Chimeric antigen receptor natural killer(CAR-NK)cell therapy is an alternative immunotherapy that provides robust tumor-eliminating effects without inducing life-threatening toxicities and graft-versus-host disease.CA...Chimeric antigen receptor natural killer(CAR-NK)cell therapy is an alternative immunotherapy that provides robust tumor-eliminating effects without inducing life-threatening toxicities and graft-versus-host disease.CAR-NK cell therapy has enabled the development of“off-the-shelf”products that bypass the lengthy and expensive cell manufacturing process1.展开更多
Neurodegenerative diseases,such as Alzheimer’s disease,Parkinson’s disease,and Huntington’s disease,are characterized by the progressive loss of neuronal function and structure,leading to severe morbidity and morta...Neurodegenerative diseases,such as Alzheimer’s disease,Parkinson’s disease,and Huntington’s disease,are characterized by the progressive loss of neuronal function and structure,leading to severe morbidity and mortality.Current therapeutic approaches are ineffective at stopping or reversing disease progression.Stem cell therapy has emerged as a promising candidate in research and treatment.Mesenchymal stem cells(MSCs)are considered ideal candidates for regenerative medicine because of their high proliferation rate and multi-differentiation potential.MSCs can differentiate into neurons and glial cells,modulate immune responses,and reduce inflammation,and their exosomes can promote neural repair and regulate neuronal function;thus,MSCs offer unique advantages for treating neurodegenerative diseases.However,challenges remain in optimizing cell delivery methods,ensuring the long-term survival and integration of transplanted cells,and fully understanding their therapeutic effects.This article primarily outlines the functions of MSCs in neurodegenerative diseases,with the intention that further research will fully harness their potential and translate these findings into clinical applications,offering new hope for patients suffering from neurodegenerative diseases.展开更多
Vascular endothelial growth factor(VEGF) is primarily known as a proangiogenic factor and is one of the most important growth and survival factors affecting the vascular endothelium. However, recent studies have shown...Vascular endothelial growth factor(VEGF) is primarily known as a proangiogenic factor and is one of the most important growth and survival factors affecting the vascular endothelium. However, recent studies have shown that VEGF also plays a vital role in the immune environment. In addition to the traditional growth factor role of VEGF and VEGF receptors(VEGFRs), they have a complicated relationship with various immune cells. VEGF also reportedly inhibits the differentiation and function of immune cells during hematopoiesis. Dendritic cells(DCs), macrophages, and lymphocytes further express certain types of VEGF receptors.VEGF can be secreted as well by tumor cells through the autocrine pathway and can stimulate the function of cancer stemness.This review will provide a paradigm shift in our understanding of the role of VEGF/VEGFR signaling in the immune and cancer environment.展开更多
Non-alcoholic fatty liver disease(NAFLD)has emerged as a significant health challenge,characterized by its widespread prevalence,intricate natural progression and multifaceted pathogenesis.Although NAFLD initially pre...Non-alcoholic fatty liver disease(NAFLD)has emerged as a significant health challenge,characterized by its widespread prevalence,intricate natural progression and multifaceted pathogenesis.Although NAFLD initially presents as benign fat accumulation,it may progress to steatosis,non-alcoholic steatohepatitis,cirrhosis,and hepatocellular carcinoma.Mesenchymal stem cells(MSCs)are recognized for their intrinsic self-renewal,superior biocompatibility,and minimal immunogenicity,positioning them as a therapeutic innovation for liver diseases.Therefore,this review aims to elucidate the potential roles of MSCs in alleviating the progression of NAFLD by alteration of underlying molecular pathways,including glycolipid metabolism,inflammation,oxidative stress,endoplasmic reticulum stress,and fibrosis.The insights are expected to provide further understanding of the potential of MSCs in NAFLD therapeutics,and support the development of MSC-based therapy in the treatment of NAFLD.展开更多
