We studied the effects of angiotensin-converting enzyme inhibitor on the response of arterial intima after balloon denudation.Captopril（3mg.kg/d）was administered to 4miniature pigs after abdominal aortic balloon den...We studied the effects of angiotensin-converting enzyme inhibitor on the response of arterial intima after balloon denudation.Captopril（3mg.kg/d）was administered to 4miniature pigs after abdominal aortic balloon denudation.展开更多
The nuclear receptor 4A1(NR4A1)plays a crucial role in maintaining cellular homeostasis and is involved in various disease processes;however,its functional role and pharmacological potential in mesangial proliferative...The nuclear receptor 4A1(NR4A1)plays a crucial role in maintaining cellular homeostasis and is involved in various disease processes;however,its functional role and pharmacological potential in mesangial proliferative glomerulonephritis(MsPGN)remain unexplored.In this study,we found that downregulation of NR4A1 promotes the pathogenesis of MsPGN by regulating inflammatory and proliferative responses in mesangial cells(MCs),whereas overexpression of NR4A1 reverses these processes.Bruceine A(BA)binds to NR4A1 at residues D481/Q568 and exhibits NR4A1-dependent anti-inflammatory and anti-proliferative effects both in vitro and in vivo.Notably,adeno-associated virus serotype 9(AAV9)-mediated overexpression of NR4A1 alleviates glomerular injury and inflammatory cascades,while knockout of NR4A1 impairs the renoprotective effects of BA.BA binds to the ligand-binding domain(LBD)of NR4A1 and further sterically blocks K48-linked polyubiquitination at K558,thereby stabilizing NR4A1 protein levels.This stabilization enables NR4A1 to auto-activate its own promoter,amplifying the transcriptional repression of nuclear factor kappa-B(NF-κB)signaling phosphorylation,which ultimately attenuates inflammatory cascades and mesangial proliferation to confer renal protection.This study provides a promising therapeutic avenue for the development of nextgeneration therapies against MsPGN.展开更多
Objective： To observe the effects of Xuebijing Injection （血必净注射液） on dendritic cells （DCs） and T lymphocytes, and the potential mechanisms of its therapeutic effect on systemic lupus erythematosus （SLE）. ...Objective： To observe the effects of Xuebijing Injection （血必净注射液） on dendritic cells （DCs） and T lymphocytes, and the potential mechanisms of its therapeutic effect on systemic lupus erythematosus （SLE）. Methods： A widely used mouse model, SLE-prone BLLF1 mice aged 8-10 weeks, was employed. Mice were randomly divided into 4 groups： a normal group, a model group and two treatment groups treated with Xuebijing Injection with a dose of 6.4 mL/kg via intraperitoneal administration for SLE-prone BLLF1 mice aged 8 weeks （treatment A group） and 10 weeks （treatment B group）. Renal tissue sections were stained with Masson＇s trichrome and periodic acid-silver methenamine. Histopathological changes in the kidney were evaluated by a light microscopy. The capacity of the DCs isolated from the spleen to stimulate the T cell proliferation in response to concanavalin A （Con A） was determined. Results： Compared with the model group, levels of anti-dsDNA antibodies in the two treatment groups decreased remarkablely （P〈0.01, P〈0.05）, and levels of serum creatinine and blood urea nitrogen increased （P〈0.01, P〈0.05）. Pathological changes were found in the kidney in the model group. Histopathological abnormalities were alleviated in the two treatment groups. Treatment with Xuebijing injection also significantly upregulated the expression of CD80, CD86 and major histocompatibility class Ⅱ by DCs compared with the model group （P〈0.05）. When splenic T lymphocytes from BLLF1 mice were co-cultured with DCs at ratios of 1：100, 1：150 and 1：200 for 3 and 5 days, the proliferation of T lymphocytes was suppressed compared with the normal group （P〈0.05）, but this was restored by Xuebijing Injection under the same conditions. In the model group, levels of tumor necrosis factor （TNF）-α in supernatants were significantly elevated compared with the normal group （P〈0.01）, interleukin-2 levels decreased （P〈0.05）, while these changes were significantly alleviated in the Xuebijing treatment groups. Conclusions： Xuebijing Injection alleviated renal injury in SLE-prone BLLF-1 mice. The mechanism might be through influencing T cell polarization mediated by DCs, and Xuebijing Injection might be a potential drug that suppresses immune dysfunction in patients with SLE.展开更多
文摘We studied the effects of angiotensin-converting enzyme inhibitor on the response of arterial intima after balloon denudation.Captopril（3mg.kg/d）was administered to 4miniature pigs after abdominal aortic balloon denudation.
