Hepatic Zbtb18 (Zinc Finger and BTB Domain Containing 18) alleviates hepatic steatohepatitis via FXR (Farnesoid X Receptor).

A lasting imbalance between fatty acid synthesis and consumption leads to non-alcoholic fatty liver disease (NAFLD), coupled with hepatitis and insulin resistance. Yet the details of the underlying mechanisms are not fully understood. Here, we unraveled that the expression of the transcription factor Zbtb18 is markedly decreased in the livers of both patients and murine models of NAFLD. Hepatic Zbtb18 knockout promoted NAFLD features like impaired energy expenditure and fatty acid oxidation (FAO), and induced insulin resistance. Conversely, hepatic Zbtb18 overexpression alleviated hepato-steatosis, insulin resistance, and hyperglycemia in mice fed on a high-fat diet (HFD) or in diabetic mice. Notably, in vitro and in vivo mechanistic studies revealed that Zbtb18 transcriptional activation of Farnesoid X receptor (FXR) mediated FAO and Clathrin Heavy Chain (CLTC) protein hinders NLRP3 inflammasome activity. This key mechanism by which hepatocyte's Zbtb18 expression alleviates NAFLD and consequent liver fibrosis was further verified by FXR's deletion and forced expression in mice and cultured mouse primary hepatocytes (MPHs). Moreover, CLTC deletion significantly abrogated the hepatic Zbtb18 overexpression-driven inhibition of NLRP3 inflammasome activity in macrophages. Altogether, Zbtb18 transcriptionally activates the FXR-mediated FAO and CLTC expression, which inhibits NLRP3 inflammasome's activity alleviating inflammatory stress and insulin resistance, representing an attractive remedy for hepatic steatosis and fibrosis.

Hepatoprotective effect of Typhaneoside on non-alcoholic fatty liver disease via farnesoid X receptor in vivo and in vitro.

Non-alcoholic fatty liver disease (NAFLD) is one of the most frequent health issues. The improvement of NAFLD is related to the activation of the farnesoid X receptor (FXR). Typhaneoside (TYP) is the main component of Typha orientalis Presl, which plays a positive role in the resistance of glucose and lipid metabolism disorders. This study aims to investigate the alleviative effect and the underlying mechanism of TYP on OAPA-induced cells and high-fat-diet (HFD)-induced mice with disorders of glucose and lipid metabolism, inflammation, oxidative stress and lower thermogenesis through FXR signaling. All the serum lipid, body weight, oxidative stress and inflammatory levels of WT mice were significantly increased after HFD administration. These mice were presented with pathological injury, liver tissue attenuation, energy expenditure, insulin resistance, and impaired glucose tolerance. These above-mentioned changes in HFD-induced mice were remarkably reversed by TYP, which improved HFD-induced energy expenditure, oxidative stress, inflammation, insulin resistance, and lipid accumulation in a dose-dependent manner by activating the expression of FXR. Furthermore, using a high throughput drug screening strategy based on fluorescent reporter genes, we found that TYP functions as a natural agonist of FXR.TYP-mediated FXR activation also significantly repressed TG hyperaccumulation in mouse primary Hepatocytes (MPHs). However, these beneficial effects of TYP were not observed in FXR-/- MPHs. Overall, activation of the FXR pathway by TYP is related to the improvement of metabolic parameters, such as blood glucose, lipid accumulation, insulin resistance, inflammation, oxidative stress and energy expenditure in vitro and in vivo.

Pachymic acid modulates sirtuin 6 activity to alleviate lipid metabolism disorders.