BACKGROUND Type 1 diabetes(T1D),a chronic metabolic and autoimmune disease,seriously endangers human health.In recent years,mesenchymal stem cell(MSC)transplantation has become an effective treatment for diabetes.Mens...BACKGROUND Type 1 diabetes(T1D),a chronic metabolic and autoimmune disease,seriously endangers human health.In recent years,mesenchymal stem cell(MSC)transplantation has become an effective treatment for diabetes.Menstrual bloodderived endometrial stem cells(MenSC),a novel MSC type derived from the decidual endometrium during menstruation,are expected to become promising seeding cells for diabetes treatment because of their noninvasive collection procedure,high proliferation rate and high immunomodulation capacity.AIM To comprehensively compare the effects of MenSC and umbilical cord-derived MSC(UcMSC)transplantation on T1D treatment,to further explore the potential mechanism of MSC-based therapies in T1D,and to provide support for the clinical application of MSC in diabetes treatment.METHODS A conventional streptozotocin-induced T1D mouse model was established,and the effects of MenSC and UcMSC transplantation on their blood glucose and serum insulin levels were detected.The morphological and functional changes in the pancreas,liver,kidney,and spleen were analyzed by routine histological and immunohistochemical examinations.Changes in the serum cytokine levels in the model mice were assessed by protein arrays.The expression of target proteins related to pancreatic regeneration and apoptosis was examined by western blot.RESULTS MenSC and UcMSC transplantation significantly improved the blood glucose and serum insulin levels in T1D model mice.Immunofluorescence analysis revealed that the numbers of insulin+and CD31+cells in the pancreas were significantly increased in MSC-treated mice compared with control mice.Subsequent western blot analysis also showed that vascular endothelial growth factor(VEGF),Bcl2,Bcl-xL and Proliferating cell nuclear antigen in pancreatic tissue was significantly upregulated in MSC-treated mice compared with control mice.Additionally,protein arrays indicated that MenSC and UcMSC transplantation significantly downregulated the serum levels of interferonγand tumor necrosis factorαand upregulated the serum levels of interleukin-6 and VEGF in the model mice.Additionally,histological and immunohistochemical analyses revealed that MSC transplantation systematically improved the morphologies and functions of the liver,kidney,and spleen in T1D model mice.CONCLUSION MenSC transplantation significantly improves the symptoms in T1D model mice and exerts protective effects on their main organs.Moreover,MSC-mediated angiogenesis,antiapoptotic effects and immunomodulation likely contribute to the above improvements.Thus,MenSC are expected to become promising seeding cells for clinical diabetes treatment due to their advantages mentioned above.展开更多
Background:The pathogenesis of Parkinson’s disease(PD)is associated with ferroptosis.The role of HIF1a is involved in several diseases,but its specific function in PD remains uncertain.Methods:In this study,we genera...Background:The pathogenesis of Parkinson’s disease(PD)is associated with ferroptosis.The role of HIF1a is involved in several diseases,but its specific function in PD remains uncertain.Methods:In this study,we generated animal and cellular models of PD using the neurotoxin 6-OHDA.The occurrence of ferroptosis was determined by measuring levels of ferroptosis-related proteins,Fe2t amount and transmission electron microscopy analysis in the PD models,and was further confirmed by using a ferroptosis inhibitor.HIF1a overexpressing and HIF1a knockdown SH-SY5Y cells were constructed by lentivirus transfection.Then,the levels of lipid peroxide,ROS,SLC7A11,and GPX4 were detected to elucidate the relationship between HIF1a and ferroptosis.Luciferase assay was used to analyze the regulation between HIF1a and SLC7A11.Results:We observed a significant downregulation of HIF1a in both animal and cellular PD models.Overexpression of HIF1a mitigated 6-OHDA-induced ferroptosis in SH-SY5Y cells,while,conversely,downregulation of HIF1a promoted ferroptosis in SH-SY5Y cells.BioEdit Sequence Alignment Editor software identified a hypoxia response element(HRE)within the promoter sequence of SLC7A11.The dual-luciferase reporter assays demonstrated that the co-expression of HIF1a and the SLC7A11 promoter significantly augmented reporter activity in SH-SY5Y cells.Moreover,introduction of a mutation into the HRE of the SLC7A11 promoter abolished the induction of SLC7A11 by HIF1a overexpression,resulted in a reduction in promoter activity compared with wild-type cells.Conclusions:The collective findings of this study indicate that HIF1a can inhibit ferroptosis by positively regulating SLC7A11.This investigation has shed light on the crucial involvement of the HIF1a/SLC7A11 signaling axis in ferroptosis in PDmodels,thereby presenting patients withPDa promising therapeutic target.展开更多
