PPARgamma Agonist Research Articles

Neuroprotective effect of PPAR gamma agonist in rat model of autism spectrum disorder: Role of Wnt/β-catenin pathway

BackgroundThe clinical manifestation of autism spectrum disorder (ASD) is linked to the disruption of fundamental neurodevelopmental pathways. Emerging evidences claim to have an upregulation of canonical Wnt/β-catenin pathway while downregulation of PPARγ pathway in ASD. This study aims to investigate the therapeutic potential of pioglitazone, a PPARγ agonist, in rat model of ASD. The study further explores the possible role of PPARγ and Wnt/β-catenin pathway and their interaction in ASD by using their modulators. Material and methodsPregnant female Wistar rats received 600 mg/kg of valproic acid (VPA) to induce autistic symptoms in pups. Pioglitazone (10 mg/kg) was used to evaluate neurobehaviors, relative mRNA expression of inflammatory (IL-1β, IL-6, IL-10, TNF-α), apoptotic markers (Bcl-2, Bax, & Caspase-3) and histopathology (H&E, Nissl stain, Immunohistochemistry). Effect of pioglitazone was evaluated on Wnt pathway and 4 μg/kg dose of 6-BIO (Wnt modulator) was used to study the PPARγ pathway. ResultsASD model was established in pups as indicated by core autistic symptoms, increased neuroinflammation, apoptosis and histopathological neurodegeneration in cerebellum, hippocampus and amygdala. Pioglitazone significantly attenuated these alterations in VPA-exposed rats. The expression study results indicated an increase in key transcription factor, β-catenin in VPA-rats suggesting an upregulation of canonical Wnt pathway in them. Pioglitazone significantly downregulated the Wnt signaling by suppressing the expression of Wnt signaling-associated proteins. The inhibiting effect of Wnt pathway on PPARγ activity was indicated by downregulation of PPARγ-associated protein in VPA-exposed rats and those administered with 6-BIO. ConclusionIn the present study, upregulation of canonical Wnt/β-catenin pathway was demonstrated in ASD rat model. Pioglitazone administration significantly ameliorated these symptoms potentially through its neuroprotective effect and its ability to downregulate the Wnt/β-catenin pathway. The antagonism between the PPARγ and Wnt pathway offers a promising therapeutic approach for addressing ASD.

Seipin deficiency-induced lipid dysregulation leads to hypomyelination-associated cognitive deficits via compromising oligodendrocyte precursor cell differentiation

Seipin is one key mediator of lipid metabolism that is highly expressed in adipose tissues as well as in the brain. Lack of Seipin gene, Bscl2, leads to not only severe lipid metabolic disorders but also cognitive impairments and motor disabilities. Myelin, composed mainly of lipids, facilitates nerve transmission and is important for motor coordination and learning. Whether Seipin deficiency-leaded defects in learning and motor coordination is underlined by lipid dysregulation and its consequent myelin abnormalities remains to be elucidated. In the present study, we verified the expression of Seipin in oligodendrocytes (OLs) and their precursors, oligodendrocyte precursor cells (OPCs), and demonstrated that Seipin deficiency compromised OPC differentiation, which led to decreased OL numbers, myelin protein, myelinated fiber proportion and thickness of myelin. Deficiency of Seipin resulted in impaired spatial cognition and motor coordination in mice. Mechanistically, Seipin deficiency suppressed sphingolipid metabolism-related genes in OPCs and caused morphological abnormalities in lipid droplets (LDs), which markedly impeded OPC differentiation. Importantly, rosiglitazone, one agonist of PPAR-gamma, substantially restored phenotypes resulting from Seipin deficiency, such as aberrant LDs, reduced sphingolipids, obstructed OPC differentiation, and neurobehavioral defects. Collectively, the present study elucidated how Seipin deficiency-induced lipid dysregulation leads to neurobehavioral deficits via impairing myelination, which may pave the way for developing novel intervention strategy for treating metabolism-involved neurological disorders.

