Colorectal tumors often create an immunosuppressive microenvironment that prevents them from responding to immunotherapy.Cannabidiol(CBD)is a non-psychoactive natural active ingredient from the cannabis plant that has...Colorectal tumors often create an immunosuppressive microenvironment that prevents them from responding to immunotherapy.Cannabidiol(CBD)is a non-psychoactive natural active ingredient from the cannabis plant that has various pharmacological effects,including neuroprotective,antiemetic,anti-inflammatory,and antineoplastic activities.This study aimed to elucidate the specific anticancer mechanism of CBD by single-cell RNA sequencing(scRNA-seq)and single-cell ATAC sequencing(scATAC-seq)technologies.Here,we report that CBD inhibits colorectal cancer progression by modulating the suppressive tumor microenvironment(TME).Our single-cell transcriptome and ATAC sequencing results showed that CBD suppressed M2-like macrophages and promoted M1-like macrophages in tumors both in strength and quantity.Furthermore,CBD significantly enhanced the interaction between M1-like macrophages and tumor cells and restored the intrinsic anti-tumor properties of macrophages,thereby preventing tumor progression.Mechanistically,CBD altered the metabolic pattern of macrophages and related anti-tumor signaling pathways.We found that CBD inhibited the alternative activation of macrophages and shifted the metabolic process from oxidative phosphorylation and fatty acid oxidation to glycolysis by inhibiting the phosphatidylinositol 3-kinase-protein kinase B signaling pathway and related downstream target genes.Furthermore,CBD-mediated macrophage plasticity enhanced the response to anti-programmed cell death protein-1(PD-1)immunotherapy in xenografted mice.Taken together,we provide new insights into the anti-tumor effects of CBD.展开更多
Ulcerative colitis(UC) is a long-term,recurrent inflammatory bowel disease for which no effective cure is yet available in the clinical setting.Repairing the barrier dysfunction of the colon and reducing intestinal in...Ulcerative colitis(UC) is a long-term,recurrent inflammatory bowel disease for which no effective cure is yet available in the clinical setting.Repairing the barrier dysfunction of the colon and reducing intestinal inflammation are considered key objectives to cure UC.Here we demonstrate a novel therapeutic strategy based on a C_(60) fullerene suspension(C_(60)FS) to treat dinitrobenzene sulfonic acid-induced UC in an animal model.C_(60)FS can repair the barrier dysfunction of UC and effectively promote the healing of ulcers;it also manifests better treatment effects compared with mesalazine enema.C_(60)FS can reduce the numbers of basophils in the blood of UC rats and mast cells in the colorectal tissue,thereby effectively alleviating inflammation.The expression of H1R,H4R,and VEGFR2 receptors in colorectal tissues is inhibited by C_(60)FS,and the levels of histamine and prostaglandin in the rat blood are reduced.This work presents a reliable strategy based on fullerene to cure UC and provides a novel guide for UC treatment.展开更多
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
In rheumatoid arthritis(RA),the presence of substantial inflammatory macrophages and osteoclasts in joints is known to contribute to the progression of articular inflammation and bone destruction.Herein,we develop a s...In rheumatoid arthritis(RA),the presence of substantial inflammatory macrophages and osteoclasts in joints is known to contribute to the progression of articular inflammation and bone destruction.Herein,we develop a sialic acid-modified tetra malonic acid derivative of C70 fullerene(STMF).STMF possesses inflammation-targeting capability that can effectively impede the differentiation of macrophages and osteoclasts,offering a potential treatment strategy for RA.STMF acts as a mimic of sialyl Lewis x,enabling it to specifically bind with E-selectin,which is overexpressed on inflamed endothelial cells.This selective binding results in a targeted distribution of STMF to inflamed joints,addressing articular in-flammation.Upon uptake by macrophages,STMF demonstrates the ability to effectively eliminate intracellular reactive oxygen species and deactivate the downstream events,thereby suppressing their differentiation into M1-phenotype and osteoclastogenesis.In our experiments using collagen-induced arthritis mouse models,STMF significantly improves paw swelling and redness,mitigates articular inflammation with reduced M1 macrophages,lessens osteoclasts,and repairs bone erosion with neglectable side effects.These findings suggest that STMF has potential as a therapeutic agent for RA,leveraging inflammation-targeting fullerene nanomaterials.展开更多
基金supported by the National Key Research and Development Plan,China(Grant No.:2022YFC3500202)the Natural Science Foundation of China(Grant Nos.:82172558,and 82205024)+4 种基金the Scientific and Technological Innovation Action Plan of Natural Science Foundation Project of Shanghai,China(Grant No.:22ZR1447400)the Scientific and Technological Innovation Action Plan,China(Grant No.:22ZR1447400)the Fundamental Research Funds for the Central Universities,China(Grant Nos.:020814380179,020814380174)the Distinguished Young Scholars of Nanjing,China(Grant No.:JQX20008)the School of Life Science(NJU)-Sipimo Joint Funds and Mountain Climbing Talents Project of Nanjing University,China(Grant No.:2015018).
