Peroxisome Proliferator-activated Receptor Gamma Agonists Research Articles

PNPLA3 I148M Variant Impairs Liver X Receptor Signaling and Cholesterol Homeostasis in Human Hepatic Stellate Cells.

The patatin‐like phospholipase domain‐containing protein 3 (PNPLA3) I148M variant predisposes to hepatic steatosis and progression to advanced liver injury with development of fibrosis, cirrhosis, and cancer. Hepatic stellate cells (HSCs) drive the wound healing response to chronic injury, and lack of liver X receptor (LXR) signaling exacerbates liver fibrogenesis by impairing HSC cholesterol homeostasis. However, the contribution of the I148M variant to this process is still unknown. We analyzed LXR expression and transcriptional activity in primary human HSCs and overexpressing LX‐2 cells according to PNPLA3 genotype (wild type [WT] versus I148M). Here we demonstrate that LXRα protein increased whereas LXR target gene expression decreased during in vitro activation of primary human HSCs. Notably, LXRα levels and signaling were reduced in primary I148M HSCs compared to WT, as displayed by decreased expression of LXR target genes. Moreover, reduced expression of cholesterol efflux and enzymes generating oxysterols was associated with higher total and free cholesterol accumulation whereas endogenous cholesterol synthesis and uptake were diminished in I148M HSCs. Luciferase assays on LXR response element confirmed decreased LXR transcriptional activity in I148M HSCs; in contrast the synthetic LXR agonist T0901317 replenished LXR functionality, supported by adenosine triphosphate‐binding cassette subfamily A member 1 (ABCA1) induction, and reduced collagen1α1 and chemokine (C‐C motif) ligand 5 expression. Conversely, the peroxisome proliferator‐activated receptor gamma (PPARγ) agonist rosiglitazone had only partial effects on the LXR target gene ABCA1, and neither diminished expression of proinflammatory cytokines nor increased de novo lipogenic genes in I148M HSCs. Conclusion: As a consequence of reduced PPARγ activity, HSCs carrying I148M PNPLA3 show impaired LXR signaling, leading to cholesterol accumulation. The use of a specific LXR agonist shows beneficial effects for diminishing sustained HSC activation and development of liver fibrogenesis.

Abstract 2349: Modulation of inflammation in the tumor microenvironment by ER and PPARγ in an NNK-induced lung carcinogenesis model

Abstract Lung cancer is the number one cause of cancer-related fatalities, and to date, there are no FDA-approved chemoprevention options for lung cancer prevention. NNK, the principal carcinogen in cigarette smoke can induce mutations in oncogenes and can also act as an inflammatory mediator of the tumor microenvironment (TME) by promoting macrophage infiltration into the lungs. Macrophages play a key role in regulation of the lung TME. Pioglitazone, a synthetic peroxisome proliferator-activated receptor gamma (PPARγ) agonist belonging to the thiazolidinediones (TZDs) drug class has been used in preclinical studies to mitigate lung tumorigenesis, progression, and metastasis. A retrospective analysis found that diabetics using TZDs experienced a 33% reduction in lung cancer incidence. Cross-talk between PPARγ and estrogen receptor (ER) signaling has been previously reported, and ER has already been implicated as a driver of lung cancer severity. Both ER and PPARγ are also known to be functional in macrophages. Agents that block ER signaling such as fulvestrant, a complete ER antagonist, have shown activity against lung cancer. We therefore tested the ability of pioglitazone and fulvestrant in combination to reduce lung tumor formation and to modulate the TME. Preliminary results from a co-culture simulation of the TME in vitro using human macrophages and lung adenocarcinoma cells show pioglitazone and fulvestrant together can significantly suppress inflammatory modulators such as IL-1β, IL-10, Amphiregulin (AREG), and VEGF compared to single treatments. Similar effects were observed in a mouse model system of the TME. This drug combination also reduced number of tumor cell colonies in a soft agar assay, suggesting a direct effects on tumor cells. In vivo use of combined pioglitazone and fulvestrant in an NNK female mouse model of former smokers showed a significant reduction in tumor size by 40% compared to placebo (p= 0.0010), 13% by pioglitazone alone and 5% by fulvestrant alone. Inflammatory cytokine array analysis of the bronchio-alveolar lavage fluid (BALF) revealed maximum down-modulation of pro-tumor inflammatory mediators with combination treatment compared to single treatments. Fulvestrant alone did not suppress tumor-promoting inflammatory pathways, suggesting possible activation of compensatory signaling pathways. Further analysis of the cell cultures and the BALF confirmed EGFR compensatory activation through release of AREG with fulvestrant single treatment, that is suppressed with the addition of pioglitazone. Thus, the strong combination effect of pioglitazone and fulvestrant on lung tumor growth and macrophage function, and the ability of the combination to suppress compensatory signaling pathways, supports the hypothesis of ER/PPARγ cross-talk in lung cancer and provides a rationale for further investigation of chemopreventive effects of this combination. Citation Format: Erika Louiselle, Oshin Miranda, Huiyu Li, MiKayla Boeder, Zhijie Li, Jill M. Siegfried, Mariya Farooqui. Modulation of inflammation in the tumor microenvironment by ER and PPARγ in an NNK-induced lung carcinogenesis model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2349.

