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

Abnormal proliferation of vascular smooth muscle cells (VSMCs) plays an important role in several pathological processes of cardiovascular diseases. In this study, the effects of XCT790, a potent and selective inverse agonist of estrogen-related receptor alpha (ERRalpha), on rat VSMCs proliferation and related signal pathways were investigated. The proliferative activity of VSMCs was determined by CCK-8 assay. The mRNA levels of ERRalpha, PGC-1alpha, OPN and MCAD were assayed by RT-PCR. The protein levels of ERRalpha, ERK2 and p-ERK1/2 were evaluated by Western blotting. ELISA was used to assess the protein expression of VEGF. The results showed that XCT790 (5-20 micromol x L(-1)) inhibited rat VSMCs proliferation, and the expression of ERRalpha and its target genes, as well as p-ERK1/2, were also inhibited. XCT790 inhibited VSMCs proliferation in a dose-dependent manner at the dose range from 5 to 20 micromol x L(-1) and in a time-dependent manner at the dose range from 10 to 20 micromol x L(-1). These findings demonstrate that XCT790 inhibits rat VSMCs proliferation by down-regulating the gene level of ERRalpha and thus inhibiting the ERK signal pathway, suggesting that ERRalpha may be a novel potential target for therapeutic approaches to inhibit VSMCs proliferation, which plays an important role in several cardiovascular diseases.
Animals ; Cadherins ; genetics ; metabolism ; Cell Proliferation ; drug effects ; Cells, Cultured ; Cytoskeletal Proteins ; genetics ; metabolism ; Dose-Response Relationship, Drug ; GTPase-Activating Proteins ; genetics ; metabolism ; MAP Kinase Signaling System ; Male ; Muscle, Smooth, Vascular ; cytology ; Myocytes, Smooth Muscle ; cytology ; drug effects ; metabolism ; Nitriles ; administration & dosage ; pharmacology ; Nuclear Proteins ; genetics ; metabolism ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; Phosphorylation ; RNA, Messenger ; metabolism ; Rats ; Rats, Sprague-Dawley ; Receptors, Estrogen ; genetics ; metabolism ; Thiazoles ; administration & dosage ; pharmacology ; Transcription Factors ; genetics ; metabolism ; Vascular Endothelial Growth Factor A ; genetics ; metabolism

This study was aimed to establish a rapid discrimination method of Pinellia ternataand its adulterants based on the odour fingerprints analysis.Typhonium flagelliforme and Arisaema Rhizome,which were the common adulterants of Pinellia ternata,were collected.The adulterants were mixed with Pinellia ternatain different proportions.E-nose technology was used to obtain the odour fingerprints of Pinellia ternataand its adulterants of different types and proportions.Chemometrics methods,such as the analysis of variance (ANOVA),principal component analysis (PCA) and discriminant factor analysis (DFA) were used in the analysis and discrimination on sensors response data collected by sensors.The results showed that there were obvious differences on the odour characteristics between Pinellia ternateand its adulterants.PCA can obviously discriminate Pinellia ternateand its adulterants.And the odour difference became obvious along with the increasing of the adulteration proportion.There was a linear relationship between e-nose signal and the proportion of Typhonium flagelliforme.The cumulative proportion in ANOVA of the DFA model was 100%.The correct recognition rate was not less than 97%.It was concluded that e-nose can be used for rapid discrimination of Pinellia ternataand its adulterants.This study provided new technology and method for the discrimination of adulterants of Chinese materia medica.

Objective To measure the in vitro antibacterial activity of tigecycline against carbapenems-resistant Acinetobacter calcoacetcus-Acinetobacter baumannii complex.Methods The isolated strains of carbapenems-resistant Acinetobacter calcoacetcus-Acinetobacter baumannii complex were collected in our hospital from December 2013 to February 2014.The MIC test strip was a-dopted to measure the MIC value of tigecycline.The break point adopted the judgment criteria published by FDA.Results All 61 strains of carbapenems-resistant Acinetobacter calcoacetcus-Acinetobacter baumannii complex had extremely high drug resistant rate to the commonly used antimicrobial agents.The sensitive rate of tigecycline was 80.3%,intermediation was 19.7% and no re-sistant strain was found in this study.MIC50 and MIC90 were 2 μg/mL and 3 μg/mL respectively.Conclusion Tigecycline has bet-ter in vitro antibacterial activity to the carbapenems-resistant Acinetobacter calcoacetcus-Acinetobacter baumannii complex isolated in our hospital.

