Role Of Peroxisome Proliferator-activated Receptors Research Articles

PPARβ/δ attenuates hepatic fibrosis by reducing SMAD3 phosphorylation and p300 levels via AMPK in hepatic stellate cells

The role of peroxisome proliferator-activated receptor (PPAR)β/δ in hepatic fibrosis remains a subject of debate. Here, we examined the effects of a PPARβ/δ agonist on the pathogenesis of liver fibrosis and the activation of hepatic stellate cells (HSCs), the main effector cells in liver fibrosis, in response to the pro-fibrotic stimulus transforming growth factor-β (TGF-β). The PPARβ/δ agonist GW501516 completely prevented glucose intolerance and peripheral insulin resistance, blocked the accumulation of collagen in the liver, and attenuated the expression of inflammatory and fibrogenic genes in mice fed a choline-deficient high-fat diet (CD-HFD). The antifibrogenic effect of GW501516 observed in the livers CD-HFD-fed mice could occur through an action on HSCs since primary HSCs isolated from Ppard-/- mice showed increased mRNA levels of the profibrotic gene Col1a1. Moreover, PPARβ/δ activation abrogated TGF-β1-mediated cell migration (an indicator of cell activation) in LX-2 cells (immortalized activated human HSCs). Likewise, GW501516 attenuated the phosphorylation of the main downstream intracellular protein target of TGF-β1, suppressor of mothers against decapentaplegic (SMAD)3, as well as the levels of the SMAD3 co-activator p300 via the activation of AMP-activated protein kinase (AMPK) and the subsequent inhibition of extracellular signal-regulated kinase-1/2 (ERK1/2) in LX-2 cells. Overall, these findings uncover a new mechanism by which the activation of AMPK by a PPARβ/δ agonist reduces TGF-β1-mediated activation of HSCs and fibrosis via the reduction of both SMAD3 phosphorylation and p300 levels.

Deciphering the Role of Peroxisome Proliferator-activated Receptor α and Phosphodiesterase Type 5 Targets in Alzheimer's Disease.

The most prevalent cause of dementia is Alzheimer's disease (AD). Although the global AD rate is on a constant rise, medical research is yet to find a cure for this neurological condition. Current available therapeutic drugs for AD treatment only provide symptomatic alleviation. Therefore, it is essential to establish effective AD treatment strategies in addressing clinical needs. The development of disease-modifying treatments for use in the disease's early stages and the advancement of symptomatic drugs principally used in the disease's later stages are priorities in AD research. Given that the etiology of AD is difficult to comprehend, using a multimodal therapy intervention that targets molecular targets of AD-related degenerative processes is a practical strategy to change the course of AD progression. The current review article discussed PPAR-α (Peroxisome proliferator-activated receptor-α) and PDE5 (Phosphodiesterase type 5) targets with evidence for their preclinical and clinical importance. Furthermore, we support the targets with AD-related processes, functions, and remedial measures. A unique synergistic method for treating AD may involve the beneficial combinatorial targeting of these two receptors. Furthermore, we reviewed different PDE chemical families in this research and identified PDE5 inhibitors as one of the promising AD-related experimental and clinical disease-modifying medications. Lastly, we suggest jointly targeting these two pathways would be more beneficial than monotherapy in AD treatments.

The role of peroxisome proliferator-activated receptors in endometriosis.

Endometriosis constitutes the most common cause of chronic pelvic pain in female patients and is associated with infertility. Although there is no known cause for the disease, it is a heritable condition that is determined by numerous genetic, epigenetic, and environmental aspects. Peroxisome proliferator-activated receptors (PPARs) represent nuclear receptor proteins that control gene expression. By using the MEDLINE and LIVIVO databases we conducted a literature review in order to look into the role of PPARs in the endometriosis pathophysiology and succeeded in revealing 36 pertinent publications between 2001 and 2022. In regards to PPAR expression in endometriosis, PPARγ seems to represent the most studied PPAR isoform in endometriosis and to influence various pathways involved in the disease onset and progression. It's interesting to note that diverse treatment agents targeting the PPAR system have been identified as innovative, effective therapeutic alternatives in the context of endometriosis treatment. In conclusion, PPARs appear to contribute an important role in both endometriosis pathophysiology and therapy.

