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信号转导与靶向治疗（英文）
信号转导与靶向治疗（英文）
信号转导与靶向治疗（英文）/Journal Signal Transduction and Targeted TherapyCSTPCDSCI
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    Development of pharmacological immunoregulatory anti-cancer therapeutics:current mechanistic studies and clinical opportunities

    Nanhao YinXintong LiXuanwei ZhangShaolong Xue...
    2477-2526页
    查看更多>>摘要：Immunotherapy represented by anti-PD-(L)1 and anti-CTLA-4 inhibitors has revolutionized cancer treatment,but challenges related to resistance and toxicity still remain.Due to the advancement of immuno-oncology,an increasing number of novel immunoregulatory targets and mechanisms are being revealed,with relevant therapies promising to improve clinical immunotherapy in the foreseeable future.Therefore,comprehending the larger picture is important.in this review,we analyze and summarize the current landscape of preclinical and translational mechanistic research,drug development,and clinical trials that brought about next-generation pharmacological immunoregulatory anti-cancer agents and drug candidates beyond classical immune checkpoint inhibitors.Along with further clarification of cancer immunobiology and advances in antibody engineering,agents targeting additional inhibitory immune checkpoints,including LAG-3,TIM-3,TIGIT,CD47,and B7 family members are becoming an important part of cancer immunotherapy research and discovery,as are structurally and functionally optimized novel anti-PD-(L)1 and anti-CTLA-4 agents and agonists of co-stimulatory molecules of T cells.Exemplified by bispecific T cell engagers,newly emerging bi-specific and multi-specific antibodies targeting immunoregulatory molecules can provide considerable clinical benefits.Next-generation agents also include immune epigenetic drugs and cytokine-based therapeutics.Cell therapies,cancer vaccines,and oncolytic viruses are not covered in this review.This comprehensive review might aid in further development and the fastest possible clinical adoption of effective immuno-oncology modalities for the benefit of patients.
      原文链接:
    • NETL
    • NSTL
    • 万方数据

    Notch signaling pathway in cancer:from mechanistic insights to targeted therapies

    Qingmiao ShiChen XueYifan ZengXin Yuan...
    2527-2563页
    查看更多>>摘要：Notch signaling,renowned for its role in regulating cell fate,organ development,and tissue homeostasis across metazoans,is highly conserved throughout evolution.The Notch receptor and its ligands are transmembrane proteins containing epidermal growth factor-like repeat sequences,typically necessitating receptor-ligand interaction to initiate classical Notch signaling transduction.Accumulating evidence indicates that the Notch signaling pathway serves as both an oncogenic factor and a tumor suppressor in various cancer types.Dysregulation of this pathway promotes epithelial-mesenchymal transition and angiogenesis in malignancies,closely linked to cancer proliferation,invasion,and metastasis.Furthermore,the Notch signaling pathway contributes to maintaining stem-like properties in cancer cells,thereby enhancing cancer invasiveness.The regulatory role of the Notch signaling pathway in cancer metabolic reprogramming and the tumor microenvironment suggests its pivotal involvement in balancing oncogenic and tumor suppressive effects.Moreover,the Notch signaling pathway is implicated in conferring chemoresistance to tumor cells.Therefore,a comprehensive understanding of these biological processes is crucial for developing innovative therapeutic strategies targeting Notch signaling.This review focuses on the research progress of the Notch signaling pathway in cancers,providing in-depth insights into the potential mechanisms of Notch signaling regulation in the occurrence and progression of cancer.Additionally,the review summarizes pharmaceutical clinical trials targeting Notch signaling for cancer therapy,aiming to offer new insights into therapeutic strategies for human malignancies.
      原文链接:
    • NETL
    • NSTL
    • 万方数据

    Molecular insights of exercise therapy in disease prevention and treatment

    David WalzikTiffany Y.Wences ChirinoPhilipp ZimmerNiklas Joisten...
    2564-2597页
    查看更多>>摘要：Despite substantial evidence emphasizing the pleiotropic benefits of exercise for the prevention and treatment of various diseases,the underlying biological mechanisms have not been fully elucidated.Several exercise benefits have been attributed to signaling molecules that are released in response to exercise by different tissues such as skeletal muscle,cardiac muscle,adipose,and liver tissue.These signaling molecules,which are collectively termed exerkines,form a heterogenous group of bioactive substances,mediating inter-organ crosstalk as well as structural and functional tissue adaption.Numerous scientific endeavors have focused on identifying and characterizing new biological mediators with such properties.Additionally,some investigations have focused on the molecular targets of exerkines and the cellular signaling cascades that trigger adaption processes.A detailed understanding of the tissue-specific downstream effects of exerkines is crucial to harness the health-related benefits mediated by exercise and improve targeted exercise programs in health and disease.Herein,we review the current in vivo evidence on exerkine-induced signal transduction across multiple target tissues and highlight the preventive and therapeutic value of exerkine signaling in various diseases.By emphasizing different aspects of exerkine research,we provide a comprehensive overview of(i)the molecular underpinnings of exerkine secretion,(ii)the receptor-dependent and receptor-independent signaling cascades mediating tissue adaption,and(iii)the clinical implications of these mechanisms in disease prevention and treatment.
      原文链接:
    • NETL
    • NSTL
    • 万方数据

