PPARγ Modulators Research Articles

Tetrahydrocannabinolic acid A (THCA-A) reduces adiposity and prevents metabolic disease caused by diet-induced obesity

Medicinal cannabis has remarkable therapeutic potential, but its clinical use is limited by the psychotropic activity of Δ9-tetrahydrocannabinol (Δ9-THC). However, the biological profile of the carboxylated, non-narcotic native precursor of Δ9-THC, the Δ9-THC acid A (Δ9-THCA-A), remains largely unexplored. Here we present evidence that Δ9-THCA-A is a partial and selective PPARγ modulator, endowed with lower adipogenic activity than the full PPARγ agonist rosiglitazone (RGZ) and enhanced osteoblastogenic effects in hMSC. Docking and in vitro functional assays indicated that Δ9-THCA-A binds to and activates PPARγ by acting at both the canonical and the alternative sites of the ligand-binding domain. Transcriptomic signatures in iWAT from mice treated with Δ9-THCA-A confirmed its mode of action through PPARγ. Administration of Δ9-THCA-A in a mouse model of HFD-induced obesity significantly reduced fat mass and body weight gain, markedly ameliorating glucose intolerance and insulin resistance, and largely preventing liver steatosis, adipogenesis and macrophage infiltration in fat tissues. Additionally, immunohistochemistry, transcriptomic, and plasma biomarker analyses showed that treatment with Δ9-THCA-A caused browning of iWAT and displayed potent anti-inflammatory actions in HFD mice. Our data validate the potential of Δ9-THCA-A as a low adipogenic PPARγ agonist, capable of substantially improving the symptoms of obesity-associated metabolic syndrome and inflammation.

Cigarette smoking differentially regulates inflammatory responses in a mouse model of nonalcoholic steatohepatitis depending on exposure time point

Cigarette smoke (CS) is a risk factor for the development of nonalcoholic fatty liver disease. However, the role of mainstream CS (MSCS) in the pathogenesis of nonalcoholic steatohepatitis (NASH) remains unclear. During the first (early exposure) or last (late exposure) three weeks of methionine-choline deficient with high fat diet feeding (6 weeks), each diet group was exposed to MSCS (300 or 600 μg/L). Hepatic or serum biochemical analysis showed that MSCS differentially modulated hepatic injury in NASH milieu, depending on exposure time points. Consistently, NASH-related hepatocellular apoptosis and fibrosis were increased in the early exposure group, but decreased in the late exposure group, except for steatosis. Ex vivo experiments showed that CS extract differentially regulated inflammatory responses in co-cultured hepatocytes and macrophages isolated from steatohepatitic livers after 10 days or 3 weeks of diet feeding. Furthermore, CS differentially up- and down-regulated the expression levels of M1/M2 polarization markers and peroxisome proliferator-activated receptor-gamma (PPARγ) in livers (29% and 38%, respectively) or co-cultured macrophages (2 and 2.5 fold, respectively). Collectively, our findings indicate that opposite effects of MSCS on NASH progression are mediated by differential modulation of PPARγ and its-associated M1/M2 polarization in hepatic macrophages, depending on exposure time points.

A novel specific peroxisome proliferator-activated receptor γ (PPARγ) modulator YR4-42 ameliorates hyperglycaemia and dyslipidaemia and hepatic steatosis in diet-induced obese mice.

