PPARγ Partial Agonists Research Articles

Identification of Novel PPARγ Partial Agonists Based on Virtual Screening Strategy: In Silico and In Vitro Experimental Validation.

Thiazolidinediones (TZDs) including rosiglitazone and pioglitazone function as peroxisome proliferator-activated receptor gamma (PPARγ) full agonists, which have been known as a class to be among the most effective drugs for the treatment of type 2 diabetes mellitus (T2DM). However, side effects of TZDs such as fluid retention and weight gain are associated with their full agonistic activities toward PPARγ induced by the AF-2 helix-involved "locked" mechanism. Thereby, this study aimed to obtain novel PPARγ partial agonists without direct interaction with the AF-2 helix. Through performing virtual screening of the Targetmol L6000 Natural Product Library and utilizing molecular dynamics (MD) simulation, as well as molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) analysis, four compounds including tubuloside b, podophyllotoxone, endomorphin 1 and paliperidone were identified as potential PPARγ partial agonists. An in vitro TR-FRET competitive binding assay showed podophyllotoxone displayed the optimal binding affinity toward PPARγ among the screened compounds, exhibiting IC50 and ki values of 27.43 µM and 9.86 µM, respectively. Further cell-based transcription assays were conducted and demonstrated podophyllotoxone's weak agonistic activity against PPARγ compared to that of the PPARγ full agonist rosiglitazone. These results collectively demonstrated that podophyllotoxone could serve as a PPARγ partial agonist and might provide a novel candidate for the treatment of various diseases such as T2DM.

Decoration of GW9662 scaffold with a fragment-like hit via copper-catalyzed azide-alkyne cycloaddition reaction into peroxisome proliferator-activated receptor γ agonists

PPARγ is a member of nuclear receptor superfamily, which possesses a large Y-shaped cavity in the ligand-binding pocket. GW9662 is a well-known PPARγ antagonist which covalently reacts with the Cys285 residue via nucleophilic substitution. In contrast to its irreversibility, the ability of GW9662 to prevent other ligands from accessing the ligand-binding pocket is partly defective. By focusing on this incompleteness, we develop an integrated approach to create a new PPARγ agonist by using a structure of GW9662 as a scaffold for linking with a fragment compound. A screening of 1,040 compounds identified a partner ligand which synergistically activates PPARγ transcription in combination with GW9662. We introduced an azido or alkyne group to GW9662 or the identified fragment hit, respectively, and then connected the two structures via copper-catalyzed azide-alkyne cycloaddition. A coupling reaction provided a series of hybrid structure with triazole linker, among which the compounds with a bent configuration function as a partial PPARγ agonist. These results highlight a potential utility of GW9662 for the decoration with a fragment compound to develop a covalent agonist for PPARγ activation.

Triclosan affects steroidogenesis in mouse primary astrocytes in vitro with engagement of Sirtuin 1 and 3

Triclosan (TCS) is a widely used antimicrobial, antifungal, and antiviral agent. To date, it has been reported that TCS can enter the human body and disrupt hormonal homeostasis. Therefore, the aim of our paper was to evaluate the impact of TCS on astrocytes, i.e. a crucial population of cells responsible for steroid hormone production. Our data showed that, in mouse primary astrocyte cultures, TCS can act as an endocrine disrupting chemical through destabilization of the production or secretion of progesterone (P4), testosterone (T), and estradiol (E2). TCS affects the mRNA expression of enzymes involved in neurosteroidogenesis, such as Cyp17a1, 17β-Hsd, and Cyp19a1. Our data showed that a partial PPARγ agonist (honokiol) prevented changes in Cyp17a1 mRNA expression caused by TCS. Similarly, honokiol inhibited TCS-stimulated P4 release. However, rosiglitazone (classic PPARγ agonist) or GW9662 (PPARγ antagonist) had a much stronger effect. Therefore, we believe that the changes observed in the P4, T, and E2 levels are a result of dysregulation of the activity of the aforementioned enzymes, whose expression can be affected by TCS through a Pparγ-dependent pathway. TCS was found to decrease the aryl hydrocarbon receptor (AhR) and Sirtuin 3 protein levels, which may be the result of the activation of the these proteins. Since our study showed dysregulation of the production or secretion of neurosteroids in astrocytes, it can be concluded that TCS reaching the brain may contribute to the development of neurodegenerative diseases in which an abnormal amount of neurosteroids is observed.

