The receptor known as peroxisome proliferator‐activated receptor gamma (PPAR γ ) is crucial for effective wound healing, and recent progress has given a deeper understanding of its complex functions. As a biological switch, PPAR γ regulates the immune response by shifting macrophages from promoting inflammation to supporting tissue regeneration, while suppressing pro‐inflammatory signals to create an ideal healing environment. At the cellular level, PPAR γ enhances the migration of keratinocytes and promotes re‐epithelialization, thereby accelerating the wound closure process. It also promotes the differentiation of preadipocytes and the formation of new blood vessels, making a significant contribution to tissue regeneration. At the molecular level, PPAR γ plays a dual role in guiding epithelial–mesenchymal transformation to aid healing while preventing excessive scarring. It improves mitochondrial efficiency to provide the energy needed for tissue repair. Despite these promising mechanisms, the clinical use of current PPAR γ agonists faces hurdles due to side effects and regulatory hurdles. Moving forward, research should aim to develop targeted delivery methods, tailor therapies to individual needs, and investigate how PPAR γ interacts synergistically with other signaling pathways, all of which are essential steps toward translating these findings into clinical practice.
Obesity is driven by chronic energy imbalance and is associated with multiple metabolic diseases. As adipocyte thermogenesis contributes to energy expenditure, it is being actively investigated as a possible target for obesity treatment. This review summarizes recent progress in the molecular regulation of adipocyte thermogenesis, focusing mainly on preclinical mechanistic evidence from cellular and animal studies, while discussing clinical and human data only where available. We review emerging regulators within the cAMP pathway, the PRDM16-PPARγ axis, and mitochondrial quality control and metabolism, together with other pathways that modulate brown and beige adipocyte function. We also discuss their metabolic effects in experimental obesity settings. Nevertheless, the therapeutic relevance of these findings remains uncertain because much of the evidence is still preclinical, and because translation is complicated by species differences, adipose depot heterogeneity, and the limited number of validated human studies. This review therefore offers an updated synthesis of recent mechanistic advances while emphasizing the key challenges that must be addressed before these insights can be reliably translated into obesity therapies.
Objective:We are aimed at investigating the relationships among muscle mass, physical activity, and calcaneal bone mineral density (BMD) in female university students, and exploring the mediating role of muscle mass in the association between physical activity and calcaneal BMD. Methods:Using stratified cluster sampling, 593 female university students aged 19-25 of different grades were selected. Anthropocentric characteristics, body composition, and calcaneal BMD were measured. Statistical methods including multiple linear/binary logistic regression models, mediation analyses, sensitivity analyses, and subgroup analysis were performed. Results:The normal and abnormal BMD groups significantly varied in both total skeletal muscle mass (TSM) and total skeletal muscle mass index (TSMI) (t[TSM] = 3.216, t[TSMI] = 3.304, p < 0.01), and also diverse in physical activity (p < 0.05). The increment in muscle mass might be related to an increase in BMD (β[TSM] = 0.089, β[TSMI] = 0.265, p < 0.01) and a decrease in the probability of abnormal BMD (β[TSM] = -0.193, β[TSMI] = -0.682, p < 0.01). The effect of physical activity on calcaneal BMD is significant (β = -0.109, p < 0.05). Muscle mass plays a mediating role in the relationship between physical activity and calcaneal BMD, and the subgroup mediation sensitivity analyses indicated that the mediation effect only in the overweight group had significant mediation effects and relatively high robustness (Rho = -0.2, R2_MR2_Y = 0.04). Conclusion:Muscle mass and physical activity both present a significant positive correlation with calcaneal BMD in female university students, and high activity level is a protective factor for abnormal BMD. Muscle mass performs a mediating role in the relationship of physical activity and calcaneal BMD in female university students of the overweight group.