Pachymic acid (Pac), a major bioactive constituent of Poria cocos, is an antioxidant that inhibits triglyceride (TG) accumulation. To the best of our knowledge, the present study investigated for the first time whether Pac activated sirtuin 6 (SIRT6) signaling to alleviate oleic acid (OA)-palmitic acid (PA)-induced lipid metabolism disorders in mouse primary hepatocytes (MPHs). In the present study, MPHs challenged with Pac were used to test the effects of Pac on intracellular lipid metabolism. Molecular docking studies were performed to explore the potential targets of Pac in defending against lipid deposition. MPHs isolated from liver-specific SIRT6-deficient mice were subjected to OA + PA incubation and treated with Pac to determine the function and detailed mechanism. It was revealed that Pac activated SIRT6 by increasing its expression and deacetylase activity. Pa prevented OA + PA-induced lipid deposition in MPHs in a dose-dependent manner. Pac (50 µM) administration significantly reduced TG accumulation and increased fatty acid oxidation rate in OA + PA-incubated MPHs. Meanwhile, as per the results of molecular docking and relative mRNA levels, Pac activated SIRT6 and increased SIRT6 deacetylation levels. Furthermore, SIRT6 deletions in MPHs abolished the protective effects of Pac against OA + PA-induced hepatocyte lipid metabolism disorders. The present study demonstrated that Pac alleviates OA + PA-induced hepatocyte lipid metabolism disorders by activating SIRT6 signaling. Overall, SIRT6 signaling increases oxidative stress burden and promotes hepatocyte lipolysis.

Ginsenoside Rc Modulates SIRT6-NRF2 Interaction to Alleviate Alcoholic Liver Disease.

Alcoholic liver disease (ALD) is a serious worldwide health problem. Ginsenoside Rc is a major active ingredient isolated from Panax ginseng, whose pharmacological effects counteract oxidative stress, inflammation, and lipid accumulation. However, it is still unclear whether ginsenoside Rc might exert beneficial effects on alcohol-induced liver injury. To this aim, mice primary hepatocytes (MPHs) were challenged with alcohol to test ginsenoside Rc's effects on their intracellular alcohol metabolism. C57BL/6J mice or SIRT6alb-/- mice were chronically fed a diet with added alcohol or given a single gavage of alcohol with or without ginsenoside Rc. Analyses of alcohol metabolism, oxidative stress, inflammation, lipid metabolism, and RNaseq expression were conducted to explore potential targets exploited by ginsenoside Rc to protect against ALD. Our results showed that ginsenoside Rc attenuated alcohol-induced liver injury by regulating oxidative stress, inflammation, and lipid accumulation both in vivo and in vitro. Ginsenoside Rc did increase the deacetylase activity of SIRT6, thereby lowering acetylated NRF2 levels, which elevated NRF2's stability, and subsequently exerting an antioxidant effect. In keeping with this, the hepatic knockout of SIRT6 almost abolished the hepatoprotective effects of ginsenoside Rc against ALD. Therefore, our results suggest that ginsenoside Rc attenuated hepatocytes' damage and oxidative stress in ALD by up-regulating the SIRT6/NRF2 pathway. Hence, ginsenoside Rc may be a promising drug to treat or relieve ALD.

Elevation of serum creatine kinase induced by anti-thyroid drugs: Two case reports and a literature review.

Anti-thyroid drugs (ATDs), such as methimazole (MMI) and propylthiouracil (PTU), are the most common treatment options for hyperthyroidism. Although effective, well-known adverse effects include agranulocytosis, toxic hepatitis, vasculitis, and arthralgias. Myalgia and elevation of serum creatine kinase (CK) are relatively rare, with an unclear mechanism. Rapid decrease in the thyroid hormone level may be associated with ATD-related myopathy; however, direct effects of the drug on muscle tissue cannot be excluded. Here we report on two Chinese patients with myalgia and an elevated CK due to ATDs. Early recognition of this rare medication-induced adverse effect and close monitoring of the CK level are particularly important. Physicians and pharmacists should inform the patients about the earliest symptoms of adverse effects for patients to know when to discontinue the drug. If adverse events occur, different treatment strategies such as ATD dose reduction and switching to alternative ATDs can be applied depending on the case.

Inhibition of NLRP3-mediated crosstalk between hepatocytes and liver macrophages by geniposidic acid alleviates cholestatic liver inflammatory injury.