Abstract 6858: PPARδ and type 1 interferon collaboratively regulate CIITA-MHCII pathway: Unveiling novel mechanisms of tumor Tregs

Abstract Regulatory T cells (Tregs) play an essential role in suppressing anti-tumor immunity, often resulting in unfavorable clinical outcomes across numerous cancers. However, systemic Treg depletion, while augmenting anti-tumor responses, also triggers detrimental autoimmune disorders. Thus, dissecting the mechanisms by which Tregs navigate and exert their functions within the tumor microenvironment (TME) is pivotal for devising innovative Treg-centric cancer therapies. Our study highlights the role of peroxisome proliferator-activated receptor β/δ (PPARδ), a nuclear hormone receptor involved in fatty acid metabolism. Remarkably, PPARδ ablation in Tregs escalated tumor growth and augmented the immunosuppressive characteristics of the TME. This absence of PPARδ spurred an increased expression of genes central to antigen presentation, notably CIITA and MHCII. Our results showcase a novel association where the absence of CIITA in PPARδ-deficient Tregs bolsters anti-tumor responses, casting CIITA as a pivotal downstream regulator of PPARδ within Tregs. In vitro assays demonstrated that elevated CIITA levels enhance the suppressive capacity of Tregs, facilitated by an antigen-independent interaction between Treg-MHCII and Tconv-TCR/CD4/Lag3. A significant revelation was the role of type 1 interferon as a TME signal that promotes the genesis of MHCII+ Tregs; this process is accentuated by PPARδ deficiency. In conclusion, the co-regulation between TME cues and PPARδ signaling shapes the adaptive and suppressive roles of Treg cells through the CIITA-MHCII pathway. Strategically targeting the potent MHCII+ Treg population could open a new avenue for cancer therapies by boosting anti-tumor defenses while curbing autoimmune threats. Citation Format: Qiyuan Yang, Yuqiong Liang, Ye Zheng. PPARδ and type 1 interferon collaboratively regulate CIITA-MHCII pathway: Unveiling novel mechanisms of tumor Tregs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6858.

Peroxisome proliferator-activated receptors and placental function in women with polycystic ovary syndrome.

Adverse pregnancy outcomes in women with polycystic ovary syndrome (PCOS) are frequently associated with abnormal placental functions. This review explores the involvement of proliferator-activated receptors (PPARs) in these processes, to gain molecular insights into abnormal pregnancy conditions associated with PCOS. Polycystic ovary syndrome (PCOS) is one of the major endocrine disorders affecting women during their reproductive ages.Given its association with other pathologies, such as insulin resistance, metabolic syndrome, type 2 diabetes, and obesity, women with PCOS could present high-risk pregnancies, including a high abortion rate, implantation failure, an increased risk of gestational diabetes, preeclampsia, and intrauterine growth restriction. These adverse pregnancy outcomes are often attributed, at least in part, to defects in placental functions. Peroxisome proliferator-activated receptors (PPARs) are important transcription factors that participate in various placental pathways, regulating the expression of genes involved in lipid and glucose metabolism and inflammation. Furthermore, PPARs have been shown to play a role in placental development and function. Taking together this evidence, the present review focuses on the role of PPARs in placental tissue and discusses their implications in the pregnancy outcomes commonly associated with the presence of PCOS. In addition, the main treatments frequently employed have also been discussed.

Identification and analysis of prognostic metabolic characteristics in colon adenocarcinoma

