This study investigated the chromium(Cr)detoxification mechanism-induced changes in growth and antioxidant defence enzyme activities in Chrysopogon zizanioides.Plant growth decreased by 36.8%and 45.0%in the shoots and...This study investigated the chromium(Cr)detoxification mechanism-induced changes in growth and antioxidant defence enzyme activities in Chrysopogon zizanioides.Plant growth decreased by 36.8%and 45.0%in the shoots and roots,respectively,in the 50 mg/L Cr treatment.Cr accumulation was higher in root(9807μg/g DW)than in shoots(8730μg/g DW).Photosynthetic pigments and malondialdehyde content increased up to the 30 mg/L Cr treatment,whereas they declined at higher doses.The activity of superoxide dismutase(SOD),catalase(CAT)and peroxidase(POX)were increased significantly with increasing of Cr dose but slightly declined at higher doses.Isozyme banding patterns revealed the expression of multiple bands for SOD,CAT and POX enzymes,and the band intensity decreased at high doses of Cr exposure.These results indicate that higher Cr doses increased the oxidative stress by over production of reactive oxygen species(ROS)in vetiver that had potential tolerance mechanism to Cr as evidenced by enhanced level of antioxidative enzymes,photosynthetic pigments,MDA contents.Therefore,vetiver has evolved a mechanism for detoxification and accumulates higher concentration of toxic Cr.This study provides a better understanding of how vetiver detoxifies Cr.展开更多
AIM： To build up the research models of hepatic fibrosis in mice.METHODS： Inbred wild-type FVB/N mice were either treated with alpha-naphthyl-isothiocyanate （ANIT）, allyl alcohol （AA）,carbon tetrachloride （CCl4...AIM： To build up the research models of hepatic fibrosis in mice.METHODS： Inbred wild-type FVB/N mice were either treated with alpha-naphthyl-isothiocyanate （ANIT）, allyl alcohol （AA）,carbon tetrachloride （CCl4）, 3,5-diethoxycarbonyl-l,4-dihydrocollidine （DDC）, and silica, or subjected to common bile duct ligation （CBDL） to induce hepatic injury. Liver biopsies were performed every 4 wk to evaluate hepatic fibrosis over a period of 6 mo. Cumulative cirrhosis and survival curves were constructed by life table method and compared with Wilcoxon test.RESULTS： Under the dosages used, there was neither mortality nor cirrhosis in AA and silica-treated groups. DDC and ANIT caused cirrhosis within 4-12 and 12-24 wk, respectively.Both showed significantly faster cirrhosis induction at high dosages without significant alteration of survival. The duration for cirrhosis induction by CCl4 ranged from 4 to 20 wk, mainly dependent upon the dosage. However, the increase in CCl4 dosage significantly worsened survival. Intraperitoneal CCl4 administration resulted in better survival in comparison with garage administration at high dosage, but not at medium and low dosages. After CBDL, all the mice developed liver cirrhosis within 4-8 wk and then died by the end of 26 wk.CONCLUSION： CBDL and administrations of ANIT, CCl4, and DDC ensured liver cirrhosis. CBDL required the least amount of time in cirrhosis induction, but caused shortened lives of mice. It was followed by DDC and ANIT administration with favorable survival. As for CCl4, the speed of cirrhosis induction and the mouse survival depended upon the dosages and the administration route.展开更多
AIM： To undertake analysis of hepatitis A viral load, alanine aminotransferase （ALT）, and viral genotypes with duration of viremia, and to correlate these parameters with CD4^＋/ CD8^＋ lymphocyte populations that ...AIM： To undertake analysis of hepatitis A viral load, alanine aminotransferase （ALT）, and viral genotypes with duration of viremia, and to correlate these parameters with CD4^＋/ CD8^＋ lymphocyte populations that control cell-mediated immunity. METHODS： Cell counts were carried out using fresh whole blood collected in EDTA vials using a fluorescence activated cell sorter. Hepatitis A virus （HAV） RNA was extracted from blood serum, reverse transcribed into cDNA and quantified by Real-Time polymerase chain reaction and was genotyped. RESULTS： Among 11 patients, 10 could be analyzed completely. Of these, 3 had severe acute hepatitis （s-AH） and the remainder had a self-limited acute hepatitis A （AHA）, with one patient with fulminant disease （encephalopathy Grade IV） dying on the 4^th d. The ALT level was significantly higher both in AHA （1070.9±894.3; P = 0.0014） and s-AH （1713.9±886.3; P = 0.001） compared to normal controls （23.6±7.2）. The prothrombin time in s-AH patients （21.0 ±2.0; P=0.02） was significantly higher than in AHA （14.3±1.1;P = 0.44）. The CD4^＋/CD8^＋ ratio in AHA patients （1.17 ＋ 0.11; P = 0.22） and s-AH （0.83 ＋ 0.12; P = 0.0002） were lower than seen in normal healthy controls （1.52）. Self-limited