The excessive accumulation of bile acids (BA) in hepatocytes can trigger inflammatory response and recruit macrophages, thereby accelerating cholestatic liver injury. The crosstalk between hepatocytes and macrophages has been recently implicated in the pathogenesis of cholestasis; however, the underlying mechanisms remain unclear. Here, we demonstrated that BA initiate NLRP3 inflammasome activation in hepatocytes to release proinflammatory cytokines and promote the communication between hepatocytes and macrophages, thus enhancing liver inflammation in an NLRP3-dependent manner. NLRP3-inhibition by geniposidic acid (GPA), a novel NLRP3-specific covalent inhibitor that directly interacts with NLRP3, in hepatocytes and macrophages abated BA-induced inflammation. Moreover, NLRP3-deletion or its inhibition mitigated ANIT-induced cholestatic inflammation, whereas disrupting the crosstalk between hepatic macrophages and hepatocytes attenuated the hepatoprotective effect of GPA against ANIT-induced cholestatic inflammation. Therefore, blocking this crosstalk by suppressing NLRP3 inflammasome activation may represent a novel therapeutic strategy for cholestasis.

Jianpi Huayu decoction inhibits the epithelial-mesenchymal transition of hepatocellular carcinoma cells by suppressing exosomal miR-23a-3p/Smad signaling.

ETHNOPHARMACOLOGICAL RELEVANCE: Jianpi Huayu decoction (JHD) is a traditional Chinese medicinal preparation used to treat a variety of malignant tumors including HCC, although the underlying mechanism remains unknown. Exosomes in the tumor microenvironment mediate intercellular signaling among cancer cells, but precise contributions to hepatocellular carcinoma (HCC) progression are still elusive. AIM OF THE STUDY: In this work, the main objective was to examine the mechanisms underlying anti-tumor effects of JHD and the potential contributions of exosomal signaling. MATERIALS AND METHODS: LC-MS/MS was used for quality control of JDH preparation, while nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM) and western blotting were used for verification of exosomes. In vitro assays included CCK8, wound healing assay, transwell invasion assay, qRT-PCR and western blotting were performed to investigate the effects of JHD on HCC cells and the molecular mechanism. Furthermore, the effects of JHD on subcutaneous tumor model of nude mice were also determined. RESULTS: JHD inhibited the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of cultured HCC cells. Further, exosomes isolated from EMT-induced HCC cells promoted the migration, invasion and EMT of other cultured HCC cells, while exosomes isolated from EMT-induced HCC cells after JHD treatment had little effect. In addition, JHD reduced the expression of exosomal miR-23a-3p in cultured HCC cells. miR-23a-3p was significantly up-regulated in tumor compared with that in adjacent non-cancerous tissues of patients with HCC. HCC patients with high miR-23a-3p expression had poor overall survival after hepatectomy. Meanwhile, miR-23a-3p enhanced HCC cell proliferation, EMT, and expression of Smad signaling proteins. More importantly, overexpression of miR-23a-3p can reverse the inhibition of EMT and Smad signaling pathway caused by JHD treatment. In vivo assays, treatment with JHD also reduced the growth of HCC-derived tumors in nude mice, reduced the expression of miR-23a-3p in serum exosomes and the level of EMT in tumor cells. CONCLUSIONS: the antitumor effects of JHD on HCC are mediated at least in part by inhibition of EMT due to downregulation of exosome-mediated intercellular miR-23a-3p transfer and subsequent blockade of Smad signaling. Disrupting this exosomal miR-23a-3p/Smad signaling pathway may be an effective treatment.

A Sensitive Liquid Chromatography-Mass Spectrometry Method for Determination of Toosendanin in Rat Plasma and its Application to Pharmacokinetic Study.

A simple, rapid and sensitive analytical method was developed for the determination of toosendanin in rat plasma using liquid chromatography tandem mass spectrometry (LC-MS/MS). Andrographolide was selected as the internal standard, and the plasma samples were extracted by liquid-liquid extraction with diethyl ether. Chromatographic separation was performed on a Dikma Spursil C18, 3.5 µm (150 × 2.1 mm i.d) analytical column with 85% methanol:water (v/v) containing 0.025% formic acid (pH = 3.9) as mobile phase. The flow rate was 0.25 mL/min, and the total run time was 3 min. Detection was performed with a triple-quadrupole tandem mass spectrometer using negative ion mode electrospray ionization (ESI) in the multiple reaction monitoring (MRM) mode. The MS/MS ion transitions monitored were m/z 573.1 â†’ 531.1 and 349.0 â†’ 287.0 for toosendanin and andrographolide, respectively. Good linearity was observed over the concentration range of 3.125-500 ng/mL in 100 µL of rat plasma with a correlation coefficient ˃0.9997. Intra- and inter-assay variabilities were ˂8.5% in plasma. The recovery and the matrix effect were in the range 71.8-73.5% and 96.4-103.8%, respectively. The analyte was stable under various conditions (at room temperature, during freeze-thaw settings, in the autosampler, and under deep-freeze conditions). The method was successfully applied to a pharmacokinetic study of toosendanin after its oral administration in rats at a dose of 10 mg/kg.

