At present the study of Marine antineoplastic drugs has already become the focus of concern around the world, Marine natural products has become an important source of clinical anti-cancer drugs. Ecteinascidin-743 from the Caribbean sea squirts Ecteinascidia turbinata extraction have been the ocean alkaloid, antitumor activity is significantly higher than the current widely used clinical antitumor drugs, inhibit a wide variety of tumor cell activity such as leukemia, ovarian cancer, soft tissue sarcoma, melanoma, cervical cancer, breast cancer, colorectal cancer, kidney cancer, prostate cancer, lung cancer and non-small cell lung cancer and other tumor cells, is the first successful application to the oceans, clinical antitumor drugs. In this paper, the drug synthesis, pharmacological and clinical research progress were reviewed.

Objective To study the impact of ribavirin cumulative dose on virological response rates in genotype 1 hepatitis C virus(HCV)infected patients.Methods The medical records of 225 genotype 1 chronic hepatitis C(CHC)patients treated with peginterferon α-2a plus ribavirin were retrospectively analyzed.These patients were divided into four groups according to ribavirin cumulative dose:>97%,80%-97%,60%-79%and<60%of standard cumulative dose.The relationship between ribavirin cumulative dose and virological response rates was studied.Data as analyzed by chisquare test or F test.Results The incidence of ribavirin cumulative dose<97%was 43.1%(97/225),which was higher than peginterferon alfa-2a(27.1%,61/225)(x2=12.641,P=0.001).The sustained virological response rate(SVR)was 27.8%(5/18)in group of ribavirin cumulative dose <60%,which was much lower than those in groups of ribavirin cumulative dose>97%(65.6%,84/128),80%-97%(60.5%,26/43),60%-79%(58.3%,21/36)(x2=9.538,P=0.023).The relapse rate was 61.5%(8/13)in group of ribavirin cumulative dose<60%,which was significantly higher than those in groups of ribavirin cumulative dose>97%(20.0%,21/105),80%-97%(23.5% ,8/34),60%-79%(27.6%,8/29)(x2=10.837,P-0.013).Among patients achieved rapid virological response(RVR),SVR in groups of ribavirin cumulative dose>97%,80%-97%,60%-79%and<60 % of standard dose were 92.0%(23/25),88.9%(8/9),85.7%(6/7)and 75.0%(3/4),respectively(x2=1.098,P=0.778).Conclusiom Mlid reduction of ribavirin dose not affect SVR of genotype 1 HCV infected patients.However,the relapse rate is high and SVR is low in patients treated with ribavirin cumulative dose<60% of standard dose.

Objective To investigate the corelation between neutropenia (ANC) incidence and infection during treatment with peginterferon alfa and ribavirin for chronic hepatitis C.Methods A retrospective cohort study of 399 patients treated with peginterferon and ribavirin derived from database of Department of Infectious Diseases, the Second Affiliated Hospital, Harbin Medical University was conducted.The incidence of infections and their relation with ANC were investigated.Potential risk factors for infection were identified by multivariate analysis.Results During treatment,neutropenia (ANC ＜ 1.50 ×109/L) occurred in 251 patients.Among which,mild neutropenia [ANC: ( ＞ 0.75-＜ 1.50) x 109/L],moderate neutropenia [ANC: ( 0.50-0.75 ) × 109/L]and severe neutropenia ( ANC ＜ 0.50 × 109/L)occurred in 132 patients,103 patients and 16 patients,respectively.A total of 80 infections (20.1％ )occurred,among which,14 infections were defined as severe.There was no significant difference in infection rate between patients with and without neutropenia ( 19.9％,50/251 vs 20.3％,50/251 ; x2 =0.007,P =0.933).There was no significant difference in infection rate between patients with and without peginterferon dose reduction ( 21.5％,31/144 vs 19.2％,49/255 ; x2 =0.307,P =0.580 ).In multivariate logistic regression analysis,the independent factors associated with infection were age (P =0.021),diabetes (P =0.004) and cirrhosis (P =0.012).Conclusions Infections during treatment with peginterferon alfa and ribavirin for chronic hepatitis C are irrelevant to neutropenia.The independent factors associated with infection are age,diabetes and cirrhosis.