Peroxisome Proliferator-Activated Receptor-gamma agonists exhibit anti-inflammatory and antiviral effects in an EcoHIV mouse model

The widespread use of combination antiretroviral therapy (cART) has resulted in significantly reduced deaths from HIV-1 associated complications and opportunistic infections. However, it is estimated that up to 50% of HIV-1 infected individuals still develop HIV-1 associated neurocognitive disorders (HAND). With no treatment currently available for patients, there is a critical need to identify therapeutic approaches that can treat this disorder. Evidence suggests that targeting Peroxisome Proliferator-Activated Receptor-gamma (PPARγ) can be anti-inflammatory in neurological disorders. Here we show that treatment with PPARγ agonists (rosiglitazone or pioglitazone) in primary cultures of mouse glial cells reversed EcoHIV-induced inflammatory genes (TNFα, IL-1β, CCL2, CCL3, CXCL10) and indicator of oxidative stress (iNOS). Furthermore, in vivo, mice administered with EcoHIV through intracranial injection resulted in upregulation of inflammatory genes (TNFα, IL-1β, IFNγ, CCL2, CCL3, CXCL10) and oxidative stress marker (iNOS) in the brain which was reversed through intraperitoneal administration of PPARγ agonists (rosiglitazone or pioglitazone). Finally, we demonstrated that treatment with these compounds in vivo reduced EcoHIV p24 protein burden in the brain. Our results suggest that treatment with PPARγ agonists are anti-inflammatory and antiviral in an in vivo model of EcoHIV infection. These drugs hold promise as potential candidates for HAND treatment in the future.

Dietary fructose-induced gut dysbiosis promotes mouse hippocampal neuroinflammation: a benefit of short-chain fatty acids

BackgroundWestern-style diets arouse neuroinflammation and impair emotional and cognitive behavior in humans and animals. Our previous study showed that a high-fructose diet caused the hippocampal neuroinflammatory response and neuronal loss in animals, but the underlying mechanisms remained elusive. Here, alterations in the gut microbiota and intestinal epithelial barrier were investigated as the causes of hippocampal neuroinflammation induced by high-fructose diet.ResultsA high-fructose diet caused the hippocampal neuroinflammatory response, reactive gliosis, and neuronal loss in C57BL/6N mice. Depletion of the gut microbiota using broad-spectrum antibiotics suppressed the hippocampal neuroinflammatory response in fructose-fed mice, but these animals still exhibited neuronal loss. Gut microbiota compositional alteration, short-chain fatty acids (SCFAs) reduction, intestinal epithelial barrier impairment, NOD-like receptor family pyrin domain-containing 6 (NLRP6) inflammasome dysfunction, high levels of serum endotoxin, and FITC-dextran were observed in fructose-fed mice. Of note, SCFAs, as well as pioglitazone (a selective peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist), shaped the gut microbiota and ameliorated intestinal epithelial barrier impairment and NLRP6 inflammasome dysfunction in fructose-fed mice. Moreover, SCFAs-mediated NLRP6 inflammasome activation was inhibited by histamine (a bacterial metabolite) in ex vivo colonic explants and suppressed in murine CT26 colon carcinoma cells transfected with NLRP6 siRNA. However, pioglitazone and GW9662 (a PPAR-γ antagonist) exerted no impact on SCFAs-mediated NLRP6 inflammasome activation in ex vivo colonic explants, suggesting that SCFAs may stimulate NLRP6 inflammasome independently of PPAR-γ activation. SCFAs and pioglitazone prevented fructose-induced hippocampal neuroinflammatory response and neuronal loss in mice. Additionally, SCFAs activated colonic NLRP6 inflammasome and increased DCX+ newborn neurons in the hippocampal DG of control mice.ConclusionsOur findings reveal that gut dysbiosis is a critical factor for a high-fructose diet-induced hippocampal neuroinflammation in C57BL/6N mice possibly mediated by impairing intestinal epithelial barrier. Mechanistically, the defective colonic NLRP6 inflammasome is responsible for intestinal epithelial barrier impairment. SCFAs can stimulate NLRP6 inflammasome and ameliorate the impairment of intestinal epithelial barrier, resulting in the protection against a high-fructose diet-induced hippocampal neuroinflammation and neuronal loss. This study addresses a gap in the understanding of neuronal injury associated with Western-style diets. A new intervention strategy for reducing the risk of neurodegenerative diseases through SCFAs supplementation or dietary fiber consumption is emphasized.