Quercetin alleviates chronic renal failure by targeting the PI3k/Akt pathway.

Chronic renal failure (CRF) threatens human health greatly and attracts worldwide concerns of health professionals in the public health sector. In our preliminary study, we found that Compound capsule (Shengqing Jiangzhuo Capsule, SQJZJN) had a significant therapeutic effect on CRF. Quercetin is one of the main components of this Compound capsule. In this study, we investigated the effect of Quercetin monomer on CRF and the regulation of PI3k/Akt pathway. Network pharmacology analysis methods were employed to analyze the SQJZJN/Quercetin/PIK3R1 network relationships. In this study, a CRF rat model was prepared using the gavage adenine solution method and detected the indicators of Creatinine (Cr), Blood Urea Nitrogen (BUN), and Uric Acid (UA). After treating the rat model with Quercetin and PIK3R1-interfering lentivirus, respectively, we observed the changes on the histological morphology of the kidney and detected apoptosis using TUNEL staining. Gene and protein expression associated with renal function were detected using qPCR, WB and immunofluorescence. Quercetin was identified as the main ingredient of SQJZJN by the network pharmacological screening and Quercetin at 1.5 and 3 g/(kg.d) concentrations could effectively alleviate the CRF symptoms, reduce the levels of Cr, BUN, and UA, and markedly inhibit cell apoptosis demonstrated by the intragastric administration. Furthermore, the protein expression of p-PI3K, p-AKT, NLRP3, caspase1, AQP1, and AQP2 in all groups was detected by immunofluorescence and western blot assays, indicating that Quercetin could reduce the expression of NLRP3, caspase1, p-PI3k, and p-Akt, and increase the expression of AQP1 and AQP2 in the renal tissues of CRF rats. Being labeled with biotin and incubated with the total protein extracted from kidney tissues, Quercetin could bind to PIK3R1. Following the PIK3R1 interference lentivirus was injected into the CRF model rats by tail vein, the CRF symptoms were effectively alleviated in the PIK3R1 interference group, consistent with the effect of Quercetin. Taken together, Quercetin, a major component of SQJZJN, might minimize renal fibrosis and apoptosis in CRF rats by inhibiting the PI3k/Akt pathway through targeting PIK3R1. By regulating AQP1 and AQP2, both water retention and toxin accumulation were reduced.

Emodin palliates high-fat diet-induced nonalcoholic fatty liver disease in mice via activating the farnesoid X receptor pathway.

