Effects Of Rosiglitazone Research Articles

Rosiglitazone attenuates Acute Kidney Injury from hepatic ischemia-reperfusion in mice by inhibiting arachidonic acid metabolism through the PPAR-γ/NF-κB pathway.

Acute Kidney Injury (AKI), a prevalent complication of Liver Transplantation (LT) that occurs during the perioperative period has been established to profoundly impact the prognosis of transplant recipients. This study aimed to investigate the mechanism of the hepatic IRI-induced AKI and to identify potential therapeutic targets for treating this condition and improving the prognosis of LT patients. An integrated transcriptomics and proteomics approach was employed to investigate transcriptional and proteomic alterations in hepatic IRI-induced AKI and the hypoxia-reoxygenation (H/R) model using TCMK-1 cells and the hepatic IRI-induced AKI mouse model using male C57BL/6J mice were employed to elucidate the underlying mechanisms. Hematoxylin-eosin staining, reverse transcription quantitative polymerase chain reaction, enzyme-linked immunosorbent assay and Western blot were used to assess the effect of Rosiglitazone(RGZ) on hepatic IRI-induced AKI in vitro and in vivo. According to the results, 322 genes and 128 proteins were differentially expressed between the sham and AKI groups. Furthermore, Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomics (KEGG) pathway analyses revealed significant enrichment in pathways related to amino acid and lipid metabolism. Additionally, the Protein-Protein Interaction (PPI) network analysis of the kidney tissues obtained from a hepatic IRI-induced AKI mouse model highlighted arachidonic acid metabolism as the most prominent pathway. Animal and cellular analyses further revealed that RGZ, a PPAR-γ agonist, could inhibit the expression of the PPAR-γ/NF-κB signaling pathway-associated proteins in in vitro and in vivo. These findings collectively suggest that RGZ ameliorates hepatic IRI-induced AKI via PPAR-γ/NF-κB signaling pathway modulation, highlighting PPAR-γ as a crucial therapeutic target for AKI prevention post-LT.

Rosiglitazone and trametinib exhibit potent anti-tumor activity in a mouse model of muscle invasive bladder cancer

Muscle invasive bladder cancers (BCs) can be divided into 2 major subgroups-basal/squamous (BASQ) tumors and luminal tumors. Since Pparg has low or undetectable expression in BASQ tumors, we tested the effects of rosiglitazone, Pparg agonist, in a mouse model of BASQ BC. We find that rosiglitazone reduces proliferation while treatment with rosiglitazone plus trametinib, a MEK inhibitor, induces apoptosis and reduces tumor volume by 91% after 1 month. Rosiglitazone and trametinib also induce a shift from BASQ to luminal differentiation in tumors, which our analysis suggests is mediated by retinoid signaling, a pathway known to drive the luminal differentiation program. Our data suggest that rosiglitazone, trametinib, and retinoids, which are all FDA approved, may be clinically active in BASQ tumors in patients.

Effect of Arthrospira maxima Phycobiliproteins, Rosiglitazone, and 17β-Estradiol on Lipogenic and Inflammatory Gene Expression during 3T3-L1 Preadipocyte Cell Differentiation.

The study evaluated the effects of Arthrospira maxima phycobiliproteins (PBPs), rosiglitazone (RSG), and 17β-estradiol (E) on the differentiation process of 3T3-L1 cells and on their regulation of lipogenic and inflammatory gene expression at different stages of the process. The results showed that phycobiliproteins promoted cell proliferation after 24 h of treatment. Furthermore, for all three treatments, the regulation of the highest number of markers occurred on days 6 and 12 of differentiation, regardless of when the treatment was applied. Phycobiliproteins reduced lipid droplet accumulation on days 3, 6, 10, and 13 of the adipogenic process, while rosiglitazone showed no differences compared to the control. On day 6, both phycobiliproteins and rosiglitazone positively regulated Acc1 mRNA. Meanwhile, all three treatments negatively regulated Pparγ and C/ebpα. Phycobiliproteins and estradiol also negatively regulated Ucp1 and Glut4 mRNAs. Rosiglitazone and estradiol, on the other hand, negatively regulated Ppara and Il-6 mRNAs. By day 12, phycobiliproteins and rosiglitazone upregulated Pparγ mRNA and negatively regulated Tnfα and Il-1β. Additionally, phycobiliproteins and estradiol positively regulated Il-6 and negatively regulated Ppara, Ucp2, Acc1, and Glut4. Rosiglitazone and estradiol upregulate C/ebpα and Ucp1 mRNAs. The regulation exerted by phycobiliproteins on the mRNA expression of the studied markers was dependent on the phase of cell differentiation. The results of this study highlight that phycobiliproteins have an anti-adipogenic and anti-inflammatory effect by reducing the expression of adipogenic, lipogenic, and inflammatory genes in 3T3-L1 cells at different stages of the differentiation process.

