Kallistatin是一种丝氨酸蛋白酶抑制剂.早期研究发现,它能与组织激肽释放酶结合并抑制其活性,随后kallistatin的抗血管生成、抗炎、抗肿瘤、抗氧化等功能也逐步被发现.Kallistatin有2个主要功能结构域:反应中心环和肝素结合结构域,各自...Kallistatin是一种丝氨酸蛋白酶抑制剂.早期研究发现,它能与组织激肽释放酶结合并抑制其活性,随后kallistatin的抗血管生成、抗炎、抗肿瘤、抗氧化等功能也逐步被发现.Kallistatin有2个主要功能结构域:反应中心环和肝素结合结构域,各自发挥不同的作用.Kallistatin通过肝素结合结构域竞争性抑制血管内皮生长因子(VEGF)和肿瘤坏死因子与它们的受体结合,进而起到抗血管生成和抗炎作用.近年研究发现,kallistatin的多种功能由不同信号通路介导,主要为PI3K-Akt信号通路和TNF-α-NF-κB信号通路.此外,kallistatin还通过丝裂原活化激酶(mitogen-activated protein kinase,MAPK)等信号通路发挥作用.本文就目前研究的kallistatin的结构功能及其在PI3K-Akt、TNF-α等多种信号通路中的调节功能和作用机制进行阐述.展开更多
AIM： TO investigate the inhibitory effect of kallistatin （KAL） on angiogenesis and HCT-116 xenograft tumor growth.METHODS： Heterotopic subcutaneous injection of 2 Seven days later, 2 x 1011 injected intratumorally...AIM： TO investigate the inhibitory effect of kallistatin （KAL） on angiogenesis and HCT-116 xenograft tumor growth.METHODS： Heterotopic subcutaneous injection of 2 Seven days later, 2 x 1011 injected intratumorally （n tumors were induced by x 106 HCT-11 cells in mice. rAAV-GFP or rAAV-KAL was = 5 for each group）. The mice were sacrificed at d 28, by which time the tumors in the rAAV-GFP group had grown to beyond 5% of the total body weight. Tumor growth was measured by calipers in two dimensions. Tumor angiogenesis was determined with tumor microvessel density （MVD） by immunohistology. Tumor cell proliferation was assessed by Ki-67 staining.RESULTS： Intratumor injection of rAAV-KAL inhibited tumor growth in the treatment group by 78% （171 ＋ 52 mm^3） at d 21 after virus infection compared to the control group （776 ＋ 241 mm^3）. Microvessel density was significantly inhibited in tumor tissues treated with rAAV-KAL, rAAV-KAL also decreased the proportion of proliferating cells （Ki-67 positive cells） in tumors compared with the control group.CONCLUSION： rAAV-mediated expression of KAL inhibits the growth of colon cancer by reducing angiogenesis and proliferation of tumor cells, and may provide a promising anti-angiogenesis-based approach to the treatment of metastatic colorectal cancer.展开更多
AIM:To investigate the effect of transgenic expression of kallistatin(Kal) on carbon tetrachloride(CCl 4)induced liver injury by intramuscular(im) electrotransfer of a Kal-encoding plasmid formulated with poly-Lglutam...AIM:To investigate the effect of transgenic expression of kallistatin(Kal) on carbon tetrachloride(CCl 4)induced liver injury by intramuscular(im) electrotransfer of a Kal-encoding plasmid formulated with poly-Lglutamate(PLG).METHODS:The pKal plasmid encoding Kal gene was formulated with PLG and electrotransferred into mice skeletal muscle before the administration of CCl 4.The expression level of Kal was measured.The serum biomarker levels of alanine aminotransferase(ALT),aspartate aminotransferase(AST),malonyldialdehyde(MDA),and tumor necrosis factor(TNF)-α were monitored.The extent of CCl 4-induced liver injury was analyzed histopathologically.RESULTS:The transgene of Kal was sufficiently expressed after an im injection of plasmid formulated with PLG followed by electroporation.In the Kal gene-transferred mice,protection against CCl 4-induced liver injury was reflected by significantly decreased serum ALT,AST,MDA and TNF-α levels compared to those in control mice(P < 0.01 to 0.05 in a dose-dependent manner).Histological observations also revealed that hepatocyte necrosis,hemorrhage,vacuolar change and hydropic degeneration were apparent in mice after CCl 4 administration.In contrast,the damage was markedly attenuated in the Kal gene-transferred mice.The expression of hepatic fibrogenesis marker transforming growth factor-β1 was also reduced in the pKal transferred mice.CONCLUSION:Intramuscular electrotransfer of plasmid pKal which was formulated with PLG significantly alleviated the CCl 4-induced oxidative stress and inflammatory response,and reduced the liver damage in a mouse model.展开更多