BACKGROUND: Cassia mimosoides Linn (CMD) is a traditional Chinese herb that clears liver heat and dampness. It has been widely administered in clinical practice to treat jaundice associated with damp-heat pathogen and obesity. Emodin (EMO) is a major bioactive constituent of CMD that has apparent therapeutic efficacy against obesity and fatty liver. Here, we investigated the protective effects and underlying mechanisms of EMO against high-fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD). OBJECTIVE: We aimed to investigate whether EMO activates farnesoid X receptor (FXR) signaling to alleviate HFD-induced NAFLD. MATERIALS AND METHODS: In vivo assays included serum biochemical indices tests, histopathology, western blotting, and qRT-PCR to evaluate the effects of EMO on glucose and lipid metabolism disorders in wild type (WT) and FXR knockout mice maintained on an HFD. In vitro experiments included intracellular triglyceride (TG) level measurement and Oil Red O staining to assess the capacity of EMO to remove lipids induced by oleic acid and palmitic acid in WT and FXR knockout mouse primary hepatocytes (MPHs). We also detected mRNA expression of FXR signaling genes in MPHs. RESULTS: After HFD administration, body weight and serum lipid and inflammation levels were dramatically increased in the WT mice. The animals also presented with impaired glucose tolerance, insulin resistance, and antioxidant capacity, liver tissue attenuation, and pathological injury. EMO remarkably reversed the foregoing changes in HFD-induced mice. EMO improved HFD-induced lipid accumulation, insulin resistance, inflammation, and oxidative stress in a dose-dependent manner in WT mice by inhibiting FXR expression. EMO also significantly repressed TG hyperaccumulation by upregulating FXR expression in MPHs. However, it did not improve lipid accumulation, insulin sensitivity, or glucose tolerance in HFD-fed FXR knockout mice. CONCLUSIONS: The present study demonstrated that EMO alleviates HFD-induced NAFLD by activating FXR signaling which improves lipid accumulation, insulin resistance, inflammation, and oxidative stress.

Hepatic Krüppel-like factor 16 (KLF16) targets PPARα to improve steatohepatitis and insulin resistance.

OBJECTIVE: Impaired hepatic fatty acids oxidation results in lipid accumulation and redox imbalance, promoting the development of fatty liver diseases and insulin resistance. However, the underlying pathogenic mechanism is poorly understood. Krüppel-like factor 16 (KLF16) is a transcription factor that abounds in liver. We explored whether and by what mechanisms KLF16 affects hepatic lipid catabolism to improve hepatosteatosis and insulin resistance. DESIGN: KLF16 expression was determined in patients with non-alcoholic fatty liver disease (NAFLD) and mice models. The role of KLF16 in the regulation of lipid metabolism was investigated using hepatocyte-specific KLF16-deficient mice fed a high-fat diet (HFD) or using an adenovirus/adeno-associated virus to alter KLF16 expression in mouse primary hepatocytes (MPHs) and in vivo livers. RNA-seq, luciferase reporter gene assay and ChIP analysis served to explore the molecular mechanisms involved. RESULTS: KLF16 expression was decreased in patients with NAFLD, mice models and oleic acid and palmitic acid (OA and PA) cochallenged hepatocytes. Hepatic KLF16 knockout impaired fatty acid oxidation, aggravated mitochondrial stress, ROS burden, advancing hepatic steatosis and insulin resistance. Conversely, KLF16 overexpression reduced lipid deposition and improved insulin resistance via directly binding the promoter of peroxisome proliferator-activated receptor α (PPARα) to accelerate fatty acids oxidation and attenuate mitochondrial stress, oxidative stress in db/db and HFD mice. PPARα deficiency diminished the KLF16-evoked protective effects against lipid deposition in MPHs. Hepatic-specific PPARα overexpression effectively rescued KLF16 deficiency-induced hepatic steatosis, altered redox balance and insulin resistance. CONCLUSIONS: These findings prove that a direct KLF16-PPARα pathway closely links hepatic lipid homeostasis and redox balance, whose dysfunction promotes insulin resistance and hepatic steatosis.

Chrysophanol Alleviates Metabolic Syndrome by Activating the SIRT6/AMPK Signaling Pathway in Brown Adipocytes.

