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

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: These results suggest that RGZ may inhibit LPS-induced endometritis through the TLR4-mediated NF-κB pathway.

Rosiglitazone regulates astrocyte polarization and neuroinflammation in a PPAR-γ dependent manner after experimental traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) is a leading cause of high mortality and disability worldwide. Overactivation of astrocytes and overexpression of inflammatory responses in the injured brain are characteristic pathological features of TBI. Rosiglitazone (ROS) is a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist known for its anti-inflammatory activity. However, the relationship between the inflammatory response involved in ROS treatment and astrocyte A1 polarization remains unclear. OBJECTIVE: This study aimed to investigate whether ROS treatment improves dysfunction and astrocyte A1 polarization induced after TBI and to elucidate the underlying mechanisms of these functions. METHODS: SD rats were randomly divided into sham operation group, TBI group, TBI+ROS group, and TBI+ PPAR-γ antagonist group (GW9662 + TBI). The rat TBI injury model was prepared by the CCI method; brain water content test and wire grip test scores suggested the prognosis; FJB staining showed the changes of ROS on the morphology and number of neurons in the peripheral area of cortical injury; ELISA, immunofluorescence staining, and western blotting analysis revealed the effects of ROS on inflammatory response and astrocyte activation with the degree of A1 polarization after TBI. RESULTS: Brain water content, inflammatory factor expression, and astrocyte activation in the TBI group were higher than those in the sham-operated group (P < 0.05); compared with the TBI group, the expression of the above indexes in the ROS group was significantly lower (P < 0.05). Compared with the TBI group, PPAR-γ content was significantly higher and C3 content was considerably lower in the ROS group (P < 0.05); compared with the TBI group, PPAR-γ content was significantly lower and C3 content was substantially higher in the inhibitor group (P < 0.05). CONCLUSION: ROS can exert neuroprotective effects by inhibiting astrocyte A1 polarization through the PPAR-γ pathway based on the reduction of inflammatory factors and astrocyte activation in the brain after TBI.

Toxicometabolomics-based cardiotoxicity evaluation of Thiazolidinedione exposure in human-derived cardiomyocytes.

INTRODUCTION: Thiazolidinediones (TZDs), represented by pioglitazone and rosiglitazone, are a class of cost-effective oral antidiabetic agents posing a marginal hypoglycaemia risk. Nevertheless, observations of heart failure have hindered the clinical use of both therapies. OBJECTIVE: Since the mechanism of TZD-induced heart failure remains largely uncharacterised, this study aimed to explore the as-yet-unidentified mechanisms underpinning TZD cardiotoxicity using a toxicometabolomics approach. METHODS: The present investigation included an untargeted liquid chromatography-mass spectrometry-based toxicometabolomics pipeline, followed by multivariate statistics and pathway analyses to elucidate the mechanism(s)of TZD-induced cardiotoxicity using AC16 human cardiomyocytes as a model, and to identify the prognostic features associated with such effects. RESULTS: Acute administration of either TZD agent resulted in a significant modulation in carnitine content, reflecting potential disruption of the mitochondrial carnitine shuttle. Furthermore, perturbations were noted in purine metabolism and amino acid fingerprints, strongly conveying aberrations in cardiac energetics associated with TZD usage. Analysis of our findings also highlighted alterations in polyamine (spermine and spermidine) and amino acid (L-tyrosine and valine) metabolism, known modulators of cardiac hypertrophy, suggesting a potential link to TZD cardiotoxicity that necessitates further research. In addition, this comprehensive study identified two groupings - (i) valine and creatine, and (ii) L-tryptophan and L-methionine - that were significantly enriched in the above-mentioned mechanisms, emerging as potential fingerprint biomarkers for pioglitazone and rosiglitazone cardiotoxicity, respectively. CONCLUSION: These findings demonstrate the utility of toxicometabolomics in elaborating on mechanisms of drug toxicity and identifying potential biomarkers, thus encouraging its application in the toxicological sciences. (245 words).

