Polarization of tumor associated macrophages(TAMs)has been a promising therapeutic paradigm for tumor.However,how to achieve precise regulation of TAMs and high efficiency of tumor immunotherapy is still a huge challe...Polarization of tumor associated macrophages(TAMs)has been a promising therapeutic paradigm for tumor.However,how to achieve precise regulation of TAMs and high efficiency of tumor immunotherapy is still a huge challenge.Here,we report dicarboxy fullerene modified with mannose(DCFM)as an immunomodulator to selectively polarize TAMs and prominently boost anti-tumor immunity.The dicarboxy fullerene molecule was synthesized through the Prato reaction and further covalently bonded with mannose,obtaining the DCFM with well-defined structure.Due to the exist of mannose in DCFM,it could accurately recognize mannose receptor in TAMs.Our cellular experiment results showed that mannose modification could notably promote the uptake of DCFM by the immunosuppressive M2-type macrophages that effectively reprogrammed M2-type macrophages into anti-tumor M1-type macrophages,leading to enhance the phagocytosis of tumor cells by macrophages and inhibiting tumor cells migration.Subsequently,we observed that DCFM could significantly distribute into tumor tissues by in vivo fluorescence imaging.Importantly,DCFM exhibited a superior anti-tumor efficiency in the subcutaneous colorectal tumor model.In addition,it showed that DCFM precisely polarized TAMs into M1-type macrophages and actively increased the infiltration of cytotoxic T lymphocytes(CTLs),inducing profound tumor growth inhibition.展开更多
The soaring global prevalence of diabetes makes it urgent to explore new drugs with high efficacy and safety.Nanomaterial-derived bioactive agents are emerging as one of the most promising candidates for biomedical ap...The soaring global prevalence of diabetes makes it urgent to explore new drugs with high efficacy and safety.Nanomaterial-derived bioactive agents are emerging as one of the most promising candidates for biomedical application.In the present study,we investigated the anti-diabetic effects of a functionalized gadofullerene(GF)using obese db/db and non-obese mouse model of type 2 diabete mellitus(MKR)mouse type 2 diabetes mellitus(T2DM)models.In both mouse models,the diabetic phenotypes,including hyperglycemia,impaired glucose tolerance,and insulin sensitivity,were ameliorated after two or four weeks of intraperitoneal administration of GF.GF lowered blood glucose levels in a dose-dependent manner.Importantly,the restored blood glucose levels could persist ten days after withdrawal of GF treatment.The hepatic AKT/GSK3β/FoxO1 pathway is shown to be the main target of GF for rebalancing gluconeogenesis and glycogen synthesis in vivo and in vitro.Furthermore,GF treatment significantly reduced weight gain of db/db mice with reduced hepatic fat storage by the inhibition of de novo lipogenesis through m TOR/S6K/SREBP1 pathway.Our data provide compelling evidence to support the promising application of GF for the treatment of T2DM.展开更多
Functional fullerene derivatives exhibit special inhibitory effects on tumor progress and metastasis via diverse tumor microenvironment regulations,while the elusive molecular mechanisms hinder their clinical transfor...Functional fullerene derivatives exhibit special inhibitory effects on tumor progress and metastasis via diverse tumor microenvironment regulations,while the elusive molecular mechanisms hinder their clinical transformation.Herein,it is initially revealed that nanosize aminated fullerene(C_(70)-EDA)can activate autophagic flux,induce G0/G1 cell cycle arrest to abrogate cancer cell proliferation,and significantly inhibit tumor growth in vivo.Mechanismly,C_(70)-EDA promotes the expression of cathepsin D involved in autophagic activation via post-transcriptional regulation,attributing to the interaction with a panel of RNA binding proteins.The accumulation of cathepsin D induces the autophagic degradation of cyclin D1,which arouses G0/G1 phase arrest.This work unveils the fantastic anti-tumor activity of aminated fullerene,elucidates the molecular mechanism,and provides a new strategy for the antineoplastic drug development on functional fullerenes.展开更多
基金supported by the Major Research Project of National Natural Science Foundation of China(92061123)the Key Research Program of the Chinese Academy of Sciences(QYZDJ-SSW-SLH01)the Youth Innovation Promotion Association of CAS(2022036)。
基金supported by the National Natural Science Foundation of China(No.92061123).M.M.Z.particularly thanks the Youth Innovation Promotion Association of CAS(No.2022036).
