The intricate interplay between the human immune system and cancer development underscores the central role of immunotherapy in cancer treatment.Within this landscape,the innate immune system,a critical sentinel prote...The intricate interplay between the human immune system and cancer development underscores the central role of immunotherapy in cancer treatment.Within this landscape,the innate immune system,a critical sentinel protecting against tumor incursion,is a key player.The cyclic GMP-AMP synthase(c GAS)and stimulator of interferon genes(STING)pathway has been found to be a linchpin of innate immunity:activation of this signaling pathway orchestrates the production of type I interferon(IFN-α/β),thus fostering the maturation,differentiation,and mobilization of immune effectors in the tumor microenvironment.Furthermore,STING activation facilitates the release and presentation of tumor antigens,and therefore is an attractive target for cancer immunotherapy.Current strategies to activate the STING pathway,including use of pharmacological agonists,have made substantial advancements,particularly when combined with immune checkpoint inhibitors.These approaches have shown promise in preclinical and clinical settings,by enhancing patient survival rates.This review describes the evolving understanding of the c GAS-STING pathway's involvement in tumor biology and therapy.Moreover,this review explores classical and non-classical STING agonists,providing insights into their mechanisms of action and potential for optimizing immunotherapy strategies.Despite challenges and complexities,the c GAS-STING pathway,a promising avenue for enhancing cancer treatment efficacy,has the potential to revolutionize patient outcomes.展开更多
Gastric cancer(GC)is a major cause of cancer-related mortality worldwide.GC is determined by multiple(epi)genetic and environmental factors;can occur at distinct anatomic positions of the stomach;and displays high het...Gastric cancer(GC)is a major cause of cancer-related mortality worldwide.GC is determined by multiple(epi)genetic and environmental factors;can occur at distinct anatomic positions of the stomach;and displays high heterogeneity,with different cellular origins and diverse histological and molecular features.This heterogeneity has hindered efforts to fully understand the pathology of GC and develop efficient therapeutics.In the past decade,great progress has been made in the study of GC,particularly in molecular subtyping,investigation of the immune microenvironment,and defining the evolutionary path and dynamics.Preclinical mouse models,particularly immunocompetent models that mimic the cellular and molecular features of human GC,in combination with organoid culture and clinical studies,have provided powerful tools for elucidating the molecular and cellular mechanisms underlying GC pathology and immune evasion,and the development of novel therapeutic strategies.Herein,we first briefly introduce current progress and challenges in GC study and subsequently summarize immunocompetent GC mouse models,emphasizing the potential application of genetically engineered mouse models in antitumor immunity and immunotherapy studies.展开更多
Obesity is one of the most serious global health problems,with an incidence that increases yearly and coincides with the development of cancer.Adipose tissue macrophages(ATMs)are particularly important in this context...Obesity is one of the most serious global health problems,with an incidence that increases yearly and coincides with the development of cancer.Adipose tissue macrophages(ATMs)are particularly important in this context and contribute to linking obesity-related inflammation and tumor progression.However,the functions of ATMs on the progression of obesity-associated cancer remain unclear.In this review,we describe the origins,phenotypes,and functions of ATMs.Subsequently,we summarize the potential mechanisms on the reprogramming of ATMs in the obesity-associated microenvironment,including the direct exchange of dysfunctional metabolites,inordinate cytokines and other signaling mediators,transfer of extracellular vesicle cargo,and variations in the gut microbiota and its metabolites.A better understanding of the properties and functions of ATMs under conditions of obesity will lead to the development of new therapeutic interventions for obesity-related cancer.展开更多
The low immunogenicity of tumors remains one of the major limitations of cancer immunotherapy.Herein,we report a bacterial metabolisminitiated and photothermal-enhanced nanocatalytic therapy strategy to completely era...The low immunogenicity of tumors remains one of the major limitations of cancer immunotherapy.Herein,we report a bacterial metabolisminitiated and photothermal-enhanced nanocatalytic therapy strategy to completely eradicate primary tumor by triggering highly effective antitumor immune responses.Briefly,a microbiotic nanomedicine,designated as Cu_(2)O@ΔSt,has been constructed by conjugating PEGylated Cu_(2)O nanoparticles on the surface of an engineered Salmonella typhimurium strain(ΔSt).Owing to the natural hypoxia tropism ofΔSt,Cu_(2)O@ΔSt could selectively colonize hypoxic solid tumors,thus minimizing the adverse effects of the bacteria on normal tis-sues.Upon bacterial metabolism within the tumor,Cu_(2)O@ΔSt generates H_(2)S gas and other acidic substances in the tumor microenvironment(TME),which will in situ trigger the sulfidation of Cu_(2)O to form CuS facilitating tumor-specific photothermal therapy(PTT)under local NIR laser irradiation on the one hand.Meanwhile,the dissolved Cu+ions from Cu_(2)O into the acidified TME enables the nanocatalytic tumor therapy by catalyzing the Fenton-like reaction of decom-posing endogenous H_(2)O_(2) into cytotoxic hydroxyl radicals(·OH)on the other hand.Such a bacterial metabolism-triggered PTT-enhanced nanocatalytic treatment could effectively destroy tumor cells and induce a massive release of tumor antigens and damage-associated molecular patterns,thereby sensitizing tumors to checkpoint blockade(ICB)therapy.The combined nanocatalytic and ICB therapy results in the much-inhibited growth of distant and metastatic tumors,and more importantly,induces a powerful immunological memory effect after the primary tumor ablation.展开更多
Cancer immunotherapy,mainly including immune checkpoints-targeted therapy and the adoptive transfer of engineered immune cells,has revolutionized the oncology landscape as it utilizes patients’own immune systems in c...Cancer immunotherapy,mainly including immune checkpoints-targeted therapy and the adoptive transfer of engineered immune cells,has revolutionized the oncology landscape as it utilizes patients’own immune systems in combating the cancer cells.Cancer cells escape immune surveillance by hijacking the corresponding inhibitory pathways via overexpressing checkpoint genes.Phagocytosis checkpoints,such as CD47,CD24,MHC-I,PD-L1,STC-1 and GD2,have emerged as essential checkpoints for cancer immunotherapy by functioning as“don’t eat me”signals or interacting with“eat me”signals to suppress immune responses.Phagocytosis checkpoints link innate immunity and adaptive immunity in cancer immunotherapy.Genetic ablation of these phagocytosis checkpoints,as well as blockade of their signaling pathways,robustly augments phagocytosis and reduces tumor size.Among all phagocytosis checkpoints,CD47 is the most thoroughly studied and has emerged as a rising star among targets for cancer treatment.CD47-targeting antibodies and inhibitors have been investigated in various preclinical and clinical trials.However,anemia and thrombocytopenia appear to be formidable challenges since CD47 is ubiquitously expressed on erythrocytes.Here,we review the reported phagocytosis checkpoints by discussing their mechanisms and functions in cancer immunotherapy,highlight clinical progress in targeting these checkpoints and discuss challenges and potential solutions to smooth the way for combination immunotherapeutic strategies that involve both innate and adaptive immune responses.展开更多
