PPARγ Modulators Research Articles

Anti-fibrotic effect of ciglitazone in HRV-induced airway remodelling cell model.

Fibrosis is an important phenomenon as it can occur early in the pathogenesis of asthma; it may be associated with disease severity and resistance to therapy. There is a strong evidence that infection caused by human rhinovirus (HRV) contributes to remodelling process, but there is lack of studies clearly explaining this pathway. Synthetic peroxisome proliferator-activated receptor (PPAR) γ presents immunomodulatory and anti-inflammatory features. In this study, we examined immunomodulatory properties of ciglitazone - PPAR-γ agonist, in development and modulation of airway remodelling. Epithelial cells (NHBE) and two lines of fibroblasts (WI-38, HFL1) were stimulated with ciglitazone and rhinovirus. The expression of genes related to airway remodelling process were analysed in the cells; moreover NF-κB, c-Myc and STAT3 were silenced in order to estimate potential pathways involved. Ciglitazone decreased mRNA expression of MMP-9 and TGF-β. It also modified the expression of α-SMA and collagen after rhinovirus infection. Transcription factors knockdown altered the levels of expression. The results suggest possible anti-fibrotic activity of PPAR-γ agonist in human airway cells. Ciglitazone has been shown to be dependent on NF-κB- and STAT3-related pathways, thus, the PPAR-γ agonist may have therapeutic potential for the treatment of airway remodelling in asthma.

The prophylactic effects of naringin on steroid-induced early-stage osteonecrosis in rats: a preliminary study.

The excessive steroid may cause dyslipidaemia and oxidative insult during femoral head osteonecrosis, inducing bone loss and impairment of the intraosseous blood system. In contrast, bio-flavanone naringin has shown antioxidant, antiresorptive and lipid-lowering bioactivities. The present research is an effort to explore the anti-ON potential of naringin in vivo and in vitro. After a 6-week treatment, the femora were dissected for histological examination following bone mineral density assay by X-ray absorptiometry. Blood samples were examined for coagulation, oxidative stress, lipid transportation and endothelial injury. Marrow samples were cultured and assayed for adipogenic and osteogenic alterations by ALP activity, mineralization, RT-qPCR and western blot analysis. The results showed that naringin exerted a dose-dependent effect on reducing ON incidence, with inhibition of osteoporosis, oxidative stress and dyslipidaemia. The mechanism included the suppression of PPARγ2 for adipogenesis of bone marrow stem cells (BMSCs) and the prevention of oxidative stress in endothelium injury. Naringin may restore steroid-impaired osteogenesis by enhancing the mRNA and protein expression of osteogenic markers in a dose-ascending manner and new bone formation can be found in naringin groups. Taken together, our findings showed that naringin may serve as a prophylactic agent and selective PPARγ modulator for the early-stage ON.

Influence of Polyphenols on Adipose Tissue: Sirtuins as Pivotal Players in the Browning Process.

Adipose tissue (AT) can be classified into two different types: (i) white adipose tissue (WAT), which represents the largest amount of total AT, and has the main function of storing fatty acids for energy needs and (ii) brown adipose tissue (BAT), rich in mitochondria and specialized in thermogenesis. Many exogenous stimuli, e.g., cold, exercise or pharmacological/nutraceutical tools, promote the phenotypic change of WAT to a beige phenotype (BeAT), with intermediate characteristics between BAT and WAT; this process is called "browning". The modulation of AT differentiation towards WAT or BAT, and the phenotypic switch to BeAT, seem to be crucial steps to limit weight gain. Polyphenols are emerging as compounds able to induce browning and thermogenesis processes, potentially via activation of sirtuins. SIRT1 (the most investigated sirtuin) activates a factor involved in mitochondrial biogenesis, peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), which, through peroxisome proliferator-activated receptor γ (PPAR-γ) modulation, induces typical genes of BAT and inhibits genes of WAT during the transdifferentiation process in white adipocytes. This review article aims to summarize the current evidence, from pre-clinical studies to clinical trials, on the ability of polyphenols to promote the browning process, with a specific focus on the potential role of sirtuins in the pharmacological/nutraceutical effects of natural compounds.