Kallistatin, which protects organs and cells against inflammation, fibrosis and oxidative stress, is mainly synthesized and secreted in liver. However, its relationship to human liver disease remains unclear. The purp...Kallistatin, which protects organs and cells against inflammation, fibrosis and oxidative stress, is mainly synthesized and secreted in liver. However, its relationship to human liver disease remains unclear. The purpose of this study was to explore the relationship between serum kallistatin and clinical evidence of both cirrhosis and hepatocellular carcinoma (HCC), and to determine if serum kallistatin levels could be used as a diagnostic indicator of hepatic health status, especially human liver cirrhosis (LC). Our cohort consisted of 115 patients with clinically proven liver fibrosis (IT), LC, or HCC by liver biopsies, and 31 healthy controls (CON). Serum kallistatin levels were quantified by ELISA. Results of the present study demonstrated that irrespective of the underlying etiology, serum kallistatin levels were significantly lower in the LF/LC group when compared with the CON group. A decrease in serum kallistatin levels appeared to reflect the extent of cirrhosis, with the lowest levels associated with higher grades of cirrhosis. Patients with 111: had a noticeable correlation between serum kallistatin levels and other serum biochemical indicators. 'the area under the curve (AUC) for LC, viral liver cirrhosis (VLC) and alcoholic liver cirrhosis (ALC) was 0.845, 0.757 and 0.931, respectively. in conclusion, our findings demonstrated that kallistatin, a plasma protein produced by the liver, can be a useful and reliable diagnostic indicator of hepatic health status, especially for LC. (C) 2015 Chinese Pharmaceutical Association and Institute of Materia IMedica, Chinese Academy of 'Medical Sciences. Production and hosting by Elsevier B.V.展开更多
文摘Kallistatin是一种丝氨酸蛋白酶抑制剂.早期研究发现,它能与组织激肽释放酶结合并抑制其活性,随后kallistatin的抗血管生成、抗炎、抗肿瘤、抗氧化等功能也逐步被发现.Kallistatin有2个主要功能结构域:反应中心环和肝素结合结构域,各自发挥不同的作用.Kallistatin通过肝素结合结构域竞争性抑制血管内皮生长因子(VEGF)和肿瘤坏死因子与它们的受体结合,进而起到抗血管生成和抗炎作用.近年研究发现,kallistatin的多种功能由不同信号通路介导,主要为PI3K-Akt信号通路和TNF-α-NF-κB信号通路.此外,kallistatin还通过丝裂原活化激酶(mitogen-activated protein kinase,MAPK)等信号通路发挥作用.本文就目前研究的kallistatin的结构功能及其在PI3K-Akt、TNF-α等多种信号通路中的调节功能和作用机制进行阐述.
基金Hong Kong University Foundation (special donation from Madame Cho So Man)Huaqiao University Foundation B105
文摘AIM： TO investigate the inhibitory effect of kallistatin （KAL） on angiogenesis and HCT-116 xenograft tumor growth.METHODS： Heterotopic subcutaneous injection of 2 Seven days later, 2 x 1011 injected intratumorally （n tumors were induced by x 106 HCT-11 cells in mice. rAAV-GFP or rAAV-KAL was = 5 for each group）. The mice were sacrificed at d 28, by which time the tumors in the rAAV-GFP group had grown to beyond 5% of the total body weight. Tumor growth was measured by calipers in two dimensions. Tumor angiogenesis was determined with tumor microvessel density （MVD） by immunohistology. Tumor cell proliferation was assessed by Ki-67 staining.RESULTS： Intratumor injection of rAAV-KAL inhibited tumor growth in the treatment group by 78% （171 ＋ 52 mm^3） at d 21 after virus infection compared to the control group （776 ＋ 241 mm^3）. Microvessel density was significantly inhibited in tumor tissues treated with rAAV-KAL, rAAV-KAL also decreased the proportion of proliferating cells （Ki-67 positive cells） in tumors compared with the control group.CONCLUSION： rAAV-mediated expression of KAL inhibits the growth of colon cancer by reducing angiogenesis and proliferation of tumor cells, and may provide a promising anti-angiogenesis-based approach to the treatment of metastatic colorectal cancer.
