Small molecule covalent inhibitors, or called as irreversible inhibitors, are a type of inhibitors that exert their biological functions by irreversibly binding to target through covalent bonds. Compared with non-covalent inhibitors, covalent inhibitors have obvious advantages in bioactivity. Nevertheless, these agents may also exhibit larger toxicity once off-target effects arise. This "double-edged swords" property often leads drug researchers to avoid attaching them. In recent years, some problems such as drug resistance are difficult to be solved with reversible inhibitors leading researchers to pay more attention on the covalent inhibitors. In this review, we shall make a short summary to the recent research progress of covalent inhibitors and the interaction modes between covalent inhibitors and their target protein residues.

Objective To research the mechanism of aqueous extract of Radix Scutellariae in relieving fever of model rats. Method The fever model rats were made by dry yeast. Rectum temperature (?T/℃) was observed, and serum IL-1?, hypothalamus cAMP and IL-1?, ventral septal area AVP were detected by RIA. Results Aqueous extract of Radix Scutellariae decreased IL-1? and cAMP content of hypothalamus, and AVP content of ventral septal area significantly (compared with model group, P

A century ago the Flexner Report facilitated the process of modern medical education reform.Half a century ago,Problem-based learning initiated the student-centered medical education model.At present training medical students' competency will usher in the third reform in medical education.Over 100 years' development and in the global context of current medical education reform,China's medical education has become an important part of the world medical education.Harbin Medical University conducted an all-around reform through international cooperation and received the accreditation referenced according to global standards in medical education,which is an epitome of the medical education reform in China.

Objective A preliminary study was conducted on the measuring tool for teachers' attitude in the medical schools towards curriculum integration of medical program.Methods Literature review and expert interview were conducted to design a questionnaire which comprised 56 items to investigate teachers' attitude towards medical curriculum integration.The method of factor analysis and Pearson correlation coefficient were used to evaluate structure validity,the content validity index I-CVI and S-CVI were used to evaluate the content validity and Cronbach's alpha coefficient and split-half reliability were used to evaluate the reliability of the questionnaire.Results Three principal components were extracted by factor analysis,which explained 59.219％ of the total variance.After rotation,the factors 1-3 were respectively defined as value recognition,participation initiative and emotional tendency.Cronbach's alpha coefficient of the three factors and all the items is 0.922,0.903,0.728 and 0.862 respectively.Conclusion The reliability and validity of the measurement tool is acceptable,and can be used as a reference for similar domestic survey

Objective The purpose of this study was to discuss the effect of visible light therapeutic equipment accompanied with electrolyzed-oxiding water (EOW) on pressure ulcer above the second phase. Methods We divided 44 patients with pressure ulcer above the second phase into the test group (23 cases, 28 spots) and the control group (21 cases, 25 spots). The test group received local decompression, debridement with EOW, exposure to visible light for 20 minutes, 10 times per day. The control group adopted local decompression, debridement with normal saline and local application of burn cream, 3 times per day. Results The effective rate of the test group was apparently higher than that of the control group (P<0.05). The healing time was also shorter than that of the control group (P<0.01). Conclusion Treatment of pressure ulcer above the second phase with visible light therapeutic equipment accompanied with electrolyzed-oxiding water proved to be an effective treatment method.

OBJECTIVE:To prepare compound ofloxacin gel and to establish its quality control method.METHODS:Ofloxacin was used as principal agent to be mixed with dexamethasone sodium phosphate,carbomer 940 was taken as base material,the content of ofloxacin and dexamethasone were determined by HPLC method.RESULTS:The linear detection concentration ranges of ofloxacin and dexamethasone were 20～300?g/ml and 5～50?g/ml,respectively,the average recovery rates of which were (99.8?0.5)%(RSD=0.84%)and (100.6?0.8)%(RSD=0.87%),respectively.CONCLUSION:The preparation is stable in quality,the prepare technique is simple and the quality control is reliable.