The Design and Evaluation of a Novel Monoamine Oxidase B Inhibitor Through in Silico Approach

Parkinson’s disease is an age related neurodegenerative disease. Pioglitazone is a Peroxisome proliferator-activated receptor gamma agonist that has been shown to display a neuroprotective effect in parkinsonian models (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treated mice). This effect was partially attributed to the ability of thiazolidinedione (TZD) moiety in Pioglitazone to selectively inhibit monoamine oxidase B (MAO-B) enzyme. In the current study, we screened several thiazolidine containing compounds against MAO-B enzyme both in silico and in vitro. Based on the resulted data and information from previous literatures, we were able to design a novel scaffold for MAO-B inhibitors. This scaffold (compound 5482440) was able to inhibit MAO-B enzyme with IC50 value of 1.447 μM. Structure-based virtual analysis showed that this compound was able to participate in water-bridge formation and obtain an extended conformation within MAO-B active site.

Adiponectin: a therapeutic target in the antiphospholipid syndrome?

The antiphospholipid syndrome (APS) is an autoimmune disease characterized by the presence of the IgG and/or IgM isotypes of the antiphospholipid antibodies, thrombosis and/or recurrent pregnancy losses. Various markers of inflammation are associated with clinical and/or laboratory features of APS. Adiponectin (Ad) is a member of the adipocytokines that exert its roles by binding to its receptors (AdR). Peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonists induced Ad production. The aged Pparg null-mice represented the first animal model that spontaneously develops APS and this model emphasized the importance of PPAR-gamma signaling in the development of APS. Recombinant Ad (rAd) application was beneficial for the improvement of glucose, insulin and lipid levels in mice. Orally active AdR agonist exerted similar effects to Ad in mice. Due to the re-occurrence of thrombotic episodes in APS patients (despite life-long anticoagulation), administration of PPAR-gamma agonists, rAd, or AdR agonists should be further tested in experimental models of APS, which eventually, will provide more data for novel therapeutic strategies that will ameliorate clinical manifestations of the APS.

Peroxisome Proliferator Activated Receptor Gamma Sensitizes Non-small Cell Lung Carcinoma to Gamma Irradiation Induced Apoptosis.

The nuclear receptors known as peroxisome proliferator activated receptor gamma (PPARG) are lipid-activated transcription factors that have emerged as key regulators of inflammation. PPARG ligands have been shown to have an anti-proliferative effect on a variety of cancers. These ligands can induce apoptosis via TP53 (Tumor protein p53) or ERK1/2 (Extracellular signal-regulated kinases 1/2) (EPHB2) pathways. However, the exact mechanism is not known. PPAR, a type II nuclear hormone receptor deserves attention as a selective target for radiotherapy. Our study examines the potential of selective agonism of PPARG for radiation therapy in non-small cell lung carcinoma (NSCLC). We found that the overexpression of PPARG protein as well as its induction using the agonist, rosiglitazone was able to stimulate radiation-induced cell death in otherwise radio resistant NSCLC A549 cell line. This cell death was apoptotic and was found to be BAX (BCL2 associated X) mediated. The treatment also inhibited radiation-induced AKT (Protein Kinase B) phosphorylation. Interestingly, the ionising radiation (IR) induced apoptosis was found to be inversely related to TP53 levels. A relatively significant increase in the levels of radiation induced apoptosis was observed in H1299 cells (TP53 null) under PPARG overexpression condition further supporting the inverse relationship between apoptosis and TP53 levels. The combination of PPARG agonist and radiation was able to induce apoptosis at a radiation dose at which A549 and H1299 are radioresistant, thus confirming the potential of the combinatorial strategy. Taken together, PPARG agonism was found to invigorate the radiosensitising effect and hence its use in combination with radiotherapy is expected to enhance sensitivity in otherwise resistant cancer types.

Rosiglitazone treatment restores renal responsiveness to atrial natriuretic peptide in rats with congestive heart failure.