Sulforaphane Inhibits Foam Cell Formation and Atherosclerosis via Mechanisms Involving the Modulation of Macrophage Cholesterol Transport and the Related Phenotype

Sulforaphane (SFN), an isothiocyanate, is one of the major dietary phytochemicals found in cruciferous vegetables. Many studies suggest that SFN can protect against cancer and cardiometabolic diseases. Despite the proposed systemic and local vascular protective mechanisms, SFN’s potential to inhibit atherogenesis by targeting macrophages remains unknown. In this study, in high fat diet fed ApoE-deficient (ApoE−/−) mice, oral SFN treatment improved dyslipidemia and inhibited atherosclerotic plaque formation and the unstable phenotype, as demonstrated by reductions in the lesion areas in both the aortic sinus and whole aorta, percentages of necrotic cores, vascular macrophage infiltration and reactive oxygen species (ROS) generation. In THP-1-derived macrophages, preadministration SFN alleviated oxidized low-density lipoprotein (ox-LDL)-induced lipid accumulation, oxidative stress and mitochondrial injury. Moreover, a functional study revealed that peritoneal macrophages isolated from SFN-treated mice exhibited attenuated cholesterol influx and enhanced apolipoprotein A-I (apoA-I)- and high-density lipoprotein (HDL)-mediated cholesterol efflux. Mechanistic analysis revealed that SFN supplementation induced both intralesional and intraperitoneal macrophage phenotypic switching toward high expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and ATP-binding cassette subfamily A/G member 1 (ABCA1/G1) and low expression of peroxisome proliferator-activated receptor γ (PPARγ) and cluster of differentiation 36 (CD36), which was further validated by the aortic protein expression. These results suggest that the regulation of macrophages’ cholesterol transport and accumulation may be mainly responsible for SFN’s potential atheroprotective properties, and the regulatory mechanisms might involve upregulating ABCA1/G1 and downregulating CD36 via the modulation of PPARγ and Nrf2.

Convolvulus pluricaulis Choisy's Extraction, Chemical Characterization and Evaluation of the Potential Effects on Glycaemic Balance in a 3T3-L1 Adipocyte Cell Model.

Convolvulus pluricaulis (CP) is a common Indian herb, largely employed in Ayurvedic medicine and known for its neuroprotective and neuroinflammatory action. Its effectiveness against several pathologic/sub-pathologic conditions is widely accepted, but it is not yet completely chemically characterized. In recent years, several researchers have pointed out the involvement of CP and other Convolvulaceae in lipidic and glucidic metabolism, particularly in the control of hyperlipidaemia and diabetic conditions. In this scenario, the aim of the study was to chemically characterize the medium polarity part of the CP whole plant and its fractions and to shed light on their biological activity in adipocyte differentiation using the 3T3-L1 cell model. Our results demonstrated that the CP extract and fractions could upregulate the adipocyte differentiation through the modulation of the nuclear receptor PPARγ (Peroxisome Proliferator-Activated Receptor γ), broadly recognized as a key regulator of adipocyte differentiation, and the glucose transporter GLUT-4, which is fundamental for cellular glucose uptake and for metabolism control. CP also showed the ability to exert an anti-inflammatory effect, downregulating cytokines such as Rantes, MCP-1, KC, eotaxin, and GM-CSF, which are deeply involved in insulin resistance and glucose intolerance. Taken together, these data suggest that CP could exert a potential beneficial effect on glycemia and could be employed as an anti-diabetic adjuvant or, in any case, a means to better control glucose homeostasis.

3-[5-(1H-Indol-3-ylmethylene)-4-oxo-2-thioxothiazolidin-3-yl]-propionic Acid as a Potential Polypharmacological Agent

Searching for new types of biological activities among preliminarily identified hit compounds is a key challenge in modern medicinal chemistry. In our study, a previously studied 3-[5-(1H-indol-3-ylmethylene)-4-oxo-2-thioxothiazolidin-3-yl]-propionic acid (Les-6614) was screened for antimicrobial, antifungal, anti-allergic, and antitumor activities. Moreover, cytotoxicity, molecular docking, and SwissAdme online target screening were accomplished. It was determined that the Les-6614 has slight antimicrobial and antitumor activity. However, the studied compound decreased IgE levels in sensitized guinea pigs by 33–86% and reduced IgA, IgM, IL-2, and TNF-α, indicating anti-inflammatory and anti-allergic aactivities. According to the SwissADME web tool, target predictions for Les-6614 potentially have an affinity for lysosomal protective protein, Thromboxane-A synthase, and PPARγ. The molecular docking confirmed that the studied 2-thioxo-4-thiazolidinone derivative showed good bonding with LLP and TXAS, leading to stable protein–ligand complexes. Additionally, Les-6614 is a potential PPARγ modulator, which is important in the pathogenesis of allergy, cancer, and cardiovascular diseases.