    Macrophages in cardiovascular diseases:molecular mechanisms and therapeutic targets

    Runkai ChenHongrui ZhangBotao TangYukun Luo...
    2598-2641页
    查看更多>>摘要：The immune response holds a pivotal role in cardiovascular disease development.As multifunctional cells of the innate immune system,macrophages play an essential role in initial inflammatory response that occurs following cardiovascular injury,thereby inducing subsequent damage while also facilitating recovery.Meanwhile,the diverse phenotypes and phenotypic alterations of macrophages strongly associate with distinct types and.severity of cardiovascular diseases,including coronary heart disease,valvular disease,myocarditis,cardiomyopathy,heart failure,atherosclerosis and aneurysm,which underscores the importance of investigating macrophage regulatory mechanisms within the context of specific diseases.Besides,recent strides in single-cell sequencing technologies have revealed macrophage heterogeneity,cell-cell interactions,and downstream mechanisms of therapeutic targets at a.higher resolution,which brings new perspectives into macrophage-mediated mechanisms and potential therapeutic targets in cardiovascular diseases.Remarkably,myocardial fibrosis,a prevalent characteristic in most cardiac diseases,remains a formidable clinical challenge,necessitating a profound investigation into the impact of macrophages on myocardial fibrosis within the context of cardiac diseases.In this review,we systematically summarize the diverse phenotypic and functional plasticity of macrophages in regulatory mechanisms of cardiovascular diseases and unprecedented insights introduced by single-cell sequencing technologies,with a focus on different causes and characteristics of diseases,especially the relationship between inflammation and fibrosis in cardiac diseases(myocardial infarction,pressure overload,myocarditis,dilated cardiomyopathy,diabetic cardiomyopathy and cardiac aging)and the relationship between inflammation and vascular injury in vascular diseases(atherosclerosis and aneurysm).Finally,we also highlight the preclinical/clinical macrophage targeting strategies and translational implications.
      原文链接:
    • NETL
    • NSTL
    • 万方数据

    Cholangiocarcinoma combined with biliary obstruction:an exosomal circRNA signature for diagnosis and early recurrence monitoring

    Ningyuan WenDingzhong PengXianze XiongGeng Liu...
    2642-2654页
    查看更多>>摘要：Cholangiocarcinoma(CCA)is a highly malignant biliary tract cancer with currently suboptimal diagnostic and prognostic approaches.We present a novel system to monitor CCA using exosomal circular RNA(circRNA)via serum and biliary liquid biopsies.A pilot cohort consisting of patients with CCA-induced biliary obstruction(CCA-BO,n=5)and benign biliary obstruction(BBO,n=5)was used to identify CCA-derived exosomal circRNAs through microarray analysis.This was followed by a discovery cohort(n=20)to further reveal a CCA-specific circRNA complex(hsa-circ-0000367,hsa-circ-0021647,and hsa-circ-0000288)in both bile and serum exosomes.In vitro and in vivo studies revealed the three circRNAs as promoters of CCA invasiveness.Diagnostic and prognostic models were established and verified by two independent cohorts(training cohort,n=184;validation cohort,n=105).An interpreter-free diagnostic model disclosed the diagnostic power of biliary exosomal circRNA signature(Bile-DS,AUROC=0.947,RR=6.05)and serum exosomal circRNA signature(Serum-DS,AUROC=0.861,RR=4.04)compared with conventional CA19-9(AUROC=0.759,RR=2.08).A prognostic model of CCA undergoing curative-intent surgery was established by calculating early recurrence score,verified with bile samples(Bile-ERS,C-index=0.783)and serum samples(Serum-ERS,C-index=0.782).These models,combined with other prognostic factors revealed by COX-PH model,enabled the establishment of nomograms for recurrence monitoring of CCA.Our study demonstrates that the exosomal triple-circRNA panel identified in both bile and serum samples serves as a novel diagnostic and prognostic tool for the clinical management of CCA.
      原文链接:
    • NETL
    • NSTL
    • 万方数据