The effects of PPARγ agonists on long‑termpotentiation and apoptosis in the hippocampusarea of juvenile hypothyroid rats.

The aim of the present study was to evaluate the effect of rosiglitazone (RSG) or pioglitazone (POG) on the synaptic plasticity, neuronal apoptosis, brain-derived neurotrophic factor (BDNF), and nitric oxide (NO) metabolites in the hippocampus of juvenile hypothyroid rats. The animals were divided into four groups: control; propylthiouracil (PTU), 0.05% dose in drinking water for 42 days; PTU-POG; and PTU-RSG. The POG (20 mg/kg) and the RSG (4 mg/kg) were administered by IP injection. We conducted long‑term potentiation (LTP) in the cornu ammonis 1 area of the hippocampus using high‑frequency stimulation of the Schaffer collateral pathway. Then, the hippocampal tissues were collected to determine BDNF and NO levels and the degree of apoptosis. PTU administration decreased the slope (10-90%) and amplitude of the fEPSPs compared to control. Injection of RSG or POG increased the slope, slope (10-90%), and amplitude of the fEPSP in the PTU‑POG or PTU‑RSG groups compared to the PTU group. TUNEL‑positive neurons and NO metabolites in the hippocampus of the PTU group were higher than those of the control group. RSG or POG increased BDNF content in PTU-POG or PTU-RSG groups. Treatment of the rats with POG or RSG decreased apoptotic neurons and NO metabolites in the hippocampus of PTU-POG or PTU-RSG groups, respectively, compared to the PTU group. This study's results revealed that POG or RSG normalized LTP impairment, neuronal apoptosis, and improved BDNF content in the hippocampal tissue of juvenile hypothyroid rats.

The autophagic regulation of rosiglitazone-promoted adipocyte browning.

Objective: Browning of white adipocytes is considered an efficient approach to combat obesity. Rosiglitazone induces the thermogenetic program of white adipocytes, but the underlying mechanisms remain elusive. Methods: Expression levels of browning and autophagy flux markers were detected by real-time PCR and immunoblotting. H&E and Oil Red O staining were performed to evaluate the lipid droplets area. Nuclear protein extraction and immunoprecipitation were used to detect the proteins interaction. Results: In this study, we reported that rosiglitazone promoted adipocyte browning and inhibited autophagy. Rapamycin, an autophagy inducer, reversed adipocyte browning induced by rosiglitazone. Autophagy inhibition by rosiglitazone does not prevent mitochondrial clearance, which was considered to promote adipose whitening. Instead, autophagy inhibition increased p62 nuclear translocation and stabilized the PPARγ-RXRα heterodimer, which is an essential transcription factor for adipocyte browning. We found that rosiglitazone activated NRF2 in mature adipocytes. Inhibition of NRF2 by ML385 reversed autophagy inhibition and the pro-browning effect of rosiglitazone. Conclusion: Our study linked autophagy inhibition with rosiglitazone-promoted browning of adipocytes and provided a mechanistic insight into the pharmacological effects of rosiglitazone.