AimsTo evaluate a novel tetrahydroisoquinoline derivative YR4‐42 as a selective peroxisome proliferator‐activated receptor γ (PPARγ) modulator (SPPARM) and explore its anti‐diabetic effects in vitro and in vivo.Materials and methodsUsing two standard full PPARγ agonists rosiglitazone and pioglitazone as controls, the PPARγ binding affinity and transactivation action of YR4‐42 were evaluated using biochemical and cell‐based reporter gene assays. The capacity of YR4‐42 to recruit coactivators of PPARγ was also assessed. The effects of YR4‐42 on adipogenesis and glucose consumption and PPARγ Ser273 phosphorylation were investigated in 3T3‐L1 adipocytes. The effects of YR4‐42 and pioglitazone, serving as positive control, on glucose and lipids metabolism were investigated in high‐fat diet‐induced obese (DIO) C57BL/6J mice. The expression of PPARγ target genes involved in glucose and lipid metabolism was also assessed in vitro and in vivo.Results In vitro biochemical and cell‐based functional assays showed that YR4‐42 has much weaker binding affinity, transactivation, and recruitment to PPARγ of the coactivators thyroid hormone receptor‐associated protein complex 220 kDa component (TRAP220) and PPARγ coactivator 1‐α (PGC1α) compared to full agonists. In 3 T3‐L1 adipocytes, YR4‐42 significantly improved glucose consumption without a lipogenesis effect, while blocking tumour necrosis factor α‐mediated phosphorylation of PPARγ at Ser273, thereby upregulating the expression of the PPARγ Ser273 phosphorylation‐dependent genes. Furthermore, in DIO mice, oral administration of YR4‐42 ameliorated the hyperglycaemia, with a similar insulin sensitization effect to that of pioglitazone. Importantly, YR4‐42 also improved hyperlipidaemia‐associated hepatic steatosis without weight gain, which avoids a major side effect of pioglitazone. Thus, YR4‐42 appeared to selectively modulate PPARγ responses. This finding was supported by the gene expression analysis, which showed that YR4‐42 selectively targets PPARγ‐regulated genes mapped to glucose and lipid metabolism in DIO mice.ConclusionsWe conclude that YR4‐42 is a novel anti‐diabetic drug candidate with significant advantages compared to standard PPARγ agonists. YR4‐42 should be further investigated in preclinical and clinical studies.

Unified total synthesis of amorfrutins A and C via the Claisen rearrangement.

A concise, unified total synthesis of the two prenylated aromatic polyketides amorfrutins A and C, which exhibit various medicinally important biological profiles such as antimicrobial, PPARγ modulating and quorum sensing inhibitory activities, has been achieved from commercially available 3,5-dimethoxybenzaldehyde in 38% and 10% overall yields through nine and ten steps, respectively. The key transformation for the synthesis of amorfrutin A was the Claisen rearrangement of a mono-O-(1,1-dimethylallyl)resorcinol derivative to install the C3-prenyl substituent, while that for the synthesis of amorfrutin C was the double Claisen rearrangement of a di-O-(1,1-dimethylallyl)resorcinol derivative to introduce the two prenyl groups at the C3 and C5 positions all at once.

599 PPARg signaling modulation protects from hair follicle bulge stem cell damage and cyclophosphamide-induced hair follicle cytotoxicity

In oncology, permanent chemotherapy-induced alopecia (pCIA) remains an unfulfilled clinical need. Irreversible hair loss may result from permanent damage of hair follicle bulge epithelial stem cells (HFeSCs), some of which may undergo epithelial-mesenchymal transition (EMT). To prove our hypothesis, we treated ex vivo full-length HFs with 4HC, a cyclophosphamide metabolite 4HC, which routinely induces reversible CIA and sometimes pCIA. PPARγ signaling is known to have a protective role in eSCs biology. Therefore, we additionally tested whether NAC-GED-0507-Levo (NACGED), a PPARγ modulator, may protect HFs from 4HC-induced damage. Ex vivo, treatment with 4HC (3μM, 30μM) induced HF cytotoxicity and promoted dystrophic catagen development. Moreover, 4HC caused reduction of CK15+ bulge cells number, mainly by inducing apoptosis. Interestingly, 4HC also induced EMT in the bulge epithelium, as indicated by decreased E-cadherin expression, upregulation of fibronectin and appearance of vimentin+ intra-bulge cells. HFs pretreatment with 0.01-1mM NACGED before addition of 4HC provided relative protection from induction of cytotoxicity without preventing catagen development. Finally, NACGED treatment also antagonized CIA-induced intra-bulge EMT by counteracting both E-cadherin expression reduction and increased vimentin+ cells number. Our data suggest that pCIA irreversibility may indeed result from apoptosis and/or EMT-mediated destruction of CK15+bulge eSCs. Modulation of PPARγ signaling could provide an effective strategy for managing permanent hair loss in chemotherapy-treated cancer patients.

