in mice fed with a high-fat diet (HFD) compared with that in mice fed with a normal diet (ND). In vitro, we also found the expression level of IL-33 was upregulated during the adipogenesis of 3T3-L1 cells. Functional test results showed that knockdown of IL-33 in 3T3-L1 cells differentiation could promote the accumulation of lipid droplets, the content of triglyceride and the expression of adipogenic–related genes (i.e. PPAR-γ, C/EBPα, FABP4, LPL, Adipoq and CD36). In contrast, overexpression of IL-33 inhibits adipogenic differentiation. Meanwhile, the above tests were repeated after over-differentiation of 3T3-L1 cells induced by oleic acid, and the results showed that IL-33 played a more significant role in the regulation of adipogenesis. To explore the mechanism, transcriptome sequencing was performed and results showed that IL-33 regulated the PPAR signaling pathway in 3T3-L1 cells. Further, Western blot and confocal microscopy showed that the inhibition of IL-33 could promote PPAR-γ expression by inhibiting the Wnt/β-catenin signal in 3T3-L1 cells. This study demonstrated that IL-33 was an important regulator of preadipocyte differentiation and inhibited adipogenesis by regulating the Wnt/β-catenin/PPAR-γ signaling pathway, which provided a new insight for further research on IL-33 as a new intervention target for metabolic disorders.

Interleukin-33 (IL-33), an emerging cytokine within the IL-1 family, assumes a pivotal function in the control of obesity. However, the specific mechanism of its regulation of obesity formation remains unclear. In this study, we found that the expression level of IL-33 increased in visceral adipose tissue in mice fed with a high-fat diet (HFD) compared with that in mice fed with a normal diet (ND). In vitro, we also found the expression level of IL-33 was upregulated during the adipogenesis of 3T3-L1 cells. Functional test results showed that knockdown of IL-33 in 3T3-L1 cells differentiation could promote the accumulation of lipid droplets, the content of triglyceride and the expression of adipogenic–related genes (i.e. PPAR-γ, C/EBPα, FABP4, LPL, Adipoq and CD36). In contrast, overexpression of IL-33 inhibits adipogenic differentiation. Meanwhile, the above tests were repeated after over-differentiation of 3T3-L1 cells induced by oleic acid, and the results showed that IL-33 played a more significant role in the regulation of adipogenesis. To explore the mechanism, transcriptome sequencing was performed and results showed that IL-33 regulated the PPAR signaling pathway in 3T3-L1 cells. Further, Western blot and confocal microscopy showed that the inhibition of IL-33 could promote PPAR-γ expression by inhibiting the Wnt/β-catenin signal in 3T3-L1 cells. This study demonstrated that IL-33 was an important regulator of preadipocyte differentiation and inhibited adipogenesis by regulating the Wnt/β-catenin/PPAR-γ signaling pathway, which provided a new insight for further research on IL-33 as a new intervention target for metabolic disorders. [ABSTRACT FROM AUTHOR]

The nuclear receptor peroxisome proliferator activated receptor-gamma (PPARg) controls adipocyte differentiation, as well as lipid metabolism and insulin sensitivity. As a result, PPARg is a promising candidate gene for a variety of human diseases, such as obesity and type 2 diabetes. Hyperglycemia associated with the metabolic syndrome and type 2 diabetes is treated with agonists of the nuclear receptor PPARg. The PPARg agonists of the thiazolidinedione type, despite being effective in normalizing blood glucose levels, have serious side effects, making the discovery of novel ligands extremely important. Natural products have historically proven to be a promising source of structures for drug development, and recent research has focused on the PPARg-activating potential of a wide range of natural products derived from traditionally used medicinal plants or dietary sources. This review highlights recent studies that have advanced our understanding of this receptor's role in metabolism, with a focus on the effects of compounds in the plant.