Interaction between Nuclear Receptor and Alpha-Adrenergic Agonist Subtypes in Metabolism and Systemic Hemodynamics of Spontaneously Hypertensive Rats.

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.

A partial agonist of PPARγ prevents paclitaxel-induced peripheral neuropathy in mice, by inhibiting neuroinflammation.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of paclitaxel, affecting 30-50% of patients. Increased survival and concern with patients' quality of life have encouraged the search for new tools to prevent paclitaxel-induced neuropathy. This study presents the glitazone 4-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-N-phenylbenzene-sulfonamide (TZD-A1) as a partial agonist of peroxisome proliferator-activated receptor γ (PPARγ), its toxicological profile and effects on paclitaxel-induced CIPN in mice. Interactions of TZD-A1 with PPARγ were analysed using in silico docking and in vitro reporter gene assays. Pharmacokinetics and toxicity were evaluated using in silico, in vitro and in vivo (C57Bl/6 mice) analyses. Effects of TZD-A1 on CIPN were investigated in paclitaxel-injected mice. Axonal and dorsal root ganglion damage, mitochondrial complex activity and cytokine levels, brain-derived neurotrophic factor (BDNF), nuclear factor erythroid 2-related factor 2 (Nrf2) and PPARγ, were also measured. Docking analysis predicted TZD-A1 interactions with PPARγ compatible with partial agonism, which were corroborated by in vitro reporter gene assays. Good oral bioavailability and safety profile of TZD-A1 were shown in silico, in vitro and in vivo. Paclitaxel-injected mice, concomitantly treated with TZD-A1 by i.p. or oral administration, exhibited decreased mechanical and thermal hypersensitivity, effects apparently mediated by inhibition of neuroinflammation and mitochondrial damage, through increasing Nrf2 and PPARγ levels, and up-regulating BDNF. TZD-A1, a partial agonist of PPARγ, provided neuroprotection and reduced hypersensitivity induced by paclitaxel. Allied to its safety profile and good bioavailability, TZD-A1 is a promising drug candidate to prevent and treat CIPN in cancer patients.

Synthesis, molecular docking, and in vivo antidiabetic evaluation of new benzylidene-2,4-thiazolidinediones as partial PPAR-γ agonists

Peroxisome proliferator-activated receptor-γ (PPAR-γ) partial agonists or antagonists, also termed as selective PPAR-γ modulators, are more beneficial than full agonists because they can avoid the adverse effects associated with PPAR-γ full agonists, such as weight gain and congestive heart disorders, while retaining the antidiabetic efficiency. In this study, we designed and synthesized new benzylidene-thiazolidine-2,4-diones while keeping the acidic thiazolidinedione (TZD) ring at the center, which is in contrast with the typical pharmacophore of PPAR-γ agonists. Five compounds (5a–e) were designed and synthesized in moderate to good yields and were characterized using spectral techniques. The in vivo antidiabetic efficacy of the synthesized compounds was assessed on streptozotocin-induced diabetic mice using standard protocols, and their effect on weight gain was also studied. Molecular docking and molecular dynamics (MD) simulation studies were performed to investigate the binding interactions of the title compounds with the PPAR-γ receptor and to establish their binding mechanism. Antidiabetic activity results revealed that compounds 5d and 5e possess promising antidiabetic activity comparable with the standard drug rosiglitazone. No compound showed considerable effect on the body weight of animals after 21 days of administration, and the findings showed statistical difference (p < 0.05 to p < 0.0001) among the diabetic control and standard drug rosiglitazone groups. In molecular docking study, compounds 5c and 5d exhibited higher binding energies (− 10.1 and − 10.0 kcal/mol, respectively) than the native ligand, non-thiazolidinedione PPAR-γ partial agonist (nTZDpa) (− 9.8 kcal/mol). MD simulation further authenticated the stability of compound 5c-PPAR-γ complex over the 150 ns duration. The RMSD, RMSF, rGyr, SASA, and binding interactions of compound 5c-PPAR-γ complex were comparable to those of native ligand nTZDpa-PPAR-γ complex, suggesting that the title compounds have the potential to be developed as partial PPAR-γ agonists.

