Modern western medicine typically focuses on treating specific symptoms or diseases,and traditional Chinese medicine(TCM)emphasizes the interconnections of the body’s various systems under external environment and ta...Modern western medicine typically focuses on treating specific symptoms or diseases,and traditional Chinese medicine(TCM)emphasizes the interconnections of the body’s various systems under external environment and takes a holistic approach to preventing and treating diseases.Phenomics was initially introduced to the field of TCM in 2008 as a new discipline that studies the laws of integrated and dynamic changes of human clinical phenomes under the scope of the theories and practices of TCM based on phenomics.While TCM Phenomics 1.0 has initially established a clinical phenomic system centered on Zhenghou(a TCM definition of clinical phenome),bottlenecks remain in data standardization,mechanistic interpretation,and precision intervention.Here,we systematically elaborates on the theoretical foundations,technical pathways,and future challenges of integrating digital medicine with TCM phenomics under the framework of“TCM phenomics 2.0”,which is supported by digital medicine technologies such as artificial intelligence,wearable devices,medical digital twins,and multi-omics integration.This framework aims to construct a closed-loop system of“Zhenghou–Phenome–Mechanism–Intervention”and to enable the digitization,standardization,and precision of disease diagnosis and treatment.The integration of digital medicine and TCM phenomics not only promotes the modernization and scientific transformation of TCM theory and practice but also offers new paradigms for precision medicine.In practice,digital tools facilitate multi-source clinical data acquisition and standardization,while AI and big data algorithms help reveal the correlations between clinical Zhenghou phenomes and molecular mechanisms,thereby improving scientific rigor in diagnosis,efficacy evaluation,and personalized intervention.Nevertheless,challenges persist,including data quality and standardization issues,shortage of interdisciplinary talents,and insufficiency of ethical and legal regulations.Future development requires establishing national data-sharing platforms,strengthening international collaboration,fostering interdisciplinary professionals,and improving ethical and legal frameworks.Ultimately,this approach seeks to build a new disease identification and classification system centered on phenomes and to achieve the inheritance,innovation,and modernization of TCM diagnostic and therapeutic patterns.展开更多
Sustained inflammatory responses are closely related to various severe diseases,and inhibiting the excessive activation of inflammasomes and pyroptosis has significant implications for clinical treatment.Natural produ...Sustained inflammatory responses are closely related to various severe diseases,and inhibiting the excessive activation of inflammasomes and pyroptosis has significant implications for clinical treatment.Natural products have garnered considerable concern for the treatment of inflammation.Huanglian-Wumei decoction(HLWMD)is a classic prescription used for treating inflammatory diseases,but the necessity of their combination and the exact underlying anti-inflammatory mechanism have not yet been elucidated.Inspired by the supramolecular self-assembly strategy and natural drug compatibility theory,we successfully obtained berberine(BBR)-chlorogenic acid(CGA)supramolecular(BCS),which is an herbal pair from HLWMD.Using a series of characterization methods,we confirmed the self-assembly mechanism of BCS.BBR and CGA were self-assembled and stacked into amphiphilic spherical supramolecules in a 2:1 molar ratio,driven by electrostatic interactions,hydrophobic interactions,andπ–πstacking;the hydrophilic fragments of CGA were outside,and the hydrophobic fragments of BBR were inside.This stacking pattern significantly improved the anti-inflammatory performance of BCS compared with that of single free molecules.Compared with free molecules,BCS significantly attenuated the release of multiple inflammatory mediators and lipopolysaccharide(LPS)-induced pyroptosis.Its anti-inflammatory mechanism is closely related to the inhibition of intracellular nuclear factor-kappaB(NF-κB)p65 phosphorylation and the noncanonical pyroptosis signalling pathway mediated by caspase-11.展开更多
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
