Background: Regulatory B cells(Bregs) is an indispensable element in inducing immune tolerance after liver transplantation. As one of the microRNAs(miRNAs), mi R-29a-3p also inhibits translation by degrading the targe...Background: Regulatory B cells(Bregs) is an indispensable element in inducing immune tolerance after liver transplantation. As one of the microRNAs(miRNAs), mi R-29a-3p also inhibits translation by degrading the target mRNA, and yet the relationship between Bregs and mi R-29a-3p has not yet been fully explored. This study aimed to investigate the impact of miR-29a-3p on the regulation of differentiation and immunosuppressive functions of memory Bregs(m Bregs) and ultimately provide potentially effective therapies in inducing immune tolerance after liver transplantation. Methods: Flow cytometry was employed to determine the levels of Bregs in peripheral blood mononuclear cells. TaqMan low-density array miRNA assays were used to identify the expression of different miRNAs, electroporation transfection was used to induce mi R-29a-3p overexpression and knockdown, and dual luciferase reporter assay was used to verify the target gene of miR-29a-3p. Results: In patients experiencing acute rejection after liver transplantation, the proportions and immunosuppressive function of m Bregs in the circulating blood were significantly impaired. mi R-29a-3p was found to be a regulator of m Bregs differentiation. Inhibition of miR-29a-3p, which targeted nuclear factor of activated T cells 5(NFAT5), resulted in a conspicuous boost in the differentiation and immunosuppressive function of m Bregs. The inhibition of mi R-29a-3p in CD19~+ B cells was capable of raising the expression levels of NFAT5, thereby promoting B cells to differentiate into m Bregs. In addition, the observed enhancement of differentiation and immunosuppressive function of m Bregs upon mi R-29a-3p inhibition was abolished by the knockdown of NFAT5 in B cells. Conclusions: mi R-29a-3p was found to be a crucial regulator for m Bregs differentiation and immunosuppressive function. Silencing mi R-29a-3p could be a potentially effective therapeutic strategy for inducing immune tolerance after liver transplantation.展开更多
BACKGROUND Posterior reversible encephalopathy syndrome(PRES),characterized by acute neurological deterioration and extensive white matter lesions on T2-fluid attenuated inversion recovery magnetic resonance imaging(M...BACKGROUND Posterior reversible encephalopathy syndrome(PRES),characterized by acute neurological deterioration and extensive white matter lesions on T2-fluid attenuated inversion recovery magnetic resonance imaging(MRI),is increasingly associated with calcineurin inhibitors(CNI)-related neurotoxicity.Prompt diagnosis is crucial,as early intervention,including the modification or discontinuation of CNI therapy,strict blood pressure management,corticosteroid treatment,and supportive care can significantly improve patient outcomes and prognosis.The growing clinical recognition of CNI-related PRES underscores the importance of identifying and managing this condition in patients presenting with acute neurological symptoms.CASE SUMMARY This report describes three cases of liver transplant recipients who developed PRES.The first case involves a 60-year-old woman who experienced seizures,aphasia,and hemiplegia on postoperative day(POD)9,with MRI revealing ischemic foci followed by extensive white matter lesions.After replacing tacrolimus,her symptoms improved,and no significant MRI abnormalities were observed after three years of follow-up.The second case concerns a 54-year-old woman with autoimmune hepatitis who developed headaches,seizures,and extensive white matter demyelination on MRI on POD24.Following the switch to rapamycin and the initiation of corticosteroids,her symptoms resolved,and she was discharged on POD95.The third case details a 60-year-old woman with hepatocellular carcinoma who developed PRES,evidenced by brain MRI abnormal-ities on POD11.Transitioning to rapamycin and corticosteroid therapy led to her full recovery,and she was discharged on POD22.These cases highlight the critical importance of early diagnosis,CNI modification,and stringent management in improving outcomes for liver transplant recipients with CNI related PRES.CONCLUSION Clinical manifestations,combined with characteristic MRI findings,are crucial in diagnosing PRES among organ transplant recipients.However,when standard treatments are ineffective or MRI results are atypical,alternative diagnoses should be taken into considered.展开更多