As an important part of tumor microenvironment,neutrophils are poorly understood due to their spatiotemporal heterogeneity in tumorigenesis.Here we defined,at single-cell resolution,CD44-CxCR2-neutrophils as tumor-spe...As an important part of tumor microenvironment,neutrophils are poorly understood due to their spatiotemporal heterogeneity in tumorigenesis.Here we defined,at single-cell resolution,CD44-CxCR2-neutrophils as tumor-specific neutrophils(tsNeus)in both mouse and human gastric cancer(GC).We uncovered a Hippo regulon in neutrophils with unique YAP signature genes(e.g.,ICAM1,CD14,EGR1)distinct from those identified in epithelial and/or cancer cells.Importantly,knockout of YAP/TAz in neutrophils impaired their differentiation into CD54+tsNeus and reduced their antitumor activity,leading to accelerated GC progression.Moreover,the relative amounts of CD54+tsNeus were found to be negatively associated with GC progression and positively associated with patient survival.Interestingly,GC patients receiving neoadjuvant chemotherapy had increased numbers of CD54+tsNeus.Furthermore,pharmacologically enhancing YAP activity selectively activated neutrophils to suppress refractory GC,with no significant inflammation-related side effects.Thus,our work characterized tumor-specific neutrophils in GC and revealed an essential role of YAP/TAZ-CD54 axis in tsNeus,opening a new possibility to develop neutrophil-based antitumor therapeutics.展开更多
The interaction between cluster of differentiation 47(CD47)and signal regulatory proteinα(SiRPa)protects healthy cells from macrophage attack,which is crucial for maintain-ing immune homeostasis.Overexpression of CD4...The interaction between cluster of differentiation 47(CD47)and signal regulatory proteinα(SiRPa)protects healthy cells from macrophage attack,which is crucial for maintain-ing immune homeostasis.Overexpression of CD47 occurs widely across various tumor cell types and transmits the"don't eat me"signal to macrophages to avoid phagocytosis through binding to SIRPa.Blockade of the CD47-SIRPa axis is therefore a promising approach for cancer treat-ment.Lymphoma is the most common hematological malignancy and is an area of unmet clin-ical need.This review mainly described the current strategies targeting the CD47-SIRPa axis,including antibodies,SiRPaFc fusion proteins,small molecule inhibitors,and peptides both in preclinical studies and clinical trials with Hodgkin lymphoma and non-Hodgkin lymphoma.展开更多
Dear Editor,Immune checkpoint therapies manipulating the immune system to eliminate tumor cells have shown remarkable clinical efficacy in treating various cancers.CD47,an emerging efficient immune checkpoint,is cruci...Dear Editor,Immune checkpoint therapies manipulating the immune system to eliminate tumor cells have shown remarkable clinical efficacy in treating various cancers.CD47,an emerging efficient immune checkpoint,is crucial for cancer cells to evade macrophagemediated phagocytosis by interaction with signal-regulatory proteinα(SIRPα).Antibodies blocking the CD47/SIRPαinteraction have been effective to promote macrophage-mediated phagocytosis in various types of cancer in mice and humans.CD47 is not only highly expressed in tumor cells,but also normal cells,such as red blood cells(RBCs).Thus,during clinical trials involving cancer patients,anti-CD47 antibodies may promote the macrophagesmediated phagocytosis of RBCs,ultimately inducing undesirable anemia side effects.In contrast,small molecule inhibitors interrupting CD47/SIRPαaxis have shown potential to overcome the anemia,possibly due to their lower immunogenicity and shorter half-life compared to antibodies.1 Hence,developing the novel strategies,especially those without the anemia side effect,to intervene in CD47/SIRPαinteraction will benefit cancer immunotherapy.展开更多
Background:Chemotherapy is a common treatment for advanced hepatocellular carcinoma,but the effect is not satisfactory.The study aimed to retrospectively evaluate the effects of adding all-trans-retinoic acid(ATRA)to ...Background:Chemotherapy is a common treatment for advanced hepatocellular carcinoma,but the effect is not satisfactory.The study aimed to retrospectively evaluate the effects of adding all-trans-retinoic acid(ATRA)to infusional fluorouracil,leucovorin,and oxaliplatin(FOLFOX4)for advanced hepatocellular carcinoma(HCC).Methods:We extracted the data of patients with advanced HCC who underwent systemic chemotherapy using FOLFOX4 or ATRA plus FOLFOX4 at the Eastern Hepatobiliary Surgery Hospital,First Hospital of Jilin University,and Zhejiang Sian International Hospital and retrospectively compared for overall survival.The Cox proportional hazards model was used to calculate the hazard ratios for overall survival and disease progression after controlling for age,sex,and disease stage.Results:From July 2013 to July 2018,111 patients with HCC were included in this study.The median survival duration was 14.8 months in the ATRA plus FOLFOX4 group and 8.2 months in the FOLFOX4 only group(P<0.001).The ATRA plus FOLFOX4 group had a significantly longer median time to progression compared with the FOLFOX4 group(3.6 monthsvs.1.8 months,P<0.001).Hazard ratios for overall survival and disease progression were 0.465(95%confidence interval:0.298–0.726;P=0.001)and 0.474(0.314–0.717;P<0.001)after adjusting for potential confounders,respectively.Conclusion:ATRA plus FOLFOX4 significantly improves the overall survival and time to disease progression in patients with advanced HCC.展开更多
Surgery is the comm on treatme nt for early lung cancer with multiple pulm onary no dules,but it is often accompanied by the problem of significant malignancy of other nodules in non-therapeutic areas.In this study,we...Surgery is the comm on treatme nt for early lung cancer with multiple pulm onary no dules,but it is often accompanied by the problem of significant malignancy of other nodules in non-therapeutic areas.In this study,we found that a combined treatment of local rad iofreq ue ncy ablati on(RFA)and melatonin(MLT)greatly improved clinical outcomes for early lung cancer patie nts with multiple pulmonary nodules by minimizing lung function injury and reducing the probability of malignant transformation or enlargement of nodules in non-ablated areas.Mechanically,as demonstrated in an associated mouse lung tumor model,RFA not only effectively remove treated tumors but also stimulate antitumor immunity,which could inhibit tumor growth in non-ablated areas.MLT enhanced RFA-stimulated NK activity and exerted synergistic antitumor effects with RFA.Transcriptomics and proteomics analyses of residual tumor tissues revealed enhanced oxidative phosphorylation and reduced acidification as well as hypoxia in the tumor microenvironment,which suggests reprogrammed tumor metabolism after combined treatment with RFA and MLT.Analysis of residual tumor further revealed the depressed activity of MAPK,NF-kappa B,Wnt,and Hedgehog pathways and upregulated P53 pathway in tumors,which was in line with the inhibited tumor growth.Combined RFA and MLT treatment also reversed the Warburg effect and decreased tumor malignancy.These findings thus demonstrated that combined treatment of RFA and MLT effectively inhibited the malignancy of non-ablated nodules and provided an innovative non-invasive strategy for treating early lung tumors with multiple pulmonary nodules.Trial registration:www.chictr.org.cn,identifier ChiCTR2100042695,http://www.chictr.org.cn/showproj.aspx?proj=120931.展开更多
