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Peroxisome proliferator-activated receptors are expressed in many tissues, including adipocytes, hepatocytes, muscles and endothelial cells; however, the affinity depends on the isoform of PPAR, and different distribution and expression profiles, which ultimately lead to different clinical outcomes. Because they play an important role in lipid and glucose homeostasis, they are called lipid and insulin sensors. Their actions are limited to specific tissue types and thus, reveal a characteristic influence on target cells. PPARα mainly influences fatty acid metabolism and its activation lowers lipid levels, while PPARγ is mostly involved in the regulation of the adipogenesis, energy balance, and lipid biosynthesis. PPARβ/δ participates in fatty acid oxidation, mostly in skeletal and cardiac muscles, but it also regulates blood glucose and cholesterol levels. Many natural and synthetic ligands influence the expression of these receptors. Synthetic ligands are widely used in the treatment of dyslipidemia (e.g. fibrates - PPARα activators) or in diabetes mellitus (e.g. thiazolidinediones - PPARγ agonists). New generation drugs - PPARα/γ dual agonists - reveal hypolipemic, hypotensive, antiatherogenic, anti-inflammatory and anticoagulant action while the overexpression of PPARβ/δ prevents the development of obesity and reduces lipid accumulation in cardiac cells, even during a high-fat diet. Precise data on the expression and function of natural PPAR agonists on glucose and lipid metabolism are still missing, mostly because the same ligand influences several receptors and a number of reports have provided conflicting results. To date, we know that PPARs have the capability to accommodate and bind a variety of natural and synthetic lipophilic acids, such as essential fatty acids, eicosanoids, phytanic acid and palmitoylethanolamide. A current understanding of the effects of PPARs, their molecular mechanisms and the role of these receptors in nutrition and therapeutic treatment are delineated in this paper.

Key Points Peroxisome proliferator-activated receptors (PPARs) have central roles in the regulation of glucose and lipid homeostasis through their functions as molecular sensors that respond to endogenous ligands, leading to the modulation of gene expression. PPARs also regulate cell proliferation, differentiation and inflammation. PPARα mediates hepatocarcinogenesis induced by long-term administration of PPARα agonists in rodent models, an effect that is not found in humans. The mechanism underlying species-specific hepatocarcinogenesis is through mouse PPARα-dependent regulation of the let-7c microRNA, which leads to increased expression of the oncoprotein MYC. The current interest in targeting PPARα for the prevention of certain cancers, including colon and leukaemia, is based on studies showing that PPARα agonists inhibit the proliferation of endothelial cells, increase the synthesis of PPARγ agonists and potentially interfere with the Warburg effect. The role of PPARβ/δ in carcinogenesis is controversial. Several studies have shown that PPARβ/δ is upregulated in cancer cells by the adenomatous polyposis coli (APC)–β-catenin–TCF4 pathway and has a pro-tumorigenic effect in many cancer types. However, other studies have shown that PPARβ/δ agonists can induce terminal differentiation and inhibit innate inflammation, suggesting anticancer effects. In addition, a retrospective study has shown that low expression levels of PPARβ/δ are associated with the decreased survival of patients with colorectal cancer. Therefore, there remains a need to further examine PPARβ/δ protein expression patterns quantitatively in tumour models and the putative mechanisms that are mediated by PPARβ/δ agonists associated with anti-apoptotic or growth stimulatory effects. PPARγ agonists can induce terminal differentiation, inhibit cell proliferation, promote apoptosis and inhibit innate inflammation in many cancer models. This has led to a number of clinical trials with PPARγ agonists, but these have generated mixed results. Moreover, some PPARγ agonists have been associated with pro-tumorigenic effects. Emerging evidence indicates that targeting PPARγ in combination with other chemopreventive or chemotherapeutic agents might increase the efficacy of the effects that are induced by monotherapies. Owing to similarities in the abilities of the three PPARs to improve different metabolic disorders that are known to be associated with increased cancer risk (such as diabetes, obesity, dyslipidemias and chronic inflammation), modulating the activities of the PPARs remains an attractive approach for the treatment and prevention of cancer. The challenge is to advance the discovery of molecular mechanisms of action in order to identify and characterize effective PPAR agonists with acceptable safety profiles. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that are involved in regulating glucose and lipid homeostasis, inflammation, proliferation and differentiation. This Review discusses the roles of PPARs in cancer and focuses on PPARβ/δ and the controversies yet to be resolved. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that are involved in regulating glucose and lipid homeostasis, inflammation, proliferation and differentiation. Although all of these functions might contribute to the influence of PPARs in carcinogenesis, there is a distinct need for a review of the literature and additional experimentation to determine the potential for targeting PPARs for cancer therapy and cancer chemoprevention. As PPAR agonists include drugs that are used for the treatment of metabolic diseases, a more complete understanding of the roles of PPARs in cancer will aid in determining any increased cancer risk for patients undergoing therapy with PPAR agonists.