Objective To investigate the synergistic effect of 11 β-hydroxysteriod dehydrogenase (11 β-HSD1) and S100A16 on the differentiation of3T3-L1 preadipocytes and its mechanism.Methods Lentiviral vectors PLJM1-11β-HSD1 and PLJM1-S100A16-GFP were respectively constructed and co-transfected into 3T3-L1 preadipocytes.The cell strains expressing 11 β-HSD1/S100A16 were screened with 2.5 μg/ml puromycin for two weeks.Western blot was employed to verify the lentiviral carrier transfection effects.The expressions of marker genes related to the adipocyte differentiation were detected by mean of realtime PCR.Oil red O staining was used to observe the lipid droplet accumulation and the content of triglyceride was measured after differentiation of preadipocytes.The effect of 11β-HSD1 and S100A16 on PPARγ promoter activity was detected by luciferase reporter gene.Results Compared with the empty vector group,the expressions of 11β-HSD1 and S100A16 protein in the lentivirus cotransfected 3T3-L1 cell strain were significantly higher.After 3T3-L1 cell strain co-expressing 1 1β-HSD1 and S100A16 was induced to differentiate for 8 days,the lipid droplets accumulation and triglyceride content were siginificantly increased,along with increased expressions of adipocyte differentiation marker genes such as PPARγ,CCAAT/enhancer binding protein α,lipoprotein lipase,fatty acid synthase,and adipocyte fatty acid-binding protein,in comparison with 11 β-HSD1 or S100A16 overexpression.The result of reporter gene indicated that 11 β-HSD1/ S100A16 enhanced PPARγ promoter activity.Conclusions 11β-HSD1 and S100A16 may jointly promote the differentiation of 3T3-L1 preadipocytes through a synergistic effect on PPARγexpression and play a critical role in the development of obesity.

Objective To investigate the neurodevelopmental outcomes and its risk factors of very low birth weight infant (VLBWI) and extremely low birth weight infants (ELBWI).Methods Data of 85 VLBWI and ELBWI hospitalized in Children's Hospital of Fudan University from October 2005 to November 2009 who had finished infant development test of Baley Scales of Infant Development Ⅱ (Bayley Ⅱ) for neurological development at corrected gestational age between 18 to 42 months were retrospectively reviewed.Twelve infants who accepted treatment in other hospital over 10 days were excluded; the rest 73 infants were divided into normal (neurodevelopment) group or abnormal group according to the definition of neurodevelopmental impairment reported by National Institute of Child Health and Human Development (NICHD) Neonatal Network.Potential risk factors of neurodevelopmental impairment were analyzed with Logistic stepwise regression.Results The mean gestational age of 73 infants was (30.4±2.3) weeks; among which 13 were smaller than 28 weeks,42 between 28 and 32 weeks,and 18 older than 32 weeks.The mean birth weight was (1208.0±208.5) g; among which 15 (20.6％) ＜1000 g,and 58 (79.4％) were between 1000 g and 1500 g.Four babies (5.5％) were diagnosed as movement retardation,and neurodevelopmental impairment occurred in 16 cases (21.9 ％),psychomotor developmental index ＜70 occurred in 6 cases (8.2％,one case complicating with cerebral palsy); mental developmental index ＜70 occurred in 2 cases (2.7％); both psychomotor developmental index and mental developmental index ＜70 occurred in 7 cases (9.6 ％,two cases complicating with cerebral palsy),and one case (1.4 ％) was cerebral palsy only.Blind in either eyes and hearing impairment requiring deaf-aid were not found in any of the 73 babies.Logistic stepwise regression showed that use of mechanical ventilation was related to neurodevelopmental impairment (OR =6.183,95％ CI:1.664-22.983,P =0.003).Psychomotor developmental index of infants who needed mechanical ventilation (77.5±15.1) was lower than that of infants did not need (87.3±15.1)(t=2.646,P=0.010).Conclusions VLBWI and ELBWI are in high risk of neurodevelopmental impairment,especially those who need mechanical ventilation.

