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
Psoriasis is an incurable chronic inflammatory disease that requires new interventions.Here,we found that fibroblasts exacerbate psoriasis progression by promoting macrophage recruitment via CCL2 secretion by single-c...Psoriasis is an incurable chronic inflammatory disease that requires new interventions.Here,we found that fibroblasts exacerbate psoriasis progression by promoting macrophage recruitment via CCL2 secretion by single-cell multi-omics analysis.The natural small molecule celastrol was screened to interfere with the secretion of CCL2 by fibroblasts and improve the psoriasis-like symptoms in both murine and cynomolgus monkey models.Mechanistically,celastrol directly bound to the low-density lipoprotein receptor-related protein 1(LRP1)β-chain and abolished its binding to the transcription factor c-Jun in the nucleus,which in turn inhibited CCL2 production by skin fibroblasts,blocked fibroblast-macrophage crosstalk,and ameliorated psoriasis progression.Notably,fibroblast-specific LRP1 knockout mice exhibited a significant reduction in psoriasis like inflammation.Taken together,from clinical samples and combined with various mouse models,we revealed the pathogenesis of psoriasis from the perspective of fibroblast-macrophage crosstalk,and provided a foundation for LRP1 as a novel potential target for psoriasis treatment.展开更多
The blood-brain barrier(BBB)is a highly selective permeability barrier that safeguards the central nervous system(CNS)from potentially harmful substances while regulating the transport of essential molecules.Its dysfu...The blood-brain barrier(BBB)is a highly selective permeability barrier that safeguards the central nervous system(CNS)from potentially harmful substances while regulating the transport of essential molecules.Its dysfunction is increasingly recognized as a pivotal factor in the pathogenesis of Alzheimer's disease(AD),contributing to the accumulation of amyloid-β(Aβ)plaques.We present a novel therapeutic strategy that targets low-density lipoprotein receptor-related protein 1(LRP1)on the BBB.Our design leverages the multivalent nature and precise size of LRP1-targeted polymersomes to modulate receptor-mediated transport,biasing LRP1 trafficking toward transcytosis and thereby upregulating its expression to promote efficient Aβremoval.In AD model mice,this intervention significantly reduced brain Aβlevels by nearly 45%and increased plasma Aβlevels by 8-fold within 2 h,as measured by ELISA.Multiple imaging techniques confirmed the reduction in brain Aβsignals after treatment.Cognitive assessments revealed that treated AD mice exhibited significant improvements in spatial learning and memory,with performance levels comparable to those of wild-type mice.These cognitive benefits persisted for up to 6 months post-treatment.This work pioneers a new paradigm in drug design,where function arises from the supramolecular nature of the nanomedicine,harnessing multivalency to elicit biological action at the membrane trafficking level.Our findings also reaffirm the critical role of the BBB in AD pathogenesis and demonstrate that targeting the BBB can make therapeutic interventions significantly more effective.We establish a compelling case for BBB modulation and LRP1-mediated Aβclearance as a transformative foundation for future AD therapies.展开更多
Local anesthetics(LAs),such as articaine(AT),exhibit limited efficacy in inflammatory environments,which constitutes a significant limitation in their clinical application within oral medicine.In our prior research,we...Local anesthetics(LAs),such as articaine(AT),exhibit limited efficacy in inflammatory environments,which constitutes a significant limitation in their clinical application within oral medicine.In our prior research,we developed AT-17,which demonstrated effective properties in chronic inflamma-tory conditions and appears to function as a novel oral LA that could address this challenge.In the present study,we further elucidated the beneficial effects of AT-17 in acute inflammation,particularly in oral acute inflammation,where mitochondrial-related apoptosis played a crucial role.Our findings indicated that AT-17 effectively inhibited lipopolysaccharide(LPS)-induced nerve cell apoptosis by ameliorating mitochondrial dysfunction in vitro.This process involved the inhibition of mitochondrial reactive oxygen species(mtROS)production and the subsequent activation of the NRF2 pathway.Most notably,improve-ments in mitochondria-related apoptosis were key contributors to AT-17’s inhibition of voltage-gated sodium channels.Additionally,AT-17 was shown to reduce mtROS production in nerve cells through the Na+/NCLX/ETC signaling axis.In conclusion,we have developed a novel local anesthetic that exhibits pronounced anesthetic functionality under inflammatory conditions by enhancing mitochondria-related apoptosis.This advancement holds considerable promise for future drug development and deepening our understanding of the underlying mechanisms of action.展开更多