389 Spectrum of actions of PPARγ modulation in acne sebum

389 Spectrum of actions of PPARγ modulation in acne sebum

Structure optimization of a new class of PPARγ antagonists

Peroxisome proliferator-activated receptor gamma (PPARγ) modulators have found wide application for the treatment of cancers, metabolic disorders and inflammatory diseases. Contrary to PPARγ agonists, PPARγ antagonists have been much less studied and although they have shown immunomodulatory effects, there is still no therapeutically useful PPARγ antagonist on the market. In contrast to non-competitive, irreversible inhibition caused by 2-chloro-5-nitrobenzanilide (GW9662), the recently described (E)-2-(5-((4-methoxy-2-(trifluoromethyl)quinolin-6-yl)methoxy)-2-((4-(trifluoromethyl)benzyl)oxy)-benzylidene)-hexanoic acid (MTTB, T-10017) is a promising prototype for a new class of PPARγ antagonists. It exhibits competitive antagonism against rosiglitazone mediated activation of PPARγ ligand binding domain (PPARγLBD) in a transactivation assay in HEK293T cells with an IC50 of 4.3 µM against 1 µM rosiglitazone. The aim of this study was to investigate the structure-activity relationships (SAR) of the MTTB scaffold focusing on improving its physicochemical properties. Through this optimization, 34 new derivatives were prepared and characterized. Two new potent compounds (T-10075 and T-10106) with much improved drug-like properties and promising pharmacokinetic profile were identified.

Ameliorative Effect of Berberine on Neonatally Induced Type 2 Diabetic Neuropathy via Modulation of BDNF, IGF-1, PPAR-γ, and AMPK Expressions.

Neonatal-streptozotocin (n-STZ)-induced diabetes mimics most of the clinicopathological symptoms of type 2 diabetes mellitus (T2DM) peripheral neuropathy. Berberine, a plant alkaloid, is reported to have antidiabetic, antioxidant, anti-inflammatory, and neuroprotective potential. The aim of the present study was to investigate the potential of berberine against n-STZ-induced painful diabetic peripheral polyneuropathy by assessing various biochemical, electrophysiological, morphological, and ultrastructural studies. Type 2 diabetes mellitus was produced neonatal at the age of 2 days (10-12 g) by STZ (90 mg/kg intraperitoneal). After confirmation of neuropathy at 6 weeks, rats were treated with berberine (10, 20, and 40 mg/kg). Administration of n-STZ resulted in T2DM-induced neuropathic pain reflected by a significant alterations (P < .05) in hyperalgesia, allodynia, and motor as well as sensory nerve conduction velocities whereas berberine (20 and 40 mg/kg) treatment significantly attenuated (P < .05) these alterations. Berberine treatment significantly inhibited (P < .05) STZ-induced alterations in aldose reductase, glycated hemoglobin, serum insulin, hepatic cholesterol, and triglyceride levels. The elevated oxido-nitrosative stress and decreased Na-K-ATPase and pulse Ox levels were significantly attenuated (P < .05) by berberine. It also significantly downregulated (P < .05) neural tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6 messenger RNA (mRNA), and protein expressions both. Streptozotocin-induced downregulated mRNA expressions of brain-derived neurotrophic factor (BDNF), insulin-like growth factor (IGF-1), and peroxisome proliferator-activated receptors-γ (PPAR-γ) in sciatic nerve were significantly upregulated (P < .05) by berberine. Western blot analysis revealed that STZ-induced alterations in adenosine monophosphate protein kinase (AMPK; Thr-172) and protein phosphatase 2C-α protein expressions in dorsal root ganglia were inhibited by berberine. It also attenuated histological and ultrastructural alterations induced in sciatic nerve by STZ. In conclusion, berberine exerts its neuroprotective effect against n-STZ-induced diabetic peripheral neuropathy via modulation of pro-inflammatory cytokines (TNF α, IL-1β, and IL-6), oxido-nitrosative stress, BDNF, IGF-1, PPAR-γ, and AMPK expression to ameliorate impaired allodynia, hyperalgesia, and nerve conduction velocity during T2DM.

