Ulcerative colitis (UC) is an idiopathic, chronic inflammatory disorder of the colon, and it has become one of the world-recognized medical problems as it is recurrent and refractory. Berberine (BBR) is an effective drug for UC treatment. However, the underlying mechanism and targets remain obscure. In this study, we systematically investigated the therapeutic effect and its mechanism of BBR in ameliorating DSS-induced mouse colitis. Expectedly, the colon inflammation was significantly relieved by BBR, and microbiota depletion by antibiotic cocktail significantly reversed the therapeutic effect. Further studies showed that BBR can regulate the abundance and component of bacteria, reestablish the broken chemical and epithelial barriers. Meanwhile, BBR administration dramatically decreased ILC1 and Th17 cells, and increased Tregs as well as ILC3 in colonic tissue of DSS-induced mice, and it was able to regulate the expression of various immune factors at the mRNA level. Moreover, a proteomic study revealed that Wnt/β-catenin pathway was remarkably enhanced in colonic tissue of BBR-treated mice, and the therapeutic effect of BBR was disappeared after the intervention of Wnt pathway inhibitor FH535. These results substantially revealed that BBR restores DSS-induced colon inflammation in a microbiota-dependent manner, and BBR performs its protective roles in colon by maintaining the structure and function of the intestinal mucosal barrier, regulating the intestinal mucosal immune homeostasis and it works through the Wnt/β-catenin pathway. Importantly, these findings also provided the proof that BBR serves as a potential gut microbiota modulator and mucosal barrier protector for UC prevention and therapy.
Background: Andrographolide (Andro) is an active compound extracted from Andrographis, which has protective anti-inflammatory effects. But, its pathological role in coronary heart disease (CHD) is unclear, the aim of this study is to investigate the therapeutic effect of Andro in CHD and explore its potential mechanism.Methods: Here, we established a mouse model of CHD, and rats were randomly divided into 5 groups (n=10): sham, Andro (50 mg/kg), CHD, CHD + Andro (10 mg/kg), and CHD + Andro (50 mg/kg). HE staining was employed to evaluate the pathological changes of myocardial injury cardiac injury. The serum levels of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), highdensity lipoprotein cholesterol (HDL-C), nitric oxide (NO), TXA2, ET-1, and prostaglandin I2 (PGI2) were detected by ELISA assay. Myocardial inflammation and the interaction between Andro and PPAR-α/NF-κB axis was measured using western blot.Results: Compared with CHD groups, Andro preserved cardiac injury and decreased the levels of TC, TG, and LDL-C while increasing the level of HDL-C. In addition, Andro also reduced the levels of TNF-α, MCP-1, hs-CRP and IL-1β by shifting the macrophage phenotype and attenuated the endothelial dysfunction by increasing the serum levels of ET-1 and TAX2 and decreasing the levels of NO and PGI2 in mice. Furthermore, Andro impeded cardiac apoptosis and inhibited the activation of PPARα and NF-κB proteins.Conclusions: Andro may represent a medicinal approach for assessing and treating CHD.
Aims Navoximod (GDC‐0919, NLG‐919) is a small molecule inhibitor of indoleamine‐2,3‐dioxygenase 1 (IDO1), developed to treat the acquired immune tolerance associated with cancer. The primary objectives of this study were to assess navoximod's absolute bioavailability (aBA), determine the mass balance and routes of elimination of [14C]‐navoximod, and characterize navoximod's metabolite profile. Methods A phase 1, open‐label, two‐part study was conducted in healthy volunteers. In Part 1 (aBA), subjects (n = 16) were randomized to receive oral (200 mg tablet) or intravenous (5 mg solution) navoximod in a crossover design with a 5‐day washout. In Part 2 (mass balance), subjects (n = 8) were administered [14C]‐navoximod (200 mg/600 μCi) as an oral solution. Results The aBA of navoximod was estimated to be 55.5%, with a geometric mean (%CV) plasma clearance and volume of distribution of 62.0 L/h (21.0%) and 1120 L (28.4%), respectively. Mean recovery of total radioactivity was 87.8%, with 80.4% detected in urine and the remainder (7.4%) in faeces. Navoximod was extensively metabolized, with unchanged navoximod representing 5.45% of the dose recovered in the urine and faeces. Glucuronidation was identified as the primary route of metabolism, with the major glucuronide metabolite, M28, accounting for 57.5% of the total drug‐derived exposure and 59.7% of the administered dose recovered in urine. Conclusions Navoximod was well tolerated, quickly absorbed and showed moderate bioavailability, with minimal recovery of the dose as unchanged parent in the urine and faeces. Metabolism was identified as the primary route of clearance and navoximod glucuronide (M28) was the most abundant metabolite in circulation with all other metabolites accounting for <10% of drug‐related exposure.
Etrolizumab is an IgG1‐humanized monoclonal antibody that specifically targets the β7 subunit of α4β7 and α4Eβ7 integrins, and it has been evaluated for the treatment of moderately‐to‐severely active ulcerative colitis (UC). Population pharmacokinetic (PK) analysis was performed to characterize etrolizumab PK properties in patients with moderately‐to‐severely active UC and evaluate covariate impacts on exposure. The population PK model was developed based on etrolizumab serum concentrations from patients with moderately‐to‐severely active UC enrolled in six studies (one phase I, one phase II, and four phase III) and validated using another phase III clinical trial. Stepwise covariate modeling was used to evaluate the impact of 23 prespecified covariates. Etrolizumab PK was best described by a two‐compartment model with first‐order absorption, with clearance decreasing over time. Population typical values were 0.260 L/day for clearance (CL) during the first dosing internal, 2.61 L for central volume, 71.2% for bioavailability, and 0.193/day for absorption rate. CL reduced over the study duration, the typical maximum reduction was 26% with an onset half‐life of 4.8 weeks. Consequently, the predicted mean terminal half‐life was shorter after a single dose (13.0 days) compared to that at steady‐state (17.1 days). Baseline body weight and albumin were the most impactful covariates for etrolizumab exposure. Final population PK model well characterized the PK properties of etrolizumab in patients with moderately‐to‐severely active UC and identified influential covariate effects.
Cryptotanshinone (CTS), an active component extracted from the root of Salvia miltiorrhiza Bunge, was reported to attenuate hepatic ischemia/reperfusion (I/R) injury. However, its protective effect against renal I/R injury remains unclear. In this study, the role of CTS in renal I/R injury in vitro and its possible mechanism were investigated. Our results showed that CTS improved cell viability in HK-2 cells exposed to hypoxia/reoxygenation (H/R). CTS also inhibited the H/Rmediated production of reactive oxygen species, as well as increased the activities of superoxide dismutase and catalase in H/R-stimulated HK-2 cells. In addition, CTS dramatically attenuated the induction of bax expression and caspase-3 activity and alleviated the reduction of bcl-2 expression in HK-2 cells cultured with H/R. Furthermore, CTS activated the levels of p-PI3K and p-Akt in H/R-injured HK-2 cells; meanwhile, the renal protective activity of CTS was inhibited by the inhibitor of the (phosphatidylinositol 3 kinase/protein kinase B) PI3K/Akt pathway (LY294002). These findings indicate that CTS can ameliorate renal I/R injury in vitro partly through regulating the PI3K/Akt pathway. K E Y W O R D S acute kidney injury, cryptotanshinone, hypoxia/reoxygenation, ischemia/reperfusion injury, oxidative stress J Cell Biochem. 2019;120:13354-13360. wileyonlinelibrary.com/journal/jcb 13354 |
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