Diabetic corneal neuropathy (DCN) is a clinically important yet frequently overlooked complication of diabetes mellitus, characterized by progressive corneal nerve loss, impaired epithelial wound healing, and ocular surface instability. Its pathogenesis is multifactorial, driven by chronic hyperglycemia, dyslipidemia, advanced glycation end-products (AGEs), mitochondrial dysfunction, oxidative stress, and persistent low-grade inflammation. These processes synergistically disrupt neurotrophic signaling and promote axonal degeneration. Current therapies—including lubricants, autologous serum eye drops, and topical nerve growth factor—provide symptomatic relief and can promote corneal nerve regeneration. However, their effects are often variable, incomplete, or transient, and they do not fully address the underlying metabolic, inflammatory, and mitochondrial drivers of DCN, underscoring the unmet need for disease-modifying treatments. Peroxisome proliferator-activated receptors (PPARs) have recently emerged as compelling therapeutic targets. These nuclear transcription factors regulate key metabolic and inflammatory pathways, including lipid homeostasis, mitochondrial function, and oxidative stress. Among them, PPARα appears particularly relevant for corneal integrity. PPARα-deficient mice exhibit mitochondrial dysregulation, delayed epithelial repair, abnormal angiogenesis, and significant corneal nerve loss. Conversely, pharmacological activation with fenofibrate or selective PPAR modulators restores mitochondrial integrity, enhances neurotrophin expression, and promotes functional axon regeneration. Human studies corroborate these findings; systemic fenofibrate increases corneal nerve fiber density and improves tear proteomic signatures in patients with Type 2 diabetes, while topical formulations may provide faster and more pronounced neurotrophic effects. Collectively, current evidence positions PPARs—particularly PPARα—as promising next-generation therapeutic targets for reprogramming corneal neurodegeneration. Future progress will require innovative ocular delivery systems, biomarker-guided patient stratification, and rigorously designed clinical trials to fully realize the translational potential of PPAR modulation in DCN.
The receptor known as peroxisome proliferator-activated receptor gamma (PPARγ) is crucial for effective wound healing, and recent progress has given a deeper understanding of its complex functions. As a biological switch, PPARγ regulates the immune response by shifting macrophages from promoting inflammation to supporting tissue regeneration, while suppressing pro-inflammatory signals to create an ideal healing environment. At the cellular level, PPARγ enhances the migration of keratinocytes and promotes re-epithelialization, thereby accelerating the wound closure process. It also promotes the differentiation of preadipocytes and the formation of new blood vessels, making a significant contribution to tissue regeneration. At the molecular level, PPARγ plays a dual role in guiding epithelial-mesenchymal transformation to aid healing while preventing excessive scarring. It improves mitochondrial efficiency to provide the energy needed for tissue repair. Despite these promising mechanisms, the clinical use of current PPARγ agonists faces hurdles due to side effects and regulatory hurdles. Moving forward, research should aim to develop targeted delivery methods, tailor therapies to individual needs, and investigate how PPARγ interacts synergistically with other signaling pathways, all of which are essential steps toward translating these findings into clinical practice.
Objective:The objective was to investigate the effects and potential molecular mechanisms of emodin on colorectal cancer via network pharmacology combined with experimental validation. Methods:The active components and targets of emodin were retrieved from TCMSP and BATMAN-TCM databases, while colorectal cancer (CRC)-related genes were screened via GeneCards, OMIM, and DisGeNET. The intersection targets were used to construct a compound-disease network and a protein-protein interaction (PPI) network. GO and KEGG enrichment analyses were conducted to reveal key biological functions and pathways. Molecular docking was used to assess binding affinities between core targets and active components. In vitro experiments (CCK-8, colony formation, and apoptosis assays) and in vivo xenograft models were performed to validate the antitumor effect of emodin. Quantitative real-time PCR and Western blot were used to evaluate the regulation of hub genes and signaling pathways. Results:A total of 37 active components and 235 targets of emodin were identified, of which 82 overlapped with CRC-related genes. Core targets (CASP3, MMP9, BCL2, PTGS2, and IL1B) were highlighted through network analysis. These targets were enriched in oxidative stress, apoptosis, inflammation, and metabolic pathways. Molecular docking showed strong interactions between emodin and hub targets. Emodin significantly suppressed proliferation, colony formation, and induced apoptosis in CRC cell lines in a dose-dependent manner. In vivo, emodin inhibited tumor growth and activated the PPARγ-TP53 signaling axis. Conclusion:Emodin exerts anti-CRC effects via a multitarget, multipathway mechanism, particularly through modulation of the PPARγ-TP53 axis. These findings support emodin's potential as a natural compound for CRC treatment.
