Background: Semaglutide, a newly once-weekly glucagon like peptide-1 (GLP-1) receptor agonist, has showed a favorable effect on glycaemic control and weight reduction in type 2 diabetes mellitus (T2DM). This meta-analysis was conducted to evaluate the clinical efficacy and safety of semaglutide in T2DM. Methods: A comprehensive searching was performed for Phase III randomized controlled trials (RCTs) which reported the efficacy and safety data of semaglutide and other therapies. The efficacy data expressed as weight mean difference (WMD) and the safety data expressed as risk ratios (RRs) were calculated by employing random-effects model. Heterogeneity was assessed through I² test, and subgroup analyses were performed by different control groups, dosage of semaglutide, and durations of follow up. Results: 9 RCTs including 9,773 subjects met the inclusion criteria. For efficacy, compared with other therapies, semaglutide resulted in a significant reduction in glycosylated hemoglobin (weight mean difference, WMD: −0.93%, 95% CI: −1.24 to −0.62, P < 0.001), fasting plasma glucose (WMD: −1.15 mmol/L, 95% CI: −1.67 to −0.63, P < 0.001), mean self-monitoring of plasma glucose (WMD: −1.19 mmol/L, 95% CI: −1.68 to −0.70, P < 0.001), body weight (WMD: –3.47 kg, 95% CI: −3.96 to −2.98, P < 0.001), body mass index (WMD: –1.25 kg/m², 95% CI: −1.45 to −1.04, P < 0.001), systolic blood pressure (WMD: −2.55 mmHg, 95% CI: −3.22 to −1.88, P < 0.001), with the exception of negative result of diastolic blood pressure (WMD: −0.29 mmHg, 95% CI: −0.65 to 0.07, P = 0.113) and increased impact on pulse rate (WMD: −2.21, 95% CI: 1.54 to 2.88, P < 0.001). The results were consistent across the key subgroups. For safety, semaglutide did not increase the risk of any adverse events, hypoglycemia and pancreatitis, but induced a higher risk of gastrointestinal disorders when compared with other therapies (RR: 1.98, 95%CI: 1.49 to 2.62, P < 0.001). Conclusion: Semaglutide was effective and acceptable in patients with T2DM except for a high risk of gastrointestinal disorders. The capacity of glycaemic and body weight control of semaglutide appeared more effective than other add-on therapies including other GLP-1 receptor agonists of exenatide release and dulaglutide.

H(+)/K(+)-ATPase is a P-type ATP-driven cation transporter which exchanges ions (protons, chloride ions, and potassium ions) across the cell membrane. Modulators of H(+)/K(+)-ATPase affect H(+)/K(+) exchange. This article describes various H(+)/K(+)-ATPase inhibitors of biological importance in clinical studies and drug development for gastric acid-related diseases and gastrointestinal disorders. H(+)/K(+)-ATPase modulators have attracted much interest for their clinical implication in gastric acid-related diseases. Future studies of gastric H(+)/K(+)-ATPase inhibitors may focus on the correlation of pharmacogenetics and pharmacogenomics with the gastric acid secretion and development of more effective H(+)/K(+)-ATPase inhibitors to increase their residence time such as tenatoprazole and novel chemical-mediated absorption chemicals. The K(+)-competitive acid pump antagonists (APAs) are invented and independent of an acidic environment with better inhibition of the pump rapidly control acid secretion with a larger extent. The most innovative and promising compounds of APAs is AZD-0865, which is a modification of SCH28080. H(+)/K(+)-ATPase inhibitors can be tried to treat other diseases, especially viral infection after numerous clinical trials, and respiratory disease.

Multidrug resistance (MDR) is a great challenge and obstacle in cancer treatment. It is a common problem in the treatment of acute myeloid leukemia (AML). Whether grape seed proanthocyanidin extract (GSPE) could reverse MDR in patients with AML is still unknown. The aim of this study was to investigate the MDR reverse ability of GSPE and its possible mechanism in vitro. Human leukemia cell line HL-60 cells and HL-ADR cells were used. MTT assay were employed to identify the cytotoxic effects of different chemotherapeutic drugs and reverse ability of GSPE. Flow cytometry assays were used to verify the cell apoptosis induced by GSPE. MDR-related genes expression was tested by real-time polymerase chain reaction (Q-PCR). MDR-related protein expression was assessed by Western blotting assays. The genes and their related protein expression of multidrug resistance-associated protein 1 (MRP1), multidrug resistance protein 1 (MDR1) and lung resistance-related protein (LRP) were tested in this study. We found that HL-60/ADR cells were resistant to a variety of chemotherapeutic drugs, including cytarabine (Ara-C), adriamycin (ADR), vincristine (VCR), daunorubicin (DNR), mitoxantrone (MTZ), pirarubicin (THP), homoharringtonine (HHT) and etoposide (VP16). Co-treatment with GSPE could significant lower the IC₅₀ of Ara-C and ADR in HL-60/ADR cells (P < 0.01). MDR related mRNA and their protein expression of MRP1 and MDR1 were significant highly expressed in HL-60/ADR cells than HL-60 cells (P < 0.01). But only protein expression of LRP was higher in HL-60/ADR cells than HL-60 cells (P < 0.05). GSPE could induce a higher intracellular level of ADR in HL-60/ADR cells. It could also inhibit Akt phosphorylation resulted in the down regulation of MRP1, MDR1 and LRP and induce cell apoptosis. 25.0 μg/mL GSPE significant inhibited the Akt phosphorylation (P < 0.05). GSPE-reversed MDR of HL-60/ADR cells might be associated with the inhibition of the PI3K/Akt signaling pathway, which resulted in the down-regulation the expression of MRP1, MDR1 and LRP. These results provide that GSPE may serve as a combination therapy in AML chemotherapy for future study.

