Idiosyncratic adverse drug reactions (IDR) induce severe medical complications or even death in patients. Alert structure in drugs can be metabolized as reactive metabolite (RM) in the bodies, which is one of the major factors to induce IDR. Structure modification and avoidance of alert structure in the drug candidates is an efficient method for reducing toxicity risks in drug design. This review briefly summarized the recent development of the methodologies for structure optimization strategy to reduce the toxicity risks of drug candidates. These methods include blocking metabolic site, altering metabolic pathway, reducing activity, bioisosterism, and prodrug.
Binding Sites ; Cytochrome P-450 Enzyme System ; metabolism ; Drug Design ; Drug Discovery ; methods ; Drug Recalls ; Drug-Related Side Effects and Adverse Reactions ; prevention & control ; Humans ; Structure-Activity Relationship

OBJECTIVETo observe effects of mild moxibustion and lovastatin on immunologic function in rabbits with chronic hyperlipidaemia and atherosclerosis (AS) to initially explain regulating rules of mild moxibustion on immunologic function.

METHODSAmong thirty-two Japanese male big-ear rabbits, 8 rabbits were randomly selec ted as a blank group, the rest 24 rabbits were fed with method of endothelial injury and high-fat diet to establish AS model. The blank group was raised with normal diet and free water. After ten weeks of model establishment, the rest 24 rabbits were randomly divided into a model group, a moxibustion group and a medicine group, eight rabbits in each one. Moxibustion was applied at "Shenque" (CV 8) and "Zusanli" (ST 36) for 10 min per acupoint per day in the moxibustion group, while intragastric administration of 3.6 mg/kg lovastatin capsule was applied in the medicine group. After treatment, serum was acquired. Spectrophotometry method was adapted to measure cholesterol (TC) and high-density lipoprotein (HDL-C) and evaluated atherosclerosis index (AI), while enzyme-linked immunosorbent assay method was used to measure interferon-gamma (IFN-gamma) and interleukin-4 (IL-4).

RESULTS(1) The serum TC and HDL-C in the model group were significantly higher than those in the blank group, moxibustion group and medicine group (all P < 0.01). The mean value of AI was 1.683 +/- 0.486 in the moxibustion group, which was obviously lower than 20.301 +/- 4.022 in the model group (P < 0.01). (2) The ratio of Th1/Th2 was 0.569 +/- 0.143 in the moxibustion group and 0.445 +/- 0.079 in the medicine group, which were significantly lower than 0.917 +/- 0.255 in the model group (both P < 0.01), but there was no statistically significant difference between the moxibustion group and the medicine group (P > 0.05).

CONCLUSIONThe moxibustion for AS could reduce atherosclerosis index, influence drift and bias of helper T cell and regulate balance between humoral immunity and cellular immunity. As a result, status of relative balance of immunity is acquired, which could slow down the development of atherosclerosis and process of thrombus burst.

Animals ; Atherosclerosis ; immunology ; therapy ; Humans ; Hyperlipidemias ; immunology ; therapy ; Interferon-gamma ; immunology ; Interleukin-4 ; immunology ; Male ; Moxibustion ; Rabbits ; Th1 Cells ; immunology ; Th2 Cells ; immunology

Dental Porcelain ; Dental Prosthesis ; Dental Restoration, Permanent ; methods ; Humans

Objective To evaluate the efficacy of different doses of glucocorticoid for prevention of postoperative complications in patients undergoing coronary artery bypass grafting (CABG).Methods We searched PubMed,EMBASE,Highwire,CENTREN and its affiliated clinical trial registration data center,Chinese Biomedical Database,and CNKI from 2000 to 2010 for randomized controlled trials involving the efficacy of different doses of glucocorticoid for prevention of postoperative complications in patients undergoing CABG.The quality of the studies was evaluated by the method recommended by Cochrane Collaboration.Evaluation indexes included development of fibrillation,requirement for insulin treatment because of hyperglycosemia,infection,and death (during stay in hospital or within 30 days after discharge from hospital) after operation and mechanical ventilation time.Meta-analysis was conducted using the RevMan 5.1 software.Results Twenty-one randomized controlled trials involving 1737 patients were included in our meta-analysis.Different doses of glucocorticoid decreased the risk of fibrillation,and did not increase the risk of various causes-induced infection and death.Moderate and large doses of glucocorticoid increased the risk of requirement for insulin treatment because of hyperglucosemia.Large dose of glucocorticoid resulted in prolongation of ventilation time.Conclusion Different doses of glucocorticoid can decrease the development of postoperative fibrillation without increasing the risk of infection and death,moderate and large doses of glucocorticoid increase the risk of requirement for insulin treatment because of hyperglucosemia and large dose of glucocorticoid increases the risk of prolonged ventilation time in patients undergoing CABG.