Harnessing peroxisome proliferator-activated receptor γ agonists to induce Heme Oxygenase-1: a promising approach for pulmonary inflammatory disorders.

The activation of peroxisome proliferator-activated receptor (PPAR)-γ has been extensively shown to attenuate inflammatory responses in conditions such as asthma, acute lung injury, and acute respiratory distress syndrome, as demonstrated in animal studies. However, the precise molecular mechanisms underlying these inhibitory effects remain largely unknown. The upregulation of heme oxygenase-1 (HO-1) has been shown to confer protective effects, including antioxidant, antiapoptotic, and immunomodulatory effects in vitro and in vivo. PPARγ is highly expressed not only in adipose tissues but also in various other tissues, including the pulmonary system. Thiazolidinediones (TZDs) are highly selective agonists for PPARγ and are used as antihyperglycemic medications. These observations suggest that PPARγ agonists could modulate metabolism and inflammation. Several studies have indicated that PPARγ agonists may serve as potential therapeutic candidates in inflammation-related diseases by upregulating HO-1, which in turn modulates inflammatory responses. In the respiratory system, exposure to external insults triggers the expression of inflammatory molecules, such as cytokines, chemokines, adhesion molecules, matrix metalloproteinases, and reactive oxygen species, leading to the development of pulmonary inflammatory diseases. Previous studies have demonstrated that the upregulation of HO-1 protects tissues and cells from external insults, indicating that the induction of HO-1 by PPARγ agonists could exert protective effects by inhibiting inflammatory signaling pathways and attenuating the development of pulmonary inflammatory diseases. However, the mechanisms underlying TZD-induced HO-1 expression are not well understood. This review aimed to elucidate the molecular mechanisms through which PPARγ agonists induce the expression of HO-1 and explore how they protect against inflammatory and oxidative responses.

Adjunctive rosiglitazone treatment for severe pediatric malaria: A randomized placebo-controlled trial in Mozambican children.

OBJECTIVES: We tested the hypothesis that adjunctive rosiglitazone treatment would reduce levels of circulating angiopoietin-2 (Angpt-2) and improve outcomes of Mozambican children with severe malaria. METHODS: A randomized, double-blind, placebo-controlled trial of rosiglitazone vs placebo as adjunctive treatment to artesunate in children with severe malaria was conducted. A 0.045 mg/kg/dose of rosiglitazone or matching placebo were administered, in addition to standard of malaria care, twice a day for 4 days. The primary endpoint was the rate of decline of Angpt-2 over 96 hours. Secondary outcomes included the longitudinal dynamics of angiopoietin-1 (Angpt-1) and the Angpt-2/Angpt-1 ratio over 96 hours, parasite clearance kinetics, clinical outcomes, and safety metrics. RESULTS: Overall, 180 children were enrolled; 91 were assigned to rosiglitazone and 89 to placebo. Children who received rosiglitazone had a steeper rate of decline of Angpt-2 over the first 96 hours of hospitalization compared to children who received placebo; however, the trend was not significant (P = 0.28). A similar non-significant trend was observed for Angpt-1 (P = 0.65) and the Angpt-2/Angpt-1 ratio (P = 0.34). All other secondary and safety outcomes were similar between groups (P >0.05). CONCLUSION: Adjunctive rosiglitazone at this dosage was safe and well tolerated but did not significantly affect the longitudinal kinetics of circulating Angpt-2.

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

OBJECTIVE: 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. DESIGN: Systematic review and meta-analysis of the literature. PATIENTS: Women with PCOS and treatment with insulin sensitisers. MEASUREMENTS: Hormonal and clinical outcomes, as well as side effects. RESULTS: 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. CONCLUSIONS: 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.

GIPR Agonism Enhances TZD-Induced Insulin Sensitivity in Obese IR Mice.

