The objective was to investigate the effect of kinsenoside(Kin) treatments on macrophage polarity and evaluate the resulting protection of chondrocytes to attenuate osteoarthritis(OA) progression.RAW264.7 macrophages ...The objective was to investigate the effect of kinsenoside(Kin) treatments on macrophage polarity and evaluate the resulting protection of chondrocytes to attenuate osteoarthritis(OA) progression.RAW264.7 macrophages were polarized to M1/M2 subtypes then administered with different concentrations of Kin. The polarization transitions were evaluated with quantitative real-time polymerase chain reaction(q RT-PCR), confocal observation and flow cytometry analysis. The mechanism of Kin repolarizing M1 macrophages was evaluated by Western blot. Further, macrophage conditioned medium(CM) and IL-1β were administered to chondrocytes. Micro-CT scanning and histological observations were conducted in vivo on anterior cruciate ligament transection(ACLT) mice with or without Kin treatment. We found that Kin repolarized M1 macrophages to the M2 phenotype. Mechanistically, Kin inhibited the phosphorylation of IκBα, which further reduced the downstream phosphorylation of P65 in nuclear factor-κB(NF-κB) signaling. Moreover, Kin inhibited mitogen-activated protein kinases(MAPK) signaling molecules p-JNK, p-ERK and p-P38. Additionally, Kin attenuated macrophage CM and IL-1β-induced chondrocyte damage. In vivo, Kin reduced the infiltration of M1 macrophages,promoted M2 macrophages in the synovium, inhibited subchondral bone destruction and reduced articular cartilage damage induced by ACLT. All the results indicated that Kin is an effective therapeutic candidate for OA treatment.展开更多
Multidimensional analyses have demonstrated the presence of a unique tumor microenvironment(TME)in liver cancer.Tumor-associated macrophages(TAMs)are among the most abundant immune cells infiltrating the TME and are p...Multidimensional analyses have demonstrated the presence of a unique tumor microenvironment(TME)in liver cancer.Tumor-associated macrophages(TAMs)are among the most abundant immune cells infiltrating the TME and are present at all stages of liver cancer progression,and targeting TAMs has become one of the most favored immunotherapy strategies.In addition,macrophages and liver cancer cells have distinct origins.At the early stage of liver cancer,macrophages can provide a niche for the maintenance of liver cancer stem cells.In contrast,cancer stem cells(CSCs)or poorly differentiated tumor cells are key factors modulating macrophage activation.In the present review,we first propose the origin connection between precursor macrophages and liver cancer cells.Macrophages undergo dynamic phenotypic transition during carcinogenesis.In this course of such transition,it is critical to determine the appropriate timing for therapy and block specific markers to suppress protumoral TAMs.The present review provides a more detailed discussion of transition trends of such surface markers than previous reviews.Complex crosstalk occurs between TAMs and liver cancer cells.TAMs play indispensable roles in tumor progression,angiogenesis,and autophagy due to their heterogeneity and robust plasticity.In addition,macrophages in the TME interact with other immune cells by directing cell-to-cell contact or secreting various effector molecules.Similarly,tumor cells combined with other immune cells can drive macrophage recruitment and polarization.Despite the latest achievements and the advancements in treatment strategies following TAMs studies,comprehensive discussions on the communication between macrophages and cancer cells or immune cells in liver cancer are currently lacking.In this review,we discussed the interactions between TAMs and liver cancer cells(from cell origin to maturation),the latest therapeutic strategies(including chimeric antigen receptor macrophages),and critical clinical trials for hepatocellular carcinoma(HCC)and intr展开更多
AIM: To investigate the correlation between lymphogenous metastasis and matrix metalloproteinases (MMPs) activity and the expression of Fas ligand of tumor cells in lymph nodes. METHODS: Fifty-six inbred 615-mice were...AIM: To investigate the correlation between lymphogenous metastasis and matrix metalloproteinases (MMPs) activity and the expression of Fas ligand of tumor cells in lymph nodes. METHODS: Fifty-six inbred 615-mice were equally divided into 2 groups and inoculated with Hca-F and Hca-P cells. Their lymph node metastatic rates were examined. Growth fraction of lymphocytes in host lymph nodes was detected by flow cytometry. The Hca-F and Hca-P cells were cultured with extract of lymph node, liver or spleen. The quantity of MMPs in these supernatants was examined by zymographic analysis. The expression of Fas ligand, PCNA, Bcl-2 protein of Hca-F and Hca-P cells in the mice were examined by immunohistochemistry. The apoptosis signals of macro-phages in lymph nodes were observed with in situ DNA fragmentation. RESULTS: On the 28th day post-inoculation, the lymph node metastatic rate of HcaF was 80%(16/20), whereas that of Hca-P was 25%(5/20). The growth fraction of lymphocytes was as follows: in the Hca-F cells, the proliferating peak of lymphocytes appeared on the 14th day post inoculation and then decreased rapidly, while in HcaP cells, the peak appeared on the 7th day post inoculation and then kept at a high level. With the extract of lymph node, the quantity of the MMP-9 activity increased (P【0.01) and active MMP-9 and MMP-2 were produced by both Hca-F and Hca-P tumor cells, which did not produce MMPs without the extract of lymph node or with the extracts of the liver and spleen. The expression of Fas Ligand of Hca-F cells was stronger than that of Hca-P cells (P 【0.01). The expressions of PCNA and Bcl-2 protein of Hca-F cells in the tumors of inoculated area were the same as that of Hca-P cells. In situ DNA fragmentation showed that the positive signals of macrophages were around Hca-F cells. CONCLUSION: Secretion of MMPs which was associated with metastatic ability of Hca-F and Hca-P tumor cells depends on the environment of lymph nodes. The increased expression of Fas ligand protein of Hca-F tumor cells with展开更多