1953-P: PPARγ Agonism and FGF-21 Synergize to Robustly Induce Browning of White Fat

Increasing brown adipose tissue abundance or activity or converting white into brown adipocytes holds promise for the treatment of type 2 diabetes and obesity. Several PPARγ agonists, including rosiglitazone, have been shown to robustly induce browning of white adipose tissue (WAT) in vitro but their effects in vivo are less pronounced, while PPARα agonists show modest browning effects both in vitro or in vivo. In the present study, we investigated whether PPARα and PPARγ dual agonism would have synergistic effects in inducing browning of WAT. We found that all tested dual PPARα/γ agonists robustly increased uncoupling protein 1 (Ucp1) expression in both mouse and human preadipocytes, with tesaglitazar giving the largest Ucp1 induction. Notably, tesaglitazar also strongly induced browning of WAT in vivo in both lean and obese mice at thermoneutrality, largely exceeding the increase in Ucp1 observed with rosiglitazone. Mechanistically, we found that selective PPARγ agonism was sufficient for the conversion of white into brown-like adipocytes in vitro, but dual PPARα/γ agonism was superior to selective PPARγ agonism at inducing white fat browning in vivo, at least in part via a PPARα-mediated increase in fibroblast growth factor 21 (FGF-21). In human preadipocytes in vitro, combined treatment with rosiglitazone and FGF-21 resulted in a robust and synergistic increase in UCP1 mRNA levels, superior to rosiglitazone- or FGF-21-monotreatments. Tesaglitazar-induced browning in obese mice was associated with increased energy expenditure, enhanced insulin sensitivity, reduced liver steatosis, and an overall improved metabolic profile compared to rosiglitazone and vehicle control groups. In conclusion, we found that dual PPARα/γ agonism robustly promotes browning of white fat in vivo, via synergistic action of FGF-21 and PPARγ agonism. Our findings identify a novel opportunity to develop compounds with robust browning of WAT, via dual modulation of PPARα and PPARγ. Disclosure T. Kroon: Employee; Self; AstraZeneca. M.J. Harms: Employee; Self; AstraZeneca. D. Nilsson: None. A. Lindblom: Employee; Self; AstraZeneca. P. Gennemark: Employee; Self; AstraZeneca. G. O'Mahony: Employee; Self; AstraZeneca. V. Osinski: None. C.A. McNamara: None. J. Boucher: Employee; Self; AstraZeneca.

Importance of the Proximity and Orientation of Ligand-Linkage to the Design of Cinnamate-GW9662 Hybrid Compounds as Covalent PPARγ Agonists.

Covalent agonists of PPARγ cause unique receptor conformational changes and behave as selective PPARγ modulators, whereas there are few covalent agonists other than endogenous unsaturated fatty acids metabolites. Previously, we established a cell-based strategy to identify new PPARγ ligands and synthesized a new-type of covalent agonist that possesses the hybrid structure of a plant-derived cinnamic acid derivative and GW9662, a covalent antagonist. Herein, we report six analogues that differ in how the two fragments are linked together. Compounds with a simplified linker showed potent agonistic activity with improved EC50 values (less than 5 nM), indicating that close proximity between the two fragments improves binding affinity. When the position of cinnamic acid moiety was placed at 4′ carbon of aniline ring, PPARγ agonist activity was completely abolished. Docking studies suggested that the activation profile likely depends on interaction with the cavity around helix 3, β-sheet, and Ω-loop region in the ligand-binding domain. Furthermore, a cell-based assay revealed that agonist-type compounds activate PPARγ transcription in a manner dependent on covalent linkage with the Cys285 residue leading to prolonged transactivation. This activation feature reflects pharmacological benefits of covalent drugs, suggesting that these hybrid compounds may serve as potential leads for a new-class of covalent PPARγ ligands.

