The mitochondrion serves many functions in the central nervous system （CNS） and other organs beyond the well-recognized role of adenosine triphosphate （ATP） production. This includes calcium-dependent cell signali...The mitochondrion serves many functions in the central nervous system （CNS） and other organs beyond the well-recognized role of adenosine triphosphate （ATP） production. This includes calcium-dependent cell signaling, regulation of gene expression, synthesis and release of cytotoxic reactive oxygen species, and the release of cytochrome c and other apoptotic cell death factors. Traumatic injury to the CNS results in a rapid and, in some cases, sustained loss of mitochondrial function. One consequence of compromised mitochondrial function is induction of the mitochondrial permeability transition （mPT） state due to formation of the cyclosporine A sensitive permeability transition pore （mPTP）. In this mini-review, we summarize evidence supporting the involvement of the mPTP as a mediator of mitochondrial and cellular demise following CNS traumatic injury and discuss the beneficial effects and limitations of the current ex- perimental strategies targeting the mPTP.展开更多
Background Vitamin D3 and its metabolites have been found to exert immunosuppressive effects both in vivo and in vitro. We investigated the synergistic effect of calcitriol and cyclosporine A （CsA） on lymphocyte pro...Background Vitamin D3 and its metabolites have been found to exert immunosuppressive effects both in vivo and in vitro. We investigated the synergistic effect of calcitriol and cyclosporine A （CsA） on lymphocyte proliferation in vitro and graft rejection following rat liver allotransplantations in vivo. Methods Alloantigen driven, human peripheral mononuclear cells＇ proliferation and cytokine production capacity were tested in the presence or absence of various concentrations of calcitriol or CsA. In vivo, liver allografts were transplanted in a high responder strain combination （SD to Wistar） rats and combination of subtherapeutical dose of CsA and calcitriol was administered in recipients, whereas the control recipients received single or no immunosuppressant. Proliferation of splenocyte from recipient was tested with mixed lymphocyte reaction. Serum intedeukin-2 （IL-2） and interferon gamma （IFN-γ） concentrations were measured with enzyme linked immunosorbent assay. Results Combined medication of 10^-9 mol/L calcitriol and 100 ng/ml CsA inhibited human peripheral mononuclear cells＇ proliferation to alloantigen and the production of IL-2 and IFN-γ but promoted that of IL-4 and IL-10. Similarly, combination of 250 ng · kg^-1·-d^-1 calcitriol and 1.0 mg · kg^-1·-d^-1 CsA showed an additive effect in liver transplant model. It restrained splenocyte proliferation to alloantigen from donor and significantly reduced serum concentration of IL-2 and IFN-γ in recipients. Consequently, aUograft rejection in combined medication group was minor （median William＇s grade was 1.0 vs 3.0 in combined medication group and in the control group, P〈0.05） and the recipients＇ survival was evidently prolonged [（93.7±5.8） days vs （12.6±1.4） days in combined medication group and in the control group, P〈0.01 ]. Conclusion A combination of calcitriol and CsA has an additive effect on limiting lymphocyte proliferation and prolonging liver graft survival. With its additional immunomodulating property, calcitriol is a potent immunosuppressant that can extend the therapeutic window of classical immunomodulators in prevention and treatment of liver graft rejection.展开更多
基金supported by a grant from the Kentucky Spinal Cord and Head Injury Research Trust
文摘The mitochondrion serves many functions in the central nervous system （CNS） and other organs beyond the well-recognized role of adenosine triphosphate （ATP） production. This includes calcium-dependent cell signaling, regulation of gene expression, synthesis and release of cytotoxic reactive oxygen species, and the release of cytochrome c and other apoptotic cell death factors. Traumatic injury to the CNS results in a rapid and, in some cases, sustained loss of mitochondrial function. One consequence of compromised mitochondrial function is induction of the mitochondrial permeability transition （mPT） state due to formation of the cyclosporine A sensitive permeability transition pore （mPTP）. In this mini-review, we summarize evidence supporting the involvement of the mPTP as a mediator of mitochondrial and cellular demise following CNS traumatic injury and discuss the beneficial effects and limitations of the current ex- perimental strategies targeting the mPTP.
文摘Background Vitamin D3 and its metabolites have been found to exert immunosuppressive effects both in vivo and in vitro. We investigated the synergistic effect of calcitriol and cyclosporine A （CsA） on lymphocyte proliferation in vitro and graft rejection following rat liver allotransplantations in vivo. Methods Alloantigen driven, human peripheral mononuclear cells＇ proliferation and cytokine production capacity were tested in the presence or absence of various concentrations of calcitriol or CsA. In vivo, liver allografts were transplanted in a high responder strain combination （SD to Wistar） rats and combination of subtherapeutical dose of CsA and calcitriol was administered in recipients, whereas the control recipients received single or no immunosuppressant. Proliferation of splenocyte from recipient was tested with mixed lymphocyte reaction. Serum intedeukin-2 （IL-2） and interferon gamma （IFN-γ） concentrations were measured with enzyme linked immunosorbent assay. Results Combined medication of 10^-9 mol/L calcitriol and 100 ng/ml CsA inhibited human peripheral mononuclear cells＇ proliferation to alloantigen and the production of IL-2 and IFN-γ but promoted that of IL-4 and IL-10. Similarly, combination of 250 ng · kg^-1·-d^-1 calcitriol and 1.0 mg · kg^-1·-d^-1 CsA showed an additive effect in liver transplant model. It restrained splenocyte proliferation to alloantigen from donor and significantly reduced serum concentration of IL-2 and IFN-γ in recipients. Consequently, aUograft rejection in combined medication group was minor （median William＇s grade was 1.0 vs 3.0 in combined medication group and in the control group, P〈0.05） and the recipients＇ survival was evidently prolonged [（93.7±5.8） days vs （12.6±1.4） days in combined medication group and in the control group, P〈0.01 ]. Conclusion A combination of calcitriol and CsA has an additive effect on limiting lymphocyte proliferation and prolonging liver graft survival. With its additional immunomodulating property, calcitriol is a potent immunosuppressant that can extend the therapeutic window of classical immunomodulators in prevention and treatment of liver graft rejection.
