Vascular endothelial cell growth inhibitor （VEGI） is a member of the tumor necrosis factor superfamily and plays an important role in vascular homeostasis. In this study, to investigate the anticancer therapeutic po...Vascular endothelial cell growth inhibitor （VEGI） is a member of the tumor necrosis factor superfamily and plays an important role in vascular homeostasis. In this study, to investigate the anticancer therapeutic potential of this gene, a secreted isoform of VEGI （VEGI-251） was inserted into a selectively replicating adenovirus with E1B 55 kDa gene deletion （ZD55） to construct ZD55-VEGI-251. We report here that secreted VEGI-251 produced from ZD55- VEGI-251-infected cancer cells potently inhibits endothelial cell proliferation, tube formation in vitro and angiogen- esis of chick chorioallantoic membrane in vivo. Additionally, ZD55-VEGI-251 infection leads to a much more severe cytopathic effect than control viruses on several human cancer cell lines, including cervical cancer cell line HeLa, hepatoma cell line SMMC-7721 and colorectal cancer cell line SW620. Further study reveals that the increased cytotoxicity is a result of VEGI-251 autocrine-dependent, mitochondria-mediated apoptosis accompanied by caspase-9 activation, enhanced caspase-3 activation and PARP cleavage. Moreover, ZD55-VEGI-251-treatment of athymic nude mice bearing human cervical and colorectal tumor xenografts markedly suppressed tumor growth. Our findings indicate that the combined effect of antiangiogenesis and apoptosis-induction activity makes the VEGI-251-armed oncolytic adenovirus a promising therapeutic agent for cancer.展开更多
Hepatocellular carcinoma （HCC） is a lethal disease in most patients, due to its aggressive course and a lack of effective systemic therapies for advanced disease. Surgical resection and liver transplantation remain ...Hepatocellular carcinoma （HCC） is a lethal disease in most patients, due to its aggressive course and a lack of effective systemic therapies for advanced disease. Surgical resection and liver transplantation remain the only curative options for a small subset of patients. Few patients with HCC are diagnosed early enough to be eli- gible for curative treatment. Angiogenesis inhibition is a natural therapeutic target for all solid tumors, but par- ticularly for the highly vascularized HCC tumors. With the approval of the targeted agent sorafenib, there are now additional options for patients with HCC. Although sorafenib does produce some improvement in survival in HCC patients, the responses are not durable. In addi- tion, there are significant dermatologic, gastrointestinal, and metabolic toxicities, and, as importantly, there is still limited knowledge of its usefulness in special sub- populations with HCC. Other angiogenesis inhibitors are in development to treat HCC both in the first-line set- ting and for use following sorafenib failure; the furthest in development is brivanib, a dual fibroblast growth factor pathway and vascular endothelial growth factor receptor inhibitor. Additional agents with antiangiogenic properties also in phase IT and Ⅲ development for the treatment of patients with HCC include bevacizumab, ramucirumab, ABT-869, everolimus and ARQ 197.展开更多
African trypanosomosis had caused lots of havocs to both humans and animals over a century with successes and failure in curtailing it. This study was aimed at screening medicinal plant, Terminalia chebula dried fruit...African trypanosomosis had caused lots of havocs to both humans and animals over a century with successes and failure in curtailing it. This study was aimed at screening medicinal plant, Terminalia chebula dried fruits against Trypanosoma evansi for trypanocidal activity. Twenty grams of powdered Terminalia chebula dried fruits was cold extracted with methanol. Obtained MPE （methanolic plant extract） was in vitro tested against Trypanosoma brucei （1 × 10^6 trypanosomes/mL of the medium in each ELISA plate wells） at concentrations （250～1,000 μg/mL） on Vero cells grown in DMEM （Debecco＇s Modified Eagle Medium） in appropriate conditions for trypanocidal activity. In-vitro cytotoxicity test of MPE of Terminalia chebula was conducted on Vero cells grown in DMEM. In-vivo assay for trypanocidal activity, each mouse was inoculated with 1 × 10^4/mL of trypanosomes and treated （48 h post inoculation） with MPE of Terminalia chebula at concentrations （12.5, 25, 50, 100 and 200 mg/kg body weight） were administered at dose rate of 100 BL per mouse via intraperitoneal route to different groups of mice, 6 mice per concentration. In-vitro cytotoxicity test was done on Veto cells at concentrations （1.58～100 μg/mL） of MPE of Terminalia chebula. Results of in-vitro trypanocidal activity varied from immobilization, reduction and to the killing of the trypanosomes. At 250 μg/mL ofMPE ofTerminalia chebula dried fruits, there was significant trypanocidal activity at 4 h of incubation and trypanosomes were not detected in corresponding ELISA plate wells at 5 h of incubation, which was statistically equivalent to reference drug, diminazine aceturate （50 μL/mL） at 4 h of incubation. Results of in-vivo trypanocidal activity revealed that at concentrations （l 2.5～25 mg/kg body weight） of MPE of Terrninalia chebula, mice in these groups survived for 6 days. While at 50 and 100 to 200 mg/kg body weight, mice in these groups survived up to 7 and 8 days, respectively. In-vitro cytotoxicity test showed that all concentrations of MPE of Terminalia chenula and diminazine aceturate were cytotoxic to cells except at 1.56 μL/mL and 6.25 μL/mL. In conclusion, MPE of Terminalia chebula dried fruits possessed trypanocidal compounds. Further study （bioassay-guided purification） is required to know the full potential of Terrninalia chebula as future trypanocide candidate.展开更多