Evidence that peroxisome proliferator-activated receptor γ suppresses squamous carcinogenesis through anti-inflammatory signaling and regulation of the immune response.

A variety of evidence suggests that peroxisome proliferator-activated receptor (PPAR)γ agonists may represent a potential pharmacologic target in the prevention or treatment of skin cancer. In particular, recent reports suggest that PPARγ activation may exert at least some of its anti-neoplastic effects through the suppression of tumor promoting chronic inflammation as well as by strengthening antitumor immune responses. This activity is thought to occur through a distinct mode of ligand interaction with PPARγ that causes transrepression of transcription factors that are involved in inflammatory and immunomodulatory signaling. However, current thiazolidinedione (TZD)-type PPARγ agonists have significant safety concerns that limit their usefulness as a preventive or therapeutic option. Due to the relatively large ligand binding pocket of PPARγ, a diverse group of ligands can be seen to interact with distinct modes of binding to PPARγ, leading to the phenomenon of partial agonist activity and selective PPARγ modulators (SPPARγM). This has led to the development of ligands that are tailored to deliver desired pharmacologic activity, but lack some of the negative side effects associated with full agonists, such as the currently utilized TZD-type PPARγ agonists. In addition, there is evidence that a number of phytochemicals that are currently being touted as antineoplastic nutraceuticals also possess PPARγ activity that may partially explain their pharmacologic activity. We propose that one or more of these partial agonists, SPPARγMs, or putative phytochemical PPARγ ligands could presumably be used as a starting point to design more efficacious anti-neoplastic PPARγ ligands that lack adverse pharmacological effects.

Critical Insight into the Design of PPAR-γ Agonists by Virtual Screening Techniques.

Design of novel PPAR-γ modulators with better binding efficiency and fewer side effects to treat type 2 diabetes is still a challenge for medicinal chemists. Cost and time efficient computational methods have presently become an integral part of research in nuclear receptors and their ligands, enabling hit to lead identification and lead optimization. This review will focus on cutting-edge technologies used in most recent studies on the design of PPAR- γ agonists and will discuss the chemistry of few molecules which emerged successful. Literature review was carried out in google scholar using customized search from 2011- 2017. Computer-aided design methods presented in this article were used as search terms to retrieve corresponding literature. Virtual screening of natural product libraries is an effective strategy to harness nature as the source of ligands for PPARs. Rigid and induced fit docking and core hopping approach in docking are rapid screening methods to predict the PPAR- γ and PPAR-α/ γ dual agonistic activity. Onedimensional drug profile matching is one of the recent virtual screening methods by which an antiprotozoal drug, Nitazoxanide was identified as a PPAR- γ agonist. It is concluded that to achieve a convincing and reliable design of PPAR-γ agonist by virtual screening techniques, customized workflow comprising of appropriate models is essential in which methods may be applied either sequentially or simultaneously.

MicroRNA 27B-3P: role in extracellular matrix regulation in osteoarthritis synovial fibroblasts