Nature has endowed gaseous molecules such as O_(2),CO_(2),CO,NO,H2 S,and N2 with critical and diverse roles in sustaining life,from supplying energy needed to power life and building blocks for life ’s physical struc...Nature has endowed gaseous molecules such as O_(2),CO_(2),CO,NO,H2 S,and N2 with critical and diverse roles in sustaining life,from supplying energy needed to power life and building blocks for life ’s physical structure to mediating and coordinating cellular functions.In this article,we give a brief introduction of the complex functions of the various gaseous molecules in life and then focus on carbon monoxide as a specific example of an endogenously produced signaling molecule to highlight the importance of this class of molecules.The past twenty years have seen much progress in understanding CO’s mechanism(s) of action and pharmacological effects as well as in developing delivery methods for easy administration.One remarkable trait of CO is its pleiotropic effects that have few parallels,except perhaps its sister gaseous signaling molecules such as nitric oxide and hydrogen sulfide.This review will delve into the sophistication of CO-mediated signaling as well as its validated pharmacological functions and possible therapeutic applications.展开更多
Incorporation of multiple functions into one nanoplatform can improve cancer diagnostic efficacy and enhance anti-cancer outcomes. Here, we constructed doxorubicin(DOX)-loaded silk fibroinbased nanoparticles(NPs) with...Incorporation of multiple functions into one nanoplatform can improve cancer diagnostic efficacy and enhance anti-cancer outcomes. Here, we constructed doxorubicin(DOX)-loaded silk fibroinbased nanoparticles(NPs) with surface functionalization by photosensitizer(N770). The obtained nanotheranostics(N770-DOX@NPs) had desirable particle size(157 nm) and negative surface charge(-25 m V). These NPs presented excellent oxygen-generating capacity and responded to a quadruple of stimuli(acidic solution, reactive oxygen species, glutathione, and hyperthermia). Surface functionalization of DOX@NPs with N770 could endow them with active internalization by cancerous cell lines, but not by normal cells. Furthermore, the intracellular NPs were found to be preferentially retained in mitochondria, which were also efficient for near-infrared(NIR) fluorescence imaging, photothermal imaging,and photoacoustic imaging. Meanwhile, DOX could spontaneously accumulate in the nucleus. Importantly, a mouse test group treated with N770-DOX@NPs plus NIR irradiation achieved the best tumorretardation effect among all treatment groups based on tumor-bearing mouse models and a patientderived xenograft model, demonstrating the unprecedented therapeutic effects of trimodal imagingguided mitochondrial phototherapy(photothermal therapy and photodynamic therapy) and chemotherapy.Therefore, the present study brings new insight into the exploitation of an easy-to-use, versatile, and robust nanoplatform for programmable targeting, imaging, and applying synergistic therapy to tumors.展开更多
Multifunctional therapeutics have emerged as a solution to the constraints imposed by drugs with singular or insufficient therapeutic effects.The primary challenge is to integrate diverse pharmacophores within a singl...Multifunctional therapeutics have emerged as a solution to the constraints imposed by drugs with singular or insufficient therapeutic effects.The primary challenge is to integrate diverse pharmacophores within a single-molecule framework.To address this,we introduced DeepSA,a novel edit-based generative framework that utilizes deep simulated annealing for the modification of articaine,a wellknown local anesthetic.DeepSA integrates deep neural networks into metaheuristics,effectively constraining molecular space during compound generation.This framework employs a sophisticated objective function that accounts for scaffold preservation,anti-inflammatory properties,and covalent constraints.Through a sequence of local editing to navigate the molecular space,DeepSA successfully identified AT-17,a derivative exhibiting potent analgesic properties and significant anti-inflammatory activity in various animal models.Mechanistic insights into AT-17 revealed its dual mode of action:selective inhibition of NaV1.7 and 1.8 channels,contributing to its prolonged local anesthetic effects,and suppression of inflammatory mediators via modulation of the NLRP3 inflammasome pathway.These findings not only highlight the efficacy of AT-17 as a multifunctional drug candidate but also highlight the potential of DeepSA in facilitating AI-enhanced drug discovery,particularly within stringent chemical constraints.