Dietary fatty acids(FAs)are associated with the therapeutic intervention under various health conditions.Human γδ-T cells are indispensable for immunosurveillance toward malignant cells.However,their impact onγδ-T...Dietary fatty acids(FAs)are associated with the therapeutic intervention under various health conditions.Human γδ-T cells are indispensable for immunosurveillance toward malignant cells.However,their impact onγδ-T cell metabolism and function remains poorly unexplored.Here,we applied targeted metabolomics analysis to serum FAs among cancer patients undergoing γδ-T cell therapy and discovered that palmitic acid(PA)or oleic acid(OA)levels were associated with the efficacy of Vγ9Vδ2-T cell therapy.We further elucidated that PA suppresses the antitumor activity of Vγ9Vδ2-T cells by disrupting metabolic processes and inhibiting the secretion of lytic granules,whereas OA restores the impaired antitumor activity of Vγ9Vδ2-T cells.Mechanistically,we surprisingly found that PA stimulates Vγ9Vδ2-T cells to secrete excessive IFNγ,which in turn induces cell pyroptosis,ultimately resulting in decreased antitumor activity.展开更多
Chemerin is present in various inflammatory sites and is closely involved in tissue inflammation. Recent studies have demonstrated that chemerin treatment can cause either anti-inflammatory or pro-inflammatory effects...Chemerin is present in various inflammatory sites and is closely involved in tissue inflammation. Recent studies have demonstrated that chemerin treatment can cause either anti-inflammatory or pro-inflammatory effects according to the disease model being investigated. Elevated circulating chemerin was recently found in patients with inflammatory bowel disease （IBD）; however, the role of chemerin in intestinal inflammation remains unknown. In this study, we demonstrated that the administration of exogenous chemerin （aa 17-156） aggravated the severity of dextran sulfate sodium （DSS）-induced colitis, which was characterized by higher clinical scores, extensive mucosal damage and significantly increased local and systemic production of pro-inflammatory cytokines, including IL-6, TNF-a and interferon （IFN-7）. Interestingly, chemerin did not appear to influence the magnitudes of inflammatory infiltrates in the colons, but did result in significantly decreased colonic expression of M2 macrophage-associated genes, including Arginase 1 （Arg-1）, Yml, FIZZ1 and IL-IO, following DSS exposure, suggesting an impaired M2 macrophage skewing in vivo. Furthermore, an in vitro experiment showed that the addition of chemerin directly suppressed M2 macrophage-associated gene expression and STAT6 phosphorylation in IL-4-stimulated macrophages. Significantly elevated chemerin levels were found in colons from DSS-exposed mice and from ulcerative colitis （UC） patients and appeared to positively correlate with disease severity. Moreover, the in vivo administration of neutralizing anti-chemerin antibody significantly improved intestinal inflammation following DSS exposure. Taken together, our findings reveal a pro-inflammatory role for chemerin in DSS-induced colitis and the ability of chemerin to suppress the anti-inflammatory M2 macrophage response. Our study also suggests that upregulated chemerin in inflamed colons may contribute to the pathogenesis of IBD.展开更多
基金supported by grants from the Noncommunicable Chronic Diseases-National Science and Technology Major Project(Grant No.2023ZD0501300)Science Technology Department of Zhejiang Province(Grant No.2021C03117)+2 种基金National Natural Science Foundation of China(Grant No.82350104 and 82170219)Natural Science Foundation of Zhejiang Province,China(Grant No.LY23H080004 and LY24H080001)Medical Health Science and Technology Project of Zhejiang Provincial Health Commission(Grant No.2021KY199)。
文摘Chimeric antigen receptor natural killer(CAR-NK)cell therapy is an alternative immunotherapy that provides robust tumor-eliminating effects without inducing life-threatening toxicities and graft-versus-host disease.CAR-NK cell therapy has enabled the development of“off-the-shelf”products that bypass the lengthy and expensive cell manufacturing process1.
