Discovery of heterocyclic replacements for the coumarin core of anti-tubercular FadD32 inhibitors

Previous work established a coumarin scaffold as a starting point for inhibition of Mycobacterium tuberculosis (Mtb) FadD32 enzymatic activity. After further profiling of the coumarin inhibitor 4 revealed chemical instability, we discovered that a quinoline ring circumvented this instability and had the advantage of offering additional substitution vectors to further optimize. Ensuing SAR studies gave rise to quinoline-2-carboxamides with potent anti-tubercular activity. Further optimization of ADME/PK properties culminated in 21b that exhibited compelling in vivo efficacy in a mouse model of Mtb infection.     

Polysaccharide PRM3 from Rhynchosia minima root enhances immune function through TLR4-NF-κB pathway

Background

Polysaccharides, one of the active ingredients in herbal medicine, are proved to enhance innate immunity against infections. The aim of this study is to explore the immunoregulatory ability of polysaccharides from Rhynchosia minima root in vitro and in vivo.

Aluminum toxicity related to SOD and expression of presenilin and CREB in Bombyx mori

Aluminum (Al) is an important environmental metal factor that can be potentially associated with pathological changes leading to neurotoxicity. The silkworm, Bombyx mori, is an important economic insect and has also been used as a model organism in various research areas. However, the toxicity of Al on silkworm physiology has not been reported. Here, we comprehensively investigate the toxic effects of Al on the silkworm, focusing on its effects on viability and development, superoxide dismutase (SOD) activity, and the expression of presenilin and cAMP response element‐binding protein (CREB) in BmE cells and silkworm larvae. BmE cell viability decreased after treatment with aluminum chloride (AlCl₃) in both dose‐ and time‐dependent manners. When AlCl₃ solution was injected into newly hatched fifth instar larvae, both larval weight gain and survival rate were significantly decreased in a manner correlating with AlCl₃ dose and developmental stage. Furthermore, when BmE cells and silkworm larvae were exposed to AlCl₃, SOD activity decreased significantly relative to the control group, whereas presenilin expression increased more than twofold. Additionally, CREB and phosphorylated CREB (p‐CREB) expression in the heads of fifth instar larvae decreased by 28.0% and 50.0%, respectively. These results indicate that Al inhibits the growth and development of silkworms in vitro and in vivo, altering SOD activity and the expressions of presenilin, CREB, and p‐CREB. Our data suggest that B. mori can serve as a model animal for studying Al‐induced neurotoxicity or neurodegeneration.     

Ideal cardiovascular health and incidence of atherosclerotic cardiovascular disease among Chinese adults: the China-PAR project

Existing evidence on the relationship between cardiovascular health(CVH) metrics and cardiovascular disease(CVD) was primarily derived from western populations. We aimed to evaluate the benefits of ideal CVH metrics on preventing incident atherosclerotic CVD(ASCVD) in Chinese population. This study was conducted among 93,987 adults from the China-PAR project(Prediction for ASCVD Risk in China) who were followed up until 2015. Cox proportional hazard regression models were used to estimate the hazard ratios(HRs) and their corresponding 95% confidence intervals(CIs) of CVH metrics for the risk of ASCVD, including coronary heart disease(CHD), stroke and ASCVD death. We further estimated the population-attributable risk percentage(PAR%) of these metrics in relation to each outcome. We observed gradient inverse associations between the number of ideal CVH metrics and ASCVD incidence. Compared with participants having ≤2 ideal CVH metrics, the multivariable-adjusted HRs(95% CIs) of ASCVD for those with 3, 4, 5, 6 and 7 ideal CVH metrics were 0.83(0.74–0.93), 0.66(0.59–0.74), 0.55(0.48–0.61), 0.44(0.38–0.50) and 0.24(0.18–0.31), respectively(P for trend 0.0001). Approximately 62.1% of total ASCVD, 38.7% of CHD, 66.4% of stroke, and 60.5% of ASCVD death were attributable to not achieving all the seven ideal CVH metrics. After adjusting effects of ideal health factors, having four ideal health behaviors could independently bring adults health benefits in preventing 17.4% of ASCVD, 18.0% of CHD, 16.7% of stroke, and 10.1% of ASCVD death. Among all the seven CVH metrics, to keep with ideal blood pressure(BP) implied the largest public health gains against various ASCVD events(PAR% between 33.0% and 47.2%), while ideal diet was the metric most difficult to be achieved in the long term. Our study indicates that the more ideal CVH metrics adults have, the less ASCVD burden there is in China. Special efforts of health education and behavior modification should be made on keeping ideal BP and dietary habits in general Chinese population to prevent the epidemic of ASCVD.     

YTH Domain: A Family of N6-methyladenosine (m6A) Readers

Like protein and DNA, different types of RNA molecules undergo various modifications. Accumulating evidence suggests that these RNA modifications serve as sophisticated codes to mediate RNA behaviors and many important biological functions. N⁶-methyladenosine (m⁶A) is the most abundant internal RNA modification found in a variety of eukaryotic RNAs, including but not limited to mRNAs, tRNAs, rRNAs, and long non-coding RNAs (lncRNAs). In mammalian cells, m⁶A can be incorporated by a methyltransferase complex and removed by demethylases, which ensures that the m⁶A modification is reversible and dynamic. Moreover, m⁶A is recognized by the YT521-B homology (YTH) domain-containing proteins, which subsequently direct different complexes to regulate RNA signaling pathways, such as RNA metabolism, RNA splicing, RNA folding, and protein translation. Herein, we summarize the recent progresses made in understanding the molecular mechanisms underlying the m⁶A recognition by YTH domain-containing proteins, which would shed new light on m⁶A-specific recognition and provide clues to the future identification of reader proteins of many other RNA modifications.