Purpose: Synovial fibrosis is a key pathological event that contributes towards joint destruction, pain and stiffness associated with osteoarthritis (OA). Fibrosis is associated with the accumulation of excessive amount of extra-cellular matrix (ECM) resulting in tissue damage. Currently, endogenous mechanisms that play a key role in the initiation and progression of synovial fibrosis during OA are not well understood. We have previously shown that the expression of a small non-coding RNA called microRNA27b-3p (miR-27b-3p) is elevated in the synovial fluid of late-stage (Kellgren-Lawrence, KL score 3 & 4) compared to early-stage (KL score 1 & 2) radiographic knee OA patients. Furthermore, we also observed that miR-27b-3p is abundantly expressed in OA synovium (Y-H. Li, G. Tavallaee, et al. 2016). Since the role of miR-27b-3p in synovial pathology associated with OA has never been studied; we investigated if miR-27b-3p plays any role in ECM regulation in the OA synovium. Methods: Synovial tissues were obtained from OA patients undergoing total knee replacement with informed written consent. Primary OA synovial fibroblasts (major cell types present in the synovium) were isolated, cultured and transfected with miR-27b-3p mimic/inhibitor and subjected to qPCR arrays specific for ECM markers. Results obtained from arrays were further validated using quantitative-PCR analysis. For in vivo studies, mice were also subjected to DMM model of OA to determine the expression of miR-27b-3p during the time course of OA development in knee joint using in situ hybridization (ISH). Results: ECM-specific qPCR-arrays followed by validation of responsive genes by quantitative-PCR analysis revealed that miR-27b-3p mimic treatment resulted in a significant upregulation of key ECM genes including pro-collagen type-I (COL1A1), A disintegrin and metalloproteinase with thrombospondin motifs 8 (ADAMTS-8), Thrombospondin 1 (THBS1), fibronectin1 (FN1), Collagen 5 A 1 (COL5A1) and Collagen 14 A 1 (COL14A1) in OA Synovial fibroblasts. Furthermore, miR-27b-3p mimic resulted in a marked increase in type-I collagen protein expression; this effect was inhibited by miR-27b-3p inhibitor. Overall, these results suggest that miR-27b-3p may play a key role in the regulation of key ECM components in OA synovial fibroblasts. Next, we employed “Watson Discovery tool” to identify direct targets of miR-27b-3p to further elucidate its signalling pathway. This tool identified a panel of 11 genes including peroxisome proliferator-activated receptor gamma (PPARγ) as direct targets for miR-27b-3p. Indeed, we confirmed that miR-27b-3p mimic treatment results in a marked suppression of PPARγ expression, while inhibition of miR-27b-3p upregulates PPARγ, suggesting that miR-27b-3p may impart its ECM regulatory effect through modulation of PPARγ. Furthermore, ISH of DMM-induced OA mice knee joints further show that miR-27b-3p expression is prominent in the synovial lining and fibrocartilage compared to sham control mice in vivo. Conclusions: Our results thus far suggest that, in OA synovial fibroblasts, miR-27b-3p is involved in the regulation of key ECM components. Our data also suggest that miR-27b-3p may signal via negative regulation of PPARγ. Our ongoing studies are confirming if miR-27b-3p signalling via PPARγ controls ECM regulation in OA synovial fibroblasts. Our in vivo studies show that miR-27b-3p expression is elevated in the synovium during OA. To comprehensively investigate the endogenous role of miR-27b-3p in synovial pathology, we have intra-articularly injected mouse knee joints with the in-vivo grade mimic of miR-27b-3p to determine any changes in the synovium upon miR-27b-3p treatment in vivo.

Zafirlukast Is a Dual Modulator of Human Soluble Epoxide Hydrolase and Peroxisome Proliferator-Activated Receptor γ.