The study is aimed to distinguish morphological characteristics of Dalbergiae Lignum collected from crude drug's markets and establish a identification methods and the quality standard for Dalbergiae Lignum. The macroscopic and microscopic features of Dalbergiae Lignum from crude drug's market were observed, analyzed and compared according to Hongmu specification issued by the People's Republic of China in 2000, and by the characteristics recorded in domestic monograph of Mucai Shibie (wood identification). The redwood of Dalbergiae Lignum cut into small pieces as medicinal material are dry heart wood of mahogany (trees from Dalbergia sp.), which characteristics of the small pieces as crude drug are different. There are differences in macroscopic and microscopic features about texture of wood and color, odor, taste, transverse section, radial section, tangential section. The results can provide basis for identification, application and improment of the quality standard of Dalbergiae Lignum as medicinal material.
China ; Dalbergia ; anatomy & histology ; chemistry ; classification ; Herbal Medicine ; economics ; Plants, Medicinal ; chemistry ; classification ; Quality Control ; Xylem ; anatomy & histology ; chemistry

Purpose To investigate the clinical value of gated myocardial perfusion imaging (GMPI) quantitative analysis technique in evaluating left ventricular remodeling and its effects on left ventricular function in patients with myocardial infarction (MI). Materials and Methods Seventy-six cases of MI patients were retrospectively analyzed, including pure left anterior descending artery (LAD) disease in 21 cases , left circumlfex artery (LCX) or right coronary branch (RCA) disease in 23 patients and multivessel disease in 32 cases. Seventy-four healthy people were additionally selected as control group. GMPI was performed on all subjects. Reconstruction images were automatically analyzed by using cardiac software QGS 2009 to obtain left ventricular remodeling index, including diastolic sphericity index (SIED) and end-systolic sphericity index (SIES). Cardiac function parameters were also obtained, including left ventricular end-diastolic volume (EDV), end-systolic volume (ESV), left ventricular ejection fraction (LVEF), and peak iflling rate (PFR). Differences of the left ventricular remodeling index and cardiac function parameters between the MI group and the control group were compared to analyze the relationship between left ventricular remodeling after myocardial infarction and coronary artery lesions. Results SIED, SIES and EDV, ESV in MI group were signiifcantly higher than those in the normal group (P<0.01). The cardiac function parameters of LVEF and PFR were significantly lower than those of the normal group (P<0.01). SIED and SIES in the group of LAD lesions and multi-vessel disease were signiifcantly higher than those in the LCX/RCA lesion group (P<0.05). The left ventricular remodeling was occurred more often in LAD lesion group and multi-vessel disease group than in the LCX/RCA lesion group (χ2=6.502 and 10.166, P<0.05). There was no significant difference between the LAD lesions group and multi-vessel disease group (χ2=0.105, P>0.05). Linear regression analysis showed that LVEF and PFR in group of left ventricular remodeling was signiifcantly lower with the increase of SIED (F=43.231 and 15.642, P<0.01). SIED and SIES analysis resulted in high correlation for both intra-observer and inter-observer (r=0.881-0.926, P<0.01). Conclusion Left ventricular remodeling after myocardial infarction can be accurately evaluated by GMPI. Patients with myocardial infarction due to LAD or multi-vessel coronary artery diseases may have left ventricular remodeling easier and more severe. Left ventricular remodeling will seriously affect the myocardial contraction and diastolic function, resulting in the entire left ventricular dysfunction.