Objective To investigate epidemiological and clinical features of patients with clonorchiasis sinensis infection. Methods The epidemiological, clinical, laboratory and treatment data of clonorchiasis patients in Department of Infectious Diseases, Second Affiliated Hospital, Harbin Medical University from 2002 to 2004 were retrospectively analyzed. Results Sixty-eight point two percent patients had a history of eating raw freshwater fish and shrimp. Patients with occupations as cook, fish stock man, fishing man and fishmonger accounted for 22.6%. The transmission route was not clear in 9.1% of patients. The common clinical manifestations were abdominal pain (60.3%), fatigue (52.3%), diarrhea (33.0%), anorexia (69.3%), jaundice (23.9%), hepatomegaly (59.1%), splenomegaly (8.0%), dizziness (20.9%), fever (5.7%) and biliary colic (14.8%). Twenty-eight point four percent were asymptomatic. Other findings included liver dysfunction (70.4 %) and eosinophile granulocyteosis(69.3 %). Negative rate of stool egg of clonorchis sinensis after treatment with praziquantel or albendazole was 91.9% or 86.5%, respectively. There was no significant difference between the two groups ( χ2 = 0.561, P = 0.454). Conclusions Clinical manifestations of patients with clonorchiasis sinensis are complicated and often accompanied with liver dysfunction. Clonorchiasis sinensis is often misdiagnosed and should be paid much attention.

Objective To analyze the genetic difference of biological characters on germplasm resources of fenugreek(Trigonella foenumgraecum) and to study the genetic diversity of them.Methods Thirty-two fenugreek germplasm resources from Ningxia, other provinces in China,and abroad were used to investigate the biological characters on plant height,pod formation height,nodes per main stem,branches number,effective pod per plant and so on.The tested materials were planted in the farm of Ningxia University.The genetic diversity based on the phenotype was analyzed by Word′s minimum variance method.Results The variance analyses of ten biological characters were of significance or the most significance except pod length.The branches number and effective pod per plant possessed the largest coefficient of variance(CV). The pairwise Euclidean distance of the tested materials ranged from 1.11 to 9.49,averaged 4.01.Mean Euclidean distance of single tested material ranged from 2.94 to 6.54.The tested germplasm resources could be divided into three groups in D=6.86,which coincided with the district of collecting germplasm resources on the whole.Conclusion There is a little genetic difference in various fenugreek germplasm resources.Compared with Euclidean distance of germplasm resources from Ningxia,the Euclidean distance of most from abroad is far away from that of other provinces in China.

Objective:Antimicrobial peptides ( AMPs ) are peptides generated in the biological defense system against exogenous pathogens ,which is all important constituent of the non-specific immune system.The immune system can react and sometimes play an important role in tumor control both in animal models and in humans.In this study,CecropinXJ were used in the BALB/c Eca109 cells-bearing mice model.To investigate whether CecropinXJ exert anti-tumor efficiency through regulating immune response when treated with tumor-bearing mice.Methods:The expression of cytokines and DC surface molecules were detected by immunohisto-chemistry and Flow cytometry.Results:The experiment of mice showed that CecropinXJ could significantly inhibit the proliferation of transplanted tumors in dose-dependent manner.There were significant difference between control group and 10mg/kg CecropinXJ group on the volume and weight of tumor ( P<0.05 ).CecropinXJ inhibited Eca 109 cells infiltrating growth in tumor tissue without affecting viscera,and the expressions of VEGF and bFGF proteins were higher than those in the control group .The expression of cytokines and DC surface molecules,the results that,compared with the control group,CecropinXJ could not significantly promote the expression of CD4,IL-4 and IFN-γ,while not involving the expression of surface molecules on DCs in spleen (P>0.05).In CecropinXJ treatment group,TNF-αlevel in serum was significantly higher than the control group ( P<0.01 ).Conclusion: CecropinXJ could significantly inhibit tumor growth in Eca109 cells-bearing mice,and might not be affected anti-tumor efficiency through regulating immune response.

