Synthesis, Biological Evaluation, and Autophagy Mechanism of 12<i>N</i>‑Substituted Sophoridinamines as Novel Anticancer Agents

A series of 12<i>N</i>-substituted sophoridinamine derivatives were synthesized and evaluated for their cytotoxic activities in human HepG2 hepatoma cells. Structure–activity relationship revealed that introduction of a suitable arylidene or arylethyl at the <i>N</i>′-end could greatly enhance antiproliferation potency. Among them, compound <b>6b</b> possessing a <i>N</i>′-trimethoxyphenyl methylene exhibited potent antiproliferation effect against three human tumor cell lines including HepG2, leukemia (K562), and breast cancer (HMLE), with IC₅₀ between 0.55 and 1.7 μM. The underlying mechanism of <b>6b</b> against tumor cells is to block autophagic flux, mainly through neutralizing lysosomal acidity. Our results indicated that compound <b>6b</b> is a potent lysosomal deacidification agent and is accordingly able to block autophagic flux and inhibit tumor cell growth

Synthesis and Biological Evaluation of Sophoridinol Derivatives as a Novel Family of Potential Anticancer Agents

New N-substituted sophoridinic acid/ester and sophoridinol derivatives were synthesized and evaluated for their cytotoxic activity in human HepG2 hepatoma cells from the lead sophoridine (1). Among the newly synthesized compounds, sophoridinol 7i displayed a potential antiproliferative activity with an IC50 of 3.1 μM. Importantly, it exerted an almost equipotent effect against both wild MCF-7 and adriamycin (AMD)-resistant MCF-7 (MCF-7/AMD) breast carcinoma cell lines. Its mode of action was to arrest the cell cycle at the G0/G1 phase, consistent with that of the parent 1. In addition, compound 7i also showed a reasonable ClogP value and favorable pharmacokinetic property with an area under the concentration–time curve (AUC) of 10.3 μM·h in rats, indicating an ideal druggable characteristic. We consider sophoridinol derivatives to be a novel family of promising antitumor agents with an advantage of inhibiting drug-resistant cancer cells

IMB5043 induces DNA damage repair and activated ATM-Chk2 pathway.

<p>SMMC7721 cells were treated with indicated doses of IMB5043 for 24 hours. Damage-associated proteins were detected by Western blot analysis and the quantitative analysis was displayed. Data shown is means ± SD. *P<0.05; **P<0.01.</p

Linking endotypes to omics profiles in difficult-to-control asthma using the diagnostic Chinese medicine syndrome differentiation algorithm

Objective: Patients with difficult-to-control asthma have difficulty breathing almost all of the time, even leading to life-threatening asthma attacks. However, only few diagnostic markers for this disease have been identified. We aimed to take advantage of unique Chinese medicine theories for phenotypic classification and to explore molecular signatures in difficult-to-control asthma. Methods: The Chinese medicine syndrome differentiation algorithm (CMSDA) is a syndrome-scoring classification method based on the Chinese medicine overall observation theory. Patients with difficult-to-control asthma were classified into Cold- and Hot-pattern groups according to the CMSDA. DNA methylation and metabolomic profiles were obtained using Infinium Human Methylation 450 BeadChip and gas chromatography-mass spectrometer. Subsequently, an integrated bioinformatics analysis was performed to compare those two patterns and identify Cold/Hot-associated candidates, followed by functional validation studies. Results: A total of 20 patients with difficult-to-control asthma were enrolled in the study. Ten were grouped as Cold and 10 as Hot according to the CMSDA. We identified distinct whole-genome DNA methylation and metabolomic profiles between Cold- and Hot-pattern groups. ALDH3A1 gene exhibited variations in the DNA methylation probe cg10791966, while two metabolic pathways were associated with those two patterns. Conclusions: Our study introduced a novel diagnostic classification approach, the CMSDA, for difficult-to-control asthma. This is an alternative way to categorize diverse syndromes and link endotypes with omics profiles of this disease. ALDH3A1 might be a potential biomarker for precision diagnosis of difficult-to-control asthma.</p

Structure-Based Design of Novel Chemical Modification of the 3′-Overhang for Optimization of Short Interfering RNA Performance

Short interfering RNAs (siRNAs) are broadly used to manipulate gene expression in mammalian cells. Although chemical modification is useful for increasing the potency of siRNAs <i>in vivo</i>, rational optimization of siRNA performance through chemical modification is still a challenge. In this work, we designed and synthesized a set of siRNAs containing modified two-nucleotide 3′-overhangs with the aim of strengthening the interaction between the 3′-end of the siRNA strand and the PAZ domain of Ago2. Their efficiency of binding to the PAZ domain was calculated using a computer modeling program, followed by measurement of RNA–Ago2 interaction in a surface plasmon resonance biochemical assay. The results suggest that increasing the level of binding of the 3′-end of the guiding strand with the PAZ domain, and/or reducing the level of binding of the sense strand through modifying the two-nucleotide 3′-overhangs, affects preferential strand selection and improves siRNA activity, while we cannot exclude the possibility that the modifications at the 3′-end of the sense strand may also affect the recognition of the 5′-end of the guiding strand by the MID domain. Taken together, our work presents a strategy for optimizing siRNA performance through asymmetric chemical modification of 3′-overhangs and also helps to develop the computer modeling method for rational siRNA design

Prenylemestrins A and B: Two Unexpected Epipolythiodioxopiperazines with a Thioethanothio Bridge from <i>Emericella</i> sp. Isolated by Genomic Analysis

Prenylemestrins A and B (1 and 2, respectively), two unusual epipolythiodioxopiperazines featuring a thioethanothio bridge instead of a polysulfide bridge, were isolated from the fungus Emericella sp. CPCC 400858 guided by genomic analysis. Their structures were determined by extensive spectroscopic data, NMR and ECD calculations, and X-ray diffraction analysis. A plausible biosynthetic pathway for 1 and 2 was proposed on the basis of gene cluster analysis. Prenylemestrins A and B exhibited cytotoxicities against human chronic myelocytic leukemia cell lines K562 and MEG-01

Association of genetic polymorphisms with mercapturic acids in the urine of young healthy subjects before and after exposure to outdoor air pollution

We aimed to identify the relationship between variations in metabolic genes and human urinary changes in mercapturic acids (MAs), including CEMA, HMPMA, SPMA, HPMA and HEMA, before and after air pollution exposure. Genotype detection for 47 relevant single nucleotide polymorphisms (SNPs) collected by literature research was performed. Five MAs expression levels in the urinary samples of 50 young healthy individuals with short-term exposure to clean, polluted and purified air at five time points were detected by targeted online solid-phase extraction liquid chromatography tandem mass spectrometry (SPE-LC-MS/MS), followed with associations of SNPs with MAs changes. Difference in MAs between polluted and clean/purified air was significantly associated with 21 SNPs mapped into 9 genes. Five SNPs in GSTP1 showed the most prominent association with the changes in SPMA expression, indicating that those SNPs in GSTP1 and SPMA might serve as biomarkers for susceptibility and the prognosis of lung cancer.</p