Transforming growth factor-β （TGF-β）, a prototype of multifunctional cytokine, is a key regulator of extracellular matrix （ECM） assembly and remodeling. Specifically, TGF-β isoforms have the ability to induce t...Transforming growth factor-β （TGF-β）, a prototype of multifunctional cytokine, is a key regulator of extracellular matrix （ECM） assembly and remodeling. Specifically, TGF-β isoforms have the ability to induce the expression of ECM proteins in mesenchymal cells, and to stimulate the production of protease inhibitors that prevent enzymatic breakdown of the ECM. Elevated TGF-β expression in affected organs, and subsequent deregulation of TGF-β functions, correlates with the abnormal connective tissue deposition observed during the onset of fibrotic diseases. During the last few years, tremendous progress has been made in the understanding of the molecular aspects of intracellular signaling downstream of the TGF-β receptors. In particular, Smad proteins, TGF-β receptor kinase substrates that translocate into the cell nucleus to act as transcription factors, have been studied extensively. The role of Smad3 in the transcriptional regulation of type I collagen gene expression and in the development of fibrosis, demonstrated both/n vitro and in animal models with a targeted deletion of Smad3, is of critical importance because it may lead to novel therapeutic strategies against these diseases. This review focuses on the mechanisms underlying Smad modulation of fibrillar collagen expression and how it relates to fibrotic processes.展开更多
AIM： To study the therapeutic effect of exogenous interleuldn-10 on CCl4-induced hepatic fibrosis in rats and its passible mechanisms. METHODS： Fourty-seven SD rats were randomly divided into control group （group N...AIM： To study the therapeutic effect of exogenous interleuldn-10 on CCl4-induced hepatic fibrosis in rats and its passible mechanisms. METHODS： Fourty-seven SD rats were randomly divided into control group （group N） and CCl4-induced hepatic fibrosis model group （group C）. After CCl4 was given for 9 wk, the model group was divided into three groups. Rats in group H were put to death immediately, rats in group T were treated with IL-10 for another three wk and then put to death, rats in group R recovered after three weeks and were then killed. The degree of hepatic fibrosis was measured by HE staining and histological activity index （HAI）. Histological activity index （HAI）, change of collagen types Ⅰ and Ⅲ were measured by Picrosirius staining. The expression of TNF-α, HHP-2 and TIMP-1 in liver tissue was measured by S-P immunohis tochemistry.RESULTS： CCl4- induced experimental rat hepatic fibrosis model was established successfully. The degree of hepatic fibrosis was markedly lower in group T than in groups H and R, and there was no difference between the two groups. The expression of collagen types I and III was significantly suppressed in group T and was slightly suppressed in groups H and R. The positive levels of TNF-α, HHP-2 and TIHP-1 in group H increased significantly compared to those in group N （P〈0.01）. The positive signals decreased significantly in groups T and R （P〈0.01）, but positive score was significantly lower in group T than in group R （P〈 0.01）. CONCLUS10N： Exogenous IL-10 can reverse CCl4-induced hepatic fibrosis in rats. IL-10 may exert its reversible effects on hepatic fibrosis by blocking CCl4-induced inflammation, inhibiting expression of HHP-2 and TIMP-1 and promoting resolution of collagen types Ⅰ and Ⅲ.展开更多