cases had peak viral load at the beginning of analysis while in s-AH patients this occurred at the 15TM or 30^th d. In acute and severe groups, one patient each belonged to genotype IA, with the remaining 8 cases belonging to genotype IIIA. The only fulminant hepatic failure case belonged to genotype IA. HAV viral load and AIT values collected during the entire course of the selflimited infection were directly correlated but this was not the case for s-AH patients.CONCLUSION： Based on a small-scale study, the persistently higher viral load of s-AH might be due to diminished cellular immunity and hemolysis. The duration of viremia was dependent on the host, as the viral genotype had no apparent role in clinical outcome of AVH and s-AH cases.展开更多
AIM： We set to determine factors that determine clinical severity after the development of resistance.METHODS： Thirty-five Asian patients with genotypic lamivudine resistance were analyzed in three groups： 13/35 （...AIM： We set to determine factors that determine clinical severity after the development of resistance.METHODS： Thirty-five Asian patients with genotypic lamivudine resistance were analyzed in three groups： 13/35 （37%） were non-cirrhotics with normal pre-treatment ALT （Group IA）, 12/35 （34%） were non-cirrhotics with elevated pre-treatment ALT （Group IB）, and 10/35 （29%） were cirrhotics （Group II）. Patients were followed for a median of 98 wk （range 26-220） after the emergence of genotypic resistance.RESULTS： Group IA patients tended to retain normal ALT. Group IB patients showed initial improvement of ALT with lamivudine but 9/12 patients （75%） developed abnormal ALT subsequently. On follow-up however, this persisted in only 33%. Group II patients also showed improvement while on treatment, but they deteriorated with the emergence of resistance with 30% death from decompensated liver disease. Pretreatment ALT levels and CPT score （in the cirrhotic group） were predictive of clinical resistance and correlated with peak ALT levels and CPT score.CONCLUSION： The phenotype of lamivudine-resistant HBV correlated with the pretreatment phenotype. The clinical course was generally benign in non-cirrhotics. However, cirrhotics had a high risk of progression and death （30%） with the development of lamivudine resistance.展开更多
AIM： To investigate the precise roles of CAR in CCI4- induced acute hepatotoxicity. METHODS： To prepare an acute liver injury model, CCI4 was intraperitoneally injected in CAR＋/＋ and CAR-/- mice. RESULTS： Elevati...AIM： To investigate the precise roles of CAR in CCI4- induced acute hepatotoxicity. METHODS： To prepare an acute liver injury model, CCI4 was intraperitoneally injected in CAR＋/＋ and CAR-/- mice. RESULTS： Elevation of serum alanine aminotransferase and extension of centrilobular necrosis were slightly inhibited in CAR-/- mice compared to CAR＋/＋ mice without PB. Administration of a CAR inducer, PB, revealed that CCl4-induced liver toxicity was partially inhibited in CAR-/- mice compared with CAR＋/＋ mice. On the other hand, androstanol, an inverse agonist ligand, inhibited hepatotoxicity in CAR＋/＋ but not in CAR./. mice. Thus, CAR activation caused CCl4 hepatotoxicity while CAR inhibition resulted in partial protection against CCl4-induced hepatotoxicity.There were no differences in the expression of CYP2E1, the main metabolizing enzyme for CCl4, between CAR＋/＋ and CAR./. mice. However, the expression of other CCI4-metabolizing enzymes, such as CYP2B10 and 3All, was induced by PB in CAR＋/＋ but not in CAR-/- mice. Although the main pathway of CCl4-induced acute liver injury is mediated by CYP2E1, CAR modulates its pathway via induction of CYP2B10 and 3All in the presence of activator or inhibitor. CONCLUSION： The nuclear receptor CAR modulates CCl4- induced liver injury via induction of CCl4-metabolizing enzymes in the presence of an activator. Our results suggest that drugs interacting with nuclear receptors such as PB might play critical roles in drug-induced liver injury or drug- drug interaction even though such drugs themselves are not hepatotoxic.展开更多