Background and Aims:The selective peroxisome proliferator-activated receptor delta (PPARD) agonist seladelpar reduces liver injury and modulates bile acid metabolism in preclinical models. Seladelpar was recently approved for the secondary treatment of primary biliary cholangitis (PBC). Despite its beneficial effects for liver diseases, the target cells of seladelpar on a single-cell level remain unknown. This study is aimed at investigating the effect of seladelpar on single liver cells. Methods and Results:CD-1 mice were gavaged with vehicle or seladelpar (10 mg/kg body weight), and the liver was harvested 6 h later. Single-nuclei RNA sequencing (snRNA-seq) analysis showed the engagement of PPARD target genes primarily in hepatocytes and cholangiocytes by seladelpar. The top two upregulated genes, Ehhadh and Cyp4a14, are related to fatty acid metabolism and were increased in hepatocytes, cholangiocytes, and Kupffer cells. Abcb4, an important canalicular transporter with hepatoprotective effects, was significantly upregulated in hepatocytes. We confirmed upregulated Abcb4 gene expression in seladelpar-treated primary mouse hepatocytes isolated from C57BL/6 mice. We further incubated nonparenchymal liver cells with seladelpar. Although there was a significant increase in the PPARD-responsive genes Pdk4 and Angptl4 in cholangiocytes, Kupffer cells, and hepatic stellate cells, seladelpar did not exert specific liver-protective effects in these cell types. Conclusion:The selective PPARD agonist seladelpar induced PPARD-responsive genes primarily in hepatocytes and cholangiocytes. Seladelpar upregulated Abcb4 in hepatocytes, which might contribute to its beneficial effects in cholestatic liver disorders.
Peroxisome proliferator-activated receptors (PPARs) modulate bile metabolism and are important therapeutic options in cholestatic diseases. This study was aimed at understanding the effects of single and multiple doses of seladelpar, a PPARδ (peroxisome proliferator-activated receptor delta) agonist, on plasma C4 (a freely diffusible metabolite accepted as a proxy for de novo bile acid biosynthesis), Fibroblast Growth Factor 21 (Fgf21), and gene expression changes in the liver of male and female mice. C57BL/6 mice were treated with seladelpar 10 mg/kg/day or vehicle through oral gavage before lights out on Day 1 (single dose) or from Day 1 to Day 7 (multiple doses). Liver samples were obtained at 0, 1, 2, 4, 8, 12, 16, and 24 h postdosing, and plasma C4 and Fgf21 levels were measured. In vehicle-treated mice, C4 levels were higher in the dark cycle compared to the light cycle, with higher levels in females than in males. Plasma Fgf21 did not vary substantially over the dark-light cycle or show a sex-specific expression pattern. Seladelpar treatment significantly reduced plasma C4 and increased Fgf21 levels in both sexes, which coincided with a decrease in cholesterol 7α-hydroxylase mRNA and an increase in Fgf21 mRNA in the livers. Untargeted RNA sequencing revealed a strong correlation between the genes differentially expressed after single- and multiple-dose seladelpar treatment. PPAR-responsive genes, including pyruvate dehydrogenase kinase 4, acyl-CoA thioesterase 2, and angiopoietin-like 4, were upregulated. No changes in nuclear receptors, clock genes, and sex-specific genes were observed. Overall, these results are consistent with a model where seladelpar treatment reduces bile acid synthesis by upregulating Fgf21 and modulating other PPAR-responsive genes.