Abstract A027: The role of nuclear receptors as promoters of luminal tumors and suppressors of basal/squamous tumors

Abstract Bladder cancers (BCs) can be divided into 2 major subgroups, basal/squamous (BASQ) tumors that are muscle invasive and luminal tumors which are relatively benign. Pparg, has been suggested to act as a tumor suppressor in BASQ tumors, where its expression is low or undetectable. Here we tested the effects of rosiglitazone, Pparg agonist in a mouse model of BASQ BC. We find that rosiglitazone alone, reduced proliferation but did not decrease tumor volume, while treatment with rosiglitazone plus trametinib, a MEK inhibitor induced apoptosis and reduced tumor volume by 91% after 1 month. Rosiglitazone and trametinib also induced a shift from BASQ to luminal differentiation in tumors, which our analysis suggests is mediated by retinoid signaling, a pathway known to drive the luminal differentiation program. Our data suggest that rosiglitazone, trametinib, and retinoids, which are all FDA approved, may be clinically active in BASQ tumors in patients. Citation Format: Cathy L. Mendelsohn, Sakina A. Plumber, Tiffany Tate. The role of nuclear receptors as promoters of luminal tumors and suppressors of basal/squamous tumors [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr A027.

Rosiglitazone, a PPAR-γ agonist inhibits extracellular matrix production in TGFβ1 induced intestinal fibrosis.

Abstract Intestinal fibrosis, a common complication of intestinal bowel disease and is defined as an excessive deposition of extracellular matrix protein in the intestinal wall. Rosiglitazone, a PPAR-γ agonist, exerts anti-fibrotic effect in several organ fibrosis; however, its inhibitory effect on intestinal fibrosis is still not completely understood. Here, we investigated the inhibitory effects of rosiglitazone on fibrotic gene expression using TGFβ1 induced intestinal fibrosis model. Intestinal organoids were treated with TGFβ1 alone (2 ng/mL) or TGFβ1 plus rosiglitazone (50 uM) for 24 hours. Markers of fibrogenesis, including collagens and fibronectin were evaluated by measuring mRNA level using RT-PCR, and protein level by immunofluorescence or Western blotting. Signaling pathways involved in fibrosis were characterized by Western blotting analysis of cell lysates using indicated antibodies. We found that rosiglitazone significantly suppressed TGFβ1-induced expression of profibrogenic genes (collagen and fibronectin), epithelial to mesenchymal transition and cytokines production in intestinal fibrosis model. Furthermore, it was found that rosiglitazone inhibited the phosphorylation of Smad2/3 and Erk1/2. Taken together, these findings indicate that rosiglitazone exerts potent anti-fibrotic effect in TGFβ1 induced intestinal fibrosis via Smad- and non-Smad pathway.

The Effect of Thiazolidinediones in Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis of Randomised Controlled Trials.

Polycystic ovary syndrome (PCOS) is a complex endocrine condition affecting women of reproductive age. It is characterised by insulin resistance and is a risk for type2 diabetes mellitus (T2DM). The aim of this study was to review the literature on the effect of pioglitazone and rosiglitazone in women with PCOS. We searched PubMed, MEDLINE, Scopus, Embase, Cochrane Library and the Web of Science in April 2020 and updated in March 2023. Studies were deemed eligible if they were randomised controlled trials (RCTs) reporting the effect of pioglitazone and rosiglitazone in PCOS. The study follows the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Two reviewers independently extracted data and assessed the risk of bias using the Cochrane risk of bias tool. Out of 814 initially retrieved citations, 24 randomised clinical trials (RCTs) involving 976 participants were deemed eligible. Among women with PCOS, treatment with rosiglitazone compared to metformin resulted in a significant increase in the mean body weight (mean difference (MD) 1.95kg; 95%CI 0.03-3.87, p = 0.05). Metformin treatment was associated with a reduction in mean body mass index (BMI) compared to pioglitazone (MD 0.85kg/m2; 95%CI 0.13-1.57, p = 0.02). Both pioglitazone compared to placebo (MD 2.56kg/m2; 95%CI 1.77-3.34, p < 0.00001) and rosiglitazone compared to metformin (MD 0.74kg/m2; 95%CI 0.07-1.41, p = 0.03) were associated with a significant increase in BMI. Treatment with pioglitazone compared to placebo showed a significant reduction in triglycerides (MD - 0.20mmol/L; 95%CI - 0.38 to - 0.03, p = 0.02) and fasting insulin levels (MD - 11.47mmol/L; 95%CI - 20.20, - 2.27, p = 0.01). Rosiglitazone compared to metformin was marginally significantly associated with a reduction in the luteinising hormone (LH) (MD - 0.62; 95%CI - 1.25-0.00, p = 0.05). Both pioglitazone and rosiglitazone were associated with significant increases in body weight and BMI when compared with metformin or placebo. Pioglitazone significantly reduced triglycerides and fasting insulin when compared with placebo while rosiglitazone showed a modest reduction of LH when compared with metformin. CRD42020178783.