AIM: To study tissue factor (TF) in acute pancreatitis and evaluate the role of TF as a predictive marker of severity. METHODS: Forty-nine consecutive patients admitted to Lund University Hospital, fulfilling the crit...AIM: To study tissue factor (TF) in acute pancreatitis and evaluate the role of TF as a predictive marker of severity. METHODS: Forty-nine consecutive patients admitted to Lund University Hospital, fulfilling the criteria of predicted severe acute pancreatitis (AP), were recruited prospectively between 2002 and 2004. Blood samples for TF analyses were drawn at inclusion in the study and 12 h, 1 d and 3 d later. RESULTS: Twenty-seven patients developed mild AP, and 22 patients severe AP. At inclusion in the study, the groups were comparable with respect to gender, aetiology, Acute Physiology and Chronic Health Evaluation Ⅱ score, and duration of pain. At inclusion in the study and at 12 h, TF was higher in the severe AP group (P = 0.035 and P = 0.049, respectively). After 1 and 3 d, no differences in TF levels were noted. Interleukin (IL)-6 was significantly higher in the severe AP group at all of the studied time points. C-reactive protein (CRP) was significantly higher in the AP group at 1 and 3 d. In receiver operating characteristic-curves, the area under the curve (AUC) for TF was 0.679 (P = 0.035) at inclusion in the study, and a cut off level for TF of 40 pg/mL showed a sensitivity of 71% and a specificity of 67%, whereas corresponding AUC for IL-6 was 0.775, P = 0.001, and for CRP was 0.653. IL-6 showed better AUC-values than TF at all time points studied. CONCLUSION: TF-levels are raised early in severe AP. TF as an early predictive marker of severe AP is superior to CRP, but inferior to IL-6.展开更多
Background The peritoneum response to peritoneal dialysis can lead to fibrosis. The transforming growth factor β1 （TGF-β1 ） plays a key role in regulating tissue repair and remodelling after injury. Connective tis...Background The peritoneum response to peritoneal dialysis can lead to fibrosis. The transforming growth factor β1 （TGF-β1 ） plays a key role in regulating tissue repair and remodelling after injury. Connective tissue growth factor （CTGF）, a downstream mediator of TGF-β1 inducing fibrosis, has been implicated in peritoneal fibrosis. Vascular endothelial growth factor （VEGF） plays a key role in angiogenesis that can hasten peritoneal fibrosis. In this study, we investigated the effect of small interfering RNA （siRNA） of CTGF by pRETRO-SUPER （PRS） retrovirus vector on the expression of CTGF and VEGF in human peritoneal mesothelial cells. Methods Retrovirus producing CTGF siRNA were constructed from the inverted oligonucleotides and transferred into packaging cell line PT67 with lipofectamine, and the virus supernatant was used to infect human peritoneal mesothelial cell （HPMC）. The cells were divided into seven groups： low glucose DMEM, low glucose DMEM ＋ TGF-β1 5 ng/ml, low glucose DMEM ＋ TGF-β1 5 ng/ml ＋ PRS-CTGF-siRNA1-4 and low glucose DMEM ＋ TGF-β1 5 ng/ml ＋ PRS. The expression of CTGF and VEGF were measured by semiquantitative RT-PCR and Western blot. Results Low levels of CTGF and VEGF were detected in confluent HPMCs. Following stimulation with TGF-β1 , the levels of CTGF and VEGF were significantly upregulated （P〈0.01）. Introduction of PRS-CTGF-siRNA1-4 resulted in the significant reduction of CTGF mRNA and protein, and VEGF mRNA （P〈0.01）, especially in groups PRS-CTGF-siRNA, and PRS-CTGF-siRNA4. The introduction of PRS void vector did not have these effects （P〉0.05）. Conclusions The expression of CTGF siRNA mediated by PRS retrovirus vector can effectively reduce the level of CTGF and VEGF induced by TGF-β1 in cultured HPMCs. This study may provide potential therapeutic strategies to prevent the peritoneal fibrosis.展开更多
Spinal cord injury usually leads to permanent disability, which could cause a huge financial problem to the patient. Up to now there is no effective method to treat this disease. The key of the treatment is to enable ...Spinal cord injury usually leads to permanent disability, which could cause a huge financial problem to the patient. Up to now there is no effective method to treat this disease. The key of the treatment is to enable the damage zone axonal regeneration and luckily it could go through the damage zone; last a connection can be established with the target neurons. This study attempts to combine stem cell, material science and genetic modification technology together, by preparing two genes modified adipose-derived stem cells and inducing them into neuron direction; then by compositing them on the