AIM： TO evaluate the validity of ultrasonographic and pathologic diagnosis of liver fibrosis in patients with chronic viral hepatitis. METHODS： The liver fibrosis status in 324 patients was evaluated by both needle ...AIM： TO evaluate the validity of ultrasonographic and pathologic diagnosis of liver fibrosis in patients with chronic viral hepatitis. METHODS： The liver fibrosis status in 324 patients was evaluated by both needle biopsy and ultrasonography. Liver fibrosis was divided into SO -S4 stages. S4 stage was designated as definite cirrhosis. The ultrasonographic examination included qualitative variables, description of liver surface and parenchyma, and quantitative parameters, such as diameter of vessels, blood flow velocity and spleen size. RESULTS： Ultrasonographic qualitative description of liver surface and parenchyma was related with the severity of fibrosis. Among the quantitative ultrasonographic parameters, cut-off value of spleen length （12.1 cm） had a sensitivity of 0.600 and a specificity of 0.753 for diagnosis of liver cirrhosis. The diameters of spleen （8 mm） and portal vein （12 mm） had a diagnostic sensitivity of 0.600 and 0.767, and a diagnostic specificity of 0.781 and 0.446, respectively. The diagnostic accuracy for liver cirrhosis was moderately satisfactory, and the negative predictive values of these parameters reached near 0.95. CONCLUSION： Ultrasonography can predict the degree of liver fibrosis or cirrhosis. A single ultrasonographic parameter is limited in sensitivity and specificity for the diagnosis of early cirrhosis. The presence or absence of liver cirrhosis in patients with chronic virus hepatitis can be detected using 2 or 3 quantitative and qualitative pa- rameters, especially the length of spleen, the diameter of spleen vein and echo pattern of liver surface.展开更多
Drug-induced liver injury is a significant and still unresolved clinical problem. Limitations to knowledge about the mechanisms of toxicity render incomplete the detection of hepatotoxic potential during preclinical d...Drug-induced liver injury is a significant and still unresolved clinical problem. Limitations to knowledge about the mechanisms of toxicity render incomplete the detection of hepatotoxic potential during preclinical development. Several xenobiotics are lipophilic substances and their transformation into hydrophilic compounds by the cytochrome P-450 system results in production of toxic metabolites. Aging, preexisting liver disease, enzyme induction or inhibition, genetic variances, local 02 supply and, above all, the intrinsic molecular properties of the drug may affect this process. Necrotic death follows antioxidant consumption and oxidation of intracellular proteins, which determine increased permeability of mitochondrial membranes, loss of potential, decreased ATP synthesis, inhibition of Ca^2＋-dependent ATPase, reduced capability to sequester Ca^2＋ within mitochondria, and membrane bleb formation. Conversely, activation of nucleases and energetic participation of mitochondria are the main intracellular mechanisms that lead to apoptosis. Non-parenchymal hepatic cells are inducers of hepatocellular injury and targets for damage. Activation of the immune system promotes idiosyncratic reactions that result in hepatic necrosis or cholestasis, in which different HLA genotypes might play a major role. This review focuses on current knowledge of the mechanisms of drug-induced liver injury and recent advances on newly discovered mechanisms of liver damage. Future perspectives including new frontiers for research are discussed.展开更多
As a fundamental component of the host cellular cytoskeleton, actin is routinely engaged by infecting viruses. Furthermore, viruses from diverse groups, and infecting diverse hosts, have convergently evolved an array ...As a fundamental component of the host cellular cytoskeleton, actin is routinely engaged by infecting viruses. Furthermore, viruses from diverse groups, and infecting diverse hosts, have convergently evolved an array of mechanisms for manipulating the actin cytoskeleton for efficacious infection. An ongoing chorus of research now indicates that the actin cytoskeleton is critical for viral replication at many stages of the viral life cycle, including binding, entry, nuclear localization, genomic transcription and reverse transcription, assembly, and egress/dissemination. Specifically, viruses subvert the force-generating and macromolecular scaffolding properties of the actin cytoskeleton to propel viral surfing, internalization, and migration within the cell. Additionally, viruses utilize the actin cytoskeleton to support and organize assembly sites, and eject budding virions for cell-to-cell transmission. It is the purpose of this review to provide an overview of current research, focusing on the various mechanisms and themes of virus-mediated actin modulation described therein.展开更多