Identification of novel PPAR-γ agonist ameliorating triple negative breast cancer by in silico methods

Triple negative breast cancer (TNBC) is still considered a medical challenge as it is an aggressive cancer characterized by poor prognosis, frequent metastasis, distinct clinical and pathological features and lack of proper treatment options. In TNBC, estrogen, progesterone and Her2 neu receptors are absent, which are usually present in otherwise breast cancers. So, hormonal therapy cannot be given in case of TNBC, leaving chemotherapy as the mainstay for treatment. However, chemotherapy is an infamous therapeutic option due to several aweful side effects like loss of appetite, extreme weight loss, hair loss, vomiting, fatigue etc. Several reports have highlighted role of Peroxisome Proliferated Activated Receptor gamma (PPAR-γ) in ameliorating breast cancer, but it is still less explored receptor for TNBC. Moreover, synthetic PPAR gamma agonists like thiazolidinediones, have good capability of activating PPAR-γ receptor, but these are also gloomy therapeutic agent due to their dreadful side effects like hepatotoxicity, bladder cancer, congestive heart failure etc. So, there is serious urge among researchers to find safer therapeutic option for TNBC. Phytochemicals are nowadays grabbing attention worldwide to treat several diseases due to their fewer or no side effects. This in silico study was performed after thorough review to select a natural, potent PPAR-γ agonist Gallotanin, as a query compound for ligand based similarity searching in PubChem database with 80% filter. Top 10 obtained compounds having highest similarity index were chosen for molecular docking in AutoDock Vina, with PPAR-γ receptor (3V9T) to know their binding patterns. Further, top 5 compounds having highest dock scores underwent ADME studies in SwissADME to assess pharmacokinetic profile of these compounds. Finally, this in silico study resulted in discovery of compound called Chamuvaritin which is still not known as a PPAR-γ agonist, efficient enough to act as potent therapeutic agent against TNBC.

Evaluation of PPAR gamma agonists: A molecular docking and QSAR study of chalcone analog

In recent years, chalcones have attracted researchers with their unique structure and promising potential across a wide range of scientific disciplines. They are naturally occurring 1,3-diphenyl-2-propen-1-ones. As well as regulating cell proliferation, differentiation, and angiogenesis, PPARs are also involved in cell differentiation. The present study evaluates the molecular activity of 60 chalcone analogs and two marketed drugs as potential PPAR gamma agonists. Molecular docking studies, structural property calculations, and 2D QSAR studies were carried out to screen the best molecule in the library. The compound coded with 2i was found to have the highest binding affinity and selectivity for PPAR gamma. Firm interactions within 5.0 Å were considered for the docking analysis. Ramachandran plot interpretations also helped us to justify the firm binding at the catalytic site. The correlational studies using the QSAR model were carried out, and the coefficient of regression was found to be 0.9247, and the results were plotted. The 2i was found to be the most suitable compound from the library.

Effects of newer-generation anti-diabetics on diabetic retinopathy: a critical review.

Diabetic retinopathy (DR) is the leading etiology of blindness in the working population of the USA. Its long-term management relies on effective glycemic control. Seven anti-diabetic classes have been introduced for patients with type 2 diabetes (T2D) in the past two decades, with different glucose-lowering and cardiovascular benefits. Yet, their effects specifically on DR have not been studied in detail. A systematic review of the literature was conducted to investigate this topic, focusing on the available clinical data for T2D. Published studies were evaluated based on their level of statistical evidence, as long as they incorporated at least one endpoint or adverse event pertaining to retinal health. Fifty nine articles met our inclusion criteria and were grouped per anti-diabetic class as follows: alpha-glucosidase inhibitors (1), peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists (8), amylin analogs (1), glucagon-like peptide-1 (GLP-1) receptor agonists (28), dipeptidyl peptidase 4 (DPP-4) inhibitors (9), and sodium glucose co-transporter-2 (SGLT-2) inhibitors (9), plus one retrospective study and two meta-analyses evaluating more than one of the aforementioned anti-diabetic categories. We also reviewed publicly-announced results of trials for the recently-introduced class of twincretins. The available data indicates that most drugs in the newer anti-diabetic classes are neutral to DR progression; however, there are subclasses differences in specific drugs and T2D populations. In particular, there is evidence suggesting there may be worse diabetic macular edema with PPAR-gamma agonists, potential slight DR worsening with semaglutide (GLP-1 receptor agonist), and potential slight increase in the incidence of retinal vein occlusion in elderly and patients with advanced kidney disease receiving SGLT-2 inhibitors. All these warrant further investigation. Longer follow-up and systematic assessment of at least one DR-related endpoint are highly recommended for all future trials in the T2D field, to ultimately address this topic.

