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 investigate the brain protection of adenosine preconditioning in infants with tetralngy of Fallot (TOF) undergoing open heart surgery. Methods 120 patients with TOF undergoing open heart surgery were randomly divided into two groups: adenosine group and control group. Total dosage of 1.5 mg/kg adenosine was intravenously dripped in the adenosine group before the cardiopulmonary bypass. Serum S-100β and neurone specific enolase (NSE) were measured before the cardipulminary bypass, 30 min and 12 hours after the aorta off clamping. Results At 30 min and 12 hour after opening the aorta, the S-100β[(0. 346±0. 162)μg/L vs. (0.717±0.260) μg/L and (0.541±0.272) μg/L vs. (1.140±0.567) μg/L,P <0.001 ]and NSE[(10.43±5.54) μg/L vs. (15.75±7.96)μg/Land (15.54±7. 98)μg/L vs. (23.67±8.00)μg/L,P<0.001]were both lower in adenosine group than that in control group. Conclusion Adenosine preconditioning can reduce the S-100β and NES in infants with TOF undergoing open heart surgery and has brain protection.

ObjectiveTo study microRNA (miRNA) expression and role of cell cycle regulation in decidualized endometrial stormal cells (ESC) in vitro.MethodsESC was induced decasualization in vitro and matched with non-decidualized cells as controls.The expression repertoire of miRNA was measured by microarray chip and was validated by real-time PCR.Flow cytometry was used to identify ESC cycle during decidual reaction in vitro and after miRNA222 inhibitor was transfected into it.Results (1) Between decidualized and undecidualized stromal cells,there were 49 miRNAs significantly different expression by microarray chip,including 16 miRNA up-regulation and 33 miRNA down-regulation.hsa-miR-27b,30c,143,101,181 b,29b,30d,507,23 a,222,221 exhibited significantly differential expression between decicualized and undecidualized stromal cells by real-time PCR (P ＜0.05).(2) After miRNA222 inhibitor (NC-FAM) transfection to decidual ESC,ESC were cultured by FBS medium for 24 hours,the rate of transfection was 70％.ESC were transfected with miRNA 222 inhibitor and cultured for 48 hours,the percentage of ESC at Sphase of (6.2 ± 0.7 ) ％ were significantly lower than ( 10.9 ± 0.8 ) ％ in control group ( P ＜ 0.05 ) ; the percentage of ESC at G0/G1 phase increased at transfection group [ (77.5 ± 1.3 ) ％ vs.(73.0 ± 1.6) ％ at control group ],but there was no significant difference (P ＞ 0.05 ).Decasualization ESC were transfected with miRNA 222 inhibitor and cultured for 48 h,the percentage of ESC at S-phase was ( 3.3 ± 0.6) ％ in transfection group,which were significantly lower than (7.8 ± 0.9 ) ％ in control group ( P ＜ 0.05 ).The percentage of ESC at G0/G1 phase was ( 80.7 ± 1.6 ) ％ in transfection group and ( 74.9 ± 1.1 ) ％.In control group,which did not reached statistical difference ( P ＞ 0.05).ConclusionmiRNA was involved in ESC decidual process in vitro by regulating cell cycle.