In the search for new anti-tumor agents, exploiting features such as the flexibility of coordination modes of metals have become an alternative strategy for synthesizing pharmaceuticals. It has been shown that the Cu...In the search for new anti-tumor agents, exploiting features such as the flexibility of coordination modes of metals have become an alternative strategy for synthesizing pharmaceuticals. It has been shown that the CuDP （copper（II）, doxycycline, and 1,10-phenanthroline） complex cleaves DNA strands by an oxidative mechanism and by intercalating the major groove, resulting in a cytotoxic action. The objective of this study was to assess the mutageinc/recombinogenic effects of the CuDP complex in vivo using the SMART （Somatic Mutation and Recombination Test） in Drosophila melanogaster. Treatments were carried out with third instar larvae at the standard cross and high bioactivation cross using three concentrations of CuDP （6.92, 13.84 or 27.67 mM）. The mutagenic doxorubicin （0.4 mM） was used as a positive control and reverse osmosis water as a negative control. For each compound, marked trans-heterozygous and balanced heterozygous individuals were analyzed to determine the mutational and recombinogenic events occurring in the cells, We found that CuDP significantly increased the frequencies of mutant cells in both standard and high bioactivation crosses, mostly by induction of recombination. These data show that CuDP is a direct recombinogenic agent that is independent of bioactivation,展开更多
The paper analyzes the influence of lead toxicity by anaerobic granule sludge inhibition and recovering experiments. The result shows that there are different inhibition types at differ-ent lead contents. Higher lead ...The paper analyzes the influence of lead toxicity by anaerobic granule sludge inhibition and recovering experiments. The result shows that there are different inhibition types at differ-ent lead contents. Higher lead content leads to more inhibition granular sludge, and at the same time, the time of gas recovery is different. Lower lead content per microorganism results in sooner sludge recovery. Microorganisms have a good ability to resist lead toxicity.展开更多
An annual topic highlight: Alcohol and Liver, 2011, covers the important and new aspects of pathogenesis of alcoholic liver diseases (ALD). It includes broad topics ranging from the exacerbation of ALD by infectious (...An annual topic highlight: Alcohol and Liver, 2011, covers the important and new aspects of pathogenesis of alcoholic liver diseases (ALD). It includes broad topics ranging from the exacerbation of ALD by infectious (viral) agents (hepatitis C virus and human immunodeficiency virus) to the influence of alcohol on liver fibrogenesis, lipid rafts, autophagy and other aspects. This issue is recommended for both basic scientists and clinicians who are involved in alcoholic liver research.展开更多
The occurrence of massive CD4+ T cell depletion is one of the most prominent characteristics of human immunodeficiency virus type 1 (HIV-1) infection during acute phase, resulting in unrestorable destruction to the im...The occurrence of massive CD4+ T cell depletion is one of the most prominent characteristics of human immunodeficiency virus type 1 (HIV-1) infection during acute phase, resulting in unrestorable destruction to the immune system. The infected host undergoes an asymptomatic period lasting several years with low viral load and ostensibly healthy status, which is presumably due to virus-specific adaptive immune responses. In the absence of therapy, an overwhelming majority of cases develop to AIDS within 8-10 years of latent infection. In this review, we discuss the roles in AIDS pathogenesis played by massive CD4+ T lymphocytes depletion in gut-associated lymphoid tissue (GALT) during acute infection and abnormal immune activation emerging in the later part of chronic phase.展开更多
Baculoviruses are a family of arthropod-specific large DNA viruses that infect insect species belonging to the orders Lepidoptera,Hymenoptera and Diptera.In nature,occlusion-derived viruses(ODVs) initiate baculovirus ...Baculoviruses are a family of arthropod-specific large DNA viruses that infect insect species belonging to the orders Lepidoptera,Hymenoptera and Diptera.In nature,occlusion-derived viruses(ODVs) initiate baculovirus primary infection in the midgut epithelium of insect hosts,and this process is largely dependent on a number of ODV envelope proteins designated as per os infectivity factors(PIFs).Interestingly,PIF homologs are also present in other invertebrate large DNA viruses,which is indicative that per os infection is an ancient and phylogenetically conserved entry mechanism shared by these viruses.Here,we review the advances in the knowledge of the functions of individual PIFs and recent discoveries about the PIF complex,and discuss the evolutionary implications of PIF homologs in invertebrate DNA viruses.Furthermore,future research highlights on the per os infection mechanism are also prospected.展开更多
