Liver regeneration and the development of effective therapies for liver failure remain formidable challenges in modern medicine.In recent years,the utilization of 3D cell-based strategies has emerged as a promising ap...Liver regeneration and the development of effective therapies for liver failure remain formidable challenges in modern medicine.In recent years,the utilization of 3D cell-based strategies has emerged as a promising approach for addressing these urgent clinical requirements.This review provides a thorough analysis of the application of 3D cell-based approaches to liver regeneration and their potential impact on patients with end-stage liver failure.Here,we discuss various 3D culture models that incorporate hepatocytes and stem cells to restore liver function and ameliorate the consequences of liver failure.Furthermore,we explored the challenges in transitioning these innovative strategies from preclinical studies to clinical applications.The collective insights presented herein highlight the significance of 3D cell-based strategies as a transformative paradigm for liver regeneration and improved patient care.展开更多
Early screening,diagnosis,and treatment of lung cancer are pivotal in clinical practice since the tumor stage remains the most dominant factor that affects patient survival.Previous initiatives have tried to develop n...Early screening,diagnosis,and treatment of lung cancer are pivotal in clinical practice since the tumor stage remains the most dominant factor that affects patient survival.Previous initiatives have tried to develop new tools for decision-making of lung cancer.In this study,we proposed the China Protocol,a complete workflow of lung cancer tailored to the Chinese population,which is implemented by steps including early screening by evaluation of risk factors and three-dimensional thin-layer image reconstruction technique for low-dose computed tomography(Tre-LDCT),accurate diagnosis via artificial intelligence(Al)and novel biomarkers,and individualized treatment through non-invasive molecule visualization strategies.The application of this protocol has improved the early diagnosis and 5-year survival rates of lung cancer in China.The proportion of early-stage(stage I)lung cancer has increased from 46.3%to 65.6%,along with a 5-year survival rate of 90.4%.Moreover,especially for stage IA1 lung cancer,the diagnosis rate has improved from 16%to 27.9%;meanwhile,the 5-year survival rate of this group achieved 97.5%.Thus,here we defined stage IA1 lung cancer,which cohort benefits significantly from early diagnosis and treatment,as the"ultra-early stage lung cancer",aiming to provide an intuitive description for more precise management and survival improvement.In the future,we will promote our findings to multicenter remote areas through medical alliances and mobile health services with the desire to move forward the diagnosis and treatment of lung cancer.展开更多
Redox signaling acts as a critical mediator in the dynamic interactions between organisms and their external environment,profoundly influencing both the onset and progression of various diseases.Under physiological co...Redox signaling acts as a critical mediator in the dynamic interactions between organisms and their external environment,profoundly influencing both the onset and progression of various diseases.Under physiological conditions,oxidative free radicals generated by the mitochondrial oxidative respiratory chain,endoplasmic reticulum,and NADPH oxidases can be effectively neutralized by NRF2-mediated antioxidant responses.These responses elevate the synthesis of superoxide dismutase(SOD),catalase,as well as key molecules like nicotinamide adenine dinucleotide phosphate(NADPH)and glutathione(GSH),thereby maintaining cellular redox homeostasis.Disruption of this finely tuned equilibrium is closely linked to the pathogenesis of a wide range of diseases.Recent advances have broadened our understanding of the molecular mechanisms underpinning this dysregulation,highlighting the pivotal roles of genomic instability,epigenetic modifications,protein degradation,and metabolic reprogramming.These findings provide a foundation for exploring redox regulation as a mechanistic basis for improving therapeutic strategies.While antioxidant-based therapies have shown early promise in conditions where oxidative stress plays a primary pathological role,their effcacy in diseases characterized by complex,multifactorial etiologies remains controversial.A deeper,context-specific understanding of redox signaling,particularly the roles of redox-sensitive proteins,is critical for designing targeted therapies aimed at re-establishing redox balance.Emerging small molecule inhibitors that target specific cysteine residues in redox-sensitive proteins have demonstrated promising preclinical outcomes,setting the stage for forthcoming clinical trials.In this review,we summarize our current understanding of the intricate relationship between oxidative stress and disease pathogenesis and also discuss how these insights can be leveraged to optimize therapeutic strategies in clinical practice.展开更多
