Multidrug-resistant (MDR) bacterial infections, especially those caused by Gram-negative pathogens, have emerged to be one of the world's greatest health threats. However, not only have recent decades shown a steady decline in the number of approved antimicrobial agents but a disappointing discovery also void. The development of novel antibiotics to treat MDR Gram-negative bacteria has been stagnated over the last half century. Though few compounds have shown activities in vitro, in animal models or even in clinical studies, the global antibiotic pipeline is not encouraging. There are a plethora of unexpected challenges that may arise and cannot always be solved to cause promising drugs to fail. This review intends to summarize recent research and development activities to meet the inevitable challenge in restricting the proliferation of MDR Gram-negative bacteria, with focus on compounds that have entered into clinical development stage. In addition to new analogues of existing antibiotic molecules, attention is also directed to alternative strategies to develop antibacterial agents with novel mechanisms of action.
Aminoglycosides ; pharmacology ; therapeutic use ; Animals ; Anti-Bacterial Agents ; pharmacology ; therapeutic use ; Antibodies, Monoclonal ; pharmacology ; therapeutic use ; Drug Discovery ; Drug Resistance, Multiple, Bacterial ; Enzyme Inhibitors ; pharmacology ; therapeutic use ; Ferrous Compounds ; pharmacology ; therapeutic use ; Gram-Negative Bacteria ; drug effects ; Gram-Negative Bacterial Infections ; drug therapy ; Humans ; Peptides ; pharmacology ; therapeutic use ; Peptidomimetics ; pharmacology ; therapeutic use ; Tetracyclines ; pharmacology ; therapeutic use ; beta-Lactamase Inhibitors ; beta-Lactams ; pharmacology ; therapeutic use

0.05). Conclusion Tianma Gouteng Decoction can reverse left ventricular hypertrophy and myocardial fibrosis,and its mechanism may be related to the inhibition of TGF-? 1 expression in cardiac muscle tissue.

The high production inulase strain was screened from the soil sample where burdock planted in Qin Village,Bayou Town,Pei County,Xuzhou.Inulase activity were determined which produced by 40 strains separated from soil.Three mold stains,C122803、D081506 and D081513,which had higher ability of producing inulase were obtained by using transparent circle method as initial screening and rocker method as re-screening.Enzyme activity of the three strains were 1.411U/ml,1.895U/ml,1.792U/ml,separately.Enzyme activity of D081506,1.895U/ml,was the highest.The fermentation conditions of D081506 were studied and the optimized conditions were lappa juice 2.0%,yeast extraction 1.6%,(NH4)2SO4 0.5%,NaCl 0.5%,K2HPO4 0.5% and pH 5.0.Inulase activity of D081506 was 2.9578U/ml which increased 56.09% under the condition of 27℃,140r/min,24h.

Osteoarthritis (Osteoarthritis, OA) is a common clinical degenerative joint disease with increased incidence rate in recent years. Animal experiment is one of the important ways to explore pathogenesis and treatment of OA, while induced animal model is the most important part in animal experiment. Intra-articular injection of drugs is a classical method for establishing animal model of OA. Choose of animal should follows the principle of correlation, appropriateness and practicability, injections should perform in accordance with experimental purposes and subject, detections means and evaluation methods also should corresponding to experimental reality. The gold standard of OA animal model and intra-articular injections has not build, need further study.
Animals ; Cytokines ; analysis ; Disease Models, Animal ; Injections, Intra-Articular ; Mice ; Osteoarthritis ; diagnosis ; etiology ; immunology ; Rabbits ; Rats

OBJECTIVEChina began providing antiretroviral therapy to people living with HIV/AIDS (PLWHA) in 2003. This study was to investigate the living conditions, including quality of life and happiness, and need for palliative care of end-of-life PLWHA in rural Henan.

METHODSOne hundred end-of-life AIDS patients were selected from Weishi, Zhenping and Tanghe counties in Henan, using convenience sampling. The World Health Organization Quality of Life for HIV (WHOQOL-HIV) BREF Chinese Version was used to measure the quality of life and the Memorial University of Newfoundland Scale of Happiness (MUNSH) was employed to measure subjective welfare. Qualitative interviews and focus group discussions were undertaken to learn about the palliative care provided and the specific needs of the end-of-life patients.

RESULTSPatients' overall quality of life was moderate (12.62±1.97). Highest scores were in the spirituality/religion/personal beliefs, higher than the average scores in the Chinese population (P<0.01), while psychological (13.58±2.06) and environment (12.50±3.28) domain scores were similar to the latter (P>0.05). Both independence (12.15±2.15) and physiological (14.04±3.16) domain scores were lower than the average of the people living with HIV/AIDS in other studies (P<0.01); however, all were in the moderate range. The average MUNSH score was 21.00±6.20, which was also moderate. The in-depth interviews indicated that the Henan Provincial Government's policy of treatment and care had a beneficial impact on end-of-life AIDS patients, although the care components could be improved.