Objective To understand the life quality of elderly person in communities, nursing homes and elderly wards, and to find out the related influencing factors for providing references for policy-makers to improve the life quality of the elderly. Methods The senior citizens in 9 communities, 3 villages, 12 nursing homes and 5 elderly wards in Shanghai Minhang District were enrolled by stratified cluster sampling. And the life quality and its influential factors among the inhabitants in communities, nursing homes and elderly wards were compared by adopting Short-Form 36 (SF-36) questionnaire. Results Regarding to the life qualities of senior citizens, community showed that physical functioning was (71. 9 ± 23. 3)scores, role physical was (73. 6 ± 43. 0) scores, bodily pain was (80. 2±20. 3)scores, general health was (53. 2± 19. 1)scores, vitality was (70. 4± 15. 7)scores, social function was ( 83. 8 ± 20. 2) scores, role emotional was ( 81. 1 ± 37. 2 ) scores, mental health was (78. 1 ± 15. 4) scores, weighted average was (74. 1 ± 17. 5) scores. Nursing home showed that physical functioning was (42. 1 ±30. 7) scores, role physical was (57. 9 ±48. 1) scores, bodily pain was (78.0±23.0)scores, general health was (50. 2± 19. 5)scores, vitality was (66. 0± 19. 5)scores, social function was (70. 8 ± 26. 3) scores, role emotional was (66. 8 ± 45. 7) scores, mental health was (73. 6 ± 19. 6) scores, weighted average was (63. 2 ± 21. 0) scores. Elderly ward showed that physical functioning was (20. 4 ± 26. 0) scores, role physical was (36. 1 ± 47. 0) scores, bodily pain was (65. 4±29. 5)scores, general health was (43. 1±17. 1)scores, vitality was (59. 0± 18. 0)scores, social function was (57. 9 ± 25. 3) scores, role emotional was (49. 5 ± 48. 7) scores, mental health was (66. 2 ± 18. 3) scores, weighted average was (49. 7 ±18. 3) scores. The major influential factors on the life quality were gender, education, marriage, profession, age, disease, residence, entertainment, physical exercise for community; Age, disease, residence, entertainment, physical exercise for nursing home; Age, etc for elderly ward. Conclusions The influences of demographic factors on life quality of the senior citizens in communities are more significant than in nursing home and elderly wards. Variations on the degree of satisfaction (in residence, entertainment, health care and transportation) and the situation of physical exercise have made vast difference in the life quality of the senior citizens both in communities and nursing homes.

Objective To obtain the optimal solid dispersion prescription of the extract of Fructus Cnidii.Methods The release rate t63.2 was used as index and uniform design was used to investigate the effect of PEG,PVP,and Poloxamer on the release of the solid dispersion of the extract of Fructus Cnidii.Results PVP,PEG can delay the release of osthole from the solid dispersion,and tween-80 can promote its release.Conclusion The optimal solid dispersion prescription consists of tween-80(10.2 %),Poloxamer(79.8 %) and the extract(10 %).

This study examined the effects of Bangdeyun on the expressions of nuclear factor-kappaB (NF-kappaB), interferon-gamma (IFN-gamma) and interleukin-10 (IL-10) in the endometrium of mice with embryo implantation dysfunction (EID) during the implantation time (namely on pregnancy day 5, 6, 7 and 8) and explored the local immune regulatory effects of Bangdeyun. The gestational mice were randomly divided into normal group, model group and Bangdeyun-treated group. EID models of mice were established by using indomethacin. The endometrial expression of NF-kappaB was detected by immunohistochemistry and Western blotting. IFN-gamma and IL-10 were measured by enzyme-linked immunosorbent assay (ELISA). The results showed that in the normal group, NF-kappaB and IFN-gamma were weakly expressed and IL-10 was strongly expressed in the endometrium during the whole implantation period. In the model group, the expressions of NF-kappaB and IFN-gamma were increased on pregnancy day 5, 6 and 7, and IL-10 expression decreased during the whole implantation time when compared with those in the normal group (P<0.01 for all). In the Bangdeyun-treated group, little amount of NF-kappaB and IFN-gamma was expressed and IL-10 expression was strong, much the way they were expressed in the normal group (P>0.05). The expressions of NF-kappaB and IFN-gamma were much lower in the Bangdeyun-treated group than those in the model group on pregnancy day 5, 6 and 7 (P<0.01 for all), while the expression of IL-10 was much higher than in the model group during the whole implantation time (P<0.01). It was suggested Bangderun may favor a shift from Th1- to Th2-type immune response, therefore inhibiting the maternal immune rejection, inducing the immune tolerance and improving the fetal implantation.
Drugs, Chinese Herbal/*pharmacology ; Embryo Implantation, Delayed/*drug effects ; Embryo Implantation, Delayed/immunology ; Endometrium/*immunology ; Endometrium/metabolism ; Interferon-gamma/genetics ; Interferon-gamma/metabolism ; Interleukin-10/genetics ; Interleukin-10/metabolism ; NF-kappa B/genetics ; NF-kappa B/metabolism