Colorectal tumorigenesis generally progresses from adenoma to adenocarcinoma,accompanied by dynamic changes in the tumor microenvironment(TME).A randomized controlled trial has confirmed the efficacy and safety of She...Colorectal tumorigenesis generally progresses from adenoma to adenocarcinoma,accompanied by dynamic changes in the tumor microenvironment(TME).A randomized controlled trial has confirmed the efficacy and safety of Shen-Bai-Jie-Du decoction(SBJDD)in preventing colorectal tumorigenesis.However,the mechanism remains unclear.In this study,we employed single-cell RNA sequencing(scRNA-seq)to investigate the dynamic evolution of the TME and validated cell infiltration with multiplex immunohistochemistry and flow cytometry.Bulk RNA sequencing was utilized to assess the underlying mechanisms.Our results constructed the mutually verifiable single-cell transcriptomic atlases in Apc^(Min/+)mice and clinical patients.There was a marked accumulation of CCL22^(+)dendritic cells(DCs)and an enhanced immunosuppressive action,which SBJDD and berberine reversed.Combined treatment with cholesterol and lipopolysaccharide induced characteristic gene expression of CCL22^(+)DCs,which may represent“exhausted DCs”.Intraperitoneal injection of these DCs after SBJDD treatment eliminated its therapeutic effects.TMEM131 derived CCL22+DCs generation by TNF signaling pathway and may be a potential target of berberine in retarding colorectal tumorigenesis.These findings emphasize the role of exhausted DCs and the regulatory mechanisms of SBJDD and berberine in colorectal cancer(CRC),suggesting that the multi-component properties of SBJDD may help restore TME homeostasis and offer novel cancer therapy.展开更多
Colorectal cancer(CRC), a malignant tumor worldwide consists of microsatellite instability(MSI) and stable(MSS) phenotypes. Although SHP2 is a hopeful target for cancer therapy, its relationship with innate immunosupp...Colorectal cancer(CRC), a malignant tumor worldwide consists of microsatellite instability(MSI) and stable(MSS) phenotypes. Although SHP2 is a hopeful target for cancer therapy, its relationship with innate immunosuppression remains elusive. To address that, single-cell RNA sequencing wasperformed to explore the role of SHP2 in all cell types of tumor microenvironment(TME) from murine MC38 xenografts. Intratumoral cells were found to be functionally heterogeneous and responded significantly to SHP099, a SHP2 allosteric inhibitor. The malignant evolution of tumor cells was remarkably arrested by SHP099. Mechanistically, STING-TBK1-IRF3-mediated type I interferon signaling was highly activated by SHP099 in infiltrated myeloid cells. Notably, CRC patients with MSS phenotype exhibited greater macrophage infiltration and more potent SHP2 phosphorylation in CD68;macrophages than MSI-high phenotypes, suggesting the potential role of macrophagic SHP2 in TME. Collectively,our data reveals a mechanism of innate immunosuppression mediated by SHP2, suggesting that SHP2 is a promising target for colon cancer immunotherapy.展开更多
Dear Editor,Colorectal cancer(CRC)is one of the most frequent diseases with high mortality around the world.Conventional treatments of CRC remain unsatisfactory due to the increasing recurrence rate and adverse reacti...Dear Editor,Colorectal cancer(CRC)is one of the most frequent diseases with high mortality around the world.Conventional treatments of CRC remain unsatisfactory due to the increasing recurrence rate and adverse reactions including neutropenia,drug resistance,etc.Recently,autophagy has been shown to be involved in regulating cancer development and progression by regulating apoptosis through pro-apoptosis proteins including caspases,in addition to being a potential target for cancer therapeutic intervention.1 Trifolirhizin(Supplementary Fig.S1a)is a natural flavonoid glycosides isolated from Sophora flavescens as well as a bioactive constituent of Xian-Lian-Ke-Li,a commercial traditional Chinese medicine for the cancer prevention.Numerous evidence manifested that trifolirhizin inhibited proliferative activity in melanoma B16 cell,lung cancer H23 cell,human ovarian A2780 cell,and human gastric cancer cell MKN45.2 However,its pharmacological effect and mechanism on CRC remain elusive.Herein,we evaluated the effect of trifolirhizin on autophagy and apoptosis on CRC as well as its related mechanisms,in order to provide evidence to develop a potential agent with less adverse effect in treating CRC.展开更多
