Diabetes mellitus (DM) is a complex metabolic disease with significant neurological complications and is reported to be closely related to the blood-brain barrier (BBB) disruption. Azilsartan is an antagonist of the Angiotensin II receptor developed for the treatment of hypertension, and it has been recently reported to have neuroprotective effects. The present study aims to investigate the protective effect of Azilsartan against hyperglycemia-induced BBB disruption and its underlying mechanism. Male db/db mice were treated with Azilsartan (20 μg/day) for 10 consecutive days. Compared to the control group, increased BBB permeability, suppressed occludin expression, excessive release of inflammatory factors, and downregulation of krüppel-like factor 2 (KLF2) were observed in diabetic mice, all of which were dramatically reversed by Azilsartan treatment. In the in vitro experiments, elevated endothelial permeability and decreased expression of occludin and KLF2 were observed in high glucose-challenged endothelial cells, which were significantly alleviated by Azilsartan. Lastly, the silencing of KLF2 abolished the protective effects of Azilsartan against the high glucose-induced expression of occludin and endothelial monolayer permeability in bEnd.3 brain endothelial cells. Based on these observations, we concluded that Azilsartan protected against hyperglycemia-induced hyperpermeability of BBB via the KLF2/occludin axis.Hydrazone is a bioactive pharmacophore that can be used to design antitumor agents. We synthesised a series of hydrazones (compounds 4-24) incorporating a 4-methylsulfonylbenzene scaffold and analysed their potential antitumor activity. Compounds 6, 9, 16, and 20 had the most antitumor activity with a positive cytotoxic effect (PCE) of 52/59, 27/59, 59/59, and 59/59, respectively, while compounds 5, 10, 14, 15, 18, and 19 had a moderate antitumor activity with a PCE of 11/59-14/59. Compound 20 was the most active and had a mean 50% cell growth inhibition (GI50) of 0.26 µM.  https://www.selleckchem.com/products/ipi-549.html  Compounds 9 and 20 showed the highest inhibitory activity against COX-2, with a half-maximal inhibitory concentration (IC50) of 2.97 and 6.94 μM, respectively. Compounds 16 and 20 significantly inhibited EGFR (IC50 = 0.2 and 0.19 μM, respectively) and HER2 (IC50 = 0.13 and 0.07 μM, respectively). Molecular docking studies of derivatives 9, 16, and 20 into the binding sites of COX-2, EGFR, and HER2 were carried out to explore the interaction mode and the structural requirements for antitumor activity.Serous ovarian cancer (SOC) is a main histological subtype of ovarian cancer, in which cancer stem cells (CSC) are responsible for its chemoresistance. However, the underlying modulation mechanisms of chemoresistance led by cancer stemness are still undefined. We aimed to investigate potential drug-response indicators among stemness-associated biomarkers in advanced SOC samples. The mRNA expression-based stemness index (mRNAsi) of The Cancer Genome Atlas (TCGA) was evaluated and corrected by tumor purity. Weighted gene co-expression network analysis (WGCNA) was utilized to explore the gene modules and key genes involved in stemness characteristics. We found that mRNAsi and corrected mRNAsi scores were both greater in tumors of Grade 3 and 4 than that of Grade 1 and 2. Forty-two key genes were obtained from the most significant mRNAsi-related gene module. Functional annotation revealed that these key genes were mainly involved in the mitotic division. Thirteen potential platinum-response indicators were selected from the genes enriched to platinum-response associated pathways. Among them, we identified 11 genes with prognostic value of progression-free survival (PFS) in advanced SOC patients treated with platinum and 7 prognostic genes in patients treated with a combination of platinum and taxol. The expressions of the 13 key genes were also validated between platinum-resistant and -sensitive SOC samples of advanced stages in two Gene Expression Omnibus (GEO) datasets. The results revealed that CDC20 was a potential platinum-sensitivity indicator in advanced SOC. These findings may provide a new insight for chemotherapies in advanced SOC patients clinically.Introduction Identifying patients at risk for chronic musculoskeletal pain can inform evaluation and treatment decisions. The ability of physical therapists to assess patients' risk for chronic pain without use of validated tools has been questioned. The Ӧrebro Musculoskeletal Pain Questionnaire (OMPQ) is used to determine risk for chronic pain.Methods The aim of this pragmatic study was to prospectively quantify the agreement between physical therapists' assessment of patients' risk for chronic symptoms compared to the OMPQ. Patients were asked to complete the OMPQ during the initial visit. Physical therapists, blinded to OMPQ risk classification, carried out their usual patient assessment procedures. The physical therapists rated patients as either high or low risk for chronic pain based on their clinical assessment. Agreement between therapist and OMPQ was determined using Cohen's Kappa (κ) and screening accuracy compared clinician risk to the OMPQ risk classification (reference standard) by way of contingency table analysis.Results Ninety-six (96) patients' risk classifications and 15 corresponding physical therapists' risk estimates were available for analysis. The OMPQ identified a 47% prevalence for high risk of chronic pain. Agreement (κ and 95% confidence interval) between physical therapist rating and OMPQ was slight, κ = 0.272 (0.033-0.421), p = .026. Therapists' sensitivity and specificity (95% CI) for determining risk classifications were 60.0% (44.3-74.3) and 62.8% (48.1-75.6), respectively. The positive and negative likelihood ratios (95% CI) were 1.61 (1.05-2.47) and 0.64 (0.42-0.97).Discussion The use of validated self-report questionnaires are recommended to supplement clinician prognosis for patients at risk of chronic musculoskeletal pain.Charge interactions play a critical role in the activation of the innate immune system by damage- and pathogen-associated molecular pattern receptors. The ability of these receptors to recognize a wide spectrum of ligands through a common mechanism is critical in host defense. In this article, we argue that platelet glycoprotein receptors that signal through conserved tyrosine-based motifs function as pattern recognition receptors (PRRs) for charged endogenous and exogenous ligands, including sulfated polysaccharides, charged proteins and nanoparticles. This is exemplified by GPVI, CLEC-2 and PEAR1 which are activated by a wide spectrum of endogenous and exogenous ligands, including diesel exhaust particles, sulfated polysaccharides and charged surfaces. We propose that this mechanism has evolved to drive rapid activation of platelets at sites of injury, but that under some conditions it can drive occlusive thrombosis, for example, when blood comes into contact with infectious agents or toxins. In this Opinion Article, we discuss mechanisms behind charge-mediated platelet activation and opportunities for designing nanoparticles and related agents such as dendrimers as novel antithrombotics.