Objective: To explore the protection and molecular mechanism of histone deacetylase inhibitors(HDACIs) on the spleen of rats with hemorrhagic shock. Methods: A total of 60 SPF male SD rats were selected for the modeli...Objective: To explore the protection and molecular mechanism of histone deacetylase inhibitors(HDACIs) on the spleen of rats with hemorrhagic shock. Methods: A total of 60 SPF male SD rats were selected for the modeling of severe hemorrhagic shock using the method of arterial and venous cannulation with the time-divided bleeding. The measurement of mean arterial blood pressure and blood lactic acid was used to verify the modeling. The modeled rats were randomly divided into shock group, shock+suberoylanilide hydroxamic acid(SAHA) group, shock+autogenous transfusion group, and shock+SAHA+autogenous transfusion group. Three hours after the treatment, the spleen of rats was collected and TUNEL method was employed to detect the apoptosis of spleen cells in each group. Afterwards, real-time PCR and western blot were employed to detect the expression of BCL-2, BAX, and caspass3 in the spleen of rats in each group. Results: A total of 55 rats had successful modeling of severe hemorrhagic shock, with success rate of 92%. Cell apoptosis in the severe hemorrhagic model group was the most serious. After the intervention of HDACIs and the autogenous transfusion, the tissue injury was a bit recovered. Cell apoptosis was least in the shock+SAHA+autogenous transfusion group(P<0.05). After the intervention of HDACIs and the autogenous transfusion, the relative expression of BCL-2 was significantly increased(P<0.05), with highest relative expression of BCL-2 in shock+SAHA+autogenous transfusion group(P<0.05). After the intervention of HDACIs and the autogenous transfusion, the relative expression of BAX was significantly decreased(P<0.05), with lowest relative expression of BAX in the intervention group of single HDACIs. The change in the expression of caspass3 was similar to BAX, namely the relative expression of caspass3 was significantly decreased after the intervention of HDACIs and the autogenous transfusion(P<0.05). Conclusions: HDACIs and autogenous transfusion can all protect the spleen injury because of the severe hemorrhagic shock. Its molecular mechanism may be related to the regulation on the expression of BCL-2/BAX and caspass3, which may affect the apoptosis process of cells.展开更多
Epigenetic mechanisms,such as DNA methylation and histone modifications(e.g.,acetylation and deacetylation),are strongly implicated in the carcinogenesis of various malignancies.During transcription,the expression and ...Epigenetic mechanisms,such as DNA methylation and histone modifications(e.g.,acetylation and deacetylation),are strongly implicated in the carcinogenesis of various malignancies.During transcription,the expression and functionality of coding gene products are altered following the histone acetylation and deacetylation.These processes are regulated by histone acetyltransferases(HATs)and histone deacetylases(HDACs),respectively.HDAC inhibitors(HDACis)have been developed as promising therapeutic agents,to limit exposure to traditional and toxic chemotherapies and offer more alternatives for some specific malignant diseases with limited options.Mechanistically,these agents affect many intracellular pathways,including cell cycle arrest,apoptosis and differentiation,and their mechanism of action mainly depends on the type of cancer.Currently,five HDACis have been approved for the treatment of several hematological malignancies(e.g.,T-cell lymphoma subtypes and multiple myeloma);while,many of them are tested for further therapeutic indications in solid tumors(e.g.,colorectal,thyroid,breast,lung and pancreatic cancer).Herein,we review the literature and gather all available evidence,from in vitro and in vivo data to clinical trial results,that recognizes the antitumor activity of HDACis on pheochromocytomas and paragangliomas;and supports their clinical implementation in the treatment of these rare neuroendocrine tumors at metastatic setting.展开更多
基金supported by the National Natural Science Foundation of China(No.81160230)the Natural Science Foundation of Jiangxi Province of China(No.20114BAB205003)
文摘Objective: To explore the protection and molecular mechanism of histone deacetylase inhibitors(HDACIs) on the spleen of rats with hemorrhagic shock. Methods: A total of 60 SPF male SD rats were selected for the modeling of severe hemorrhagic shock using the method of arterial and venous cannulation with the time-divided bleeding. The measurement of mean arterial blood pressure and blood lactic acid was used to verify the modeling. The modeled rats were randomly divided into shock group, shock+suberoylanilide hydroxamic acid(SAHA) group, shock+autogenous transfusion group, and shock+SAHA+autogenous transfusion group. Three hours after the treatment, the spleen of rats was collected and TUNEL method was employed to detect the apoptosis of spleen cells in each group. Afterwards, real-time PCR and western blot were employed to detect the expression of BCL-2, BAX, and caspass3 in the spleen of rats in each group. Results: A total of 55 rats had successful modeling of severe hemorrhagic shock, with success rate of 92%. Cell apoptosis in the severe hemorrhagic model group was the most serious. After the intervention of HDACIs and the autogenous transfusion, the tissue injury was a bit recovered. Cell apoptosis was least in the shock+SAHA+autogenous transfusion group(P<0.05). After the intervention of HDACIs and the autogenous transfusion, the relative expression of BCL-2 was significantly increased(P<0.05), with highest relative expression of BCL-2 in shock+SAHA+autogenous transfusion group(P<0.05). After the intervention of HDACIs and the autogenous transfusion, the relative expression of BAX was significantly decreased(P<0.05), with lowest relative expression of BAX in the intervention group of single HDACIs. The change in the expression of caspass3 was similar to BAX, namely the relative expression of caspass3 was significantly decreased after the intervention of HDACIs and the autogenous transfusion(P<0.05). Conclusions: HDACIs and autogenous transfusion can all protect the spleen injury because of the severe hemorrhagic shock. Its molecular mechanism may be related to the regulation on the expression of BCL-2/BAX and caspass3, which may affect the apoptosis process of cells.
文摘Epigenetic mechanisms,such as DNA methylation and histone modifications(e.g.,acetylation and deacetylation),are strongly implicated in the carcinogenesis of various malignancies.During transcription,the expression and functionality of coding gene products are altered following the histone acetylation and deacetylation.These processes are regulated by histone acetyltransferases(HATs)and histone deacetylases(HDACs),respectively.HDAC inhibitors(HDACis)have been developed as promising therapeutic agents,to limit exposure to traditional and toxic chemotherapies and offer more alternatives for some specific malignant diseases with limited options.Mechanistically,these agents affect many intracellular pathways,including cell cycle arrest,apoptosis and differentiation,and their mechanism of action mainly depends on the type of cancer.Currently,five HDACis have been approved for the treatment of several hematological malignancies(e.g.,T-cell lymphoma subtypes and multiple myeloma);while,many of them are tested for further therapeutic indications in solid tumors(e.g.,colorectal,thyroid,breast,lung and pancreatic cancer).Herein,we review the literature and gather all available evidence,from in vitro and in vivo data to clinical trial results,that recognizes the antitumor activity of HDACis on pheochromocytomas and paragangliomas;and supports their clinical implementation in the treatment of these rare neuroendocrine tumors at metastatic setting.