The chemical and biological mechanisms of life processes mostly consist of multistep and programmed processes at nanoscale levels. Interestingly enough, cell, the basic functional unit and platform that maintains life...The chemical and biological mechanisms of life processes mostly consist of multistep and programmed processes at nanoscale levels. Interestingly enough, cell, the basic functional unit and platform that maintains life processes, is composed of various organelles fulfilling sophisticated functions through the precise control on the biomolecules （e.g., proteins, phospholipid, nucleic acid and ions） in a spatial dimension of nanoscale sizes. Thus, understanding of the activities of manufactured nanoscale materials including their interaction with biological sys- tems is of great significance in chemistry, materials sci- ence, life science, medicine, environmental science and toxicology. In this brief review, we summarized the recent advances in nanotoxicological chemistry through the dis- section of pivotal factors （primarily focusing on dose and nanosurface chemistry） in determining nanomaterial- induced biological/toxic responses with particular empha- sis on the nanomaterial bioaccumulation （and interaction organs or target organs） at intact animal level. Due to the volume of manufacture and material application, we deliberately discussed carbon nanotubes, metal/metal oxide nanomaterials and quantum dots, severing as representativematerial types to illustrate the impact of dose and nanosurface chemistry in these toxicological scenarios. Finally, we have also delineated the grand challenges in this field in a conceptual framework of nanotoxicological chemistry. It is noted that this review is a part of our persistent endeavor of building the systematic knowledge framework for toxicological properties of engineered nanomaterials.展开更多
基金Project(41771512)supported by the National Natural Science Foundation of ChinaProject(2018RS3004)supported by Hunan Science&Technology Innovation Program,China
文摘This study investigated the chromium(Cr)detoxification mechanism-induced changes in growth and antioxidant defence enzyme activities in Chrysopogon zizanioides.Plant growth decreased by 36.8%and 45.0%in the shoots and roots,respectively,in the 50 mg/L Cr treatment.Cr accumulation was higher in root(9807μg/g DW)than in shoots(8730μg/g DW).Photosynthetic pigments and malondialdehyde content increased up to the 30 mg/L Cr treatment,whereas they declined at higher doses.The activity of superoxide dismutase(SOD),catalase(CAT)and peroxidase(POX)were increased significantly with increasing of Cr dose but slightly declined at higher doses.Isozyme banding patterns revealed the expression of multiple bands for SOD,CAT and POX enzymes,and the band intensity decreased at high doses of Cr exposure.These results indicate that higher Cr doses increased the oxidative stress by over production of reactive oxygen species(ROS)in vetiver that had potential tolerance mechanism to Cr as evidenced by enhanced level of antioxidative enzymes,photosynthetic pigments,MDA contents.Therefore,vetiver has evolved a mechanism for detoxification and accumulates higher concentration of toxic Cr.This study provides a better understanding of how vetiver detoxifies Cr.
基金Supported by the Chang Gung Memorial Hospital, Taoyuan, Taiwan, China, CMRPG 33014, CMRPG 33063 and CMRP 800
文摘AIM： To build up the research models of hepatic fibrosis in mice.METHODS： Inbred wild-type FVB/N mice were either treated with alpha-naphthyl-isothiocyanate （ANIT）, allyl alcohol （AA）,carbon tetrachloride （CCl4）, 3,5-diethoxycarbonyl-l,4-dihydrocollidine （DDC）, and silica, or subjected to common bile duct ligation （CBDL） to induce hepatic injury. Liver biopsies were performed every 4 wk to evaluate hepatic fibrosis over a period of 6 mo. Cumulative cirrhosis and survival curves were constructed by life table method and compared with Wilcoxon test.RESULTS： Under the dosages used, there was neither mortality nor cirrhosis in AA and silica-treated groups. DDC and ANIT caused cirrhosis within 4-12 and 12-24 wk, respectively.Both showed significantly faster cirrhosis induction at high dosages without significant alteration of survival. The duration for cirrhosis induction by CCl4 ranged from 4 to 20 wk, mainly dependent upon the dosage. However, the increase in CCl4 dosage significantly worsened survival. Intraperitoneal CCl4 administration resulted in better survival in comparison with garage administration at high dosage, but not at medium and low dosages. After CBDL, all the mice developed liver cirrhosis within 4-8 wk and then died by the end of 26 wk.CONCLUSION： CBDL and administrations of ANIT, CCl4, and DDC ensured liver cirrhosis. CBDL required the least amount of time in cirrhosis induction, but caused shortened lives of mice. It was followed by DDC and ANIT administration with favorable survival. As for CCl4, the speed of cirrhosis induction and the mouse survival depended upon the dosages and the administration route.