基金Supported by The State High Technology Research and Development Program of China (863 Program),No.2008AA02Z135the Important National Science and Technology Specific Projects,No.2009ZX09103-643the Natural Science Foundation of China,No.30973591
文摘AIM:To investigate the effect of transgenic expression of kallistatin(Kal) on carbon tetrachloride(CCl 4)induced liver injury by intramuscular(im) electrotransfer of a Kal-encoding plasmid formulated with poly-Lglutamate(PLG).METHODS:The pKal plasmid encoding Kal gene was formulated with PLG and electrotransferred into mice skeletal muscle before the administration of CCl 4.The expression level of Kal was measured.The serum biomarker levels of alanine aminotransferase(ALT),aspartate aminotransferase(AST),malonyldialdehyde(MDA),and tumor necrosis factor(TNF)-α were monitored.The extent of CCl 4-induced liver injury was analyzed histopathologically.RESULTS:The transgene of Kal was sufficiently expressed after an im injection of plasmid formulated with PLG followed by electroporation.In the Kal gene-transferred mice,protection against CCl 4-induced liver injury was reflected by significantly decreased serum ALT,AST,MDA and TNF-α levels compared to those in control mice(P < 0.01 to 0.05 in a dose-dependent manner).Histological observations also revealed that hepatocyte necrosis,hemorrhage,vacuolar change and hydropic degeneration were apparent in mice after CCl 4 administration.In contrast,the damage was markedly attenuated in the Kal gene-transferred mice.The expression of hepatic fibrogenesis marker transforming growth factor-β1 was also reduced in the pKal transferred mice.CONCLUSION:Intramuscular electrotransfer of plasmid pKal which was formulated with PLG significantly alleviated the CCl 4-induced oxidative stress and inflammatory response,and reduced the liver damage in a mouse model.
基金supported by the National Natural Science Foundation of China,China (Nos.81072578 and 81271692)The Hundred Talents Program of Fujian Provincial Government to Ruian Xu,with an additional support from Huaqiao University Grant Committee
文摘Kallistatin, which protects organs and cells against inflammation, fibrosis and oxidative stress, is mainly synthesized and secreted in liver. However, its relationship to human liver disease remains unclear. The purpose of this study was to explore the relationship between serum kallistatin and clinical evidence of both cirrhosis and hepatocellular carcinoma (HCC), and to determine if serum kallistatin levels could be used as a diagnostic indicator of hepatic health status, especially human liver cirrhosis (LC). Our cohort consisted of 115 patients with clinically proven liver fibrosis (IT), LC, or HCC by liver biopsies, and 31 healthy controls (CON). Serum kallistatin levels were quantified by ELISA. Results of the present study demonstrated that irrespective of the underlying etiology, serum kallistatin levels were significantly lower in the LF/LC group when compared with the CON group. A decrease in serum kallistatin levels appeared to reflect the extent of cirrhosis, with the lowest levels associated with higher grades of cirrhosis. Patients with 111: had a noticeable correlation between serum kallistatin levels and other serum biochemical indicators. 'the area under the curve (AUC) for LC, viral liver cirrhosis (VLC) and alcoholic liver cirrhosis (ALC) was 0.845, 0.757 and 0.931, respectively. in conclusion, our findings demonstrated that kallistatin, a plasma protein produced by the liver, can be a useful and reliable diagnostic indicator of hepatic health status, especially for LC. (C) 2015 Chinese Pharmaceutical Association and Institute of Materia IMedica, Chinese Academy of 'Medical Sciences. Production and hosting by Elsevier B.V.