Selective PPARγ modulator diosmin improves insulin sensitivity and promotes browning of white fat

Peroxisome proliferator-activated receptor γ (PPARγ) is a master regulator of adipocyte differentiation, glucolipid metabolism, and inflammation. Thiazolidinediones are PPARγ full agonists with potent insulin-sensitizing effects, whereas their oral usage is restricted because of unwanted side effects, including obesity and cardiovascular risks. Here, via virtual screening, microscale thermophoresis analysis, and molecular confirmation, we demonstrate that diosmin, a natural compound of wide and long-term clinical use, is a selective PPARγ modulator that binds to PPARγ and blocks PPARγ phosphorylation with weak transcriptional activity. Local diosmin administration in subcutaneous fat (inguinal white adipose tissue [iWAT]) improved insulin sensitivity and attenuated obesity via enhancing browning of white fat and energy expenditure. Besides, diosmin ameliorated inflammation in WAT and liver and reduced hepatic steatosis. Of note, we determined that iWAT local administration of diosmin did not exhibit obvious side effects. Taken together, the present study demonstrated that iWAT local delivery of diosmin protected mice from diet-induced insulin resistance, obesity, and fatty liver by blocking PPARγ phosphorylation, without apparent side effects, making it a potential therapeutic agent for the treatment of metabolic diseases.

The PPAR-γ Agonist Pioglitazone Modulates Proliferation and Migration in HUVEC, HAOSMC and Human Arteriovenous Fistula-Derived Cells.

The failure of arteriovenous fistulas (AVFs) following intimal hyperplasia (IH) increases morbidity and mortality rates in patients undergoing hemodialysis for chronic kidney disease. The peroxisome-proliferator associated receptor (PPAR-γ) may be a therapeutic target in IH regulation. In the present study, we investigated PPAR-γ expression and tested the effect of pioglitazone, a PPAR-γ agonist, in different cell types involved in IH. As cell models, we used Human Endothelial Umbilical Vein Cells (HUVEC), Human Aortic Smooth Muscle Cells (HAOSMC), and AVF cells (AVFCs) isolated from (i) normal veins collected at the first AVF establishment (T0), and (ii) failed AVF with IH (T1). PPAR-γ was downregulated in AVF T1 tissues and cells, in comparison to T0 group. HUVEC, HAOSMC, and AVFC (T0 and T1) proliferation and migration were analyzed after pioglitazone administration, alone or in combination with the PPAR-γ inhibitor, GW9662. Pioglitazone negatively regulated HUVEC and HAOSMC proliferation and migration. The effect was antagonized by GW9662. These data were confirmed in AVFCs T1, where pioglitazone induced PPAR-γ expression and downregulated the invasive genes SLUG, MMP-9, and VIMENTIN. In summary, PPAR-γ modulation may represent a promising strategy to reduce the AVF failure risk by modulating cell proliferation and migration.

Development of novel thiazolidine-2,4-dione derivatives as PPAR-γ agonists through design, synthesis, computational docking, MD simulation, and comprehensive in vitro and in vivo evaluation.

The present study was conducted to develop new novel 2,4-thiazolidinedione derivatives (3h-3j) as peroxisome proliferator-activated receptor-γ (PPAR-γ) modulators for antidiabetic activity. The objective was to overcome the adverse effects of existing thiazolidinediones while maintaining their pharmacological benefits. The synthesized compounds were elucidated based on FT-IR, 1H-NMR, 13C-NMR, and MS techniques. Molecular docking was utilized to investigate the interaction binding modes, binding free energy, and amino acids engaged in the compounds' interactions with the target protein. Subsequently, molecular dynamics modelling was used to assess the stability of the top-docked complexes and an assay was utilized to assess the cytotoxicity of the compounds to C2C12 myoblasts. Compounds 3h-3j exhibited PPAR-γ modulatory activity and demonstrated significant hypoglycaemic effects when compared to the reference drug pioglitazone. The new compounds were evaluated for their in vivo blood glucose-lowering potential by using a dexamethasone-induced diabetic rat model. All the compounds showed a hypoglycaemic effect of 108.04 ± 4.39, 112.55 ± 6.10, and 117.48 ± 43.93, respectively, along with pioglitazone (153.93 ± 4.61) compared to the diabetic control. Additionally, all the compounds significantly reduced AST and ALT levels and did not cause liver damage.