PPARγ partial agonist LPSF/GQ-16 prevents dermal and pulmonary fibrosis in HOCl-induced systemic sclerosis (SSc) and modulates cytokine production in PBMC of SSc patients.

Thiazolidinediones (TZD) are synthetic molecules that have a range of biological effects, including antifibrotic and anti-inflammatory, and they may represent a promising therapeutic strategy for systemic sclerosis (SSc). The aim of this study was to investigate the immunomodulatory and antifibrotic properties of LPSF/GQ-16, a TZD derivative, in peripheral blood mononuclear cells (PBMC) from SSc patients and in a murine model of SSc HOCl-induced. The PBMC of 20 SSc patients were stimulated with phytohemagglutinin (PHA) and treated with LPSF/GQ-16 for 48h, later cytokines in the culture supernatants were quantified by sandwich enzyme-linked immunosorbent assay (ELISA) or cytometric bead array (CBA). Experimental SSc was induced by intradermal injections of hypochlorous acid (HOCl) for 6weeks. HOCl-induced SSc mice received daily treatment with LPSF/GQ-16 (30mg/kg) through intraperitoneal injections during the same period. Immunological parameters were evaluated by flow cytometry and ELISA, and dermal and pulmonary fibrosis were evaluated by RT-qPCR, hydroxyproline dosage and histopathological analysis. In PBMC cultures, it was possible to observe that LPSF/GQ-16 modulated the secretion of cytokines IL-2 (p < 0.001), IL-4 (p < 0.001), IL-6 (p < 0.001), IL-17A (p = 0.006), TNF (p < 0.001) and IFN-γ (p < 0.001). In addition, treatment with LPSF/GQ-16 in HOCl-induced SSc mice promoted a significant reduction in dermal thickening (p < 0.001), in the accumulation of collagen in the skin (p < 0.001), down-regulated the expression of fibrosis markers in the skin (Col1a1, α-Sma and Tgfβ1, p < 0.001 for all) and lungs (Il4 and Il13, p < 0.001 for both), as well as reduced activation of CD4 + T cells (p < 0.001), B cells (p < 0.001) and M2 macrophages (p < 0.001). In conclusion, LPSF/GQ-16 showed immunomodulatory and antifibrotic properties, demonstrating the therapeutic potential of this molecule for SSc.

Comparative Computational Screening of Natural-based Partial Agonists for PPARγ Receptor.

The nuclear transcription factor PPARγ, which can modulate cell growth via proliferation and apoptosis-related mechanisms, is a promising target in cancer therapy. This study aims to focus on PPARγ as the target and use virtual screening to find hits. A set of 5,677 flavonoid compounds were filtered by subjecting them to descriptor-based drug-likeness and ADMET strategies to discover drug-like compounds. The candidates' modes of binding to PPARγ were then evaluated using docking and MD simulation. PharmMapper was used to identify the potential targets of selected hits. The pharmacological network was constructed based on the GO and KEGG pathway analysis. In primary screening, 3,057 compounds met various drug-likeness criteria and docked well as partial agonists in the PPARγ-LBD. Five compounds (euchrenone b1, kaempferol-7-Orhamnoside, vincetoxicoside B, morusin, and karanjin) were selected with the use of ADMET profiles for further MD simulation investigation. Based on the PharmMapper findings, 52 proteins were then submitted to GO and KEGG enrichment analysis. As expected by GO and KEGG pathway enrichment studies, core targets were enriched in the PI3K-Akt signaling pathway (p < 0.01), indicating that certain chemicals may be involved in cancer processes. Our results suggested that the selected compounds might have sufficient drug-likeness, pharmacokinetics, and in silico bioactivity by acting as PPARγ partial agonists. Although much work remains to illuminate extensive cancer therapeutic/ chemopreventive efficacy of flavonoids in vivo, in silico methodology of our cheminformatics research may be able to provide additional data regarding the efficacy and safety of potential candidates for therapeutic targets.