基金supported by National Natural Science Foundation of China(32141005).
文摘The nuclear receptor 4A1(NR4A1)plays a crucial role in maintaining cellular homeostasis and is involved in various disease processes;however,its functional role and pharmacological potential in mesangial proliferative glomerulonephritis(MsPGN)remain unexplored.In this study,we found that downregulation of NR4A1 promotes the pathogenesis of MsPGN by regulating inflammatory and proliferative responses in mesangial cells(MCs),whereas overexpression of NR4A1 reverses these processes.Bruceine A(BA)binds to NR4A1 at residues D481/Q568 and exhibits NR4A1-dependent anti-inflammatory and anti-proliferative effects both in vitro and in vivo.Notably,adeno-associated virus serotype 9(AAV9)-mediated overexpression of NR4A1 alleviates glomerular injury and inflammatory cascades,while knockout of NR4A1 impairs the renoprotective effects of BA.BA binds to the ligand-binding domain(LBD)of NR4A1 and further sterically blocks K48-linked polyubiquitination at K558,thereby stabilizing NR4A1 protein levels.This stabilization enables NR4A1 to auto-activate its own promoter,amplifying the transcriptional repression of nuclear factor kappa-B(NF-κB)signaling phosphorylation,which ultimately attenuates inflammatory cascades and mesangial proliferation to confer renal protection.This study provides a promising therapeutic avenue for the development of nextgeneration therapies against MsPGN.
基金Supported by Grants from the National Natural Science Foundation(No.81130035,81071545,and 30971192)the National Basic Research Program of China(No. 2012CB518102)
文摘Objective： To observe the effects of Xuebijing Injection （血必净注射液） on dendritic cells （DCs） and T lymphocytes, and the potential mechanisms of its therapeutic effect on systemic lupus erythematosus （SLE）. Methods： A widely used mouse model, SLE-prone BLLF1 mice aged 8-10 weeks, was employed. Mice were randomly divided into 4 groups： a normal group, a model group and two treatment groups treated with Xuebijing Injection with a dose of 6.4 mL/kg via intraperitoneal administration for SLE-prone BLLF1 mice aged 8 weeks （treatment A group） and 10 weeks （treatment B group）. Renal tissue sections were stained with Masson＇s trichrome and periodic acid-silver methenamine. Histopathological changes in the kidney were evaluated by a light microscopy. The capacity of the DCs isolated from the spleen to stimulate the T cell proliferation in response to concanavalin A （Con A） was determined. Results： Compared with the model group, levels of anti-dsDNA antibodies in the two treatment groups decreased remarkablely （P〈0.01, P〈0.05）, and levels of serum creatinine and blood urea nitrogen increased （P〈0.01, P〈0.05）. Pathological changes were found in the kidney in the model group. Histopathological abnormalities were alleviated in the two treatment groups. Treatment with Xuebijing injection also significantly upregulated the expression of CD80, CD86 and major histocompatibility class Ⅱ by DCs compared with the model group （P〈0.05）. When splenic T lymphocytes from BLLF1 mice were co-cultured with DCs at ratios of 1：100, 1：150 and 1：200 for 3 and 5 days, the proliferation of T lymphocytes was suppressed compared with the normal group （P〈0.05）, but this was restored by Xuebijing Injection under the same conditions. In the model group, levels of tumor necrosis factor （TNF）-α in supernatants were significantly elevated compared with the normal group （P〈0.01）, interleukin-2 levels decreased （P〈0.05）, while these changes were significantly alleviated in the Xuebijing treatment groups. Conclusions： Xuebijing Injection alleviated renal injury in SLE-prone BLLF-1 mice. The mechanism might be through influencing T cell polarization mediated by DCs, and Xuebijing Injection might be a potential drug that suppresses immune dysfunction in patients with SLE.