Copper-based nanomaterials demonstrate promising potential in cancer therapy.Cu^(+) efficiently triggers a Fenton-like reaction and further consumes the high level of glutathione,initiating chemical dynamic therapy(CD...Copper-based nanomaterials demonstrate promising potential in cancer therapy.Cu^(+) efficiently triggers a Fenton-like reaction and further consumes the high level of glutathione,initiating chemical dynamic therapy(CDT)and ferroptosis.Cuproptosis,a newly identified cell death modality that represents a great prospect in cancer therapy,is activated.However,active homeostatic systems rigorously keep copper levels within cells exceptionally low,which hinders the application of cooper nanomaterials-based therapy.Herein,a novel strategy of CRISPR-Cas9 RNP nanocarrier to deliver cuprous ions and suppress the expression of copper transporter protein ATP7A for maintaining a high level of copper in cytoplasmic fluid is developed.The Cu_(2)O and organosilica shell would degrade under the high level of glutathione and weak acidic environment,further releasing RNP and Cu^(+).The liberated Cut triggered a Fenton-like reaction for CDT and partially transformed to Cu^(2+),consuming intracellular GSH and initiating cuproptosis and ferroptosis efficiently.Meanwhile,the release of RNP effectively reduced the expression of copper transporter ATP7A,subsequently increasing the accumulation of cooper and enhancing the efficacy of CDT,cuproptosis,and ferroptosis.Such tumor microenvironment responsive multimodal nanoplatform opens an ingenious avenue for colorectal cancer therapy based on gene editing enhanced synergistic cuproptosis/CDT/ferroptosis.展开更多
In recent years,traditional Chinese medicine(TCM)has made great progress in the prevention and treatment of cancer.It has gradually revealed its characteristics and advantages in clinical practice,including alleviatin...In recent years,traditional Chinese medicine(TCM)has made great progress in the prevention and treatment of cancer.It has gradually revealed its characteristics and advantages in clinical practice,including alleviating clinical symptoms,prolonging survival time,decreasing the adverse effects of chemotherapy,and improving living quality.However,clinical TCM treatment of cancer lacks systematic theoretical guidance,because ancient TCM has not formed a recognized theoretical system of cognitive cancer,and there still are different opinions on the pathogenesis of cancer.Due to the complexity of cancer,the essence of cancer pathogenesis has not been described accurately by using common pathogenic factors,such as pathogenic wind,cold,dampness,summer heat,dryness,and fire.Ancient and modern TCM physicians have a similar understanding that the occurrence of cancer is related to toxin.In the 1990s,the thought of cancerous toxin was first proposed by Prof Zhou Zhongying,a TCMmaster based onmore than 60 years of clinical practice,who used“pandemic Qi(Li-Qi)is a specific pathogenic factor of epidemic disease”in Wenyi Lun(Treatise on Pestilence)for references.The pathogenesis theory of cancerous toxin was gradually established under the guidance of the thought of cancerous toxin.It holds that the cancerous toxin,a special pathogenic factor of cancer,is the key pathogenesis of the occurrence of malignant tumors.According to the pathogenesis theory of cancerous toxin,the basic pathogenesis of malignant tumors is the accumulation of pathogenic factors and cancerous toxin,and the deficiency of the vital Qi(Zheng-Qi).Therefore,the treatment principle involves eliminating pathogenic factors,resolving cancerous toxin,and supporting the vital Qi.The anticancer detoxification methods and the classification of Chinese medicinal herbs with anticancer detoxification effects were put forward.System theory has much in common with the concepts in the theory system of TCM,such as the universal relation theory,asking for a concrete analysis of concrete conditions,the humanism thought,and so on.This article aims to describe,review,and analyze the pathogenesis theory of cancerous toxin based on system theory for clinical practices.展开更多
基金Science and Technology strategic cooperation Programs of Luzhou Municipal People’s Government and Southwest Medical University (2019LZXNYD-P01DUAN)National Key R&D Program of China (2024YFC3505400)Regional Key R&D Program of Ningxia Hui Autonomous Region (2024BEG01003)。
