Background. Peroxisome proliferator activated receptors (PPARs) are ligand-activated transcription factors with multiple effects on target cell function. PPAR gamma activity is regulated by extracellular signal-regulated protein kinase (ERK), mitogen-activated protein (MAP) kinase, and PPAR gamma ligands have varying effects on activity of ERK. Different PPAR gamma ligands have been shown to have both protective and detrimental effects in the kidney. Since transcriptional activation by different PPAR agonists is ligand- and depot-specific PPAR gamma, we have examined the effects of different agonists on PPAR activity in the proximal tubule.

Background: The continuously increasing association of Alzheimer's disease (AD) with increased mortality rates indicates an unmet medical need and the critical need for establishing novel molecular targets for therapeutic potential. Agonists for peroxisomal proliferator activating receptors (PPAR) are known to regulate energy in the body and have shown positive effects against Alzheimer's disease. There are three members of this class (delta, gamma, and alpha), with PPAR-gamma being the most studied, as these pharmaceutical agonists offer promise for AD because they reduce amyloid beta and tau pathologies, display anti-inflammatory properties, and improve cognition. However, they display poor brain bioavailability and are associated with several adverse side effects on human health, thus limiting their clinical application. Methods: We have developed a novel series of PPAR-delta and PPAR-gamma agonists in silico with AU9 as our lead compound that displays selective amino acid interactions focused upon avoiding the Tyr-473 epitope in the PPAR-gamma AF2 ligand binding domain. Results: This design helps to avoid the unwanted side effects of current PPAR-gamma agonists and improve behavioral deficits and synaptic plasticity while reducing amyloid-beta levels and inflammation in 3xTgAD animals. Conclusions: Our innovative in silico design of PPAR-delta/gamma agonists may offer new perspectives for this class of agonists for AD.

The peroxisome proliferator-activated receptor gamma (PPAR gamma) plays an important role in vascular regulation. However, the impact of oxidative stress on PPAR gamma expression and activity has not been clearly defined. Human umbilical vein endothelial cells (HUVECs) were exposed to graded concentrations of H(2)O(2) for 0.5-72h, or bovine aortic endothelial cells (BAECs) were exposed to alterations in extracellular thiol/disulfide redox potential (E(h)) of the cysteine/cystine couple. Within 2h, H(2)O(2) reduced HUVEC PPAR gamma mRNA and activity and reduced the expression of two PPAR gamma-regulated genes without altering PPAR gamma protein levels. After 4h H(2)O(2) exposure, mRNA levels remained reduced, whereas PPAR gamma activity returned to control levels. PPAR gamma mRNA levels remained depressed for up to 72 h after exposure to H(2)O(2), without any change in PPAR gamma activity. Catalase prevented H(2)O(2)-induced reductions in PPAR gamma mRNA and activity. H(2)O(2) (1) reduced luciferase expression in HUVECs transiently transfected with a human PPAR gamma promoter reporter, (2) failed to alter PPAR gamma mRNA half-life, and (3) transiently increased expression and activity of c-Fos and phospho-c-Jun. Treatment with the AP1 inhibitor curcumin prevented H(2)O(2)-mediated reductions in PPAR gamma expression. In addition, medium having an oxidized E(h) reduced BAEC PPAR gamma mRNA and activity. These findings demonstrate that oxidative stress, potentially through activation of inhibitory redox-regulated transcription factors, attenuates PPAR gamma expression and activity in vascular endothelial cells through suppression of PPAR gamma transcription.

