Antiproliferative piperidine alkaloids from the leaves of Alocasia macrorrhiza.

Seventeen piperidine alkaloids, including 15 previously undescribed 2-substituted-6-(9-phenylnonyl)-piperidine-3,4-diol alkaloids and a previously undescribed 2-substituted-6-(9-phenylnonyl)-piperidine-3-ol alkaloid, were isolated from the leaves of Alocasia macrorrhiza (L.) Schott. Their planar structures and configurations were elucidated based on HR-ESI-MS, 1D and 2D NMR, Snatzke's method, modified Mosher method, single-crystal X-ray crystallography, as well as quantum chemical calculation. It was found that ΔδH5b-H5a can be used to elucidate the relative configuration of 2,3,4,6-tetrasubstituted piperidine, by analyzing the NMR data of 2-substituted-6-(9-phenylnonyl)-piperidine-3,4-diol. Antiproliferative activity was evaluated for all of the alkaloids, and compounds 6-8 showed considerable inhibitory activity against K562 cell line, with the IC50 values of 17.24 ± 1.62, 19.31 ± 0.9 and 18.77 ± 1.09µM, respectively. Furthermore, compounds 6 and 7 exerted an antiproliferative effect by inducing apoptosis.

Causal effect of beta-blockers on the risk of lung cancer: a Mendelian randomization study.

Background: It remains uncertain whether there is a causal association of the use of beta-blockers (BBs) on lung cancer risk. We used a two-sample Mendelian randomization (MR) approach to identify the causal association of BBs and lung cancer risk. Methods: Twenty-two BB-related single-nucleotide polymorphisms (SNPs) were obtained from the UK Biobank as the instrumental variables (IVs). Genetic summary data information of lung cancer was extracted from the International Lung Cancer Consortium, with a total of 11,348 cases and 15,861 controls. We adopted the inverse-variance weighted (IVW) approach to conduct the MR analyses. Egger-intercept analysis was further performed as sensitivity analysis for pleiotropy evaluation. Additionally, we investigated whether BBs could causally affect the risk of lung cancer through their pharmacological effects. Results: The current IVW analysis suggested a decreased lung cancer risk in BB users [odds ratio (OR) =0.83; 95% confidence interval (CI): 0.73-0.95; P<0.01]. Results of Egger-intercept analysis demonstrated that no pleiotropy was found (P=0.94), which suggested the robustness of the causality. However, there was little evidence that pharmacological effects mediate the association between BBs and lung cancer. Conclusions: The current analysis suggested that BBs could decrease the risk of lung cancer but may be not via its pharmacological effects. Further research is in need for elucidating the underlying mechanisms.

Pregnancy Status Is Associated with Lower Hemoglobin A1c among Nondiabetes Women in the United States from NHANES 2005-2016.

BACKGROUND: It has been verified that the incidence rate of diabetes mellitus (DM) is sharply increased in pregnant female adults. However, the relationship between pregnant status and hemoglobin A1c (HbA1c) in nondiabetes women remains unclear. METHODS: We conducted a cross-sectional study of 7762 participants in the National Health and Nutrition Examination Survey (NHANES) 2005-2016. Multivariable linear regression models were performed to evaluate the associations between pregnant status with HbA1c and serum glucose in nondiabetes women. RESULTS: HbA1c was significantly lower in the pregnant group than in the nonpregnant group. There was a negative association between urine pregnancy test and HbA1c in all three models (model 1: ß = -0.23, 95% CI: (-0.18 to -0.27); model 2: ß = -0.20, 95% CI: (-0.15 to -0.24); model 3: ß = -0.24, 95% CI: (-0.20 to -0.29)). In the subgroup analysis stratified by age, this negative association existed in all age subgroups (age <20: ß = -0.20, 95% CI: (-0.04 to -0.27); age ≥20, <35: ß = -0.24, 95% CI: (-0.20 to -0.29); age ≥35: ß = -0.28, 95% CI: (-0.17, -0.39)). In the subgroup analysis stratified by race, the negative associations steadily existed in different subgroups (Mexican American:ß = -0.20, 95% CI:(-0.11 to -0.29); Other Hispanic:ß = -0.31, 95% CI: (-0.16 to -0.46); Non-Hispanic White: ß = -0.24, 95% CI: (-0.17 to -0.31); Non-Hispanic Black: ß = -0.21, 95% CI: (-0.12 to -0.31); Other races:ß = -0.22, 95% CI: (-0.08 to -0.35)). On the other hand, a negative association between self-reported pregnant status and HbA1c was also found (model 1: ß = -0.22, 95% CI: (-0.18 to -0.27); model 2: ß = -0.19, 95% CI: (-0.15 to -0.2); model 3: ß = -0.23, 95% CI: (-0.19 to -0.28)). In the subgroup analysis stratified by age, this negative association also existed in all age subgroups. CONCLUSIONS: The study indicated that nondiabetes women with pregnant status had significantly lower HbA1c compared with those nonpregnant. Moreover, the negative associations between pregnant status and HbA1c steadily existed in subgroups stratified by age and gender.

Design, Synthesis, and Biological Evaluation of Membrane-Active Bakuchiol Derivatives as Effective Broad-Spectrum Antibacterial Agents.

Infections caused by drug-resistant bacteria seriously endanger human health and global public health. Therefore, it is urgent to discover and develop novel antimicrobial agents to combat multidrug-resistant bacteria. In this study, we designed and synthesized a series of new membrane-active bakuchiol derivatives by biomimicking the structure and function of cationic antibacterial peptides. The most promising compound 28 displayed potent antibacterial activity against both Gram-positive bacteria (minimum inhibitory concentration, MIC = 1.56-3.125 µg/mL) and Gram-negative bacteria (MIC = 3.125 µg/mL), very weak hemolytic activity, and low cytotoxicity. Compound 28 had rapid bactericidal properties and avoided bacterial resistance. More importantly, compound 28 showed strong in vivo antibacterial efficacy against Staphylococcus aureus and Pseudomonas aeruginosa in murine corneal infection models. This design strategy is expected to provide an effective solution to the antibiotic crisis.

Development of Highly Potent Carbazole Amphiphiles as Membrane-Targeting Antimicrobials for Treating Gram-Positive Bacterial Infections.

The development of new antimicrobial agents capable of curing drug-resistant bacteria-induced infections is becoming a major challenge to the global healthcare system. To develop antimicrobials with new molecular entities, a series of novel carbazole-based compounds were designed and synthesized by biomimicking the structural properties and biological function of antimicrobial peptides. Compound 29 was selected as a lead compound from the structure-activity relationship analyses and biological activity evaluation. Compound 29 showed excellent antimicrobial activity against Gram-positive bacteria (MICs = 0.78-1.56 µg/mL), poor hemolytic activity (HC50 > 200 µg/mL), and low cytotoxicity to mammalian cells. Compound 29 had fast bactericidal properties and effectively prevented bacterial resistance in laboratory simulations. Antibacterial mechanism studies revealed that compound 29 directly destroyed bacterial cell membranes, leading to bacterial deaths. Importantly, compound 29 displayed an excellent efficacy in a murine bacterial keratitis model caused by Staphylococcus aureus ATCC29213.