Colon adenocarcinoma (COAD) is a highly lethal gastrointestinal malignancy. The five-year survival rate of metastatic colorectal cancer remains low, at 14 percent. Numerous publications have suggested a role for peroxisome proliferator-activated receptors (PPARs) in malignancy. Recent studies have shown that PPARs, as nuclear transcription factors, may serve as potential targets for the treatment of metabolic syndrome tumors and their associated complications. However, the molecular mechanism has not been thoroughly investigated. Hence, in order to enhance the prediction of personalized medicine for PPAR-associated modulators in malignancy treatment, a timely review becomes essential. Utilizing TCGA-COAD expression profile data and patient overall survival (OS) information, this study systematically conducted investigations to identify and develop Hub stem cell-related diagnostic and prognostic identification models, aiming to enhance the multi-gene markers for COAD. Utilizing the differential expression profiles of stem cell-related genes, an 11-gene (SLC27A4, CPT1C, CPT1B, CPT2, CYP4A11, FABP3, FABP7, AQP7, MMP1, ACOX1, ANGPTL4) diagnostic and prognostic model was developed. This model demonstrated precise diagnostic and prognostic capabilities and holds the potential to characterize the clinicopathologic features of COAD. Univariate and multivariate Cox proportional hazards regression analyses were conducted to ascertain the independent factors influencing OS outcomes in COAD. The results revealed that CPT1B, SLC27A4, and FABP3 were identified as independent risk prognostic factors for OS in COAD, whereas ACOX1 and CPT2 served as independent protective prognostic factors. The hub genes associated with PPARs were identified through the differential expression of contrast agent COAD and normal tissues. Finally, the investigation of variations in immune infiltration and the analysis of relevant biological pathways validate the prognostic significance of the independent post-factors within this molecular model. This research aims to provide references for comprehending the mechanism of post-transcriptional regulation of COAD and molecular therapy.

The role of peroxisome proliferator-activated receptors in the regulation of bile acid metabolism.

Bile acids are synthesized from cholesterol in the liver. Dysregulation of bile acid homeostasis, characterized by excessive accumulation in the liver, gallbladder and blood, can lead to hepatocellular damage and the development of cholestatic liver disease. Nuclear receptors play a crucial role in the control of bile acid metabolism by efficiently regulating bile acid synthesis and transport in the liver. Among these receptors, peroxisome proliferator-activated receptor (PPAR), a ligand-activated transcription factor belonging to the nuclear hormone receptor superfamily, controls the expression of genes involved in adipogenesis, lipid metabolism, inflammation and glucose homeostasis and has emerged as a potential therapeutic target for the treatment of the metabolic syndrome in the past two decades. Emerging evidence suggests that PPAR activation holds promise as a therapeutic target for cholestatic liver disease, as it affects both bile acid production and transport. This review provides a comprehensive overview of recent advances in elucidating the role of PPAR in the regulation of bile acid metabolism, highlighting the current position of PPAR agonists in the treatment of primary biliary cholangitis. By summarizing the specific regulatory effects of PPAR on bile acids, this review contributes to the exploration of novel therapeutic strategies for cholestatic liver diseases.

Roles of peroxisome proliferator-activated receptors in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC), the main pathological type of liver cancer, is linked to risk factors such as viral hepatitis, alcohol intake and non-alcoholic fatty liver disease (NAFLD). Recent advances have greatly improved our understanding that NAFLD is playing a major risk factor for HCC. Peroxisome proliferator-activated receptors (PPARs) are a class of transcription factors divided into three subtypes: PPARα (PPARA), PPARδ/β (PPARD) and PPARγ (PPARG). As important nuclear receptors, PPARs are involved in many physiological processes, and PPARs can improve NAFLD by regulating lipid metabolism, accelerating fatty acid oxidation and inhibiting inflammation. In recent years, some studies have shown that PPARs can participate in the occurrence and development of HCC by regulating metabolic pathways. In addition, PPAR modulators have been reported to inhibit the proliferation and metastasis of HCC cells and can enhance the curative effect of conventional treatments. This article reviews the role of PPARs in the occurrence and development of HCC, as well as its value in the diagnosis, treatment and prognosis of HCC, in order to provide directions for future research.

An Overview of the Role of Peroxisome Proliferator-activated Receptors in Liver Diseases.

Peroxisome proliferator-activated receptors (PPARs) are a superfamily of nuclear transcription receptors, consisting of PPARα, PPARγ, and PPARβ/δ, which are highly expressed in the liver. They control and modulate the expression of a large number of genes involved in metabolism and energy homeostasis, oxidative stress, inflammation, and even apoptosis in the liver. Therefore, they have critical roles in the pathophysiology of hepatic diseases. This review provides a general insight into the role of PPARs in liver diseases and some of their agonists in the clinic.

PPARs at the crossroads of T cell differentiation and type 1 diabetes.