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 National Key Research and Development Plan(2022YFC3500202,China)the National Natural Science Foundation of China(Nos.82230116,81872877,82204715,81803142,82404639,and 82073975)+7 种基金the Natural Science Foundation of Jiangsu Province(No.BK20220476,China)the Jiangsu Provincial Double-Innovation Doctor Program(No.JSSCBS20220477,China)the Natural Science Foundation of Nanjing University of Chinese Medicine(No.XPT82204715,China)the Fundamental Research Funds for the Central Universities(Nos.020814380179 and 020814380174,China)the Fundamental Science(Natural Science)Research Project of the Jiangsu Higher Education Institutions of China(No.22KJB360005)the Innovation Project of Guangdong Provincial Education Department(No.2023KTSCX320,China)the Shenzhen Science and Technology Program(Nos.20231126130044001 and 20230731094501002,China)the School of Life Science(NJU)-Sipimo Joint Funds,and the Mountain-Climbing Talents Project of Nanjing.
文摘Psoriasis is an incurable chronic inflammatory disease that requires new interventions.Here,we found that fibroblasts exacerbate psoriasis progression by promoting macrophage recruitment via CCL2 secretion by single-cell multi-omics analysis.The natural small molecule celastrol was screened to interfere with the secretion of CCL2 by fibroblasts and improve the psoriasis-like symptoms in both murine and cynomolgus monkey models.Mechanistically,celastrol directly bound to the low-density lipoprotein receptor-related protein 1(LRP1)β-chain and abolished its binding to the transcription factor c-Jun in the nucleus,which in turn inhibited CCL2 production by skin fibroblasts,blocked fibroblast-macrophage crosstalk,and ameliorated psoriasis progression.Notably,fibroblast-specific LRP1 knockout mice exhibited a significant reduction in psoriasis like inflammation.Taken together,from clinical samples and combined with various mouse models,we revealed the pathogenesis of psoriasis from the perspective of fibroblast-macrophage crosstalk,and provided a foundation for LRP1 as a novel potential target for psoriasis treatment.
基金supported by the National Key R&D Program of China(2022YFC2009900)the Alzheimer’s Association New to the Field award,ERC Consolidator grant H2020-ERC-2018-CoG(769798 CheSSTag)+1 种基金the Plan de Recuperacion Nacional Biotech for Health Project(ADNano),Activitat científica dels grups de recerca de Catalunya(SGR-Cat 2021)the Spanish Research Agency Proyectos I+D+I PID2020-119914RB-I00。
文摘The blood-brain barrier(BBB)is a highly selective permeability barrier that safeguards the central nervous system(CNS)from potentially harmful substances while regulating the transport of essential molecules.Its dysfunction is increasingly recognized as a pivotal factor in the pathogenesis of Alzheimer's disease(AD),contributing to the accumulation of amyloid-β(Aβ)plaques.We present a novel therapeutic strategy that targets low-density lipoprotein receptor-related protein 1(LRP1)on the BBB.Our design leverages the multivalent nature and precise size of LRP1-targeted polymersomes to modulate receptor-mediated transport,biasing LRP1 trafficking toward transcytosis and thereby upregulating its expression to promote efficient Aβremoval.In AD model mice,this intervention significantly reduced brain Aβlevels by nearly 45%and increased plasma Aβlevels by 8-fold within 2 h,as measured by ELISA.Multiple imaging techniques confirmed the reduction in brain Aβsignals after treatment.Cognitive assessments revealed that treated AD mice exhibited significant improvements in spatial learning and memory,with performance levels comparable to those of wild-type mice.These cognitive benefits persisted for up to 6 months post-treatment.This work pioneers a new paradigm in drug design,where function arises from the supramolecular nature of the nanomedicine,harnessing multivalency to elicit biological action at the membrane trafficking level.Our findings also reaffirm the critical role of the BBB in AD pathogenesis and demonstrate that targeting the BBB can make therapeutic interventions significantly more effective.We establish a compelling case for BBB modulation and LRP1-mediated Aβclearance as a transformative foundation for future AD therapies.