文摘Modern western medicine typically focuses on treating specific symptoms or diseases,and traditional Chinese medicine(TCM)emphasizes the interconnections of the body’s various systems under external environment and takes a holistic approach to preventing and treating diseases.Phenomics was initially introduced to the field of TCM in 2008 as a new discipline that studies the laws of integrated and dynamic changes of human clinical phenomes under the scope of the theories and practices of TCM based on phenomics.While TCM Phenomics 1.0 has initially established a clinical phenomic system centered on Zhenghou(a TCM definition of clinical phenome),bottlenecks remain in data standardization,mechanistic interpretation,and precision intervention.Here,we systematically elaborates on the theoretical foundations,technical pathways,and future challenges of integrating digital medicine with TCM phenomics under the framework of“TCM phenomics 2.0”,which is supported by digital medicine technologies such as artificial intelligence,wearable devices,medical digital twins,and multi-omics integration.This framework aims to construct a closed-loop system of“Zhenghou–Phenome–Mechanism–Intervention”and to enable the digitization,standardization,and precision of disease diagnosis and treatment.The integration of digital medicine and TCM phenomics not only promotes the modernization and scientific transformation of TCM theory and practice but also offers new paradigms for precision medicine.In practice,digital tools facilitate multi-source clinical data acquisition and standardization,while AI and big data algorithms help reveal the correlations between clinical Zhenghou phenomes and molecular mechanisms,thereby improving scientific rigor in diagnosis,efficacy evaluation,and personalized intervention.Nevertheless,challenges persist,including data quality and standardization issues,shortage of interdisciplinary talents,and insufficiency of ethical and legal regulations.Future development requires establishing national data-sharing platforms,strengthening international collaboration,fostering interdisciplinary professionals,and improving ethical and legal frameworks.Ultimately,this approach seeks to build a new disease identification and classification system centered on phenomes and to achieve the inheritance,innovation,and modernization of TCM diagnostic and therapeutic patterns.
基金supported by the Project of National Natural Science Foundation of China(Grant No.:82274219 and 81930117)the Key Project of Traditional Chinese Medicine Technology Development Plan of Jiangsu Province,China(Grant No.:ZD202201)Jiangsu Province Postgraduate Scientific Research Practice and Innovation Plan Project,China(Grant Nos.:KYCX21_1735 and SJCX21_0679).
文摘Sustained inflammatory responses are closely related to various severe diseases,and inhibiting the excessive activation of inflammasomes and pyroptosis has significant implications for clinical treatment.Natural products have garnered considerable concern for the treatment of inflammation.Huanglian-Wumei decoction(HLWMD)is a classic prescription used for treating inflammatory diseases,but the necessity of their combination and the exact underlying anti-inflammatory mechanism have not yet been elucidated.Inspired by the supramolecular self-assembly strategy and natural drug compatibility theory,we successfully obtained berberine(BBR)-chlorogenic acid(CGA)supramolecular(BCS),which is an herbal pair from HLWMD.Using a series of characterization methods,we confirmed the self-assembly mechanism of BCS.BBR and CGA were self-assembled and stacked into amphiphilic spherical supramolecules in a 2:1 molar ratio,driven by electrostatic interactions,hydrophobic interactions,andπ–πstacking;the hydrophilic fragments of CGA were outside,and the hydrophobic fragments of BBR were inside.This stacking pattern significantly improved the anti-inflammatory performance of BCS compared with that of single free molecules.Compared with free molecules,BCS significantly attenuated the release of multiple inflammatory mediators and lipopolysaccharide(LPS)-induced pyroptosis.Its anti-inflammatory mechanism is closely related to the inhibition of intracellular nuclear factor-kappaB(NF-κB)p65 phosphorylation and the noncanonical pyroptosis signalling pathway mediated by caspase-11.
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 R&D Program of China(2022YFC3500200,2022YFC3500202)National Natural Science Foundation of China(U24A20794,82103197)+4 种基金Jiangsu Province Postgraduate Training Innovation Project Grant(KYCX23_2132,China)the Integrated Traditional Chinese and Western Medicine Clinical Medicine Innovation Center Fund for Colorectal Polyps from Jiangsu Province Hospital of Chinese Medicine(No.Y2023zx10)the project funding from Jiangsu Province Hospital of Chinese Medicine(No.kgr0253,China)Natural Science Foundation of Jiangsu Province(BK20210686,China)Nanjing University of Chinese Medicine’s Key Project:“Leading the Charge with Open Competition”(AD202405,China).