CONCLUSIONSLiving conditions of the end-of-life AIDS patients were moderate, and the HIV/AIDS palliative care model used was beneficial to them. Care could be improved by assisting the family unit as a whole.

Acquired Immunodeficiency Syndrome ; drug therapy ; epidemiology ; psychology ; therapy ; Adult ; Antiretroviral Therapy, Highly Active ; Blood Donors ; psychology ; China ; Critical Illness ; Female ; HIV Infections ; drug therapy ; epidemiology ; psychology ; therapy ; Humans ; Male ; Palliative Care ; standards ; Plasma Exchange ; statistics & numerical data ; Quality of Health Care ; Quality of Life ; Rural Population ; Surveys and Questionnaires

Objective To observe the effect of small doses of thrombin inhibitor(Shuxuetong injection)on the absorption of hematoma and the volume of low-density areas in acute stage of cerebral hemorrhage.Methods One hundred and twenty patients with acute cerebral hemorrhage,admitted to our hospital from February 2004 to April 2009,were randomly divided into treatment and control groups (n=60).The treatment group was treated with routine western medicine combined with thrombin inhibitor (Shuxuetong injection)4 mL dairy intravenously for 15 consecutive d.CT scan was employed to evaluate the hematomas volume and changes of low-density areas 7 and 21 d after the treatment.Results The volume of hematomas in the treatment group(17.8±2.1 mL,8.2±2.1 mL)reduced significantly as compared with that in the control group(21.3±1.6 mL,15.1±1.2 mL)on the 7~(th) and 21~(st) d(P<0.05).The volume of low-density area in the treatment group(1.433 mm)was significantly reduced as compared with that in the control group(3.041 mm,P<0.05).Conclusion Small doses of thrombin inhibitor (Shuxuetong injection)can promote the absorption of hematoma,reduce the volume of low-density areas surrounding hematomas in acute stage of cerebral hemorrhage.

OBJECTIVE To explore the neuro-protective effects of saffron (Crocus satius L.) on chronic focal cerebral ischemia in rats.METHODS SD rats were randomly divided into 6 groups:sham control group,MCAO group,edaravone group and saffron 30,100,300 mg·kg-1groups.Focal cerebral ischemia was induced by middle cerebral artery occlusion(MCAO).Saffron was administered orally by once daily from 2 h to 42 d after ischemia. At 42 d after cerebral ischemia, neurological deficit score, spontaneous activity test,elevated plus maze test,marble burying test and novel objective recognition test were used to evaluate the effects of saffron on the behevioural change. Infarct volume, survival neuron density, activated astrocyte number, and the thickness of glial scar were also detected. GFAP expression and inflammatory cytokine contents in ischemic peripheral region were detected by Western blot and ELISA,separately.RESULTS Saffron(100,300 mg·kg-1)improved the body weight decrease, neurological deficit and spontaneous activity. Saffron (30-300 mg·kg- 1) increased the traveled distance ratio and total time in open arm, decreased the buried marble number, which indicated that saffron could ameliorate anxiety- and depression-like behaviors. Saffron (100, 300 mg·kg-1)improved the learning and memory function,which manifested by increased discrimination ratio(DR)and discrim-ination index (DI) in T2test. The results of toluidine blue found saffron treatment (100, 300 mg·kg-1) decreased the infarct volume and increased the neuron density in cortex and hippocampal.The activated astrocyte number,the thickness of glial scar and GFAP expression in ischemic peripheral region decreased after saffron. Saffron (100, 300 mg·kg-1) decreased the contents of IL-6 and IL-1β, increased the content of IL-10 in ischemic peripheral region.CONCLUSION Saffron exerted neuro-protective effects on chronic focal cerebral ischemia,which could be related with inhibiting the activation of astrocyte and glial scar,following with the decrease of inflammatory reaction.

AIMTo investigate the effects of transforming growth factor-beta1 (TGF-beta1) and signal protein Smad3 on rat myocardial hypertrophy.

METHODSThe total protein was analysed by flow cytometer assay to judge the hypertrophy of myocardial cell incubated with different level of TGF-beta1 in cultured myocardial cells of neonatal rats. The models of rat cardiac hypertrophy were produced with constriction of the abdominal aorta. At the different time after the operation, the rats were killed, and the left ventricular mass indexes (LVMl) were investigated. The mRNA expressions of TGF-beta1 and Smad3 of cultured cells and hypertrophic left ventricles were assessed by RT-PCR, the protein expressions of Smad3 were assessed by Western blot.