Introduction: The α₄β₇ integrin is heterodimeric cell surface receptors expressed on most leukocytes. Mucosal addressing cell adhesion molecule 1(MAdCAM-1) is an exclusive ligand for α₄β₇ integrin. Areas covered: This article will highlight the progress that has been made in the discovery and development of α₄β₇ integrin inhibitors, and their use in the treatment of inflammatory bowel diseases, multiple sclerosis, asthma, hepatic disorders, human immunodeficiency virus, allergic conjunctivitis and type 1 diabetes. Expert opinion: α₄β₇ integrin inhibitors have attracted much interest for their clinical implication. Natalizumab and Vedolizumab are monoclonal antibodies (mAbs) successfully utilized clinically. Natalizumab is a mAbs of α₄-subunit blocking both α₄β₁ and α₄β₇ integrin. Vedolizumab selectively targets the α₄β₇ integrin. Several mAbs are still in the process of research and development. Among these mAbs, etrolizumab selectively against the β₇-subunit and AMG-181 specifically against the α₄β₇ integrin are the most promising anti-α₄β₇ integrin antibodies. Despite the unclear development stage of TR-14035 and R411, several low molecular compounds show bright future of further development, such as AJM300 and CDP323. In addition, results from laboratory data show that peptide inhibitors, such as peptide X, are effective α₄β₇ integrin inhibitors.

Background: Whereas the cardiovascular safety of sodium-glucose co-transporter 2 (SGLT2) inhibitors has been well reported, there is limited data from controlled clinical trials regarding the non-cardiovascular safety. This was the focus of our study. Methods and Findings: We systematically searched MEDLINE, EMBASE, and Cochrane Library (5^th Sep 2018) for randomized controlled trials (RCTs) that reported safety data for SGLT2 inhibitors and placebo. Relative risks (RRs) and their 95% confidence intervals (CIs) were pooled using random-effects models. Seventy RCTs (83 studies enrolling 36,958 patients in 78 publications) were identified. SGLT2 inhibitors were associated with a lower risk of serious adverse events (RR 0.90, 95% CI 0.86 to 0.94, P < 0.001), death (RR 0.78, 95% CI 0.64 to 0.94, P < 0.05), gastroenteritis (RR 0.38, 95% CI 0.20 to 0.72, P < 0.05), arthralgia (RR 0.72, 95% CI 0.54 to 0.96, P < 0.05), hypertension (RR 0.61, 95% CI 0.50 to 0.75, P < 0.001), and edema/peripheral edema (RR 0.49, 95% CI 0.33 to 0.72, P < 0.001) compared to placebo. SGLT2 inhibitors were associated with higher risk of infections compared to placebo (RR 1.27, 95% CI 1.17 to 1.37, P < 0.001), especially for genital mycotic infection (GMI) (RR 3.71, 95% CI 3.19 to 4.32, P < 0.001). Other significant effects were observed for osmotic diuresis–related AEs (RR 2.73, 95% CI 2.20 to 3.40, P < 0.001), volume-related AEs (RR 1.26, 95% CI 1.08 to 1.46, P < 0.05), renal-related AEs (RR 1.36, 95% CI 1.02 to 1.80, P < 0.05), hypoglycemia (RR 1.18, 95% CI 1.10 to 1.26, P < 0.001), and increased blood ketone bodies (RR 2.00, 95% CI 1.01 to 3.97, P < 0.05). Subgroup and sensitivity analyses strengthened the robustness of primary results. Conclusion: Results from RCTs confirmed lower risk of death, serious adverse events, hypertension, and edema associated with type 2 diabetes mellitus (T2DM) patients treated with SGLT2 inhibitors when compared with placebo. The use of SGLT2 inhibitors were associated with higher risk of infection, osmotic diuresis, volume depletion effects, renal related AEs, and higher blood ketone bodies when compared with placebo.

CircRNAs (circRNAs) are commonly dysregulated in a variety of human diseases and are involved in the development and progression of cancer. However, the role of circRNAs in hepatic fibrosis (HF) is still unclear. Our previous high throughput screen revealed changes in many circRNAs in mice with carbon tetrachloride (CCl4)-induced HF. For example, circCREBBP was significantly down-regulated in primary hepatic stellate cells (HSCs) and liver tissue of HF mice induced by CCl4 compared to those in the vehicle group. Overexpression of circCREBBP with AAV8-circCREBBP in vivo prevented CCl4-induced HF worsening by reducing serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) contents, liver hydroxyproline levels, collagen deposition, and levels of pro-fibrosis genes and pro-inflammatory cytokines. Furthermore, in vitro function loss and function gain analysis showed that circCREBBP inhibited HSCs activation and proliferation. Mechanically, circCREBBP acts as a sponge for hsa-miR-1291 and subsequently promotes LEFTY2 expression. In conclusion, our current results reveal a novel mechanism by which circCREBBP alleviates liver fibrosis by targeting the hsa-miR-1291/LEFTY2 axis, and also suggest that circCREBBP may be a potential biomarker for heart failure.