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
High electro-optical conversion efficiency is one of the most distinctive features of semiconductor lasers as compared to other types of lasers.Its further increase remains a significant objective.Further enhancing th...High electro-optical conversion efficiency is one of the most distinctive features of semiconductor lasers as compared to other types of lasers.Its further increase remains a significant objective.Further enhancing the efficiency of edgeemitting lasers(EEL),which represent the highest efficiency among semiconductor lasers at present,is challenging.The efficiency of vertical cavity surface emitting lasers(VCSELs)has always been relatively low compared to EEL.This paper,combining modeling with experiments,demonstrates the potential of multi-junction cascaded VCSELs to achieve high efficiency beyond that of EELs,our simulations show,that a 20-junction VCSEL can achieve an efficiency of more than 88%at room temperature.We fabricated VCSEL devices with different numbers of junctions and compared their energy efficiency.15-junction VCSELs achieved a maximum efficiency of 74%at room temperature under nanosecond driving current,the corresponding differential quantum efficiency exceeds 1100%,being the largest electro-optical conversion efficiency and differential quantum efficiency reported until now for VCSELs.展开更多
Tyrosine phosphatase SHP2 is a promising drug target in cancer immunotherapy due to its bidirectional role in both tumor growth promotion and T-cell inactivation. Its allosteric inhibitor SHP099 is known to inhibit ca...Tyrosine phosphatase SHP2 is a promising drug target in cancer immunotherapy due to its bidirectional role in both tumor growth promotion and T-cell inactivation. Its allosteric inhibitor SHP099 is known to inhibit cancer cell growth both in vitro and in vivo. However, whether SHP099-mediated SHP2 inhibition retards tumor growth in vivo via anti-tumor immunity remains elusive. To address this, a CT-26 colon cancer xenograft model was established in mice since this cell line is insensitive to SHP099.Consequently, SHP099 minimally affected CT-26 tumor growth in immuno-deficient nude mice, but significantly decreased the tumor burden in CT-26 tumor-bearing mice with intact immune system.SHP099 augmented anti-tumor immunity, as shown by the elevated proportion of CD8tIFN-γtT cells and the upregulation of cytotoxic T-cell related genes including Granzyme B andPerforin, which decreased the tumor load. In addition, tumor growth in mice with SHP2-deficient T-cells was markedly slowed down because of enhanced anti-tumor responses. Finally, the combination of SHP099 and antiPD-1 antibody showed a higher therapeutic efficacy than either monotherapy in controlling tumor growthin two colon cancer xenograft models, indicating that these agents complement each other. Our study suggests that SHP2 inhibitor SHP099 is a promising candidate drug for cancer immunotherapy.展开更多
Metabolic syndrome is a clustering of metabolic disorder with unclear molecular mechanism.Increasing studies have found that the pathogenesis and progression of metabolic syndrome are closely related to inflammation.H...Metabolic syndrome is a clustering of metabolic disorder with unclear molecular mechanism.Increasing studies have found that the pathogenesis and progression of metabolic syndrome are closely related to inflammation.Here,we report celastrol,a traditional Chinese medicine,can improve high fat diet-induced metabolic syndrome through suppressing resistin-induced inflammation.Mechanistically,celastrol binds to adenylyl cyclase associated protein 1(CAP1)and inhibits the interaction between CAP1 and resistin,which restrains the cyclic adenylate monophosphate(cAMP)-protein kinase A(PKA)-nuclear factor kappa-B(NF-kB)signaling pathway and ameliorates high fat diet-induced murine metabolic syndrome.Knockdown of CAP1 in macrophages abrogated the resistin-mediated inflammatory activity.In contrast,overexpression of CAP1 in macrophages aggravated inflammation.Taken together,our study identifies celastrol,which directly targets CAP1 in macrophages,might be a promising drug candidate for the treatment of inflammatory metabolic diseases,such as metabolic syndrome.展开更多
Impairment of glucose(Glu)uptake and storage by skeletal muscle is a prime risk factor for the development of metabolic diseases.Heterogeneous nuclear ribonucleoprotein A1(hnRNP Al)is a highly abundant RNA-binding pro...Impairment of glucose(Glu)uptake and storage by skeletal muscle is a prime risk factor for the development of metabolic diseases.Heterogeneous nuclear ribonucleoprotein A1(hnRNP Al)is a highly abundant RNA-binding protein that has been implicated in diverse cellular functions.The aim of this study was to investigate the function of hnRNP A1 on muscle tissue insulin sensitivity and systemic Glu homeostasis.Our results showed that conditional deletion of hnRNP Al in the muscle gave rise to a severe insulin resistance phenotype in mice fed a high-fat diet(HFD).Conditional knockout mice fed a HFD showed exacerbated obesity,insulin resistance,and hepatic steatosis.In vitro interference of hnRNP Al in C2C12 myotubes impaired insulin signal transduction and inhibited Glu uptake,whereas hnRNP Al overexpression in C2C12 myotubes protected against insulin resistance induced by supraphysiological concentrations of insulin.The expression and stability of glycogen synthase(gysl)mRNA were also decreased in the absence of hnRNP A l.Mechanistically,hnRNP Al interacted with gys l and stabilized its mRNA,thereby promoting glycogen synthesis and maintaining the insulin sensitivity in muscle tissue.Taken together,our findings are the first to show that reduced expression of hnRNP Al in skeletal muscle affects the metabolic properties and systemic insulin sensitivity by inhibiting glycogen synthesis.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 China Scholarship Council(CSC)No.202106240176.
