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 evaluate the effect of Qishen Yizhi formula on improving learning and memory ability in D-galactose subcutaneous injection induced subacute aging mice.METHODS Subacute aging mice model mice were developed by D-galactose subcutaneous injection and then treated with positive drug donepezil(2 mg·kg-1·d-1)and Qishen Yizhi formula water extracts in low(1.33 g·kg-1·d-1)and high dose group(2.67 g·kg-1·d-1).The learning and memory abilities of mice were evaluated using Morris water maze and Y maze tests;HE staining was used to examine hippocampal damage in model mice;TUNEL was used to detect apoptosis of mouse hippocampal tissue;ELISA was used to detect the expression levels of oxidative stress factors and inflammatory fac-tors in the mouse hippocampus tissue;Western blot was used to detect the expression of signaling pathway proteins related to apoptosis,oxidative stress and inflammatory stress in the hippocampus of mice.RESULTS The water extract of Qishen Yizhi formula signifi-cantly shortened the latency and distance of model mice for reaching the platform in the water maze test(P<0.01),and significantly increased the number of crossing the platform(P<0.01);increased the exploration time and number of the Y maze new arm in model mice(P<0.05);inhibited the TUNEL fluorescence expression in the hippocampus of model mice(P<0.01);upregulated the activity of the oxidative stress factor superoxide dismutase(SOD)(P<0.05)and glutathione(GSH)content(P<0.05),and downregulated malondialdehyde(MDA)content(P<0.05);reduced interleukin(IL)-1β,IL-6 and tumor necrosis factor(TNF-α)expression levels(P<0.05,P<0.01);decreased the expression of apoptosis signaling pathway proteins Cleaved Caspase-3 and Caspase-3(P<0.05),upregulated the expression of oxidative stress signaling pathway proteins Nrf2 and HO-1(P<0.05),and downregulated the expression of inflammatory stress signaling pathway proteins p-NF-κB and NF-κB(P<0.05).CONCLUSION Qishen Yizhi for-mula can improve the learning and memory ability of subacute aging model mice injected with D-galactose,which may be related to its inhibitory effect on hippocampal oxidative stress and inflammatory stress.

Objective To investigate the morphological features and immunophenotypes of eosinophilic renal tumors in order to provide references for the differential diagnosis of this tumor.Methods A cohort of 75 cases of eosinophilic renal tumors were collected.The morphological features of the tumors were observed under microscope, and the immunophenotypes of the tumors were detected using tissue microarray and immunoshistochemistry.Results There were some overlaps between the different types of eosinophilic renal tumors in morphology, but each had its distinct characteristics.Immunohistochemically, renal oncocytoma ( RO) and eosinophilic chromophobe renal cell carcinoma ( ChRCC) shared some common immumophenotypes, except for the expression of CK7, with the expression rates of 2/19 in RO and 17/20 in eosinophilic ChRCC, respectively.Eosinophilic clear cell renal cell carcinoma mainly showed positive immunostaining for Vimentin and CAⅨ, whereas negative for CK7 and CD117 in most cases ( 10/15 ).AMACR was diffusely expressed in the majority of eosinophilic papillary renal cell carcinoma ( PRCC, 10/13).Furthermore, vimentin, CK7 and CD10 were positively expressed in eosinophilic PRCC with the expression rates of 8/13, 9/13 and 6/13, respectively;while CAⅨ, CD117 and TFE3 were all negatively expressed in eosinophilic PRCC.Epithelioid angiomyolipoma generally showed positive expression of vimentin,SMA and HMB45, but negative expression of CAⅨ and CK7.Vimentin, CD10, AMACR and TFE3 were strongly expressed in XP11.2 translocation renal cell carcinoma;on the contrary, CK7, CD117and HMB45 were not expressed in the majority of the tumor.Conclusion With full understanding of the morphology of different types of eosinophilic renal tumors, the immunostaining of vimentin, CAⅨ, CK7, CD10, AMACR, CD117, TFE3 and HMB45 could play a crucial role in the differential diagnosis of these tumors.

Objective To analyze the efficacy of kaolin intake amount as an index for motion sickness (MS)induced by different motion patterns stimulating the vestibular receptors of rats.Methods Rats were randomly divided into 5 groups.Three groups were subjected to one of the following stimulations,respectively-linear acceleration along either the interaural axis(IA)or body axis (AP),and double rotation(DR)stimulation.Other 2 groups were used as control.Kaolin intake was recorded for consecutive 6 d,3 d before and 3 d after stimulation,and the data were statistically analyzed.Results It was found that:1)following IA,AP and DR stimulations,25%,17% and 58% of the rats in each group increased mean kaolin intake by 1 g in the 3 d phase post-stimulation compared with that in the same duration of pre-stimulation,respectively;2)in contrast to some prewous reports,the present observation showed that high Ievel of kaolin intake post-stimulation may persist for more than one day.Conclusion All 3 tvpes of stimulation methods can serve as ways of specifically stimulating vestibular end-organs to induce kaolin intake increase,and double rotation iS the most effective.