Severe influenza remains unusual in its virulence for humans. Complications or ultimately death arising from these infections are often associated with hyperinduction of proinflammatory cytokine production, which is also known as ＇cytokine storm＇. For this disease, it has been proposed that immunomodulatory therapy may improve the outcome, with or without the combination of antiviral agents. Here, we review the current literature on how various effectors of the immune system initiate the cytokine storm and exacerbate pathological damage in hosts. We also review some of the current immunomodulatory strategies for the treatment of cytokine storms in severe influenza, including corticosteroids, peroxisome proliferator-activated receptor agonists, sphingosine-l-phosphate receptor 1 agonists, cyclooxygenase-2 inhibitors, antioxidants, anti-tumour-necrosis factor therapy, intravenous immunoglobulin therapy, statins, arbidol, herbs, and other potential therapeutic strategies.

Non-alcoholic fatty liver disease (NAFLD) affects one-third of the population worldwide, of which a substantial number of patients suffer from non-alcoholic steatohepatitis (NASH). NASH is a severe condition characterized by steatosis and concomitant liver inflammation and fibrosis, for which no drug is yet available. NAFLD is also generally conceived as the hepatic manifestation of the metabolic syndrome. Consequently, well-established drugs that are indicated for the treatment of type 2 diabetes and hyperlipidemia are thought to exert effects that alleviate the pathological features of NASH. One class of these drugs targets peroxisome proliferator-activated receptors (PPARs), which are nuclear receptors that play a regulatory role in lipid metabolism and inflammation. Therefore, PPARs are now also being investigated as potential anti-NASH druggable targets. In this paper, we review the mechanisms of action and physiological functions of PPARs and discuss the position of the different PPAR agonists in the therapeutic landscape of NASH. We particularly focus on the PPAR agonists currently under evaluation in clinical phase II and III trials. Preclinical strategies and how refinement and optimization may improve PPAR-targeted anti-NASH drug testing are also discussed. Finally, potential caveats related to PPAR agonism in anti-NASH therapy are stipulated.

Polydatin (PD), a stilbenoid resveratrol-derivative in Vitaceae , Liliaceae , and Leguminosae , exhibits pharmacological protection in metabolic disorders. This study investigated Polydatin, as a potential pan-PPAR agonist for treating non-alcoholic fatty liver disease (NAFLD). High-throughput-virtual-screening (HTVS) was performed to identify potential pan-PPAR agonists, followed by in vitro testing of Polydatin in HepG2 steatosis model. Effects on lipid metabolism and oxidative stress, PPAR signaling gene expression analysis, and GC-MS profiling were compared with the hepatoprotectant Silymarin. Pan-PPAR targeted HTVS of PhytoHub natural products database, followed by molecular docking/dynamics simulations, revealed lead-candidate, Polydatin, which was tested in steatotic cells for gene and protein deregulations by qRT-PCR and western blot, followed by GC-MS analysis of biochemical metabolites. HTVS revealed 53 potential pan-PPAR agonists. Molecular docking and dynamics simulations suggested that PD, a stable ligand for PPARs (α,β/δ,γ), exhibited strong binding. Polydatin treatment decreased ALT, triglycerides, and oxidative stress, wherein ROS and malondialdehyde levels decreased by 60.94% and 28%, respectively. PD upregulated PPARs, AMPK, GLUT2, and CPT1α, while downregulating lipogenic enzymes (ACC1, FASN, SCD1). GC-MS analysis revealed Polydatin mediated impact on saturated FFAs-palmitic acid, stearic acid, and unsaturated fatty acid product of SCD1, oleic acid. HTVS identified PD as a promising pan-PPAR agonist, which favorably ameliorated changes in lipid, glucose, and overall energy metabolism in steatotic NAFLD, by modulating PPAR(α,β/δ,γ) expressions and associated downstream lipogenic and lipid-utilization mechanisms, supporting anti-steatotic efficacy of Polydatin.