Cyclin-dependent kinases 4 and 6 inhibitors(CDK4/6i)have been demonstrated to trigger antitumor immunity for tumor regression.However,the therapeutic performance of CDK4/6i-meadiated cancer immunotherapy was impaired ...Cyclin-dependent kinases 4 and 6 inhibitors(CDK4/6i)have been demonstrated to trigger antitumor immunity for tumor regression.However,the therapeutic performance of CDK4/6i-meadiated cancer immunotherapy was impaired by the immunosuppressive tumor microenvironment(ITM)due to overexpression of programmed death ligand 1(PD-L1)on the surface of cancer cell membrane.To improve the immunotherapeutic performance of CDK4/6i,we herein developed endosomal acidactivatable micelleplex for si RNA delivery and PD-L1 knockdown in the tumor cells in vitro and in vivo.We further demonstrated that the combination of PD-L1 knockdown and CDK4/6 inhibition facilitated intratumoral infiltration of cytotoxic T lymphocytes(CTLs),and elicited protective immune response and efficiently suppressed tumor growth in vivo.This study revealed the importance of molecular design of the micelleplex for highly efficient si RNA delivery,which might provide a novel insight for RNAi-based cancer immunotherapy.展开更多
The majority of hepatocellular carcinoma(HCC)cases are diagnosed at an advanced stage.Currently,there are only a few therapeutic methods available for patients with advanced HCC and extrahepatic metastasis(EHM).System...The majority of hepatocellular carcinoma(HCC)cases are diagnosed at an advanced stage.Currently,there are only a few therapeutic methods available for patients with advanced HCC and extrahepatic metastasis(EHM).Systemic chemotherapy,such as FOLFOX4(infusions of fluorouracil,leucovorin,and oxaliplatin),has been reported for treating advanced HCC with EHM,but its effectiveness is very poor.展开更多
To explore the role of forkhead box protein O1(FOXO1)in the progression of glioblastoma multiforme(GBM)and related drug resistance,we deciphered the roles of FOXO1 and miR-506 in proliferation,apoptosis,migration,inva...To explore the role of forkhead box protein O1(FOXO1)in the progression of glioblastoma multiforme(GBM)and related drug resistance,we deciphered the roles of FOXO1 and miR-506 in proliferation,apoptosis,migration,invasion,autophagy,and temozolomide(TMZ)sensitivity in the U251 cell line using in vitro and in vivo experiments.Cell viability was tested by a cell counting kit-8(CCK8)kit;migration and invasion were checked by the scratching assay;apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick-end labeling(TUNEL)staining and flow cytometry.The construction of plasmids and dual-luciferase reporter experiment were carried out to find the interaction site between FOXO1 and miR-506.Immunohistochemistry was done to check the protein level in tumors after the in vivo experiment.We found that the FOXO1-miR-506 axis suppresses GBM cell invasion and migration and promotes GBM chemosensitivity to TMZ,which was mediated by autophagy.FOXO1 upregulates miR-506 by binding to its promoter to enhance transcriptional activation.MiR-506 could downregulate E26 transformation-specific 1(ETS1)expression by targeting its 3'-untranslated region(UTR).Interestingly,ETS1 promoted FOXO1 translocation from the nucleus to the cytosol and further suppressed the FOXO1-miR-506 axis in GBM cells.Consistently,both miR-506 inhibition and ETS1 overexpression could rescue FOXO1 overactivation-mediated TMZ chemosensitivity in mouse models.Our study demonstrated a negative feedback loop of FOXO1/miR-506/ETS1/FOXO1 in GBM in regulating invasiveness and chemosensitivity.Thus,the above axis might be a promising therapeutic target for GBM.展开更多
Objective:Although the neurological and olfactory symptoms of coronavirus disease 2019 have been identified,the neurotropic properties of the causative virus,severe acute respiratory syndrome-associated coronavirus 2(...Objective:Although the neurological and olfactory symptoms of coronavirus disease 2019 have been identified,the neurotropic properties of the causative virus,severe acute respiratory syndrome-associated coronavirus 2(SARS-CoV-2),remain unknown.We sought to identify the susceptible cell types and potential routes of SARS-CoV-2 entry into the central nervous system,olfactory system,and respiratory system.Methods:We collected single-cell RNA data from normal brain and nasal epithelium specimens,along with bronchial,tracheal,and lung specimens in public datasets.The susceptible cell types that express SARS-CoV-2 entry genes were identified using single-cell RNA sequencing and the expression of the key genes at protein levels was verified by immunohistochemistry.We compared the coexpression patterns of the entry receptor angiotensin-converting enzyme 2(ACE2)and the spike protein priming enzyme transmembrane serine protease(TMPRSS)/cathepsin L among the specimens.Results:The SARS-CoV-2 entry receptor ACE2 and the spike protein priming enzyme TMPRSS/cathepsin L were coexpressed by pericytes in brain tissue;this coexpression was confirmed by immunohistochemistry.In the nasal epithelium,ciliated cells and sustentacular cells exhibited strong coexpression of ACE2 and TMPRSS.Neurons and glia in the brain and nasal epithelium did not exhibit coexpression of ACE2 and TMPRSS.However,coexpression was present in ciliated cells,vascular smooth muscle cells,and fibroblasts in tracheal tissue;ciliated cells and goblet cells in bronchial tissue;and alveolar epithelium type 1 cells,AT2 cells,and ciliated cells in lung tissue.Conclusion:Neurological symptoms in patients with coronavirus disease 2019 could be associated with SARS-CoV-2 invasion across the blood-brain barrier via pericytes.Additionally,SARS-CoV-2-induced olfactory disorders could be the result of localized cell damage in the nasal epithelium.展开更多
Ubiquitination,an important type of protein posttranslational modification(PTM),plays a crucial role in controlling substrate degradation and subsequently mediates the“quantity”and“quality”of various proteins,serv...Ubiquitination,an important type of protein posttranslational modification(PTM),plays a crucial role in controlling substrate degradation and subsequently mediates the“quantity”and“quality”of various proteins,serving to ensure cell homeostasis and guarantee life activities.The regulation of ubiquitination is multifaceted and works not only at the transcriptional and posttranslational levels(phosphorylation,acetylation,methylation,etc.)but also at the protein level(activators or repressors).When regulatory mechanisms are aberrant,the altered biological processes may subsequently induce serious human diseases,especially various types of cancer.In tumorigenesis,the altered biological processes involve tumor metabolism,the immunological tumor microenvironment(TME),cancer stem cell(CSC)stemness and so on.With regard to tumor metabolism,the ubiquitination of some key proteins such as RagA,mTOR,PTEN,AKT,c-Myc and P53 significantly regulates the activity of the mTORC1,AMPK and PTEN-AKT signaling pathways.In addition,ubiquitination in the TLR,RLR and STING-dependent signaling pathways also modulates the TME.Moreover,the ubiquitination of core stem cell regulator triplets(Nanog,Oct4 and Sox2)and members of the Wnt and Hippo-YAP signaling pathways participates in the maintenance of CSC stemness.Based on the altered components,including the proteasome,E3 ligases,E1,E2 and deubiquitinases(DUBs),many molecular targeted drugs have been developed to combat cancer.Among them,small molecule inhibitors targeting the proteasome,such as bortezomib,carfilzomib,oprozomib and ixazomib,have achieved tangible success.In addition,MLN7243 and MLN4924(targeting the E1 enzyme),Leucettamol A and CC0651(targeting the E2 enzyme),nutlin and MI‐219(targeting the E3 enzyme),and compounds G5 and F6(targeting DUB activity)have also shown potential in preclinical cancer treatment.In this review,we summarize the latest progress in understanding the substrates for ubiquitination and their special functions in tumor metabolism regulation,TME modulation and CSC stemness maintenance.Moreover,potential therapeutic targets for cancer are reviewed,as are the therapeutic effects of targeted drugs.展开更多