Outer membrane(OM)lipoproteins serve vital roles in Gram-negative bacteria,contributing to their pathogenicity and drug resistance.For these lipoproteins to function,they must be transported from the inner membrane(IM...Outer membrane(OM)lipoproteins serve vital roles in Gram-negative bacteria,contributing to their pathogenicity and drug resistance.For these lipoproteins to function,they must be transported from the inner membrane(IM),where they are assembled,to the OM by the ABC transporter LolCDE.We have previously captured structural snapshots of LolCDE in multiple states,revealing its dynamic conformational changes.However,the exact mechanism by which LolCDE recognizes and transfers lipoprotein between domains remains unclear.Here,we characterized the E.coli LolCDE complex bound with endogenous lipoprotein or ATP to explore the molecular features governing its substrate binding and transport functions.We found that the N-terminal unstructured linker of lipoprotein is critical for efficient binding by LolCDE;it must be sufficiently long to keep the lipoprotein’s main body outside the complex while allowing the triacyl chains to bind within the central cavity.Mutagenic assays identified key residues that mediate allosteric communication between the cytoplasmic and transmembrane domains and in the periplasmic domain to form a lipoprotein transport pathway at the LolC-LolE interface.This study provides insights into the OM lipoprotein relocation process mediated by LolCDE,with significant implications for antimicrobial drug development.展开更多
Uncontrolled hemorrhage remains the leading cause of death in clinical and emergency care,posing a major threat to human life.To achieve effective bleeding control,many hemostatic materials have emerged.Among them,nat...Uncontrolled hemorrhage remains the leading cause of death in clinical and emergency care,posing a major threat to human life.To achieve effective bleeding control,many hemostatic materials have emerged.Among them,nature-derived biopolymers occupy an important position due to the excellent inherent biocompatibility,biodegradability and bioactivity.Additionally,sponges have been widely used in clinical and daily life because of their rapid blood absorption.Therefore,we provide the overview focusing on the latest advances and smart designs of biopolymer-based hemostatic sponge.Starting from the component,the applications of polysaccharide and polypeptide in hemostasis are systematically introduced,and the unique bioactivities such as antibacterial,antioxidant and immunomodulation are also concerned.From the perspective of sponge structure,different preparation processes can obtain unique physical properties and structures,which will affect the material properties such as hemostasis,antibacterial and tissue repair.Notably,as development frontier,the multifunctions of hemostatic materials is summarized,mainly including enhanced coagulation,antibacterial,avoiding tumor recurrence,promoting tissue repair,and hemorrhage monitoring.Finally,the challenges facing the development of biopolymer-based hemostatic sponges are emphasized,and future directions for in vivo biosafety,emerging materials,multiple application scenarios and translational research are proposed.展开更多
Oxidative stress plays a crucial role in organ aging and related diseases, yet the endogenous regulators involved remain largelyunknown. This work highlights the importance of metabolic homeostasis in protecting again...Oxidative stress plays a crucial role in organ aging and related diseases, yet the endogenous regulators involved remain largelyunknown. This work highlights the importance of metabolic homeostasis in protecting against oxidative stress in the large intestine.By developing a low-input and user-friendly pipeline for the simultaneous profiling of five distinct cysteine (Cys) states, includingfree SH, total Cys oxidation (Sto), sulfenic acid (SOH), S-nitrosylation (SNO), and S-glutathionylation (SSG), we shed light on Cysredox modification stoichiometries and signaling with regional resolution in the aging gut of monkeys. Notably, the proteinsmodified by SOH and SSG were associated primarily with cell adhesion. In contrast, SNO-modified proteins were involved inimmunity. Interestingly, we observed that the Sto levels ranged from 0.97% to 99.88%, exhibiting two distinct peaks and increasingwith age. Crosstalk analysis revealed numerous age-related metabolites potentially involved in modulating oxidative stress and Cysmodifications. Notably, we elucidated the role of fumarate in alleviating intestinal oxidative stress in a dextran sulfate sodium (DSS)-induced colitis mouse model. Our findings showed that fumarate treatment promotes the recovery of several cell types, signalingpathways, and genes involved in oxidative stress regulation. Calorie restriction (CR) is a known strategy for alleviating oxidativestress. Two-month CR intervention led to the recovery of many antioxidative metabolites and reshaped the Cys redoxome. Thiswork decodes the complexities of redoxomics during the gut aging of non-human primates and identifies key metabolic regulatorsof oxidative stress and redox signaling.展开更多