基金Supported by Natural Science Foundation of Henan Province,No.242300421199 and No.252300421395Henan Province Joint Fund for Science and Technology Research and Development,No.235101610002+1 种基金Key Technologies R&D Program of Henan Province,No.242102310134Henan Province Foundation for University Key Teacher,No.2024GGJS088.
文摘Neurodegenerative diseases,such as Alzheimer’s disease,Parkinson’s disease,and Huntington’s disease,are characterized by the progressive loss of neuronal function and structure,leading to severe morbidity and mortality.Current therapeutic approaches are ineffective at stopping or reversing disease progression.Stem cell therapy has emerged as a promising candidate in research and treatment.Mesenchymal stem cells(MSCs)are considered ideal candidates for regenerative medicine because of their high proliferation rate and multi-differentiation potential.MSCs can differentiate into neurons and glial cells,modulate immune responses,and reduce inflammation,and their exosomes can promote neural repair and regulate neuronal function;thus,MSCs offer unique advantages for treating neurodegenerative diseases.However,challenges remain in optimizing cell delivery methods,ensuring the long-term survival and integration of transplanted cells,and fully understanding their therapeutic effects.This article primarily outlines the functions of MSCs in neurodegenerative diseases,with the intention that further research will fully harness their potential and translate these findings into clinical applications,offering new hope for patients suffering from neurodegenerative diseases.
基金supported by grants from the key program of the National Basic Research Program of China (973 program) (Grant No. 2012CB9333004)the National Natural Science Foundation of China (Grant No. 81401888)
文摘Vascular endothelial growth factor(VEGF) is primarily known as a proangiogenic factor and is one of the most important growth and survival factors affecting the vascular endothelium. However, recent studies have shown that VEGF also plays a vital role in the immune environment. In addition to the traditional growth factor role of VEGF and VEGF receptors(VEGFRs), they have a complicated relationship with various immune cells. VEGF also reportedly inhibits the differentiation and function of immune cells during hematopoiesis. Dendritic cells(DCs), macrophages, and lymphocytes further express certain types of VEGF receptors.VEGF can be secreted as well by tumor cells through the autocrine pathway and can stimulate the function of cancer stemness.This review will provide a paradigm shift in our understanding of the role of VEGF/VEGFR signaling in the immune and cancer environment.
文摘Non-alcoholic fatty liver disease(NAFLD)has emerged as a significant health challenge,characterized by its widespread prevalence,intricate natural progression and multifaceted pathogenesis.Although NAFLD initially presents as benign fat accumulation,it may progress to steatosis,non-alcoholic steatohepatitis,cirrhosis,and hepatocellular carcinoma.Mesenchymal stem cells(MSCs)are recognized for their intrinsic self-renewal,superior biocompatibility,and minimal immunogenicity,positioning them as a therapeutic innovation for liver diseases.Therefore,this review aims to elucidate the potential roles of MSCs in alleviating the progression of NAFLD by alteration of underlying molecular pathways,including glycolipid metabolism,inflammation,oxidative stress,endoplasmic reticulum stress,and fibrosis.The insights are expected to provide further understanding of the potential of MSCs in NAFLD therapeutics,and support the development of MSC-based therapy in the treatment of NAFLD.
基金Henan Province Foundation of China,No.202300410307 and No.212102310611Xinxiang City Foundation of China,No.GG2020009.
