A total of seven novel benzimidazoles were synthesized by a 4-step reaction starting from 4-fluoro-3-nitrobenzoic acid under relatively mild reaction conditions. The synthesized compounds were screened for their antimycobacterial activity against M. tuberculosis H₃₇Rv (MTB-H₃₇Rv) and INH-resistant M. tuberculosis (INHR-MTB) strains using agar dilution method. Three of them displayed good activity with MIC of less than 0.2 μM. Compound ethyl 1-(2-(4-(4-(ethoxycarbonyl)-2-aminophenyl)piperazin-1-yl)ethyl)-2-(4-(5-(4-fluorophenyl)pyridin-3-ylphenyl-1H-benzo[d]imidazole-5-carboxylate (5 g) was found to be the most active with MIC of 0.112 μM against MTB-H₃₇Rv and 6.12 μM against INHR-MTB, respectively.
The significance of protein S-palmitoylation in angiogenesis has been largely overlooked, leaving various aspects unexplored. Recent identification of Gpx1 as a palmitoylated protein has generated interest in exploring its potential involvement in novel pathological mechanisms related to angiogenesis. In this study, we demonstrate that Gpx1 undergoes palmitoylation at cysteine-76 and -113, with PPT1 playing a crucial role in modulating the depalmitoylation of Gpx1. Furthermore, we find that PPT1-regulated depalmitoylation negatively impacts Gpx1 protein stability. Interestingly, inhibiting Gpx1 palmitoylation, either through expression of a non-palmitoylated Gpx1 mutant or by expressing PPT1, significantly enhances neovascular angiogenesis. Conversely, in PPT1-deficient mice, angiogenesis is notably attenuated compared to wild-type mice in an Oxygen-Induced Retinopathy (OIR) model, which mimics pathological angiogenesis. Physiologically, under hypoxic conditions, Gpx1 palmitoylation levels are drastically reduced, suggesting that increasing Gpx1 palmitoylation may have beneficial effects. Indeed, enhancing Gpx1 palmitoylation by inhibiting PPT1 with DC661 effectively suppresses retinal angiogenesis in the OIR disease model. Overall, our findings highlight the pivotal role of protein palmitoylation in angiogenesis and propose a novel mechanism whereby the PPT1-Gpx1 axis modulates angiogenesis, thereby providing a potential therapeutic strategy for targeting PPT1 to combat angiogenesis.
The burden of leukemia and related diseases is rapidly growing in Asia. Currently, there is a paucity of regional collaborative groups/initiatives that focus exclusively on the management of leukemia in the Asia-Pacific (APAC) region. The Asia-Pacific Leukemia Consortium (APLC) was established on the 8 September 2021 to understand the status quo, unmet needs, and ways to improve the management of leukemia and related diseases in the APAC region. The APLC working group set up a group of experts from various countries (Singapore, Malaysia, Thailand, Hong Kong, Japan, South Korea, Taiwan, China, and Australia) to discuss on the status of: (i) clinical trials; (ii) disease registry database; (iii) genetic and tissue repository; (iv) patient advocacy and care; and (v) disease prevention and education in the APAC region. Low levels of awareness about leukemia amongst the public, lack of financial support, and limited access to newly approved therapies were identified as barriers to the implementation of effective leukemia management in low- or mid-income Asian countries. Patients often enroll in clinical trials to gain access to novel/approved therapies. The APLC group aims to address the growing threat of leukemia through a collaborative approach to advance disease prevention, research, clinical trials, and education.