This article analyzes the relationship between financial intermediary development and economic fluctuation in the last 50 years in China. It was found that a steady and long-term relation existed between these two var...This article analyzes the relationship between financial intermediary development and economic fluctuation in the last 50 years in China. It was found that a steady and long-term relation existed between these two variables, and that different aspects of the development of the financial intermediary system had different effects on the economic fluctuation. The improvement of the intermediary＇s efficiency can repress the economic fluctuation , but the increase of financial intermediaries can intensify the fluctuation. On that basis, some suggestions about the development of the financial intermediary are proposed in this essay.展开更多
Admittedly, the stratospheric rise of Informal African Immigrant Traders （IAIT） in the Johannesburg inner city within a climate of discrimination, harassment, hostility, and xenophobia has engendered survival strate...Admittedly, the stratospheric rise of Informal African Immigrant Traders （IAIT） in the Johannesburg inner city within a climate of discrimination, harassment, hostility, and xenophobia has engendered survival strategies which border on the illegal and underground. Based on an in-depth interview study of 40 IAIT, operating in the Johannesburg inner city and specialising in clothes, cellphone and accessories, household goods, fruits and vegetables, and a courier company, this paper posits that the registered and unregistered IAIT operate side by side with the latter operating from undesignated sites, either bribing or deceitful evading the Johannesburg Metropolitan Police （JMP）. Is this the characteristic of IAIT in the Johannesburg inner city？ Ostensibly, the success of challenging the institutional regulatory regime points to the possibility of African immigrant traders existing on the edge of impropriety or lawlessness. To this end, there is a need for comprehensive policy initiatives starting from the national and cascading to the provincial and municipality levels that will effectively address and manage urban informality, including the activities of the IAIT, failing which these will fuel operations outside the regulatory regimes and the mushrooming of the underground economic activities.展开更多
Powered by the mitochondrial membrane potential,Ca2+ permeates the mitochondria via a Ca2+ channel termed Ca2+ uniporter and is pumped out by a Na+/Ca2+ exchanger,both of which are located on the inner mitochondrial m...Powered by the mitochondrial membrane potential,Ca2+ permeates the mitochondria via a Ca2+ channel termed Ca2+ uniporter and is pumped out by a Na+/Ca2+ exchanger,both of which are located on the inner mitochondrial membrane.Mitochondrial Ca2+ transients are critical for metabolic activity and regulating global Ca2+ responses.On the other hand,failure to control mitochondrial Ca2+ is a hallmark of ischemic and neurodegenerative diseases.Despite their importance,identifying the uniporter and exchanger remains elusive and their inhibitors are non-specific.This review will focus on the mitochondrial exchanger,initially describing how it was molecularly identified and linked to a novel member of the Na+/Ca2+ exchanger superfamily termed NCLX.Molecular control of NCLX expression provides a selective tool to determine its physiological role in a variety of cell types.In lymphocytes,NCLX is essential for refilling the endoplasmic reticulum Ca2+ stores required for antigen-dependent signaling.Communication of NCLX with the store-operated channel in astroglia controls Ca2+ influx and thereby neuro-transmitter release and cell proliferation.The refilling of the Ca2+ stores in the sarcoplasmic reticulum,which is controlled by NCLX,determines the frequency of action potential and Ca2+ transients in cardiomyocytes.NCLX is emerging as a hub for integrating glucose-dependent Na+ and Ca2+ signaling in pancreatic β cells,and the specific molecular control of NCLX expression resolved the controversy regarding its role in neurons and β cells.Future studies on an NCLX knockdown mouse model and identification of human NCLX mutations are expected to determine the role of mitochondrial Ca2+ efflux in organ activity and whether NCLX inactivation is linked to ischemic and/or neurodegenerative syndromes.Structure-function analysis and protein analysis will identify the NCLX mode of regulation and its partners in the inner membrane of the mitochondria.展开更多
基金We thank Lanying Sun, Yang Xiao, Yuelei Chen, Hua Zhou and Cell Analysis Center （Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences） for professional technical assistance. This work was supported in part by grants from Hi-Tech Research Development Program of China （863 Program, No. 2007AA021006） the Key Project of the Chinese Academy of Sciences （No. KSCX2-YW- R-09）+1 种基金 the 973 Project （No. 2004CB518804） Grant 30623003 from National Nature Science Foundation of China and Grant 06DZ22032 from Science and Technology Commission of Shang- hai Municipality.