文摘BACKGROUND Type 1 diabetes(T1D),a chronic metabolic and autoimmune disease,seriously endangers human health.In recent years,mesenchymal stem cell(MSC)transplantation has become an effective treatment for diabetes.Menstrual bloodderived endometrial stem cells(MenSC),a novel MSC type derived from the decidual endometrium during menstruation,are expected to become promising seeding cells for diabetes treatment because of their noninvasive collection procedure,high proliferation rate and high immunomodulation capacity.AIM To comprehensively compare the effects of MenSC and umbilical cord-derived MSC(UcMSC)transplantation on T1D treatment,to further explore the potential mechanism of MSC-based therapies in T1D,and to provide support for the clinical application of MSC in diabetes treatment.METHODS A conventional streptozotocin-induced T1D mouse model was established,and the effects of MenSC and UcMSC transplantation on their blood glucose and serum insulin levels were detected.The morphological and functional changes in the pancreas,liver,kidney,and spleen were analyzed by routine histological and immunohistochemical examinations.Changes in the serum cytokine levels in the model mice were assessed by protein arrays.The expression of target proteins related to pancreatic regeneration and apoptosis was examined by western blot.RESULTS MenSC and UcMSC transplantation significantly improved the blood glucose and serum insulin levels in T1D model mice.Immunofluorescence analysis revealed that the numbers of insulin+and CD31+cells in the pancreas were significantly increased in MSC-treated mice compared with control mice.Subsequent western blot analysis also showed that vascular endothelial growth factor(VEGF),Bcl2,Bcl-xL and Proliferating cell nuclear antigen in pancreatic tissue was significantly upregulated in MSC-treated mice compared with control mice.Additionally,protein arrays indicated that MenSC and UcMSC transplantation significantly downregulated the serum levels of interferonγand tumor necrosis factorαand upregulated the serum levels of interleukin-6 and VEGF in the model mice.Additionally,histological and immunohistochemical analyses revealed that MSC transplantation systematically improved the morphologies and functions of the liver,kidney,and spleen in T1D model mice.CONCLUSION MenSC transplantation significantly improves the symptoms in T1D model mice and exerts protective effects on their main organs.Moreover,MSC-mediated angiogenesis,antiapoptotic effects and immunomodulation likely contribute to the above improvements.Thus,MenSC are expected to become promising seeding cells for clinical diabetes treatment due to their advantages mentioned above.
基金the Xinxiang Medical University Doctor Support Foundation(XYBSKYZZ201902)the Key Scientific Research Project of Henan Province Colleges and Universities(24A180026)+2 种基金the Project of Science and Technology Department of Henan Province(212102310822)the Key Technologies R&D Program of Henan Province(242102310134)the Henan Province Foundation for University Key Teacher(2024GGJS088).
文摘Background:The pathogenesis of Parkinson’s disease(PD)is associated with ferroptosis.The role of HIF1a is involved in several diseases,but its specific function in PD remains uncertain.Methods:In this study,we generated animal and cellular models of PD using the neurotoxin 6-OHDA.The occurrence of ferroptosis was determined by measuring levels of ferroptosis-related proteins,Fe2t amount and transmission electron microscopy analysis in the PD models,and was further confirmed by using a ferroptosis inhibitor.HIF1a overexpressing and HIF1a knockdown SH-SY5Y cells were constructed by lentivirus transfection.Then,the levels of lipid peroxide,ROS,SLC7A11,and GPX4 were detected to elucidate the relationship between HIF1a and ferroptosis.Luciferase assay was used to analyze the regulation between HIF1a and SLC7A11.Results:We observed a significant downregulation of HIF1a in both animal and cellular PD models.Overexpression of HIF1a mitigated 6-OHDA-induced ferroptosis in SH-SY5Y cells,while,conversely,downregulation of HIF1a promoted ferroptosis in SH-SY5Y cells.BioEdit Sequence Alignment Editor software identified a hypoxia response element(HRE)within the promoter sequence of SLC7A11.The dual-luciferase reporter assays demonstrated that the co-expression of HIF1a and the SLC7A11 promoter significantly augmented reporter activity in SH-SY5Y cells.Moreover,introduction of a mutation into the HRE of the SLC7A11 promoter abolished the induction of SLC7A11 by HIF1a overexpression,resulted in a reduction in promoter activity compared with wild-type cells.Conclusions:The collective findings of this study indicate that HIF1a can inhibit ferroptosis by positively regulating SLC7A11.This investigation has shed light on the crucial involvement of the HIF1a/SLC7A11 signaling axis in ferroptosis in PDmodels,thereby presenting patients withPDa promising therapeutic target.