Chrysophanol, a primary active ingredient of Cassia mimosoides Linn or Rhei radix et rhizoma, has various pharmacological properties, including anticancer, antidiabetic, and anti-inflammatory, as well as blood lipid regulation. However, whether chrysophanol can mitigate obesity, and its underlying mechanisms remains unclear. This study investigated whether chrysophanol effects energy metabolism in high-fat diet- (HFD-) induced obese mice and fat-specific Sirtuin 6- (SIRT6-) knockout (FKO) mice, targeting the SIRT6/AMPK signaling pathway in brown and white fat tissue. Our results showed that chrysophanol can effectively inhibit lipid accumulation in vitro and reduce mice's body weight, improve insulin sensitivity and reduced fat content of mice, and induce energy consumption in HFD-induced obese mice by activating the SIRT6/AMPK pathway. However, a treatment with OSS-128167, an SIRT6 inhibitor, or si-SIRT6, SIRT6 target specific small interfering RNA, in vitro blocked chrysophanol inhibition of lipid accumulation. Similar results were obtained when blocking the AMPK pathway. Moreover, in the HFD-induced obese model with SIRT6 FKO mice, histological analysis and genetic test results showed that chrysophanol treatment did not reduce lipid droplets and upregulated the uncoupling protein 1 (UCP1) expression. Rather, it upregulated the expression of thermogenic genes and activated white fat breakdown by inducing phosphorylation of adenosine 5'-monophosphate- (AMP-) activated protein kinase (AMPK), both in vitro and in vivo. OSS-128167 or si-SIRT6 blocked chrysophanol's upregulation of peroxisome proliferator-activated receptor-γ coactivator-1α (Pgc-1α) and Ucp1 expression. In conclusion, this study demonstrated that chrysophanol can activate brown fat through the SIRT6/AMPK pathway and increase energy consumption, insulin sensitivity, and heat production, thereby alleviating obesity and metabolic disorders.

Activation of Farnesoid X Receptor by Schaftoside Ameliorates Acetaminophen-Induced Hepatotoxicity by Modulating Oxidative Stress and Inflammation.

Aims: Acetaminophen (APAP) overdose leads to acute liver injury by inducing hepatic mitochondrial oxidative stress and inflammation. However, the molecular mechanisms involved are still unclear. Farnesoid X receptor (FXR) serves as a therapeutic target for the treatment of liver disorders, whose activation has been proved to protect APAP-induced hepatotoxicity. In this study, we examined whether FXR activation by schaftoside (SS), a naturally occurring flavonoid from Desmodium styracifolium, could protect mice against APAP-induced hepatotoxicity via regulation of oxidative stress and inflammation. Results: We first found that SS exhibited potent protective effects against APAP-induced hepatotoxicity in mice. The study reveals that SS is a potential agonist of FXR, which protects mice from hepatotoxicity mostly via regulation of oxidative stress and inflammation. Mechanistically, the hepatoprotective SS is associated with the induction of the genes of phase II detoxifying enzymes (e.g., UGT1A1, GSTα1), phase III drug efflux transporters (e.g., bile salt export pump, organic solvent transporter protein ß), and glutathione metabolism-related enzymes (e.g., glutamate-cysteine ligase modifier subunit [Gclm], glutamate-cysteine ligase catalytic subunit [Gclc]). More importantly, SS-mediated FXR activation could fine-tune the pro- and anti-inflammatory eicosanoids generation via altering eicosanoids metabolic pathway, thereby resulting in decrease of hepatic inflammation. In contrast, FXR deficiency can abrogate the above effects. Innovation and Conclusion: Our results provided the direct evidence that FXR activation by SS could attenuate APAP-induced hepatotoxicity via inhibition of nuclear factor kappa-B signaling and fine-tuning the generation of proinflammatory mediators' eicosanoids. Our findings indicate that strategies to activate FXR signaling in hepatocytes may provide a promising therapeutic approach to alleviate liver injury induced by APAP overdose.

Patchouli alcohol activates PXR and suppresses the NF-κB-mediated intestinal inflammatory.