Recent studies have found that glucose-dependent insulinotropic polypeptide receptor (GIPR) agonism can enhance the metabolic efficacy of glucagon-like peptide-1 receptor agonist treatment by promoting both weight-dependent and -independent improvements on systemic insulin sensitivity. These findings have prompted new investigations aimed at better understanding the broad metabolic benefit of GIPR activation. Herein, we determined whether GIPR agonism favorably influenced the pharmacologic efficacy of the insulin-sensitizing thiazolidinedione (TZD) rosiglitazone in obese insulin-resistant (IR) mice. Genetic and pharmacological approaches were used to examine the role of GIPR signaling on rosiglitazone-induced weight gain, hyperphagia, and glycemic control. RNA sequencing was conducted to uncover potential mechanisms by which GIPR activation influences energy balance and insulin sensitivity. In line with previous findings, treatment with rosiglitazone induced the mRNA expression of the GIPR in white and brown fat. However, obese GIPR-null mice dosed with rosiglitazone had equivalent weight gain to that of wild-type (WT) animals. Strikingly, chronic treatment of obese IR WT animals with a long-acting GIPR agonist prevented rosiglitazone-induced weight-gain and hyperphagia, and it enhanced the insulin-sensitivity effect of this TZD. The systemic insulin sensitization was accompanied by increased glucose disposal in brown adipose tissue, which was underlined by the recruitment of metabolic and thermogenic genes. These findings suggest that GIPR agonism can counter the negative consequences of rosiglitazone treatment on body weight and adiposity, while improving its insulin-sensitizing efficacy at the same time.

Rosiglitazone improves insulin resistance but does not improve exercise capacity in individuals with impaired glucose tolerance: A randomized clinical study.

Dysmetabolic states, such as type 2 diabetes (T2D), characterized by insulin resistance (IR), are associated with fatty liver, increased cardiovascular disease (CVD) risk, and decreased functional exercise capacity (FEC). Rosiglitazone (RO) improves exercise capacity and IR in T2D. However, the effects of RO on FEC and other markers of CVD risk in prediabetes are unknown. We hypothesized that insulin sensitization with RO would improve exercise capacity and markers of CVD risk in participants with impaired glucose tolerance (IGT). Exercise performance (peak oxygen consumption and oxygen uptake kinetics), IR (homeostasis model assessment of IR and quantitative insulin sensitivity check index), and surrogate cardiovascular endpoints (coronary artery calcium (CAC) volume and density and C-reactive protein (CRP)) were measured in participants with IGT after 12 and 18 months of RO or placebo (PL). RO did not significantly improve exercise capacity. Glycemic measures and IR were significantly lower in people on RO compared to PL at 18 months. CAC volume progression was not different between PL and RO groups. RO did not improve exercise capacity during an 18-month intervention despite improved IR and glycemia in people with IGT. Future studies should explore why effects on FEC with RO occur in T2D but not IGT. Understanding these questions may help in targeting therapeutic approaches in T2D and IGT.

Head-to-head comparison of BAM15, semaglutide, rosiglitazone, NEN, and calorie restriction on metabolic physiology in female db/db mice.

Metabolic disorders such as type 2 diabetes, fatty liver disease, hyperlipidemia, and obesity commonly co-occur but clinical treatment options do not effectively target all disorders. Calorie restriction, semaglutide, rosiglitazone, and mitochondrial uncouplers have all demonstrated efficacy against one or more obesity-related metabolic disorders, but it currently remains unclear which therapeutic strategy best targets the combination of hyperglycaemia, liver fat, hypertriglyceridemia, and adiposity. Herein we performed a head-to-head comparison of 5 treatment interventions in the female db/db mouse model of severe metabolic disease. Treatments included ∼60 % calorie restriction (CR), semaglutide, rosiglitazone, BAM15, and niclosamide ethanolamine (NEN). Results showed that BAM15 and CR improved body weight and liver steatosis to levels superior to semaglutide, NEN, and rosiglitazone, while BAM15, semaglutide, and rosiglitazone improved glucose tolerance better than CR and NEN. BAM15, CR, semaglutide, and rosiglitazone all had efficacy against hypertriglyceridaemia. These data provide a comprehensive head-to-head comparison of several key treatment strategies for metabolic disease and highlight the efficacy of mitochondrial uncoupling to correct multiple facets of the metabolic disease milieu in female db/db mice.