Gabapentin is an anticonvulsant drug that is also used for post-herpetic neuralgia and neuropathic pain. Recently, gabapentin showed anti-inflammatory effect. Nuclear factor kappa B (NFκB) is a regulator of the inflammatory process, and Peroxisome Proliferator-activated Receptor gamma (PPAR-gamma) is an important receptor involved in NFκB regulation. The aim of the present work was to study the potential role of PPAR-gamma receptor in gabapentin-mediated anti-inflammatory effects in a colitis experimental model. We induced colitis in rats using trinitrobenzenosulfonic acid and treated them with gabapentin and bisphenol A dicyldidyl ether (PPAR-gamma inhibitor). Macroscopic lesion scores, wet weight, histopathological analysis, mast cell count, myeloperoxidase, malondialdehyde acid, glutathione, nitrate/nitrite, and interleukin levels in the intestinal mucosa were determined. In addition, western blots were performed to determine the expression of Cyclooxygenase-2 (COX-2) and NFκB; Nitric Oxide Inducible Synthase (iNOS) and Interleukin 1 beta (IL-1β) levels were also determined. Gabapentin was able to decrease all inflammatory parameters macroscopic and microscopic in addition to reducing markers of oxidative stress and cytokines such as IL-1β and Tumor Necrosis Factor alpha (TNF-α) as well as enzymes inducible nitric oxide synthase and cyclooxygenase 2 and inflammatory genic regulator (NFκB). These effect attributed to gabapentin was observed to be lost in the presence of the specific inhibitor of PPAR-gamma. Gabapentin inhibits bowel inflammation by regulating mast cell signaling. Furthermore, it activates the PPAR-gamma receptor, which in turn inhibits the activation of NFκB, and consequently results in reduced activation of inflammatory genes involved in inflammatory bowel diseases.

Tocopherols are lipid soluble antioxidants that exist as eight structurally different isoforms. The intake of gamma-tocopherol is higher than alpha-tocopherol in the average US diet. The clinical results of the effects of vitamin E as a cancer preventive agent have been inconsistent. All published clinical trials with vitamin E have used alpha-tocopherol. Recent epidemiological, experimental and molecular studies suggest that gamma-tocopherol may be a more potent chemopreventive form of vitamin E compared to the more-studied alpha-tocopherol. Gamma-tocopherol exhibits differences in its ability to detoxify nitrogen dioxide, growth inhibitory effects on selected cancer cell lines, inhibition of neoplastic transformation in embryonic fibroblasts, and inhibition of cyclooxygenase-2 (COX-2) activity in macrophages and epithelial cells. Peroxisome proliferator activator receptor gamma (PPARgamma) is a promising molecular target for colon cancer prevention. Upregulation of PPARgamma activity is anticarcinogenic through its effects on downstream genes that affect cellular proliferation and apoptosis. The thiazolidine class of drugs are powerful PPARgamma ligands. Vitamin E has structural similarity to the thiazolidine, troglitazone. In this investigation, we tested the effects of both alpha and gamma tocopherol on the expression of PPARgamma mRNA and protein in SW 480 colon cancer cell lines. We also measured the intracellular concentrations of vitamin E in SW 480 colon cancer cell lines.

Necrotizing enterocolitis (NEC) remains a lethal condition for many premature infants. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a member of the nuclear hormone receptor family, has been shown to play a protective role in cellular inflammatory responses; however, its role in NEC is not clearly defined. We sought to examine the expression of PPAR-gamma in the intestine using an ischemia-reperfusion (I/R) model of NEC, and to assess whether PPAR-gamma agonist treatment would ameliorate I/R-induced gut injury. Swiss-Webster mice were randomized to receive sham (control) or I/R injury to the gut induced by transient occlusion of superior mesenteric artery for 45 min with variable periods of reperfusion. I/R injury resulted in early induction of PPAR-gamma expression and activation of NF-kappaB in small intestine. Pretreatment with PPAR-gamma agonist, 15d-PGJ(2), attenuated intestinal NF-kappaB response and I/R-induced gut injury. Activation of PPAR-gamma demonstrated a protective effect on small bowel during I/R-induced gut injury.

Vascular endothelial insulin resistance (IR) is a critically initial factor in cardiocerebrovascular events resulted from diabetes and is becoming a worldwide public health issue. Thiazolidinediones (TZDs) are clinical insulin-sensitizers acting through a canonical peroxisome proliferator-activated receptor gamma (PPARγ)-dependent insulin trans-activation pathway. However, it remains elusive whether there are other mechanisms. In current study, we investigated whether TZDs improve endothelial IR induced by high glucose concentration or hyperglycemia via a non-canonical PPARγ-dependent nuclear factor-kappa B (NF-κB) trans-repression pathway. Our results showed that pre-treatment with TZDs dramatically decrease the susceptibility of endothelial cell to IR, while post-treatment notably improve the endothelial IR both in vitro and in vivo. Moreover, TZDs substantially increase the levels of endothelial nitric oxide synthase (eNOS) and inhibitory κB alpha (IκBα), whereas decrease those of the phosphorylated inhibitory κB kinase alpha/beta (phosphor-IKKα/β) and the cytokines including tumor necrosis factor alpha (TNFα), interleukin-6 (IL-6), soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cellular adhesion molecule-1 (sVCAM-1), suggesting that TZDs act indeed through a PPARγ-dependent NF-κB trans-repression pathway. These findings highlighted a non-canonical mechanism for TZDs to ameliorate endothelial IR which might provide a potential strategy to prevent and treat the diabetic vascular complications clinically.

