Identification and validation of a new target is one of the most important steps for new antituberculosis (TB) drug discovery. Researches have shown that Mycobacterium tuberculosis (Mtb) encodes 20 CYP450 enzymes which play important roles in the synthesis and metabolism of lipid, cholesterol utilization, and the electron transport of respiratory chain in Mtb. With the critical roles within the organism as well as the protein structures of six Mtb CYP450 enzymes being clarified, some of them have been highlighted as potential anti-tuberculosis targets. In this paper, the phylogenetic analysis, the structural features, and the enzymatic functions of Mtb CYPs, as well as the mechanism of interactions with selective inhibitors such as azole antifungal agents for the CYPs have been reviewed and summarized. The druggability of the CYPs has also been analyzed for their further utility as targets in high throughput screening and rational design of more selective inhibitors.
Antitubercular Agents ; chemistry ; pharmacology ; Azoles ; chemistry ; pharmacology ; Cytochrome P-450 Enzyme Inhibitors ; chemistry ; pharmacology ; Cytochrome P-450 Enzyme System ; genetics ; metabolism ; Drug Delivery Systems ; methods ; Drug Discovery ; Humans ; Mycobacterium tuberculosis ; drug effects ; enzymology ; genetics ; Phylogeny ; Tuberculosis ; drug therapy ; microbiology

Identification and validation of a new target is one of the most important steps for new antituberculosis (TB) drug discovery. Researches have shown that Mycobacterium tuberculosis (Mtb) encodes 20 CYP450 enzymes which play important roles in the synthesis and metabolism of lipid, cholesterol utilization, and the electron transport of respiratory chain in Mtb. With the critical roles within the organism as well as the protein structures of six Mtb CYP450 enzymes being clarified, some of them have been highlighted as potential anti-tuberculosis targets. In this paper, the phylogenetic analysis, the structural features, and the enzymatic functions of Mtb CYPs, as well as the mechanism of interactions with selective inhibitors such as azole antifungal agents for the CYPs have been reviewed and summarized. The druggability of the CYPs has also been analyzed for their further utility as targets in high throughput screening and rational design of more selective inhibitors.

Adolescent ; Adult ; Anemia, Aplastic ; etiology ; therapy ; Benzene ; poisoning ; Bone Marrow Cells ; drug effects ; pathology ; Female ; Humans ; Male ; Occupational Diseases ; etiology ; therapy ; Occupational Exposure ; adverse effects

BACKGROUND: There has been a change in the causes of aortic stenosis when comparence of rheumatioc aortic stenosis in recent year. Therefore, we studied the etiology factor of pure aortic stenosis. METHODS: The gross surgical pathologic features of the aortic valves were reviewed in 92 patients with pure aotic stenosis whom underwent aortic valve replacement at Yonsei University, Cardiovascular center between July 1989 and June 1994. RESULTS: The three most frequent causes were 1) calcification of congenital bicuspid valve in 30%, 2) degenerative calcification of aortic valve in 22%, 3) rheumatioc valvular change in 48%. The mean age at the time of aortic valve replacement for the entire series of patients was 54.4 years. The range of age was from 18 years to 77 years. Males predominated for degenerative disease and congenital bicuspid valves, but there were reversed rheumatic origin. One or more complications occured in 17% of patients undergoing operation. The surgical mortality was 3.3%. CONCLUSION: Our data suggest that more common cause of aortic stenosis is non-rheumatic disease rather than rheumatinc origin.
Adult* ; Aortic Valve ; Aortic Valve Stenosis ; Constriction, Pathologic* ; Humans ; Male ; Mitral Valve ; Mortality

Objective To identify the mechanisms of oral administered rapamycin on the prevention of restenosis after stent implantation with intravascular ultrasound (IVUS) and pathology.Methods Twenty-four New Zealand white rabbits underwent balloon-induced abdominal aortic wall injury and were given a diet of 1 ％ cholesterol for 8 weeks.Then,the rabbits were divided into three groups:the bare metal stent group(BMS group),the bare metal stent with oral rapamycin group(BMS + RAPA group) and the rapamycin eluting stent group(DES group).Rabbits in the RAPA and BMS + RAPA groups received a daily oral dose of rapamycin(0.5 mg/kg),whereas rabbits in the DES group received no drugs.All the rabbits were euthanized after the 4-week intervention.Serum lipids were measured.IVUS and pathologic studies were performed.The minimal luminal diameter (MLD),external elastic membrane (EEM) area,lumen area (LA),and plaque area(PA),plaque burden(PB) were measured.Mammalian target of rapamycin(mTOR) expression level was examined by immunohistochemistry.Results After the 4-week intervention,there was no significant difference of serum lipid levels among the three groups.IVUS showed that oral administration of rapamycin in the BMS + RAPA groups showed similar effects in reducing PA and PB as the DES group,which all were better than the BMS group.The BMS + RAPA and DES groups showed much more MLD and less lumen reduction,compared with the BMS group( P ＜0.05).Level of mTOR expression of the BMS + RAPA group and DES group was significantly lower than that of BMS group.Conclusions Oral administration of rapamycin demonstrates the same effect in the reduction of plaque burden and stent restenosis as the rapamycin eluting stent.Inhibition of mTOR by rapamycin involves in the stent restenosis.