The thiazolidinedione (TZD) class of Peroxisome proliferator‐activated receptor gamma agonists has restricted clinical use for diabetes mellitus due to fluid retention and potential cardiovascular risks. These side effects are attributed in part to direct salt‐retaining effect of TZDs at the renal collecting duct. A recent study from our group revealed that prolonged rosiglitazone (RGZ) treatment caused no Na+/H2O retention or up‐regulation of Na+ transport‐linked channels/transporters in experimental congestive heart failure (CHF) induced by surgical aorto‐caval fistula (ACF). The present study examines the effects of RGZ on renal and cardiac responses to atrial natriuretic peptide (ANP), Acetylcholine (Ach) and S‐Nitroso‐N‐acetylpenicillamine (SNAP‐NO donor). Furthermore, we assessed the impact of RGZ on gene expression related to the ANP signalling pathway in animals with ACF. Rats subjected to ACF (or sham) were treated with either RGZ (30 mg/kg/day) or vehicle for 4 weeks. Cardiac chambers pressures and volumes were assessed invasively via Miller catheter. Kidney excretory and renal hemodynamic in response to ANP, Ach and SNAP were examined. Renal clearance along with cyclic guanosine monophosphate (cGMP), gene expression of renal CHF‐related genes and ANP signalling in the kidney were determined. RGZ‐treated CHF rats exhibited significant improvement in the natriuretic responses to ANP infusion. This ‘sensitization’ to ANP was not associated with increases in neither urinary cGMP nor in vitro cGMP production. However, RGZ caused down‐regulation of several genes in the renal cortex (Ace, Nos3 and Npr1) and up‐regulation of ACE2, Agtrla, Mme and Cftr along down‐regulation of Avpr2, Npr1,2, Nos3 and Pde3 in the medulla. In conclusion, CHF+RGZ rats exhibited significant enhancement in the natriuretic responses to ANP infusion, which are known to be blunted in CHF. This ‘sensitization’ to ANP is independent of cGMP signalling, yet may involve post‐cGMP signalling target genes such as ACE2, CFTR and V2 receptor. The possibility that TZD treatment in uncomplicated CHF may be less detrimental than thought before deserves additional investigations.

CORR® ORS Richard A. Brand Award: Disruption in Peroxisome Proliferator-Activated Receptor-γ (PPARG) Increases Osteonecrosis Risk Through Genetic Variance and Pharmacologic Modulation.

The pathophysiology of osteonecrosis of the femoral head (ONFH) is poorly understood, and the diagnosis is idiopathic in as many as 40% of patients. Genetic and epigenetic etiologies have been postulated, yet no single nucleotide polymorphisms (SNPs) with intuitive biologic implications have been elucidated. (1) Do individuals with ONFH share common biologically relevant genetic variants associated with disease development? (2) What is the mechanism by which these SNPs may impact the expression or function of the affected gene or protein? This retrospective genome-wide association study (GWAS) evaluated participants from the Mayo Clinic Biobank and Mayo Clinic Genome Consortium between August 2009 and March 2017. We included every patient with atraumatic ONFH in each of these respective registries and every control patient in a previous GWAS with an acceptable platform to perform statistical imputation. The study was performed in two phases, with an initial discovery cohort and a subsequent validation cohort. The initial discovery cohort consisted of 102 patients with ONFH and 4125 controls. A logistic regression analysis was used to evaluate associations between SNPs and the risk of ONFH, adjusted for age and sex. Seven SNPs were identified in a gene of biological interest, peroxisome proliferator-activated receptor gamma (PPARG), which were then evaluated in a subsequent validation cohort of 38 patients with ONFH and 464 controls. Age, sex, race, and previous steroid exposure were similar between patients with ONFH and controls in both the discovery and validation cohorts. Separate from the two-phase genetic investigation, we performed targeted pharmacosurveillance to evaluate the risk association between the use of antidiabetic thiazolidinediones, a class of PPARG agonists, and development of ONFH by referencing 9,638,296 patient records for individuals treated at Mayo Clinic. A combined analysis of the discovery and validation cohorts revealed that seven SNPs were tightly clustered adjacent to the 3' end of PPARG, suggesting an association with the risk of ONFH (p = 1.58 x 10-5.50 x10). PPARG gene-level significance was achieved (p = 3.33 x 10) when all seven SNPs were considered. SNP rs980990 had the strongest association with the risk of ONFH (odds ratio [OR], 1.95; 95% CI, 1.46-2.59; p = 5.50 x 10).The seven identified SNPs were mapped to a region near the PPARG gene and fell in a highly conserved region consisting of several critical transcription factor binding sites. Nucleotide polymorphisms at these sites may compromise three-dimensional chromatin organization and alter PPARG 3' end interactions with its 5' promoter and transcription start site. Pharmacosurveillance identified that patients who were exposed to thiazolidinediones had an increased relative risk of developing ONFH of 5.6 (95% CI, 4.5-7.1). We found that disruption of PPARG regulatory domains is linked to an increased risk of ONFH. Mechanistically, aberrant regulation of PPARG compromises musculoskeletal differentiation because this master regulator creates a proadipogenic and antiosteogenic state. Furthermore, PPARG alters steroid metabolism and vasculogenesis, processes that are inextricably linked with ONFH. Pharmacologically, predisposition to ONFH was further exposed with thiazolidinedione use, which upregulates the expression of PPARG and is known to alter bone metabolism. Collectively, these findings provide a foundation to perform confirmatory studies of our proposed mechanism in preclinical models to develop screening diagnostics and potential therapies in patients with limited options. Level III, prognostic study.