BACKGROUND: Cerebral infarction is commonly associated with blood stasis syndrome. Abnormal alternation of blood rheology is generally manifested as increased blood viscosity and hematocrit (HCT). In isometric hemodilution, a certain amount of red blood cell (RBC) is shifted by bleeding and simultaneously, isometric diluter is supplemented to reduce whole blood viscosity.OBJECTIVE: To observe the improvement of astragalus injection, the Chinese herb for qi tonification and isometric hemodilution on blood rheology in blood stasis syndrome of cerebral infarction.DESIGN: Randomized controlled experiment and case-control analysis were designed.SETTING: Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology. PARTICIPANTS: In cerebral infarction group (infarction group), 64 inpatients of senile ischemic cerebral vascular disease were collected from Union Hospital Affiliated to Huazhong University of Science and Technology from March 2002 to March 2004. Al l of cases were aged over 60 years and were in conformity with the diagnostic criteria on blood stasis syndrome. According to random number table, routine treatment group (routine group) and the group of integrative therapy of Chinese and western medicine (experimental group) were divided, 32 cases in each one. 47 healthy people of similar age and diagnosed with routine physical examination were selected in normal control. METHODS: In routine group, cerebral infarction was treated with routine therapy, including extending capacity, reducing viscosity, resisting coagulation, blocking aggregation of platelet and dehydration and general symp tomatic supporting treatment. In experimental group, on basis of routine treatment, isometric hemodilution and astragalus injection, the Chinese herb for qi tonification were used. 10% of total blood amount (about 450-650 mL) was collected from vein, and colloid solution of same volume was injected intravenously. The treatment was applied once every 5 days, continuously for 3 times. Astragalus injection 50 mL mixed with physical saline 250 mL was intravenous dropped, once per day, continuously for 3 weeks. MAIN OUTCOME MEASURES: ① Comparison of indexes in bloodrheology before and after treatment in routine group and experimental group. ② Comparison of indexes in blood rheology between normal control and infarction group. RESULTS: According to intention management, 64 patients and 47 normal persons all entered result analysis. ① Comparison between infarction group and normal control: RVB, HCT and PFC (fibrinogen) were higher than normal control [(3.90±0.73), (3.40±0.28) mPa·s; (46.39±6.03) %,(42.61±2.91)%; (3.25±0.75), (3.08±0.46) g/L, P < 0.01, 0.05], MTIE (de formity index of RBC) was lower than normal control (0.958±0.006, 0.961 Shen H,Lu YD.Study on quantitative messurement of immunohistochemical ±0.004, P < 0.05). ② Comparison between routine group and experimental group: Difference in some indexes presented before the treatment. After treatment, RVB, HCT and PFC in experimental grou p were all lower than routine group [(3.90±0.52), (4.21±0.68) mPa·s; (43.80±3.29)%, (48.47±4.50)%; (3.31±0.60), (3.68±0.67) g/L, P < 0.01, 0.05]. CONCLUSION: Isometric hemodilution therapy and astragalus injection reduces blood viscosity, improves blood rheology and alleviates clinical svmptoms of blood stasis syndrome in senile cerebral infarction.

Objective To evaluate the role of early cleavage embryo in combination with embryo growth rate and morphology scoring in embryo selection in in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycles. Methods Six hundred and ten IVF/ICSI cycles were randomly assigned to group A(269 cycles) and group B(341 cycles). In group A, transferred embryos were chosen according to embryo growth rate and morphology scoring by 72 h(D3) after fertilization, while early cleavage embryo was added to the selecting system in group B. The pregnancy rate and implantation rate were compared between two groups, and the clinic outcomes were compared between transfers with early cleavage embryos and without early cleavage embryos in group B. Results The pregnancy rate and implantation rate in group B were significantly higher than those in group A (P < 0.05). Transfers with early cleavage embryos also achieved much higher pregnancy rate and implantation rate in group B (P < 0.01). Conclusion Compared with embryo growth rate and morphology scoring, early cleavage embryo in combination with embryo growth rate and morphology scoring can improve the clinical outcomes in IVF/ICSI cycles.