T-cell-mediated autoimmune type 1 diabetes (T1D) is characterized by the immune-mediated destruction of pancreatic beta cells (β-cells). The increasing prevalence of T1D poses significant challenges to the healthcare system, particularly in countries with struggling economies. This review paper highlights the multifaceted roles of Peroxisome Proliferator-Activated Receptors (PPARs) in the context of T1D, shedding light on their potential as regulators of immune responses and β-cell biology. Recent research has elucidated the intricate interplay between CD4+ T cell subsets, such as Tregs and Th17, in developing autoimmune diseases like T1D. Th17 cells drive inflammation, while Tregs exert immunosuppressive functions, highlighting the delicate balance crucial for immune homeostasis. Immunotherapy has shown promise in reinstating self-tolerance and restricting the destruction of autoimmune responses, but further investigations are required to refine these therapeutic strategies. Intriguingly, PPARs, initially recognized for their role in lipid metabolism, have emerged as potent modulators of inflammation in autoimmune diseases, particularly in T1D. Although evidence suggests that PPARs affect the β-cell function, their influence on T-cell responses and their potential impact on T1D remains largely unexplored. It was noted that PPARα is involved in restricting the transcription of IL17A and enhancing the expression of Foxp3 by minimizing its proteasomal degradation. Thus, antagonizing PPARs may exert beneficial effects in regulating the differentiation of CD4+ T cells and preventing T1D. Therefore, this review advocates for comprehensive investigations to delineate the precise roles of PPARs in T1D pathogenesis, offering innovative therapeutic avenues that target both the immune system and pancreatic function. This review paper seeks to bridge the knowledge gap between PPARs, immune responses, and T1D, providing insights that may revolutionize the treatment landscape for this autoimmune disorder. Moreover, further studies involving PPAR agonists in non-obese diabetic (NOD) mice hold promise for developing novel T1D therapies.

PPARα/γ synergism activates UCP1-dependent and -independent thermogenesis and improves mitochondrial dynamics in the beige adipocytes of high-fat fed mice

ObjectiveThe aim of this study was to investigate the role of peroxisome proliferator-activated receptor (PPAR) activation (single PPARα or PPARγ, and dual PPARα/γ) on UCP1-dependent and -independent thermogenic pathways and mitochondrial metabolism in the subcutaneous white adipose tissue of mice fed a high-fat diet. MethodsMale C57BL/6 mice received either a control diet (10% lipids) or a high-fat diet (HF; 50% lipids) for 12 wk. The HF group was divided to receive the treatments for 4 wk: HFγ (pioglitazone, 10 mg/kg), HFα (WY-14643, 3.5 mg/kg), and HFα/γ (tesaglitazar, 4 mg/kg). ResultsThe HF group was overweight, insulin resistant, and had subcutaneous white adipocyte dysfunction. Treatment with PPARα and PPARα/γ reduced body mass, mitigated insulin resistance, and induced browning with increased UCP1-dependent and -independent thermogenesis activation and improved mitochondrial metabolism to support the beige adipocyte phenotype. ConclusionPPARα and dual PPARα/γ activation recruited UCP1+ beige adipocytes and favored UCP1-independent thermogenesis, yielding body mass and insulin sensitivity normalization. Preserved mitochondrial metabolism emerges as a potential target for obesity treatment using PPAR agonists, with possible clinical applications.

Pioglitazone protects PC12 cells against oxidative stress injury: An invitro study of its antiapoptotic effects via the PPARγ pathway.

To the best of our knowledge, the role of peroxisome proliferator-activated receptor γ (PPARγ) in oxidative stress-induced PC12 cell damage is unknown. Using a PC12 cell model with H2O2 treatment, the present study investigated the expression levels of apoptosis-related genes and neuronal apoptosis after oxidative stress injury. The present study further investigated the protective effect and mechanism of pioglitazone, a PPARγ agonist. PC12 cells treated with H2O2 were used as a model of oxidative stress injury. An MTT assay and flow cytometry were used to detect the effect of H2O2 on PC12 cell viability and the protective effect of pioglitazone. A TUNEL assay was used to detect neuronal apoptosis. The expression levels of PPARγ, Bax, Bcl-2 and caspase-3 were examined by reverse transcription-quantitative PCR and western blotting. H2O2 reduced PC12 cell viability in a dose- and time-dependent manner. H2O2 significantly upregulated the protein expression levels of Bax and the cleaved caspase-3/caspase-3 ratio (P<0.01), decreased the protein expression levels of Bcl-2 (P<0.01), and increased the apoptosis rate of PC12 cells. Pioglitazone significantly reduced the protein expression levels of Bax and the cleaved caspase-3/caspase-3 ratio (P<0.01), increased the expression levels of Bcl-2 (P<0.01), decreased the Bax/Bcl-2 expression ratio (P<0.01) and increased the viability of H2O2-damaged PC12 cells in a dose-dependent manner. Treatment with the PPARγ antagonist GW9662 or PPARγ small interfering RNA counteracted the protective effect of pioglitazone on PC12 cells to different extents (P<0.01). Therefore, the present study reported the role of PPARγ in protecting PC12 cells against oxidative stress injury, which may lead to novel therapeutic approaches for neurodegenerative diseases.