PPARγ alleviates preeclampsia development by regulating lipid metabolism and ferroptosis

The study aims to explore the effect of PPARγ signaling on ferroptosis and preeclampsia (PE) development. Serum and placental tissue are collected from healthy subjects and PE patients. The PPARγ and Nrf2 decreases in the PE. Rosiglitazone intervention reverses hypoxia-induced trophoblast ferroptosis and decreases lipid synthesis by regulating Nfr2 and SREBP1. Compared to the Hypoxia group, the migratory and invasive abilities enhance after rosiglitazone and ferr1 treatment. Rosiglitazone reduces the effect of hypoxia and erastin. The si-Nrf2 treatment attenuats the effects of rosiglitazone on proliferation, migration, and invasion. The si-Nrf2 does not affect SREBP1 expression. PPARγ agonists alleviates ferroptosis in the placenta of the PE rats. The study confirms that PPARγ signaling and ferroptosis-related indicators were dysregulated in PE. PPARγ/Nrf2 signaling affects ferroptosis by regulating lipid oxidation rather than SREBP1-mediated lipid synthesis. In conclusion, our study find that PPARγ can alleviate PE development by regulating lipid oxidation and ferroptosis.

Rosiglitazone alleviates LPS-induced endometritis via suppression of TLR4-mediated NF-κB activation.

The aim of this study was to investigate the anti-inflammatory effect of Rosiglitazone (RGZ) on lipopolysaccharide (LPS) -induced Endometritis and explore its possible mechanism. The preventive and therapeutic effects of RGZ on Endometritis were studied in vivo and in vitro. A total of 40 female C57BL/6 mice were randomly divided into the following 4 groups: RGZ+LPS, RGZ control, LPS and DMSO control. The mice uterine tissue sections were performed with HE and immunohistochemical staining. Human endometrial stromal cells (HESCs) were cultured, and different concentrations of LPS stimulation groups and RGZ and/or a TLR4 signaling inhibitor TAK-242 pretreatment +LPS groups were established to further elucidate the underlying mechanisms of this protective effect of RGZ. The HE results in mice showed that RGZ+LPS group had less tissue loss than LPS group. Immunohistochemical staining (IHC) results showed that the expression of TLR4 after RGZ treatment was significantly lower than that in LPS group. These findings suggested that RGZ effectively improves the pathological changes associated with LPS-induced endometritis by inhibiting TLR4. Reverse transcription-polymerase chain reaction and western blot analysis demonstrated that RGZ pretreatment suppresses the expression of Toll-like receptor 4 (TLR4) and its downstream activation of nuclear factor-κB (NF-κB). In vitro, RGZ inhibited LPS-stimulated expression of proinflammatory cytokines in a dose-dependent manner and also downregulated LPS induced toll-like receptor 4 (TLR4) expression and inhibited phosphorylation of LPS-induced nuclear transcription factor-kappa B (NF-κB) P65 protein. These results suggest that RGZ may inhibit LPS-induced endometritis through the TLR4-mediated NF-κB pathway.

Antidiabetic drug administration prevents bone mineral density loss: Evidence from a two-sample Mendelian randomization study.

The aim of this study was to investigate the effect of common antidiabetic drugs on BMD by two-sample Mendelian randomization (MR). The single nucleotide polymorphisms that were strongly associated with insulin, metformin, rosiglitazone and gliclazide were extracted as instrumental variables (IVs) for MR analysis. The inverse variance weighted (IVW) method was used as the primary MR method to assess the causal effect of antidiabetic drugs on BMD, and other MR methods, including Weighted median, MR Egger and Weighted mode, were used for complementary analysis. Reliability and stability were assessed by the leave-one-out test. In the present work, IVW estimation of the causal effect of insulin on heel BMD demonstrated that there was a null effect of insulin on heel BMD (β = 0.765; se = 0.971; P = 0.430), while metformin treatment had a positive effect on heel BMD (β = 1.414; se = 0.460; P = 2.118*10-3). The causal relationship between rosiglitazone and heel BMD analysed by IVW suggested that there was a null effect of rosiglitazone on heel BMD (β = -0.526; se = 1.744; P = 0.763), but the causal effect of gliclazide on heel BMD evaluated by IVW demonstrated that there was a positive effect of gliclazide on heel BMD (β = 2.671; se = 1.340; P = 0.046). In summary, the present work showed that metformin and gliclazide have a role in reducing BMD loss in patients with diabetes and are recommended for BMD loss prevention in diabetes.