Nutriments have been deemed to impact all physiopathologic processes.Recent evidences in molecular medicine and clinical trials have demonstrated that adequate nutrition treatments are the golden criterion for extendi...Nutriments have been deemed to impact all physiopathologic processes.Recent evidences in molecular medicine and clinical trials have demonstrated that adequate nutrition treatments are the golden criterion for extending healthspan and delaying ageing in various species such as yeast,drosophila,rodent,primate and human.It emerges to develop the precision-nutrition therapeutics to slow age-related biological processes and treat diverse diseases.However,the nutritive advantages frequently diversify among individuals as well as organs and tissues,which brings challenges in this field.In this review,we summarize the different forms of dietary interventions extensively prescribed for healthspan improvement and disease treatment in pre-clinical or clinical.We discuss the nutrient-mediated mechanisms including metabolic regulators,nutritive metabolism pathways,epigenetic mechanisms and circadian clocks.Comparably,we describe diet-responsive effectors by which dietary interventions influence the endocrinic,immunological,microbial and neural states responsible for improving health and preventing multiple diseases in humans.Furthermore,we expatiate diverse patterns of dietotheroapies,including different fasting,calorie-restricted diet,ketogenic diet,high-fibre diet,plants-based diet,protein restriction diet or diet with specific reduction in amino acids or microelements,potentially affecting the health and morbid states.Altogether,we emphasize the profound nutritional therapy,and highlight the crosstalk among explored mechanisms and critical factors to develop individualized therapeutic approaches and predictors.展开更多
Receptor-interacting protein(RIP)kinase 1 is involved in immune-mediated inflammatory diseases including ulcerative colitis(UC)by regulating necroptosis and inflammation.Our group previously identified TAK-632(5)as an...Receptor-interacting protein(RIP)kinase 1 is involved in immune-mediated inflammatory diseases including ulcerative colitis(UC)by regulating necroptosis and inflammation.Our group previously identified TAK-632(5)as an effective necroptosis inhibitor by dual-targeting RIP1 and RIP3.In this study,using ligand-based substituent-anchoring design strategy,we focused on the benzothiazole ring to obtain a series of TAK-632 analogues showing significantly improving on the anti-necroptosis activity and RIP1 selectivity over RIP3.Among them,a conformational constrained fluorine-substituted derivative(25)exhibited 333-fold selectivity for RIP1(K_(d)= 15 nmol/L)than RIP3(K_(d)>5000 nmol/L).This compound showed highly potent activity against cell necroptosis(EC_(50)=8 nmol/L)and systemic inflammatory response syndrome(SIRS)induced by TNF-α in vivo.Especially,it was able to exhibit remarkable anti-inflammatory treatment efficacy in a DSS-induced mouse model of UC.Taken together,the highly potent,selective,orally active anti-necroptosis inhibitor represents promising candidate for clinical treatment of UC.展开更多
Dear Editor,The ongoing outbreak of pneumonia(coronavirus disease 2019,COVID-19)caused by severe acute respiratory syndrome coronavirus-2(SARS-CoV-2)has become a global health emergency.Scutellaria Baicalensis Georgi ...Dear Editor,The ongoing outbreak of pneumonia(coronavirus disease 2019,COVID-19)caused by severe acute respiratory syndrome coronavirus-2(SARS-CoV-2)has become a global health emergency.Scutellaria Baicalensis Georgi extract,a Traditional Chinese Medicine(TCM)widely used for treating infection of multiple different viruses,1 also shows beneficial effects when treating COVID-19.However,underline mechanism for broad antiviral activity of Scutellaria B.extract remains elusive,which limits its further application.展开更多
Dear Editor,Programmed death ligand-1(PD-L1)is a type 1 transmembrane protein and highly expressed in various cancers that binds to PD-1 on T cells,inhibits T cell activity and proliferation,facilitates cancer cells t...Dear Editor,Programmed death ligand-1(PD-L1)is a type 1 transmembrane protein and highly expressed in various cancers that binds to PD-1 on T cells,inhibits T cell activity and proliferation,facilitates cancer cells to escape T cell-mediated immune surveillance.Immunotherapies by PD-L1/PD-1 blockade have shown effectiveness against different cancer types and revolutionizes cancer treatment in the clinic.However,the response rate to anti-PD-L1/PD-1 antibody remains at about 15-30%as a single agent.1 Thus,there is more to understand regarding the function of PD-L1 in cancer.展开更多
基金the National Key Research and Development Program of China(Grant Nos.2022YFC3401500 and 2020YFA0803201 to P.W.,and 2021YFA1302200 to L.F.)the National Natural Science Foundation of China(Grant Nos.31830053,31920103007,and 82341028 to P.W.+1 种基金82122056,82073153,and 31871398 to L.F.and 31900568 to P.W.)the Natural Science Foundation of Shanghai(Grant No.22ZR1450700 to Z.J.W.)。
文摘The intricate interplay between the human immune system and cancer development underscores the central role of immunotherapy in cancer treatment.Within this landscape,the innate immune system,a critical sentinel protecting against tumor incursion,is a key player.The cyclic GMP-AMP synthase(c GAS)and stimulator of interferon genes(STING)pathway has been found to be a linchpin of innate immunity:activation of this signaling pathway orchestrates the production of type I interferon(IFN-α/β),thus fostering the maturation,differentiation,and mobilization of immune effectors in the tumor microenvironment.Furthermore,STING activation facilitates the release and presentation of tumor antigens,and therefore is an attractive target for cancer immunotherapy.Current strategies to activate the STING pathway,including use of pharmacological agonists,have made substantial advancements,particularly when combined with immune checkpoint inhibitors.These approaches have shown promise in preclinical and clinical settings,by enhancing patient survival rates.This review describes the evolving understanding of the c GAS-STING pathway's involvement in tumor biology and therapy.Moreover,this review explores classical and non-classical STING agonists,providing insights into their mechanisms of action and potential for optimizing immunotherapy strategies.Despite challenges and complexities,the c GAS-STING pathway,a promising avenue for enhancing cancer treatment efficacy,has the potential to revolutionize patient outcomes.