Objective The aim of this study was to investigate the effect of hepatitis C virus (HCV) replication on expression of silent information regulator 1 (SIRT1) and glucose metabolism of hepatocytes using Huh 7.5 cells harboring HCV replicon.Methods The level of reactive oxygen species (ROS),value of nicotinamide adenine dinucleotide (NAD+)/reduced form of nicotinamide adenine dinucleotide (NADH) was detected by flow cytometry and chromatometry.The activity,mRNA expression,and protein level of SIRT1 were detected by a scintillation counter,real-time fluorescence quantitative polymerase chain reaction (RT-PCR),and Western blot,respectively.Glucose uptake by hepatocytes and gluconeogenesis were detected using radioactive isotope method and glucose oxidase method.The mRNA levels of SIRT1 downstream glucose-metabolism genes were measured by RT-PCR.Measurement date were compared by t test.Results In replicon cells,the level of ROS (3.8±0.5 vs 1.0±0.2; t=12.736,P＜0.01) was increased and the value of NAD+/NADH (0.03±0.01 vs 0.12±0.03; t=6.971,P＜0.01) decreased compared with Huh 7.5 cells.The activity (0.3±0.1 vs 1.0±0.2; t=7.668,P＜0.01),mRNA expression(0.4±0.1 vs 1.0± 0.3; t=4.648,P＜0.01) and protein level(0.3±0.1 vs 0.8±0.2; t=5.941,P＜0.01) of SIRT1 were reduced.Inhibition of SIRT1 not only increased insulin receptor substrate-1 (IRS-1) phosphorylation (0.7±0.2 vs 0.4±0.1; t=3.286,P＜0.01),decreased protein kinase B (Akt) phosphorylation (0.3 ± 0.1 vs 0.6 ± 0.2; t=3.286,P＜0.01),down regulated cell surface expression of glucose transporler 2 (GLUT2,0.4±0.1 vs 1.0 ± 0.2; t =6.573,P＜0.01) and suppressed cellular glucose uptake (count per minute:4600±500 vs 21 000±4600; t=8.682,P＜0.01); but also decreased phosphorylation of forkhead box O1 (FoxO1,0.2＝0.1 vs 0.5±0.1; t=5.196,P＜ 0.01),up-regulated phosphoenolpyruvate carboxykinase (PEPCK,2.8±0.6 vs 1.0±0.3; t=6.573,P＜0.01) and glucose 6-phosphatase (2.6±0.5 vs 1.0±0.2; t=7.278,P＜0.01) genes,and promoted glucose production (2.5±0.5 vs 1.0±0.2; t=5.543,P＜0.01).Conclusions HCV replication decreases NAD+/NADH ratio,which might down-regulate the activity and the expression of SIRT1,leading to changes in the expression profile of glucose metabolism related genes and causing glucose metabolism disorders of hepatocytes by a decrease in glucose uptake and an increase in glucose production,and promotes HCV replication.

Objective To study the role of silent mating type information regulation 2 homolog1 (SIRT1)-adenosine monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway in hepatitis C virus core protein (HCV-core) induced energy metabolism disorders of hepatocytes.Methods HepG2 cells were transfected with recombined expressed plasmid pcDNA3.1-core.The level of reactive oxygen species (ROS),value of ATP/ADP and activity of AMPK α-2,and nicotinamide adenine dinucleotide (NAD)+/NADH in HepG2 cells expressing HCV-core were detected by flow cytometry,liquid scintillation counter and chromatometry,respectively.The activity of SIRT1 was detected with a fluorometric assay kit.Reverse transcription polymerase chain reaction (RT-PCR) and Western blot assay were performed to examine the expression of SIRT1 and AMPK α-2.Quantitative data were analyzed by t-test.Results It was confirmed by Western blot assay that HepG2 cells expressed HCV-core with relative molecular weight of 22 000.Compared to HepG2 cells,the level of ROS in HepG2 cells expressing HCV-core was significantly increased (1.0 ±0.1 vs 4.0±0.5,t=14.411,P＜0.01),the values of ATP/ADP were similar (8.2±2.2 vs 9.3±2.8,t=0.757,P＞0.05),AMPK α-2 (0.8±0.2 vs 0.2±0,t=7.345,P＜0.01),the values of NAD+/NADH (0.08±0.02 vs 0.02±0,t=7.348,P＜0.01),the activity of SIRT1 [(0.30±0.05) pmol· μg-1 · min-1 vs (0.15±0.04) pmol · μg 1 · min 1,t=5.738,P＜0.01] and the mRNA levels of SIRT1 (0.8±0.2 vs 0.4±0.1,t=4.382,P＜0.01) and AMPK α-2 mRNA (0.9±0.3 vs 0.2±0,t=5.715,P＜0.01),and the expression of SIRT1 (0.8±0.2 vs 0.3±0,t=5.941,P＜0.01) and phosphorylated AMPK protein (0.5±0.1 vs 0.1±0,t=9.608,P＜0.01) were all significantly decreased.Conclusion HCV core protein induces energy metabolism disorders of hepatocytes by down-regulation of SIRT1-AMPK signaling pathway.