文摘Vascular endothelial cell growth inhibitor （VEGI） is a member of the tumor necrosis factor superfamily and plays an important role in vascular homeostasis. In this study, to investigate the anticancer therapeutic potential of this gene, a secreted isoform of VEGI （VEGI-251） was inserted into a selectively replicating adenovirus with E1B 55 kDa gene deletion （ZD55） to construct ZD55-VEGI-251. We report here that secreted VEGI-251 produced from ZD55- VEGI-251-infected cancer cells potently inhibits endothelial cell proliferation, tube formation in vitro and angiogen- esis of chick chorioallantoic membrane in vivo. Additionally, ZD55-VEGI-251 infection leads to a much more severe cytopathic effect than control viruses on several human cancer cell lines, including cervical cancer cell line HeLa, hepatoma cell line SMMC-7721 and colorectal cancer cell line SW620. Further study reveals that the increased cytotoxicity is a result of VEGI-251 autocrine-dependent, mitochondria-mediated apoptosis accompanied by caspase-9 activation, enhanced caspase-3 activation and PARP cleavage. Moreover, ZD55-VEGI-251-treatment of athymic nude mice bearing human cervical and colorectal tumor xenografts markedly suppressed tumor growth. Our findings indicate that the combined effect of antiangiogenesis and apoptosis-induction activity makes the VEGI-251-armed oncolytic adenovirus a promising therapeutic agent for cancer.
文摘Hepatocellular carcinoma （HCC） is a lethal disease in most patients, due to its aggressive course and a lack of effective systemic therapies for advanced disease. Surgical resection and liver transplantation remain the only curative options for a small subset of patients. Few patients with HCC are diagnosed early enough to be eli- gible for curative treatment. Angiogenesis inhibition is a natural therapeutic target for all solid tumors, but par- ticularly for the highly vascularized HCC tumors. With the approval of the targeted agent sorafenib, there are now additional options for patients with HCC. Although sorafenib does produce some improvement in survival in HCC patients, the responses are not durable. In addi- tion, there are significant dermatologic, gastrointestinal, and metabolic toxicities, and, as importantly, there is still limited knowledge of its usefulness in special sub- populations with HCC. Other angiogenesis inhibitors are in development to treat HCC both in the first-line set- ting and for use following sorafenib failure; the furthest in development is brivanib, a dual fibroblast growth factor pathway and vascular endothelial growth factor receptor inhibitor. Additional agents with antiangiogenic properties also in phase IT and Ⅲ development for the treatment of patients with HCC include bevacizumab, ramucirumab, ABT-869, everolimus and ARQ 197.