Cysteinyl leukotriene receptor 1 antagonists (CysLT1RA) are frequently used as add-on medication for the treatment of asthma. Recently, these compounds have shown protective effects in cardiovascular diseases. This prompted us to investigate their influence on soluble epoxide hydrolase (sEH) and peroxisome proliferator activated receptor (PPAR) activities, two targets known to play an important role in CVD and the metabolic syndrome. Montelukast, pranlukast and zafirlukast inhibited human sEH with IC50 values of 1.9, 14.1, and 0.8 μM, respectively. In contrast, only montelukast and zafirlukast activated PPARγ in the reporter gene assay with EC50 values of 1.17 μM (21.9% max. activation) and 2.49 μM (148% max. activation), respectively. PPARα and δ were not affected by any of the compounds. The activation of PPARγ was further investigated in 3T3-L1 adipocytes. Analysis of lipid accumulation, mRNA and protein expression of target genes as well as PPARγ phosphorylation revealed that montelukast was not able to induce adipocyte differentiation. In contrast, zafirlukast triggered moderate lipid accumulation compared to rosiglitazone and upregulated PPARγ target genes. In addition, we found that montelukast and zafirlukast display antagonistic activities concerning recruitment of the PPARγ cofactor CBP upon ligand binding suggesting that both compounds act as PPARγ modulators. In addition, zafirlukast impaired the TNFα triggered phosphorylation of PPARγ2 on serine 273. Thus, zafirlukast is a novel dual sEH/PPARγ modulator representing an excellent starting point for the further development of this compound class.

Connectivity mapping of angiotensin-PPAR interactions involved in the amelioration of non-alcoholic steatohepatitis by Telmisartan

Nonalcoholic fatty liver disease (NAFLD) is a global health problem that is associated with various metabolic disorders. Telmisartan is a potential treatment for NAFLD due to its ability to improve insulin sensitivity and decrease hepatic fat accumulation via modulation of PPARγ, and to suppress hepatic fibrosis by blocking angiotensin II receptors. However, the underlying mechanisms of action of telmisartan have yet to be fully elucidated. In the present study, diabetic nonalcoholic steatohepatitis (NASH) mice (STAM mice) received daily administrations of telmisartan for 6 weeks to assess the improvements in NASH. Hepatic transcriptome analyses revealed that the amelioration of NASH likely occurred through the regulation of inflammatory- and fibrosis-related gene responses. An integrated network analysis including transcriptional and non-transcriptional genes regulated by telmisartan showed that the NAFLD pathway is interconnected with the dysregulated RAS-PPAR-NFκB pathways. The downstream targets of PPARα, PPARδ, and RELA in this network significantly overlapped with telmisartan-induced differentially expressed genes (DEGs), which were verified in palmitate-treated Hepa1c1c7 cell line. This transcriptome approach accompanied with cell-based molecular analyses provided the opportunity to understand the fundamental molecular mechanisms underpinning the therapeutic effects of telmisartan, and will contribute to the establishment of a novel pharmacological treatment for NASH patients.

Structure-Activity Relationship Studies of 3- or 4-Pyridine Derivatives of DS-6930.

Derivatization efforts were continued to discover backups for a potent selective PPARγ modulator, DS-6930. In this Letter, the replacement of 2-pyridine ring in DS-6930 with 3- or 4-pyridyl group is reported. As the introduction of substituents on the pyridine ring did not provide potent partial agonists, modifications of benzimidazole ring were explored to discover potent intermediate agonists. 4'-Alkoxy substituted benzimidazoles failed to show potent efficacy in vivo, whereas 7'-fluoro benzimidazole 3g (DS19161384) was found to result in robust plasma glucose reductions with excellent DMPK profiles.

Possible role of PPAR-γ and COX-2 receptor modulators in the treatment of Non-Small Cell lung carcinoma

Non-Small Cell lung cancer (NSCLC) accounts for 85% of total lung cancers worldwide, affecting more than 1.5 million people every year. Recent studies reported that lung adenocarcinoma express Peroxisome Proliferator Activated Receptor-γ (PPAR-γ) which is believed to be inactivated due to cytoplasmic accumulation or somatic ‘loss of function’ of the gene. PPAR-γ reported to play an important role in cell proliferation, cell differentiation and apoptosis via inhibition of NF-kβ pathway. Adenocarcinoma also overexpress cyclooxygenase-2 (COX-2), which is reported to promote angiogenesis and metastasis via TX-A2 production. Therefore, we hypothesize that activation of PPAR-γ (through PPAR-γ agonists) and inhibition of COX-2 (through COX-2 inhibitors) will have beneficial effects in the treatment of NSCLC.