CD8^(+)T cell-based immune-therapeutics,including immune checkpoint inhibitors and adoptive cell therapies(tumor-infiltrating lymphocytes(TILs),T cell receptor-engineered T cells(TCR-T),chimeric antigen receptor T cel...CD8^(+)T cell-based immune-therapeutics,including immune checkpoint inhibitors and adoptive cell therapies(tumor-infiltrating lymphocytes(TILs),T cell receptor-engineered T cells(TCR-T),chimeric antigen receptor T cells(CAR-T)),have achieved significant successes and prolonged patient survival to varying extents and even achieved cure in some cases.However,immunotherapy resistance and tumor insusceptibility frequently occur,leading to treatment failure.Recent evidences have highlighted the ponderance of tumor cells metabolic reprogramming in establishing an immunosuppressive milieu through the secretion of harmful metabolites,immune-inhibitory cytokines,and alteration of gene expression,which suppress the activity of immune cells,particularly CD8^(+)T cells to evade immune surveillance.Therefore,targeting tumor cell metabolic adaptations to reshape the immune microenvironment holds promise as an immunomodulatory strategy to facilitate immunotherapy.Here,we summarize recent advances in the crosstalk between immunotherapy and tumor reprogramming,focusing on the regulatory mechanisms underlying tumor cell glucose metabolism,amino acid metabolism,and lipid metabolism in influencing CD8^(+)T cells to provide promising metabolic targets or combinational strategies for immunotherapy.展开更多
Bispecific antibody‒drug conjugates(BsADCs)represent an innovative therapeutic category amalgamating the merits of antibody‒drug conjugates(ADCs)and bispecific antibodies(BsAbs).Positioned as the next-generation ADC a...Bispecific antibody‒drug conjugates(BsADCs)represent an innovative therapeutic category amalgamating the merits of antibody‒drug conjugates(ADCs)and bispecific antibodies(BsAbs).Positioned as the next-generation ADC approach,BsADCs hold promise for ameliorating extant clinical challenges associated with ADCs,particularly pertaining to issues such as poor internalization,off-target toxicity,and drug resistance.Presently,ten BsADCs are undergoing clinical trials,and initial findings underscore the imperative for ongoing refinement.This review initially delves into specific design considerations for BsADCs,encompassing target selection,antibody formats,and the linker–payload complex.Subsequent sections delineate the extant progress and challenges encountered by BsADCs,illustrated through pertinent case studies.The amalgamation of BsAbs with ADCs offers a prospective solution to prevailing clinical limitations of ADCs.Nevertheless,the symbiotic interplay among BsAb,linker,and payload necessitates further optimizations and coordination beyond a simplistic“1+1”to effectively surmount the extant challenges facing the BsADC domain.展开更多
Pulmonary infections pose formidable challenges in clinical settings with high mortality rates across all age groups worldwide.Accurate diagnosis and early intervention are crucial to improve patient outcomes.Artifici...Pulmonary infections pose formidable challenges in clinical settings with high mortality rates across all age groups worldwide.Accurate diagnosis and early intervention are crucial to improve patient outcomes.Artificial intelligence(AI)has the capability to mine imaging features specific to different pathogens and fuse multimodal features to reach a synergistic diagnosis,enabling more precise investigation and individualized clinical management.In this study,we successfully developed a multimodal integration(MMI)pipeline to differentiate among bacterial,fungal,and viral pneumonia and pulmonary tuberculosis based on a real-world dataset of 24,107 patients.The area under the curve(AUC)of the MMI system comprising clinical text and computed tomography(CT)image scans yielded 0.910(95%confidence interval[CI]:0.904–0.916)and 0.887(95%CI:0.867–0.909)in the internal and external testing datasets respectively,which were comparable to those of experienced physicians.Furthermore,the MMI system was utilized to rapidly differentiate between viral subtypes with a mean AUC of 0.822(95%CI:0.805–0.837)and bacterial subtypes with a mean AUC of 0.803(95%CI:0.775–0.830).Here,the MMI system harbors the potential to guide tailored medication recommendations,thus mitigating the risk of antibiotic misuse.Additionally,the integration of multimodal factors in the AI-driven system also provided an evident advantage in predicting risks of developing critical illness,contributing to more informed clinical decision-making.To revolutionize medical care,embracing multimodal AI tools in pulmonary infections will pave the way to further facilitate early intervention and precise management in the foreseeable future.展开更多
