Human carboxylesterase 2A (hCES2A) plays pivotal roles in prodrug activation and hydrolytic metabolism of ester-bearing chemicals. Targeted inhibition of intestinal hCES2A represents a feasible strategy to mitigate irinotecan-triggered gut toxicity (ITGT), but the orally active, selective, and efficacious hCES2A inhibitors are rarely reported. Here, a novel drug-like hCES2A inhibitor was developed via three rounds of structure-based drug design (SBDD) and structural optimization. Initially, donepezil was identified as a moderate hCES2A inhibitor from 2000 US Food and Drug Administration (FDA)-approved drugs. Following two rounds of SBDD and structural optimization, a donepezil derivative (B7) was identified as a strong reversible hCES2A inhibitor. Subsequently, nine B7 carbamates were rationally designed, synthesized and biologically assayed. Among all synthesized carbamates, C3 showed the most potent time-dependent inhibition on hCES2A (IC₅₀ = 0.56 nmol/L), excellent specificity and favorable drug-like properties. C3 could covalently modify the catalytic serine of hCES2A with high selectivity, while this agent also showed favorable safety profiles, high intestinal exposure, and impressive effects for ameliorating ITGT in both human intestinal organoids and tumor-bearing mice. Collectively, this study showcases a rational strategy for developing drug-like and serine-targeting covalent inhibitors against target serine hydrolase(s), while C3 emerges as a promising orally active drug candidate for ameliorating ITGT.

Objective To investigate the clinical application value of pulp mummification therapy and root canal therapy in senile chronic pulpitis. Methods The clinical data of elderly patients with chronic pulpitis who were admitted to our department from January 2016 to January 2017 were analyzed retrospectively. According to the different treatment methods, 120 elderly patients were divided into two groups: the pulp mummification therapy group and the root canal group. The clinical efficacy of the two groups were observed and the patients were followed up for a period of six months. The prognosis of the patients was recorded and counted. Results There were 60 patients in the pulp mummification therapy group, of which 34 were markedly effective, 19 were effective and 7 were ineffective. There were 60 patients in the root canal treatment group, of which 33 were markedly effective, 17 effective and 10 ineffective. There was no significant difference between data of the two groups (P＞0. 05). Six months after treatment, the patients were followed up for half a year. There were 2 adverse reaction cases in 60 patients of the pulp mummification therapy group. The incidence of adverse reactions was 3. 33％. Among the 60 patients in the root canal treatment group, 1 patient developed adverse reactions, The incidence of adverse reactions was 1. 67％. There was no difference in the incidence of adverse reactions between the two groups (P＞0. 05). Conclusion Both pulp mummification therapy and root canal therapy have a good clinical effect on elderly patients with chronic pulpitis. However, the pulp mummification therapy is suitable for patients whose radicular pulp have not been infected and the root canal is suitable for patients whose radicular pulp have been infected. Therefore, appropriate treatment should be selected based on patient characteristics to improve the treatment effect during the process of treatment.

Objective To examine the effects of comprehensive family intervention on family function among HIV-infected injection drug users (IDUs). Methods Ninety-eight HIV-infected IDUs in 3 AIDS treatment sites in Hunan Province were selected by random cluster sampling and were randomly divided into the intervention group (50 cases) and the control group (48 cases). Subjects in the intervention group were given a 9-month comprehensive family intervention, while those in the control group received standard treatment and care. When the study was completed, APGAR questionnaire was used to analyze the effects of comprehensive family intervention. Results Before the intervention ,the scores of family function were not significantly different the intervention group and the control group. After the intervention, the scores of family function among the control group were(4.26± 3.73) points and the intervention group was (6.53± 4.29) points, the scores of family function were significantly different between the two groups. Conclusions The comprehensive family intervention is an effective model to improve the family function of HIV-infected injection drug users.