文摘AIM： To undertake analysis of hepatitis A viral load, alanine aminotransferase （ALT）, and viral genotypes with duration of viremia, and to correlate these parameters with CD4^＋/ CD8^＋ lymphocyte populations that control cell-mediated immunity. METHODS： Cell counts were carried out using fresh whole blood collected in EDTA vials using a fluorescence activated cell sorter. Hepatitis A virus （HAV） RNA was extracted from blood serum, reverse transcribed into cDNA and quantified by Real-Time polymerase chain reaction and was genotyped. RESULTS： Among 11 patients, 10 could be analyzed completely. Of these, 3 had severe acute hepatitis （s-AH） and the remainder had a self-limited acute hepatitis A （AHA）, with one patient with fulminant disease （encephalopathy Grade IV） dying on the 4^th d. The ALT level was significantly higher both in AHA （1070.9±894.3; P = 0.0014） and s-AH （1713.9±886.3; P = 0.001） compared to normal controls （23.6±7.2）. The prothrombin time in s-AH patients （21.0 ±2.0; P=0.02） was significantly higher than in AHA （14.3±1.1;P = 0.44）. The CD4^＋/CD8^＋ ratio in AHA patients （1.17 ＋ 0.11; P = 0.22） and s-AH （0.83 ＋ 0.12; P = 0.0002） were lower than seen in normal healthy controls （1.52）. Self-limited cases had peak viral load at the beginning of analysis while in s-AH patients this occurred at the 15TM or 30^th d. In acute and severe groups, one patient each belonged to genotype IA, with the remaining 8 cases belonging to genotype IIIA. The only fulminant hepatic failure case belonged to genotype IA. HAV viral load and AIT values collected during the entire course of the selflimited infection were directly correlated but this was not the case for s-AH patients.CONCLUSION： Based on a small-scale study, the persistently higher viral load of s-AH might be due to diminished cellular immunity and hemolysis. The duration of viremia was dependent on the host, as the viral genotype had no apparent role in clinical outcome of AVH and s-AH cases.
基金Supported by the National University of Singapore Grant, No. R-182-000-0001-731
文摘AIM： We set to determine factors that determine clinical severity after the development of resistance.METHODS： Thirty-five Asian patients with genotypic lamivudine resistance were analyzed in three groups： 13/35 （37%） were non-cirrhotics with normal pre-treatment ALT （Group IA）, 12/35 （34%） were non-cirrhotics with elevated pre-treatment ALT （Group IB）, and 10/35 （29%） were cirrhotics （Group II）. Patients were followed for a median of 98 wk （range 26-220） after the emergence of genotypic resistance.RESULTS： Group IA patients tended to retain normal ALT. Group IB patients showed initial improvement of ALT with lamivudine but 9/12 patients （75%） developed abnormal ALT subsequently. On follow-up however, this persisted in only 33%. Group II patients also showed improvement while on treatment, but they deteriorated with the emergence of resistance with 30% death from decompensated liver disease. Pretreatment ALT levels and CPT score （in the cirrhotic group） were predictive of clinical resistance and correlated with peak ALT levels and CPT score.CONCLUSION： The phenotype of lamivudine-resistant HBV correlated with the pretreatment phenotype. The clinical course was generally benign in non-cirrhotics. However, cirrhotics had a high risk of progression and death （30%） with the development of lamivudine resistance.
基金Supported by a Grant-in Aid for Scientific Research, No. 15790337from the Ministry of Education, Science, Sports and Culture of the Japanese Government
文摘AIM： To investigate the precise roles of CAR in CCI4- induced acute hepatotoxicity. METHODS： To prepare an acute liver injury model, CCI4 was intraperitoneally injected in CAR＋/＋ and CAR-/- mice. RESULTS： Elevation of serum alanine aminotransferase and extension of centrilobular necrosis were slightly inhibited in CAR-/- mice compared to CAR＋/＋ mice without PB. Administration of a CAR inducer, PB, revealed that CCl4-induced liver toxicity was partially inhibited in CAR-/- mice compared with CAR＋/＋ mice. On the other hand, androstanol, an inverse agonist ligand, inhibited hepatotoxicity in CAR＋/＋ but not in CAR./. mice. Thus, CAR activation caused CCl4 hepatotoxicity while CAR inhibition resulted in partial protection against CCl4-induced hepatotoxicity.There were no differences in the expression of CYP2E1, the main metabolizing enzyme for CCl4, between CAR＋/＋ and CAR./. mice. However, the expression of other CCI4-metabolizing enzymes, such as CYP2B10 and 3All, was induced by PB in CAR＋/＋ but not in CAR-/- mice. Although the main pathway of CCl4-induced acute liver injury is mediated by CYP2E1, CAR modulates its pathway via induction of CYP2B10 and 3All in the presence of activator or inhibitor. CONCLUSION： The nuclear receptor CAR modulates CCl4- induced liver injury via induction of CCl4-metabolizing enzymes in the presence of an activator. Our results suggest that drugs interacting with nuclear receptors such as PB might play critical roles in drug-induced liver injury or drug- drug interaction even though such drugs themselves are not hepatotoxic.