Intriguing Thiazolidinediones as PPAR γ Agonists: A Review

Diabetes mellitus is a chronic metabolic disorder marked by persistently elevated blood sugar levels. left untreatedover a long duration can cause multiple body disorders and may cause a person's early death. Though a traditional disorder, typeII diabetes prevalence is increasing daily, especially in the adolescent population worldwide. Peroxisome proliferator-activatedreceptor (PPAR) is a group of receptors consisting of three isoforms (PPAR α, PPAR β/δ, and PPAR γ. PPAR γ is involved inglucose metabolism by facilitating insulin's actions. Thiazolidinedione is a heterocyclic moiety standing pre-eminent in treatingdiabetes mellitus as a PPAR Gamma activator. Thiazolidinedione is a five-membered heterocyclic organic compound, athiazolidine derivative consisting of two carbonyl groups at positions 2 and 4 of the thiazolidine ring. Thiazolidinediones possessan idiosyncratic scaffold featuring a hydrogen bond acceptor region and hydrogen bond donating region at the third and fifthpositions. Thiazolidinedione is an indispensable pharmacophore with many pharmacological activities like antiproliferative,antiviral, antibacterial, tyrosine kinase inhibitory, aldose reductase inhibitory, alpha-glucosidase inhibitory, anti-inflammatory,antioxidant, antitubercular, antihyperlipidemic, etc. Many drugs have been introduced but later have been reticent because ofserious side effects like liver toxicity, CVS toxicity, etc. Pioglitazone and Rosiglitazone have been marketed medications fortreating type II diabetes. This review article deliberates all the cardinal points of thiazolidinediones as PPAR agonists in treatingdiabetes mellitus, which were precluded in some articles. We aim to have an all-embracing review of thiazolidinediones as PPARgamma agonists. The review's objective is to inspire researchers to develop a more superior, secure, and efficient anti-diabeticmedication by thoroughly understanding the molecular mechanisms of thiazolidinediones at the PPAR gamma receptors, theirrisks, and the effect of the various substitutions on the thiazolidinedione.

PPAR-gamma agonist pioglitazone recovers mitochondrial quality control in fibroblasts from PITRM1-deficient patients.

Introduction: Biallelic variants in PITRM1 are associated with a slowly progressive syndrome characterized by intellectual disability, spinocerebellar ataxia, cognitive decline and psychosis. The pitrilysin metallopeptidase 1 (PITRM1) is a mitochondrial matrix enzyme, which digests diverse oligopeptides, including the mitochondrial targeting sequences (MTS) that are cleaved from proteins imported across the inner mitochondrial membrane by the mitochondrial processing peptidase (MPP). Mitochondrial peptidases also play a role in the maturation of Frataxin, the protein affected in Friedreich's ataxia. Recent studies in yeast indicated that the mitochondrial matrix protease Ste23, which is a homologue of the human insulin-degrading enzyme (IDE), cooperates with Cym1 (homologue of PITRM1) to ensure the proper functioning of the preprotein processing machinery. In humans, IDE could be upregulated by Peroxisome Proliferator-Activated Receptor Gamma (PPARG) agonists. Methods: We investigated preprotein processing, mitochondrial membrane potential and MTS degradation in control and patients' fibroblasts, and we evaluated the pharmacological effect of the PPARG agonist Pioglitazone on mitochondrial proteostasis. Results: We discovered that PITRM1 dysfunction results in the accumulation of MTS, leading to the disruption and dissipation of the mitochondrial membrane potential. This triggers a feedback inhibition of MPP activity, consequently impairing the processing and maturation of Frataxin. Furthermore, we found that the pharmacological stimulation of PPARG by Pioglitazone upregulates IDE and also PITRM1 protein levels restoring the presequence processing machinery and improving Frataxin maturation and mitochondrial function. Discussion: Our findings provide mechanistic insights and suggest a potential pharmacological strategy for this rare neurodegenerative mitochondrial disease.