silk fibroin/chitosan scaffold and implanting them into the spinal cord injury model, seed cells can have features of neuron cells. At the same time, it could stably express the brain-derived neurotrophic factor and neurotrophin-3, both of which could produce synergistic effects, which have a positive effect on the recovery of spinal cord. The spinal cord scaffold bridges the broken end of the spinal cord and isolates with the surrounding environment, which could avoid a scar effect on the nerve regeneration and provide three-dimensional space for the seed cell growth, and at last we hope to provide a new treatment for spinal cord injury with the tissue engineering technique.展开更多
基金Programme National de Recherche Dermatologie 2006, Institut Nationale de la Santé Et de la Recherche Médicale, Groupe Franais de Recherche sur la Sclérodermie, and Associa-tion des Slérodermiques de France
文摘Transforming growth factor-β （TGF-β）, a prototype of multifunctional cytokine, is a key regulator of extracellular matrix （ECM） assembly and remodeling. Specifically, TGF-β isoforms have the ability to induce the expression of ECM proteins in mesenchymal cells, and to stimulate the production of protease inhibitors that prevent enzymatic breakdown of the ECM. Elevated TGF-β expression in affected organs, and subsequent deregulation of TGF-β functions, correlates with the abnormal connective tissue deposition observed during the onset of fibrotic diseases. During the last few years, tremendous progress has been made in the understanding of the molecular aspects of intracellular signaling downstream of the TGF-β receptors. In particular, Smad proteins, TGF-β receptor kinase substrates that translocate into the cell nucleus to act as transcription factors, have been studied extensively. The role of Smad3 in the transcriptional regulation of type I collagen gene expression and in the development of fibrosis, demonstrated both/n vitro and in animal models with a targeted deletion of Smad3, is of critical importance because it may lead to novel therapeutic strategies against these diseases. This review focuses on the mechanisms underlying Smad modulation of fibrillar collagen expression and how it relates to fibrotic processes.
基金Supported by Nature Science Foundation of Fujian Province. No.2005D094 and No.C0410025
文摘AIM： To study the therapeutic effect of exogenous interleuldn-10 on CCl4-induced hepatic fibrosis in rats and its passible mechanisms. METHODS： Fourty-seven SD rats were randomly divided into control group （group N） and CCl4-induced hepatic fibrosis model group （group C）. After CCl4 was given for 9 wk, the model group was divided into three groups. Rats in group H were put to death immediately, rats in group T were treated with IL-10 for another three wk and then put to death, rats in group R recovered after three weeks and were then killed. The degree of hepatic fibrosis was measured by HE staining and histological activity index （HAI）. Histological activity index （HAI）, change of collagen types Ⅰ and Ⅲ were measured by Picrosirius staining. The expression of TNF-α, HHP-2 and TIMP-1 in liver tissue was measured by S-P immunohis tochemistry.RESULTS： CCl4- induced experimental rat hepatic fibrosis model was established successfully. The degree of hepatic fibrosis was markedly lower in group T than in groups H and R, and there was no difference between the two groups. The expression of collagen types I and III was significantly suppressed in group T and was slightly suppressed in groups H and R. The positive levels of TNF-α, HHP-2 and TIHP-1 in group H increased significantly compared to those in group N （P〈0.01）. The positive signals decreased significantly in groups T and R （P〈0.01）, but positive score was significantly lower in group T than in group R （P〈 0.01）. CONCLUS10N： Exogenous IL-10 can reverse CCl4-induced hepatic fibrosis in rats. IL-10 may exert its reversible effects on hepatic fibrosis by blocking CCl4-induced inflammation, inhibiting expression of HHP-2 and TIMP-1 and promoting resolution of collagen types Ⅰ and Ⅲ.