基金Supported by the Key Project of Shanghai Medical Development Foundation.No.99ZDI001Shanghai Leading Academic Discipline project,No.Y0205
文摘AIM： TO evaluate the validity of ultrasonographic and pathologic diagnosis of liver fibrosis in patients with chronic viral hepatitis. METHODS： The liver fibrosis status in 324 patients was evaluated by both needle biopsy and ultrasonography. Liver fibrosis was divided into SO -S4 stages. S4 stage was designated as definite cirrhosis. The ultrasonographic examination included qualitative variables, description of liver surface and parenchyma, and quantitative parameters, such as diameter of vessels, blood flow velocity and spleen size. RESULTS： Ultrasonographic qualitative description of liver surface and parenchyma was related with the severity of fibrosis. Among the quantitative ultrasonographic parameters, cut-off value of spleen length （12.1 cm） had a sensitivity of 0.600 and a specificity of 0.753 for diagnosis of liver cirrhosis. The diameters of spleen （8 mm） and portal vein （12 mm） had a diagnostic sensitivity of 0.600 and 0.767, and a diagnostic specificity of 0.781 and 0.446, respectively. The diagnostic accuracy for liver cirrhosis was moderately satisfactory, and the negative predictive values of these parameters reached near 0.95. CONCLUSION： Ultrasonography can predict the degree of liver fibrosis or cirrhosis. A single ultrasonographic parameter is limited in sensitivity and specificity for the diagnosis of early cirrhosis. The presence or absence of liver cirrhosis in patients with chronic virus hepatitis can be detected using 2 or 3 quantitative and qualitative pa- rameters, especially the length of spleen, the diameter of spleen vein and echo pattern of liver surface.
文摘Drug-induced liver injury is a significant and still unresolved clinical problem. Limitations to knowledge about the mechanisms of toxicity render incomplete the detection of hepatotoxic potential during preclinical development. Several xenobiotics are lipophilic substances and their transformation into hydrophilic compounds by the cytochrome P-450 system results in production of toxic metabolites. Aging, preexisting liver disease, enzyme induction or inhibition, genetic variances, local 02 supply and, above all, the intrinsic molecular properties of the drug may affect this process. Necrotic death follows antioxidant consumption and oxidation of intracellular proteins, which determine increased permeability of mitochondrial membranes, loss of potential, decreased ATP synthesis, inhibition of Ca^2＋-dependent ATPase, reduced capability to sequester Ca^2＋ within mitochondria, and membrane bleb formation. Conversely, activation of nucleases and energetic participation of mitochondria are the main intracellular mechanisms that lead to apoptosis. Non-parenchymal hepatic cells are inducers of hepatocellular injury and targets for damage. Activation of the immune system promotes idiosyncratic reactions that result in hepatic necrosis or cholestasis, in which different HLA genotypes might play a major role. This review focuses on current knowledge of the mechanisms of drug-induced liver injury and recent advances on newly discovered mechanisms of liver damage. Future perspectives including new frontiers for research are discussed.
基金supported by US Public Health Service grant 1R01MH102144 from NIMH to Y. W
文摘As a fundamental component of the host cellular cytoskeleton, actin is routinely engaged by infecting viruses. Furthermore, viruses from diverse groups, and infecting diverse hosts, have convergently evolved an array of mechanisms for manipulating the actin cytoskeleton for efficacious infection. An ongoing chorus of research now indicates that the actin cytoskeleton is critical for viral replication at many stages of the viral life cycle, including binding, entry, nuclear localization, genomic transcription and reverse transcription, assembly, and egress/dissemination. Specifically, viruses subvert the force-generating and macromolecular scaffolding properties of the actin cytoskeleton to propel viral surfing, internalization, and migration within the cell. Additionally, viruses utilize the actin cytoskeleton to support and organize assembly sites, and eject budding virions for cell-to-cell transmission. It is the purpose of this review to provide an overview of current research, focusing on the various mechanisms and themes of virus-mediated actin modulation described therein.
文摘In the search for new anti-tumor agents, exploiting features such as the flexibility of coordination modes of metals have become an alternative strategy for synthesizing pharmaceuticals. It has been shown that the CuDP （copper（II）, doxycycline, and 1,10-phenanthroline） complex cleaves DNA strands by an oxidative mechanism and by intercalating the major groove, resulting in a cytotoxic action. The objective of this study was to assess the mutageinc/recombinogenic effects of the CuDP complex in vivo using the SMART （Somatic Mutation and Recombination Test） in Drosophila melanogaster. Treatments were carried out with third instar larvae at the standard cross and high bioactivation cross using three concentrations of CuDP （6.92, 13.84 or 27.67 mM）. The mutagenic doxorubicin （0.4 mM） was used as a positive control and reverse osmosis water as a negative control. For each compound, marked trans-heterozygous and balanced heterozygous individuals were analyzed to determine the mutational and recombinogenic events occurring in the cells, We found that CuDP significantly increased the frequencies of mutant cells in both standard and high bioactivation crosses, mostly by induction of recombination. These data show that CuDP is a direct recombinogenic agent that is independent of bioactivation,
基金Supported by The national natural Science Foundation of China (Grant No.50172009).