Selective PPAR-Delta/PPAR-Gamma Activation Improves Cognition in a Model of Alzheimer's Disease.

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

PPAR Gamma Agonist Leriglitazone Recovers Alterations Due to Pank2-Deficiency in hiPS-Derived Astrocytes

The novel brain-penetrant peroxisome proliferator-activated receptor gamma agonist leriglitazone, previously validated for other rare neurodegenerative diseases, is a small molecule that acts as a regulator of mitochondrial function and exerts neuroprotective, anti-oxidative and anti-inflammatory effects. Herein, we tested whether leriglitazone can be effective in ameliorating the mitochondrial defects that characterize an hiPS-derived model of Pantothenate kinase-2 associated Neurodegeneration (PKAN). PKAN is caused by a genetic alteration in the mitochondrial enzyme pantothenate kinase-2, whose function is to catalyze the first reaction of the CoA biosynthetic pathway, and for which no effective cure is available. The PKAN hiPS-derived astrocytes are characterized by mitochondrial dysfunction, cytosolic iron deposition, oxidative stress and neurotoxicity. We monitored the effect of leriglitazone in comparison with CoA on hiPS-derived astrocytes from three healthy subjects and three PKAN patients. The treatment with leriglitazone did not affect the differentiation of the neuronal precursor cells into astrocytes, and it improved the viability of PKAN cells and their respiratory activity, while diminishing the iron accumulation similarly or even better than CoA. The data suggest that leriglitazone is well tolerated in this cellular model and could be considered a beneficial therapeutic approach in the treatment of PKAN.

Five-Year Follow-up of the Phase I/II Discontinuation Trial of Imatinib after Pioglitazone (EDI-PIO) in Chronic Myeloid Leukemia Patients in Deep Molecular Response

Treatment-free remission (TFR) is successful in approximately 40-60% of CML patients who achieve a stable and deep molecular response. Relapses may occur due to the persistence of quiescent leukemic stem cells (LSC). Pioglitazone, a drug used for diabetes, is a PPAR gamma agonist and reduces STAT5 activity, and its downstream targets HIF2α and CITED2, key guardians of the quiescent LSC. Residual LSC can be gradually purged from bone marrow niches by pioglitazone. Objectives: to evaluate the efficacy and safety of pioglitazone used with imatinib before treatment discontinuation. Methods: EDI-PIO (from the Portuguese Estudo de Descontinuação de Imatinibe após Pioglitazona) is a prospective, single arm, phase I/II discontinuation trial. Inclusion criteria: CML in chronic phase, treated with IM for at least 3 years, with MR4.5 reported by the International Scale (IS) for 2 years. Patients received pioglitazone 30 mg/day orally for three months before IM discontinuation. After discontinuation, BCR-ABL levels were measured by real-time quantitative PCR monthly for 12 months, every two months in the second year, and then every three months. IM was re-initiated at molecular relapse (single sample with a value of >0.1% or two consecutive samples >0.01%). TFR was calculated from IM discontinuation until molecular relapse, progression, or death to causes related to CML. Overall survival (OS) was calculated from IM discontinuation until the last seen or death date by any cause. This trial is registered with Clinicaltrials.gov, NCT02852486. Results: Between Jun/2016 and Jan/2019, we evaluated 32 CML patients, with a median age of 54 years (29-77), treated with imatinib for a median time of 9.5 years (3-16). The median duration of MR4 and MR4.5 was 106 and 93 months, respectively. The cut-off date for this analysis was July 1st, 2022. One patient left the trial before imatinib discontinuation and was not analyzed for TFR. There were no grade 3 or 4 adverse events related to pioglitazone. The median follow-up of the 31 patients that discontinued IM was 61 months (37-69). As previously reported, 15/31(48%) patients presented symptoms related to withdrawal syndrome. Twelve patients presented molecular relapse after a median time of 5 months (2-30). Nine relapses in the first six months and three at 7, 13, and 30 months after stopping imatinib. All relapsed patients re-achieved MMR in a median time of 3 months (1.8-4.1). One patient developed an anal canal adenocarcinoma in the third year after discontinuation and was treated with surgery and chemotherapy. TFR was 71%, 67%, 61% and 61% at 6,12, 30 and 60 months (Figure 1A), respectively. 60-month OS was 95% (CI 95%: 85-100%)(Figure 1B). There were 5 cases of COVID-19 among the 19 patients in TFR (26%) and two suspects. Four cases were mild, and one patient in MR4.5 died due to severe COVID-19. Sokal score and MR4.5 duration were significant factors for prolonged TFR (P=0.032 and 0.012, respectively). Conclusions: the combination of pioglitazone and IM was feasible and safe, with TFR rates consistent with previous discontinuation trials. The 5-year long-term follow-up demonstrated durable and stable molecular responses. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