Podocyte injury is an important cause of proteinuria.Angiopoietin-like protein 4(Angptl4)is a secreted glycoprotein and has a role in proteinuria.However,the exact role of Angptl4 in podocyte injury and its upstream r...Podocyte injury is an important cause of proteinuria.Angiopoietin-like protein 4(Angptl4)is a secreted glycoprotein and has a role in proteinuria.However,the exact role of Angptl4 in podocyte injury and its upstream regulators has not been clarified.In this study,we used lipopolysaccharide(LPS)-induced mice and cultured podocytes as podocyte injury models.Our results indicated that LPS increased the expression of podocyte Angptl4 in vivo and in vitro.Furthermore,we showed that Angptl4 overexpression deteriorated LPS-induced podocyte injury by inducing podocyte cytoskeleton rearrangement,reducing the expression of synaptopodin while Angptl4 knockdown alleviated LPS-induced podocyte injury.In addition,we found that inhibitors and siRNA targeting TLR4/MyD88/NF-κB signaling inhibited the upregulation of Angptl4 in LPS-induced podocytes.Moreover,inhibitors and siRNA targeting calcineurin/NFAT signaling also relieved LPS-induced Angptl4 expression and podocyte injury in vivo and in vitro.Taken together,our study has elucidated that both of the TLR4/MyD88/NF-κB and calcineurin/NFAT signaling mediate the upregulation of Angptl4 in LPS-induced podocytes,which has important implications for further understanding the molecular mechanism of LPS-induced podocyte injury.展开更多
目的 观察中医不同治法对大鼠骨质疏松症模型骨骼、骨骼肌中钙调神经磷酸酶(Calcineurin, CaN)、T细胞活化核因子(Nuclear Factor of the Activated T cell, NFAT)含量的影响,探讨中医药治疗骨质疏松症的分子机制。方法 将雌性SD大鼠随...目的 观察中医不同治法对大鼠骨质疏松症模型骨骼、骨骼肌中钙调神经磷酸酶(Calcineurin, CaN)、T细胞活化核因子(Nuclear Factor of the Activated T cell, NFAT)含量的影响,探讨中医药治疗骨质疏松症的分子机制。方法 将雌性SD大鼠随机分为正常组、模型对照组、补肾法组、健脾法组、活血法组。采用酶联免疫吸附(ELISA)法进行测定,比较不同组别CaN、NFAT的含量变化。结果 模型对照组与正常组比较,骨骼、骨骼肌的CaN含量有显著降低(P<0.01);补肾法组、健脾法组、活血法组与模型对照组比较,骨骼、骨骼肌的CaN的含量均明显升高(P<0.01),其中补肾法组升高程度比较明显,骨骼的CaN含量其次为活血法组,骨骼肌的CaN含量其次为健脾组。模型对照组与正常组比较,骨骼、骨骼肌的NFAT含量显著降低(P<0.01);补肾法组、健脾法组、活血法组与模型对照组比较,NFAT含量明显升高,其中补肾法组升高程度比较明显,其次为健脾法组。结论 (1)骨骼、骨骼肌中CaN、NFAT的含量变化可能与骨质疏松症的发生有一定的相关性。(2)补肾法和健脾法可明显改善骨质疏松症大鼠骨骼、骨骼肌中CaN、NFAT的含量,预防骨质疏松的发生发展。(3)中医不同治法能够有效改善骨质疏松,补肾法、健脾法是治疗骨质疏松的重要治法。展开更多
基金supported by grants from the National Natural Science Foundation of China (82070676)Jiangsu Provincial Medi-cal Innovation Center (CXZX202203)Jiangsu Provincial Medi-cal Key Laboratory (ZDXYS202201)。
文摘Background: Regulatory B cells(Bregs) is an indispensable element in inducing immune tolerance after liver transplantation. As one of the microRNAs(miRNAs), mi R-29a-3p also inhibits translation by degrading the target mRNA, and yet the relationship between Bregs and mi R-29a-3p has not yet been fully explored. This study aimed to investigate the impact of miR-29a-3p on the regulation of differentiation and immunosuppressive functions of memory Bregs(m Bregs) and ultimately provide potentially effective therapies in inducing immune tolerance after liver transplantation. Methods: Flow cytometry was employed to determine the levels of Bregs in peripheral blood mononuclear cells. TaqMan low-density array miRNA assays were used to identify the expression of different miRNAs, electroporation transfection was used to induce mi R-29a-3p overexpression and knockdown, and dual luciferase reporter assay was used to verify the target gene of miR-29a-3p. Results: In patients experiencing acute rejection after liver transplantation, the proportions and immunosuppressive function of m Bregs in the circulating blood were significantly impaired. mi R-29a-3p was found to be a regulator of m Bregs differentiation. Inhibition of miR-29a-3p, which targeted nuclear factor of activated T cells 5(NFAT5), resulted in a conspicuous boost in the differentiation and immunosuppressive function of m Bregs. The inhibition of mi R-29a-3p in CD19~+ B cells was capable of raising the expression levels of NFAT5, thereby promoting B cells to differentiate into m Bregs. In addition, the observed enhancement of differentiation and immunosuppressive function of m Bregs upon mi R-29a-3p inhibition was abolished by the knockdown of NFAT5 in B cells. Conclusions: mi R-29a-3p was found to be a crucial regulator for m Bregs differentiation and immunosuppressive function. Silencing mi R-29a-3p could be a potentially effective therapeutic strategy for inducing immune tolerance after liver transplantation.