    Combination therapy with oncolytic virus and T cells or mRNA vaccine amplifies antitumor effects

    Rao FuRuoyao QiHualong XiongXing Lei...
    2655-2668页
    查看更多>>摘要：Antitumor therapies based on adoptively transferred T cells or oncolytic viruses have made significant progress in recent years,but the limited efficiency of their infiltration into solid tumors makes it difficult to achieve desired antitumor effects when used alone.In this study,an oncolytic virus(rVSV-LCMVG)that is not prone to induce virus-neutralizing antibodies was designed and combined with adoptively transferred T cells.By transforming the immunosuppressive tumor microenvironment into an immunosensitive one,in B16 tumor-bearing mice,combination therapy showed superior antitumor effects than monotherapy.This occurred whether the OV was administered intratumorally or intravenously.Combination therapy significantly increased cytokine and chemokine levels within tumors and recruited CD8+T cells to the TME to trigger antitumor immune responses.Pretreatment with adoptively transferred T cells and subsequent oncolytic virotherapy sensitizes refractory tumors by boosting T-cell recruitment,down-regulating the expression of PD-1,and restoring effector T-cell function.To offer a combination therapy with greater translational value,mRNA vaccines were introduced to induce tumor-specific T cells instead of adoptively transferred T cells.The combination of OVs and mRNA vaccine also displays a significant reduction in tumor burden and prolonged survival.This study proposed a rational combination therapy of OVs with adoptive T-cell transfer or mRNA vaccines encoding tumor-associated antigens,in terms of synergistic efficacy and mechanism.
      原文链接:
    • NETL
    • NSTL
    • 万方数据

    Haploidentical hematopoietic cell transplantation with or without an unrelated cord blood unit for adult acute myeloid leukemia:a multicenter,randomized,open-label,phase 3 trial

    Biqi ZhouJia ChenTianhui LiuYishan Ye...
    2669-2678页
    查看更多>>摘要：Coinfusion of unrelated cord blood(UCB)units in haploidentical hematopoietic cell transplantation(haplo-HCT)(haplo-cord HCT)for hematopoietic malignancies showed promising results in previous reports,but the efficiency of haplo-cord HCT in acute myeloid leukemia(AML)still lacks sufficient evidence.This multicenter,randomized,phase 3 trial(ClinicalTrials.gov NCT03719534)aimed to assess the efficacy and safety of haplo-cord HCT in AML patients.A total of 268 eligible patients aged 18-60 years,diagnosed with measurable residual disease in AML(excluding acute promyelocytic leukemia),with available haploidentical donors and suitable for allotransplantation,were randomly allocated(1:1)to receive haplo-cord HCT(n=134)or haplo-HCT(n=134).The 3-year overall survival(OS)was the primary endpoint in this study.Overall median follow-up was 36.50 months(IQR 24.75-46.50).The 3-year OS of Haplo-cord HCT group was better than haplo-HCT group(80.5％,95％confidence interval[CI]:73.7-87.9 vs.67.8％95％CI 60.0-76.5,p=0.013).Favorable progression-free survival(70.3％,95％CI 62.6-78.8 vs.57.6％,95％CI 49.6-67.0,p=0.012)and cumulative incidence of relapse(12.1％,95％CI 12.0-12.2 vs.30.3％,95％CI 30.1-30.4,p=0.024)were observed in haplo-cord HCT group.Grade 3-4 adverse events(AEs)within two years posttransplantation in the two groups were similar.Haplo-cord HCT patients exhibited a faster cumulative incidence of neutrophil recovery(p=0.026)and increased T-cell reconstitution in the early period posttransplantation.Haplo-cord HCT can improve OS in AML patients without excessive AEs,which may exert additional benefits for recipients of haplo-HCT.
      原文链接:
    • NETL
    • NSTL
    • 万方数据

    A pathological joint-liver axis mediated by matrikine-activated CD4+T cells

    Junzhi YiHui ZhangFangyuan BaoZhichu Chen...
    2679-2693页
    查看更多>>摘要：The knee joint has long been considered a closed system.The pathological effects of joint diseases on distant organs have not been investigated.Herein,our clinical data showed that post-traumatic joint damage,combined with joint bleeding(hemarthrosis),exhibits a worse liver function compared with healthy control.With mouse model,hemarthrosis induces both cartilage degeneration and remote liver damage.Next,we found that hemarthrosis induces the upregulation in ratio and differentiation towards Th17 cells of CD4+T cells in peripheral blood and spleen.Deletion of CD4+T cells reverses hemarthrosis-induced liver damage.Degeneration of cartilage matrix induced by hemarthrosis upregulates serological type Ⅱ collagen(COL Ⅱ),which activates CD4+T cells.Systemic application of a COL Ⅱ antibody blocks the activation.Furthermore,bulk RNAseq and single-cell qPCR analysis revealed that the cartilage Akt pathway is inhibited by blood treatment.Intra-articular application of Akt activator blocks the cartilage degeneration and thus protects against the liver impairment in mouse and pig models.Taken together,our study revealed a pathological joint-liver axis mediated by matrikine-activated CD4+T cells,which refreshes the organ-crosstalk axis and provides a new treatment target for hemarthrosis-related disease.
      原文链接:
    • NETL
    • NSTL
    • 万方数据