基金supported by the National Natural Science Foundation of China(No.81672205)National Key R&D Programme(No.2016YFC1102100,China)the Shanghai Science and Technology Development Fund(Nos.18DZ2291200and 18441902700,China)
文摘The objective was to investigate the effect of kinsenoside(Kin) treatments on macrophage polarity and evaluate the resulting protection of chondrocytes to attenuate osteoarthritis(OA) progression.RAW264.7 macrophages were polarized to M1/M2 subtypes then administered with different concentrations of Kin. The polarization transitions were evaluated with quantitative real-time polymerase chain reaction(q RT-PCR), confocal observation and flow cytometry analysis. The mechanism of Kin repolarizing M1 macrophages was evaluated by Western blot. Further, macrophage conditioned medium(CM) and IL-1β were administered to chondrocytes. Micro-CT scanning and histological observations were conducted in vivo on anterior cruciate ligament transection(ACLT) mice with or without Kin treatment. We found that Kin repolarized M1 macrophages to the M2 phenotype. Mechanistically, Kin inhibited the phosphorylation of IκBα, which further reduced the downstream phosphorylation of P65 in nuclear factor-κB(NF-κB) signaling. Moreover, Kin inhibited mitogen-activated protein kinases(MAPK) signaling molecules p-JNK, p-ERK and p-P38. Additionally, Kin attenuated macrophage CM and IL-1β-induced chondrocyte damage. In vivo, Kin reduced the infiltration of M1 macrophages,promoted M2 macrophages in the synovium, inhibited subchondral bone destruction and reduced articular cartilage damage induced by ACLT. All the results indicated that Kin is an effective therapeutic candidate for OA treatment.
基金National Natural Science Foundation of China,Grant/Award Numbers:8187111473,8217113337。
文摘Multidimensional analyses have demonstrated the presence of a unique tumor microenvironment(TME)in liver cancer.Tumor-associated macrophages(TAMs)are among the most abundant immune cells infiltrating the TME and are present at all stages of liver cancer progression,and targeting TAMs has become one of the most favored immunotherapy strategies.In addition,macrophages and liver cancer cells have distinct origins.At the early stage of liver cancer,macrophages can provide a niche for the maintenance of liver cancer stem cells.In contrast,cancer stem cells(CSCs)or poorly differentiated tumor cells are key factors modulating macrophage activation.In the present review,we first propose the origin connection between precursor macrophages and liver cancer cells.Macrophages undergo dynamic phenotypic transition during carcinogenesis.In this course of such transition,it is critical to determine the appropriate timing for therapy and block specific markers to suppress protumoral TAMs.The present review provides a more detailed discussion of transition trends of such surface markers than previous reviews.Complex crosstalk occurs between TAMs and liver cancer cells.TAMs play indispensable roles in tumor progression,angiogenesis,and autophagy due to their heterogeneity and robust plasticity.In addition,macrophages in the TME interact with other immune cells by directing cell-to-cell contact or secreting various effector molecules.Similarly,tumor cells combined with other immune cells can drive macrophage recruitment and polarization.Despite the latest achievements and the advancements in treatment strategies following TAMs studies,comprehensive discussions on the communication between macrophages and cancer cells or immune cells in liver cancer are currently lacking.In this review,we discussed the interactions between TAMs and liver cancer cells(from cell origin to maturation),the latest therapeutic strategies(including chimeric antigen receptor macrophages),and critical clinical trials for hepatocellular carcinoma(HCC)and intr
基金the Mational Natural Science Foundation of China,No.39470776
文摘AIM: To investigate the correlation between lymphogenous metastasis and matrix metalloproteinases (MMPs) activity and the expression of Fas ligand of tumor cells in lymph nodes. METHODS: Fifty-six inbred 615-mice were equally divided into 2 groups and inoculated with Hca-F and Hca-P cells. Their lymph node metastatic rates were examined. Growth fraction of lymphocytes in host lymph nodes was detected by flow cytometry. The Hca-F and Hca-P cells were cultured with extract of lymph node, liver or spleen. The quantity of MMPs in these supernatants was examined by zymographic analysis. The expression of Fas ligand, PCNA, Bcl-2 protein of Hca-F and Hca-P cells in the mice were examined by immunohistochemistry. The apoptosis signals of macro-phages in lymph nodes were observed with in situ DNA fragmentation. RESULTS: On the 28th day post-inoculation, the lymph node metastatic rate of HcaF was 80%(16/20), whereas that of Hca-P was 25%(5/20). The growth fraction of lymphocytes was as follows: in the Hca-F cells, the proliferating peak of lymphocytes appeared on the 14th day post inoculation and then decreased rapidly, while in HcaP cells, the peak appeared on the 7th day post inoculation and then kept at a high level. With the extract of lymph node, the quantity of the MMP-9 activity increased (P【0.01) and active MMP-9 and MMP-2 were produced by both Hca-F and Hca-P tumor cells, which did not produce MMPs without the extract of lymph node or with the extracts of the liver and spleen. The expression of Fas Ligand of Hca-F cells was stronger than that of Hca-P cells (P 【0.01). The expressions of PCNA and Bcl-2 protein of Hca-F cells in the tumors of inoculated area were the same as that of Hca-P cells. In situ DNA fragmentation showed that the positive signals of macrophages were around Hca-F cells. CONCLUSION: Secretion of MMPs which was associated with metastatic ability of Hca-F and Hca-P tumor cells depends on the environment of lymph nodes. The increased expression of Fas ligand protein of Hca-F tumor cells with