Alternatively Spliced Landscape of PPARγ mRNA in Podocytes Is Distinct from Adipose Tissue.

Podocytes are highly differentiated epithelial cells, and their structural and functional integrity is compromised in a majority of glomerular and renal diseases, leading to proteinuria, chronic kidney disease, and kidney failure. Traditional agonists (e.g., pioglitazone) and selective modulators (e.g., GQ-16) of peroxisome-proliferator-activated-receptor-γ (PPARγ) reduce proteinuria in animal models of glomerular disease and protect podocytes from injury via PPARγ activation. This indicates a pivotal role for PPARγ in maintaining glomerular function through preservation of podocytes distinct from its well-understood role in driving insulin sensitivity and adipogenesis. While its transcriptional role in activating adipokines and adipogenic genes is well-established in adipose tissue, liver and muscle, understanding of podocyte PPARγ signaling remains limited. We performed a comprehensive analysis of PPARγ mRNA variants due to alternative splicing, in human podocytes and compared with adipose tissue. We found that podocytes express the ubiquitous PPARγ Var 1 (encoding γ1) and not Var2 (encoding γ2), which is mostly restricted to adipose tissue and liver. Additionally, we detected expression at very low level of Var4, and barely detectable levels of other variants, Var3, Var11, VartORF4 and Var9, in podocytes. Furthermore, a distinct podocyte vs. adipocyte PPAR-promoter-response-element containing gene expression, enrichment and pathway signature was observed, suggesting differential regulation by podocyte specific PPARγ1 variant, distinct from the adipocyte-specific γ2 variant. In summary, podocytes and glomeruli express several PPARγ variants, including Var1 (γ1) and excluding adipocyte-specific Var2 (γ2), which may have implications in podocyte specific signaling and pathophysiology. This suggests that that new selective PPARγ modulators can be potentially developed that will be able to distinguish between the two forms, γ1 and γ2, thus forming a basis of novel targeted therapeutic avenues.

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.

Structure-based screening and biological validation of the anti-thrombotic drug-dicoumarol as a novel and potent PPARγ-modulating ligand

PPARγ full agonists, thiazolidinediones (TZDs), have been known as a class of most effective drugs for the treatment of type 2 diabetes mellitus (T2DM). However, recently their therapeutic benefits have been compromised by several undesirable side effects. In this study, a host-based repurposing strategy and in combination with comprehensive biological evaluations were synergistically employed to seek for potent PPARγ ligands, which led to the identification of an anti-thrombotic drug, dicoumarol (Dic), as the novel and safer selectively PPARγ modulator (SPPARγM) with advantages over current TZD drugs. The results in vitro showed that Dic had a potent binding affinity and weakly agonistic activity for PPARγ and its downstream key genes. Moreover, in diabetic model, it significantly reduced blood glucose without leading to the weight gain of both body and main organ tissues. Further mechanistic investigations revealed that Dic possessed such desired pharmacological properties mainly through effectively inhibiting the phosphorylation of PPARγ-Ser273 and selectively regulating the expressions of insulin-sensitive and resistance genes. Finally, the docking studies on the analysis of the potent binding mode of Dic with PPARγ revealed a remarkable difference on interaction region compared with other developed PPARγ agonists, which not only gave a proof of concept for the abovementioned mechanism but also provided the molecular basis for the discrimination of Dic from other PPARγ ligands, especially TZD drugs. Taken together, our findings suggested that Dic could serve as a new and promising candidate with good therapeutic index for treating T2DM, especially for those T2DM patients with thrombosis.

Bergenin ameliorates cognitive deficits and neuropathological alterations in sodium azide-induced experimental dementia.

