The causal relationship between anti-diabetic drugs and gastrointestinal disorders: a drug-targeted mendelian randomization study.

BACKGROUND: The incidence of diabetic gastrointestinal diseases is increasing year by year. This study aimed to investigate the causal relationship between antidiabetic medications and gastrointestinal disorders, with the goal of reducing the incidence of diabetes-related gastrointestinal diseases and exploring the potential repurposing of antidiabetic drugs. METHODS: We employed a two-sample Mendelian randomization (TSMR) design to investigate the causal association between antidiabetic medications and gastrointestinal disorders, including gastroesophageal reflux disease (GERD), gastric ulcer (GU), chronic gastritis, acute gastritis, Helicobacter pylori infection, gastric cancer (GC), functional dyspepsia (FD), irritable bowel syndrome (IBS), ulcerative colitis (UC), Crohn's disease (CD), diverticulosis, and colorectal cancer (CRC). To identify potential inhibitors of antidiabetic drug targets, we collected single-nucleotide polymorphisms (SNPs) associated with metformin, GLP-1 receptor agonists, SGLT2 inhibitors, DPP-4 inhibitors, insulin, and its analogs, thiazolidinediones, sulfonylureas, and alpha-glucosidase inhibitors from published genome-wide association study statistics. We then conducted a drug-target Mendelian randomization (MR) analysis using inverse variance weighting (IVW) as the primary analytical method to assess the impact of these inhibitors on gastrointestinal disorders. Additionally, diabetes was selected as a positive control. RESULTS: Sulfonylureas were found to significantly reduce the risk of CD (IVW: OR [95% CI] = 0.986 [0.978, 0.995], p = 1.99 × 10- 3), GERD (IVW: OR [95% CI] = 0.649 [0.452, 0.932], p = 1.90 × 10- 2), and chronic gastritis (IVW: OR [95% CI] = 0.991 [0.982, 0.999], p = 4.50 × 10- 2). However, they were associated with an increased risk of GU development (IVW: OR [95%CI] = 2 0.761 [1.259, 6.057], p = 1 0.12 × 10- 2). CONCLUSIONS: The results indicated that sulfonylureas had a positive effect on the prevention of CD, GERD, and chronic gastritis but a negative effect on the development of gastric ulcers. However, our research found no causal evidence for the impact of metformin, GLP-1 agonists, SGLT2 inhibitors, DPP 4 inhibitors, insulin and its analogs, thiazolidinediones, or alpha-glucosidase inhibitors on gastrointestinal diseases.

Cathepsins and cancer risk: a Mendelian randomization study.

Background: Previous observational epidemiological studies reported an association between cathepsins and cancer, however, a causal relationship is uncertain. This study evaluated the causal relationship between cathepsins and cancer using Mendelian randomization (MR) analysis. Methods: We used publicly available genome-wide association study (GWAS) data for bidirectional MR analysis. Inverse variance weighting (IVW) was used as the primary MR method of MR analysis. Results: After correction for the False Discovery Rate (FDR), two cathepsins were found to be significantly associated with cancer risk: cathepsin H (CTSH) levels increased the risk of lung cancer (OR = 1.070, 95% CI = 1.027-1.114, P = 0.001, PFDR = 0.009), and CTSH levels decreased the risk of basal cell carcinoma (OR = 0.947, 95% CI = 0.919-0.975, P = 0.0002, P FDR = 0.002). In addition, there was no statistically significant effect of the 20 cancers on the nine cathepsins. Some unadjusted low P-value phenotypes are worth mentioning, including a positive correlation between cathepsin O (CTSO) and breast cancer (OR = 1.012, 95% CI = 1.001-1.025, P = 0.041), cathepsin S (CTSS) and pharyngeal cancer (OR = 1.017, 95% CI = 1.001-1.034, P = 0.043), and CTSS and endometrial cancer (OR = 1.055, 95% CI = 1.012-1.101, P = 0.012); and there was a negative correlation between cathepsin Z and ovarian cancer (CTSZ) (OR = 0.970, 95% CI = 0.949-0.991, P = 0.006), CTSS and prostate cancer (OR = 0.947, 95% CI = 0.902-0.944, P = 0.028), and cathepsin E (CTSE) and pancreatic cancer (OR = 0.963, 95% CI = 0.938-0.990, P = 0.006). Conclusion: Our MR analyses showed a causal relationship between cathepsins and cancers and may help provide new insights for further mechanistic and clinical studies of cathepsin-mediated cancer.

