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 discuss the effect of apolipoprotein C1(APOC1)expression on the proliferation and apoptosis of the hepatocellular carcinoma cells,and to preliminarily clarify the related molecular mechanism.Methods:The expression level of APOC1 mRNA in hepatocellular carcinoma tissue and its relationship with the prognosis of the patient were analyzed by The Cancer Genome Atlas(TCGA)Database;real-time fluorescence quantitative PCR(RT-qPCR)method was used to detect the expression levels of APOC1 mRNA in different hepatocellular carcinoma cells;the human liver cancer HepG2 cells with low APOC1 expression were selected as the subjects.The HepG2 cells were transfected with pcDNA3.1-APOC1 plasmid to over-express APOC1(APOC1 over-expression group),and the HepG2 cells transfected with empty vector pcDNA3.1 were regarded as control group.MTS assay and 5-ethynyl-2'-deoxyuridine(EdU)staining were used to detect the proliferative activities and proliferation rates of the cells in two groups;Transwell chamber assay was used to detect the numbers of migration cells in two groups;flow cytometry and TUNEL assay were used to detect the percentages of the cells at different cell cycles and apoptotic rates in two groups;Western blotting method was used to detect the expression levels of extracellular regulated protein kinase(ERK),phosphorylated ERK(p-ERK),protein kinase B(AKT),phosphorylated AKT(p-AKT),B-cell lymphoma-2(Bcl-2),and cleaved cysteinyl aspartate specific proteinase-3(cleaved caspase-3)proteins in the cells in two groups.Results:The TCGA Database results showed that the expression level of APOC1 mRNA in hepatocellular carcinoma tissue was lower than that in normal liver tissue(P<0.05),and the patients with low expression of APOC1 mRNA had poor prognosis.The RT-qPCR results showed that the expression level of APOC1 mRNA in the HepG2 cells was the lowest,and the HepG2 cells were chosen for the subsequent research.Compared with control group,the proliferative activity and proliferation rate of the cells in APOC1 over-expression group were decreased(P<0.05 or P<0.01),the number of migration cells was decreased(P<0.01),and the percentage of the cells at S phase and the apoptotic rate were significantly increased(P<0.01).Compared with control group,the expression levels of p-ERK,p-AKT,and Bcl-2 proteins in the cells in APOC1 over-expression group were significantly decreased(P<0.05),and the expression level of cleaved caspase-3 protein was increased(P<0.01).Conclusion:High expression of APOC1 can inhibit the proliferation of the human liver cancer HepG2 cells and induce the apoptosis,and its mechanism may be related to inhibition of the expressions of p-ERK,p-AKT,Bcl-2 proteins and promotion of the expression of cleaved caspase-3 protein.

Based on a retrospective study design, this article was aimed to discuss the transformation path and method of hospital medical records information into analyzable data, in order to solve the problem of text-based information digitalization, and improve the credibility of statistical results. The hospital medical records information of traditional Chinese medicine (TCM) treatment for infantile cerebral palsy was taken as example. After the identification of research purpose, the study contained 8 steps, which were index identification, index definition, coding and assignment, database design, data entry, quality control, and database locking. The database contained research-related indicators was received. The results showed that a set of path and method based on indicator extraction and conversion of hospital medical records information into data. It was concluded that in the retrospective study design, the conversion of text information into analyzable data was the key step. Extraction and digitalization of indicators should be based on the research plan. Key elements such as the crowd, treatment plan, evaluation indicator, should be paid attention to for the systematic analysis, in order to ensure the system integrity of research indicators.

Objective To explore clinical effect of repairing soft tissue defect in forearm, hand and foot with free super-thin anterolateral thigh perforator flaps. Methods At first the site of perforator vessels were determined by Doppler, then the flaps were designed and harvested with the site as center; the fascia lata and subcutaneous fat were removed by sandhill-likely only the 4.0 cm × 3.0 cm - 3.0 cm×2.5 cm disc-like fascia lata and dermis layer were reserved. 15 traumatic soft tissue defects including forearm, hand and foot were repaired with the ree super-thin antemlateral thigh perforator flaps. Results No vascular crisis happened and all skin grafts survived in donor sites. 2.0 cm×1.2 cm of the distal of flap was necrosis in 1 case and it was healed by dress changing. 15 cases were followed up 3 months-2 years and the average is 6 months. The contour and texture of all flaps were good and two point discrimination (2-PD) was about 8-10 mm of. Conclusions The contour and texture of free super-thin anterolateral thigh perforator flap are good, the feeling of recipient site recovered well, it's less injury for donor site and there is no reshaping for flap. It is a fineness donor site for repairing soft tissue defects in hand and foot.

Objective To summarize clinical experience of application of muliplefoliated flap combined with tendon graft from dorsal foot for repairing soft tissue defects of multi-fingers. Methods Based on the results of microdissection researches, muliplefoliated flap including medial foot flap, the first metatarsal dorsal flap, lateral foot flap, extensor pollicis brevis of toe and extensor proprius of the fifth toe pedicled by anterior tibial vessels and dorsal pedis vessels as trunk, anterior medial malleolus vessels, the first metatarsal vessels and anterior lateral malleolus vessels as branches respective was designed for repairing soft tissue and tendon defects of multi-fingers. Results In all 12 cases, total survival of flap was 11 cases , 1 case had partial necrosis of distal flap and it was healed by dress changing. Conclusion Transplantation of muliplefoliated flap combined with tendon graft from dorsal foot is a good method to repair soft tissue and tendon defects of multi-fingers.