ObjectiveTo investigate the effect of adding metformin to peginterferon alfa-2a and ribavirin on the efficacy in patients with genotype 1 chronic hepatitis C and insulin resistance.Methods Ninety-eight patients with genotype 1 chronic hepatitis C and insulin resistance were randomized into the treatment group (n=49) and the control group (n=49).The patients in the control group were treated with peginterferon alfa-2a and ribavirin,and those in the treatment group were treated with metformin in addition to peginterferon alfa-2a and ribavirin. The virologic response rate,the homeostasis model assessment for insulin resistence index (HOMA-IR) and incidence of side effects were compared between two groups.The related factors of sustained virological response (SVR) were studied by multivariate logistic regression analysis.ResultsThe SVR rate of the patients in the treatment group was significantly higher than that of the control group (59.2％ vs 38.8％; x2 =4.083,P=0.043).The HOMA-IR of patients in the treatment group at week 12,24,48 of treatment and week 24 of follow-up were 3.00±0.65,1.90±0.45,1.75±0.40 and 1.60±0.35,respectively,which were all lower than those in the control group (3.50±0.72,2.90±0.64,2.74± 0.48 and 2.60±0.55,respectively) (t=3.610,8.947,11.091 and 10.738,respectively; all P＜ 0.01).The incidence of diarrhea in the treatment group was higher than the control group (28.6％ vs 10.2％ ; x2 =5.288,P=0.021).In multivariate logistic regression analysis,the independent factors associated with SVR were metformin treatment (P =0.009) and HOMA-IR＜ 2 at week 24 of treatment (P=0.011 ). Conclusion The combination of metformin,peginterferon alfa-2a and ribavirin improves insulin sensitivity and increases SVR rate of patients with hepatitis C genotype 1 and insulin resistance with good safety profile.

ObjectiveTo investigate the impact of age and sex on virologic responses rates to peginterferon alfα-2a and ribavirin treatment in patients with chronic hepatitis C.MethodsThe medical records of 449 chronic hepatitis C patients,treated with peginterferon and ribavirin in Department of Infectious Diseases,the Second Affiliated Hospital,Harbin Medical University,were retrospectively analyzed.These patients were divided into three groups according to age:patients ＜40 years (n =131 ),patients 40-50 years ( n =131 ) and patients ＞ 50 years ( n =187 ).The virologic response rates,the incidences of side events,and the rates of patients receiving ≥ 80％ of planned peginterferon alfα-2a or ribavirin dose were compared between male and female patients in the three groups.The influential factors on sustained virologic response (SVR) of patients were studied by multivariate analysis.Results For genotype 1,in patients ＜ 40 years group,the SVR rate of female was significantly higher than that of male (75.0％,30/40 vs 54.0％,27/50; P ＜0.05 ) ; in patients 40-50 years group,there was no significant difference in the SVR rate between male and female (51.0％,25/49 vs 53.7％,22/41 ; P ＞ 0.05 ) ; in patients ＞50 years group,the SVR rate of female was significantly lower than that of male (31.1％,19/61 vs 50.7％,34/67; P ＜0.05).For genotype 2,there were no significant differences in virologic response rates between male and female in the three groups.The incidence of adverse events of patients aged ＜ 40 years group,40-50 years group,＞ 50 years group,were 51.1％ (67/131),51.1％ (67/131),and 70.6％ (132/187),respectively,and the incidence of adverse events of patients aged ＞ 50 years was significantly higher than those of other groups ( P ＜ 0.001 ).For genotype 1,in patients ＞ 50 years group,the rate of patients receiving ≥80％ of planned ribavirin dose of female was significantly lower than that of male (42.6％,26/61 vs 62.7％,42/67; P ＜ 0.05).In multivariate analysis,the independent factors associated with SVR of patients aged ＞ 50 years were sex ( P =0.013 ),genotypes ( P =0.002 ),cirrhosis ( P =0.004 ),≥ 80％ of planned ribavirin dose ( P =0.008 ) and presence of rapid virologic response (RVR) ( P =0.001 ).ConclusionsFor genotype 1 patients,in patients ＜ 40 years group the SVR rate of female is higher than that of male; in patients 40-50 years group,male and female share similar SVR rates;in patients ＞ 50 years group the SVR rate of female is lower than that of male.Age and sex has no impact on virologic responses rates for genotype 2 patients.