An effective therapeutic regimen for hepatic fibrosis requires a deep understanding of the pathogenesis mechanism.Hepatic fibrosis is characterized by activated hepatic stellate cells(aHSCs)with an excessive productio...An effective therapeutic regimen for hepatic fibrosis requires a deep understanding of the pathogenesis mechanism.Hepatic fibrosis is characterized by activated hepatic stellate cells(aHSCs)with an excessive production of extracellular matrix.Although promoted activation of HSCs by M2 macrophages has been demonstrated,the molecular mechanism involved remains ambiguous.Herein,we propose that the vitamin D receptor(VDR)involved in macrophage polarization may regulate the communication between macrophages and HSCs by changing the functions of exosomes.We confirm that activating the VDR can inhibit the effect of M2 macrophages on HSC activation.The exosomes derived from M2 macrophages can promote HSC activation,while stimulating VDR alters the protein profiles and reverses their roles in M2 macrophage exosomes.Smooth muscle cell-associated protein 5(SMAP-5)was found to be the key effector protein in promoting HSC activation by regulating autophagy flux.Building on these results,we show that a combined treatment of a VDR agonist and a macrophage-targeted exosomal secretion inhibitor achieves an excellent anti-hepatic fibrosis effect.In this study,we aim to elucidate the association between VDR and macrophages in HSC activation.The results contribute to our understanding of the pathogenesis mechanism of hepatic fibrosis,and provide potential therapeutic targets for its treatment.展开更多
AIM: To investigate the co-regulation of dendritic cell- associated C-type lectin-1 (Dectin-1), Toll-like receptor 2 (TLR2), and relative chemotactic factors in the Telomease- immortalized human corneal epitheli...AIM: To investigate the co-regulation of dendritic cell- associated C-type lectin-1 (Dectin-1), Toll-like receptor 2 (TLR2), and relative chemotactic factors in the Telomease- immortalized human corneal epithelial (THCE) cells after exposure to ,Aspergillus fumigatus (Af) hyphae. METHODS: The normal THCE cells were investigated as control. After cultured in vitro with Af hyphae, with or without laminarin and anti-TLR2 antibody for 4, 8, 16 and 24h, THCE cells were harvested. The expression of Dectin-1, TLR2, CXCL1 and CXCL8 mRNA were measured by real-time quantitative polymerase chain reaction at the stimulation of 4, 8 and 16h separately. The protein expression of Dectin-1 and TLR2 were analyzed at 8, 16, and 24h by Western blot. ~ RESULTS: The mRNA CXCL8 increased in THCE expression of CXCL1 and cells after stimulated by Af hyphae. The stimulatory effects on these inflammatory chemokines were shown in a dose-dependent manner and reached the peak at 8h. Af hyphae significantly stimulated the production of Dectin-1 and TLR2 in THCE cells at both mRNA and protein levels. The protein of Dectin-1 and TLR2 gradually increased till 16h. While pretreated with laminarin (a Dectin-1 inhibitor), the expression of TLR2, CXCL1 and CXCL8 all decreased dramatically at the peak point, interestingly, when pretreated with TLR2 neutralizing antibody, the expression of Dectin -1, CXCL1 and CXCL8 also decreased dramatically at the peak point. CONCLUSION: These findings suggest that Dectin-1 and TLR2 co-regulated with each other after treated with inactive Af hyphae in the THCE cells, and they contribute together to the inflammatory responses by induction of chemokines CXCL1 and CXCL8.展开更多
The combination of the immunotherapy(i.e.,the use of monoclonal antibodies)and the conventional chemotherapy increases the long-term survival of patients with lymphoma.However,for patients with relapsed or treatment-r...The combination of the immunotherapy(i.e.,the use of monoclonal antibodies)and the conventional chemotherapy increases the long-term survival of patients with lymphoma.However,for patients with relapsed or treatment-resistant lymphoma,a novel treatment approach is urgently needed.Chimeric antigen receptor T(CAR-T)cells were introduced as a treatment for these patients.Based on recent clinical data,approximately 50%of patients with relapsed or refractory B-cell lymphoma achieved complete remission after receiving the CD19 CAR-T cell therapy.Moreover,clinical data revealed that some patients remained in remission for more than two years after the CAR-T cell therapy.Other than the CD19-targeted CAR-T,the novel target antigens,such as CD20,CD22,CD30,and CD37,which were greatly expressed on lymphoma cells,were studied under preclinical and clinical evaluations for use in the treatment of lymphoma.Nonetheless,the CAR-T therapy was usually associated with potentially lethal adverse effects,such as the cytokine release syndrome and the neurotoxicity.Therefore,optimizing the structure of CAR,creating new drugs,and combining CAR-T cell therapy with stem cell transplantation are potential solutions to increase the effectiveness of treatment and reduce the toxicity in patients with lymphoma after the CAR-T cell therapy.展开更多
基金supported by the National Natural Science Foundation of China(Nos.81930099,81773664,82130102,92159304,81703585,and 81903651)the Natural Science Foundation of Jiangsu Province(Nos.BK20212011 and BK20180565)+4 种基金the Technology Innovation Project of Nucleic Acid Drug from National Center of Technology Innovation for Biopharmaceuticals(No.NCTIB2022HS01014)the“Double First-Class”University Project(No.CPU2022QZ05)the 111 Project from the Ministry of Education of China and the State Administration of Foreign Expert Affairs of China(Nos.111-2-07 and B17047)the Fundamental Research Funds for the Central Universities of China(No.2632022ZD11)the Open Project of State Key Laboratory of Natural Medicines(No.SKLNMZZ202017),China.