    Effect of plateletcrit and methylenetetrahydrofolate reductase(MTHFR)C677T genotypes on folic acid efficacy in stroke prevention

    Yuncong ShiZhengzhipeng ZhangBinyan WangYu Wang...
    2694-2701页
    查看更多>>摘要：Previous studies have shown that low platelet count combined with high plasma total homocysteine(tHcy)increased stroke risk and can be lowered by 73％with folic acid.However,the combined role of other platelet activation parameters and the methylenetetrahydrofolate reductase(MTHFR)C677T genotypes on stroke risk and folic acid treatment benefit remain to be examined.This study aimed to investigate if platelet activation parameters and MTHFR genotypes jointly impact folic acid treatment efficacy in first stroke prevention.Data were derived from the China Stroke Primary Prevention Trial.This study includes a total of 11,185 adult hypertensive patients with relevant platelet activation parameters and MTHFR genotype data.When simultaneously considering both platelet activation parameters(plateletcrit,platelet count,mean platelet volume,platelet distribution width)and MTHFR genotypes,patients with both low plateletcrit(Q1)and the TT genotype had the highest stroke incidence rate(5.6％)in the enalapril group.This subgroup significantly benefited from folic acid treatment,with a 66％reduction in first stroke(HR:0.34;95％Cl:0.14-0.82;p=0.016).Consistently,the subgroup with low plateletcrit(Q1)and the CC/CT genotype also benefited from folic acid treatment(HR:0.40;95％Cl:0.23-0.70;p=0.001).In Chinese hypertensive adults,low plateletcrit can identify those who may greatly benefit from folic acid treatment,in particular,those with the TT genotype,a subpopulation known to have the highest stroke risk.
      原文链接:
    • NETL
    • NSTL
    • 万方数据

    SARS-CoV-2 aberrantly elevates mitochondrial bioenergetics to induce robust virus propagation

    Hye Jin ShinWooseong LeeKeun Bon KuGun Young Yoon...
    2702-2715页
    查看更多>>摘要：Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is a highly transmissible respiratory pathogen,leading,to severe multi-organ damage.However,knowledge regarding SARS-CoV-2-induced cellular alterations is limited.In this.study,we report that SARS-CoV-2 aberrantly elevates mitochondrial bioenergetics and activates the EGFR-mediated cell survival signal cascade during the early stage of viral infection.SARS-CoV-2 causes an increase in mitochondrial transmembrane potential via the SARS-CoV-2 RNA-nucleocapsid cluster,thereby abnormally promoting mitochondrial elongation and the OXPHOS process,followed by enhancing ATP production.Furthermore,SARS-CoV-2 activates the EGFR signal cascade and subsequently induces mitochondrial EGFR trafficking,contributing to abnormal OXPHOS process and viral propagation.Approved EGFR inhibitors remarkably reduce SARS-CoV-2 propagation,among which vandetanib exhibits the highest antiviral efficacy.Treatment of.SARS-CoV-2-infected cells with vandetanib decreases SARS-CoV-2-induced EGFR trafficking to the mitochondria and restores SARS-CoV-2-induced aberrant elevation in OXPHOS process and ATP generation,thereby resulting in the reduction of SARS-CoV-2 propagation.Furthermore,oral administration of vandetanib to SARS-CoV-2-infected hACE2 transgenic mice reduces SARS-CoV-2 propagation in lung tissue and mitigates SARS-CoV-2-induced lung inflammation.Vandetanib also exhibits potent antiviral activity against various SARS-CoV-2 variants of concern,including alpha,beta,delta and omicron,in in vitro cell culture experiments.Taken together,our findings provide novel insight into SARS-CoV-2-induced alterations in mitochondrial dynamics and EGFR trafficking during the early stage of viral infection and their roles in robust SARS-CoV-2 propagation,suggesting that EGFR is an attractive host target for combating COVID-19.
      原文链接:
    • NETL
    • NSTL
    • 万方数据