Background and purpose: Hepatocellular carcinoma (HCC) is a hypervascular tumor associated with a poor prognosis and lack of effective treatments. Consequently, identifying novel therapeutic strategies are urgently needed. We have previously shown that the kringle 1 domain of human hepatocyte growth factor (HGFK1) is a more effective anti-angiogenesis molecule than angiostatin. In this study, we observed the effects and mechanisms of HGFK1 gene on the HCC. Methods: A recombinant adeno-associated vires carrying the HGFK1 gene (rAAV-HGFK1) was constructed.HCC of rat was induced by McA-RH7777. rAAV-HGFK1 was used to treat the rat, median survival time and metastasis rate were observed. Results: Ten days after tumor cell inoculation, surgery were performed to confirm the tumor formation, PBS, rAAV-EGFP or rAAV-HGFK1 was injected directly into the tumor nodule followed by portal vein injection. Results from our study demonstrated that rAAV-HGFK1 treatment significantly prolonged the median survival time of the HCC bearing rats from 30 days (PBS and rAAV-EGFP groups) to 49 days (rAAV-HGFK1 group). More importantly rAAV-HGFK1 inhibited tumor growth and completely prevented liver, lung and peritoneal metastasis. In the controlled PBS and AAV-EGFP group, liver and peritoneal metastasis rate were both 100%, and lung metastasis rate was 100% and 83%, respectively. While there was no metastasis found in treatment group, with only 33% of ascites happened. This was most possibly due to the primary tumor in liver but not due to the metastasis. Moreover, at a higher magnification (1000×), it was clear that the HGFK1 protein was expressed mainly in the cytoplasma of liver cells. In parallel, IHC staining of CD31 also demonstrated a significantly lower level of microvessel density (MVD) (6.21±1.6) in the liver tumor of the AAV-HGFK1 treatment group, as compared to the two control PBS and AAV-EGFP groups (25.1±2.1 and 26.8±2.5, respectively, P<0.01). HE staining showed that AAV-HGFK1 treatment induced large areas of necrosis in the tumor tissues, while minimal areas of necrosis were observed in the tumor tissue in the control groups. In addition, no toxicity appeared when high dosage (4.8× 1012 vg/rat) of rAAV-HGFK1 was administered in rats. Conclusion: Results from this study demonstrated that HGFK1 inhibited the growth and metastasis of HCC and prolonged the survival time of animals with HCC through anti-angiogenesis effects. No obvious toxicity was observed. It might be the novel promising treatment for HCC and other cancers.

Objective To evaluate the value of echo‐contrast RT‐3DE for assessment of left ventricular volume and function in patients with left ventricular non‐compaction(LVNC) .Methods Twenty‐one patients of LVNC were involved and underwent non‐enhanced and contrast‐enhanced RT‐3DE to evaluate left ventricular end‐diastolic volume (LVEDV) ,left ventricular end‐systolic volume (LVESV) ,left ventricular ejection fraction (LVEF) .The endocardial border definition of LV was graded for each of the 16 LV segments as follows :0 = border invisible ,1 = border visualized only partially ,and 2 = complete visualization of the border .Three image‐quality groups (good ,fair ,and uninterpretable) were identified . Results ①Duringcontrast‐enhancedRT‐3DE,ascomparedwithnon‐enhancedRT‐3DE,thenumberof segments with complete visualization of the endocardial border increased significantly (55% vs 82% ,P <0.01) ,and the number of patients with a good‐quality echocardiogram increased significantly (33% vs 81% , P <0.01) .②Contrast‐enhanced RT‐3DE provided significantly larger values of LVEDV ( P < 0 0.1) and LVESV ( P < 0 0.1) as compared with non‐enhanced RT‐3DE ,the values of LVEF were not statistically different between the two techniques ( P =0.07) .③Intra‐and inter‐observer agreement for assessment of LV volumes and systolic function improved during contrast‐enhanced RT‐3DE ,as compared with non‐enhanced RT‐3DE .Conclusions Contrast‐enhanced RT‐3DE can increase the prevalence of good‐quality echocardiograms and significantly improve the reproducibility of LV volumes and function measurements .

Objective To investigate the effects of low density lipoprotein receptor (LDLr) pathway on podocyte injury in diabetic nephropathy (DN) under inflammatory stress.Methods Male db/db mice and db/m mice were randomly divided into four groups (8 mice in each group):db/m group (control),casein injected db/m group (db/m + casein),db/db group (db/db),and casein injected db/db group (db/db + casein).An inflamed model of DN was established according to our previous study.24-hour urinary protein was measured every week.The plasma lipid profile was detected by clinical biochemistry assay.Podocyte changes were evaluated by electron microscope and immunofluorescent staining.Lipid accumulation in the kidney was evaluated by oil red O staining and intracellular cholesterol quantitative assay.The protein expression of Wilm's tumor-1 (WT-1),nephrin,α-smooth muscle actin (t-SMA),and molecules correlated with LDLr pathway were examined by immunohistochemical staining or Western blotting.The colocalized protein expression of LDLr with WT-1 was examined by immunofluorescent staining and laser confocal microscopy.Results There were no differences in plasma levels of LDL and HDL among four groups.Compared with db/db group,the db/db+ casein group showed markedly increased 24-hour urinary protein,more significant podocyte foot process effacement and podocyte damage,increased lipid droplet accumulation in kidneys,increased protein expressions of LDLr,SCAP and SREBP-2 in kidneys (all P ＜ 0.05).Interestingly,increased LDLr protein expression in kidneys of db/db mice was negatively correlated with decreased nephrin protein expression (r =-0.855,P ＜ 0.01) and positively correlated with increased α-SMA protein expression (r=0.768,P ＜ 0.01).Conclusions The disruption of LDLr pathway induced by inflammation contributes to podocyte injuries in diabetic nephropathy.

In this study, 5'-CMP was sulfonated, and then the modified 5'-CMP was connected to a protein carrier as an immunogen to immunize BALB/c mice. After cell hybridization, screening and recloning , a McAb (B10) with high sensitivity and specificity was selected. In a dot Hot using the McAb B10, less than 0.05 pg of sulfonated DNA could be detected while 10 ng of DNA was not coloured The result showed that the sensitivity of McAb B10 was higher than that of the McAb from "Chemiprobe" kit