基金supported by the National Key R&D Program of China(Grant No.2020YFA0803200 and 2023YFC2505903)National Natural Science Foundation of China(Grant Nos.82003014,31930026,81972876,82150112,92168116,81725014,81822035,and 82222052)+1 种基金China Postdoctoral Science Foundation(Grant No.2020M671231)Fundamental Research Funds for the Central Universities(Grant No.22120240327)。
文摘Gastric cancer(GC)is a major cause of cancer-related mortality worldwide.GC is determined by multiple(epi)genetic and environmental factors;can occur at distinct anatomic positions of the stomach;and displays high heterogeneity,with different cellular origins and diverse histological and molecular features.This heterogeneity has hindered efforts to fully understand the pathology of GC and develop efficient therapeutics.In the past decade,great progress has been made in the study of GC,particularly in molecular subtyping,investigation of the immune microenvironment,and defining the evolutionary path and dynamics.Preclinical mouse models,particularly immunocompetent models that mimic the cellular and molecular features of human GC,in combination with organoid culture and clinical studies,have provided powerful tools for elucidating the molecular and cellular mechanisms underlying GC pathology and immune evasion,and the development of novel therapeutic strategies.Herein,we first briefly introduce current progress and challenges in GC study and subsequently summarize immunocompetent GC mouse models,emphasizing the potential application of genetically engineered mouse models in antitumor immunity and immunotherapy studies.
基金supported by the Fundamental Research Funds for the Central Universities(2042021kf0102,2042021kf0083)supported by two National Natural Science Foundation of China(NSFC)Grants(81903166,82203629)+1 种基金a Natural Science Foundation of Hubei(2018CKB916)sponsored by Shanghai Pujiang Program(22PJD054).
文摘Obesity is one of the most serious global health problems,with an incidence that increases yearly and coincides with the development of cancer.Adipose tissue macrophages(ATMs)are particularly important in this context and contribute to linking obesity-related inflammation and tumor progression.However,the functions of ATMs on the progression of obesity-associated cancer remain unclear.In this review,we describe the origins,phenotypes,and functions of ATMs.Subsequently,we summarize the potential mechanisms on the reprogramming of ATMs in the obesity-associated microenvironment,including the direct exchange of dysfunctional metabolites,inordinate cytokines and other signaling mediators,transfer of extracellular vesicle cargo,and variations in the gut microbiota and its metabolites.A better understanding of the properties and functions of ATMs under conditions of obesity will lead to the development of new therapeutic interventions for obesity-related cancer.
基金Wencheng Wu and Yinying Pu contributed equally to this work.We greatly acknowledge the financial support from CAMS Innovation Fund for Medical Sciences(No.2021-I2M-5-012)National Natural Science Foundation of China(No.21835007)+2 种基金Key Research Program of Frontier Sciences,Chinese Academy of Sciences(No.ZDBS-LY-SLH029)Basic Research Program of Shanghai Municipal Government(No.21JC1406000)China National Postdoctoral Program for Innovative Talents(No.BX20220318).
文摘The low immunogenicity of tumors remains one of the major limitations of cancer immunotherapy.Herein,we report a bacterial metabolisminitiated and photothermal-enhanced nanocatalytic therapy strategy to completely eradicate primary tumor by triggering highly effective antitumor immune responses.Briefly,a microbiotic nanomedicine,designated as Cu_(2)O@ΔSt,has been constructed by conjugating PEGylated Cu_(2)O nanoparticles on the surface of an engineered Salmonella typhimurium strain(ΔSt).Owing to the natural hypoxia tropism ofΔSt,Cu_(2)O@ΔSt could selectively colonize hypoxic solid tumors,thus minimizing the adverse effects of the bacteria on normal tis-sues.Upon bacterial metabolism within the tumor,Cu_(2)O@ΔSt generates H_(2)S gas and other acidic substances in the tumor microenvironment(TME),which will in situ trigger the sulfidation of Cu_(2)O to form CuS facilitating tumor-specific photothermal therapy(PTT)under local NIR laser irradiation on the one hand.Meanwhile,the dissolved Cu+ions from Cu_(2)O into the acidified TME enables the nanocatalytic tumor therapy by catalyzing the Fenton-like reaction of decom-posing endogenous H_(2)O_(2) into cytotoxic hydroxyl radicals(·OH)on the other hand.Such a bacterial metabolism-triggered PTT-enhanced nanocatalytic treatment could effectively destroy tumor cells and induce a massive release of tumor antigens and damage-associated molecular patterns,thereby sensitizing tumors to checkpoint blockade(ICB)therapy.The combined nanocatalytic and ICB therapy results in the much-inhibited growth of distant and metastatic tumors,and more importantly,induces a powerful immunological memory effect after the primary tumor ablation.
基金the National Natural Science Foundation of China(Nos.31830053,31920103007,8207112072,82122056)the National Key Research and Development Program of China(2020YFA0803201)the Science Technology Commission of Shanghai Municipality(No.20S11900700).
文摘Cancer immunotherapy,mainly including immune checkpoints-targeted therapy and the adoptive transfer of engineered immune cells,has revolutionized the oncology landscape as it utilizes patients’own immune systems in combating the cancer cells.Cancer cells escape immune surveillance by hijacking the corresponding inhibitory pathways via overexpressing checkpoint genes.Phagocytosis checkpoints,such as CD47,CD24,MHC-I,PD-L1,STC-1 and GD2,have emerged as essential checkpoints for cancer immunotherapy by functioning as“don’t eat me”signals or interacting with“eat me”signals to suppress immune responses.Phagocytosis checkpoints link innate immunity and adaptive immunity in cancer immunotherapy.Genetic ablation of these phagocytosis checkpoints,as well as blockade of their signaling pathways,robustly augments phagocytosis and reduces tumor size.Among all phagocytosis checkpoints,CD47 is the most thoroughly studied and has emerged as a rising star among targets for cancer treatment.CD47-targeting antibodies and inhibitors have been investigated in various preclinical and clinical trials.However,anemia and thrombocytopenia appear to be formidable challenges since CD47 is ubiquitously expressed on erythrocytes.Here,we review the reported phagocytosis checkpoints by discussing their mechanisms and functions in cancer immunotherapy,highlight clinical progress in targeting these checkpoints and discuss challenges and potential solutions to smooth the way for combination immunotherapeutic strategies that involve both innate and adaptive immune responses.