Perivascular adipose tissue (PVAT) plays a crucial role in vascular homeostasis. Recent studies in adipose tissue demonstrated that endoplasmic reticulum (ER) stress and autophagy are activated in Type 2 diabetes mellitus (T2DM), while the precise role of ER stress and autophagy in PVAT is unclear. We aimed to investigate the possible influence of pioglitazone on ER stress and autophagy response in PVAT of T2DM rats. T2DM was induced by high‐fat diet/low‐dose streptozotocin (HFD/STZ) in male Wistar rats (8–10 weeks), and pioglitazone (20 mg/kg/p.o.) was administered for 6 weeks. Changes in biochemical parameters (nonfasting glucose, total cholesterol, and triglyceride) were verified in blood samples. ER stress–related ( ATF4 , CHOP , and GRP78 ) and autophagy‐related ( MAP1LC3B /LC3‐II, BECN-1/ Beclin, and SQSTM1 /p62) gene expression levels in thoracic PVAT were measured by RT‐PCR. Pioglitazone treatment reversed the increased nonfasting glucose and triglyceride levels in T2DM. ER stress and autophagy responses were significantly increased in PVAT of T2DM rats. Pioglitazone increased ER stress–related GRP78 gene expression while decreasing autophagy‐related MAP1LC3B and BECN-1 gene expression levels in T2DM. Interestingly, SQSTM1 gene expression levels were increased by pioglitazone in the control and T2DM groups. The current study provides original findings regarding the effects of pioglitazone on ER stress and autophagy response in PVAT of HFD/STZ‐induced T2DM rats. Pioglitazone treatment in T2DM increased GRP78 and SQSTM1 gene expressions, which both play a crucial role in adipocyte differentiation and adipogenesis, besides ER stress and autophagy. Further studies clarifying the adipogenic effect of pioglitazone on PVAT are needed for a better understanding of its effect on the vascular system.
Background: Hyperlipidemia is a critical risk factor for obesity, diabetes, cardiovascular diseases, and other chronic diseases. Our study was to determine the effects and mechanism of mangiferin (MF) and epigallocatechin gallate (EGCG) compounds on improving hyperlipidemia in HepG2 cells. Methods: HepG2 cells were treated with 0.25 mM palmitic acid (PA) and then incubated with MF (12.5, 25, and 50 μM) or EGCG (25, 50, and 100 μM) or MF:EGCG (0:0, 6.25:12.5, 25:50, and 50:100 μM:μM) for 24 h. The improvement of hyperlipidemia was verified by Oil Red O staining, changes in triglyceride (TG) and free fatty acid (FFA) levels, and the expression of lipid metabolizing proteins in western blotting. Results: MF (12.5, 25, and 50 μM) or EGCG (25, 50, and 100 μM) markedly lowered lipid accumulations by lipid index levels. Furthermore, we found that the optimum concentration of MF and EGCG compounds was 25:50 (μM:μM), which significantly reduced the FFA level, TG, and total cholesterol (TC) accumulations and increased FFA uptake in HepG2 cells, and the effect was better than that of single phytochemicals. The adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) protein and its downstream proteins sirtuin 1 (SIRT1), peroxisome proliferator-activated receptor α (PPARα), and those involved in fatty acid translocase (CD36) and carnitine palmitoyltransferase 1 (CPT1) were also markedly increased in HepG2 cells. The upregulation of protein expression was reversed when AMPK-specific inhibitor Compound C was added. Conclusions: MF and EGCG (25:50 μM) compounds protect against hyperlipidemia by promoting the FFA oxidation, alleviating TG and TC accumulations via the AMPK/PPARα pathway in PA-treated HepG2 cells.