Reverting Metabolic Dysfunction in Cortex and Cerebellum of APP/PS1 Mice, a Model for Alzheimer's Disease by Pioglitazone, a Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) Agonist.

Identification of molecular mechanisms underlying early-stage Alzheimer's disease (AD) is important for the development of new therapies against and diagnosis of AD. In this study, gas chromatography time-of-flight mass spectrometry (GC-TOF-MS)-based metabolomics approach was employed to investigate the metabolic profiles in plasma and brain tissues harvested from 5-month-old APP/PS1 transgenic mice and their wildtype counterparts. Since different brain regions were expected to have their own distinct metabolic signals, four different brain regions, namely cortex, hippocampus, midbrain and cerebellum tissues, were dissected and had their metabolic profiles studied separately. Biochemical assays were also performed on plasma and brain cortex tissue of transgenic mice and wildtype mice, with a focus on mitochondrial health. Amyloid precursor protein and amyloid-β levels in plasma, brain cortex tissue and mitochondria fractions isolated from brain cortex were measured to assess the amyloid pathology. Our findings include the observation of extensive metabolic alterations in cortex and cerebellum of APP/PS1 mice, but not in their hippocampus, midbrain and plasma. The major pathways affected in cortex and cerebellum of APP/PS1 mice were closely related to impaired energy metabolism and perturbation of amino acid metabolism in these mice. APP/PS1 mice also exhibited higher amyloid-β40 and amyloid-β42 in their cortex, accumulation of mitochondria APP in their cortex, and presented an altered oxidative state in their brain. Treatment with the peroxisome proliferator-activated receptor gamma (PPARγ) agonist pioglitazone (PIO) successfully restored the energy metabolism, lowered amyloid-β levels and afforded the APP/PS1 mice a better antioxidative capacity in their cortex.

15-Deoxy-Δ-12, 14-prostaglandin J2 acts cooperatively with prednisolone to reduce TGF-β-induced pro-fibrotic pathways in human osteoarthritis fibroblasts

Background/AimsSynovial fibrosis is a pathological process that is observed in several musculoskeletal disorders and characterized by the excessive deposition of extracellular matrix, as well as cell migration and proliferation. Despite the fact that glucocorticoids are widely employed in the treatment of rheumatic pathologies such as osteoarthritis (OA) and rheumatoid arthritis, the mechanisms by which glucocorticoids act in the joint and their impacts on pro-fibrotic pathways are still unclear. MaterialsHuman OA synovial fibroblasts were obtained from knee and hip joints. Cells were treated with prednisolone (1 mM) or transforming growth factor-beta 1 (TGF-β1) (10 ng/ml) for 1 and 7 days for quantification of RNA and protein expression (by real-time quantitative reverse transcription-PCR and western blot, respectively), 72 h for immunocytochemistry analysis, and 48 h for proliferation (by BrdU assay) and migration (by wound assay) studies. In addition, cells were preincubated with prednisolone and/or the peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist 15-deoxy-Δ-12,14-prostaglandin J2 (15d-PGJ2) for 6 h before adding TGF-β1. pSmad1/5, pSmad2 and β-catenin levels were analyzed by Western blot. The activin receptor-like kinase-5 (ALK-5) inhibitor (SB-431542) was employed for the mechanistic assays. ResultsPrednisolone showed a predominant anti-fibrotic impact on fibroblast-like synoviocytes as it attenuated the spontaneous and TGF-β-induced gene expression of pro-fibrotic markers. Prednisolone also reduced α-sma protein and type III collagen levels, as well as cell proliferation and migration after TGF-β stimulation. However, prednisolone did not downregulate the gene expression of all the pro-fibrotic markers tested and did not restore the reduced PPAR-γ levels after TGF-β stimulation. Interestingly, anti-fibrotic actions of the glucocorticoid were reinforced in the presence of the PPAR-γ agonist 15d-PGJ2. Combined pretreatment modulated Smad2/3 levels and, similar to the ALK-5 inhibitor, blocked β-catenin accumulation elicited by TGF-β. ConclusionsPrednisolone, along with 15d-PGJ2, modulates pro-fibrotic pathways activated by TGF-β in synovial fibroblasts at least partially through the inhibition of ALK5/Smad2 signaling and subsequent β-catenin accumulation. These findings shed light on the potential therapeutic effects of glucocorticoids treatment combined with a PPAR-γ agonist against synovial fibrosis, although future studies are warranted to further evaluate this concern.