基金supported by the National Key R&D Program ofChina(Nos.2020YFA0803200,2017YFA0504504,and 2018YFA0107500)National Natural Science Foundation of China Grants(Nos.82003014,82150112,81725014,92168116,31930026,81972599,82173276,81822035)+3 种基金the Key Program for Basic Research of Shanghai(No.19JC1415600)Shanghai Rising-Star Program(Nos.22QA1407200,22QA1407300)Open Research Fund of State Key Laboratory of Genetic Engineering,Fudan University(No.SKLGE2103)the China Postdoctoral Science Foundation(No.2020M671231).
文摘As an important part of tumor microenvironment,neutrophils are poorly understood due to their spatiotemporal heterogeneity in tumorigenesis.Here we defined,at single-cell resolution,CD44-CxCR2-neutrophils as tumor-specific neutrophils(tsNeus)in both mouse and human gastric cancer(GC).We uncovered a Hippo regulon in neutrophils with unique YAP signature genes(e.g.,ICAM1,CD14,EGR1)distinct from those identified in epithelial and/or cancer cells.Importantly,knockout of YAP/TAz in neutrophils impaired their differentiation into CD54+tsNeus and reduced their antitumor activity,leading to accelerated GC progression.Moreover,the relative amounts of CD54+tsNeus were found to be negatively associated with GC progression and positively associated with patient survival.Interestingly,GC patients receiving neoadjuvant chemotherapy had increased numbers of CD54+tsNeus.Furthermore,pharmacologically enhancing YAP activity selectively activated neutrophils to suppress refractory GC,with no significant inflammation-related side effects.Thus,our work characterized tumor-specific neutrophils in GC and revealed an essential role of YAP/TAZ-CD54 axis in tsNeus,opening a new possibility to develop neutrophil-based antitumor therapeutics.
基金supported by the National Key Research and Development Program of China(No.2020YFA0803201)the National Natural Science Foundation of China(No.31830053,31920103007,22207084)the Fundamental ResearchFunds fortheCornellUniversity(No.22120220463).
文摘The interaction between cluster of differentiation 47(CD47)and signal regulatory proteinα(SiRPa)protects healthy cells from macrophage attack,which is crucial for maintain-ing immune homeostasis.Overexpression of CD47 occurs widely across various tumor cell types and transmits the"don't eat me"signal to macrophages to avoid phagocytosis through binding to SIRPa.Blockade of the CD47-SIRPa axis is therefore a promising approach for cancer treat-ment.Lymphoma is the most common hematological malignancy and is an area of unmet clin-ical need.This review mainly described the current strategies targeting the CD47-SIRPa axis,including antibodies,SiRPaFc fusion proteins,small molecule inhibitors,and peptides both in preclinical studies and clinical trials with Hodgkin lymphoma and non-Hodgkin lymphoma.
基金was supported by grants from the National Natural Science Foundation of China(2220708,82341028,82103973)Shanghai Sailing Program(22YF1433500,22YF1457500)Key R&D Projects in Ningxia Hui Autonomous Region(2021BFH03001).
文摘Dear Editor,Immune checkpoint therapies manipulating the immune system to eliminate tumor cells have shown remarkable clinical efficacy in treating various cancers.CD47,an emerging efficient immune checkpoint,is crucial for cancer cells to evade macrophagemediated phagocytosis by interaction with signal-regulatory proteinα(SIRPα).Antibodies blocking the CD47/SIRPαinteraction have been effective to promote macrophage-mediated phagocytosis in various types of cancer in mice and humans.CD47 is not only highly expressed in tumor cells,but also normal cells,such as red blood cells(RBCs).Thus,during clinical trials involving cancer patients,anti-CD47 antibodies may promote the macrophagesmediated phagocytosis of RBCs,ultimately inducing undesirable anemia side effects.In contrast,small molecule inhibitors interrupting CD47/SIRPαaxis have shown potential to overcome the anemia,possibly due to their lower immunogenicity and shorter half-life compared to antibodies.1 Hence,developing the novel strategies,especially those without the anemia side effect,to intervene in CD47/SIRPαinteraction will benefit cancer immunotherapy.
基金National Natural Science Foundation of China(No.82073293)Clinical Science and Technology Innovation Project of Shanghai Shenkang Hospital Development Center(Joint Project of Emerging Frontier Technology)(SHDC12018116)the Key Project of Natural Science Foundation of China(No:81730097)。
文摘Background:Chemotherapy is a common treatment for advanced hepatocellular carcinoma,but the effect is not satisfactory.The study aimed to retrospectively evaluate the effects of adding all-trans-retinoic acid(ATRA)to infusional fluorouracil,leucovorin,and oxaliplatin(FOLFOX4)for advanced hepatocellular carcinoma(HCC).Methods:We extracted the data of patients with advanced HCC who underwent systemic chemotherapy using FOLFOX4 or ATRA plus FOLFOX4 at the Eastern Hepatobiliary Surgery Hospital,First Hospital of Jilin University,and Zhejiang Sian International Hospital and retrospectively compared for overall survival.The Cox proportional hazards model was used to calculate the hazard ratios for overall survival and disease progression after controlling for age,sex,and disease stage.Results:From July 2013 to July 2018,111 patients with HCC were included in this study.The median survival duration was 14.8 months in the ATRA plus FOLFOX4 group and 8.2 months in the FOLFOX4 only group(P<0.001).The ATRA plus FOLFOX4 group had a significantly longer median time to progression compared with the FOLFOX4 group(3.6 monthsvs.1.8 months,P<0.001).Hazard ratios for overall survival and disease progression were 0.465(95%confidence interval:0.298–0.726;P=0.001)and 0.474(0.314–0.717;P<0.001)after adjusting for potential confounders,respectively.Conclusion:ATRA plus FOLFOX4 significantly improves the overall survival and time to disease progression in patients with advanced HCC.
基金supported by the National Natural Science Foundation of China(Nos.31770131,81473469)International Cooperation Project of the Belt and Road(No.20400750600)+1 种基金Shanghai Shen Kang Hospital Development Center Plan(SHDC12018119)Shanghai Municipal Commission of Health and Family Plan(201840056).
文摘Surgery is the comm on treatme nt for early lung cancer with multiple pulm onary no dules,but it is often accompanied by the problem of significant malignancy of other nodules in non-therapeutic areas.In this study,we found that a combined treatment of local rad iofreq ue ncy ablati on(RFA)and melatonin(MLT)greatly improved clinical outcomes for early lung cancer patie nts with multiple pulmonary nodules by minimizing lung function injury and reducing the probability of malignant transformation or enlargement of nodules in non-ablated areas.Mechanically,as demonstrated in an associated mouse lung tumor model,RFA not only effectively remove treated tumors but also stimulate antitumor immunity,which could inhibit tumor growth in non-ablated areas.MLT enhanced RFA-stimulated NK activity and exerted synergistic antitumor effects with RFA.Transcriptomics and proteomics analyses of residual tumor tissues revealed enhanced oxidative phosphorylation and reduced acidification as well as hypoxia in the tumor microenvironment,which suggests reprogrammed tumor metabolism after combined treatment with RFA and MLT.Analysis of residual tumor further revealed the depressed activity of MAPK,NF-kappa B,Wnt,and Hedgehog pathways and upregulated P53 pathway in tumors,which was in line with the inhibited tumor growth.Combined RFA and MLT treatment also reversed the Warburg effect and decreased tumor malignancy.These findings thus demonstrated that combined treatment of RFA and MLT effectively inhibited the malignancy of non-ablated nodules and provided an innovative non-invasive strategy for treating early lung tumors with multiple pulmonary nodules.Trial registration:www.chictr.org.cn,identifier ChiCTR2100042695,http://www.chictr.org.cn/showproj.aspx?proj=120931.