PPARγ agonist treatment reduces fibroadipose tissue in secondary lymphedema by exhausting fibroadipogenic PDGFRα+ mesenchymal cells.

Secondary lymphedema occurs in up to 20% of patients after lymphadenectomy performed for the surgical management of tumors involving the breast, prostate, uterus, and skin. Patients develop progressive edema of the affected extremity due to retention of protein-rich lymphatic fluid. Despite compression therapy, patients progress to chronic lymphedema in which noncompressible fibrosis and adipose tissue are deposited within the extremity. The presence of fibrosis led to our hypothesis that rosiglitazone, a PPARγ agonist that inhibits fibrosis, would reduce fibrosis in a mouse model of secondary lymphedema after hind limb lymphadenectomy. In vivo, rosiglitazone reduced fibrosis in the hind limb after lymphadenectomy. Our findings verified that rosiglitazone reestablished the adipogenic features of TGF-ß1-treated mesenchymal cells in vitro. Despite this, rosiglitazone led to a reduction in adipose tissue deposition. Single-cell RNA-Seq data obtained from human tissues and flow cytometric and histological evaluation of mouse tissues demonstrated increased presence of PDGFRα+ cells in lymphedema; human tissue analysis verified these cells have the capacity for adipogenic and fibrogenic differentiation. Upon treatment with rosiglitazone, we noted a reduction in the overall quantity of PDGFRα+ cells and LipidTOX+ cells. Our findings provide a framework for treating secondary lymphedema as a condition of fibrosis and adipose tissue deposition, both of which, paradoxically, can be prevented with a pro-adipogenic agent.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Effects of Moringa Oleifera Leaf Extract Plus Rosiglitazone on Serum Leptin and Glucose and Lipid Metabolism in Type 2 Diabetic Rats.

Objective: To investigate the effects of Moringa Oleifera Leaf Extract (MOLE) plus rosiglitazone (RSG) on glucose and lipid metabolism, serum leptin, and the Akt/GSK3ß/ß-Catenin signaling pathway in type 2 diabetic (T2D) rats. Methods: Sixty male Sprague-Dawley (SD) rats were randomly divided into six groups: the normal group, the model group, the RSG group, the low- and high-dose MOLE group, and the MOLE+RSG group. The normal group was fed a standard rat diet, while the other groups were given a single intraperitoneal injection of low-dose streptozomycin (STZ) (35 mg/kg) and fed a high-sugar and high-fat diet. After 8 weeks, the treatment outcomes were evaluated by measuring key parameters of blood glucose and lipid metabolism and the protein kinase B (AKT) / Glycogen synthase kinase 3beta (GSK3ß) /ß-Catenin signaling pathway in the T2D rats. Results: Compared with the normal group, the model group showed significantly increased levels of blood glucose, blood lipids, serum leptin, free fatty acid (FFA), and tumor necrosis factor-α (TNF-α). Compared with the model group, the RSG, low-dose MOLE, and high-dose MOLE groups displayed effective control of blood glucose, blood lipids, serum leptin, FFA, and TNF-α. The MOLE+RSG group surpassed the RSG group in regulating glucose, lipid metabolism, and serum leptin levels in T2D rats. In addition, the MOLE+RSG group also had superiority over the RSG group in activating the AKT/GSK3ß/ß-Catenin pathway. Conclusion: MOLE plus RSG can effectively reduce blood glucose and blood lipids in T2DM rats.