文摘Colorectal tumorigenesis generally progresses from adenoma to adenocarcinoma,accompanied by dynamic changes in the tumor microenvironment(TME).A randomized controlled trial has confirmed the efficacy and safety of Shen-Bai-Jie-Du decoction(SBJDD)in preventing colorectal tumorigenesis.However,the mechanism remains unclear.In this study,we employed single-cell RNA sequencing(scRNA-seq)to investigate the dynamic evolution of the TME and validated cell infiltration with multiplex immunohistochemistry and flow cytometry.Bulk RNA sequencing was utilized to assess the underlying mechanisms.Our results constructed the mutually verifiable single-cell transcriptomic atlases in Apc^(Min/+)mice and clinical patients.There was a marked accumulation of CCL22^(+)dendritic cells(DCs)and an enhanced immunosuppressive action,which SBJDD and berberine reversed.Combined treatment with cholesterol and lipopolysaccharide induced characteristic gene expression of CCL22^(+)DCs,which may represent“exhausted DCs”.Intraperitoneal injection of these DCs after SBJDD treatment eliminated its therapeutic effects.TMEM131 derived CCL22+DCs generation by TNF signaling pathway and may be a potential target of berberine in retarding colorectal tumorigenesis.These findings emphasize the role of exhausted DCs and the regulatory mechanisms of SBJDD and berberine in colorectal cancer(CRC),suggesting that the multi-component properties of SBJDD may help restore TME homeostasis and offer novel cancer therapy.
基金supported by National Natural Science Foundation of China(Nos.91853109,81730100,81872877,and 81673436)Mountain-Climbing Talents Project of Nanjing University(China)。
文摘Colorectal cancer(CRC), a malignant tumor worldwide consists of microsatellite instability(MSI) and stable(MSS) phenotypes. Although SHP2 is a hopeful target for cancer therapy, its relationship with innate immunosuppression remains elusive. To address that, single-cell RNA sequencing wasperformed to explore the role of SHP2 in all cell types of tumor microenvironment(TME) from murine MC38 xenografts. Intratumoral cells were found to be functionally heterogeneous and responded significantly to SHP099, a SHP2 allosteric inhibitor. The malignant evolution of tumor cells was remarkably arrested by SHP099. Mechanistically, STING-TBK1-IRF3-mediated type I interferon signaling was highly activated by SHP099 in infiltrated myeloid cells. Notably, CRC patients with MSS phenotype exhibited greater macrophage infiltration and more potent SHP2 phosphorylation in CD68;macrophages than MSI-high phenotypes, suggesting the potential role of macrophagic SHP2 in TME. Collectively,our data reveals a mechanism of innate immunosuppression mediated by SHP2, suggesting that SHP2 is a promising target for colon cancer immunotherapy.
基金supported by the National Natural Science Foundation of China(81930117,81673559,81973523)National Key Research and Development Project(2017YFC1700602)funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions.
文摘Dear Editor,Colorectal cancer(CRC)is one of the most frequent diseases with high mortality around the world.Conventional treatments of CRC remain unsatisfactory due to the increasing recurrence rate and adverse reactions including neutropenia,drug resistance,etc.Recently,autophagy has been shown to be involved in regulating cancer development and progression by regulating apoptosis through pro-apoptosis proteins including caspases,in addition to being a potential target for cancer therapeutic intervention.1 Trifolirhizin(Supplementary Fig.S1a)is a natural flavonoid glycosides isolated from Sophora flavescens as well as a bioactive constituent of Xian-Lian-Ke-Li,a commercial traditional Chinese medicine for the cancer prevention.Numerous evidence manifested that trifolirhizin inhibited proliferative activity in melanoma B16 cell,lung cancer H23 cell,human ovarian A2780 cell,and human gastric cancer cell MKN45.2 However,its pharmacological effect and mechanism on CRC remain elusive.Herein,we evaluated the effect of trifolirhizin on autophagy and apoptosis on CRC as well as its related mechanisms,in order to provide evidence to develop a potential agent with less adverse effect in treating CRC.
基金the National Natural Science Foundation of China(82374287,82174466,81930117)National Key Research and Development Project(2022YFC3500200,China)+3 种基金Key research and development projects of Ningxia(Grant No.2021BEG02040,China)Natural Science Foundation Project of Jiangsu Province(BK20211390,China)Open Projects of the Discipline of Chinese Medicine of Nanjing University of Chinese Medicine Supported by the Subject of Academic priority discipline of Jiangsu Higher Education Institutions,Program for Leading Talents of Traditional Chinese Medicine of Jiangsu Province(SLJ0314)Blue Project of Jiangsu province.
