A novel tubulin inhibitor, 6h, suppresses tumor-associated angiogenesis and shows potent antitumor activity against non-small cell lung cancers.

Tumor angiogenesis is closely associated with the metastasis and progression of non-small cell lung cancer (NSCLC), a highly vascularized solid tumor. However, novel therapeutics are lacking for the treatment of this cancer. Here, we developed a series of 2-aryl-4-(3,4,5-trimethoxy-benzoyl)-5-substituted-1,2,3-triazol analogs (6a-6x) as tubulin colchicine-binding site inhibitors, aiming to find a novel promising drug candidate for NSCLC treatment. We first identified 2-(2-fluorophenyl)-3-(3,4,5-trimethoxybenzoyl)-5-(3-hydroxyazetidin-1-yl)-2H-1,2,3-triazole (6h) as a hit compound, which inhibited angiogenesis induced by NSCLC cells both in vivo and in vitro. In addition, our data showed that 6h could tightly bind to the colchicine-binding site of tubulin and inhibit tubulin polymerization. We also found that 6h could effectively induce G2/M cell cycle arrest of A549 and H460 cells, inhibit cell proliferation, and induce apoptosis. Furthermore, we showed 6h had the potential to inhibit the migration and invasion of NSCLC cells, two basic characteristics of tumor metastasis. Finally, we found 6h could effectively inhibit tumor progression in A549 xenograft mouse models with minimal toxicity. Taken together, these findings provide strong evidence for the development of 6h as a promising microtubule colchicine-binding site inhibitor for NSCLC treatment.

Global Transcriptome Analysis Reveals Acclimation-Primed Processes Involved in the Acquisition of Desiccation Tolerance in Boea hygrometrica.

Boea hygrometrica resurrection plants require a period of acclimation by slow soil-drying in order to survive a subsequent period of rapid desiccation. The molecular basis of this observation was investigated by comparing gene expression profiles under different degrees of water deprivation. Transcripts were clustered according to the expression profiles in plants that were air-dried (rapid desiccation), soil-dried (gradual desiccation), rehydrated (acclimated) and air-dried after acclimation. Although phenotypically indistinguishable, it was shown by principal component analysis that the gene expression profiles in rehydrated, acclimated plants resemble those of desiccated plants more closely than those of hydrated acclimated plants. Enrichment analysis based on gene ontology was performed to deconvolute the processes that accompanied desiccation tolerance. Transcripts associated with autophagy and α-tocopherol accumulation were found to be activated in both air-dried, acclimated plants and soil-dried non-acclimated plants. Furthermore, transcripts associated with biosynthesis of ascorbic acid, cell wall catabolism, chaperone-assisted protein folding, respiration and macromolecule catabolism were activated and maintained during soil-drying and rehydration. Based on these findings, we hypothesize that activation of these processes leads to the establishment of an optimal physiological and cellular state that enables tolerance during rapid air-drying. Our study provides a novel insight into the transcriptional regulation of critical priming responses to enable survival following rapid dehydration in B. hygrometrica.

Effectiveness Evaluation of a Primary School-Based Intervention against Heatwaves in China.

BACKGROUND: Evidence of the effectiveness of intervention against extreme heat remains unclear, especially among children, one of the vulnerable populations. This study aimed to evaluate the effectiveness of a primary school-based intervention program against heatwave and climate change in China to provide evidence for development of policies for adaptation to climate change. METHODS: Two primary schools in Dongtai City, Jiangsu Province, China, were randomly selected as intervention and control schools (CTR registration number: ChiCTR2200056005). Health education was conducted at the intervention school to raise students' awareness and capability to respond to extreme heat during May to September in 2017. Knowledge, attitude, and practice (KAP) of students and their parents at both schools were investigated by questionnaire surveys before and after intervention. The changes in KAP scores after intervention were evaluated using multivariable difference-in-difference (DID) analysis, controlling for age, sex, etc. Results: The scores of knowledge, attitude, and practice of students and their parents increased by 19.9% (95%CI: 16.3%, 23.6%) and 22.5% (95%CI: 17.8%, 27.1%); 9.60% (95%CI: 5.35%, 13.9%) and 7.22% (95%CI: 0.96%, 13.5%); and 9.94% (95%CI: 8.26%, 18.3%) and 5.22% (95%CI: 0.73%, 9.71%), respectively, after intervention. The KAP score changes of boys were slightly higher than those of girls. Older students had higher score changes than younger students. For parents, the higher the education level, the greater the score change, and change in scores was greater in females than in males. All the health education activities in the program were significantly correlated with the changes in KAP scores of primary school students after intervention, especially those curricula with interesting activities and experiential learning approaches. CONCLUSIONS: Heat and health education program in primary school was an effective approach to improve cognition and behavior for both students and their parents to better adapt to heatwaves and climate change. The successful experience can be generalized to respond to the increasing extreme weather/climate events in the context of climate change, such as heatwaves, and other emergent occasions or public health education, such as the control and prevention of COVID-19.

Design, synthesis and bio-evaluation of novel 2-aryl-4-(3,4,5-trimethoxy-benzoyl)-5-substituted-1,2,3-triazoles as the tubulin polymerization inhibitors.

A series of 2-aryl-4-(3,4,5-trimethoxybenzoyl)-5-substituted-1,2,3-triazoles were designed, synthesized and evaluated for the anticancer activities. Based on the model of DMAM-colchicine-tubulin complex interactions, various saturated nitrogen-containing heterocycles were introduced to the C5-position of 1,2,3-triazol to interact with a tolerant region at the entrance of the binding-pocket and increase the aqueous solubility of the compounds. All designed compounds were concisely synthesized by one-pot oxidative cyclization. Most compounds exhibited moderate antiproliferative activity with IC50 values in the micromolar to sub-micromolar range. Among them, 5g posed N-acyl-piperazine moiety at the C5-position of B-ring showed most potent against cancer cells, with IC50 values of 0.084-0.221 µM 5g potently disrupted microtubule/tubulin dynamics, induced cell cycle arrest at G2/M phase in SGC-7901 cells. In addition, molecular modeling studies suggested that 5g probably binds to the colchicine site of tubulin.

Endogenous IGF Signaling Directs Heterogeneous Mesoderm Differentiation in Human Embryonic Stem Cells.

During embryogenesis, various cell types emerge simultaneously from their common progenitors under the influence of intrinsic signals. Human embryonic stem cells can differentiate to diverse cell types of three embryonic lineages, making them an excellent system for understanding the regulatory mechanism that maintains the balance of different cell types in embryogenesis. In this report, we demonstrate that insulin-like growth factor (IGF) proteins are endogenously expressed during differentiation, and their temporal expression contributes to the cell fate diversity in mesoderm differentiation. Small molecule LY294002 inhibits the IGF pathway to promote cardiomyocyte differentiation while suppressing epicardial and noncardiac cell fates. LY294002-induced cardiomyocytes demonstrate characteristic cardiomyocyte features and provide insights into the molecular mechanisms underlying cardiac differentiation. We further show that LY294002 induces cardiomyocytes through CK2 pathway inhibition. This study elucidates the crucial roles of endogenous IGF in mesoderm differentiation and shows that the inhibition of the IGF pathway is an effective approach for generating cardiomyocytes.