Tuberculosis (TB) is a major health problem characterized by an immuno-endocrine imbalance: elevated plasma levels of cortisol and pro- and anti-inflammatory mediators, as well as reduced levels of dehydroepiandrosterone. The etiological agent, Mycobacterium tuberculosis (Mtb), is captured by pulmonary macrophages (Mf), whose activation is necessary to cope with the control of Mtb, however, excessive activation of the inflammatory response also leads to tissue damage. Glucocorticoids (GC) are critical elements to counteract the immunoinflammatory reaction, and peroxisome proliferator-activated receptors (PPARs) are also involved in this regard. The primary forms of these receptors are PPARϒ, PPARα, and PPARβ/δ, the former being the most involved in anti-inflammatory responses. In this work, we seek to gain some insight into the contribution of PPARϒ in immuno-endocrine-metabolic interactions by focusing on clinical studies in pulmonary TB patients and in vitro experiments on a Mf cell line.

Hyperhomocysteinemia (HHcy) and hyperglycemia cause diabetic cardiomyopathy by inducing oxidative stress and attenuating peroxisome proliferator- activated receptor (PPAR) gamma. However, their synergistic contribution is not clear.

The gamma isoform of the peroxisome proliferator-activated receptor, PPAR gamma, regulates adipocyte differentiation and has recently been shown to be expressed in neoplasia of the colon and other tissues. We have found four somatic PPAR gamma mutations among 55 sporadic colon cancers: one nonsense, one frameshift, and two missense mutations. Each greatly impaired the function of the protein. c.472delA results in deletion of the entire ligand binding domain. Q286P and K319X retain a total or partial ligand binding domain but lose the ability to activate transcription through a failure to bind to ligands. R288H showed a normal response to synthetic ligands but greatly decreased transcription and binding when exposed to natural ligands. These data indicate that colon cancer in humans is associated with loss-of-function mutations in PPAR gamma.

Studies of human genetics have implicated the role of SIRT1 in regulating obesity, insulin resistance, and longevity. These researches motivated the identification of novel SIRT1 activators. The current study aimed to investigate the potential efficacy of agrimol B, a polyphenol derived from Agrimonia pilosa Ledeb., on mediating SIRT1 activity and fat metabolism. Results showed that agrimol B significantly induced cytoplasm-to-nucleus shuttle of SIRT1. Furthermore, we confirmed that agrimol B dramatically inhibited 3T3-L1 adipocyte differentiation by reducing PPARγ, C/EBPα, FAS, UCP-1, and apoE expression. Consequently, adipogenesis was blocked by treatment of agrimol B at the early stage of differentiation in a dose-dependent manner, the IC50 value was determined as 3.35 ± 0.32 μM. Taken together, our data suggest a therapeutic potential of agrimol B on alleviating obesity, through modulation of SIRT1-PPARγ signal pathway.

Cerebral ischemia is the most common cerebrovascular disease worldwide. Recent studies have demonstrated that curcumin had beneficial effect to attenuate cerebral ischemic injury. However, it is unclear how curcumin protects against cerebral ischemic injury. In the present study, using rat middle cerebral artery occlusion model, we found that curcumin was a potent PPAR γ agonist in that it upregulated PPAR γ expression and PPAR γ -PPRE binding activity. Administration of curcumin markedly decreased the infarct volume, improved neurological deficits, and reduced neuronal damage of rats. In addition, curcumin suppressed neuroinflammatory response by decreasing inflammatory mediators, such as IL-1 β , TNF- α , PGE2, NO, COX-2, and iNOS induced by cerebral ischemia of rats. Furthermore, curcumin suppressed I κ B degradation that was caused by cerebral ischemia. The present data also showed that PPAR γ interacted with NF- κ B-p65 and thus inhibited NF- κ B activation. All the above protective effects of curcumin on cerebral ischemic injury were markedly attenuated by GW9662, an inhibitor of PPAR γ . Our results as described above suggested that PPAR γ induced by curcumin may play a critical role in protecting against brain injury through suppression of inflammatory response. It also highlights the potential of curcumin as a therapeutic agent against cerebral ischemia.