An Update on the Current and Emerging Use of Thiazolidinediones for Type 2 Diabetes.

Guidelines have increasingly stressed the concept that adequate glycemic control is required to prevent or decrease the macro- and microvascular complications of type 2 diabetes mellitus (T2DM). PPAR-gamma agonists (“glitazones”) are no longer prioritized due to their effects on heart failure. However, the association between these drugs and innovative therapies could be a valuable tool to attenuate the risk factors of the metabolic syndrome. Glitazones are used for the treatment of diabetes and associated comorbidities. There is substantial scientific evidence demonstrating the effect of glitazones at a cardiometabolic level, as well as on hematological and neurological pathologies that point to their usefulness. The use of glitazones has always been controversial both for the type of patients who must take these drugs and for the side effects associated with them. Unfortunately, the recent guidelines do not include them among the preferred drugs for the treatment of hyperglycemia and rosiglitazone is out of the market in many countries due to an adverse cardiovascular risk profile. Even though real-life studies have proven otherwise, and their pleiotropic effects have been highlighted, they have been unable to achieve primacy in the choice of antihyperglycemic drugs. It would be appropriate to demonstrate the usefulness of pioglitazone and its therapeutic benefit with further cardiovascular safety studies.

A diet-independent zebrafish model for NAFLD recapitulates patient lipid profiles and offers a system for small molecule screening

Non-alcoholic Fatty Liver Disease (NAFLD) or pathological hepatic lipid overload, is considered to affect obese individuals. However, NAFLD in lean individuals is prevalent, especially in South Asian population. The pathophysiology of lean NAFLD is not well understood and most animal models of NAFLD use the high-fat diet paradigm. To bridge this gap, we have developed a diet-independent model of NAFLD in zebrafish. We have previously shown that chronic systemic inflammation causes metabolic changes in the liver leading to hepatic fat accumulation in an IL6 overexpressing (IL6-OE) zebrafish model. In the present study, we compared the hepatic lipid composition of adult IL6-OE zebrafish to the controls and found an accumulation of saturated triacylglycerols and a reduction in the unsaturated triacylglycerol species reminiscent of NAFLD patients. Zebrafish is an ideal system for chemical genetic screens. We tested whether the hepatic lipid accumulation in the IL6-OE is responsive to chemical treatment. We found that PPAR-gamma agonist Rosiglitazone, known to reduce lipid overload in the high-fat diet models of NAFLD, could ameliorate the fatty liver phenotype of the IL6-OE fish. Rosiglitazone treatment reduced the accumulation of saturated lipids and showed a concomitant increase in unsaturated TAG species in our inflammation-induced NAFLD model. Our observations suggest that the IL6-OE model can be effective for small molecule screening to identify compounds that can reverse hepatic lipid accumulation, especially relevant to lean NAFLD.