Triple-negative breast cancer (TNBC) is highly heterogeneous and poses a significant medical challenge due to limited treatment options and poor outcomes. Peroxisome proliferator-activated receptors (PPARs) play a crucial role in regulating metabolism and cell fate. While the association between PPAR signal and human cancers has been a topic of concern, its specific relationship with TNBC remains unclear. Integrated analysis of large published datasets from clinical cohorts and cell lines through databases has proven to be a powerful and essential approach for understanding cancer and uncovering new molecular targets. Here, we conducted a comprehensive study investigating the clinical relevance and drug modulation of the PPAR signaling pathway in TNBC, using data from The Cancer Genome Atlas (TCGA) for TNBC patients and Genomics of Drug Sensitivity in Cancer (GDSC) for TNBC cell lines, along with drug perturbation information from Connectivity Map (CMap). In the TCGA-TNBC cohort, higher PPAR signaling activity was not associated with clinical stage, prognosis, tumor mutational burden, microsatellite instability, homologous recombination deficiency, stemness, or proliferation status. However, it was linked to older age; an elevated rate of piccolo presynaptic cytomatrix protein (PCLO) mutations; and oncogenic signal transduction involving MAPK, Ras, and PI3K-Akt pathways. Additionally, it influenced biological pathways including fatty acid metabolism, AMPK signaling, and ferroptosis. Strikingly, higher PPAR activity appeared to promote the formation of an antitumor immune and microbial microenvironment. In the GDSC-TNBC cells, nevertheless, it seemed to incur chemoresistance. Furthermore, we identified a batch of potential compounds that can regulate the PPAR signaling pathway. Lastly, our experimental validation demonstrated the ability of the histone deacetylase (HDAC) inhibitor chidamide to activate the PPAR signal in TNBC cells. In conclusion, the PPAR signaling pathway likely has pleiotropic biological effects in TNBC. These preliminary but interesting findings enhance our understanding of the role played by PPAR signal and provide new insights into the heterogeneity driven by it in TNBC.
Paraquat (PQ) is an herbicide toxin that induces injury in different organs. The anti‐inflammatory and antioxidant effects of carvacrol were reported previously. The effects of carvacrol and pioglitazone (Pio) alone and their combination on inhaled PQ‐induced systemic and lung oxidative stress and inflammation as well as behavioral changes were examined in rats. In this study, animals were exposed to saline (control [Ctrl]) or PQ (PQ groups) aerosols. PQ‐exposed animals were treated with 0.03 mg/kg/day dexamethasone (Dexa), 20 and 80 mg/kg/day carvacrol (C‐L and C‐H), 5 mg/kg/day Pio, and Pio+C‐L for 16 days. Inhaled PQ markedly enhanced total and differential white blood cell (WBC) counts, nitric oxide (NO), and malondialdehyde (MDA) levels but decreased catalase (CAT) and superoxide dismutase (SOD) activities and thiol levels both in the bronchoalveolar lavage fluid (BALF) and blood and increased interferon‐gamma (INF‐ γ ) and interleukin‐10 (IL‐10) levels in the BALF ( p < 0.001 for all cases) except lymphocyte count in blood which was not significantly changed. The escape latency and traveled distance were increased in the PQ group. However, the time spent in the target quadrant in the Morris water maze (MWM) test and the duration of time latency in the dark room in the shuttle box test were reduced after receiving an electrical shock ( p < 0.05– p < 0.001). Inhaled PQ‐induced changes were significantly improved in carvacrol, Pio, Dexa, and especially in the combination of the Pio+C‐L treated groups ( p < 0.05– p < 0.001). Carvacrol and Pio improved PQ‐induced changes similar to Dexa, but ameliorative effects produced by combination treatments of Pio+C‐L were more prominent than Pio and C‐L alone, suggesting a potentiating effect for the combination of the two agents.
Partial and full PPAR‐γ agonists have shown promising effects and antihypertensive and antidiabetic agents through increased plasma adiponectin concentration. This study is aimed at examining the role of PPAR‐γ, alpha‐adrenoceptors, and adiponectin receptors in the modulation of vasopressor responses to angiotensin II (Ang II) and adrenergic agonists, after a subset treatment of partial and full PPAR‐γ agonists, each individually, and also when coupled with adiponectin in SHRs. The antioxidant potential and metabolic indices for these animals were also determined. Group I (WKY) and group II (SHR) were designated as normotensive control and hypertensive control, respectively. Groups III (SHR) and IV (SHR) received irbesartan (30 mg/kg) and pioglitazone (10 mg/kg) orally for 28 days, and groups V (SHR), VI (SHR), and VII (SHR) were treated with adiponectin (2.5 μg/kg) intraperitoneally alone, in combination with irbesartan, and in combination with pioglitazone, respectively, from days 21 to 28 only. On day 29, sodium pentobarbitone (60 mg/kg) was used to anesthetize all test animals, and systemic hemodynamic and plasma adiponectin concentrations and in vitro and in vivo antioxidant potential were measured. As compared to the WKY control, the SHR control group’s noninvasive blood pressure and basal mean arterial pressure were significantly greater, along with increased arterial stiffness, lower plasma nitric oxide, adiponectin concentration, and antioxidant enzyme levels (all P < 0.05). However, they were gradually normalized by single drug treatments in all groups, and to a greater extent in the SHR + Irb + Adp group (P < 0.05). In the acute study, the dose dependant mean arterial pressure responses to intravenously administered adrenergic agonists and angiotensin‐II were significantly larger in SHRs as compared to WKY by 20‐25%. Adiponectin alone and in combination significantly blunted vasopressor responses to these alpha‐adrenergic agonists in the SHR + Pio + Adp group by 63%, whereas attenuated responses to ANG‐II administration to 70% in SHR + Irb + Adp. In conclusion, the combined treatment of adiponectin with PPAR‐agonists reduced the systemic vascular responses to adrenergic agonists and improved arterial stiffness. This an evidence of the interaction of adiponectin receptors, PPAR‐γ, alpha‐adrenoceptors, and ANG‐II in the systemic vasculature of SHRs. A significant level of synergism has also been proved among full PPAR‐γ agonists and adiponectin receptors.