Worldwide, three-quarters of a million babies are born extremely preterm (<28 weeks gestation) with devastating outcomes: 20% die in the newborn period, a further 35% develop bronchopulmonary dysplasia (BPD), and 10% suffer from cerebral palsy. Pioglitazone, a Peroxisome Proliferator Activated Receptor Gamma (PPARγ) agonist, may reduce the incidence of BPD and improve neurodevelopment in extreme preterm babies. Pioglitazone exerts an anti-inflammatory action mediated through Nuclear Factor-kappa B repression. PPARγ signalling is underactive in preterm babies as adiponectin remains low during the neonatal period. In newborn animal models, pioglitazone has been shown to be protective against BPD, necrotising enterocolitis, and lipopolysaccharide-induced brain injury. Single Nucleotide Polymorphisms of PPARγ are associated with inhibited preterm brain development and impaired neurodevelopment. Pioglitazone was well tolerated by the foetus in reproductive toxicology experiments. Bladder cancer, bone fractures, and macular oedema, seen rarely in adults, may be avoided with a short treatment course. The other effects of pioglitazone, including improved glycaemic control and lipid metabolism, may provide added benefit in the context of prematurity. Currently, there is no formulation of pioglitazone suitable for administration to preterm babies. A liquid formulation of pioglitazone needs to be developed before clinical trials. The potential benefits are likely to outweigh any anticipated safety concerns. [ABSTRACT FROM AUTHOR]

Although the functional roles of M1 and M2 macrophages in the immune response and drug resistance are important, the expression and role of cytochrome P450s (CYPs) in these cells remain largely unknown. Differential expression of the 12 most common CYPs (CYP1A1, 1A2, 1B1, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 2J2, 3A4, and 3A5) were screened in THP-1-cell-derived M1 and M2 macrophages using reverse transcription PCR. CYP2C19 was highly expressed in THP-1-cell-derived M2 macrophages, but it was negligibly expressed in THP-1-cell-derived M1 macrophages at the mRNA and protein levels as analyzed by reverse transcription quantitative PCR and Western blot, respectively. CYP2C19 enzyme activity was also very high in THP-1-cell-derived M2 compared to M1 macrophages (> 99%, p < 0.01), which was verified using inhibitors of CYP2C19 activity. Endogenous levels of the CYP2C19 metabolites 11,12-epoxyeicosatrienoic acid (11,12-EET) and 14,15-EET were reduced by 40% and 50% in cells treated with the CYP2C19 inhibitor and by 50% and 60% in the culture medium, respectively. Both 11,12-EET and 14,15-EET were identified as PPARγ agonists in an in vitro assay. When THP-1-cell-derived M2 cells were treated with CYP2C19 inhibitors, 11,12- and 14,15-EETs were significantly reduced, and in parallel with the reduction of these CYP2C19 metabolites, the expression of M2 cell marker genes was also significantly decreased (p < 0.01). Therefore, it was suggested that CYP2C19 may contribute to M2 cell polarization by producing PPARγ agonists. Further studies are needed to understand the endogenous role of CYP2C19 in M2 macrophages with respect to immunologic function and cell polarization. [ABSTRACT FROM AUTHOR]

Macrophage polarization is a process whereby macrophages develop a specific phenotype and functional response to different pathophysiological stimuli and tissue environments. In general, two main macrophage phenotypes have been identified: inflammatory (M1) and alternatively activated (M2) macrophages characterized specifically by IL-1b and IL-10 production, respectively. In the cardiotoxin-induced skeletal muscle injury model bone marrow-derived macrophages (BMDMs) play the central role in regulating tissue repair. Bone marrow-derived monocytes arriving at the site of injury differentiate first to M1 BMDMs that clear cell debris and trigger proliferation and differentiation of the muscle stem cells, while during the process of efferocytosis they change their phenotype to M2 to drive resolution of inflammation and tissue repair. The M2 population is formed from at least three distinct subsets: antigen presenting, resolution-related and growth factor producing macrophages, the latest ones expressing the transcription factor PPARg. Nuclear receptor subfamily 4 group A member 1 (NR4A1; also termed Nur77) transcription factor is expressed as an early response gene, and has been shown to suppress the expression of proinflammatory genes during efferocytosis. Here we demonstrate that (1) Nur77 null BMDMs are characterized by elevated expression of PPARg resulting in enhanced efferocytosis capacity; (2) Nur77 and PPARg regulate transcription in different subsets of M2 skeletal muscle macrophages during muscle repair; (3) the loss of Nur77 prolongs M1 polarization characterized by increased and prolonged production of IL-1b by the resolution-related macrophages normally expressing Nur77; whereas, in contrast, (4) it promotes M2 polarization detected via the increased number of IL-10 producing CD206+ macrophages generated from the PPARg-expressing subset. [ABSTRACT FROM AUTHOR]