Metabolic syndrome (Mets) is a major health hazard. The syndrome is strongly linked to cardiovascular disease. The objective of the current study was to address whether or not crocin could protect against experimentally-induced MetS in rats as well as the possible underlying mechanisms. Animals were allocated into 4 groups. The first one served as control and was kept on regular food pellets and drinking water. The other three groups were subjected to experimental MetS. Induction of MetS was achieved by keeping rats on food pellets containing 3% NaCl; and drinking water enriched with 10% fructose. The first and second groups were daily gavaged with saline. The third and fourth groups were daily administered crocin 5 and 10 mg/kg, respectively. The treatment continued for 12 consecutive weeks. Crocin significantly reduced body weight gain and adiposity index as compared to MetS group. Also, crocin protected against the occurrence of hyperglycemia and insulin resistance as indicated by controlled values of HOMA-IR. Crocin protected against MetS-induced dyslipidemia as well as the rise blood pressure. These beneficial effects were accompanied by enhanced serum levels of PPARγ & AMPK and inhibited serum levels of IL-6 and TNF-α. In conclusion, crocin protects against experimentally-induced MetS. This can be attributed, at least partly, to activation of PPARγ and AMPK as well as inhibiting inflammation.

Ligands of peroxisome proliferator-activated receptor-gamma (PPAR(gamma)) are thought to possess anti-inflammatory properties mediated via both PPAR(gamma) dependent and independent mechanisms. This work investigates the effects of PPAR(gamma) ligands on the regulation of cyclooxygenase-2 (COX-2) in the human lung epithelial cell line, A549. The synthetic ligand troglitazone activated the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase pathway (MAPK), whereas the endogenous ligand, 15-deoxy-Delta(12,14)-prostaglandin J2 (15d-PGJ2), only activated the PI3K pathway. 15d-PGJ2 had no detectable effects on COX-2, mPGES expression, or PGE2 production. However, troglitazone induced time-dependent COX-2 expression, which was insensitive to PPAR(gamma) antagonists, but was abrogated by inhibitors of PI3K and the ERK MAP kinase pathway. Furthermore, troglitazone induced mPGES expression and PGE2 production. Neither troglitazone nor 15d-PGJ2 was able to convincingly activate NF-kappaB in A549 cells. Further heterogeneity in the responses to troglitazone and 15d-PGJ2 was observed in the regulation of gene expression as assessed by microarray analysis. In summary, this study provides compelling evidence that troglitazone (like 15d-PGJ2) can exert functional effects independently of actions via PPAR(gamma). Moreover, we have identified unique biochemical and functional actions of troglitazone that are not shared by 15d-PGJ2, which may influence the therapeutic potential of this compound in inflammatory settings.

A pivotal role for adipose tissue homeostasis in systemic sclerosis (SSc) skin fibrosis is increasingly recognized. The nuclear receptor PPAR-γ is the master regulator of adipogenesis. Peroxisome proliferator activated receptor-γ (PPAR-γ) has antifibrotic effects by blocking transforming growth factor-β (TGF-β) and is dysregulated in SSc. To unravel the impact of dysregulated PPAR-γ in SSc, we focused on nuclear corepressor (NCoR), which negatively regulates PPAR-γ activity and suppresses adipogenesis.

Therapy-induced tumour microenvironment (TME) remodelling poses a major hurdle for cancer cure. As the majority of patients with hepatocellular carcinoma (HCC) exhibits primary or acquired resistance to antiprogrammed cell death (ligand)-1 (anti-PD-[L]1) therapies, we aimed to investigate the mechanisms underlying tumour adaptation to immune-checkpoint targeting.