PO096 / #810 SYNERGY OF ANTISEIZURE ACTION OF RAPAMYCIN, MINOCYCLIN, AND PIOGLITAZONE ON THE ACUTE PENTYLENETETRAZOL (PTZ)-INDUCED SEIZURES: E-POSTER VIEWING

Different mechanisms of antiseizure action of rapamycin – blocker of mTOR, pioglitazone - agonist of PPAR-gamma, and minocycline hydrochloride – suppression of microglia justifies the reasonability of their combined administration with the purpose of getting

PPARgamma agonism inhibits progression of premalignant lesions in a murine lung squamous cell carcinoma model.

The N-nitroso-trischloroethylurea (NTCU)-induced mouse model of squamous lung carcinoma recapitulates human disease from premalignant dysplasia through invasive tumors, making it suitable for preclinical chemoprevention drug testing. Pioglitazone is a peroxisome proliferator-activated receptor γ (PPARγ) agonist shown to prevent lung tumors in preclinical models. We investigated pioglitazone's effect on lesion development and markers of potential preventive mechanisms in the NTCU model. Female FVB/N mice were exposed to vehicle, NTCU or NTCU + oral pioglitazone for 32 weeks. NTCU induces the appearance of basal cells in murine airways while decreasing/changing their epithelial cell makeup, resulting in development of bronchial dysplasia. H&E and keratin 5 (KRT5) staining were used to detect and grade squamous lesions in formalin fixed lungs. mRNA expression of epithelial to mesenchymal transition (EMT) markers and basal cell markers were measured by qPCR. Dysplasia persistence markers desmoglein 3 and polo like kinase 1 were measured by immunohistochemistry. Basal cell markers KRT14 and p63, club cell specific protein and ciliated cell marker acetylated tubulin were measured by immunofluorescence. Pioglitazone treatment significantly reduced squamous lesions and the presence of airway basal cells, along with increasing normal epithelial cells in the airways of NTCU-exposed mice. Pioglitazone also significantly influenced EMT gene expression to promote a more epithelial, and less mesenchymal, phenotype. Pioglitazone reduced the presence of squamous dysplasia and maintained normal airway cell composition. This work increases the knowledge of mechanistic pathways in PPARγ agonism for lung cancer interception and provides a basis for further investigation to advance this chemoprevention strategy.

A Novel PPAR Gamma Agonist ELB00824 Suppresses Oxaliplatin-induced Pain, Neuronal Hypersensitivity, and Oxidative Stress

Chemotherapy-induced neuropathic pain (CINP) is a debilitating and difficult-to-treat side effect of chemotherapeutic drugs (e.g., oxaliplatin). CINP is marked with oxidative stress and neuronal hypersensitivities. The peroxisome proliferator-activated receptor gamma (PPARϒ) is a transcription factor that regulates genes involved in oxidative stress and inflammation. We hypothesize that PPARϒ agonists are protective against CIPN by reducing oxidative stress and inhibiting neuronal hypersensitivities. To test our hypothesis, we used a novel BBB (blood-brain barrier) penetrable PPARϒ agonist ELB00824 we characterized previously and a low BBB permeable PPARϒ agonist pioglitazone. CIPN was introduced in BALB/c mice (8-12 week old female) with two established treatment schedules of oxaliplatin injection (a short-lasting model with daily intraperitoneal (IP, 3 mg/kg) injection for 5 consecutive days and a long-lasting model with intravenous (IV, 5 mg/kg) injection twice per week for 4 weeks). 3, 10, or 30 mg/kg ELB00824 or pioglitazone was IP injected 5 min before each oxaliplatin treatment, and 30% DMSO, 15% Cremophor@EL in PBS buffer was used as a vehicle control. Cold allodynia, mechanical allodynia, motor coordination, sedation and addiction were measured with dry ice, von Frey filaments, beam-walking tests, and conditioned place preference, respectively. Oxidative stress was accessed by measuring spinal carbonyl groups, thiobarbituric acid reactive substance (TBARS), and nitrotyrosine levels. Neuronal hypersensitivities were measured using whole-cell current clamp recordings in isolated dorsal root ganglion neurons. In both models ELB00824, but not pioglitazone, reduced oxaliplatin-induced cold and mechanical allodynia and spinal oxidative stress. ELB0824 suppressed oxaliplatin-induced firing in IB4- neurons. ELB00824 did not cause motor discoordination or sedation/addiction or reduce the antineoplastic activity of oxaliplatin (measured with an MTS-based cell proliferation assay) in a human colon cancer cell line (HCT116) and a human oral cancer cell line (HSC-3). Our results demonstrated that ELB00824 prevents oxaliplatin-induced pain, likely via inhibiting neuronal hypersensitivities and oxidative stress. Grant support from NIH grants R01DE029493 (Y. Ye).