文摘The paper analyzes the influence of lead toxicity by anaerobic granule sludge inhibition and recovering experiments. The result shows that there are different inhibition types at differ-ent lead contents. Higher lead content leads to more inhibition granular sludge, and at the same time, the time of gas recovery is different. Lower lead content per microorganism results in sooner sludge recovery. Microorganisms have a good ability to resist lead toxicity.
文摘An annual topic highlight: Alcohol and Liver, 2011, covers the important and new aspects of pathogenesis of alcoholic liver diseases (ALD). It includes broad topics ranging from the exacerbation of ALD by infectious (viral) agents (hepatitis C virus and human immunodeficiency virus) to the influence of alcohol on liver fibrogenesis, lipid rafts, autophagy and other aspects. This issue is recommended for both basic scientists and clinicians who are involved in alcoholic liver research.
文摘The occurrence of massive CD4+ T cell depletion is one of the most prominent characteristics of human immunodeficiency virus type 1 (HIV-1) infection during acute phase, resulting in unrestorable destruction to the immune system. The infected host undergoes an asymptomatic period lasting several years with low viral load and ostensibly healthy status, which is presumably due to virus-specific adaptive immune responses. In the absence of therapy, an overwhelming majority of cases develop to AIDS within 8-10 years of latent infection. In this review, we discuss the roles in AIDS pathogenesis played by massive CD4+ T lymphocytes depletion in gut-associated lymphoid tissue (GALT) during acute infection and abnormal immune activation emerging in the later part of chronic phase.
基金supported by the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB11030400)the National Natural Science Foundation of China(31130058,31621061)+1 种基金the Key Research Program of Frontier Sciences of the Chinese Academy of Sciences(QYZDJ-SSW-SMC021)the Virology Key Frontier Science Program of the State Key Laboratory of Virology(klv-2016-03)
文摘Baculoviruses are a family of arthropod-specific large DNA viruses that infect insect species belonging to the orders Lepidoptera,Hymenoptera and Diptera.In nature,occlusion-derived viruses(ODVs) initiate baculovirus primary infection in the midgut epithelium of insect hosts,and this process is largely dependent on a number of ODV envelope proteins designated as per os infectivity factors(PIFs).Interestingly,PIF homologs are also present in other invertebrate large DNA viruses,which is indicative that per os infection is an ancient and phylogenetically conserved entry mechanism shared by these viruses.Here,we review the advances in the knowledge of the functions of individual PIFs and recent discoveries about the PIF complex,and discuss the evolutionary implications of PIF homologs in invertebrate DNA viruses.Furthermore,future research highlights on the per os infection mechanism are also prospected.
基金supported by the National Natural Science Foundation of China(11305182,21277037,21320102003)the National Basic Research Program of China(2011CB933403)
文摘The chemical and biological mechanisms of life processes mostly consist of multistep and programmed processes at nanoscale levels. Interestingly enough, cell, the basic functional unit and platform that maintains life processes, is composed of various organelles fulfilling sophisticated functions through the precise control on the biomolecules （e.g., proteins, phospholipid, nucleic acid and ions） in a spatial dimension of nanoscale sizes. Thus, understanding of the activities of manufactured nanoscale materials including their interaction with biological sys- tems is of great significance in chemistry, materials sci- ence, life science, medicine, environmental science and toxicology. In this brief review, we summarized the recent advances in nanotoxicological chemistry through the dis- section of pivotal factors （primarily focusing on dose and nanosurface chemistry） in determining nanomaterial- induced biological/toxic responses with particular empha- sis on the nanomaterial bioaccumulation （and interaction organs or target organs） at intact animal level. Due to the volume of manufacture and material application, we deliberately discussed carbon nanotubes, metal/metal oxide nanomaterials and quantum dots, severing as representativematerial types to illustrate the impact of dose and nanosurface chemistry in these toxicological scenarios. Finally, we have also delineated the grand challenges in this field in a conceptual framework of nanotoxicological chemistry. It is noted that this review is a part of our persistent endeavor of building the systematic knowledge framework for toxicological properties of engineered nanomaterials.