Cannabinoids act at two classical cannabinoid receptors (CB1 and CB2), a 7TM orphan receptor and the transmitter‐gated channel transient receptor potential vanilloid type‐1 receptor. Recent evidence also points to cannabinoids acting at members of the nuclear receptor family, peroxisome proliferator‐activated receptors (PPARs, with three subtypes α, β (δ) and γ), which regulate cell differentiation and lipid metabolism. Much evidence now suggests that endocannabinoids are natural activators of PPARα. Oleoylethanolamide regulates feeding and body weight, stimulates fat utilization and has neuroprotective effects mediated through activation of PPARα. Similarly, palmitoylethanolamide regulates feeding and lipid metabolism and has anti‐inflammatory properties mediated by PPARα. Other endocannabinoids that activate PPARα include anandamide, virodhamine and noladin. Some (but not all) endocannabinoids also activate PPARγ; anandamide and 2‐arachidonoylglycerol have anti‐inflammatory properties mediated by PPARγ. Similarly, ajulemic acid, a structural analogue of a metabolite of Δ9‐tetrahydrocannabinol (THC), causes anti‐inflammatory effects in vivo through PPARγ. THC also activates PPARγ, leading to a time‐dependent vasorelaxation in isolated arteries. Other cannabinoids which activate PPARγ include N‐arachidonoyl‐dopamine, HU210, WIN55212‐2 and CP55940. In contrast, little research has been carried out on the effects of cannabinoids at PPARδ. In this newly emerging area, a number of research questions remain unanswered; for example, why do cannabinoids activate some isoforms and not others? How much of the chronic effects of cannabinoids are through activation of nuclear receptors? And importantly, do cannabinoids confer the same neuro‐ and cardioprotective benefits as other PPARα and PPARγ agonists? This review will summarize the published literature implicating cannabinoid‐mediated PPAR effects and discuss the implications thereof. British Journal of Pharmacology (2007) 152, 576–582; doi:10.1038/sj.bjp.0707423; published online 20 August 2007

Peroxisome proliferator-activated receptors (PPARs) belong to the family of ligand-activated nuclear receptors. The PPAR family consists of three subtypes encoded by three separate genes: PPARα (NR1C1), PPARβ/δ (NR1C2), and PPARγ (NR1C3). PPARs are critical regulators of metabolism and exhibit tissue and cell type-specific expression patterns and functions. Specific PPAR ligands have been proposed as potential therapies for a variety of diseases such as metabolic syndrome, cancer, neurogenerative disorders, diabetes, cardiovascular diseases, endometriosis, and retinopathies. In this review, we focus on the knowledge of PPAR function in angiogenesis, a complex process that plays important roles in numerous pathological conditions for which therapeutic use of PPAR modulation has been suggested.

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.

The nuclear receptor PPARs are fundamentally important for energy homeostasis. Through their distinct yet overlapping functions and tissue distribution, the PPARs regulate many aspects of energy metabolism at the transcriptional level. Functional impairment or dysregulation of these receptors leads to a variety of metabolic diseases, while their ligands offer many metabolic benefits. Studies of these receptors have advanced our knowledge of the transcriptional basis of energy metabolism and helped us understand the pathogenic mechanisms of metabolic syndrome.

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