基金supported in part by the General Research Fund(17122519,17126317,1712222217119123,17106624)+5 种基金the Collaborative Research Fund(C4008-23W)Research Grants Council of Hong Kongthe Health and Medical Research Fund,Food and Health Bureau(18192021)Hong Kong SAR GovernmentSeed Funding for Strategic Interdisciplinary Research Scheme,University of Hong Kong Hong Kong SAR,ChinaShenzhen Institute of Synthetic Biology Scientific Research Program(ZTXM20214004),Shenzhen,China.
文摘Dietary fatty acids(FAs)are associated with the therapeutic intervention under various health conditions.Human γδ-T cells are indispensable for immunosurveillance toward malignant cells.However,their impact onγδ-T cell metabolism and function remains poorly unexplored.Here,we applied targeted metabolomics analysis to serum FAs among cancer patients undergoing γδ-T cell therapy and discovered that palmitic acid(PA)or oleic acid(OA)levels were associated with the efficacy of Vγ9Vδ2-T cell therapy.We further elucidated that PA suppresses the antitumor activity of Vγ9Vδ2-T cells by disrupting metabolic processes and inhibiting the secretion of lytic granules,whereas OA restores the impaired antitumor activity of Vγ9Vδ2-T cells.Mechanistically,we surprisingly found that PA stimulates Vγ9Vδ2-T cells to secrete excessive IFNγ,which in turn induces cell pyroptosis,ultimately resulting in decreased antitumor activity.
基金ACKNOWLEDGEMENTS We thank Dr Hongguang Zhu from the Department of Pathology, Fudan University for his useful advice on the histological analysis. This work was supported by the National Natural Science Foundation of China Grant 81172797 （to RH） and the Program of Shanghai Pujiang Talent 11PJ1400400 （to RH）.
文摘Chemerin is present in various inflammatory sites and is closely involved in tissue inflammation. Recent studies have demonstrated that chemerin treatment can cause either anti-inflammatory or pro-inflammatory effects according to the disease model being investigated. Elevated circulating chemerin was recently found in patients with inflammatory bowel disease （IBD）; however, the role of chemerin in intestinal inflammation remains unknown. In this study, we demonstrated that the administration of exogenous chemerin （aa 17-156） aggravated the severity of dextran sulfate sodium （DSS）-induced colitis, which was characterized by higher clinical scores, extensive mucosal damage and significantly increased local and systemic production of pro-inflammatory cytokines, including IL-6, TNF-a and interferon （IFN-7）. Interestingly, chemerin did not appear to influence the magnitudes of inflammatory infiltrates in the colons, but did result in significantly decreased colonic expression of M2 macrophage-associated genes, including Arginase 1 （Arg-1）, Yml, FIZZ1 and IL-IO, following DSS exposure, suggesting an impaired M2 macrophage skewing in vivo. Furthermore, an in vitro experiment showed that the addition of chemerin directly suppressed M2 macrophage-associated gene expression and STAT6 phosphorylation in IL-4-stimulated macrophages. Significantly elevated chemerin levels were found in colons from DSS-exposed mice and from ulcerative colitis （UC） patients and appeared to positively correlate with disease severity. Moreover, the in vivo administration of neutralizing anti-chemerin antibody significantly improved intestinal inflammation following DSS exposure. Taken together, our findings reveal a pro-inflammatory role for chemerin in DSS-induced colitis and the ability of chemerin to suppress the anti-inflammatory M2 macrophage response. Our study also suggests that upregulated chemerin in inflamed colons may contribute to the pathogenesis of IBD.