The Protective Role of Peroxisome Proliferator-Activated Receptor-Gamma in Seizure and Neuronal Excitotoxicity.

The peroxisome proliferator-activated receptor (PPAR) family, type II nucleus receptors have been successfully tested for their neuroprotective potential in certain central nervous system diseases. The aim of the present study was to determine if modulation by PPAR-γ could attenuate pilocarpine-induced seizures and decrease neuronal excitability. Adult male C57BL/6 mice were divided into two groups: one group received pretreatment with pioglitazone and the other received dimethyl sulfoxide (DMSO) for a period of 2weeks. Status epilepticus was then induced in both groups by lithium-pilocarpine, after which seizure susceptibility, severity, and mortality were evaluated. Hippocampal histopathology was carried out on all mice at 24h post-status epilepticus as well as blood-brain barrier (BBB) damage analysis. With the aid of patch clamp technology, the hippocampal neuronal excitability from mice with PPAR-γ 50% expression (PpargC/C) and PPAR-γ 25% expression (PpargC/-), as well as the effect of pioglitazone on the sodium currents in hippocampal neurons, were evaluated. It was found that pioglitazone, a PPAR-γ agonist, could attenuate pilocarpine-induced seizure severity in mice. Pathological examination showed that pioglitazone significantly attenuated pilocarpine-induced status epilepticus-related hippocampal neuronal loss and BBB damage. Further characterization of neuronal excitability revealed higher excitability in the brain slices from mice with PpargC/- expression, compared with the PpargC/C group. It was also found that pioglitazone could decrease sodium currents in hippocampal neurons. In conclusion, PPAR-γ deficiency aggravated neuronal excitability and excitotoxicity. PPAR-γ attenuated pilocarpine-induced seizure severity, neuronal loss, BBB damage, and sodium currents in hippocampal neurons. Modulation of PPAR-γ could be a potential novel treatment for epileptic seizures.

Hydroxytyrosol supplementation ameliorates the metabolic disturbances in white adipose tissue from mice fed a high-fat diet through recovery of transcription factors Nrf2, SREBP-1c, PPAR-γ and NF-κB

BackgroundWhite adipose tissue (WAT) have a relevant metabolic and inflammatory function, in overweight or obesity conditions. In this regard, the WAT under over feeding nutrition present a significant increment in oxidative stress, pro-inflammatory status and depletion of n-3 long chain polyunsaturated fatty acid. Hydroxytyrosol (HT) is a polyphenol with important cytoprotective effects, and this molecule can modulate the gene expression, transcription factors and enzymatic activity. ObjectiveTherefore, the purpose of this study was evaluate the anti-inflammatory, anti-oxidant and anti-lipogenic effects of HT supplementation mice and the molecular adaptations involved, on dysfunctional WAT from high-fat diet (HFD)-fed mice. Methods and resultsMale C57BL/6 J mice received (i) control diet (10% fat); (ii) control diet + HT (daily doses of 5 mg kg body weight), (iii) HFD (60% fat); or (iv) HFD + HT for 12 weeks. HFD-fed mice exhibited: (i) WAT hypertrophy; (ii) oxidative stress and depletion of antioxidant defenses, (iii) increased lipogenesis and pro-inflammatory status, (iv) depletion of n-3 LCPUFA and (v) up-regulation of NF-κB and SREBP 1c with down-regulation Nrf2, and PPAR-γ. HT supplementation attenuated the metabolic impairment produced by HFD in WAT, attenuating increment of NF-κB and SREBP 1c, and increasing the activity of Nrf2 and PPAR-γ. ConclusionSupplementation with HT improve the WAT dysfunction induced by HDF in mice through the modulation of transcription factors NF-κB, Nrf2, SREBP-1c and PPAR-γ as well as their target genes, involved in inflammation, antioxidant defenses and lipogenesis.

SnapshotDx Quiz: December 2018

SnapshotDx Quiz: December 2018