基金supported by the National Natural Science Foun-dation of China(82425054 and 82273784)the Research and Develop Program,West China Hospital of Stomatology Sichuan University(RD-03-202004,China)+6 种基金Health Commission of Sichuan Province Medical Science and Technology Program(No.24CGZH05,China)the 1.3.5 Projects for Disciplines of Excel-lence,West China Hospital,Sichuan University(ZYGD25002 and ZYGD23025,China)the Sichuan Science and Technology Pro-grams(2024NSFSC0048,2023ZYD0168,2024YFFK0374 and 2023ZYD0168,China)the National Natural Science Foundation of China(82425054 and 82273784)the 1.3.5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(ZYGD25002 and ZYGD23025,China)Nature Science Foundation of Sichuan Province(2024NSFSC0048,China)Sichuan Science and Technology Program(2023ZYD0168,China).
文摘Local anesthetics(LAs),such as articaine(AT),exhibit limited efficacy in inflammatory environments,which constitutes a significant limitation in their clinical application within oral medicine.In our prior research,we developed AT-17,which demonstrated effective properties in chronic inflamma-tory conditions and appears to function as a novel oral LA that could address this challenge.In the present study,we further elucidated the beneficial effects of AT-17 in acute inflammation,particularly in oral acute inflammation,where mitochondrial-related apoptosis played a crucial role.Our findings indicated that AT-17 effectively inhibited lipopolysaccharide(LPS)-induced nerve cell apoptosis by ameliorating mitochondrial dysfunction in vitro.This process involved the inhibition of mitochondrial reactive oxygen species(mtROS)production and the subsequent activation of the NRF2 pathway.Most notably,improve-ments in mitochondria-related apoptosis were key contributors to AT-17’s inhibition of voltage-gated sodium channels.Additionally,AT-17 was shown to reduce mtROS production in nerve cells through the Na+/NCLX/ETC signaling axis.In conclusion,we have developed a novel local anesthetic that exhibits pronounced anesthetic functionality under inflammatory conditions by enhancing mitochondria-related apoptosis.This advancement holds considerable promise for future drug development and deepening our understanding of the underlying mechanisms of action.
基金the general financial support of the Georgia Research Alliance through an Eminent Scholar endowmentinternal financial sources at Georgia State University, USAsupported by The German Research Foundation (Deutsche Forschungsgemeinschaftd DFG), Germany, grant number: DFG #374031971 CRC/TR 240, Projekt B03。
文摘Nature has endowed gaseous molecules such as O_(2),CO_(2),CO,NO,H2 S,and N2 with critical and diverse roles in sustaining life,from supplying energy needed to power life and building blocks for life ’s physical structure to mediating and coordinating cellular functions.In this article,we give a brief introduction of the complex functions of the various gaseous molecules in life and then focus on carbon monoxide as a specific example of an endogenously produced signaling molecule to highlight the importance of this class of molecules.The past twenty years have seen much progress in understanding CO’s mechanism(s) of action and pharmacological effects as well as in developing delivery methods for easy administration.One remarkable trait of CO is its pleiotropic effects that have few parallels,except perhaps its sister gaseous signaling molecules such as nitric oxide and hydrogen sulfide.This review will delve into the sophistication of CO-mediated signaling as well as its validated pharmacological functions and possible therapeutic applications.