Role of JAK-STAT and PPAR-Gamma Signalling Modulators in the Prevention of Autism and Neurological Dysfunctions.

The Janus-kinase (JAK) and signal transducer activator of transcription (STAT) signalling pathways regulate gene expression and control various factors involved in normal physiological functions such as cell proliferation, neuronal development, and cell survival. JAK activation phosphorylates STAT3 in astrocytes and microglia, and this phosphorylation has been linked to mitochondrial damage, apoptosis, neuroinflammation, reactive astrogliosis, and genetic mutations. As a regulator, peroxisome proliferator-activated receptor gamma (PPAR-gamma), in relation to JAK-STAT signalling, prevents this phosphorylation and aids in the treatment of the above-mentioned neurocomplications. Changes in cellular signalling may also contribute to the onset and progression of autism. Thus, PPAR-gamma agonist upregulation may be associated with JAK-STAT signal transduction downregulation. It may also be responsible for attenuating neuropathological changes by stimulating SOCS3 or involving RXR or SMRT, thereby reducing transcription of the various cytokine proteins and genes involved in neuronal damage. Along with JAK-STAT inhibitors, PPAR-gamma agonists could be used as target therapeutic interventions for autism. This research-based review explores the potential involvement and mutual regulation of JAK-STAT and PPAR-gamma signalling in controlling multiple pathological factors associated with autism.

Brown adipose tissue involution associated with progressive restriction in progenitor competence.

Human brown adipose tissue (BAT) undergoes progressive involution. This involution process is not recapitulated in rodents, and the underlying mechanisms are poorly understood. Here we show that the interscapular BAT (iBAT) of rabbits whitens rapidly during early adulthood. The transcriptomic remodeling and identity switch of mature adipocytes are accompanied by loss of brown adipogenic competence of progenitors. Single-cell RNA sequencing reveals that rabbit and human iBAT progenitors highly express the FSTL1 gene. When iBAT involutes in rabbits, adipocyte progenitors reduce FSTL1 expression and are refractory to brown adipogenic recruitment. Conversely, FSTL1 is constitutively expressed in mouse iBAT to sustain WNT signaling and prevent involution. Progenitor incompetence and iBAT paucity can be induced in mice by genetic deletion of the Fstl1 gene or ablation of Fstl1+ progenitors. Our results highlight the hierarchy and dynamics of the BAT progenitor compartment and implicate the functional incompetence of FSTL1-expressing progenitors in BAT involution.

Beneficial antipruritic effects of lowering Interleukin -17 and/or IgE by anti-IgE monoclonal antibodies and PPAR gamma agonist in experimentally induced atopic dermatitis in mice

Beneficial antipruritic effects of lowering Interleukin -17 and/or IgE by anti-IgE monoclonal antibodies and PPAR gamma agonist in experimentally induced atopic dermatitis in mice

Pioglitazone Ameliorates Acute Endotoxemia-Induced Acute on Chronic Renal Dysfunction in Cirrhotic Ascitic Rats.