We have previously reported the identification of a novel splicing variant of the mouse peroxisome proliferator‐activated receptor‐γ (Pparγ), referred to as Pparγ1sv. This variant, encoding the PPARγ1 protein, is abundantly and ubiquitously expressed, playing a crucial role in adipogenesis. Pparγ1sv possesses a unique promoter and 5 ′ untranslated region (5 ′UTR), distinct from those of the canonical mouse Pparγ1 and Pparγ2 mRNAs. We observed a significant increase in DNA methylation at two CpG sites within the proximal promoter region (‐733 to ‐76) of Pparγ1sv during adipocyte differentiation. Concurrently, chromatin immunoprecipitation‐quantitative PCR (ChIP‐qPCR) using antibodies against H3K4me3 and H3K27ac indicated marked elevations in both methylation and acetylation of histone H3, while the repressive histone mark H3K9me2 significantly decreased, at the transcription start sites of both Pparγ1sv and Pparγ2 following differentiation. Knocking down Pparγ1sv using specific siRNA also led to a decrease in Pparγ2 mRNA and PPARγ2 protein levels; conversely, knocking down Pparγ2 resulted in reduced Pparγ1sv mRNA and PPARγ1 protein levels, suggesting synergistic transcriptional regulation of Pparγ1sv and Pparγ2 during adipogenesis. Furthermore, our experiments utilizing the CRISPR‐Cas9 system identified crucial PPARγ‐binding sites within the Pparγ gene locus, underscoring their significance in adipogenesis. Based on these findings, we propose a model of positive feedback regulation for Pparγ1sv and Pparγ2 expression during the adipocyte differentiation process in 3T3‐L1 cells.
It has been demonstrated that PPARG may interact with the PTEN-PI3K/AKT pathway, contributing to its involvement in the chemotherapy treatment of hypopharyngeal squamous cell carcinoma (HSCC). However, the underlying mechanism remains largely unknown. In this study, gene expression profiles of 17 HSCC patients, comprising 8 chemotherapy-sensitive patients (CSP) and 9 chemotherapy-nonsensitive patients (CNSP), were collected and analyzed to investigate expression patterns, correlations, influencing factors of the PPARG-PTEN-PI3K/AKT pathway, and its role in regulating chemosensitivity. The results revealed significantly increased expression (p<0.04) of AKT1, AKT2, AKT3, PIK3CA, PPARG, and PTEN in the CSP group compared to the CNSP group. Specifically, AKT2 exhibited significant overexpression in tumor tissue (p=0.01), while AKT2, AKT3, PPARG, and PTEN displayed significant increases in normal tissue (p≤0.04). Positive correlations (R∈0.43,0.71, p<0.014) were observed between PIK3CA, AKT1, AKT2, AKT3, and PTEN, with AKT2, AKT3, and PTEN also showing significant correlations with PPARG (R∈0.35,0.47, p<0.04). Age, gender, and disease stage had no influence on PPARG, PIK3CA, and PTEN expression, but they may affect AKT expressions. Pathway analysis revealed that PPARG may interact with the PTEN-PI3K/AKT signaling pathway, playing a crucial role in regulating chemosensitivity in the normal tissue microenvironment. Our results suggest that AKT1 and PIK3CA may be associated with chemosensitivity in HSCC tumor cells, while PPARG and PTEN might exhibit a correlation with a specific segment of the PI3K/AKT pathway, potentially influencing chemosensitivity in the normal tissue microenvironment of HSCC patients.
