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 study the correlation between fractional excretion of uric acid (FEUA) and blood uric acid,body mass index (BMI),blood pressure,blood glucose,blood lipid and other metabolic factors in patients with primary gout.Methods Sixty-two patients with primary gout (gout group) and 32 healthy people (control group) were selected in this study.Gout group was divided into uric acid excretion decreasing group (FEUA ＜ 7％,29 cases),mixed group (7％ ≤FEUA ≤ 12％,25 cases) and uric acid production increasing group (FEUA ＞ 12％,8 cases) according to the level of FEUA.The fasting blood glucose (FPG),2-hour postprandial blood glucose (2 h PBG),blood lipid,serum creatinine,blood uric acid,glycosylated hemoglobin were tested.24 hours urine was collected and urinary uric acid and urinary creatinine was measured,FEUA was calculated and analyzed.Results BMI,mean arterial pressure,blood uric acid,glycosylated hemoglobin,total cholesterol,2 h PBG in gout group was higher than that in control group,and high density lipoprotein cholesterol,FEUA was lower than that in control group,and there was significant difference (P ＜ 0.05).There was no significant difference in age,FPG,low density lipoprotein cholesterol,triacylglycerol between two groups (P＞ 0.05).There was no significant difference in age,blood uric acid,FPG,2 h PBG,glycosylated hemoglobin,total cholesterol,low density lipoprotein cholesterol,high density hpoprotein cholesterol among uric acid excretion decreasing group,mixed group and uric acid production increasing group (P ＞ 0.05),and there was significant difference in BMI,mean arterial pressure,triacylglycerol,FEUA among three groups(P＜ 0.05).FEUA was negatively correlated with blood uric acid in control group and gout group (r =-3.900,-0.476,P ＜0.05).FEUA was positively correlated with 24 h urinary uric acid in gout group (r =0.465,P =0.001),and nagatively correlated with triacylglycerol (r =-0.304,P ＜ 0.05).Pearson analysis showed that FEUA was negatively correlated with blood uric acid in uric acid excretion decreasing group (FEUA ＜ 7％) (r =-0.392,P ＜ 0.05),FEUA was positively correlated with blood uric acid in non uric acid excretion decreasing group (FEUA ≥7％)(r =0.437,P ＜ 0.05),but 24 h urinary uric acid was not correlated with blood uric acid(P ＞ 0.05).Multi-stepwise regression analysis showed that blood uric acid,glycosylated hemoglobin,FEUA was significantly correlated with the onset of the gout (P ＜ 0.05).Conclusions Besides blood uric acid level,there are significant changes in primary gout in blood pressure,serum glucose and lipid levels.FEUA could be used to estimate the ability of renal excrete the uric acid.Mean arterial pressure,glycosylated hemoglobin and FEUA are the risk factors for gout.

Objective To evaluate the relationship of the hepatocyte growth factor (HGF) and the nuclear matrix protein 22 (NMP22) in urine and the stage and grade of bladder uroepithelium carcinoma.Methods A total of 48 post-operative patients (males 39, females 9) with bladder cancer enrolled in this study were perfused with THP. The voided urine of all the patients before and 6 months after perfusion were recovered selectively. HGF and NMP22 ELISA kits were used to detect bladder cancer. Results The recurrence rate was 12.5 %. The HGF level had positive correlation with the stage and grade of bladder uroepithelium carcinoma (P ＜0.05). The NMP22 level had positive correlation with the grade of bladder cancer. The sensitivity and specificity of HGF, NMP22 and cytology were 100 % (6/6), 83.3 % (5/6), 66.7 %(4/6) and 61.9 % (26/42), 57.1% (24/42), 97.6 % (41/42), respectively. Conclusion The HGF and NMP22 are both valuable tumor markers in the urine of bladder uroepithelium carcinoma. They have intimate relation with the stage and grade of bladder uroepithelium carcinoma. Hence combined with cytology, they could be selected as the significance level of early screening and diagnosing.

Objective To explore the change of CD4+CD25+Foxp3+ regulatory T (Treg) cells during aging and the relation with lung tumor. Methods The Lewis lung cancer model was set up in C57BL/6 female mice, and the 36 mice were divided into young health group, middle-aged health group, elderly health group, young tumor group, middle-aged tumor group and elderly tumor group. The percentages of CD4+CD25+Foxp3+ Treg in CD4+ T cells in mice spleen cells were measured by flow cytometry, for reflecting the quantity of CD4+CD25+Foxp3+ Treg cells. And the level of Foxp3 mRNA in splenocyte was tested by real-time PCR method. Results The level of CD4+CD25+Foxp3+/CD4+ T cells and the quantity of Foxp3 mRNA were higher in tumor groups than in healthy groups(both P＜0.05 ). Besides, in the healthy groups, there were statistical differences in the level of CD4+CD25+Foxp3+/CD4+ T cells (F=47.70, P=0.000) and the quantity of Foxp3 mRNA among the different months groups. Accumulation of the CD4+CD25+Foxp3+ Treg cells was accompanied with aging, the elderly mice contained a significantly larger population of CD4+CD25+Foxp3+ Treg cells in their spleen when compared with the younger counterparts, and the highest was the elderly tumor group. So it was with the functional gene Foxp3 mRNA (F=6.56, P=0.009). Conclusions The results suggest a close relationship of the change of CD4+CD25+Foxp3+Treg cells with aging and the genesis and development of lung tumor.