Background: Bergenin, 4-O-methyl gallic acid glucoside, is a bioactive compound found in the cortex of Mallotus japonicus (L.f.) Müll.Arg. along with many other natural resources including that from Bergenia species. The present study delineates the neuroprotective potential of bergenin through the modulation of PPAR-γ receptors. Method: Dementia was induced in the Wistar rats by intraperitoneal (i.p.) administration of sodium azide (12.5 mg/kg for the first 5 days followed by 10 mg/kg for the next 9 days). The rats were then exposed to the Morris water maze test to assess the effect on cognitive abilities followed by a series of biochemical and histopathological evaluations. Results: Sodium azide-treated rats exhibited a severe deterioration of memory as suggested by poor performance in the spatial learning task in addition to the enhancement of brain acetylcholinesterase potential, oxidative stress, inflammation, and amyloid-β (Aβ) accumulation. Administration of bergenin to sodium azide-treated rats significantly recovered cognition and related biochemical variations. Further, co-administration of Bisphenol A diglycidyl ether (BADGE), a PPAR-γ antagonist with bergenin challenged its neuroprotective effects. Conclusions: The findings of our study exhibit that the cognitive restoration potential of bergenin may be attributed to its modulatory effects against cholinesterase, oxidative stress, and inflammatory markers, as well as its neuroprotective actions, thus aligning it as a possible therapy for Alzheimer’s disease-related dementia. The study also fortifies the significance of PPAR-γ receptors in dementia.

Identification of a novel PPARγ modulator with good anti-diabetic therapeutic index via structure-based screening, optimization and biological validation

PPARγ is well-known as the target receptor of TZD anti-diabetic drugs. However, recently the therapeutic benefits of these TZD drugs have been compromised by many severe side effects because of their full PPARγ agonistic action to lock the AF-2 helix. Herein, we conducted a virtual screening in the combination with structure-based design, synthesis and biological evaluation both in vitro and in vivo, leading to the identification of a potent candidate YG-C-20 as the SPPARγM with improved and safer anti-diabetic therapeutics. Mechanistically, this compound presented such desired pharmacological profiles (e.g., preferable anti-diabetic efficiencies and minimized side effects) mainly via selectively inhibiting the CDK5-mediated phosphorylation of PPARγ-Ser273 and up-regulating the expression of insulin-sensitive genes Adiponectin and Glut4, yet lacking the classical full agonism to induce the adipogenesis and the expression of key adipogenic genes including PPARγ, aP2, CD36, LPL, C/EBPα and FASN. Further validation led to the final recognition of its (R)-configured isomer as the potential conformational form. Subsequent molecular docking studies revealed a unique hydrogen-bonding network of (R)-YG-C-20 with three full PPARγ agonism-unrelated residues, especially with PPARγ-Ser273 phosphorylation-associated site Ser342, which not only gives a clear verification for our structure-based design but also provides a proof of concept for the abovementioned molecular mechanism.

New 4-thiazolidinone-based molecules Les-2769 and Les-3266 as possible PPARγ modulators

Development of cancer drug-resistance is still an ongoing problem in the modern anticancer treatment. Therefore, there is a need to search for a new active substance, which may become a potential anticancer agent. 4-Thiazolidinones are well-described substances with cytotoxicity against cancer cells in vitro. Therefore, the aim of this study was to evaluate the effect of two 4-thiazolidinone-based derivatives (Les-2769 and Les-3266) on the PPARγ-dependent cytotoxicity in normal human skin fibroblasts (BJ) and squamous cell carcinoma (SCC-15) in vitro. The data obtained showed a cytotoxic effect of Les-2769 and Les-3266 used in micromolar concentrations on SCC-15 and BJ cells, manifesting by a decrease in the metabolic activity, an increase in the release of lactate dehydrogenase, and caspase-3 activity. The co-treatment of the cells with Les-3266 and an antagonist (GW9662) or an agonist (rosiglitazone) of the PPARγ receptor induced changes in the above-mentioned parameters in the BJ and SCC-15 cells, compared to the Les-3266 alone exposure; this was not found in the Les-2769-treated cells. The further analysis of the compounds indicated changes in the expression of the PPARγ, KI67, and NF-κB genes. Moreover, the tested compounds caused an increase in the level of PPARγ mRNA expression in a similar way to rosiglitazone in SCC-15, which may indicate the affinity of the compounds for PPARγ. Molecular docking is consistent with experimental in vitro data about the potential agonistic activity of Les-2769 and Les-3266 towards PPARγ receptors. Summarizing, the anticancer effect of both compounds was observed in the SCC-15 cells in vitro; moreover, the mechanism of action of Les-3266 in cells is mediated probably by interaction with the PPARγ receptor pathway, which needs in-depth study.