The ameliorating effects of Guizhi Fuling Wan combined with rosiglitazone in a rat ovarian model of polycystic ovary syndrome by the PI3K/AKT/NF-κB and Nrf2/HO-1 pathways.

OBJECTIVE: GuizhiFulingWan (GFW) has been reported to be effective against polycystic ovary syndrome (PCOS) by possessing oxidative stress and inflammation which related to PI3K/AKT/NF-κB, Nrf2/HO-1 pathway. This study aims to probe the effects and mechanisms of GFW combined with rosiglitazone on PCOS via PI3K/AKT/NF-κB and Nrf2/HO-1 pathways. METHODS: A rat PCOS model established by dehydroepiandrosterone (DHEA) injection. The experiment was allocated to control, DHEA, GFW, rosiglitazone, GFW + rosiglitazone groups. Treatment for 30 days, we monitored weight and ovarian weight of rats. Fasting blood glucose (FBG), fasting insulin (FINS), homeostasis model assessment of insulin resistance (HOMA-IR), lipid metabolism indexes, estrous cycle and sex hormone-, inflammation-, oxidative stress-related factors were examined. Hematoxylin&eosin staining assessed ovarian tissue pathological changes. Western blot determined PI3K/AKT/NF-κB, Nrf2/HO-1 pathways-related markers. RESULTS: GFW and rosiglitazone treatment suppressed body weight and ovarian weight in PCOS rats. They also decreased FBG, FINS, HOMA-IR while inhibited total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL) and enhanced high-density lipoprotein (HDL). They ameliorated estrous cycle, ovarian histological changes and follicular development. They restrained testosterone (T), luteinizing hormone (LH) and accelerated estradiol (E2), progesterone (P), follicle stimulating hormone (FSH). They inhibited glutathione peroxidase (GSH-Px), malondialdehyde (MDA), superoxide dismutase (SOD) in serum while increased GSH-Px, SOD and decrease MDA in ovarian tissues. They reduced C-reactive protein, interleukin-18 (IL-18), tumor necrosis factor-α (TNF-α), IL-6, IL-1ß levels. GFW and rosiglitazone co-intervention regulated PI3K/AKT/NF-κB and Nrf2/HO-1 pathways in PCOS rats. CONCLUSION: GFW alleviated ovarian dysfunction in PCOS rats, which may be related to the PI3K/AKT/NF-κB, Nrf2/HO-1 pathways.

Exact inference for fixed effects meta-analysis of 2 × 2 $$ 2\times 2 $$ tables.

Meta-analysis of associations between rare outcomes and binary exposures are particularly important in studies of a drug's potential side-effects. But meta-analysis of the resulting 2 × 2 $$ 2\times 2 $$ contingency tables presents substantial practical difficulties, as analysts are currently forced to pick between "exact" inference-that eliminates concern over using large-sample approximations with small cell counts-and explicitly allowing for heterogeneity of the underlying effects. A controversial example is given by the Avandia meta-analysis (Nissen and Wolski. N Engl J Med. 2007;356(24):2457-2471) of rosiglitazone's effects on myocardial infarction and death. While the initial Avandia analysis-using simple methods-found a significant effect, its results conflict with subsequent re-analyses that use either exact methods, or that explicitly acknowledge the plausible heterogeneity. In this article, we aim to resolve these difficulties, by providing an exact (albeit conservative) method that is valid under heterogeneity. We also provide a measure of the degree of conservatism, that indicates the approximate extent of the excess coverage. Applied to the Avandia data, we find support for Nissen and Wolski 2007's original results. Given that our method does not require strong assumptions or large cell counts, and provides intervals around the well-known conditional maximum likelihood estimate, we anticipate that it could be an attractive default method for meta-analysis of 2 × 2 $$ 2\times 2 $$ tables featuring rare events.