文摘African trypanosomosis had caused lots of havocs to both humans and animals over a century with successes and failure in curtailing it. This study was aimed at screening medicinal plant, Terminalia chebula dried fruits against Trypanosoma evansi for trypanocidal activity. Twenty grams of powdered Terminalia chebula dried fruits was cold extracted with methanol. Obtained MPE （methanolic plant extract） was in vitro tested against Trypanosoma brucei （1 × 10^6 trypanosomes/mL of the medium in each ELISA plate wells） at concentrations （250～1,000 μg/mL） on Vero cells grown in DMEM （Debecco＇s Modified Eagle Medium） in appropriate conditions for trypanocidal activity. In-vitro cytotoxicity test of MPE of Terminalia chebula was conducted on Vero cells grown in DMEM. In-vivo assay for trypanocidal activity, each mouse was inoculated with 1 × 10^4/mL of trypanosomes and treated （48 h post inoculation） with MPE of Terminalia chebula at concentrations （12.5, 25, 50, 100 and 200 mg/kg body weight） were administered at dose rate of 100 BL per mouse via intraperitoneal route to different groups of mice, 6 mice per concentration. In-vitro cytotoxicity test was done on Veto cells at concentrations （1.58～100 μg/mL） of MPE of Terminalia chebula. Results of in-vitro trypanocidal activity varied from immobilization, reduction and to the killing of the trypanosomes. At 250 μg/mL ofMPE ofTerminalia chebula dried fruits, there was significant trypanocidal activity at 4 h of incubation and trypanosomes were not detected in corresponding ELISA plate wells at 5 h of incubation, which was statistically equivalent to reference drug, diminazine aceturate （50 μL/mL） at 4 h of incubation. Results of in-vivo trypanocidal activity revealed that at concentrations （l 2.5～25 mg/kg body weight） of MPE of Terrninalia chebula, mice in these groups survived for 6 days. While at 50 and 100 to 200 mg/kg body weight, mice in these groups survived up to 7 and 8 days, respectively. In-vitro cytotoxicity test showed that all concentrations of MPE of Terminalia chenula and diminazine aceturate were cytotoxic to cells except at 1.56 μL/mL and 6.25 μL/mL. In conclusion, MPE of Terminalia chebula dried fruits possessed trypanocidal compounds. Further study （bioassay-guided purification） is required to know the full potential of Terrninalia chebula as future trypanocide candidate.
文摘This article analyzes the relationship between financial intermediary development and economic fluctuation in the last 50 years in China. It was found that a steady and long-term relation existed between these two variables, and that different aspects of the development of the financial intermediary system had different effects on the economic fluctuation. The improvement of the intermediary＇s efficiency can repress the economic fluctuation , but the increase of financial intermediaries can intensify the fluctuation. On that basis, some suggestions about the development of the financial intermediary are proposed in this essay.
文摘Admittedly, the stratospheric rise of Informal African Immigrant Traders （IAIT） in the Johannesburg inner city within a climate of discrimination, harassment, hostility, and xenophobia has engendered survival strategies which border on the illegal and underground. Based on an in-depth interview study of 40 IAIT, operating in the Johannesburg inner city and specialising in clothes, cellphone and accessories, household goods, fruits and vegetables, and a courier company, this paper posits that the registered and unregistered IAIT operate side by side with the latter operating from undesignated sites, either bribing or deceitful evading the Johannesburg Metropolitan Police （JMP）. Is this the characteristic of IAIT in the Johannesburg inner city？ Ostensibly, the success of challenging the institutional regulatory regime points to the possibility of African immigrant traders existing on the edge of impropriety or lawlessness. To this end, there is a need for comprehensive policy initiatives starting from the national and cascading to the provincial and municipality levels that will effectively address and manage urban informality, including the activities of the IAIT, failing which these will fuel operations outside the regulatory regimes and the mushrooming of the underground economic activities.
文摘Powered by the mitochondrial membrane potential,Ca2+ permeates the mitochondria via a Ca2+ channel termed Ca2+ uniporter and is pumped out by a Na+/Ca2+ exchanger,both of which are located on the inner mitochondrial membrane.Mitochondrial Ca2+ transients are critical for metabolic activity and regulating global Ca2+ responses.On the other hand,failure to control mitochondrial Ca2+ is a hallmark of ischemic and neurodegenerative diseases.Despite their importance,identifying the uniporter and exchanger remains elusive and their inhibitors are non-specific.This review will focus on the mitochondrial exchanger,initially describing how it was molecularly identified and linked to a novel member of the Na+/Ca2+ exchanger superfamily termed NCLX.Molecular control of NCLX expression provides a selective tool to determine its physiological role in a variety of cell types.In lymphocytes,NCLX is essential for refilling the endoplasmic reticulum Ca2+ stores required for antigen-dependent signaling.Communication of NCLX with the store-operated channel in astroglia controls Ca2+ influx and thereby neuro-transmitter release and cell proliferation.The refilling of the Ca2+ stores in the sarcoplasmic reticulum,which is controlled by NCLX,determines the frequency of action potential and Ca2+ transients in cardiomyocytes.NCLX is emerging as a hub for integrating glucose-dependent Na+ and Ca2+ signaling in pancreatic β cells,and the specific molecular control of NCLX expression resolved the controversy regarding its role in neurons and β cells.Future studies on an NCLX knockdown mouse model and identification of human NCLX mutations are expected to determine the role of mitochondrial Ca2+ efflux in organ activity and whether NCLX inactivation is linked to ischemic and/or neurodegenerative syndromes.Structure-function analysis and protein analysis will identify the NCLX mode of regulation and its partners in the inner membrane of the mitochondria.