文摘Copper-based nanomaterials demonstrate promising potential in cancer therapy.Cu^(+) efficiently triggers a Fenton-like reaction and further consumes the high level of glutathione,initiating chemical dynamic therapy(CDT)and ferroptosis.Cuproptosis,a newly identified cell death modality that represents a great prospect in cancer therapy,is activated.However,active homeostatic systems rigorously keep copper levels within cells exceptionally low,which hinders the application of cooper nanomaterials-based therapy.Herein,a novel strategy of CRISPR-Cas9 RNP nanocarrier to deliver cuprous ions and suppress the expression of copper transporter protein ATP7A for maintaining a high level of copper in cytoplasmic fluid is developed.The Cu_(2)O and organosilica shell would degrade under the high level of glutathione and weak acidic environment,further releasing RNP and Cu^(+).The liberated Cut triggered a Fenton-like reaction for CDT and partially transformed to Cu^(2+),consuming intracellular GSH and initiating cuproptosis and ferroptosis efficiently.Meanwhile,the release of RNP effectively reduced the expression of copper transporter ATP7A,subsequently increasing the accumulation of cooper and enhancing the efficacy of CDT,cuproptosis,and ferroptosis.Such tumor microenvironment responsive multimodal nanoplatform opens an ingenious avenue for colorectal cancer therapy based on gene editing enhanced synergistic cuproptosis/CDT/ferroptosis.
基金supported by the National Natural Science Foundation of China(No.81973737)National Key R&D Program of China(No.2022YFC3500200 and 2022YFC3500201)+2 种基金Innovation Team and Talents Cultivation Program of National Administration of TraditionalChinese Medicine(No.ZYYCXTD-C-202208)NATCM’s Project of High-level Construction of Key TCM Disciplines,Qing Lan Project of Jiangsu Higher Education Institutions,Jiangsu Postgraduate Practice Innovation Plan(No.SJCX22_0706)General Project of Universities’Philosophy and Social Science in Jiangsu Province.
文摘In recent years,traditional Chinese medicine(TCM)has made great progress in the prevention and treatment of cancer.It has gradually revealed its characteristics and advantages in clinical practice,including alleviating clinical symptoms,prolonging survival time,decreasing the adverse effects of chemotherapy,and improving living quality.However,clinical TCM treatment of cancer lacks systematic theoretical guidance,because ancient TCM has not formed a recognized theoretical system of cognitive cancer,and there still are different opinions on the pathogenesis of cancer.Due to the complexity of cancer,the essence of cancer pathogenesis has not been described accurately by using common pathogenic factors,such as pathogenic wind,cold,dampness,summer heat,dryness,and fire.Ancient and modern TCM physicians have a similar understanding that the occurrence of cancer is related to toxin.In the 1990s,the thought of cancerous toxin was first proposed by Prof Zhou Zhongying,a TCMmaster based onmore than 60 years of clinical practice,who used“pandemic Qi(Li-Qi)is a specific pathogenic factor of epidemic disease”in Wenyi Lun(Treatise on Pestilence)for references.The pathogenesis theory of cancerous toxin was gradually established under the guidance of the thought of cancerous toxin.It holds that the cancerous toxin,a special pathogenic factor of cancer,is the key pathogenesis of the occurrence of malignant tumors.According to the pathogenesis theory of cancerous toxin,the basic pathogenesis of malignant tumors is the accumulation of pathogenic factors and cancerous toxin,and the deficiency of the vital Qi(Zheng-Qi).Therefore,the treatment principle involves eliminating pathogenic factors,resolving cancerous toxin,and supporting the vital Qi.The anticancer detoxification methods and the classification of Chinese medicinal herbs with anticancer detoxification effects were put forward.System theory has much in common with the concepts in the theory system of TCM,such as the universal relation theory,asking for a concrete analysis of concrete conditions,the humanism thought,and so on.This article aims to describe,review,and analyze the pathogenesis theory of cancerous toxin based on system theory for clinical practices.