Genetic causality and site-specific relationship between sarcopenia and osteoarthritis: a bidirectional Mendelian randomization study.

Background: Previous studies demonstrated a controversial relationship between sarcopenia (SP) and osteoarthritis (OA) and their genetic causality is unclear. Thus, we conducted a Mendelian randomization (MR) analysis to evaluate the possible causal association between sarcopenia-related traits (appendicular lean mass (ALM), grip strength, usual walking pace) and OA. Method: We used pooled genetic data from the UK Biobank for ALM(n = 450,243), left-hand grip strength (n = 461,026), right-hand grip strength (n = 461,089) and usual walking pace (n = 459,915). Moreover, summary statistics for OA were obtained from the latest study conducted by the Genetics of Osteoarthritis Consortium, including all OA (n = 826,690), hand OA (n = 303,7782), hip OA (n = 353,388) and knee OA (n = 396,054). The primary method for estimating causal effects was the inverse-variance weighted (IVW) method, with the utilizing of false discovery rate adjusted p values (P FDR). Additional MR methods such as MR-Egger regression, MR pleiotropy residual sum and outlier (MR-PRESSO), weighted median were employed as supplementary analyses. Results: We discovered ALM (odds ratio (OR) = 1.103, 95% confidence interval (CI) = 1.052-1.156, P FDR = 2.87E-04), hand grip strength (left, IVW OR = 0.823, 95% CI = 0.712 to 0.952, P FDR = 0.020; right, OR = 0.826, 95% CI = 0.718 to 0.950, P FDR = 0.020), and usual walking pace (OR = 0.339, 95% CI = 0.204 to 0.564, P FDR = 2.38E-04) were causally associated with OA risk. In the reverse MR analysis, we identified a causal effect of OA on ALM (ß = -0.258, 95% CI = -0.369 to 0.146, P FDR = 0.6.07E-06), grip strength (left, ß = -0.064, 95% CI = -0.104 to 0.024, P FDR = 0.002; right, ß = -0.055, 95% CI = -0.095 to 0.014, P FDR = 0.008), and usual walking pace (ß = -0.104, 95% CI = -0.147 to 0.061, P FDR = 1.61E-05). Conclusion: This present study suggests an obvious causality of SP on OA, with condition exhibiting site-specific effects, while evidence was also provided for the causal effect of OA on SP.

DBU-Catalyzed Aerobic CDC Reaction of Thiophenols.

A convenient method was developed for the preparation of thiolated compounds via a DBU-catalyzed aerobic cross-dehydrogenative coupling (CDC) reaction. The established protocol is environmentally friendly and operationally simple. Substrates like (hetero)aryl acetates, (hetero)aryl ketones, and indoles could be transformed into the corresponding thiolated products in moderate to high yields and further applied in the preparation of bioactive compounds in a prefunctionalization-free manner.

Synthesis and antibiofilm evaluation of N-acyl-2-aminopyrimidine derivatives against Acinetobacter baumannii.

The overuse of antibiotics will led to the increase of drug resistance. Especially, the multidrug-resistant A. baumannii became the leading cause of nosocomial infections with high rates of morbimortality. The drug resistance of A. baumannii is greatly attributed to its biofilm. To alleviate the burden of drug resistance, the anti-virulence signaling strategies was developed. By specifically interfering with the ability of the bacteria to recognize host signals that are needed to establish infection, the bacteria are less able to colonize the host. In this paper, 39 N-acyl-2-aminopyrimidine derivatives were synthesized and tested for their biofilm inhibition efficacy. The screening results reveal that some of the analogues (3ac, 8d) efficiently inhibited the biofilm formation of A. baumannii (IC50 as low as 3.8 µM), and the biofilm inhibition ability was further demonstrated with laser confocal results and extracellular polysaccharides inhibition test. Further motility test reveals our compounds are quorum sensing inhibitors. Besides, the synergistic effect of compounds 3ac and 8d with different antibiotics suggest its potential clinical significance, which was further enhanced by the long time biofilm inhibition test after coating with PLGA. Finally, we also look into the safety of the compounds with cytotoxicity assay.

Enantioselective amination of 4-alkylisoquinoline-1,3(2H,4H)-dione derivatives.

A mild and efficient enantioselective amination of 4-alkylisoquinoline-1,3(2H,4H)-dione derivatives was established, which is compatible with a broad range of substrates and delivers the final products in excellent yields (up to 99%) and ee values (up to 99%) with low catalyst loading (down to 1 mol%). The synthetic potential of this methodology was also demonstrated in the gram scale level.