Objective To study the changes of serum NO, TGF-β1, IL-10 and IL-17 Levels and study of the efficacy of Bismuth - containing quadruple and standard triple therapy for patients with Hp positive peptic ulcer. Methods 109 cases of peptic ulcer treated in our hospital were retrospectively selected, and Hp test was positive. According to different dosing regimen, the patients were divided into two groups. There were 54 patients in the control group, using standard triple therapy, and the regimen was lansoprazole, amoxicillin, and metronidazole. 55 patients in the study group were treated with bismuth-based western therapy with bismuth potassium citrate, rabeprazole, amoxicillin, and furazolidone. Two weeks after treatment were regarded as the observation period, and the levels of serum NO, TGF-β1, IL-10 and IL-17 in the two groups were compared before and after treatment. The effective rate of ulcer healing, Hp clearance rate and incidence of adverse reactions were compared. Results The level of serum NO, TGF-β1, IL-10 and IL-17 was significantly lower than that in the control group (P <0.05). The effective rates of ulcer healing and Hp clearance in the study group were significantly higher than those in the control group (P <0.05). There was no significant differences between the study group and the control group in the incidence of adverse reactions. Conclusion Western medicine with bismuth in the treatment of Hp peptic ulcer patients, the serum NO, TGF-β1, IL-10 and IL-17 levels of indicators have significantly improved, and has obvious advantages in clinical treatment, and it is a reasonable dosing regimen of high efficiency and low recurrence.

Objective To investigate the effects of reactive oxygen species (ROS) inhibition on the down-regulation of adiponectin (ADPN) in mouse 3T3-L1 adipocytes by advanced glycation end-products (AGEs).Methods AGEs were prepared for incubating with cell.3T3-L1 preadipocytes were cultured in vitro and differentiated into mature adipocytes.Cell differentiation and lipid accumulation were determined by oil red O staining.After being intervened with AGEs,2',7'-dichlorofluorescein diacetate (DCFH-DA) was used as a reactive oxygen species (ROS) capture agent and the fluorescent intensity of 2',7 '-dichlorofluorescein (DCF) was detected by flow cytometry.Adiponectin expression under AGEs in 3T3-L1 adipocytes pretreated with N-acetyl-L-cysteine(NAC) or not was detected by real-time fluorescent PCR and ELISA.Results The level of ROS in 3T3-L1 adipocytes treated with AGEs was increased.mRNA and protein of ADPN were down-regulated.After inhibition with ROS,mRNA and protein expressions of ADPN injured by AGEs were ameliorated.Conclusion Exposure of 3T3-L1 adipocytes to AGEs induces oxidative stress in vitro,which decreases the expression of ADPN,and causes functional impairment of adipose cells and insulin resistance.

Objective To investigate the relationship of urinary liver-type fatty-acid binding protein and progression of ne-phropathy in diabetic patients .Methods A total of 132 cases of type 1 and type 2 diabetic patients were recruited in this study , and were divided into four groups based on the urine albumin /creatinine and serum creatinine levels , including normal albuminuria group ( n =45), microalbuminuria group ( n =36), clinical albuminuria group ( n =30), and renal failure group ( n =21), Additional 65 healthy subjects were recruited as control group .The levels of urinary liver-type fatty-acid binding protein ( L-FABP) were measured with enzyme-linked immunosorbent assay (ELISA), and serum creatinine, urine creatinine, Liver function, hemoglobin, glycated he-moglobin (HbA1c), albumin (Alb), and 24h urinary protein were measured by respective biochemical or immunological methods . Results With the progression of diabetic nephropathy , the level of urinary L-FABP was gradually increased ( P <0.01 ) , subgroup analysis showed that the level of urine L-FABP of normal albuminuria group was significantly higher than that of healthy group ( P <0.05 ) .The level of urine L-FABP of microalbuminuria group was significantly higher than that of normal albuminuria group ( P <0.01 ) .The level of urine L-FABP of clinical albuminuria group was significantly higher than that of microalbuminuria group ( P <0.01 ) .The level of urine L-FABP of renal failure group was significantly higher than that of clinical albuminuria group ( P <0.01 ) . The levels of urinary L-FABP was negatively correlated with estimated glomerular filtration rate ( eGFR) ( r =-0.812 , P <0.01 ) , was positively correlated with Scr ( r =0.901, P <0.01), and was no correlation with HbA1c ( P >0.05).Conclusions The uri-nary L-FABP level can predict the occurrence of early diabetic nephropathy , and also monitor the progression of diabetic nephropathy .

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 .