文摘Colorectal tumors often create an immunosuppressive microenvironment that prevents them from responding to immunotherapy.Cannabidiol(CBD)is a non-psychoactive natural active ingredient from the cannabis plant that has various pharmacological effects,including neuroprotective,antiemetic,anti-inflammatory,and antineoplastic activities.This study aimed to elucidate the specific anticancer mechanism of CBD by single-cell RNA sequencing(scRNA-seq)and single-cell ATAC sequencing(scATAC-seq)technologies.Here,we report that CBD inhibits colorectal cancer progression by modulating the suppressive tumor microenvironment(TME).Our single-cell transcriptome and ATAC sequencing results showed that CBD suppressed M2-like macrophages and promoted M1-like macrophages in tumors both in strength and quantity.Furthermore,CBD significantly enhanced the interaction between M1-like macrophages and tumor cells and restored the intrinsic anti-tumor properties of macrophages,thereby preventing tumor progression.Mechanistically,CBD altered the metabolic pattern of macrophages and related anti-tumor signaling pathways.We found that CBD inhibited the alternative activation of macrophages and shifted the metabolic process from oxidative phosphorylation and fatty acid oxidation to glycolysis by inhibiting the phosphatidylinositol 3-kinase-protein kinase B signaling pathway and related downstream target genes.Furthermore,CBD-mediated macrophage plasticity enhanced the response to anti-programmed cell death protein-1(PD-1)immunotherapy in xenografted mice.Taken together,we provide new insights into the anti-tumor effects of CBD.
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 (51832008,51772300,and 52072374)。
文摘Ulcerative colitis(UC) is a long-term,recurrent inflammatory bowel disease for which no effective cure is yet available in the clinical setting.Repairing the barrier dysfunction of the colon and reducing intestinal inflammation are considered key objectives to cure UC.Here we demonstrate a novel therapeutic strategy based on a C_(60) fullerene suspension(C_(60)FS) to treat dinitrobenzene sulfonic acid-induced UC in an animal model.C_(60)FS can repair the barrier dysfunction of UC and effectively promote the healing of ulcers;it also manifests better treatment effects compared with mesalazine enema.C_(60)FS can reduce the numbers of basophils in the blood of UC rats and mast cells in the colorectal tissue,thereby effectively alleviating inflammation.The expression of H1R,H4R,and VEGFR2 receptors in colorectal tissues is inhibited by C_(60)FS,and the levels of histamine and prostaglandin in the rat blood are reduced.This work presents a reliable strategy based on fullerene to cure UC and provides a novel guide for UC treatment.
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(grant no.52272048)the Beijing Natural Science Foundation(grant no.2222090)+1 种基金the Ministry of Science and Technology of China(grant no.2022YFA1205900),the Key Research Program of the Chinese Academy of Sciences(grant no.QYKJZD-SSW-SLH01)Natural Science Foundation of Shandong Province(grant no.ZR2020QB016).
文摘In rheumatoid arthritis(RA),the presence of substantial inflammatory macrophages and osteoclasts in joints is known to contribute to the progression of articular inflammation and bone destruction.Herein,we develop a sialic acid-modified tetra malonic acid derivative of C70 fullerene(STMF).STMF possesses inflammation-targeting capability that can effectively impede the differentiation of macrophages and osteoclasts,offering a potential treatment strategy for RA.STMF acts as a mimic of sialyl Lewis x,enabling it to specifically bind with E-selectin,which is overexpressed on inflamed endothelial cells.This selective binding results in a targeted distribution of STMF to inflamed joints,addressing articular in-flammation.Upon uptake by macrophages,STMF demonstrates the ability to effectively eliminate intracellular reactive oxygen species and deactivate the downstream events,thereby suppressing their differentiation into M1-phenotype and osteoclastogenesis.In our experiments using collagen-induced arthritis mouse models,STMF significantly improves paw swelling and redness,mitigates articular inflammation with reduced M1 macrophages,lessens osteoclasts,and repairs bone erosion with neglectable side effects.These findings suggest that STMF has potential as a therapeutic agent for RA,leveraging inflammation-targeting fullerene nanomaterials.