基金financially supported by the National Natural Science Foundation of China(Nos.51873228 and 31671024)Basic Research Program of Shenzhen(No.JCYJ20180227175420974)+1 种基金Science and Technology Development Fund,Macao SAR(No.083/2017/A2)Open Research Fund of State Key Laboratory of Polymer Physics and Chemistry,Changchun Institute of Applied Chemistry,Chinese Academy of Sciences。
文摘Cyclin-dependent kinases 4 and 6 inhibitors(CDK4/6i)have been demonstrated to trigger antitumor immunity for tumor regression.However,the therapeutic performance of CDK4/6i-meadiated cancer immunotherapy was impaired by the immunosuppressive tumor microenvironment(ITM)due to overexpression of programmed death ligand 1(PD-L1)on the surface of cancer cell membrane.To improve the immunotherapeutic performance of CDK4/6i,we herein developed endosomal acidactivatable micelleplex for si RNA delivery and PD-L1 knockdown in the tumor cells in vitro and in vivo.We further demonstrated that the combination of PD-L1 knockdown and CDK4/6 inhibition facilitated intratumoral infiltration of cytotoxic T lymphocytes(CTLs),and elicited protective immune response and efficiently suppressed tumor growth in vivo.This study revealed the importance of molecular design of the micelleplex for highly efficient si RNA delivery,which might provide a novel insight for RNAi-based cancer immunotherapy.
基金supported by the National Natural Science Foundation of China(81571693,82171950,81871361,82271997,and 82003182)the National Science Foundation for Young Scientists of China(82102085)+4 种基金UNSW-CAS Collaborative Research Seed Program(GJHZ2072)Shanghai Science and Technology Program(21010500100,22140901700,22DZ2204700,and 22142202200)Basic Research Program of Shanghai Municipal Government(21JC1406002)Shanghai Municipal Health Commission(202140250)Pudong Health Bureau of Shanghai(PWRl201806)。
基金The authors thank all the patients and their families.We would like to acknowledge Dr.Yuchao Zhang from the Shanghai Institute of Nutrition and Health,Chinese Academy of Sciences for his suggestions in the analysis of the proteomics data of this study.This work is supported by the National Natural Science Foundation of China(no:82073293)the National Key R&D Program of China(no:2022YFC2503700)+3 种基金the State Key Project of Natural Science Foundation of China(no:81730097)Shanghai Top Priority Research Center Project(no.2023Zz02005)the Clinical Science and Technology Innovation Project of Shanghai Shenkang Hospital Development Center(Joint Project of Emerging Frontier Technology)(no.SHDC12018116)the Clinical Research Plan of Shanghai Hospital Development Center(no.SHDC2020CR1004A).
文摘The majority of hepatocellular carcinoma(HCC)cases are diagnosed at an advanced stage.Currently,there are only a few therapeutic methods available for patients with advanced HCC and extrahepatic metastasis(EHM).Systemic chemotherapy,such as FOLFOX4(infusions of fluorouracil,leucovorin,and oxaliplatin),has been reported for treating advanced HCC with EHM,but its effectiveness is very poor.
基金supported by the National Natural Science Foundation of China(Nos.81402076,81872072,and 82073274)the Science Technology Commission of Shanghai Municipality(No.20S11900700)。
文摘To explore the role of forkhead box protein O1(FOXO1)in the progression of glioblastoma multiforme(GBM)and related drug resistance,we deciphered the roles of FOXO1 and miR-506 in proliferation,apoptosis,migration,invasion,autophagy,and temozolomide(TMZ)sensitivity in the U251 cell line using in vitro and in vivo experiments.Cell viability was tested by a cell counting kit-8(CCK8)kit;migration and invasion were checked by the scratching assay;apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick-end labeling(TUNEL)staining and flow cytometry.The construction of plasmids and dual-luciferase reporter experiment were carried out to find the interaction site between FOXO1 and miR-506.Immunohistochemistry was done to check the protein level in tumors after the in vivo experiment.We found that the FOXO1-miR-506 axis suppresses GBM cell invasion and migration and promotes GBM chemosensitivity to TMZ,which was mediated by autophagy.FOXO1 upregulates miR-506 by binding to its promoter to enhance transcriptional activation.MiR-506 could downregulate E26 transformation-specific 1(ETS1)expression by targeting its 3'-untranslated region(UTR).Interestingly,ETS1 promoted FOXO1 translocation from the nucleus to the cytosol and further suppressed the FOXO1-miR-506 axis in GBM cells.Consistently,both miR-506 inhibition and ETS1 overexpression could rescue FOXO1 overactivation-mediated TMZ chemosensitivity in mouse models.Our study demonstrated a negative feedback loop of FOXO1/miR-506/ETS1/FOXO1 in GBM in regulating invasiveness and chemosensitivity.Thus,the above axis might be a promising therapeutic target for GBM.
基金supported by the National Natural Ascience Foundation of China(No.31821003 to HX)the China Ministry of Science and Technology(No.2018AAA0100300 to HX).
文摘Objective:Although the neurological and olfactory symptoms of coronavirus disease 2019 have been identified,the neurotropic properties of the causative virus,severe acute respiratory syndrome-associated coronavirus 2(SARS-CoV-2),remain unknown.We sought to identify the susceptible cell types and potential routes of SARS-CoV-2 entry into the central nervous system,olfactory system,and respiratory system.Methods:We collected single-cell RNA data from normal brain and nasal epithelium specimens,along with bronchial,tracheal,and lung specimens in public datasets.The susceptible cell types that express SARS-CoV-2 entry genes were identified using single-cell RNA sequencing and the expression of the key genes at protein levels was verified by immunohistochemistry.We compared the coexpression patterns of the entry receptor angiotensin-converting enzyme 2(ACE2)and the spike protein priming enzyme transmembrane serine protease(TMPRSS)/cathepsin L among the specimens.Results:The SARS-CoV-2 entry receptor ACE2 and the spike protein priming enzyme TMPRSS/cathepsin L were coexpressed by pericytes in brain tissue;this coexpression was confirmed by immunohistochemistry.In the nasal epithelium,ciliated cells and sustentacular cells exhibited strong coexpression of ACE2 and TMPRSS.Neurons and glia in the brain and nasal epithelium did not exhibit coexpression of ACE2 and TMPRSS.However,coexpression was present in ciliated cells,vascular smooth muscle cells,and fibroblasts in tracheal tissue;ciliated cells and goblet cells in bronchial tissue;and alveolar epithelium type 1 cells,AT2 cells,and ciliated cells in lung tissue.Conclusion:Neurological symptoms in patients with coronavirus disease 2019 could be associated with SARS-CoV-2 invasion across the blood-brain barrier via pericytes.Additionally,SARS-CoV-2-induced olfactory disorders could be the result of localized cell damage in the nasal epithelium.