Juniper Berries Regulate Diabetes and Obesity Markers Through Modulating PPARα, PPARγ, and LXR: In Vitro and In Vivo Effects.

The berries of Juniperus communis have been traditionally used for therapeutic purposes. They have been reported to possess various pharmacological effects such as anti-inflammatory, hypoglycemic and hypolipidemic activities. In this study, a methanolic extract of J. communis berries (JB) was evaluated for its effects on peroxisome proliferator-activated receptors alpha and gamma (PPARα and PPARγ), liver X receptor (LXR), glucose uptake and lipid accumulation using various cellular systems. At a concentration of 25 µg/mL, JB caused 3.77-fold activation of PPARα, 10.90-fold activation of PPARγ, and 4.43-fold activation of LXR in hepatic cells. JB inhibited (11%) the adipogenic effect induced by rosiglitazone in adipocytes and increased glucose uptake (90%) in muscle cells. In high-fat diet (HFD) fed mice, JB at a dose of 25 mg/kg body weight exhibited a 21% decrease in body weight. Fasting glucose levels in mice treated with 12.5 mg/kg of JB were significantly decreased (39%) indicating its efficacy in regulating hyperglycemia and obesity induced by HFD thus ameliorating the symptoms of type 2 diabetes. A series of energy metabolic genes, including Sirt1 (2.00-fold) and RAF1 (2.04-fold), were upregulated by JB, while rosiglitazone regulated the hepatic PPARγ only. Phytochemical analysis of JB indicated presence of a number of flavonoids and biflavonoids which seem to be responsible for the observed activity. It was concluded that JB acted as a multiple agonist of PPARα, PPARγ and LXR without the undesired effect of adipogenesis and exhibited the property of enhancing glucose uptake. The regulation of PPARα, PPARγ and LXR seems to be through Sirt1 and RAF1. In vivo results confirmed the antidiabetic and antiobesity potential of JB and indicated its utility in metabolic disorder and type 2 diabetes.

PPAR-γ alleviates the inflammatory response in TNF-α-induced fibroblast-like synoviocytes by binding to p53 in rheumatoid arthritis.

Rheumatoid arthritis (RA) is characterized by synovial inflammation, synoviocyte expansion and damage to cartilage and bone. We recently reported that peroxisome proliferator-activated receptor (PPAR)-γ inhibited the proliferation and activation of fibroblast-like synoviocytes (FLS), and was downregulated in RA synovial. In this study we investigated the role of PPAR-γ in RA and the underlying mechanisms. Adjuvant-induced arthritis (AIA) was induced in rats; from D15, AIA rats were orally administered pioglitazone (30 mg·kg-1·d-1) or rosiglitazone (4 mg·kg-1·d-1) for 14 days. Collagen-induced arthritis (CIA) was induced in wild-type and Ppar-γ+/- mice. We showed that the expression of PPAR-γ was significantly reduced, whereas that of TNF-α was markedly increased in human RA FLS. In CIA mice, knockdown of PPAR-γ expression (Ppar-γ+/-) aggravated the ankle inflammation. Similarly, T0070907 (a PPAR-γ antagonist) or si-PPAR-γ promoted the activation and inflammation of TNF-α-induced FLS in vitro. On the contrary, administration of PPAR-γ agonist pioglitazone or rosiglitazone, or injection of ad-Ppar-γ into the ankle of AIA rat in vivo induced overexpression of PPAR-γ, reduced the paw swelling and inflammation, and downregulated activation and inflammation of FLS in RA. Interesting, injection of ad-Ppar-γ into the ankle also reversed the ankle inflammation in Ppar-γ+/- CIA mice. We conducted RNA-sequencing and KEGG pathway analysis, and revealed that PPAR-γ overexpression was closely related to p53 signaling pathway in TNF-α-induced FLS. Co-IP study confirmed that p53 protein was bound to PPAR-γ in RA FLS. Taken together, PPAR-γ alleviates the inflammatory response of TNF-α-induced FLS by binding p53 in RA.