The effects of pioglitazone and rosiglitazone on liver function in hypothyroid rats.

This study aimed to investigate the antioxidant effect of rosiglitazone (ROG) and pioglitazone (POG) on oxidative damage and dysfunction of hepatic tissue in hypothyroid rats. The male rats were classified into six groups: (1) Control; (2) Hypothyroid, (3) Hypothyroid-POG 10, (4) Hypothyroid-POG 20, (5) Hypothyroid-ROG 2, and (6) Hypothyroid-ROG 4. To induction hypothyroidism in rats, propylthiouracil (PTU) (0.05 %w/v) was added to drinking water. In groups 2-6, besides PTU, the rats were also intraperitoneal administrated with 10 or 20 mg/kg POG or 2 or 4 mg/kg ROG for six weeks. Finally, after deep anesthesia, the blood was collected to measure the serum biochemical markers and hepatic tissue was separated for biochemical oxidative stress markers. Administration of PTU significantly reduced serum thyroxin concentration, total thiol levels, activity of superoxide dismutase (SOD) and catalase (CAT) enzymes, and increased serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (Alk-P) and malondialdehyde (MDA) in the liver. Additionally, our results showed that prescription of POG or ROG for six weeks to hypothyroid rats resulted in an improvement in liver dysfunction (decrease in serum levels of AST, ALT, and ALK-P) through reducing oxidative damage in hepatic tissue (increase in CAT, SOD, or total thiols and decrease in MDA levels). The findings of the present study presented that the IP administration of POG and ROG for six weeks improves liver dysfunction induced by hypothyroidism in juvenile rats by reducing oxidative damage.

A comparative study of the benefits of monotherapy rosiglitazone versus rosiglitazone with insulin in streptozotocin-induced diabetes in rats

Background: Diabetes is often associated with dyslipidemia, where plasma lipid and lipoprotein profile alterations increase the risk of coronary heart disease. Insulin resistance increases the risk of hyperinsulin and atherosclerosis, developing hypertension and diabetes. Patients with diabetes suffer from metabolic disorders in carbohydrates, fat, and proteins associated with hyperglycemia. Hence reducing insulin resistance is a therapeutic approach to treating diabetes. Aims and Objectives: The aim of the study was to evaluate the beneficial effects of monotherapy rosiglitazone, gemfibrozil, and insulin versus rosiglitazone, gemfibrozil, and insulin combination in streptozotocin-induced diabetes in rats. Materials and Methods: 42-Wistar rats of either sex were used in this study, except for the control group, streptozocin was used to induce diabetes. These rats were further allocated into five groups, each group consists of eight animals. Blood serum was used to estimate blood glucose and serum lipid levels were observed after a period of 6 weeks. Results were analyzed using SPSS software version 21.0. Results: Combination therapy of insulin + rosiglitazone + gemfibrozil showed a significant decrease in serum blood glucose, lipid levels in compared with vehicle and rosiglitazone groups. Conclusion: The results of our study demonstrated a more favorable lipid profile than the monotherapy regimen; adding gemfibrozil and insulin to rosiglitazone could help reverse the cardiovascular adverse events it causes.

Cytosolic phospholipase A2 regulates lipid homeostasis under osmotic stress through PPARγ.