Effects of enteral nutrition supplemented with octanoic acid on lipopolysaccharide-induced intestinal injury: role of peroxisome proliferator-activated receptor γ/STAT-1/myeloid differentiation factor 88 pathway

ObjectiveEnteral nutrition is the key therapy in septic patients. Different formulas of enteral nutrition have various effects on gastrointestinal sepsis. Therefore, we investigated the effects of enteral nutrition supplemented with octanoic acid on lipopolysaccharide-induced intestinal injury and explored the potential mechanism. MethodsFirst, to investigate the effects of enteral nutrition supplemented with octanoic acid on lipopolysaccharide-induced intestinal injury, rats were randomly divided into four groups: sham, lipopolysaccharide, lipopolysaccharide + enteral nutrition, and lipopolysaccharide + enteral nutrition + octanoic acid. Then, to explore whether enteral nutrition supplemented with octanoic acid can prevent lipopolysaccharide-induced intestinal injury via the peroxisome proliferator-activated receptor γ/STAT-1/myeloid differentiation factor 88 pathway, rats were randomly divided into five groups: sham, lipopolysaccharide, lipopolysaccharide + enteral nutrition + octanoic acid, lipopolysaccharide + enteral nutrition + octanoic acid + SR202, and lipopolysaccharide + pioglitazone. All rats received nutritional support for 3 d. We examined the serum levels of inflammatory factors, pathologic changes, goblet cell density, intestinal tight junction protein expression, and the peroxisome proliferator-activated receptor γ/STAT-1/myeloid differentiation factor 88 pathway in the ileum and colon. The effect of octanoic acid on intestinal epithelium injury was also explored in vitro. ResultsEnteral nutrition supplemented with octanoic acid significantly decreased the serum levels of inflammatory factors and prevented intestinal barrier dysfunction compared with enteral nutrition alone (P < 0.05). Inhibiting the peroxisome proliferator-activated receptor γ/STAT-1/myeloid differentiation factor 88 pathway exacerbated effects of enteral nutrition supplemented with octanoic acid on intestinal injury (P < 0.05). Activation of the peroxisome proliferator-activated receptor γ/STAT-1/myeloid differentiation factor 88 pathway prevented intestinal injury (P < 0.05). Octanoic acid also exerted a similar effect on intestinal epithelium injury in vitro. ConclusionsEnteral nutrition supplemented with octanoic acid prevents lipopolysaccharide-induced intestinal injury via the peroxisome proliferator-activated receptor γ/STAT-1/myeloid differentiation factor 88 pathway.

The role of peroxisome proliferator-activated receptor γ in lipid metabolism and inflammation in atherosclerosis.

Cardiovascular disease events are the result of functional and structural abnormalities in the arteries and heart. Atherosclerosis is the main cause and pathological basis of cardiovascular diseases. Atherosclerosis is a multifactorial disease associated with dyslipidemia, inflammation, and oxidative stress, among which dyslipidemia and chronic inflammation occur in all processes. Under the influence of lipoproteins, the arterial intima causes inflammation, necrosis, fibrosis, and calcification, leading to plaque formation in specific parts of the artery, which further develops into plaque rupture and secondary thrombosis. Foam cell formation from macrophages is an early event in the development of atherosclerosis. Lipid uptake causes a vascular inflammatory response, and persistent inflammatory infiltration in the lesion area further promotes the development of the disease. Inhibition of macrophage differentiation into foam cell and reduction of the level of proinflammatory factors in macrophages can effectively alleviate the occurrence and development of atherosclerosis. Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated nuclear receptor that plays an important antiatherosclerotic role by regulating triglyceride metabolism, lipid uptake, cholesterol efflux, macrophage polarity, and inhibiting inflammatory signaling pathways. In addition, PPARγ shifts its binding to ligands and co-activators or co-repressors of transcription of target genes through posttranslational modification, thereby affecting the regulation of its downstream target genes. Many ligand agonists have also been developed targeting PPARγ. In this review, we summarized the role of PPARγ in lipid metabolism and inflammation in development of atherosclerosis, the posttranslational regulatory mechanism of PPARγ, and further discusses the value of PPARγ as an antiatherosclerosis target.