CRISPR‒Cas7-11 is a Type Ⅲ-E CRISPR-associated nuclease that functions as a potent RNA editing tool.Tetratrico-peptide repeat fused with Cas/HEF1-associated signal transducer(TPR-CHAT)acts as a regulatory protein tha...CRISPR‒Cas7-11 is a Type Ⅲ-E CRISPR-associated nuclease that functions as a potent RNA editing tool.Tetratrico-peptide repeat fused with Cas/HEF1-associated signal transducer(TPR-CHAT)acts as a regulatory protein that interacts with CRISPR RNA(crRNA)-bound Cas7-11 to form a CRISPR-guided caspase complex(Craspase).However,the precise modulation of Cas7-11’s nuclease activity by TPR-CHAT to enhance its utility requires further study.Here,we report cryo-electron microscopy(cryo-EM)structures of Desulfonema ishimotonii(Di)Cas7-11-crRNA,complexed with or without the full length or the N-terminus of TPR-CHAT.These structures unveil the molecular features of the Craspase complex.Structural analysis,combined with in vitro nuclease assay and electrophoretic mobility shift assay,reveals that DiTPR-CHAT negatively regulates the activity of DiCas7-11 by preventing target RNA from binding through the N-terminal 65 amino acids of DiTPR-CHAT(DiTPR-CHAT_(NTD)).Our work demonstrates that DiTPRCHAT_(NTD) can function as a small unit of DiCas7-11 regulator,potentially enabling safe applications to prevent overcutting and offtarget effects of the CRISPR‒Cas7-11 system.展开更多
Characterized by their pivotal roles in cell-to-cell communication,cell proliferation,and immune regulation during tissue repair,exosomes have emerged as a promising avenue for“cell-free therapy”in clinical applicat...Characterized by their pivotal roles in cell-to-cell communication,cell proliferation,and immune regulation during tissue repair,exosomes have emerged as a promising avenue for“cell-free therapy”in clinical applications.Hydrogels,possessing commendable biocompatibility,degradability,adjustability,and physical properties akin to biological tissues,have also found extensive utility in tissue engineering and regenerative repair.The synergistic combination of exosomes and hydrogels holds the potential not only to enhance the efficiency of exosomes but also to collaboratively advance the tissue repair process.This review has summarized the advancements made over the past decade in the research of hydrogel-exosome systems for regenerating various tissues including skin,bone,cartilage,nerves and tendons,with a focus on the methods for encapsulating and releasing exosomes within the hydrogels.It has also critically examined the gaps and limitations in current research,whilst proposed future directions and potential applications of this innovative approach.展开更多
Collagen-based biomaterials(CBB) are highly esteemed by researchers in materials science and biomedicine due to their extensive applications across various biomedical disciplines.In recent years,owing to advancements ...Collagen-based biomaterials(CBB) are highly esteemed by researchers in materials science and biomedicine due to their extensive applications across various biomedical disciplines.In recent years,owing to advancements in developmental biology techniq ues,this superior biomaterial has seen increasing utilization in 3D in vitro tissue culture.Three-dimensional cell cultures,often referred to as organoids,have emerged in response to technological advancements in biomaterials and the growing need in the field of medical research.They serve as important models for simulating normal physiological activities in vivo,addressing limitations in experimental material sources,and resolving ethical issues.In this review,we discuss the material characteristics of CBBs commonly used for organoid culture,integrating aspects such as Matrigel and decellularized ECM as culture matrices.We also analyzed the development prospects and directions of various materials in the context of biology,clinical medicine,and partic ularly reproductive medicine.Currently,despite the FDA approval and clinical research incorporating numerous CBBs,existing challenges in multiple studies indicate a significant unmet need in the development of key tissue models for both medical research and clinical applications.In summary,CBBs are swiftly broadening their applicability in the realms of organoid nature and medical research,serving as a versatile and high-performing material for 3D in vitro tissue culture.展开更多
Antibody-drug conjugates(ADCs),which combine the advantages of monoclonal antibodies with precise targeting and payloads with efficient killing,show great clinical therapeutic value.The ADCs’payloads play a key role ...Antibody-drug conjugates(ADCs),which combine the advantages of monoclonal antibodies with precise targeting and payloads with efficient killing,show great clinical therapeutic value.The ADCs’payloads play a key role in determining the efficacy of ADC drugs and thus have attracted great attention in the field.An ideal ADC payload should possess sufficient toxicity,low immunogenicity,high stability,and modifiable functional groups.Common ADC payloads include tubulin inhibitors and DNA damaging agents,with tubulin inhibitors accounting for more than half of the ADC drugs in clinical development.However,due to clinical limitations of traditional ADC payloads,such as inadequate efficacy and the development of acquired drug resistance,novel highly efficient payloads with diverse targets and reduced side effects are being developed.This perspective summarizes the recent research advances of traditional and novel ADC payloads with main focuses on the structure-activity relationship studies,co-crystal structures,and designing strategies,and further discusses the future research directions of ADC payloads.This review also aims to provide valuable references and future directions for the development of novel ADC payloads that will have high efficacy,low toxicity,adequate stability,and abilities to overcome drug resistance.展开更多