Physiologically, renal medullary cells are surrounded by a hyperosmolar interstitium. However, different pathological situations can induce abrupt changes in environmental osmolality, causing cell stress. Therefore, renal cells must adapt to survive in this new condition. We previously demonstrated that, among the mechanisms involved in osmoprotection, renal cells upregulate triglyceride biosynthesis (which helps preserve glycerophospholipid synthesis and membrane homeostasis) and cyclooxygenase-2 (which generates prostaglandins from arachidonic acid) to maintain lipid metabolism in renal tissue. Herein, we evaluated whether hyperosmolality modulates phospholipase A2 (PLA2 ) activity, leading to arachidonic acid release from membrane glycerophospholipid, and investigated its possible role in hyperosmolality-induced triglyceride synthesis and accumulation. We found that hyperosmolality induced PLA2 expression and activity in Madin-Darby canine kidney cells. Cytosolic PLA2 (cPLA2) inhibition, but not secreted or calcium-independent PLA2 (sPLA2 or iPLA2 , respectively), prevented triglyceride synthesis and reduced cell survival. Inhibition of prostaglandin synthesis with indomethacin not only failed to prevent hyperosmolality-induced triglyceride synthesis but also exacerbated it. Similar results were observed with the peroxisomal proliferator activated receptor gamma (PPARγ) agonist rosiglitazone. Furthermore, hyperosmolality increased free intracellular arachidonic acid levels, which were even higher when prostaglandin synthesis was inhibited by indomethacin. Blocking PPARγ with GW-9662 prevented the effects of both indomethacin and rosiglitazone on triglyceride synthesis and even reduced hyperosmolality-induced triglyceride synthesis, suggesting that arachidonic acid may stimulate triglyceride synthesis through PPARγ activation. These results highlight the role of cPLA2 in osmoprotection, since it is essential to provide arachidonic acid, which is involved in PPARγ-regulated triglyceride synthesis, thus guaranteeing cell survival.

Effects of different insulin sensitisers in the management of polycystic ovary syndrome: A systematic review and meta-analysis.

Characteristic features of polycystic ovary syndrome (PCOS) include insulin resistance and an increased risk for type 2 diabetes. To promote improved insulin sensitivity, insulin sensitisers have been used in PCOS. However, direct comparisons across these agents are limited. This study compared the effects of metformin, rosiglitazone and pioglitazone in the management of PCOS to inform the 2023 International Evidence-based PCOS Guideline. Systematic review and meta-analysis of the literature. Women with PCOS and treatment with insulin sensitisers. Hormonal and clinical outcomes, as well as side effects. Of 1660 publications identified, 13 randomised controlled trials were included. Metformin was superior in lowering weight (mean difference [MD]:-4.39, 95% confidence interval [CI]:-7.69 to -1.08 kg), body mass index(MD: -0.95, 95% CI: -1.41 to -0.49 kg/m2 ) and testosterone (MD:-0.10, 95% CI: -0.18 to -0.03 nmol/L) versus rosiglitazone, whereas there was no difference when comparing metformin to pioglitazone. Adding rosiglitazone or pioglitazone to metformin did not improve metabolic outcomes. However, rosiglitazone seemed superior to metformin in lowering lipid concentrations. Metformin should remain the first-line insulin sensitising treatment in adults with PCOS for the prevention and management of weight and metabolic features. The addition of thiazolidinediones appears to offer little benefit.

Abnormal expression of PRKAG2-AS results in dysfunction of cardiomyocytes through regulating PRKAG2 transcription by interacting with PPARG

The role of PRKAG2 in the maintenance of heart function is well established, but little is known about how PRKAG2 is regulated in cardiomyocytes. In this study, we investigated the role of the lncRNA PRKAG2-AS, which is present at the PRKAG2 promoter, in the regulation of PRKAG2 expression. PRKAG2-AS expression was predominantly nuclear, as determined by RNA nucleoplasmic separation and fluorescence in situ hybridization. Knockdown of PRKAG2-AS in the nucleus, but not the cytoplasm, significantly decreased the expression of PRKAG2b and PRKAG2d. Interestingly, we found that PRKAG2-AS and its target genes, PRKAG2b and PRKAG2d, were reduced in the hearts of patients with ischemic cardiomyopathy, suggesting a potential role for PRKAG2-AS in myocardial ischemia. Indeed, knockdown of PRKAG2-AS in the nucleus resulted in apoptosis of cardiomyocytes. We further elucidated the mechanism by which PRKAG2-AS regulates PRKAG2 transcription by identifying 58 PRKAG2-AS interacting proteins. Among them, PPARG was selected for further investigation based on its correlation and potential interaction with PRKAG2-AS in regulating transcription. Overexpression of PPARG, or its activation with rosiglitazone, led to a significant increase in the expression of PRKAG2b and PRKAG2d in cardiomyocytes, which could be attenuated by PRKAG2-AS knockdown. This finding suggests that PRKAG2-AS mediates, at least partially, the protective effects of rosiglitazone on hypoxia-induced apoptosis. However, given the risk of rosiglitazone in heart failure, we also examined the involvement of PRKAG2-AS in this condition and found that PRKAG2-AS, as well as PRKAG2b and PRKAG2d, was elevated in hearts with dilated cardiomyopathy (DCM) and that overexpression of PRKAG2-AS led to a significant increase in PRKAG2b and PRKAG2d expression, indicating that up-regulation of PRKAG2-AS may contribute to the mechanism of heart failure by promoting transcription of PRKAG2. Consequently, proper expression of PRKAG2-AS is essential for maintaining cardiomyocyte function, and aberrant PRKAG2-AS expression induced by hypoxia or other stimuli may cause cardiac dysfunction.