Synthesis, Anti‐adipogenic, and Insulin‐sensitizing Potential of Benzosuberene‐alkyl Sulfone (BSAS) Analogues

AbstractObesity and diabetes are the leading cause of mortality worldwide. Promising modulators exhibiting insulin sensitivity and anti‐adipogenic actions are highly desirable. Organic sulfone analogues are prominent structural units present in diverse bioactive molecules. However, sulfones‐derived anti‐adipogenic agents are currently unavailable. Therefore, different benzosuberene‐alkyl sulfone (BSAS) analogues were synthesized inspired by the molecular diversity of the essential oil of Cedrus deodara. Among the series, five BSAS analogues were assessed in‐silico for their binding towards native Peroxisome Proliferator‐Activated Receptor Gamma (PPARγ) and further validated in‐vitro for their anti‐adipogenic potential in differentiated 3T3‐L1 pre‐adipocytes. Their ability to improve insulin sensitivity was also examined in L6 myotubes to ascertain their role in insulin resistance. Our results demonstrated that BSAS‐1 was the partial PPARγ agonist. It has reduced adipogenesis efficiently by downregulating adipogenic genes, resulting in lower triglyceride levels. BSAS‐1 lowered oxidative stress, protected myotubes from insulin resistance, and improved glucose uptake by promoting GLUT4 translocation. Overall, BSAS‐1 has the potential to treat obesity and obesity‐induced insulin resistance.

Design, Synthesis, and Biological Evaluation of Novel Quercetin Derivatives as PPAR-γ Partial Agonists by Modulating Epithelial-Mesenchymal Transition in Lung Cancer Metastasis.

Epithelial-to-mesenchymal transition (EMT) is responsible for driving metastasis of multiple cancer types including lung cancer. Peroxisome proliferator-activated receptor (PPAR)-γ, a ligand-activated transcription factor, controls expression of variety of genes involved in EMT. Although several synthetic compounds act as potent full agonists for PPAR-γ, their long term application is restricted due to serious adverse effects.Therefore, partial agonists involving reduced and balanced PPAR-γ activity are more effective and valued. A previous study discerned the efficacy of quercetin and its derivatives to attain favorable stabilization with PPAR-γ. Here this work is extended by synthesizing five novel quercetin derivatives (QDs) namely thiosemicarbazone (QUETSC)) and hydrazones (quercetin isonicotinic acid hydrazone (QUEINH), quercetin nicotinic acid hydrazone (QUENH), quercetin 2-furoic hydrazone (QUE2FH), and quercetin salicyl hydrazone (QUESH)) and their effects are analyzed in modulating EMT in lung cancer cell lines via PPAR-γ partial activation. QDs-treated A549 cells diminish cell proliferation strongly at nanomolar concentration compared to NCI-H460 cells. Of the five screened derivatives, QUETSC, QUE2FH, and QUESH exhibit the property of partial activation as compared to the overexpressive level of rosiglitazone. Consistently, these QDs also suppress EMT process by markedly downregulating the levels of mesenchymal markers (Snail, Slug, and zinc finger E-box binding homeobox 1) and concomitant upregulation of epithelial marker (E-cadherin).

Prenylated Chrysin Derivatives as Partial PPARγ Agonists with Adiponectin Secretion-Inducing Activity.

Decreased circulating adiponectin levels are associated with an increased risk of human metabolic diseases. The chemical-mediated upregulation of adiponectin biosynthesis has been proposed as a novel therapeutic approach to managing hypoadiponectinemia-associated diseases. In preliminary screening, the natural flavonoid chrysin (1) exhibited adiponectin secretion-inducing activity during adipogenesis in human bone marrow mesenchymal stem cells (hBM-MSCs). Here, we provide the 7-prenylated chrysin derivatives, chrysin 5-benzyl-7-prenylether compound 10 and chrysin 5,7-diprenylether compound 11, with the improved pharmacological profile compared with chrysin (1). Nuclear receptor binding and ligand-induced coactivator recruitment assays revealed that compounds 10 and 11 functioned as peroxisome proliferator-activated receptor (PPAR)γ partial agonists. These findings were supported by molecular docking simulation, followed by experimental validation. Notably, compound 11 showed PPARγ binding affinity as potent as that of the PPARγ agonists pioglitazone and telmisartan. This study presents a novel PPARγ partial agonist pharmacophore and suggests that prenylated chrysin derivatives have therapeutic potential in various human diseases associated with hypoadiponectinemia.