A ligand-activated transcription factor, peroxisome proliferator-activated receptor (PPAR) regulates fatty acid uptake and transport. In several studies, upregulation of PPAR expression/activity by cancer cells has been associated with cancer progression. Worldwide, cancer of the cervix ranks fourth among women’s cancers. Angiogenesis inhibitors have improved treatment for recurrent and advanced cervical cancer since their introduction 5 years ago. In spite of that, the median overall survival rate for advanced cervical cancer is 16.8 months, indicating that treatment effectiveness is still lacking. Thus, it is imperative that new therapeutic methods be developed. In this work, we first downloaded the PPAR signaling pathway-related genes from the previous study. In addition, the single-sample gene set enrichment analysis (ssGSEA) algorithm was applied to calculate the PPAR score of patients with cervical cancer. Furthermore, cervical cancer patients with different PPAR scores show different sensitivity to immune checkpoint therapy. In order to screen the genes to serve as the best biomarker for cervical cancer patients, we then construct the PPAR-based prognostic prediction model. The results revealed that PCK1, MT1A, AL096855.1, AC096711.2, FAR2P2, and AC099568.2 not only play a key role in the PPAR signaling pathway but also show good predictive value in cervical cancer patients. The gene set variation analysis (GSVA) enrichment analysis also proved that the PPAR signaling pathway is one of the most enriched pathways in the prognostic prediction model. Finally, further analysis revealed that AC099568.2 may be the most promising biomarker for the diagnosis, treatment, and prognosis in cervical cancer patients. Both the survival analysis and Receiver Operating Characteristic curve demonstrated that AC099568.2 plays a key role in cervical cancer patients. However, to our knowledge, this is the first time a study focused on the role of AC099568.2 in cervical cancer patients. Our work successfully revealed a new biomarker for cervical cancer patients, which also provides a new direction for future research.
Introduction Buspirone, as a partial agonist for a 5-hydroxytryptamine (serotonin) receptor 1A (5-HT1A), has been prescribed as an anxiolytic drug for patients. In addition, the lowering effect of serotonin on blood pressure was reported in hypertensive animal model. We investigated the therapeutic mechanism of buspirone against lipid metabolism disturbed by hypertension of early stage via hypertensive and obese animal model. Methods The levels of various biomarkers related to lipid metabolism and hypertension were estimated through the measurement of body weight and fat weight, blood analysis, western blotting, immunohistochemistry, and staining methods. Results The lipid accumulation was lowered in differentiated 3T3-L1 cells by buspirone treatments of 50 and 100 μM compared with untreated differentiated control. Body weight and abdominal fat weight were lowered in spontaneously hypertensive rats (SHRs) administered with buspirone of 10 mg/kg/day for 4 weeks than 8-week untreated group. Triglyceride (TG) level was decreased in SHRs administered with buspirone of 5 and 10 mg/kg/day compared to 8-week untreated group. High-density lipoprotein (HDL)-cholesterol concentration was elevated by buspirone 10 mg/kg/day treatment compared to 8-week untreated group. Blood pressures in SHRs were lowered by buspirone treatments of 5 and 10 mg/kg/day compared with 8-week untreated group. Protein levels for peroxisome proliferator-activated receptor δ (PPARδ), 5′ adenosine monophosphate-activated protein kinase (AMPK), and PPARγ coactivator-1 alpha (PGC-1α) were increased both in C2C12 cells treated by buspirone of 100 μM and in SHRs administered by buspirone of 1, 5, and 10 mg/kg/day compared to untreated control cells and 8-week untreated group. Fat cell numbers decreased in 8-week untreated group were increased in SHRs administered by buspirone treats of 1, 5, and 10 mg/kg/day. Protein expression levels for angiotensin II type 1 receptor (AT1R) and vascular cell adhesion molecule 1 (VCAM1) were increased in 8-week untreated group compared to 4-week group, however, they were decreased by buspirone treatments of 1, 5, and 10 mg/kg/day. Conclusion Buspirone may induce the losses of body weight and abdominal fat weight through the activation of PPARδ dependent catabolic metabolism producing energy, and eventually, the ameliorated lipid metabolism could normalize high blood pressure.