ETHNOPHARMACOLOGICAL RELEVANCE: The pregnane-X-receptor (PXR) is involved in inflammatory bowel disease (IBD). Patchouli alcohol (PA) has anti-inflammatory effects; however, the effect of PA on IBD pathogenesis remains largely unknown. AIM OF THE STUDY: The aim of the present study was to investigate the anti-inflammatory effect of PA, primarily focused on crosstalk between PA-mediated PXR activation and NF-κB inhibition. MATERIALS AND METHODS: We evaluated the anti-inflammatory effect of PA with respect to PXR/NF-κB signalling using in vitro and in vivo models. In vitro, PA, identified as a PXR agonist, was evaluated by hPXR transactivation assays and through assessing for CYP3A4 expression and activity. NF-κB inhibition was analysed based on NF-κB luciferase assays, NF-κB-mediated pro-inflammatory gene expression, and NF-κB nuclear translocation after activation of PXR by PA. In vivo, colonic mPXR and NF-κB signalling were analysed to assess PA-mediated the protective effect against dextran sulphate sodium (DSS)-induced colitis. Furthermore, pharmacological inhibition of PXR was further evaluated by examining PA protection against DSS-induced colitis. RESULTS: PA induced CYP3A4 expression and activity via an hPXR-dependent mechanism. PA-mediated PXR activation attenuated inflammation by inhibiting NF-κB activity and nuclear translocation. The anti-inflammatory effect of PA on NF-κB was abolished by PXR knockdown. PA prevented DSS-induced inflammation by regulating PXR/NF-κB signalling, whereas pharmacological PXR inhibition abated PA-mediated suppressive effects on NF-κB inflammation signalling. CONCLUSIONS: PA activates PXR signalling and suppresses NF-κB signalling, consequently causing amelioration of inflammation. Our results highlight the importance of PXR-NF-κB crosstalk in colitis and suggest a novel therapeutic reagent.

The effectiveness of metformin, oral contraceptives, and lifestyle modification in improving the metabolism of overweight women with polycystic ovary syndrome: a network meta-analysis.

PURPOSE: We designed a network meta-analysis that investigated relatively different interventions that included the effects of metformin, oral contraceptives, and lifestyle modification on the metabolic parameters of patients with polycystic ovary syndrome. In addition, we searched for eligible interventions that improved the metabolism of glucose and lipids. METHODS: We searched the PubMed, EMBASE, and Cochrane Central databases from inception to May 2018. Publication types that were categorized as randomized controlled trials met our inclusion criteria. The main outcome included the homeostasis model assessment of insulin resistance, total cholesterol, low-density lipoprotein cholesterol, and total triglycerides. We performed both a pairwise meta-analysis and a network meta-analysis to evaluate the mean difference value and 95% credibility intervals, and we calculated the surface cumulative rank curve. RESULTS: There were a total of 12 kinds of interventions: metformin, 2 mg cyproterone acetate plus 0.05 mg ethinylestradiol (EE/CA), 0.15 mg desogestrel plus 0.03 mg ethinylestradiol (EE/DSG), and 3 mg drospirenone plus 0.03 mg ethinylestradiol (EE/DRSP), lifestyle, exercise, diet, metformin + lifestyle, metformin + diet, EE/CA + lifestyle, metformin + EE/CA, and EE/DRSP + lifestyle from the 20 eligible RCTs that were included in this study. Our meta-analysis results showed that metformin + lifestyle (MD = -2.04, 95% CrI = -3.64 to -0.41), EE/CA + lifestyle (MD = -2.23, 95% CrI = -4.11 to -0.35), and EE/DRSP + lifestyle (MD = -2.59, 95% CrI = -4.66 to -0.50) resulted in lower in the levels of total cholesterol. Women treated with metformin + lifestyle (MD = -1.82, 95% CrI = -2.88 to -0.79), EE/CA + lifestyle (MD = -2.25, 95% CrI = -3.58 to -1.08), or EE/DRSP + lifestyle (MD = -2.29, 95% CrI = -3.69 to -1.07) exhibited significantly lower low-density lipoprotein cholesterol when compared with the placebo group. There was no significant difference between any of the interventions compared with a placebo in the levels of homeostasis model assessment of insulin resistance and total triglycerides. The surface cumulative rank curve revealed that metformin + lifestyle might be the best intervention with respect to the improvement of the homeostasis model of assessment insulin resistance and EE/DRSP + lifestyle appeared to be the best intervention for the reduction of total cholesterol and low-density lipoprotein cholesterol. Moreover, the metformin + diet intervention was more effective in reducing the level of total triglycerides. CONCLUSIONS: For overweight polycystic ovary syndrome patients, our evidence revealed that EE/CA and EE/SRSP combined with metformin or lifestyle changes can reduce the adverse effects on glucose and lipid metabolism of the use of oral contraceptive agents alone. Conventional PCOS treatments, such as metformin, EE/CA, and EE/DRSP, combined with lifestyle control can be particularly effective in improving the homeostasis model assessment of insulin resistance and lipid metabolism.