Nature is abundant in protein scaffolds.By selecting suitable protein scaffold,display and screening methods,the rational and constrained random peptide library(RPL)can be constructed.Compared with the non-constrained RPL,it offered more opportunities for obtaining novel protein structures and more higher affinity ligands against the target molecules.At present,the protein scaffold constrained RPLs have been shown great potential in applications such as target selection,basic research,clinical diagnosis,medical therapy and so on.It is systematically introduced the structure bases,classification and construction of constrained RPL based on scaffolds,as well the recent great advances of application in selection against target molecules with S-S constrained scaffolds,antibodies,Zinc finger protein,Z domain,FN3 domain as important examples.

OBJECTIVETo explore effects and action mechanism of warm moxibustion on regulation of blood lipids and anti-atherosclerosis.

METHODSForty-one male Japanese big-ear white rabbits were randomly divided into a blank group (10 rabbits), a model group (10 rabbits), a moxibustion group (10 rabbits) and a medication group (11 rabbits). Normal diet was applied in the blank group while high-cholesterol diet combined with injection of bovine serum albumin were applied in the rest groups to establish rabbit model of atherosclerosis. After establishment, the model group was not intervened and warm moxibustion was applied in the moxibustion group at "Zusan-li" (ST 36) and "Shenque" (CV 8), 10 min per acupoint per day for continuous 4 weeks. The medication group was treated with intragastric administration of lovastatin capsule (3.6 mg/kg) for continuous 4 weeks. The level of blood lipids, such as total cholesterol (TC), triglyceride (TG), and content of CD40 ligand (CD40L), soluble CD40 ligand (sCD40L) and expression of nuclear factor NF-kappaB were tested after 4 weeks.

RESULTSCompared with the model group, the moxibustion group and medication group could effectively reduce the contents of TC and low density lipoprotein (all P < 0.05), lower the level of sCD40L [(8.310 +/- 1.221) ng/mL in the model group, (7.097 +/- 0.846) ng/mL in the moxibustion group and (7.354 +/- 0.631) ng/mL in the medication group], reduce expression of CD40L [(0.235 +/- 0.179) mm2 in the model group, (0.072 +/- 0.079) mm2 in the moxibustion group and (0.039 +/- 0.015) mm2 in the medication group] and NF-kappaB [(0.145 +/- 0.052)mm2 in the model group, (0.052 +/- 0.012) mm2 in the moxibustion group and (0.036 +/- 0.013) mm2 in the medication group], indicating the significant difference (P < 0.05, P < 0.001). There was no statistical difference between the moxibustion group and medication group (all P > 0.05).

CONCLUSIONThe warm moxibustion has great effect on regulation of blood lipids and anti-atherosclerosis, in which lowering expression of CD40-CD40L could be one of possible mechanisms to take effect of anti-atherosclerosis.

Animals ; Atherosclerosis ; blood ; therapy ; CD40 Antigens ; blood ; CD40 Ligand ; blood ; Humans ; Lipids ; blood ; Male ; Moxibustion ; methods ; Rabbits

Objective To identify a unique protein as a novel genetic marker for rapid molecular typing of Mycobacteriutn tuberculosis Beijing genotype strains by comparing the proteome of Beijing genotype strains with non-Beijing strains.Methods Fifty-six clinical isolates of Mycobacterium tuber- culosis were analyzed by spoligotyping to determine genotypes.The two-dimensional electrophoresis (2 DE)was used to compare the global protein patterns between Beijing genotype strains and non Bei jing strains.Differential expressed proteins were measured by matrix assisted laser desorption ioniza tion lime of flight mass spectrometry(MALDI-TOF-MS).The data obtained from peptide mass fingerprinting were compared in protein database.The genes encoding differential expressed proteins and their upstream were sequenced.Results Forty nine of the 56 isolates were Beijing genotype strains and 7 isolates were non-Beijing strains.A unique protein Rv0927c was identified,which is absent in Beijing genotype strains compared with 7 non Beijing strains and H37Rv.There were two characteristic mutations in Beijing genotype strains,a deletion of AGC at nucleotide position 421 of Rv0927c and a 127 G→A muta- tion in the upstream of Rv0927c.but not in non Beijing strains and H37Rv.Conclusion Characteris tic mutations of Rv0927c in Beijing genotype strains can be used as a novel genetic marker for rapid molecular typing of Mycobacteriuln tuberculosis Beijing genotype strains and non Beijing strains.