Osteoarthritis (OA) is a common degenerative joint disease with a gradually increasing morbidity in the aging and obese population. Emerging evidence has implicated pyroptosis in the etiology of OA and it may be recognized as a therapeutic target in OA. We have previously reported regarding another disease that peroxisome proliferator-activated receptor gamma (PPAR-γ) activation exerts an anti-inflammatory effect by suppressing the nucleotide-binding and oligomerization domain-like receptor containing protein (NLRP) 3 inflammasome. However, the relationship between PPAR-γ and NLRP3-mediated pyroptosis in OA cartilage and its underlying mechanisms is fully unclear. In this study, we found that the level of NLRP3-mediated pyroptosis in severe lateral femoral condyle cartilage wear in the knee of an OA patient was significantly higher than that in the mild lateral femoral condyle cartilage wear areas. Moreover, in lipopolysaccharide (LPS)/adenosine triphosphate (ATP)-induced primary chondrocytes and knee OA rat models, we demonstrated that activation of PPAR-γ by pioglitazone (Piog) attenuated LPS/ATP-induced chondrocyte pyroptosis and arthritis. These effects were partially counteracted by either blocking the nuclear factor erythroid-2-related factor (Nrf2)/NLRP3 or PGC1-α/Δψm signaling pathway. Simultaneous depression of these two signaling pathways can completely abrogate the protective effects of Piog on OA and chondrocytes. Taken together, Piog protects OA cartilage against pyroptosis-induced damage by simultaneously activating both the Nrf2/NLRP3 and PGC-1α/Δψm pathways, which enhances antioxidative and anti-inflammatory responses as well as mitochondrial biogenesis. Therefore, Piog may be a promising agent for human OA cartilage damage in future clinical treatments.
Peroxisome proliferator-activated receptor gamma (PPARγ) is a key nuclear receptor transcription factor that is highly expressed in trophoblastic cells during embryonic attachment and is accompanied by rapid cell proliferation and increased lipid accumulation. We previously showed that the autophagy pathway is activated in cells after activation of PPARγ, accompanied by increased lipid accumulation. In this study, we used PPARγ agonist rosiglitazone and inhibitor GW9662, as well as autophagy activator rapamycin and inhibitor 3-methyladenine, to unravel the probable mechanism of PPARγ engaged in lipid metabolism in sheep trophoblast cells (STCs). After 12 h, 24 h, and 48 h of drug treatment, the levels of autophagy-related proteins were detected by Western blot, the triglyceride content and MDA level of cells were detected by colorimetry, and the lipid droplets and lysosomes were localized by immunofluorescence. We found that PPARγ inhibited the activity of mammalian target of rapamycin (mTOR) pathway in STCs for a certain period of time, promoted the increase of autophagy and lysosome formation, and enhanced the accumulation of lipid droplets and triglycerides. Compared with cells whose PPARγ function is activated, blocking autophagy before activating PPARγ will hinder lipid accumulation in STCs. Pretreatment of cells with rapamycin promoted autophagy with results similar to rosiglitazone treatment, while inhibition of autophagy with 3-methyladenine reduced lysosome and lipid accumulation. Based on these observations, we conclude that PPARγ can induce autophagy by blocking the mTOR pathway, thereby promoting the accumulation of lipid droplets and lysosomal degradation, providing an energy basis for the rapid proliferation of trophoblast cells during embryo implantation. In brief, this study partially revealed the molecular regulatory mechanism of PPARγ, mTOR pathway, and autophagy on trophoblast cell lipid metabolism, which provides a theoretical basis for further exploring the functional regulatory network of trophoblast cells during the attachment of sheep embryos.