Citrus Flavanones Enhance β-Carotene Uptake in Vitro Experiment Using Caco-2 Cell: Structure-Activity Relationship and Molecular Mechanisms.

Flavonoids can interfere with the absorption of carotenoids. In this study, the inherent mechanisms of 12 citrus flavanones for β-carotene (Bc) cellular uptake and the structure-activity relationship were investigated. The results showed that multiple hydroxyl groups had the lowest promoting effect. O-Glycosylation at C7 of the A ring led to the greatest promoting effect on Bc absorption. O-Glycosylation at C7 exhibited a strong affinity with the cell membrane and subsequently fluidized the cell membrane. Aglycon molecules significantly induced transient increases of paracellular permeability by decreasing tight junction proteins (ZO-1, claudin-1) expression. In addition, citrus flavanones might enhance scavenger receptor class B type I (SR-BI) expression via their actions as agonists of peroxisome proliferator-activated receptor-gamma (PPARγ). Catechol structure in the B-ring attenuated the activate action of SR-BI expression. The structure-dependent membrane permeability and activation of specific membrane proteins are mechanistically associated with the promoting effect on Bc cellular uptake by citrus flavanones.

Anticonvulsant and ameliorative effects of pioglitazone on cognitive deficits, inflammation and apoptosis in the hippocampus of rat pups exposed to febrile seizure.

Objective(s):Pioglitazone (PGZ), a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist, has significant neuroprotective effects and has been reported to regulate inflammatory processes.Materials and Methods:We evaluated the effects of PGZ on febrile seizure (FS) in rat pups. Three groups of male rat pups received intraperitoneal (IP) injections of PGZ (5, 10, and 20 mg/kg). Lipopolysaccharide (LPS) and kainic acid (KA) were injected to induce FS. The rat pups behaviors were recorded and analyzed. Seizure latency, duration, and severity were recorded to evaluate the effect of PGZ on FS. Novel object recognition task (NORT) was used to evaluate the effect of PGZ on cognitive deficits induced by FS. At the end of the experimental protocol, molecular and histological tests were done.Results:PGZ significantly increased seizure latency and decreased seizure duration and median of seizure scores (P<0.05, P<0.01, and P<0.001) after induction of FS. Rat pups exposed to FS had memory deficits both in short-term and long-term memories in the NORT that were reversed by PGZ-treatment (P<0.01 and P<0.001). PGZ significantly reduced interleukin-1β, tumor necrosis factor-α, and inducible nitric oxide synthase concentration in the hippocampus (P<0.05 and P<0.01). In addition, PGZ decreased the number of degenerating and TUNEL positive neurons in CA1, CA3, and DG subfields of the hippocampus (P<0.05, P<0.01 and P<0.001).Conclusion:The present results indicated that PGZ had anticonvulsant, anti-inflammatory, and anti-apoptotic effects with ameliorative effects on cognitive deficits induced by FS in rat pups.

Current Progress on Peroxisome Proliferator-activated Receptor Gamma Agonist as an Emerging Therapeutic Approach for the Treatment of Alzheimer's Disease: An Update.

Alzheimer’s disease (AD) is an age-related progressive neurodegenerative disorder, characterized by the deposition of amyloid-β within the brain parenchyma resulting in a significant decline in cognitive functions. The pathophysiological conditions of the disease are recognized by the perturbation of synaptic function, energy and lipid metabolism. In Addition deposition of amyloid plaques also triggers inflammation upon the induction of microglia. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors known to play important role in the regulation of glucose ab-sorption, homeostasis of lipid metabolism and are further known to involved in repressing the expression of genes related to inflammation. Therefore, agonists of this receptor represent an attractive therapeutic target for AD. Recently, both clinical and preclinical studies showed that use of Peroxisome proliferator-activated receptor gamma (PPARγ) agonist improves both learning and memory along with other AD related pathology. Thus, PPARγ signifies a significant new therapeutic target in treating AD. In this review, we have shed some light on the recent progress of how, PPARγ agonist selectively modulated different cellular targets in AD and its amazing potential in the treatment of AD.