文摘An effective therapeutic regimen for hepatic fibrosis requires a deep understanding of the pathogenesis mechanism.Hepatic fibrosis is characterized by activated hepatic stellate cells(aHSCs)with an excessive production of extracellular matrix.Although promoted activation of HSCs by M2 macrophages has been demonstrated,the molecular mechanism involved remains ambiguous.Herein,we propose that the vitamin D receptor(VDR)involved in macrophage polarization may regulate the communication between macrophages and HSCs by changing the functions of exosomes.We confirm that activating the VDR can inhibit the effect of M2 macrophages on HSC activation.The exosomes derived from M2 macrophages can promote HSC activation,while stimulating VDR alters the protein profiles and reverses their roles in M2 macrophage exosomes.Smooth muscle cell-associated protein 5(SMAP-5)was found to be the key effector protein in promoting HSC activation by regulating autophagy flux.Building on these results,we show that a combined treatment of a VDR agonist and a macrophage-targeted exosomal secretion inhibitor achieves an excellent anti-hepatic fibrosis effect.In this study,we aim to elucidate the association between VDR and macrophages in HSC activation.The results contribute to our understanding of the pathogenesis mechanism of hepatic fibrosis,and provide potential therapeutic targets for its treatment.
基金Supported by the National Scientific Foundation of China (No. 81170825)
文摘AIM: To investigate the co-regulation of dendritic cell- associated C-type lectin-1 (Dectin-1), Toll-like receptor 2 (TLR2), and relative chemotactic factors in the Telomease- immortalized human corneal epithelial (THCE) cells after exposure to ,Aspergillus fumigatus (Af) hyphae. METHODS: The normal THCE cells were investigated as control. After cultured in vitro with Af hyphae, with or without laminarin and anti-TLR2 antibody for 4, 8, 16 and 24h, THCE cells were harvested. The expression of Dectin-1, TLR2, CXCL1 and CXCL8 mRNA were measured by real-time quantitative polymerase chain reaction at the stimulation of 4, 8 and 16h separately. The protein expression of Dectin-1 and TLR2 were analyzed at 8, 16, and 24h by Western blot. ~ RESULTS: The mRNA CXCL8 increased in THCE expression of CXCL1 and cells after stimulated by Af hyphae. The stimulatory effects on these inflammatory chemokines were shown in a dose-dependent manner and reached the peak at 8h. Af hyphae significantly stimulated the production of Dectin-1 and TLR2 in THCE cells at both mRNA and protein levels. The protein of Dectin-1 and TLR2 gradually increased till 16h. While pretreated with laminarin (a Dectin-1 inhibitor), the expression of TLR2, CXCL1 and CXCL8 all decreased dramatically at the peak point, interestingly, when pretreated with TLR2 neutralizing antibody, the expression of Dectin -1, CXCL1 and CXCL8 also decreased dramatically at the peak point. CONCLUSION: These findings suggest that Dectin-1 and TLR2 co-regulated with each other after treated with inactive Af hyphae in the THCE cells, and they contribute together to the inflammatory responses by induction of chemokines CXCL1 and CXCL8.
基金This work was supported by grants from the National Natural Science Foundation of China(Nos.81230014,81470341,81520108002,and 81500157)the Key Project of Science and Technology Department of Zhejiang Province(No.2018C03016-2)the Key Research and Development Program of Zhejiang Province(No.2019C03016).
文摘The combination of the immunotherapy(i.e.,the use of monoclonal antibodies)and the conventional chemotherapy increases the long-term survival of patients with lymphoma.However,for patients with relapsed or treatment-resistant lymphoma,a novel treatment approach is urgently needed.Chimeric antigen receptor T(CAR-T)cells were introduced as a treatment for these patients.Based on recent clinical data,approximately 50%of patients with relapsed or refractory B-cell lymphoma achieved complete remission after receiving the CD19 CAR-T cell therapy.Moreover,clinical data revealed that some patients remained in remission for more than two years after the CAR-T cell therapy.Other than the CD19-targeted CAR-T,the novel target antigens,such as CD20,CD22,CD30,and CD37,which were greatly expressed on lymphoma cells,were studied under preclinical and clinical evaluations for use in the treatment of lymphoma.Nonetheless,the CAR-T therapy was usually associated with potentially lethal adverse effects,such as the cytokine release syndrome and the neurotoxicity.Therefore,optimizing the structure of CAR,creating new drugs,and combining CAR-T cell therapy with stem cell transplantation are potential solutions to increase the effectiveness of treatment and reduce the toxicity in patients with lymphoma after the CAR-T cell therapy.