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Acta Pharmaceutica Sinica B ; (6): 729-750, 2024.
Article in English | WPRIM | ID: wpr-1011253


Chemotherapy-induced complications, particularly lethal cardiovascular diseases, pose significant challenges for cancer survivors. The intertwined adverse effects, brought by cancer and its complication, further complicate anticancer therapy and lead to diminished clinical outcomes. Simple supplementation of cardioprotective agents falls short in addressing these challenges. Developing bi-functional co-therapy agents provided another potential solution to consolidate the chemotherapy and reduce cardiac events simultaneously. Drug repurposing was naturally endowed with co-therapeutic potential of two indications, implying a unique chance in the development of bi-functional agents. Herein, we further proposed a novel "trilogy of drug repurposing" strategy that comprises function-based, target-focused, and scaffold-driven repurposing approaches, aiming to systematically elucidate the advantages of repurposed drugs in rationally developing bi-functional agent. Through function-based repurposing, a cardioprotective agent, carvedilol (CAR), was identified as a potential neddylation inhibitor to suppress lung cancer growth. Employing target-focused SAR studies and scaffold-driven drug design, we synthesized 44 CAR derivatives to achieve a balance between anticancer and cardioprotection. Remarkably, optimal derivative 43 displayed promising bi-functional effects, especially in various self-established heart failure mice models with and without tumor-bearing. Collectively, the present study validated the practicability of the "trilogy of drug repurposing" strategy in the development of bi-functional co-therapy agents.

Acta Pharmaceutica Sinica B ; (6): 1671-1685, 2023.
Article in English | WPRIM | ID: wpr-982808


Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been reapproved for heart failure (HF) therapy in patients with and without diabetes. However, the initial glucose-lowering indication of SGLT2i has impeded their uses in cardiovascular clinical practice. A challenge of SGLT2i then becomes how to separate their anti-HF activity from glucose-lowering side-effect. To address this issue, we conducted structural repurposing of EMPA, a representative SGLT2 inhibitor, to strengthen anti-HF activity and reduce the SGLT2-inhibitory activity according to structural basis of inhibition of SGLT2. Compared to EMPA, the optimal derivative JX01, which was produced by methylation of C2-OH of the glucose ring, exhibited weaker SGLT2-inhibitory activity (IC50 > 100 nmol/L), and lower glycosuria and glucose-lowering side-effect, better NHE1-inhibitory activity and cardioprotective effect in HF mice. Furthermore, JX01 showed good safety profiles in respect of single-dose/repeat-dose toxicity and hERG activity, and good pharmacokinetic properties in both mouse and rat species. Collectively, the present study provided a paradigm of drug repurposing to discover novel anti-HF drugs, and indirectly demonstrated that SGLT2-independent molecular mechanisms play an important role in cardioprotective effects of SGLT2 inhibitors.

Protein & Cell ; (12): 336-359, 2022.
Article in English | WPRIM | ID: wpr-929159


Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular mortality in patients with diabetes mellitus but the protective mechanism remains elusive. Here we demonstrated that the SGLT2 inhibitor, Empagliflozin (EMPA), suppresses cardiomyocytes autosis (autophagic cell death) to confer cardioprotective effects. Using myocardial infarction (MI) mouse models with and without diabetes mellitus, EMPA treatment significantly reduced infarct size, and myocardial fibrosis, thereby leading to improved cardiac function and survival. In the context of ischemia and nutritional glucose deprivation where autosis is already highly stimulated, EMPA directly inhibits the activity of the Na+/H+ exchanger 1 (NHE1) in the cardiomyocytes to regulate excessive autophagy. Knockdown of NHE1 significantly rescued glucose deprivation-induced autosis. In contrast, overexpression of NHE1 aggravated the cardiomyocytes death in response to starvation, which was effectively rescued by EMPA treatment. Furthermore, in vitro and in vivo analysis of NHE1 and Beclin 1 knockout mice validated that EMPA's cardioprotective effects are at least in part through downregulation of autophagic flux. These findings provide new insights for drug development, specifically targeting NHE1 and autosis for ventricular remodeling and heart failure after MI in both diabetic and non-diabetic patients.

Animals , Humans , Mice , Diabetes Mellitus , Diabetes Mellitus, Type 2/drug therapy , Glucose , Myocardial Infarction/metabolism , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Ventricular Remodeling
Chinese Journal of School Health ; (12): 1315-1317, 2019.
Article in Chinese | WPRIM | ID: wpr-816598


Objective@#To analyze the relationship between daily behavior and self-perceived academic performance among students in Jiangxi, and to provide a scientific basis for developing health behavior among adolescents and children.@*Methods@#By using stratified cluster sampling, 12 primary and secondary schools from six counties of Jiangxi Province were selected, and a total of 2 284 students were investigated with questions including breakfast consumption, number of days participating in sports activities (≥45 min) and the average screen time during the past 7 days. Regression analysis was carried out by using ordered multi-classification logistic.@*Results@#Of the 2 284 students surveyed, 1 374(60.16%) perceived their academic performance as very good or good, 613 (26.84%) and 297(13.00%) perceived as moderate or poor. Primary school, having breakfast every day, not playing on mobile or computer during weekday was positively associated with higher self-perceived academic performance (OR=0.50, 0.57 and 0.64, respectively, P<0.05), no sports activities ≥45 min during the past 7 d was associated with poor(OR=1.57, P<0.01). Among the 2 284 students, 67.43% students ate breakfast every day in the past 7 d, 75.39% students did not play mobile phones or computers at school, 40.89% students did not participate in sports activities (≥45 min).@*Conclusion@#Breakfast skipping and insufficient physical exercise shows adverse effects, and no/limited screen time during weekdays shows positive effects on academic performance. Intervention of visky behaviors should to carried out from different perspectives to promote the develpment of the health habits among students.

Chinese Journal of Schistosomiasis Control ; (6): 72-73, 2010.
Article in Chinese | WPRIM | ID: wpr-415275


Objective To explore the relationship between the distribution of infected snails and transmission of acute schistosomiasis in hilly regions.Methods The data concerning the distribution of the infected snails and acute schistosomiasis in Shitai County,Anhui Province from 1999 to 2008 were collected and analyzed.Results The sehistosome infection rate of human increased as the distance between the settings with infected snails and activity sites of humans shortened.Conclusions Acute infection of schistosome of human is associated with the distance between the settings with infected snails and activity sites of them.Strengthening the measures of snail control in key regions,protecting key populations and carrying out health education for schistosomiasis control are important approaches to control the transmission of acute schistosomiasis in hilly regions.

Chinese Journal of Schistosomiasis Control ; (6)1989.
Article in Chinese | WPRIM | ID: wpr-553574


Objective To understand the molluscicidal effects of water extract of Ginkgo biloba's peel on Oncomelania hupensis Methods Immersion methods with a series of six concentrations from 0.3 percent to 3 percent were used to determine the molluscicidal effect. Results The LC 50 of the water extract of 1.0 percent was 28.8 mg/L for 24 hours immersion,12.6 mg/L for 48 hours,and 0.48 mg/L for 72 hours, respectively. The LC 50 of the extract of 2 percent was 19.9 mg/L for 24 hours,11.2 mg/L for 48 hours and 0.48 mg/L for 72 hours,respectively.The LC 50 of the extract of 3 percent was 19.1 mg/L for 24 hours,10.9 mg/L for 48 hours and 0.48 mg/L for 72 hours,respectively. The higher of the concentration, the better of the effect. Meantime, it's poisoning to crops and fishes was very low. Conclusion Ginkgo biloba's peel has molluscicidal effect. It is a good candidate of potential plant molluscicides.