Citrus nutraceutical eriocitrin and its metabolites are partial agonists of peroxisome proliferator-activated receptor gamma (PPARγ): a molecular docking and molecular dynamics study

Peroxisome proliferator-activated receptor gamma (PPARγ) agonists are potent insulin sensitizers in treating type 2 diabetes. Despite being very effective in the fight against diabetes-mediated complications, PPARγ agonists are accompanied by severe side effects leading to complicated health problems, making the discovery of novel safe ligands highly pertinent. A significant intense research effort is in progress to explore the PPARγ activating potential of a wide range of natural compounds. Lemon (Citrus limon) contains various bioactive flavonoids, and eriocitrin is the major flavonoid. It possesses substantial antioxidant and anticancer, lipid-lowering activities and prevents obesity-associated metabolic diseases. Eriocitrin is metabolized to eriodictyol in the intestine, and the absorbed eriodictyol undergoes conversion to numerous metabolites in vivo. It is unclear if eriocitrin or its metabolites are responsible for their beneficial effects. We have used molecular docking, ADMET properties, drug-likeness score and molecular dynamics simulation study to find if eriocitrin and its metabolites are potent binders for PPARγ. Docking studies revealed that eriocitrin binds to PPARγ with the highest binding energy, but ADMET properties and in vivo studies show that the bioavailability of eriocitrin is very poor. Molecular dynamics studies were carried out to validate the docking results, and multiple parameters like RMSD, RMSF, Radius of gyration, SASA, hydrogen bond analysis, interaction energy, principal component analysis, Gibbs free energy and MM-PBSA were calculated. Based on our studies, eriodictyol, eriodictyol 7-O-glucuronide, eriodictyol 3′-O-glucuronide, homoeriodictyol and homoeriodictyol 7-O-glucuronide which are metabolites of eriocitrin appear to be potent partial agonists of PPARγ under physiological conditions. Communicated by Ramaswamy H. Sarma

Valerenic Acid Promotes Adipocyte Differentiation, Adiponectin Production, and Glucose Uptake via Its PPARγ Ligand Activity.

Although valerenic acid (VA) is an important marker compound for quantitative assessment of Valeriana officinalis products, little is known about its potential effects on adipocytes. We investigated the effects of VA on adipocyte differentiation, adiponectin production, and glucose uptake using 3T3-L1 adipocytes. The results showed that VA promoted adipocyte differentiation and increased the gene expression of adipogenesis and glucose uptake-related proteins, including peroxisome proliferator-activated receptor gamma (PPARγ), cytosine-cytosine-adenosine-adenosine-thymidine enhancer binding protein alpha (C/EBPα), adiponectin, and glucose transporter 4 (GLUT4). Additionally, cell cultures treated with VA had elevated adiponectin secretion and glucose uptake. The PPARγ luciferase assay indicated VA as a partial agonist of PPARγ, while the analysis using its antagonist, GW9662, and a docking simulation between PPARγ and VA revealed the binding site of VA as likely adjacent to the Ω loop pocket of PPARγ. Taken together, these results demonstrate that VA acts as a PPARγ partial agonist to promote adipocyte differentiation, adiponectin production, and glucose uptake.

Metabolites of endophytic fungi isolated from leaves of Bauhinia variegata exhibit antioxidant activity and agonist activity on peroxisome proliferator-activated receptors α, β/δ and γ.