The VGVAPG Peptide Regulates the Production of Nitric Oxide Synthases and Reactive Oxygen Species in Mouse Astrocyte Cells In Vitro

The products of elastin degradation, namely elastin-derived peptides (EDPs), are detectable in the cerebrospinal fluid of healthy individuals and in patients after ischemic stroke, and their number increases with age. Depending on their concentrations, both nitric oxide (NO) and reactive oxygen species (ROS) take part either in myocardial ischemia reperfusion injury or in neurovascular protection after ischemic stroke. The aim of our study was to determine the impact of VGVAPG peptide on ROS and NO production and expression of endothelial nitric oxide synthase (eNos), inducible nitric oxide synthase (iNos) and neuronal nitric oxide synthase (nNos) in mouse cortical astrocytes in vitro. Primary astrocytes were maintained in DMEM/F12 without phenol red supplemented with 10% fetal bovine serum. The cells were exposed to rising VGVAPG peptide concentrations, and ROS and NO production was measured. After 6 h (for mRNA) and 24 (for the protein) of exposure to 10 nM and 1 µM of the peptide, expression of nNos, iNos and eNos was measured. Moreover, the Glb1 siRNA gene knockdown method and Pioglitazone, a peroxisome proliferator-activated receptor gamma (Pparγ) agonist, were applied. Our study shows that the VGVAPG peptide decreased eNos, iNos and nNos mRNA and protein expression in mouse astrocytes in vitro. The VGVAPG peptide also decreased NO production while increasing ROS production in the cells. Furthermore, silencing of the Glb1 gene reversed all effects caused by the VGVAPG peptide. However, due to the lack of sufficient data explaining the molecular mechanism of action of the VGVAPG peptide in the nervous system, more studies in this area are necessary.

Peroxisome proliferator-activated receptor gamma and BRCA1.

Peroxisome proliferator-activated receptor gamma agonists have been proposed as breast cancer preventives. Individuals who carry a mutated copy of BRCA1, DNA repair-associated gene, are at increased risk for development of breast cancer. Published data in the field suggest there could be interactions between peroxisome proliferator-activated receptor gamma and BRCA1 that could influence the activity of peroxisome proliferator-activated receptor gamma agonists for prevention. This review explores these possible interactions between peroxisome proliferator-activated receptor gamma, peroxisome proliferator-activated receptor gamma agonists and BRCA1 and discusses feasible experimental directions to provide more definitive information on the potential connections.

Frontal fibrosing alopecia: An update on the hypothesis of pathogenesis and treatment.

Frontal fibrosing alopecia (FFA) is a relatively new scarring alopecia that is considered a variant of lichen planopilaris (LPP) with no recognized promising treatments. In this study, we tried to clarify the underlying signaling pathways and their roles in the pathogenesis and progression of FFA. Because of several differences in clinical manifestations, response to treatments, and pathological findings, these two conditions could be differentiated from each other. Taking into account the already discussed signaling pathways and involved players such as T cells, mast cells, and sebaceous glands, different possible therapeutic options could be suggested. In addition to treatments supported by clinical evidence, such as 5 alpha-reductase inhibitors, topical calcineurin inhibitors, hydroxychloroquine, peroxisome proliferator-activated receptor gamma agonists, and oral retinoid agents, various other treatment strategies and drugs, such as phototherapy, Janus kinase inhibitors, dehydroepiandrosterone, sirolimus, cetirizine, and rituximab, could be suggested to mitigate disease progression. Of course, such lines of treatment need further evaluation in clinical trials.