Impact of pharmacological interventions on biochemical hyperandrogenemia in women with polycystic ovary syndrome: a systematic review and meta-analysis of randomised controlled trials.

CONTEXT: Polycystic ovary syndrome (PCOS) is a complex endocrine disease that affects women of reproductive age and is characterised by biochemical and clinical androgen excess. AIM: To evaluate the efficacy of pharmacological interventions used to decrease androgen hormones in women with PCOS. DATA SOURCE: We searched PubMed, MEDLINE, Scopus, Embase, Cochrane library and the Web of Science from inception up to March 2021. DATA SYNTHESIS: Two reviewers selected eligible studies and extracted data, and the review is reported according to the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). RESULTS: Of the 814 randomised clinical trials (RCTs) located in the search, 92 met the eligibility criteria. There were significant reductions in total testosterone level with metformin versus (vs) placebo (SMD: - 0.33; 95% CI  - 0.49 to  - 0.17, p < 0.0001, moderate grade evidence) and dexamethasone vs placebo (MD:-0.86 nmol/L; 95% CI  - 1.34 to  - 0.39, p = 0.0004, very low-grade evidence). Significant reductions in the free testosterone with sitagliptin vs placebo (SMD:  - 0.47; 95% CI  - 0.97 to 0.04, p = 0.07, very low-grade evidence), in dehydroepiandrosterone sulphate (DHEAS) with flutamide vs finasteride (MD:  - 0.37 µg/dL; 95% CI  - 0.05 to  - 0.58, p = 0.02, very low-grade evidence), a significant reduction in androstenedione (A4) with rosiglitazone vs placebo (SMD:  - 1.67; 95% CI  - 2.27 to  - 1.06; 59 participants, p < 0.00001, very low-grade evidence), and a significant increase in sex hormone-binding globulin (SHBG) with oral contraceptive pill (OCP) (35 µg Ethinyl Estradiol (EE)/2 mg cyproterone acetate (CPA)) vs placebo (MD: 103.30 nmol/L; 95% CI 55.54-151.05, p < 0.0001, very low-grade evidence) were observed. CONCLUSION: Metformin, OCP, dexamethasone, flutamide, and rosiglitazone use were associated with a significant reduction in biochemical hyperandrogenemia in women with PCOS, though their individual use may be limited due to their side effects. PROSPERO REGISTRATION NO: CRD42020178783.

Identification of Selective PPAR-γ Modulators by Combining Pharmacophore Modeling, Molecular Docking, and Adipogenesis Assay.

The clinically used glitazones (rosiglitazone and pioglitazone) for type 2 diabetes mellitus therapy have been linked to serious side effects such as fluid retention, congestive heart failure, weight gain, bone loss, and an increased risk of bladder cancer. The complete activation of PPAR-γ receptors in target tissues is linked to these effects. Many studies have demonstrated that partial PPAR-γ activators (GW0072, PAT5A, GQ16) give equivalent therapeutic benefits to full PPAR-γ agonists without the associated side effects. These breakthroughs cleared the path for the development of partial agonists or selective PPAR-γ modulators (SPPARγMs). This study combined pharmacophore modeling, molecular docking, and an adipogenesis experiment to identify thiazolidine analogs as SPPARMs/partial agonists. A custom library of 220 molecules was created and virtual screened to discover 90 compounds as SPPARγMs/ partial agonists. The chosen eight compounds were synthesized and tested for adipogenesis using 3T3L1 cell lines. These compounds' partial agonistic activity was evaluated in 3T3L1 cell lines by comparing their capacity to stimulate PPAR-γ mediated adipogenesis to that of a full agonist, rosiglitazone. The findings of the adipogenesis experiment demonstrate that all eight compounds examined had a partial potential to stimulate adipogenesis when compared to the full agonist, rosiglitazone. The current investigation identified eight possible PPAR-γ partial agonists or SPPARγMs that may be effective in the treatment of type 2 diabetes mellitus.

