Nonalcoholic Fatty Liver Disease (NAFLD) is the most common chronic liver disease in the world, which is characterized by liver fat accumulation unrelated to excessive drinking. Indeed, it attracts growing attention and becomes a global health problem. Due to the complexity of the NAFLD pathogenic mechanism, no related drugs were approved by Food and Drug Administration (FDA) till now. However, it is encouraging that a series of candidate drugs have entered the clinical trial stage with expectation to treat NAFLD. In this review, we summarized the main pathways and pathogenic mechanisms of NAFLD, as well as introduced the main potential therapeutic targets and the corresponding compounds involved in metabolism, inflammation and fibrosis. Furthermore, we also discuss the progress of these compounds, such as drug design and optimization, the choice of pharmacological properties and druglikeness, and the analysis of structure-activity relationship. This review offers a medium on future drug design and development, to be beneficial to relevant studies. Inhibition of tubulin polymerisation with small molecules has been clinically validated as a promising therapy for multiple solid tumours. Herein, a series of chiral azetidin-2-ones were asymmetrically synthesised and biologically evaluated for antitumour activities. Among them, a chiral fluorinated azetidin-2-one, 18, was found to exhibit the most potent activities against five cancer cell lines, including a drug-resistant cell line, with IC50 values ranging from 1.0 to 3.6 nM. Further mechanistic studies revealed that the compound 18 worked by disrupting tubulin polymerisation, blocking the cell cycle in the G2/M phase, inducing cellular apoptosis, and suppressing angiogenesis. Additionally, 18 exhibited higher human-microsomal metabolic stability and aqueous solubility compared to those of combretastatin A-4. Finally, 18 was also found to effectively inhibit tumour growth in a xenograft mice model with low toxicity and thus might be a promising lead for further clinical development. A series of novel isocombretapyridines were designed and synthesized based on a lead compound isocombretastatin A-4 (isoCA-4) by replacing 3,4,5-trimethoxylphenyl with substituent pyridine nucleus. The MTT assay results showed that compound 20a possessed the most potent activities against all tested cell lines with IC50 values at nanomolar concentration ranges. Moreover, 20a inhibited tubulin polymerization at a micromolar level and also displayed potent anti-vascular activity in vitro. Further mechanistic studies were conducted to demonstrate that compound 20a could bind to the colchicine site of tubulin,and disrupte the cell microtubule networks, induce G2/M phase arrest, promote apoptosis and depolarize mitochondria of K562 cells in a dose-dependent manner. Notably, 20a exhibited more potent tumor growth inhibition activity with 68.7% tumor growth inhibition than that of isoCA-4 in H22 allograft mouse model without apparent toxicity. The present results suggested that compound 20a may serve as a promising potent microtubule-destabilizing agent candidate for the development of therapeutics to treat cancer. Crown All rights reserved.The potential adverse health effects of acrylamide have drawn worldwide attention and the World Health Organization has urged further urgent studies on its health threat. Herein we explored the exposure-response relationship and underlying mechanism between internal acrylamide exposure and heart rate variability (HRV) alteration, a marker of cardiac autonomic dysfunction. We measured six HRV indices and two urinary acrylamide metabolites (N-Acetyl-S-(2-carbamoylethyl)-l-cysteine, AAMA; N-Acetyl-S-(2-carbamoyl-2-hydroxyethyl)-l-cysteine, GAMA) for 2997 general Chinese adults from the Wuhan-Zhuhai cohort, of whom 2414 had data on plasma transforming growth factor-β1 (TGF-β1). The associations among urinary acrylamide metabolites, HRV and TGF-β1 were evaluated by linear mixed models and restricted cubic spline models. The mediating role of TGF-β1 was investigated by conducting mediation analysis. We found significantly negative dose-response relationships of all urinary acrylamide metabolites and TGF-β1 with all six HRV indices after adjusting for potential confounders (all P  0.05) was positively and dose-dependently associated with TGF-β1, which in turn significantly mediated 5.71-7.41 % of the GAMA-associated HRV reduction. Our findings suggest for the first time that daily exposure of general population to acrylamide is associated with cardiac autonomic dysfunction, where a mechanism involving TGF-β pathway may be involved. OBJECTIVES Nursing and healthcare-associated pneumonia (NHCAP) was proposed by the Japanese Respiratory Society to refer to healthcare-associated pneumonia. This study aimed to investigate whether antipseudomonal antibiotic therapy improved the prognosis of NHCAP patients at high risk for antimicrobial-resistant pathogens. METHODS Consecutive hospitalised NHCAP patients in Kurashiki Central Hospital between October 2010 and December 2016 were prospectively enrolled. NHCAP patients who were at high risk for antimicrobial-resistance were defined as those who received antimicrobials in the preceding 90 days and/or were on tube feeding. The patients who received antipseudomonal antibiotics were defined as the guideline-concordant therapy (GC) group, and the others as the guideline-discordant therapy (GD) group. The primary outcome was 30-day mortality. Inverse probability of treatment weighting (IPTW) analysis was used to reduce biases. RESULTS There were 277 patients with NHCAP; a majority (78.0%) were discharged from a hospital in the preceding 90 days. There were 52 patients in the GC group and 225 patients in the GD group. The 30-day mortality rate was significantly higher in the GC group than in the GD group (17.3%, 9/52 vs. 7.1%, 16/225;P =  0.03). After IPTW analysis, the GC therapy, compared with GD therapy, did not improve the 30-day mortality (OR 1.71, 95% CI 0.65-4.47, P =  0.28). CONCLUSIONS Not all NHCAP patients, even those at high risk for antimicrobial resistance, need antipseudomonal antimicrobial treatment. The treatment strategy for NHCAP patients should be individualised, according to the pneumonia severity, risk for antimicrobial-resistant pathogens, and antibiogram in each hospital.  https://www.selleckchem.com/products/azd-5462.html