Biochemical and histological characterisation of an experimental rodent model of non-alcoholic steatohepatitis – Effects of a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist and a glucagon-like peptide-1 analogue

BackgroundNon-alcoholic steatohepatitis (NASH) is a prevalent disease that is highly associated with the metabolic syndrome and type II diabetes. The development of in vivo models that reflect all nuances of the human NASH pathology is essential for drug discovery and development. We aimed to further characterise a dietary induced model of NASH both biochemically and histologically. In addition, we also investigated whether pioglitazone and liraglutide, drugs that have both been investigated as potential NASH treatments, could modulate the pathological changes induced by the NASH diet. Furthermore, to aid the translation of data from pre-clinical in vivo models, we aimed to adapt the NASH Clinical Research Network (CRN) histological score system for use in rodent studies. MethodsSprague Dawley rats were fed a high-fat diet (HFD) for 9 weeks, after which they were switched to a high fat, high cholesterol and cholate diet (HFCC) for 12 weeks. The rats were divided into treatment groups, receiving either 30 mg/kg pioglitazone p.o. SID or liraglutide s.c. 200 μg/kg BID or the respective vehicles. Serum levels of triglycerides (TG), cholesterol (Chol), LDL, HDL, AST and ALT, as well as body weight were assessed in all subjects. Upon termination, the liver was weighed and evaluated histologically using modified NASH-CRN criteria. ResultsHFCC feeding induced severe hepatic injury and hepatomegaly as indicated by significant increases in AST, ALT and an increased liver weight. Additionally, HFCC feeding induced dyslipidaemia, significant increases in circulating cholesterol and LDL were observed. No obesogenic effect of the HFCC diet was observed, though the diet did induce insulin resistance. Histological analysis showed that the HFCC diet induced several NASH like features, though it did not induce the development of severe fibrosis. However, microgranulomas were often prevalent in addition to lobular inflammatory foci. Pioglitazone showed little efficacy upon both biochemical and histological features. However, liraglutide induced weight loss, improved glycaemic control, reduced ALT and AST and showed some beneficial effects upon steatosis and lobular inflammation. ConclusionSimilar to previous reports we have shown that the atherogenic diet, HFCC, induces a phenotype akin to that seen in human NASH patients. Despite inducing all histological features of NASH, HFCC feeding does not promote the development of significant fibrosis within rodents. Pioglitazone and liraglutide have been investigated as potential NASH treatments. Within this model of NASH we have shown that pioglitazone has little efficacy, whereas liraglutide reduced the levels of circulating aminotransferases and had some beneficial effects upon NASH histological parameters.

Future Strategies in Management of Diabetes Mellitus: A Brief Report

Diabetes Mellitus is a disorder of altered glucose and lipid metabolism having hyperglycemia as characteristic feature. Long term uncontrolled Diabetes Mellitus primarily leads to rise in microvascular and macrovascular events involving many organ systems. Strict glycemic control remains the key to avoid such complications. The management of Diabetes and its co-morbid conditions affect patients not only economically but also psychologically. Currently about nine different varieties of medications are being employed in treatment of Diabetes Mellitus. Even after having many varieties of drugs available co-morbid conditions associated with Diabetes Mellitus are on rise as the global burden of disease is also increasing. In last decade drugs against some new targets in management of Diabetes are approved Glucagon like Peptide-1 (GLP-1) agonist, Dipeptidyl Peptidase-IV (DPP-IV) inhibitors and Sodium-Glucose linked Transporter-2 (SGLT-2) inhibitors and Peroxisome Proliferator-activated receptor –alpha and gamma agonist. Although numerous drugs are available roughly one third patients achieve desired glycemic control that’s why newer drugs acting on novel targets are required. The objective of review is to throw light on newer drug targets which are in various stages of development to have latest drugs against Diabetes.

The prevention of tracheal graft occlusion using pioglitazone: A mouse tracheal transplant model study

Bronchiolitis obliterans (BO), which begins with lymphocytic bronchiolitis (LB), is the most serious manifestations of chronic rejection following lung transplantation. We have evaluated the effects of intraperitoneal administration of pioglitazone, a peroxisome proliferator-activated receptor (PPAR) gamma agonist, on LB in mice tracheal transplant model. Tracheal grafts from BALB/c or C57BL/6 were transplanted to C57BL/6 recipients. Animals were divided into three groups (n = 8), isograft (IG) and allograft with (AGP) or without (AGN) pioglitazone. Occlusion rate (OR) of transplanted trachea, CD3, FoxP3 positive cell infiltration, and cytokine levels in the transplanted grafts were analyzed at day 7. In the AGP group, OR was significantly lower than in the AGN group (p < .01). An average of 305 ± 56, and 317 ± 84 CD3-positive T-cells/section was shown in the AGN and AGP groups, respectively (p = .761). Interestingly, an average of 24 ± 18, and 88 ± 28 FoxP3-positive regulatory T-cells (Tregs)/section was shown in AGN and AGP groups, respectively (p = .001). FoxP3 and IL-4 mRNA expression was significantly higher in the AGP group. Pioglitazone can suppress the luminal occlusions of the tracheal graft in an allograft through enhanced Treg infiltration, and may provide new therapies to prevent BO.