The Role of Peroxisome Proliferator-Activated Receptors in Endometrial Cancer.

Endometrial carcinoma is the most common malignant tumor of the female genital tract in the United States. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptor proteins which regulate gene expression. In order to investigate the role of PPARs in endometrial cancer, we conducted a literature review using the MEDLINE and LIVIVO databases and were able to identify 27 relevant studies published between 2000 and 2023. The PPARα and PPARβ/δ isoforms seemed to be upregulated, whereas PPARγ levels were reported to be significantly lower in endometrial cancer cells. Interestingly, PPAR agonists were found to represent potent anti-cancer therapeutic alternatives. In conclusion, PPARs seem to play a significant role in endometrial cancer.

The role of peroxisome proliferator-activated receptors in the tumor microenvironment, tumor cell metabolism, and anticancer therapy.

Peroxisome proliferator-activated receptors (PPARs) have been extensively studied for over 3decades and consist of three isotypes, including PPARα, γ, and β/δ, that were originally considered key metabolic regulators controlling energy homeostasis in the body. Cancer has become a leading cause of human mortality worldwide, and the role of peroxisome proliferator-activated receptors in cancer is increasingly being investigated, especially the deep molecular mechanisms and effective cancer therapies. Peroxisome proliferator-activated receptors are an important class of lipid sensors and are involved in the regulation of multiple metabolic pathways and cell fate. They can regulate cancer progression in different tissues by activating endogenous or synthetic compounds. This review emphasizes the significance and knowledge of peroxisome proliferator-activated receptors in the tumor microenvironment, tumor cell metabolism, and anti-cancer treatment by summarizing recent research on peroxisome proliferator-activated receptors. In general, peroxisome proliferator-activated receptors either promote or suppress cancer in different types of tumor microenvironments. The emergence of this difference depends on various factors, including peroxisome proliferator-activated receptor type, cancer type, and tumor stage. Simultaneously, the effect of anti-cancer therapy based on drug-targeted PPARs differs or even opposes among the three peroxisome proliferator-activated receptor homotypes and different cancer types. Therefore, the current status and challenges of the use of peroxisome proliferator-activated receptors agonists and antagonists in cancer treatment are further explored in this review.

Comprehensive Analysis Identifies the PPAR-Targeted Genes Associated with Ovarian Cancer Prognosis and Tumor Microenvironment.

There is a significant role for peroxisome proliferator-activated receptors (PPARs) in the development of cancer. Nevertheless, the role of PPARs-related genes in ovarian cancer (OC) remains unclear. The open-accessed data used for analysis were downloaded from The Cancer Genome Atlas database, which was analyzed using the R software. In our study, we comprehensively investigated the PPAR target genes in OC, including their biological role. Meanwhile, a prognosis signature consisting of eight PPAR target genes was established, including apolipoprotein A-V, UDP glucuronosyltransferase 2 family, polypeptide B4, TSC22 domain family, member 1, growth hormone inducible transmembrane protein, renin, dedicator of cytokinesis 4, enoyl CoA hydratase 1, peroxisomal (ECH1), and angiopoietin-like 4, which showed a good prediction efficiency. A nomogram was constructed by combining the clinical feature and risk score. Immune infiltration and biological enrichment analysis were applied to investigate the difference between high- and low-risk patients. Immunotherapy analysis indicated that low-risk patients might respond better to immunotherapy. Drug sensitivity analysis indicated that high-risk patients might respond better to bleomycin, nilotinib, pazopanib, pyrimethamine, and vinorelbine, yet worse to cisplatin and gefitinib. Furthermore, the gene ECH1 was selected for further analysis. Our study identified a prognosis signature that could effectively indicates patients survival. Meanwhile, our study can provide the direction for future studies focused on the PPARs in OC.