Current patent protection of traditional Chinese medicine (TCM) compounds is far from being satisfactory with increasing research and development achievements. As patent protection of traditional Chinese medicine compounds is closely related with many fields such as research and development of new TCM drugs, industrial development and TCM internationalization, the development of research and harmonious development of TCM compounds and their patent protection is bound to have a far-reaching influence on domestic and even international societies.
Chemistry, Pharmaceutical ; economics ; legislation & jurisprudence ; China ; Drugs, Chinese Herbal ; chemistry ; economics ; Humans ; Medicine, Chinese Traditional ; economics ; Patents as Topic

We analyzed the epidemiological investigation results of the first case of human infected with avian influenza (H5N6) ,and summarized epidemiological characteristics of this case to provide reference to H 5N6 case screening and investiga‐tion in future works .We retrospectively described and analyzed the investigation progress ,specimen detection results of epi‐demic spot and intimate contact people ,and summarize epidemiological characteristics of this case .Result showed that the first case of human infected with H5N6 in Yunnan was a single case ,and did not showed human‐to‐human transmission .This case had contacts with wild bird and had birds’ market activity before diagnoses ;some environment specimen of birds market near patient’s home has detection results of H5N6 positive .This is a cases of local infection and did not show human‐to‐human transmission .From the investigation ,we could deduced that the transmission route is from birds to human or from birds to en‐vironment and then to human .

Objective To evaluate carotid intima-media thickness(IMT) and elasticity in patients with pregnancy-induced hypertension(PIH) using ultrasound radio-frequency data(RF-data) technology.Methods Twenty-seven PIH women(mean brachial blood pressure:108 mm Hg,1 mm Hg=0.133 kPa)were included and thirty age- and gestational week-matched normal pregnant women served as controls.Carotid IMT and stiffness were evaluated using quality IMT(QIMT) and quantitative artery stiffness(QAS)techniques with color Doppler.Results Carotid IMT and elasticity parameters,including pulse wave velocity,pressure at T1,arterial augmented pressure(AP) and arterial augmented pressure index(AIx) were significantly higher in PIH group than in the normal group[IMT:(466.84±118.50)μm vs (386.58±125.79)μm;PWV:(7.09±1.97)m/s vs (5.95±1.11) m/s;PT1:(127.50±14.29) mm Hg vs (105.89±11.02)mm Hg;AP:(5.14±3.39) mm Hg vs (1.98±2.19)mm Hg;AIx:(7.58±8.73)% vs (-4.79±7.92)%)], and there were significant differences(t=2.660,2.660,3.460,3.460,3.460,all P＜0.01).Conclusions PIH women have significantly increased carotid IMT and decreased elasticity compared with normal pregnant women.Radio-frequency technique could reliably reflect the changes of the carotid arterial structure and elasticity in patients with pregnancy-induced hypertension.

Objective Analyse the change of left ventricular (LV) longitudinal and radial strain in patients with aortic regurgitation (AR) and discuss the relationship between the 2D strain parameter and the filling and ejection of LV. Methods Thirty healthy controls and 45 patients with AR (24 patients with moderate AR and 21 with severe AR) were enrolled in this study, LV systolic global peak radial strain(GRS), systolic global peak longitudinal strain(GLS) and systolic peak longitudinal strain(S), systolic peak longitudinal strain rate(SRs), early diastolic peak longitudinal strain rate(SRe) of every segment were measured or calculated using 2D-STE, early and late diastolic transmitral flow velocity (E, A) were recorded by pulsed Doppler echocardiography and early diastolic mitral annular velocity (Ea) were assessed by tissue Doppler imaging,the E/A and E/Ea ratio were calculated. Discuss the relationship of GLS and LV ejection fraction (LVEF), GLS and E/Ea using the Pearson correlation analysis. Results The GLS were (-20.09±1.47)%, (-18.68±1.52)%, (-12.56±3.25)%and the GRS were (46.71±7.65)%, (43.01±5.95)%, (28.52±6.13)% in control group, patients with moderate and severe AR (MAR group and SAR group) respectively. There were significant differences among the groups (F =82.08,47.69, both P < 0.01) as following:SAR group with control group and MAR group [ q=17.56,13.60 (GLS), q=13.44, 10.20 (GRS), all P<0.01),MAR group and control group [ q=3.42 (GLS), P<0.01]. The SRs of the apical segment were (-1.24±0.22)s-1, (-1.19±0.25)s-1, (-1.04±0.28)s-1 in control group,MAR group and SAR group respectively. There were significant differences among the groups (F=4.47, P < 0.05) as following:SAR group with control group and MAR group ( q=4.02,3.28, both P<0.01). The S, SRe of apical segment and the S,SRs,SRe of basal and midventricular in MAR group were all lower than the control group ( q=4.42, 5.01, 3.48, 3.24, 4.78, 4.12, 3.61, 6.72, all P < 0.01). Pearson correlation analysis revealed the GLS had a relationship with LVEF and E/Ea ( r=-0.73, 0.64, both P<0.01). Conclusion The reduced longitudinal strain and strain rate could detect LV dysfunction in patients with AR in early stage and the GLS had the ability to reflect the diastolic filling and systolic ejecting of the LV.

Traditional clinical students training model is teacher-centered this education model has some defects.Whether an education model is advanced or not is relative to whether we can cultivate creative students with high quality.We use“one center, two auxiliarys,three stages”in our clinical education and fully utilize advanced education methods,combine theory with practice and cultivate creative students wiht high quality.