Role of PPAR-γ in diabetes-induced testicular dysfunction, oxidative DNA damage and repair in leptin receptor-deficient obese type 2 diabetic mice

The testis expresses peroxisome proliferator-activated receptor-γ (PPAR-γ), but its involvement in regulating diabetes-induced testicular dysfunction and DNA damage repair is not known. Pioglitazone-induced activation of PPAR-γ for 12 weeks in db/db obese diabetic mice increases bodyweights and reduces blood glucose levels, but PPAR-γ inhibition by 2-chloro-5-nitro-N-phenylbenzamide does not alter these parameters; instead, improves testis and epididymis weights and sperm count. Neither activation nor inhibition of PPAR-γ normalizes the diabetes-induced seminiferous epithelial degeneration. The PPAR-γ activation normalizes testicular lipid peroxidation, but its inhibition reduces lipid peroxidation and oxidative DNA damage (8-oxo-dG) in diabetic mice. As a response to diabetes-induced oxidative DNA damage, the base-excision repair (BER) mechanism proteins- 8-oxoguanine DNA glycosylases (OGG1/2) and X-ray repair cross-complementing protein-1 (XRCC1) increase, whereas the redox-factor-1 (REF1), DNA polymerase (pol) δ and poly (ADP-ribose) polymerase-1 (PARP1) show a tendency to increase suggesting an attempt to repair the oxidative DNA damage. The PPAR-γ stimulation inhibits OGG2, DNA pol δ, and XRCC1 in diabetic mice testes, but PPAR-γ inhibition reduces oxidative DNA damage and normalizes BER protein levels. In conclusion, type 2 diabetes negatively affects testicular structure and function and increases oxidative DNA damage and BER protein levels due to increased DNA damage. The PPAR-γ modulation does not significantly affect the structural changes in the testis. The PPAR-γ stimulation aggravates diabetes-induced effects on testis, including oxidative DNA damage and BER proteins, but PPAR-γ inhibition marginally recovers these diabetic effects indicating the involvement of the receptor in the reproductive effects of diabetes.

Selective modulator of nuclear receptor PPARγ with reduced adipogenic potential ameliorates experimental nephrotic syndrome

SummaryGlomerular disease manifests as nephrotic syndrome (NS) with high proteinuria and comorbidities, and is frequently refractory to standard treatments. We hypothesized that a selective modulator of PPARγ, GQ-16, will provide therapeutic advantage over traditional PPARγ agonists for NS treatment. We demonstrate in a pre-clinical NS model that proteinuria is reduced with pioglitazone to 64%, and robustly with GQ-16 to 81% of nephrosis, comparable to controls. Although both GQ-16 and pioglitazone restore glomerular-Nphs1, hepatic-Pcsk9 and serum-cholesterol, only GQ-16 restores glomerular-Nrf2, and reduces hypoalbuminemia and hypercoagulopathy. GQ-16 and pioglitazone restore common and distinct glomerular gene expression analyzed by RNA-seq and induce insulin sensitizing adipokines to various degrees. Pioglitazone but not GQ-16 induces more lipid accumulation and aP2 in adipocytes and white adipose tissue. We conclude that selective modulation of PPARγ by a partial agonist, GQ-16, is more advantageous than pioglitazone in reducing proteinuria, NS associated comorbidities, and adipogenic side effects of full PPARγ agonists.

Synthesis, In Vitro, In Vivo and In Silico Antidiabetic Bioassays of 4-Nitro(thio)phenoxyisobutyric Acids Acting as Unexpected PPARγ Modulators: An In Combo Study.