The correction notice in the journal "Frontiers in Endocrinology" addresses an error in the Funding statement of an article on familial partial lipodystrophy. The correct funding source is Chiesi Global Rare Diseases (GRD), and the authors clarify that this does not impact the scientific conclusions of the study. The authors emphasize that the views expressed in the article are their own and may not reflect those of their organizations or the publisher. [Extracted from the article]

Background and objectives: Zingiber officinale extract can control cardiovascular risk factors. Moreover, endurance training may effectively rehabilitate myocardial infarction by strengthening the myocardial muscle tissue. In-silico analysis identified essential genes involved in the heart damage process based on data from the DisGeNET database. Hence, we estimated the affinity of chemical and bioactive molecules for PPARγ. Therefore, this study aimed to investigate the effect of endurance exercise alone or combined with Zingiber officinale extract on Myocardial infarction rats. Material and Methods: Twenty-five male rats were randomly divided into five groups, including (1) group of myocardial infarctions (MI) induced by subcutaneous injection of isoproterenol, (2) myocardial infarction+exercise (MI+EX), (3) myocardial infarction+Zingiber Officinale extraction administered orally (MI+GE), (4) myocardial infarction+exercise+Zingiber Officinale extract (MI+EX+GE), and (5) Control group. The qPCR-Real Time technique was used to measure the expression of PGC1-ɑ, PPARγ, and TNF-ɑ genes. We evaluated the concentration of Troponin-1 as a vital myocardial ischemia marker. Results: In bioinformatics analysis, we found that the PPARγ, PGC1-ɑ, and TNF-ɑ pathways were critical in heart injury. Also, the effects of Zingiber officinale on heart tissue were detected through PPARγ by drug design. Endurance training combined with Zingiber officinale consumption reduced the expression of TNF-ɑ, Troponin-1 and increased the PGC1-ɑ, PPARγ genes. Furthermore, consumption of Zingiber officinale extraction improved the levels of PGC1-ɑ, PPARγ, TNF-ɑ, and Troponin-1. Conclusion: Our data indicated that six weeks of endurance training and consumption of Zingiber officinale extract could reduce the relative expression of the TNF-ɑ and significantly increase the level of PGC1-ɑ, PPARγ.

Macrophage polarization is a process whereby macrophages develop a specific phenotype and functional response to different pathophysiological stimuli and tissue environments. In general, two main macrophage phenotypes have been identified: inflammatory (M1) and alternatively activated (M2) macrophages characterized specifically by IL-1β and IL-10 production, respectively. In the cardiotoxin-induced skeletal muscle injury model bone marrow-derived macrophages (BMDMs) play the central role in regulating tissue repair. Bone marrow-derived monocytes arriving at the site of injury differentiate first to M1 BMDMs that clear cell debris and trigger proliferation and differentiation of the muscle stem cells, while during the process of efferocytosis they change their phenotype to M2 to drive resolution of inflammation and tissue repair. The M2 population is formed from at least three distinct subsets: antigen presenting, resolution-related and growth factor producing macrophages, the latest ones expressing the transcription factor PPARγ. Nuclear receptor subfamily 4 group A member 1 (NR4A1; also termed Nur77) transcription factor is expressed as an early response gene, and has been shown to suppress the expression of pro-inflammatory genes during efferocytosis. Here we demonstrate that (1) Nur77 null BMDMs are characterized by elevated expression of PPARγ resulting in enhanced efferocytosis capacity; (2) Nur77 and PPARγ regulate transcription in different subsets of M2 skeletal muscle macrophages during muscle repair; (3) the loss of Nur77 prolongs M1 polarization characterized by increased and prolonged production of IL-1β by the resolution-related macrophages normally expressing Nur77; whereas, in contrast, (4) it promotes M2 polarization detected via the increased number of IL-10 producing CD206+ macrophages generated from the PPARγ-expressing subset.