基金supported by grants from the National Natural Science Foundation of China(Nos.31801177,81702659,31830053,31920103007,81625019)the Science Technology Commission of Shanghai Municipality(No.18410722000)+1 种基金the Shanghai Sailing Program(No.18YF1419500)the Fundamental Research Funds for the Central Universities(No.22120180043).
文摘Ubiquitination,an important type of protein posttranslational modification(PTM),plays a crucial role in controlling substrate degradation and subsequently mediates the“quantity”and“quality”of various proteins,serving to ensure cell homeostasis and guarantee life activities.The regulation of ubiquitination is multifaceted and works not only at the transcriptional and posttranslational levels(phosphorylation,acetylation,methylation,etc.)but also at the protein level(activators or repressors).When regulatory mechanisms are aberrant,the altered biological processes may subsequently induce serious human diseases,especially various types of cancer.In tumorigenesis,the altered biological processes involve tumor metabolism,the immunological tumor microenvironment(TME),cancer stem cell(CSC)stemness and so on.With regard to tumor metabolism,the ubiquitination of some key proteins such as RagA,mTOR,PTEN,AKT,c-Myc and P53 significantly regulates the activity of the mTORC1,AMPK and PTEN-AKT signaling pathways.In addition,ubiquitination in the TLR,RLR and STING-dependent signaling pathways also modulates the TME.Moreover,the ubiquitination of core stem cell regulator triplets(Nanog,Oct4 and Sox2)and members of the Wnt and Hippo-YAP signaling pathways participates in the maintenance of CSC stemness.Based on the altered components,including the proteasome,E3 ligases,E1,E2 and deubiquitinases(DUBs),many molecular targeted drugs have been developed to combat cancer.Among them,small molecule inhibitors targeting the proteasome,such as bortezomib,carfilzomib,oprozomib and ixazomib,have achieved tangible success.In addition,MLN7243 and MLN4924(targeting the E1 enzyme),Leucettamol A and CC0651(targeting the E2 enzyme),nutlin and MI‐219(targeting the E3 enzyme),and compounds G5 and F6(targeting DUB activity)have also shown potential in preclinical cancer treatment.In this review,we summarize the latest progress in understanding the substrates for ubiquitination and their special functions in tumor metabolism regulation,TME modulation and CSC stemness maintenance.Moreover,potential therapeutic targets for cancer are reviewed,as are the therapeutic effects of targeted drugs.
基金supported by the National Key Research and Development Program of China(2020YFA0803201)the Grants from the National Natural Science Foundation of China(31830053,31920103007)to Prof.Ping Wang.
文摘Nutriments have been deemed to impact all physiopathologic processes.Recent evidences in molecular medicine and clinical trials have demonstrated that adequate nutrition treatments are the golden criterion for extending healthspan and delaying ageing in various species such as yeast,drosophila,rodent,primate and human.It emerges to develop the precision-nutrition therapeutics to slow age-related biological processes and treat diverse diseases.However,the nutritive advantages frequently diversify among individuals as well as organs and tissues,which brings challenges in this field.In this review,we summarize the different forms of dietary interventions extensively prescribed for healthspan improvement and disease treatment in pre-clinical or clinical.We discuss the nutrient-mediated mechanisms including metabolic regulators,nutritive metabolism pathways,epigenetic mechanisms and circadian clocks.Comparably,we describe diet-responsive effectors by which dietary interventions influence the endocrinic,immunological,microbial and neural states responsible for improving health and preventing multiple diseases in humans.Furthermore,we expatiate diverse patterns of dietotheroapies,including different fasting,calorie-restricted diet,ketogenic diet,high-fibre diet,plants-based diet,protein restriction diet or diet with specific reduction in amino acids or microelements,potentially affecting the health and morbid states.Altogether,we emphasize the profound nutritional therapy,and highlight the crosstalk among explored mechanisms and critical factors to develop individualized therapeutic approaches and predictors.
基金funded by grants from the National Natural Science Foundation of China(82022065,81872791,81872880,82073696,and U20A20136)the Sanhang Program of Second Military Medical Universitythe Key Research and Development Program of Ningxia(2019BFG02017,China)。
文摘Receptor-interacting protein(RIP)kinase 1 is involved in immune-mediated inflammatory diseases including ulcerative colitis(UC)by regulating necroptosis and inflammation.Our group previously identified TAK-632(5)as an effective necroptosis inhibitor by dual-targeting RIP1 and RIP3.In this study,using ligand-based substituent-anchoring design strategy,we focused on the benzothiazole ring to obtain a series of TAK-632 analogues showing significantly improving on the anti-necroptosis activity and RIP1 selectivity over RIP3.Among them,a conformational constrained fluorine-substituted derivative(25)exhibited 333-fold selectivity for RIP1(K_(d)= 15 nmol/L)than RIP3(K_(d)>5000 nmol/L).This compound showed highly potent activity against cell necroptosis(EC_(50)=8 nmol/L)and systemic inflammatory response syndrome(SIRS)induced by TNF-α in vivo.Especially,it was able to exhibit remarkable anti-inflammatory treatment efficacy in a DSS-induced mouse model of UC.Taken together,the highly potent,selective,orally active anti-necroptosis inhibitor represents promising candidate for clinical treatment of UC.
基金supported by fundings from National Natural Science Foundation of China(8207112072)the Science Technology Commission of Shanghai Municipality(20S11900700 and 20400750600).
文摘Dear Editor,The ongoing outbreak of pneumonia(coronavirus disease 2019,COVID-19)caused by severe acute respiratory syndrome coronavirus-2(SARS-CoV-2)has become a global health emergency.Scutellaria Baicalensis Georgi extract,a Traditional Chinese Medicine(TCM)widely used for treating infection of multiple different viruses,1 also shows beneficial effects when treating COVID-19.However,underline mechanism for broad antiviral activity of Scutellaria B.extract remains elusive,which limits its further application.
文摘Dear Editor,Programmed death ligand-1(PD-L1)is a type 1 transmembrane protein and highly expressed in various cancers that binds to PD-1 on T cells,inhibits T cell activity and proliferation,facilitates cancer cells to escape T cell-mediated immune surveillance.Immunotherapies by PD-L1/PD-1 blockade have shown effectiveness against different cancer types and revolutionizes cancer treatment in the clinic.However,the response rate to anti-PD-L1/PD-1 antibody remains at about 15-30%as a single agent.1 Thus,there is more to understand regarding the function of PD-L1 in cancer.