Unraveling the Role of Peroxisome Proliferator-Activated Receptor β/Δ (PPAR β/Δ) in Angiogenesis Associated with Multiple Myeloma.

Growing evidence suggests a role for peroxisome proliferator-activated receptor β/δ (PPAR β/δ) in the angiogenesis, growth, and metastasis of solid tumors, but little is known about its role in multiple myeloma (MM). Angiogenesis in the bone marrow (BM) is characteristic of disease transition from monoclonal gammopathy of undetermined significance (MGUS) to MM. We examined the expression and function of PPAR β/δ in endothelial cells (EC) from the BM of MGUS (MGEC) and MM (MMEC) patients and showed that PPAR β/δ was expressed at higher levels in MMEC than in MGEC and that the overexpression depended on myeloma plasma cells. The interaction between myeloma plasma cells and MMEC promoted the release of the PPAR β/δ ligand prostaglandin I2 (PGI2) by MMEC, leading to the activation of PPAR β/δ. We also demonstrated that PPAR β/δ was a strong stimulator of angiogenesis in vitro and that PPAR β/δ inhibition by a specific antagonist greatly impaired the angiogenic functions of MMEC. These findings define PGI2-PPAR β/δ signaling in EC as a potential target of anti-angiogenic therapy. They also sustain the use of PPAR β/δ inhibitors in association with conventional drugs as a new therapeutic approach in MM.

The role of peroxisome proliferator-activated receptors in the modulation of hyperinflammation induced by SARS-CoV-2 infection: A perspective for COVID-19 therapy.

Coronavirus disease 2019 (COVID-19) is a severe respiratory disease caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that affects the lower and upper respiratory tract in humans. SARS-CoV-2 infection is associated with the induction of a cascade of uncontrolled inflammatory responses in the host, ultimately leading to hyperinflammation or cytokine storm. Indeed, cytokine storm is a hallmark of SARS-CoV-2 immunopathogenesis, directly related to the severity of the disease and mortality in COVID-19 patients. Considering the lack of any definitive treatment for COVID-19, targeting key inflammatory factors to regulate the inflammatory response in COVID-19 patients could be a fundamental step to developing effective therapeutic strategies against SARS-CoV-2 infection. Currently, in addition to well-defined metabolic actions, especially lipid metabolism and glucose utilization, there is growing evidence of a central role of the ligand-dependent nuclear receptors and peroxisome proliferator-activated receptors (PPARs) including PPARα, PPARβ/δ, and PPARγ in the control of inflammatory signals in various human inflammatory diseases. This makes them attractive targets for developing therapeutic approaches to control/suppress the hyperinflammatory response in patients with severe COVID-19. In this review, we (1) investigate the anti-inflammatory mechanisms mediated by PPARs and their ligands during SARS-CoV-2 infection, and (2) on the basis of the recent literature, highlight the importance of PPAR subtypes for the development of promising therapeutic approaches against the cytokine storm in severe COVID-19 patients.

The Role of PPARs in Breast Cancer.

Breast cancer is a malignant tumor with high morbidity and lethality. Its pathogenesis is related to the abnormal expression of many genes. The peroxisome proliferator-activated receptors (PPARs) are a class of ligand-dependent transcription factors in the nuclear receptor superfamily. They can regulate the transcription of a large number of target genes, which are involved in life activities such as cell proliferation, differentiation, metabolism, and apoptosis, and regulate physiological processes such as glucose metabolism, lipid metabolism, inflammation, and wound healing. Further, the changes in its expression are associated with various diseases, including breast cancer. The experimental reports related to "PPAR" and "breast cancer" were retrieved from PubMed since the discovery of PPARs and summarized in this paper. This review (1) analyzed the roles and potential molecular mechanisms of non-coordinated and ligand-activated subtypes of PPARs in breast cancer progression; (2) discussed the correlations between PPARs and estrogen receptors (ERs) as the nuclear receptor superfamily; and (3) investigated the interaction between PPARs and key regulators in several signaling pathways. As a result, this paper identifies PPARs as targets for breast cancer prevention and treatment in order to provide more evidence for the synthesis of new drugs targeting PPARs or the search for new drug combination treatments.