Background & Aims: Macrophages display remarkable plasticity and can interact with surrounding cells to affect hepatic immunity and tissue remodelling during the progression of liver diseases. Peroxisome proliferator‐activated receptor gamma (PPARγ) plays a critical role in macrophage maturation, polarization and metabolism. In this study, we investigated the role of PPARγ in macrophage–hepatic stellate cell (HSC) interaction during non‐alcoholic steatohepatitis (NASH) development. Methods: Wild‐type, Ppargfl/fl and PpargΔLyz2 mice were fed a methionine‐ and choline‐deficient (MCD) diet to induce NASH. Depletion of macrophages was performed using an injection of gadolinium chloride intraperitoneally. PPARγ‐overexpressing or PPARγ‐knockout macrophages were stimulated with saturated fatty acid (SFA) and cocultured with HSCs in a conditioned medium or the transwell coculture system. Results: Depletion of macrophages inhibited HSC activation and ameliorated NASH progression in MCD diet‐fed mice. Coculturing HSCs with macrophages or culturing HSCs in a macrophage‐conditioned medium‐facilitated HSC activation, and this effect was magnified when macrophages were metabolically activated by SFA. Moreover, the absence of PPARγ in macrophages enhanced metabolic activation, promoting the migration and activation of HSCs through IL‐1β and CCL2. In contrast, overexpression of PPARγ in macrophages obtained the opposite effects. In vivo, macrophage‐specific PPARγ knockout affected the phenotype of hepatic macrophages and HSCs, involving the MAPK and NLRP3/caspase‐1/IL‐1β signalling pathways. Infiltrating hepatic monocyte‐derived macrophages became the predominant macrophages in NASH liver, especially in PpargΔLyz2 mice, paralleling with aggravated inflammation and fibrosis. Conclusions: Regulating macrophage PPARγ affected the metabolic activation of macrophages and their interaction with HSCs. Macrophage‐specific PPARγ may be an attractive therapeutic target for protecting against NASH‐associated inflammation and fibrosis. [ABSTRACT FROM AUTHOR]

The case of Lumbar spinal stenosis (LSS) combined with tophi due to gout is rarely reported. In the course of our clinic work, we encountered a young male patient who was diagnosed with a history of gout for 5 years and was targeted as LSS combined with gouty tophi, and we would like to share this case. In addition, in order to further investigate the deep mechanism of LSS associated with gout, we obtained the intersecting genes of the two diseases based on a machine learning approach by obtaining the dataset GSE113212 related to LSS from the Gene Expression Omnibus (GEO) database, and the genes related to gout from the human gene database. We found that TGFB1, PPARG, and SAMRCC1 may be important biomarkers for treating of both diseases. From a clinical perspective, clinicians should be vigilant about the possibility of gouty lumbar spinal stenosis with tophi in young patients presenting with back pain, hyperuricemia, and elevated inflammatory markers. A combined surgical and pharmacological treatment plan has a favorable prognosis. Investigating the mechanisms of action of core genes may provide new insights for treatment, ultimately leading to the development of comprehensive and personalized diagnostic and therapeutic strategies., Competing Interests: Declarations. Ethics approval and consent to participate: Informed consent was obtained from the participant and reviewed by the Ningxia Medical University General Hospital Ethics Council (Ethics number: KYLL-2023-0026). Consent for publication: Consent for publication was obtained from the patients. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background and Aims: The ongoing antimicrobial resistant crisis heralds the need for new therapeutics against enteric infection. In mouse models, colon epithelial peroxisome proliferator-activated receptor-γ (PPAR-γ) signaling limits oxygen and nitrate luminal bioavailability, thereby preventing bacterial pathogen colonization. However, whether this mechanism operates similarly in humans remains uncertain., Methods: To investigate, we used the cloud-based TriNetX Analytics Platform which aggregates health records from 117 million patients across 66 US healthcare organizations, to assess the risk of bacterial enteric infection among diabetic patients prescribed thiazolidinediones, a class of PPAR-γ agonists, to other anti-diabetes medications., Results: Among 85,117 thiazolidinedione users, we observed a 22-49% lower risk of bacterial enteric infections compared to users of other anti-diabetes medications. This reduction in risk was consistent across high-risk individuals, regardless of sex or age. Similar results were replicated in high-risk patients when thiazolidinedione users were directly compared to those on DPP-4 inhibitors., Conclusion: These findings support the potential protective role of PPAR-γ signaling against bacterial enteric infection and call for further clinical investigation., Competing Interests: Conflict of Interest: VN has served as a consultant and on the scientific advisory board for Cellics Therapuetics, I2Pure Inc, Clarametyx Therapeutics, and has licensed technology from lab sponsored research with Vaxcyte, Inc. AZ is a co-founder and acting CMO of Endure Biotherapeutics. He holds equity in the company.

The peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor and controls a number of gene expressions. The ligand binding domain (LBD) of PPARγ is large and involves two binding sites: orthosteric and allosteric binding sites. Increased evidence has shown that PPARγ is an oncogene and thus the PPARγ antagonists have potential as anticancer agents. In this paper, we use Glide Dock approach to determine which binding site, orthosteric or allosteric, would be a preferred pocket for PPARγ antagonist binding, though antidiabetic drugs such as thiazolidinediones (TZDs) bind to the orthosteric site. The Glide Dock results show that the binding of PPARγ antagonists at the allosteric site yielded results that were much closer to the experimental data than at the orthosteric site. The PPARγ antagonists seem to selectively bind to residues Lys265, Ser342 and Arg288 at the allosteric binding site, whereas PPARγ agonists would selectively bind to residues Leu228, Phe363, and His449, though Phe282 and Lys367 may also play a role for agonist binding at the orthosteric binding pocket. This finding will provide new perspectives in the design and optimization of selective and potent PPARγ antagonists or agonists. [ABSTRACT FROM AUTHOR]

Peroxisome proliferator-activated receptor-gamma (PPAR-γ) plays a central role in health and is an essential cardioprotective factor because of its effect on lipid and glucose metabolism, inflammation, and oxidative stress. We hypothesized that nutritional strategies positively regulate PPAR-γ expression in patients with noncommunicable diseases (NCDs). A systematic search was conducted using PubMed, Scientific Electronic Library Online (SciELO), and LILACS databases from May 2020 to January 2021. Eligibility criteria included placebo-controlled randomized clinical trials in adults with chronic diseases involving nutritional strategies, which performed PPAR-γ analysis (majority on mononuclear cells) before and after the intervention. The exclusion criteria included studies published more than 10 years ago, studies not published in English or Spanish, theses, reviews, and other study designs. The review was developed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Methodological quality was assessed based on 7 criteria obtained from the Cochrane Handbook. A total of 7 studies were included that reported the effects of different nutritional strategies (such as anthocyanins, fish oil, Berberis vulgaris juice, ketogenic diet, flaxseed oil, olive oil) on 346 patients with NCDs (such as type 2 diabetes, hypertension, obesity, and cancer) between 18 and 85 years of age. These results suggest that anthocyanins, flaxseed oil, and olive oil may function as putative PPAR-γ agonists. Supplementation of foods in adults with chronic noncommunicable diseases increased the expression of proliferator-activated receptor-gamma. When expressed, it is to perform gene expression demonstrating benefits in glucose, lipid metabolism, and decrease of inflammatory markers. [Display omitted] [ABSTRACT FROM AUTHOR]

Background Peroxisome proliferator-activated receptor-gamma (PPAR-γ) ligands have been widely shown to correlate with epithelial-mesenchymal transition (EMT) and cancer progression. Lobeglitazone (LGZ) is a novel ligand of PPAR-γ; and its role in EMT and metastasis in papillary thyroid carcinoma (PTC) is poorly understood. We aimed to investigate the role of LGZ in metastatic behavior of PTC cells. Methods Half maximal inhibitory concentration (IC50) values of LGZ in BRAF-mutated PTC cell lines (BCPAP and K1) were determined using MTT assay. Rosiglitazone (RGZ), the PPAR-γ ligand was used as a positive control. The protein expression of PPAR-γ, cell-surface proteins (E-cadherin, N-cadherin), cytoskeletal protein (Vimentin), transcription factor (Snail), p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK) 1/2 pathway, and matrix metalloproteinase (MMP)-2 expression were measured using Western blotting. Changes in E-cadherin expression were also determined using immunocytochemistry. Cell migration and invasion were analyzed using wound healing and Matrigel invasion assays. Results Treatment with LGZ or RGZ significantly inhibited transforming growth factor-beta1 (TGF-β1)-induced EMT-associated processes such as fibroblast-like morphological changes, EMT-related protein expression, and increased cell migration and invasion in BCPAP and K1 cells. LGZ restored TGF-β1-induced loss of E-cadherin, as observed using immunocytochemistry. Furthermore, LGZ and RGZ suppressed TGF-β1-induced MMP-2 expression and phosphorylation of p38 MAPK, but not ERK1/2. Although there was no change in PPAR-γ expression after treatment with LGZ or RGZ, the effect of downstream processes mediated by LGZ was hampered by GW9662, a PPAR-γ antagonist. Conclusion LGZ inhibits TGF-β1-induced EMT, migration, and invasion through the p38 MAPK signaling pathway in a PPAR-γ-dependent manner in PTC cells.