Inhibitory effect and mechanism of Rosiglitazone on M1 type polarization of central microglia in intracerebral hemorrhage mice based on JNK/STAT3 signaling pathway.

Intracerebral hemorrhage (ICH) seriously threatens the health of people. In addition, microglia M1 polarization was confirmed to be involved in the progression of ICH. Rosiglitazone was able to be used as an antidiabetic agent, which could activate PPAR-γ, and PPAR-γ was reported to inhibit inflammation in microglia. However, the detailed function of Rosiglitazone in ICH remains unclear. In vivo and in vitro experiments were used to test the function of Rosiglitazone in ICH. In addition, RT-qPCR and western blot were performed to evaluate the mRNA and protein level of PPAR-γ, respectively. Immunofluorescence staining was performed to detect the levels of CD206 and CD86, and ELISA was used to measure the levels of pro-inflammatory cytokines. PPAR-γ was downregulated in ICH mice, whereas p-JNK and p-STAT3 were upregulated. Thrombin notably downregulated the level of PPAR-γ in BV2 cells, whereas Rosiglitazone partially reversed this phenomenon. In addition, Rosiglitazone markedly reversed thrombin-induced microglia M1 polarization. Consistently, thrombin-induced inflammatory response in BV2 cells was abolished in the presence of Rosiglitazone. SP600125 (JNK/STAT3 inhibitor) greatly reversed thrombin-induced M1 polarization in microglia, and GW9662 abolished the effect of SP600125. Meanwhile, Rosiglitazone could inactivate JNK/STAT3 pathway through the upregulation of PPAR-γ. Furthermore, Rosiglitazone notably alleviated the symptom of ICH in vivo through inhibiting the apoptosis and mediating PPAR-γ/JNK/STAT3 axis. Rosiglitazone could attenuate the inflammation in ICH through inhibiting microglia M1 polarization. Thus, our research would shed now lights on exploring new therapeutic strategies against ICH.

Loss of PPARγ activity characterizes early protumorigenic stromal reprogramming and dictates the therapeutic window of opportunity

Although robustly expressed in the disease-free (DF) breast stroma, CD36 is consistently absent from the stroma surrounding invasive breast cancers (IBCs). In this study, we primarily observed CD36 expression in adipocytes and intralobular capillaries within the DF breast. Larger vessels concentrated in interlobular regions lacked CD36 and were instead marked by the expression of CD31. When evaluated in perilesional capillaries surrounding ductal carcinoma in situ, a nonobligate IBC precursor, CD36 loss was more commonly observed in lesions associated with subsequent IBC. Peroxisome proliferator-activated receptor γ (PPARγ) governs the expression of CD36 and genes involved in differentiation, metabolism, angiogenesis, and inflammation. Coincident with CD36 loss, we observed a dramatic suppression of PPARγ and its target genes in capillary endothelial cells (ECs) and pericytes, which typically surround and support the stability of the capillary endothelium. Factors present in conditioned media from malignant cells repressed PPARγ and its target genes not only in cultured ECs and pericytes but also in adipocytes, which require PPARγ for proper differentiation. In addition, we identified a role for PPARγ in opposing the transition of pericytes toward a tumor-supportive myofibroblast phenotype. In mouse xenograft models, early intervention with rosiglitazone, a PPARγ agonist, demonstrated significant antitumor effects; however, following the development of a palpable tumor, the antitumor effects of rosiglitazone were negated by the repression of PPARγ in the mouse stroma. In summary, PPARγ activity in healthy tissues places several stromal cell types in an antitumorigenic state, directly inhibiting EC proliferation, maintaining adipocyte differentiation, and suppressing the transition of pericytes into tumor-supportive myofibroblasts.