文摘BACKGROUND Posterior reversible encephalopathy syndrome(PRES),characterized by acute neurological deterioration and extensive white matter lesions on T2-fluid attenuated inversion recovery magnetic resonance imaging(MRI),is increasingly associated with calcineurin inhibitors(CNI)-related neurotoxicity.Prompt diagnosis is crucial,as early intervention,including the modification or discontinuation of CNI therapy,strict blood pressure management,corticosteroid treatment,and supportive care can significantly improve patient outcomes and prognosis.The growing clinical recognition of CNI-related PRES underscores the importance of identifying and managing this condition in patients presenting with acute neurological symptoms.CASE SUMMARY This report describes three cases of liver transplant recipients who developed PRES.The first case involves a 60-year-old woman who experienced seizures,aphasia,and hemiplegia on postoperative day(POD)9,with MRI revealing ischemic foci followed by extensive white matter lesions.After replacing tacrolimus,her symptoms improved,and no significant MRI abnormalities were observed after three years of follow-up.The second case concerns a 54-year-old woman with autoimmune hepatitis who developed headaches,seizures,and extensive white matter demyelination on MRI on POD24.Following the switch to rapamycin and the initiation of corticosteroids,her symptoms resolved,and she was discharged on POD95.The third case details a 60-year-old woman with hepatocellular carcinoma who developed PRES,evidenced by brain MRI abnormal-ities on POD11.Transitioning to rapamycin and corticosteroid therapy led to her full recovery,and she was discharged on POD22.These cases highlight the critical importance of early diagnosis,CNI modification,and stringent management in improving outcomes for liver transplant recipients with CNI related PRES.CONCLUSION Clinical manifestations,combined with characteristic MRI findings,are crucial in diagnosing PRES among organ transplant recipients.However,when standard treatments are ineffective or MRI results are atypical,alternative diagnoses should be taken into considered.
基金This study was supported by the National Natural Science Foundation of China(No.81400716)the Zhejiang Provincial Natural Science Foundation of China(No.LY20H050007,LY19H050005)Medical Health Science and Technology Project of Zhejiang Provincial Health Commission(No.2020383770).
文摘Podocyte injury is an important cause of proteinuria.Angiopoietin-like protein 4(Angptl4)is a secreted glycoprotein and has a role in proteinuria.However,the exact role of Angptl4 in podocyte injury and its upstream regulators has not been clarified.In this study,we used lipopolysaccharide(LPS)-induced mice and cultured podocytes as podocyte injury models.Our results indicated that LPS increased the expression of podocyte Angptl4 in vivo and in vitro.Furthermore,we showed that Angptl4 overexpression deteriorated LPS-induced podocyte injury by inducing podocyte cytoskeleton rearrangement,reducing the expression of synaptopodin while Angptl4 knockdown alleviated LPS-induced podocyte injury.In addition,we found that inhibitors and siRNA targeting TLR4/MyD88/NF-κB signaling inhibited the upregulation of Angptl4 in LPS-induced podocytes.Moreover,inhibitors and siRNA targeting calcineurin/NFAT signaling also relieved LPS-induced Angptl4 expression and podocyte injury in vivo and in vitro.Taken together,our study has elucidated that both of the TLR4/MyD88/NF-κB and calcineurin/NFAT signaling mediate the upregulation of Angptl4 in LPS-induced podocytes,which has important implications for further understanding the molecular mechanism of LPS-induced podocyte injury.
文摘目的 观察中医不同治法对大鼠骨质疏松症模型骨骼、骨骼肌中钙调神经磷酸酶(Calcineurin, CaN)、T细胞活化核因子(Nuclear Factor of the Activated T cell, NFAT)含量的影响,探讨中医药治疗骨质疏松症的分子机制。方法 将雌性SD大鼠随机分为正常组、模型对照组、补肾法组、健脾法组、活血法组。采用酶联免疫吸附(ELISA)法进行测定,比较不同组别CaN、NFAT的含量变化。结果 模型对照组与正常组比较,骨骼、骨骼肌的CaN含量有显著降低(P<0.01);补肾法组、健脾法组、活血法组与模型对照组比较,骨骼、骨骼肌的CaN的含量均明显升高(P<0.01),其中补肾法组升高程度比较明显,骨骼的CaN含量其次为活血法组,骨骼肌的CaN含量其次为健脾组。模型对照组与正常组比较,骨骼、骨骼肌的NFAT含量显著降低(P<0.01);补肾法组、健脾法组、活血法组与模型对照组比较,NFAT含量明显升高,其中补肾法组升高程度比较明显,其次为健脾法组。结论 (1)骨骼、骨骼肌中CaN、NFAT的含量变化可能与骨质疏松症的发生有一定的相关性。(2)补肾法和健脾法可明显改善骨质疏松症大鼠骨骼、骨骼肌中CaN、NFAT的含量,预防骨质疏松的发生发展。(3)中医不同治法能够有效改善骨质疏松,补肾法、健脾法是治疗骨质疏松的重要治法。