The objectives of the present study were to investigate the effect of induced activation of peroxisome proliferator-activated receptor gamma (PPARγ) through ligands, rosiglitazone (RG), kaempferol (KEM) and GW9662 (GW) in pathophysiological alterations and inflammation by regulating the expression of PPARγ-regulated genes in a rat model of nonalcoholic fatty liver disease (NAFLD). Male wistar rats (N=45) were fed high fat diet (HFD; 35%) in combination with single dose of carbon tetrachloride (CCl4; 0.5ml/kg/intraperitoneally) to induce NAFLD. The effects of synthetic PPARγ agonist; RG (15mg/kg) and PPARγ antagonist; GW (10mg/kg) were evaluated in comparison with putative natural ligand; KEM (12mg/kg). Co-administration of HFD and CCl4 mimicked NAFLD as evident by elevation of hepatic injury markers and lipid profile in serum. The results of AST/ALT ratio and AST to platelet ratio index indicated NAFLD without advanced liver disease. RG and KEM, in contrast to GW, countered NAFLDassociated effects by ameliorating hepatic injury markers, insulin resistance and lipid profile. KEM and RG treatment increased the expression of IL-33, an antiinflammatory cytokine, while the expression of TNFα, a pro-inflammatory cytokine was non-significantly decreased. The results suggested that PPARγ activation by agonist ligands might contribute towards amelioration of NAFLD-associated pathophysiology of metabolic syndrome and hepatic inflammation through regulation of IL-33 and TNFα. [ABSTRACT FROM AUTHOR]

Peroxisome proliferator-activated receptor gamma (PPARγ) is one of the immune and metabolic regulatory agents. This study examined the serum PPARγ levels and metabolic syndrome (MetS) parameters in pediatric bipolar disorder (PBD) adolescents and compared them with healthy subjects. Serum PPARγ levels, fasting blood glucose (FBG), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), and fasting insulin levels of 39 PBD-type I (age range: 14–18) and 36 age- and sex-matched healthy control subjects were compared. The anthropometric measurements were also analyzed, including body weight, height, body mass index (BMI), waist circumference (WC), and blood pressure measurements. The PPARγ levels were significantly lower, and the MetS prevalence was significantly higher in the PBD group than in the control group. The mean BMI, WC, serum TG, and FBG values of the PBD group were statistically higher than the healthy control group. There was no significant relationship between the PPARγ levels and metabolic parameters except fasting glucose. Lower PPARγ activity and higher MetS prevalence in PBD indicate dysregulation of immune and metabolic regulatory parameters. These results may shed light on developing new PBD medications. [ABSTRACT FROM AUTHOR]