Nuclear receptors are a superfamily of ligand-activated transcription factors that play critical roles in the regulation of normal biological processes and several disease states. Of the nuclear receptors expressed within the prostate, the androgen receptor (AR) promotes the differentiation of prostatic epithelial cells and stimulates production of enzymes needed for liquefaction of semen. Multiple forms of AR also promote the growth of both early and late stage prostate cancers. As a result, drugs that target the AR signaling pathway are routinely used to treat patients with advanced forms of prostate cancer. Data also suggest that a second member of the nuclear receptor superfamily, the peroxisome proliferator activated receptor gamma (PPARγ), is a tumor suppressor that regulates growth of normal prostate and prostate cancers. Recent studies indicate there is a bidirectional interaction between AR and PPARγ, with each receptor influencing the expression and/or activity of the other within prostatic tissues. In this review, we examine how AR and PPARγ each regulate the growth and development of normal prostatic epithelial cells and prostate cancers. We also discuss interactions between the AR and PPARγ signaling pathways and how those interactions may influence prostate biology.

Sepsis is one of the major causes of death reported in intensive care units. Acute kidney injury (AKI) and hypotension are important in the pathogenesis and mortality of systemic inflammatory response (SIR). Sesamol delays mortality in sepsis; however, its effects on AKI and hypotension and the role of peroxisome proliferator-activated receptor-ɣ (PPAR-γ) activation have not been established. We investigated the effect of sesamol on SIR in cecal ligation and puncture (CLP)-induced acute kidney injury and lipopolysaccharide (LPS)-induced hypotension in rats. Sesamol was subcutaneously injected 1 h after SIR. Renal function (BUN and CRE) and proinflammatory mediators interleukin (IL)-1β and IL-6 were increased after CLP. Tumor necrosis factor (TNF)-α, IL-1β, IL-10, and nitrite production were significantly increased 6 h after LPS-induced hypotension (mean arterial pressure was significantly decreased). Sesamol significantly inhibited BUN, CRE, IL-1β, IL-6, and nitrite after CLP-induced acute renal injury. In addition, sesamol increased mean arterial pressure and IL-10, inhibited TNF-α and IL-1β, but did not affect nitrite production in LPS-induced hypotension. Sesamol increased PPAR-γ in the leucocytes and peritoneal macrophages in LPS-induced SIR. We conclude that sesamol regulates leucocyte and macrophage PPAR-γ-associated systemic cytokines expression, thereby ameliorates acute kidney injury and hypotension in rats.

Increased propensity of bone marrow-derived mesenchymal stem cells (BM-MSCs) toward adipogenic differentiation has been implicated in the fatty bone marrow and defective hematopoiesis of aplastic anemia (AA). However, the underlying molecular mechanism remains to be investigated. In this study, we found that microRNA 199a-5p (miR-199a-5p) exhibits significantly higher expression in AA BM-MSCs compared with the normal control and is demonstrated to facilitate adipogenic differentiation of BM-MSCs through lentivirus-mediated miR-199a overexpression. Mechanistic investigation reveals that miR-199a-5p could be regulated by PPAR gamma (PPARγ) in a transcription-independent manner and regulates adipogenic differentiation by targeting the expression of transforming growth factor beta induced (TGFBI), which is subsequently validated as a negative regulator of adipogenesis. Besides, the positive correlation between PPARγ and miR-199a-5p expression as well as the inverse relationship between miR-199a-5p and TGFBI expression in normal and AA BM-MSCs was observed. Altogether, our work demonstrates that PPARγ-regulated miR-199a-5p promotes adipogenesis of BM-MSCs by inhibiting TGFBI expression, which might be a novel mechanism underlying the bone marrow adiposity in AA, and provides promising therapeutic targets for AA treatment.

Peroxisome Proliferator-Activated Receptor Gamma (PPARG) is one of the three members of the PPAR family of transcription factors. Besides its roles in adipocyte differentiation and lipid metabolism, we recently demonstrated an association between PPARG and metastasis in prostate cancer. In this study a functional effect of PPARG on AKT serine/threonine kinase 3 (AKT3), which ultimately results in a more aggressive disease phenotype was identified. AKT3 has previously been shown to regulate PPARG co-activator 1 alpha (PGC1α) localisation and function through its action on chromosome maintenance region 1 (CRM1). AKT3 promotes PGC1α localisation to the nucleus through its inhibitory effects on CRM1, a known nuclear export protein. Collectively our results demonstrate how PPARG over-expression drives an increase in AKT3 levels, which in turn has the downstream effect of increasing PGC1α localisation within the nucleus, driving mitochondrial biogenesis. Furthermore, this increase in mitochondrial mass provides higher energetic output in the form of elevated ATP levels which may fuel the progression of the tumour cell through epithelial to mesenchymal transition (EMT) and ultimately metastasis.