To further uncover the scientific significance and molecular mechanism of the Chinese herbs with pungent hot or warm natures, endogenous and exogenous expression systems were established by isolation of dorsal root ganglion (DRG) neurons and transfection of HEK293 cells with TRPV1 channel gene separately. On this basis, the regulation action of capsaicin, one main ingredient from chili pepper, on TRPV1 channel was further explored by using confocal microscope. Besides, the three-sites one-unit technique and method were constructed based on the brown adipose tissue (BAT), anal and tail skin temperatures. Then the effect of capsaicin on mouse energy metabolism was evaluated. Both endogenous and exogenous TRPV1 channel could be activated and this action could be specifically blocked by the TRPV1 channel inhibitor capsazepine. Simultaneously, the mice's core body temperature and BAT temperature fall down and then go up, accompanied by the increase of temperature of the mice's tail skin. Promotion of the energy metabolism by activation of TRPV1 channel might be the common way for the pungent-hot (warm) herbs to demonstrate their natures.
Adipose Tissue, Brown ; drug effects ; physiology ; Animals ; Capsaicin ; analogs & derivatives ; pharmacology ; Energy Metabolism ; Ganglia, Spinal ; cytology ; HEK293 Cells ; Humans ; Mice ; Neurons ; drug effects ; physiology ; Plants, Medicinal ; chemistry ; TRPV Cation Channels ; physiology ; Temperature ; Thermogenesis

Objective To investigate the intestinal pathophysiological mechanism of bacterial translocation and endotoxemia in rabbits with acute spinal cord injury (SCI). Methods Paraplegia was induced by injuring the spinal cord of 30 rabbits by the method of Fehlings. Twelve rabbits were used for recording the changes of gastrointestinal (GI) electrophysiology and colon pressure. The left 18 rabbits were experimental group and were killed in 24, 48 and 72 h after injury. The other 6 rabbits served as normal group. Under aseptic condition, samples of blood and mesenteric lymph node were collected for bacterial cultures and endotoxin detection. The small intestines were observed by light and electron microscopy. The colons were inspected by light microscopy. Results After SCI, the electrophysiology of the GI tract was changed especially at the middle and distal colon. The peristalsis of the middle and distal colon was reduced and sometimes even disappeared. In the early stage, the main pathology was hyperemia of blood vessel and infiltration of inflammatory cells. The interepithelial tight junctions became wider and the columnar epithelium was disintegrated. All of the pathological changes may lead to the destruction of the intestinal barrier. The endotoxin level were increased since 24 h after SCI and had statistically significant difference compared with that at 72 h (P0.05). Conclusion After SCI, the middle and distal colon dysfunction induces constipation, bacterial overgrowth, and blood flow congestion. These factors may accelerate the destruction of the intestinal barrier and lead to bacterial translocation and endotoxemia.

Objective To explore the effect of vascular endothelial growth factor antisense oligonucleotides(AS-VEGF)on HL60 cell and HL60/VCR multidrug resistance cell and analyze the function of P-gp and the expression of related multidrug resistance genes including Bcl-2,Mcl-1,MDR1,MRP,GST?,TopoⅡ? and TopoⅡ?.Methods A vector AS-VEGF which expressed in eukaryotic cell was established,then transfected the vector into HL60 and HL60/VCR by limposome transfection technology,observed and drew the growth curve by Tapanlan taining,RT-PCR was used to detect the expression of Bcl-2,Mcl-1,MDR1,MRP,GST?,TopoⅡ? and TopoⅡ? in mRNA level after transfected 24 h and 48 h.Western Blot was used to detect the expression of P-gp in proteinum level after transfected 24 h and 48 h.Results The growth of HL60 and HL60/VCR was inhibited by AS-VEGF(1.25 mmol/L).Between HL60 and HL60/VCR,AS-VEGF decreased the expression of MDR1,MRP,GST? and TopoⅡ? but could not influence the expression of Bcl-2,Mcl-1 and TopoⅡ?,and the expression of P-gp was also obviously decreased in 48 h compared with that in 24 h.Conclusions AS-VEGF can inhibite the growth of HL60 and HL60/VCR and reverse multidrug resistance by changing cell microenvironment and the cell membrane correlated protein transportating channel,reduce the cell disintoxicating and the self-repair ability.