文摘High electro-optical conversion efficiency is one of the most distinctive features of semiconductor lasers as compared to other types of lasers.Its further increase remains a significant objective.Further enhancing the efficiency of edgeemitting lasers(EEL),which represent the highest efficiency among semiconductor lasers at present,is challenging.The efficiency of vertical cavity surface emitting lasers(VCSELs)has always been relatively low compared to EEL.This paper,combining modeling with experiments,demonstrates the potential of multi-junction cascaded VCSELs to achieve high efficiency beyond that of EELs,our simulations show,that a 20-junction VCSEL can achieve an efficiency of more than 88%at room temperature.We fabricated VCSEL devices with different numbers of junctions and compared their energy efficiency.15-junction VCSELs achieved a maximum efficiency of 74%at room temperature under nanosecond driving current,the corresponding differential quantum efficiency exceeds 1100%,being the largest electro-optical conversion efficiency and differential quantum efficiency reported until now for VCSELs.
基金supported by National Natural Science Foundation of China(Nos.81673436,21472091,81872877,81673437)Mountain-Climbing Talents Project of Nanjing University,the Open Fund of State Key Laboratory of Pharmaceutical Biotechnology,Nanjing University(No.KF-GN-201703,China)+1 种基金Open Project Program of Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica(No.JKLPSE201802,China)the Project of the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD,China)
文摘Tyrosine phosphatase SHP2 is a promising drug target in cancer immunotherapy due to its bidirectional role in both tumor growth promotion and T-cell inactivation. Its allosteric inhibitor SHP099 is known to inhibit cancer cell growth both in vitro and in vivo. However, whether SHP099-mediated SHP2 inhibition retards tumor growth in vivo via anti-tumor immunity remains elusive. To address this, a CT-26 colon cancer xenograft model was established in mice since this cell line is insensitive to SHP099.Consequently, SHP099 minimally affected CT-26 tumor growth in immuno-deficient nude mice, but significantly decreased the tumor burden in CT-26 tumor-bearing mice with intact immune system.SHP099 augmented anti-tumor immunity, as shown by the elevated proportion of CD8tIFN-γtT cells and the upregulation of cytotoxic T-cell related genes including Granzyme B andPerforin, which decreased the tumor load. In addition, tumor growth in mice with SHP2-deficient T-cells was markedly slowed down because of enhanced anti-tumor responses. Finally, the combination of SHP099 and antiPD-1 antibody showed a higher therapeutic efficacy than either monotherapy in controlling tumor growthin two colon cancer xenograft models, indicating that these agents complement each other. Our study suggests that SHP2 inhibitor SHP099 is a promising candidate drug for cancer immunotherapy.
基金supported by National Natural Science Foundation of China(Nos.81673436,91853109,81872877,and 81872838)Natural Science Foundation of Jiangsu Province(BK20180079,China)Mountain-Climbing Talents Project of Nanjing University(China)。
文摘Metabolic syndrome is a clustering of metabolic disorder with unclear molecular mechanism.Increasing studies have found that the pathogenesis and progression of metabolic syndrome are closely related to inflammation.Here,we report celastrol,a traditional Chinese medicine,can improve high fat diet-induced metabolic syndrome through suppressing resistin-induced inflammation.Mechanistically,celastrol binds to adenylyl cyclase associated protein 1(CAP1)and inhibits the interaction between CAP1 and resistin,which restrains the cyclic adenylate monophosphate(cAMP)-protein kinase A(PKA)-nuclear factor kappa-B(NF-kB)signaling pathway and ameliorates high fat diet-induced murine metabolic syndrome.Knockdown of CAP1 in macrophages abrogated the resistin-mediated inflammatory activity.In contrast,overexpression of CAP1 in macrophages aggravated inflammation.Taken together,our study identifies celastrol,which directly targets CAP1 in macrophages,might be a promising drug candidate for the treatment of inflammatory metabolic diseases,such as metabolic syndrome.
基金This work was supported by the National Natural Science Foundation of China(81673436,91853109,81872877,and 91229109)the open fund of State Key Laboratory of Drug Research(SIMM1903KF-10)the Mountain-Climbing Talents Project of Nanjing University to Y.S.
文摘Impairment of glucose(Glu)uptake and storage by skeletal muscle is a prime risk factor for the development of metabolic diseases.Heterogeneous nuclear ribonucleoprotein A1(hnRNP Al)is a highly abundant RNA-binding protein that has been implicated in diverse cellular functions.The aim of this study was to investigate the function of hnRNP A1 on muscle tissue insulin sensitivity and systemic Glu homeostasis.Our results showed that conditional deletion of hnRNP Al in the muscle gave rise to a severe insulin resistance phenotype in mice fed a high-fat diet(HFD).Conditional knockout mice fed a HFD showed exacerbated obesity,insulin resistance,and hepatic steatosis.In vitro interference of hnRNP Al in C2C12 myotubes impaired insulin signal transduction and inhibited Glu uptake,whereas hnRNP Al overexpression in C2C12 myotubes protected against insulin resistance induced by supraphysiological concentrations of insulin.The expression and stability of glycogen synthase(gysl)mRNA were also decreased in the absence of hnRNP A l.Mechanistically,hnRNP Al interacted with gys l and stabilized its mRNA,thereby promoting glycogen synthesis and maintaining the insulin sensitivity in muscle tissue.Taken together,our findings are the first to show that reduced expression of hnRNP Al in skeletal muscle affects the metabolic properties and systemic insulin sensitivity by inhibiting glycogen synthesis.