Diamond-like carbon(DLC) was prepared by means of plasma source ion implantation-ion beam enhanced deposition. Through the heat treatment upon DLC in air and in depressed Ar gas, the DLC rich in graphite, DLC rich in diamond, and other kinds of DLC used in the study were obtained respectively. For the three kinds of DLC, the components of carbonaceous phase were analysed by X-ray photoelectron spectroscopy (XPS), the adsorptive amounts of human serum albumin (HSA), human serum fibrinogen (HFG) and human serum immunoglobin (IgG) on their surfaces in the condition of constant temperature were determined by radio isotope 125I labelling method. Results showed the graphite phase and diamond phase in DLC increased by two times or so respectively after the aforementioned different heat treatment. In pace with the increase of these foreign phases, the adsorptive amounts of HFG and IgG on DLC greatly increase but the adsorptive amounts of HSA on DLC decrease; furthermore, there is a change from non-selective adsorption of three human serum proteins into selective adsorptions of HFG and IgG prior to HSA. These results indicate that the foreign phases in DLC such as graphite, diamond, C-H phase and C-O phase have a great effect on protein adsorption on DLC and hence a negative effect on the hemocompatibility of DLC. The mechanisms for the increase of graphite phase and diamond phase in the process of heat treatment were also discussed in this paper.
Adsorption ; Biocompatible Materials ; chemistry ; Carbon ; chemistry ; Diamond ; chemistry ; Fibrinogen ; metabolism ; Humans ; Immunoglobulin G ; metabolism ; Proteins ; metabolism ; Serum Albumin ; metabolism ; Surface Properties

In the present paper, the influence of carbon phase components of three kinds of diamond like carbon (DLC) films, viz. DLC, DLC rich in graphite and DLC rich in diamond films, on adsorption of human serum albumin (HSA), human serum fibrinogen (HFG) and immunoglobin (IgG) was quantitatively analyzed by use of T-type correlation degree in the grey system theory. Through the analysis, the rational explanation for adsorptive amounts variations of the serum proteins with phase components in the experiment is reached and some essential conclusions have been obtained: (1) The effect of graphite phase and C-H phase on HSA adsorption are greater than that of other phase components; with the increase of these two phase coumponents, the adsorptive amounts of HSA decrease; (2) The powerful influence on HFG adsorption stems from DLC phase and C-O phase; with the decrease of DLC phase or the increase of C-O phase, the adsorptive amounts of HFG increase; (3) All of the carbon phase components have only limited influence on IgG adsorption in positive or negative fashion with a little difference in degree; (4) DLC phase has both effects of enhancing adsorption for HSA and weakening adsorption for HFG and IgG, thus its influence on the hemocompatibility of DLC films is much more important than that of other phase components.
Adsorption ; Carbon ; chemistry ; Coated Materials, Biocompatible ; chemistry ; Diamond ; chemistry ; Humans ; Materials Testing ; Membranes, Artificial ; Serum Albumin ; chemistry ; Surface Properties

In this paper, the adsorption of human serum albumin(HSA), human serum fibrinogen (HFG) and human serum immunoglobin(IgG) on diamond like carbon film(DLC) has been studied in comparison with diamond film (DF) and graphite. The isothermal adsorption of the protein solution with single component and the competitive adsorption of binary protein system have been investigated by radio isotope 125I labelling method. Results showed that (1) the adsorptive amounts of three proteins on three material surfaces are all increased with the increasing concentration of protein solution, then the adsorption tends to reach an equilibrium; (2) the adsorptive amounts of three protein on graphite far exceed that on DLC and DF; (3) the adsorptive amounts of HSA on DLC are more than that on DF, while the adsorptive amounts of HFG and IgG on DF and graphite are apparently more than that on DLC; (4) the differences among the adsorptive amounts of three proteins on DLC are small, but adsorptive amounts of HFG and IgG on DF and graphite are much more than that of HSA; (5) the relative competitive adsorption ability of three proteins on DF and graphite is HFG > IgG > HSA, but on DLC, the sequence is HFG approximately HSA > IgG. Comparing with HSA, HFG has no apparent competitive adsorption superiority to DLC. These results indicate that there is no apparent difference for the adsorption of three human serum proteins on DLC, but the adsorption of HFG and IgG on DF and graphite takes precedence of various degrees. It probably makes a rational explanation for the result of hemocompatibility tests in vitro that DLC is superior to, DF and graphite.
Adsorption ; Biocompatible Materials ; chemistry ; Blood Proteins ; chemistry ; Diamond ; chemistry ; Fibrinogen ; chemistry ; Humans ; Immunoproteins ; chemistry ; In Vitro Techniques ; Materials Testing ; Membranes, Artificial ; Serum Albumin ; chemistry