文摘Polarization of tumor associated macrophages(TAMs)has been a promising therapeutic paradigm for tumor.However,how to achieve precise regulation of TAMs and high efficiency of tumor immunotherapy is still a huge challenge.Here,we report dicarboxy fullerene modified with mannose(DCFM)as an immunomodulator to selectively polarize TAMs and prominently boost anti-tumor immunity.The dicarboxy fullerene molecule was synthesized through the Prato reaction and further covalently bonded with mannose,obtaining the DCFM with well-defined structure.Due to the exist of mannose in DCFM,it could accurately recognize mannose receptor in TAMs.Our cellular experiment results showed that mannose modification could notably promote the uptake of DCFM by the immunosuppressive M2-type macrophages that effectively reprogrammed M2-type macrophages into anti-tumor M1-type macrophages,leading to enhance the phagocytosis of tumor cells by macrophages and inhibiting tumor cells migration.Subsequently,we observed that DCFM could significantly distribute into tumor tissues by in vivo fluorescence imaging.Importantly,DCFM exhibited a superior anti-tumor efficiency in the subcutaneous colorectal tumor model.In addition,it showed that DCFM precisely polarized TAMs into M1-type macrophages and actively increased the infiltration of cytotoxic T lymphocytes(CTLs),inducing profound tumor growth inhibition.
基金supported by the National Natural Science Foundation of China(51472248 and 51502301)National Major Scientific Instruments and Equipments Development Project(ZDYZ2015-2)the Key Research Program of the Chinese Academy of Sciences(QYZDJ-SSW-SLH025)
基金supported by the National Major Scientific Instruments and Equipments Development Project(ZDYZ2015-2)the Key Research Program of the Chinese Academy of Sciences(QYZDJSSW-SLH025)the National Natural Science Foundation of China(51902313)。
基金supported by the National Natural Science Foundation of China (31871163, 81471000)the Ministry of Science and Technology of China (2014DFA32120)
文摘The soaring global prevalence of diabetes makes it urgent to explore new drugs with high efficacy and safety.Nanomaterial-derived bioactive agents are emerging as one of the most promising candidates for biomedical application.In the present study,we investigated the anti-diabetic effects of a functionalized gadofullerene(GF)using obese db/db and non-obese mouse model of type 2 diabete mellitus(MKR)mouse type 2 diabetes mellitus(T2DM)models.In both mouse models,the diabetic phenotypes,including hyperglycemia,impaired glucose tolerance,and insulin sensitivity,were ameliorated after two or four weeks of intraperitoneal administration of GF.GF lowered blood glucose levels in a dose-dependent manner.Importantly,the restored blood glucose levels could persist ten days after withdrawal of GF treatment.The hepatic AKT/GSK3β/FoxO1 pathway is shown to be the main target of GF for rebalancing gluconeogenesis and glycogen synthesis in vivo and in vitro.Furthermore,GF treatment significantly reduced weight gain of db/db mice with reduced hepatic fat storage by the inhibition of de novo lipogenesis through m TOR/S6K/SREBP1 pathway.Our data provide compelling evidence to support the promising application of GF for the treatment of T2DM.
基金This work was supported by the National Natural Science Foundation of China(No.51802310)All animal experiments were conducted according to protocols approved by the Institutional Animal Care and Use Committee in the Institute of Chemistry,Chinese Academy of Sciences.
文摘Functional fullerene derivatives exhibit special inhibitory effects on tumor progress and metastasis via diverse tumor microenvironment regulations,while the elusive molecular mechanisms hinder their clinical transformation.Herein,it is initially revealed that nanosize aminated fullerene(C_(70)-EDA)can activate autophagic flux,induce G0/G1 cell cycle arrest to abrogate cancer cell proliferation,and significantly inhibit tumor growth in vivo.Mechanismly,C_(70)-EDA promotes the expression of cathepsin D involved in autophagic activation via post-transcriptional regulation,attributing to the interaction with a panel of RNA binding proteins.The accumulation of cathepsin D induces the autophagic degradation of cyclin D1,which arouses G0/G1 phase arrest.This work unveils the fantastic anti-tumor activity of aminated fullerene,elucidates the molecular mechanism,and provides a new strategy for the antineoplastic drug development on functional fullerenes.