RESULTSIn cultured neonatal myocardial cells, different level TGF-beta1 could significantly increase the total protein, and TGF-beta1 (3 ng/ml) could increase the expression of mRNA and protein of Smad3 and continued for 8 h of cultured cardiomyocytes. The LVMI and the expression of TGF-beta1 mRNA and Smad3 mRNA/protein of hypertrophic left ventricle were increased at the 3rd day after the operation and continued for 4 weeks. The peak expression of them was in 2 weeks after operation.

CONCLUSIONTGF-beta1 has the effects on rat myocardial hypertrophy, signal protein Smad3 is included in the pathologic progress of rat myocardial hypertrophy.

Animals ; Cardiomegaly ; metabolism ; pathology ; Cells, Cultured ; Male ; Myocytes, Cardiac ; metabolism ; Rats ; Rats, Sprague-Dawley ; Signal Transduction ; Smad3 Protein ; metabolism ; Transforming Growth Factor beta1 ; pharmacology

AIMTo investigate the molecular mechanisms of saponins from the rhizome of Anemarrhena asphodeloides Bunge.

METHODSOligonucleotide microarrays consisting of 87 probes representing 87 human cardiovascular disease-related genes were constructed. Effects of saponins on gene expression in human umbilical vein endothelial cells were analyzed by comparing hybridization of Cy 5-labeled cDNAs from saponins-treated human umbilical vein endothelial cells and Cy 3-labeled cDNAs from untreated human umbilical vein endothelial cells.

RESULTSThe results indicate that angiotensinogen gene, alpha 2A-adrenoceptor gene and endothelin-converting enzyme 1 gene were downregulated 2.8, 1.9 and 3.1 folds respectively after human umbilical vein endothelial cells were incubated in medium containing 80 mg.L-1 saponins.

CONCLUSIONThese results suggest that saponins may have beneficial effect on cardiovascular diseases by modulating the function of vein endothial cells and microarray can be used to investigate the biological action of extracts from traditional Chinese medicine.

Anemarrhena ; chemistry ; Angiotensinogen ; genetics ; metabolism ; Aspartic Acid Endopeptidases ; genetics ; metabolism ; Cells, Cultured ; Down-Regulation ; drug effects ; Endothelin-Converting Enzymes ; Endothelium, Vascular ; cytology ; metabolism ; Gene Expression ; drug effects ; Humans ; Metalloendopeptidases ; Oligonucleotide Array Sequence Analysis ; Plants, Medicinal ; chemistry ; Receptors, Adrenergic, alpha-2 ; genetics ; metabolism ; Rhizome ; chemistry ; Saponins ; isolation & purification ; pharmacology ; Umbilical Veins ; cytology ; metabolism

OBJECTIVETo observe effects of Fengbaisan (, FBS) on the expression of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in lung tissue of rats with chronic obstructive pulmonary disease (COPD) and to investigate the preventive and therapeutic mechanisms of FBS.

METHODSThe COPD rat model was established by cigarette smoke exposure and lipopolysaccharide (LPS) intra-tracheal dripping. The histopathological changes of lung tissue was observed via hematoxylin/eosin staining. The expression of MMP-9 and TIMP-1 in lung tissue was measured by reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry.

RESULTSThe typical histopathological changes of COPD were displayed in the model group, Ambroxol Hydrochloride group and FBS group, and the pathological lesions in the FBS group were less than those in the model group. The expression of MMP-9 and TIMP-1 in the model group increased significantly compared with those in the normal group (P<0.05). After treatment for successive 28 days, the expression of MMP-9 and TIMP-1 in the FBS group decreased remarkably as compared with the model group (P<0.05).

CONCLUSIONSFBS can regulate MMP-9/TIMP-1 imbalance to prevent airway and lung parenchyma remodeling process via reducing the expression of MMP-9 and TIMP-1 in the lung tissue of COPD rats, and this may be a possible therapeutic mechanism of FBS on COPD.

Animals ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Gene Expression Regulation, Enzymologic ; drug effects ; Immunohistochemistry ; Lung ; drug effects ; enzymology ; pathology ; Male ; Matrix Metalloproteinase 9 ; genetics ; metabolism ; Pulmonary Disease, Chronic Obstructive ; drug therapy ; enzymology ; RNA, Messenger ; genetics ; metabolism ; Rats ; Rats, Wistar ; Tissue Inhibitor of Metalloproteinase-1 ; genetics ; metabolism