基金supported by the National Natural Science Foundation of China(82072060,81773685,and 81571807)the Fundamental Research Funds for the Central Universities(XDJK2019TY002,China)+3 种基金the Chengdu Science and Technology Program(2018-CY02-00042-GX,China)the 1.3.5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(ZYYC21002,ZYJC18032 and ZY2016101,China)the Natural Scienceof Chongqing(cstc2020jcyj-msxm X0292,China)the Venture&Innovation Support Program for Chongqing Overseas Returnees(cx2018029,China)。
文摘Incorporation of multiple functions into one nanoplatform can improve cancer diagnostic efficacy and enhance anti-cancer outcomes. Here, we constructed doxorubicin(DOX)-loaded silk fibroinbased nanoparticles(NPs) with surface functionalization by photosensitizer(N770). The obtained nanotheranostics(N770-DOX@NPs) had desirable particle size(157 nm) and negative surface charge(-25 m V). These NPs presented excellent oxygen-generating capacity and responded to a quadruple of stimuli(acidic solution, reactive oxygen species, glutathione, and hyperthermia). Surface functionalization of DOX@NPs with N770 could endow them with active internalization by cancerous cell lines, but not by normal cells. Furthermore, the intracellular NPs were found to be preferentially retained in mitochondria, which were also efficient for near-infrared(NIR) fluorescence imaging, photothermal imaging,and photoacoustic imaging. Meanwhile, DOX could spontaneously accumulate in the nucleus. Importantly, a mouse test group treated with N770-DOX@NPs plus NIR irradiation achieved the best tumorretardation effect among all treatment groups based on tumor-bearing mouse models and a patientderived xenograft model, demonstrating the unprecedented therapeutic effects of trimodal imagingguided mitochondrial phototherapy(photothermal therapy and photodynamic therapy) and chemotherapy.Therefore, the present study brings new insight into the exploitation of an easy-to-use, versatile, and robust nanoplatform for programmable targeting, imaging, and applying synergistic therapy to tumors.
基金supported by the National Natural Science Foundation of China(82273784,China)the Research and Develop Program,West China Hospital of Stomatology Sichuan University(RD-03-202004,China)+3 种基金the 1.3.5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(ZYYC 21002,ZYGD23025,China)the Clinical Research Innovation Project,West China Hospital,Sichuan University(2019 HXCX006,China)the Science and Technology Major Project of Tibetan Autonomous Region of China(XZ202201ZD0001G,China)the Sichuan Science and Technology Program(2023 ZYD0168,China).
文摘Multifunctional therapeutics have emerged as a solution to the constraints imposed by drugs with singular or insufficient therapeutic effects.The primary challenge is to integrate diverse pharmacophores within a single-molecule framework.To address this,we introduced DeepSA,a novel edit-based generative framework that utilizes deep simulated annealing for the modification of articaine,a wellknown local anesthetic.DeepSA integrates deep neural networks into metaheuristics,effectively constraining molecular space during compound generation.This framework employs a sophisticated objective function that accounts for scaffold preservation,anti-inflammatory properties,and covalent constraints.Through a sequence of local editing to navigate the molecular space,DeepSA successfully identified AT-17,a derivative exhibiting potent analgesic properties and significant anti-inflammatory activity in various animal models.Mechanistic insights into AT-17 revealed its dual mode of action:selective inhibition of NaV1.7 and 1.8 channels,contributing to its prolonged local anesthetic effects,and suppression of inflammatory mediators via modulation of the NLRP3 inflammasome pathway.These findings not only highlight the efficacy of AT-17 as a multifunctional drug candidate but also highlight the potential of DeepSA in facilitating AI-enhanced drug discovery,particularly within stringent chemical constraints.