Background/Aims Ulcerative colitis (UC) is a chronic inflammatory disorder with indefinite etiology; however, environmental, genetic, immune factors and microbial agents could be implicated in its pathogenesis. UC treatment is lifelong, therefore; the potential side effects and cost of the therapy are significant. Yarrow is a promising medicinal plant with the ability to treat many disorders, owing to its bioactive compounds especially the essential oil. The main aim of this research was to investigate the therapeutic effect of the yarrow oil on colitis including the involved mechanism of action. Methods In 21-female C57BL/6 mice were divided into 3 groups; control group, colitis model group, and oil-treated group. Groups 2 and 3 received 5% dextran sulfate sodium (DSS) in drinking water for 9 days, and concomitantly, only group 3 was given 100 mg/kg yarrow oil. Mice were examined for their body weight, stool consistency and bleeding, and the disease activity indexes were calculated. Results Oral administration of yarrow oil markedly repressed the severity of UC via the reduction of the inflammatory signs and restoring colon length. The oil was able to down-regulate nuclear factor kappa light chain enhancer of activated B cells (NF-κB), up-regulate peroxisome proliferator-activated receptor gamma (PPAR-γ), and enhance transforming growth factor-β expression. The oil normalized the tumor necrosis factor-α expression, restored the normal serum level of interleukin-10 (IL-10) and reduced the serum level of IL-6. Conclusions Yarrow oil mitigated UC symptoms and regulated the inflammatory cytokines secretion via regulation of NF-κB and PPAR-γ pathways in the mice model, however, this recommendation requires further investigations using clinical studies to confirm the use of the oil on humans.

Background Protease-activated protein-2 (PAR2) has been reported to regulate hepatic insulin resistance condition in type 2 diabetes mice. However, the mechanism of lipid metabolism through PAR2 in obesity mice have not yet been examined. In liver, Forkhead box O1 (FoxO1) activity induces peroxisome proliferator-activated receptor γ (PPARγ), leading to accumulation of lipids and hyperlipidemia. Hyperlipidemia significantly influence hepatic steatoses, but the mechanisms underlying PAR2 signaling are complex and have not yet been elucidated. Methods To examine the modulatory action of FoxO1 and its altered interaction with PPARγ, we utilized db/db mice and PAR2-knockout (KO) mice administered with high-fat diet (HFD). Results Here, we demonstrated that PAR2 was overexpressed and regulated downstream gene expressions in db/db but not in db+ mice. The interaction between PAR2/β-arrestin and Akt was also greater in db/db mice. The Akt inhibition increased FoxO1 activity and subsequently PPARγ gene in the livers that led to hepatic lipid accumulation. Our data showed that FoxO1 was negatively controlled by Akt signaling and consequently, the activity of a major lipogenesis-associated transcription factors such as PPARγ increased, leading to hepatic lipid accumulation through the PAR2 pathway under hyperglycemic conditions in mice. Furthermore, the association between PPARγ and FoxO1 was increased in hepatic steatosis condition in db/db mice. However, HFD-fed PAR2-KO mice showed suppressed FoxO1-induced hepatic lipid accumulation compared with HFD-fed control groups. Conclusion Collectively, our results provide evidence that the interaction of FoxO1 with PPARγ promotes hepatic steatosis in mice. This might be due to defects in PAR2/β-arrestin-mediated Akt signaling in diabetic and HFD-fed mice.

Abstract Autosomal dominant polycystic kidney disease (ADPKD) is an inherited chronic kidney disorder (CKD) that is characterized by the development of numerous fluid-filled cysts in kidneys. It is caused either due to the mutations in the PKD1 or PKD2 gene that encodes polycystin-1 and polycystin-2, respectively. This condition progresses into end-stage renal disorder if the renal or extra-renal clinical manifestations remain untreated. Several clinical trials with a variety of drugs have failed, and the only Food and Drugs Administration (FDA) approved drug to treat ADPKD to date is tolvaptan that works by antagonizing the vasopressin-2 receptor (V2R). The pathology of ADPKD is complex and involves the malfunction of different signaling pathways like cAMP, Hedgehog, and MAPK/ERK pathway owing to the mutated product that is polycystin-1 or 2. A measured yet substantial number of preclinical studies have found pioglitazone to decrease the cystic burden and improve the renal function in ADPKD. The peroxisome proliferator-activated receptor-gamma is found on the epithelial cells of renal collecting tubule and when it gets agonized by pioglitazone, confers efficacy in ADPKD treatment through multiple mechanisms. There is only one clinical trial (ongoing) wherein it is being assessed for its benefits and risk in patients with ADPKD, and is expected to get approval from the regulatory body owing to its promising therapeutic effects. This article would encompass the updated information on the epidemiology, pathophysiology of ADPKD, different mechanisms of action of pioglitazone in the treatment of ADPKD with preclinical and clinical shreds of evidence, and related safety updates.