基金Supported by The Skane County Council Research and Development Foundation, No. REGSKANE-61401the Erik and Angelica Sparre Foundation, No. 081230
文摘AIM: To study tissue factor (TF) in acute pancreatitis and evaluate the role of TF as a predictive marker of severity. METHODS: Forty-nine consecutive patients admitted to Lund University Hospital, fulfilling the criteria of predicted severe acute pancreatitis (AP), were recruited prospectively between 2002 and 2004. Blood samples for TF analyses were drawn at inclusion in the study and 12 h, 1 d and 3 d later. RESULTS: Twenty-seven patients developed mild AP, and 22 patients severe AP. At inclusion in the study, the groups were comparable with respect to gender, aetiology, Acute Physiology and Chronic Health Evaluation Ⅱ score, and duration of pain. At inclusion in the study and at 12 h, TF was higher in the severe AP group (P = 0.035 and P = 0.049, respectively). After 1 and 3 d, no differences in TF levels were noted. Interleukin (IL)-6 was significantly higher in the severe AP group at all of the studied time points. C-reactive protein (CRP) was significantly higher in the AP group at 1 and 3 d. In receiver operating characteristic-curves, the area under the curve (AUC) for TF was 0.679 (P = 0.035) at inclusion in the study, and a cut off level for TF of 40 pg/mL showed a sensitivity of 71% and a specificity of 67%, whereas corresponding AUC for IL-6 was 0.775, P = 0.001, and for CRP was 0.653. IL-6 showed better AUC-values than TF at all time points studied. CONCLUSION: TF-levels are raised early in severe AP. TF as an early predictive marker of severe AP is superior to CRP, but inferior to IL-6.
基金the National Natural Science Foundation of China(No. 30370811)
文摘Background The peritoneum response to peritoneal dialysis can lead to fibrosis. The transforming growth factor β1 （TGF-β1 ） plays a key role in regulating tissue repair and remodelling after injury. Connective tissue growth factor （CTGF）, a downstream mediator of TGF-β1 inducing fibrosis, has been implicated in peritoneal fibrosis. Vascular endothelial growth factor （VEGF） plays a key role in angiogenesis that can hasten peritoneal fibrosis. In this study, we investigated the effect of small interfering RNA （siRNA） of CTGF by pRETRO-SUPER （PRS） retrovirus vector on the expression of CTGF and VEGF in human peritoneal mesothelial cells. Methods Retrovirus producing CTGF siRNA were constructed from the inverted oligonucleotides and transferred into packaging cell line PT67 with lipofectamine, and the virus supernatant was used to infect human peritoneal mesothelial cell （HPMC）. The cells were divided into seven groups： low glucose DMEM, low glucose DMEM ＋ TGF-β1 5 ng/ml, low glucose DMEM ＋ TGF-β1 5 ng/ml ＋ PRS-CTGF-siRNA1-4 and low glucose DMEM ＋ TGF-β1 5 ng/ml ＋ PRS. The expression of CTGF and VEGF were measured by semiquantitative RT-PCR and Western blot. Results Low levels of CTGF and VEGF were detected in confluent HPMCs. Following stimulation with TGF-β1 , the levels of CTGF and VEGF were significantly upregulated （P〈0.01）. Introduction of PRS-CTGF-siRNA1-4 resulted in the significant reduction of CTGF mRNA and protein, and VEGF mRNA （P〈0.01）, especially in groups PRS-CTGF-siRNA, and PRS-CTGF-siRNA4. The introduction of PRS void vector did not have these effects （P〉0.05）. Conclusions The expression of CTGF siRNA mediated by PRS retrovirus vector can effectively reduce the level of CTGF and VEGF induced by TGF-β1 in cultured HPMCs. This study may provide potential therapeutic strategies to prevent the peritoneal fibrosis.
文摘Spinal cord injury usually leads to permanent disability, which could cause a huge financial problem to the patient. Up to now there is no effective method to treat this disease. The key of the treatment is to enable the damage zone axonal regeneration and luckily it could go through the damage zone; last a connection can be established with the target neurons. This study attempts to combine stem cell, material science and genetic modification technology together, by preparing two genes modified adipose-derived stem cells and inducing them into neuron direction; then by compositing them on the silk fibroin/chitosan scaffold and implanting them into the spinal cord injury model, seed cells can have features of neuron cells. At the same time, it could stably express the brain-derived neurotrophic factor and neurotrophin-3, both of which could produce synergistic effects, which have a positive effect on the recovery of spinal cord. The spinal cord scaffold bridges the broken end of the spinal cord and isolates with the surrounding environment, which could avoid a scar effect on the nerve regeneration and provide three-dimensional space for the seed cell growth, and at last we hope to provide a new treatment for spinal cord injury with the tissue engineering technique.