THU553 Anti-tumor Effect Of Rosiglitazone Via Upregulating 15-PDGH In Prolactin Secreting Adenoma

Abstract Disclosure: C. Kang: None. J. Oh: None. E. Wang: None. S. Lee: None. J. Nam: None. J. Hong: None. E. Lee: None. C. Ku: None. Background: Rosiglitazone, a synthetic peroxisome proliferator-activated receptor γ (PPAR γ) ligand, are used to treat type II diabetes. Over the last few years, PPAR γ has received much attention for its ability to exert variable tumors. Objective: The aim of this study is to investigate the anti-tumor effect of rosiglitazone on prolactin secreting pituitary adenomas and its mechanism. Materials &amp; Methods: Lactotroph cell line (GH4, MMQ) were treated with Phosphate-buffered saline (PBS) or rosiglitazone. In vitro analysis such as qPCR, immunoblot, prolactin (PRL) ELISA, Cell proliferation assay, and Fluorescence-activating cell sorting (FACS) analysis were performed to examine the effect of rosiglitazone on Lactotroph cell lines. Result: To investigate the direct effect of rosiglitazone on PRL secretion of the pituitary adenomas, GH4 and MMQ cells were treated with rosiglitazone 1, 5, 10, 50 μM for 72 hr. Both PRL mRNA and secretion levels were significantly decreased by rosiglitazone in a dose-dependent manner. In previous studies, 15-PDGH has been implicated as a tumor suppressor gene with the property that inhibits the tumor growth. Interestingly, 5 μM rosiglitazone upregulated the mRNA and protein levels of 15-PDGH in both GH4 (4.73-fold) and MMQ (4.04-fold) cells. Next, we investigated whether rosiglitazone had any effects on the proliferation of prolactinoma cells. Proliferation of the GH4 and MMQ cells were significantly decreased by rosiglitazone in a dose-dependent manner after treatment. Rosiglitazone potently induced cell cycle arrest in sub-G1inGH4 and MMQ cells. Furthermore, rosiglitazone treatment significantly increased both early (2.31-fold) and late apoptosis (1.9-fold) of GH4 and MMQ cells. Conclusion: These results collectively position 15-PDGH as a potential new therapeutic target for prolactinomas and implicate rosiglitazone as a possible alternative pharmacological approach for prolactinomas. Presentation: Thursday, June 15, 2023

New role for the anandamide metabolite prostaglandin F2α ethanolamide: Rolling preadipocyte proliferation

White adipose tissue regulation is key to metabolic health, yet still perplexing. The chief endocannabinoid anandamide metabolite, prostaglandin F2α ethanolamide (PGF2αEA), inhibits adipogenesis, that is, the formation of mature adipocytes. We observed that adipocyte progenitor cells—preadipocytes—following treatment with PGF2αEA yielded larger pellet sizes. Thus, we hypothesized that PGF2αEA might augment preadipocyte proliferation. Cell viability MTT and crystal violet assays, cell counting, and 5-bromo-2′-deoxyuridine incorporation in cell proliferation ELISA analyses confirmed our prediction. Additionally, we discovered that PGF2αEA promotes cell cycle progression through suppression of the expression of cell cycle inhibitors, p21 and p27, as shown by flow cytometry and qPCR. Enticingly, concentrations of this compound that showed no visible effect on cell proliferation or basal transcriptional activity of peroxisome proliferator-activated receptor gamma could, in contrast, reverse the anti-proliferative and peroxisome proliferator-activated receptor gamma-transcription activating effects of rosiglitazone (Rosi). MTT and luciferase reporter examinations supported this finding. The PGF2αEA pharmaceutical analog, bimatoprost, was also investigated and showed very similar effects. Importantly, we suggest the implication of the mitogen-activated protein kinase pathway in these effects, as they were blocked by the selective mitogen-activated protein kinase kinase inhibitor, PD98059. We propose that PGF2αEA is a pivotal regulator of white adipose tissue plasticity, acting as a regulator of the preadipocyte pool in adipose tissue.