PPARγ/RAD21 alleviates peripheral secondary brain injury in rat cerebral hemorrhage model through promoting M2 polarization of microglial cells.

BACKGROUND: PPARγ has been reported to participate in intracerebral hemorrhage (ICH) progression, and recruit RAD21 through binding DNA. Our study aimed to explore the roles of PPARγ/RAD21 in ICH and their related mechanisms. METHODS: ICH models in vitro and in vivo were established using thrombin and autologous blood injection, respectively. After that, rosiglitazone (RSG), GW9662, and RAD21 knockdown/overexpression plasmids were used to treat the ICH models. The cell apoptosis, the related inflammatory cytokines levels, and the neurological function of the rats were examined. Real-time quantitative PCR (RT-qPCR), western blot and immunofluorescence were employed to determine the expression of the M1/M2 polarization-related markers. Finally, the interaction of PPARγ and RAD21 in microglial cells was observed using double labeled immunofluorescence and co-immunoprecipitation. RESULTS: After thrombin induction, the cell apoptosis, and TNF-α, IL-1ß and IL-10 contents were all significantly increased (P < 0.05); whereas RSG and RAD21 overexpression evidently inhibited the apoptosis of thrombin-caused microglial cells, reduced TNF-α and IL-1ß contents, further increased IL-10 content (P < 0.05). The combination of RAD21 and PPARγ was enhanced by RSG and RAD21 overexpression. In vivo experiments showed that RSG and RAD21 overexpression decreased neurological deficit score, brain water content and hematoma volume. Additionally, RSG and RAD21 overexpression up-regulated the expression of PPARγ, RAD21, Arg1, KLF4, and TGF-ß, whereas down-regulated iNOS and CD32 expression. The actions of GW9662 and RAD21 knockdown were opposite to those of RSG and RAD21 overexpression. CONCLUSION: PPARγ/RAD21 may alleviate ICH progression through promoting M2-type polarization of microglial cells and inhibiting inflammatory response.

A novel therapy for hepatic cholestasis treatment-the combination of rosiglitazone and fenofibrate.

Hepatic cholestasis can develop into liver fibrosis and eventually liver failure. Currently, ursodeoxycholic acid (UDCA) or UDCA combined with fenofibrate is used for cholestasis treatment. Rosiglitazone inhibited α-naphthyl isothiocyanate (ANIT)-induced cholestasis in mice. In this study, we compared the effect of rosiglitazone, UDCA, fenofibrate, combined rosiglitazone and fenofibrate or UDCA and fenofibrate on ANIT-induced cholestasis. C57BL/6J mice were induced cholestasis by ANIT while treated with rosiglitazone, UDCA, fenofibrate, combination of rosiglitazone and fenofibrate, or combination of UDCA and fenofibrate. Liver and serum samples were collected to determine liver necrosis and serum biochemical parameters. Rosiglitazone alone or combined with fenofibrate demonstrated better effects than UDCA alone or UDCA combined with fenofibrate in reduction of cholestasis-induced serum biochemical parameters and liver necrosis. Surprisingly, UDCA combined with fenofibrate, but not rosiglitazone combined with fenofibrate, potently increased accumulation of free fatty acids (FFAs) in the liver. Mechanistically, the protection of combination of rosiglitazone and fenofibrate against cholestasis was attributed to activated adiponectin pathway to enhance FXR and mitochondrial functions and reduce apoptosis in the liver. The accumulation of FFAs in the liver by combination of UDCA and fenofibrate was caused by activation of fatty acid biosynthesis and uptake, and triglyceride hydrolysis. Taken together, our study not only demonstrates the adverse effect of combination therapy of UDCA and fenofibrate, but also suggests the combination of rosiglitazone and fenofibrate can be another option for cholestasis treatment.