Diabetes mellitus is a metabolic disorder that affects millions of people worldwide and is linked to oxidative stress and inflammation. Thiazolidinediones (TZD) improve insulin sensitization and glucose homeostasis mediated by the activation of peroxisome proliferator-activated receptors γ (PPARγ) in patients with type 2 diabetes. However, their use is associated with severe adverse effects such as loss of bone mass, retention of body fluids, liver and heart problems, and increased risk of bladder cancer. Partial PPARγ agonists can promote the beneficial effects of thiazolidinediones with fewer adverse effects. Endophytic fungi colonize plant tissues and have a particularly active metabolism caused by the interaction with them, which leads to the production of natural products with significant biological effects that may be like that of the colonized plant. Here, we identify seven endophytic fungi isolated from Bauhinia variegata leaves that have antioxidant activities. Also, one of the extracts presented pan-agonist activity on PPAR, and another showed activity in PPARα and PPARβ/δ. A better understanding of this relationship could help to comprehend the mechanism of action of antioxidants in treating diabetes and its complications. Moreover, compounds with these capabilities to reduce oxidative stress and activate the receptor that promotes glucose homeostasis are promising candidates in treatment of diabetes.

Identification of Selective PPAR-γ Modulators by Combining Pharmacophore Modeling, Molecular Docking, and Adipogenesis Assay.

The clinically used glitazones (rosiglitazone and pioglitazone) for type 2 diabetes mellitus therapy have been linked to serious side effects such as fluid retention, congestive heart failure, weight gain, bone loss, and an increased risk of bladder cancer. The complete activation of PPAR-γ receptors in target tissues is linked to these effects. Many studies have demonstrated that partial PPAR-γ activators (GW0072, PAT5A, GQ16) give equivalent therapeutic benefits to full PPAR-γ agonists without the associated side effects. These breakthroughs cleared the path for the development of partial agonists or selective PPAR-γ modulators (SPPARγMs). This study combined pharmacophore modeling, molecular docking, and an adipogenesis experiment to identify thiazolidine analogs as SPPARMs/partial agonists. A custom library of 220 molecules was created and virtual screened to discover 90 compounds as SPPARγMs/ partial agonists. The chosen eight compounds were synthesized and tested for adipogenesis using 3T3L1 cell lines. These compounds' partial agonistic activity was evaluated in 3T3L1 cell lines by comparing their capacity to stimulate PPAR-γ mediated adipogenesis to that of a full agonist, rosiglitazone. The findings of the adipogenesis experiment demonstrate that all eight compounds examined had a partial potential to stimulate adipogenesis when compared to the full agonist, rosiglitazone. The current investigation identified eight possible PPAR-γ partial agonists or SPPARγMs that may be effective in the treatment of type 2 diabetes mellitus.

PPAR-γ Partial Agonists in Disease-Fate Decision with Special Reference to Cancer.

Peroxisome proliferator-activated receptor-γ (PPAR-γ) has emerged as one of the most extensively studied transcription factors since its discovery in 1990, highlighting its importance in the etiology and treatment of numerous diseases involving various types of cancer, type 2 diabetes mellitus, autoimmune, dermatological and cardiovascular disorders. Ligands are regarded as the key determinant for the tissue-specific activation of PPAR-γ. However, the mechanism governing this process is merely a contradictory debate which is yet to be systematically researched. Either these receptors get weakly activated by endogenous or natural ligands or leads to a direct over-activation process by synthetic ligands, serving as complete full agonists. Therefore, fine-tuning on the action of PPAR-γ and more subtle modulation can be a rewarding approach which might open new avenues for the treatment of several diseases. In the recent era, researchers have sought to develop safer partial PPAR-γ agonists in order to dodge the toxicity induced by full agonists, akin to a balanced activation. With a particular reference to cancer, this review concentrates on the therapeutic role of partial agonists, especially in cancer treatment. Additionally, a timely examination of their efficacy on various other disease-fate decisions has been also discussed.

Diisooctyl Phthalate Isolated from Rourea mimosoides: A Partial PPARγ Agonist Potently Blocks Adipocyte Differentiation

a peer-reviewed, open access online international journal which publishes original research papers. The journal welcomes submission from scholars and experts for possible publication from all over the world. The scope of the journal includes: Pharmaceutical research, chemistry and biochemistry of naturally occurring compounds, biological evaluation of crude extracts, ethnomedicine, traditional and complementary medicine, ethnopharmacology, biomedical research, Biotechnology, Evaluation of natural substances of land and sea and of plants, microbes and animals, pharmacognosy, bioavailability, clinical, pharmacological, toxicological studies and pharmacokinetics of phytochemicals, Isolation and characterization of compounds, structure elucidation, synthesis and experimental biosynthesis of natural Product as well as developments of methods in these areas are welcomed in the journal.