Endotoxemia-activated tumor necrosis factor (TNFα)/nuclear factor kappa B (NFκB) signals result in acute on chronic inflammation-driven renal dysfunction in advanced cirrhosis. Systemic activation of peroxisome proliferator-activated receptor gamma (PPARγ) with pioglitazone can suppress inflammation-related splanchnic and pulmonary dysfunction in cirrhosis. This study explored the mechanism and effects of pioglitazone treatment on the abovementioned renal dysfunction in cirrhotic rats. Cirrhotic ascitic rats were induced with renal dysfunction by bile duct ligation (BDL). Then, 2 weeks of pioglitazone treatment (Pio, PPAR gamma agonist, 12 mg/kg/day, using the azert osmotic pump) was administered from the 6th week after BDL. Additionally, acute lipopolysaccharide (LPS, Escherichia coli 0111:B4; Sigma, 0.1 mg/kg b.w, i.p. dissolved in NaCl 0.9%) was used to induce acute renal dysfunction. Subsequently, various circulating, renal arterial and renal tissue pathogenic markers were measured. Cirrhotic BDL rats are characterized by decreased mean arterial pressure, increased cardiac output and portal venous pressure, reduced renal arterial blood flow (RABF), increased renal vascular resistance (RVR), increased relative renal weight/hydroxyproline, downregulated renal PPARγ expression, upregulated renal inflammatory markers (TNFα, NFκB, IL-6, MCP-1), increased adhesion molecules (VCAM-1 and ICAM-1), increased renal macrophages (M1, CD68), and progressive renal dysfunction (increasing serum and urinary levels of renal injury markers (lipocalin-2 and IL-18)). In particular, acute LPS administration induces acute on chronic renal dysfunction (increasing serum BUN/creatinine, increasing RVR and decreasing RABF) by increased TNFα-NFκB-mediated renal inflammatory markers as well as renal M1 macrophage infiltration. In comparison with the BDL+LPS group, chronic pioglitazone pre-treatment prevented LPS-induced renal pathogenic changes in the BDL-Pio+LPS group. Activation of systemic, renal vessel and renal tissue levels of PPARγ by chronic pioglitazone treatment has beneficial effects on the endotoxemia-related TNFα/NFκB-mediated acute and chronic renal inflammation in cirrhosis. This study revealed that normalization of renal and renal arterial levels of PPARγ effectively prevented LPS-induced acute and chronic renal dysfunction in cirrhotic ascitic rats.

PPAR-Gamma Activation May Inhibit the In Vivo Degeneration of Bioprosthetic Aortic and Aortic Valve Grafts under Diabetic Conditions.

Background: We aimed to examine the anti-calcification and anti-inflammatory effects of pioglitazone as a PPAR-gamma agonist on bioprosthetic-valve-bearing aortic grafts in a rat model of diabetes mellitus (DM). Methods: DM was induced in male Wistar rats by high-fat diet with an intraperitoneal streptozotocin (STZ) injection. The experimental group received additional pioglitazone, and controls received normal chow without STZ (n = 20 each group). Cryopreserved aortic donor grafts including the aortic valve were analyzed after 4 weeks and 12 weeks in vivo for analysis of calcific bioprosthetic degeneration. Results: DM led to a significant media proliferation at 4 weeks. The additional administration of pioglitazone significantly increased circulating adiponectin levels and significantly reduced media thickness at 4 and 12 weeks, respectively (p = 0.0002 and p = 0.0107, respectively). Graft media calcification was highly significantly inhibited by pioglitazone after 12 weeks (p = 0.0079). Gene-expression analysis revealed a significant reduction in relevant chondro-osteogenic markers osteopontin and RUNX-2 by pioglitazone at 4 weeks. Conclusions: Under diabetic conditions, pioglitazone leads to elevated circulating levels of adiponectin and to an inhibition of bioprosthetic graft degeneration, including lower expression of chondro-osteogenic genes, decreased media proliferation, and inhibited graft calcification in a small-animal model of DM.