Four isobutyric acids (two nitro and two acetamido derivatives) were prepared in two steps and characterized using spectral analysis. The mRNA concentrations of PPARγ and GLUT-4 (two proteins documented as key diabetes targets) were increased by 3T3-L1 adipocytes treated with compounds 1–4, but an absence of in vitro expression of PPARα was observed. Docking and molecular dynamics studies revealed the plausible interaction between the synthesized compounds and PPARγ. In vivo studies established that compounds 1–4 have antihyperglycemic modes of action associated with insulin sensitization. Nitrocompound 2 was the most promising of the series, being orally active, and one of multiple modes of action could be selective PPARγ modulation due to its extra anchoring with Gln-286. In conclusion, we demonstrated that nitrocompound 2 showed strong in vitro and in vivo effects and can be considered as an experimental antidiabetic candidate.

Protective mechanisms of telmisartan against hepatic ischemia/reperfusion injury in rats may involve PPARγ-induced TLR4/NF-κB suppression.

Hepatic ischemia-reperfusion (I/R) is an important cause of liver damage in many clinical situations. Toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) is an inflammatory pathway activated in hepatic I/R injury. Telmisartan, a selective angiotensin II type 1 receptor antagonist and peroxisome proliferator-activated receptor-gamma (PPARγ) partial agonist, can inhibit the expression of pro-inflammatory cytokines. The present work investigated the possible protective effect of telmisartan against hepatic I/R injury and explored its possible mechanisms in rats. Rats were divided into four equal groups: sham-operated control, telmisartan-treated sham-operated control, I/R untreated, and I/R telmisartan-treated groups. Hepatic injury was evaluated biochemically by serum activity of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and histopathological examination. Hepatic oxidative stress biomarkers, myeloperoxidase level, PPARγ and TLR4 mRNA expression, and NF-κB and active caspase 3 immunoexpression were determined. The study showed that telmisartan attenuated hepatic I/R, as evidenced by decreased serum ALT and AST activities and confirmed by improvement of the histopathological changes. The protective effect of telmisartan was associated with modulation of oxidative stress parameters, myeloperoxidase level, PPARγ and TLR4 mRNA expression, and NF-κB and caspase 3 immunoexpression. Taken together, the current study showed that telmisartan could protect the rat liver from I/R injury. This hepatoprotective effect was attributed to, at least in part, increase in PPARγ expression and suppression of TLR4/NF-κB pathway.

Peroxisome proliferator-activated receptor-γ signalling protects hair follicle stem cells from chemotherapy-induced apoptosis and epithelial-mesenchymal transition.

Permanent chemotherapy-induced alopecia (pCIA), for which preventive interventions remain limited, can manifest with scarring. While the underlying pathomechanisms of pCIA are unclear, depletion of epithelial hair follicle (HF) stem cells (eHFSCs) is likely to play a role. To explore the hypothesis that, besides apoptosis, eHFSCs undergo pathological epithelial-mesenchymal transition (EMT) in pCIA, thus explaining the scarring phenotype. Furthermore, we tested whether a peroxisome proliferator-activated receptor (PPAR)-γ modulator could prevent pCIA-associated pathomechanisms. Organ-cultured human scalp HFs were treated with the cyclophosphamide metabolite 4-hydroperoxycyclophosphamide (4-HC). Additionally, HFs were pretreated with the agonistic PPAR-γ modulator N-acetyl-GED-0507-34-Levo (NAGED), which has previously been shown to promote K15 expression and antagonize EMT in eHFSCs. In accordance with anticipated hair bulb cytotoxicity, dystrophy and catagen induction, 4-HC promoted apoptosis along with increased p53 expression, DNA damage and pathological EMT in keratin 15+ (K15) eHFSCs, as evidenced by decreased E-cadherin expression and the appearance of fibronectin+ and vimentin+ cells in the hair bulge. Pretreatment with NAGED protected against 4-HC-induced hair bulb cytotoxicity/dystrophy, and apoptosis, p53 upregulation and EMT in the bulge, thereby significantly preventing depletion of K15+ human eHFSCs ex vivo. Since a key cyclophosphamide metabolite alone suffices to damage and deplete human scalp eHFSCs by promoting apoptosis, DNA damage and EMT ex vivo, strategies to prevent pCIA need to target these pathomechanisms. Given the ability of NAGED to prevent chemotherapy-induced eHFSCs damage exvivo, our study introduces the stimulation of PPAR-γ signalling as a novel intervention strategy for the prevention of pCIA.