Angiotensin II Receptor Blocker Irbesartan Enhanced SIRT1 longevity Signaling Replaces the Mitochondrial Biogenetic Survival Pathway to Attenuate Hypertension-Induced Heart Apoptosis.

Background: The present study investigated whether angiotensin II type 1 receptor blocker irbesartan (ARB) and partial agonist of PPAR-γ prevents heart apoptosis by suppressing cardiac Fas/FasL-mediated to mitochondria-mediated apoptosis in the hearts of hypertensive rat model. Methods: Cardiac function using echocardiography, H&E staining, TUNEL assay, and Western blotting were measured in the excised hearts from three groups, i.e., an untreated hypertensive group (SHR), an ARB-treated hypertensive group (50 mg/kg/day, S.C., SHR-ARB), and untreated normotensive Wistar-Kyoto rats (WKY). Results: Fas Ligand, Fas death receptors, FADD, active caspase-8, active caspase-3 (Fas/FasL-mediated apoptotic pathway), as well as Bax, cytochrome c, active caspase-9 and -3 (mitochondria-mediated apoptotic pathway), IGF-II, and p-JNK were decreased in SHR-ARB group when compared with the SHR group. SIRT1, PGC-1α, Bcl2, and Bcl-xL (SIRT1/PGC-1α pro-survival pathway) were increased in the SHR-ARB group when compared with the SHR group. Conclusions: Our findings suggested that the ARB might prevent cardiac Fas/FasL-mediated to mitochondria-mediated apoptosis pathway in the hypertensive model associated with IGF-II, p-JNK deactivation, and SIRT1/PGC-1α pro-survival pathway upregulation. ARB prevents hypertension-enhanced cardiac apoptosis via enhancing SIRT1 longevity signaling and enhances the mitochondrial biogenetic survival pathway.

Indazole MRL-871 interacts with PPARγ via a binding mode that induces partial agonism

The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) plays a central role in metabolic processes. PPARγ full agonists have side effects, arguing for the discovery of PPARγ partial agonists with novel chemotypes. We report the unique binding mode of the known allosteric retinoic acid receptor-related orphan receptor gamma t (RORγt) ligand MRL-871 to PPARγ. MRL-871 binds between PPARγ helices 3, 5, 7 and 11, where it stabilizes the beta-sheet region with a hydrogen bond between its carboxylic acid moiety and PPARγ Ser370. Its unique binding mode differs from that of the benzoyl 2-methyl indoles which are well-studied, structurally similar, PPARγ ligands. MRL-871′s high affinity for PPARγ induces only limited coactivator stabilization, highlighting its attractive partial agonistic characteristics. Affinity comparison of MRL-871 and related compounds towards both RORγt and PPARγ indicates the possibility for tuning of selectivity, bringing MRL-871 forward as an interesting starting point for novel PPARγ ligands.

Arylalkynyl amide-type peroxisome proliferator-activated receptor γ (PPARγ)-selective antagonists covalently bind to the PPARγ ligand binding domain with a unique binding mode

Peroxisome proliferator-activated receptor γ (PPARγ) antagonists are drug candidates for the treatment of type 2 diabetes, obesity, and osteoporosis. Previously, we have designed and synthesized a series of substituted phenylalkynyl amide-type PPARγ antagonists. The representative compound, MMT-160, exhibited nanomolar-order PPARγ antagonistic activity. To understand the antagonistic mode of action of MMT-160, mass spectrometric and X-ray crystallographic analysis of MMT-160 in the presence of the PPARγ ligand binding domain (LBD) were performed. The mass spectrometry results clearly indicated that alkynyl amide-type PPARγ antagonists were covalently bound to the PPARγ LBD. The X-ray crystallographic analysis indicated that MMT-160 acted as a Michael acceptor and covalently bound to the PPARγ LBD via Cys285. In addition, MMT-160 bound to the PPARγ LBD with a binding mode that was different from the binding modes observed for PPARγ agonists and partial agonists.