Despite the remarkable success of immune checkpoint inhibitors(ICIs),primary resistance to ICIs causes only subsets of patients to achieve durable responses due to the complex tumor microenvironment(TME).Oncolytic vir...Despite the remarkable success of immune checkpoint inhibitors(ICIs),primary resistance to ICIs causes only subsets of patients to achieve durable responses due to the complex tumor microenvironment(TME).Oncolytic viruses(OVs)can overcome the immunosuppressive TME and promote systemic antitumor immunity in hosts.Engineered OVs armed with ICIs would likely have improved effectiveness as a cancer therapy.According to the diverse immune cell landscapes among different types of tumors,we rationally and precisely generated three recombinant oncolytic adenoviruses(OAds):OAd-SIRPα-Fc,OAd-Siglec10-Fc and OAd-TIGIT-Fc.These viruses were designed to locally deliver SIRPα-Fc,Siglec10-Fc or TIGIT-Fc fusion proteins recognizing CD47,CD24 or CD155,respectively,in the TME to achieve enhanced antitumor effects.Our results suggested that OAd-SIRPα-Fc and OAd-Siglec10-Fc both showed outstanding efficacy in tumor suppression of macrophage-dominated tumors,while OAd-TIGIT-Fc showed the best antitumor immunity in CD8+T-cell-dominated tumors.Importantly,the recombinant OAds activated an inflammatory immune response and generated long-term antitumor memory.In addition,the combination of OAd-Siglec10-Fc with anti-PD-1 significantly enhanced the antitumor effect in a 4T1 tumor model by remodeling the TME.In summary,rationally designed OAds expressing ICIs tailored to the immune cell landscape in the TME can precisely achieve tumor-specific immunotherapy of cancer.展开更多
Hydroxycarboxylic acid receptor 2(HCAR2),a member of Class A G-protein-coupled receptor(GPCR)family,plays a pivotal role in anti-lipolytic and anti-inflammatory effects,establishing it as a significant therapeutic tar...Hydroxycarboxylic acid receptor 2(HCAR2),a member of Class A G-protein-coupled receptor(GPCR)family,plays a pivotal role in anti-lipolytic and anti-inflammatory effects,establishing it as a significant therapeutic target for treating dyslipidemia and inflammatory diseases.展开更多
Respiratory syncytial virus(RSV)is a nonsegmented,negative strand RNA virus that has caused severe lower respiratory tract infections of high mortality rates in infants and the elderly,yet no effective vaccine or anti...Respiratory syncytial virus(RSV)is a nonsegmented,negative strand RNA virus that has caused severe lower respiratory tract infections of high mortality rates in infants and the elderly,yet no effective vaccine or antiviral therapy is available.The RSV genome encodes the nucleoprotein(N)that forms helical assembly to encapsulate and protect the RNA genome from degradation,and to serve as a template for transcription and replication.Previous crystal structure revealed a decameric ring architecture of N in complex with the cellular RNA(N-RNA)of 70 nucleotides(70-nt),whereas cryo-ET reconstruction revealed a low-resolution left-handed filament,in which the crystal monomer structure was docked with the helical symmetry applied to simulate a nucleocapsid-like assembly of RSV.However,the molecular details of RSV nucleocapsid assembly remain unknown,which continue to limit our complete understanding of the critical interactions involved in the nucleocapsid and antiviral development that may target this essential process during the viral life cycle.Here we resolve the near-atomic cryo-EM structure of RSV N-RNA that represents roughly one turn of the helical assembly that unveils critical interaction interfaces of RSV nucleocapsid and may facilitate development of RSV antiviral therapy.展开更多
基金This work was supported by grants fromthe Sichuan Science and Technology Program(2023NSFSC1877).
文摘Liver regeneration and the development of effective therapies for liver failure remain formidable challenges in modern medicine.In recent years,the utilization of 3D cell-based strategies has emerged as a promising approach for addressing these urgent clinical requirements.This review provides a thorough analysis of the application of 3D cell-based approaches to liver regeneration and their potential impact on patients with end-stage liver failure.Here,we discuss various 3D culture models that incorporate hepatocytes and stem cells to restore liver function and ameliorate the consequences of liver failure.Furthermore,we explored the challenges in transitioning these innovative strategies from preclinical studies to clinical applications.The collective insights presented herein highlight the significance of 3D cell-based strategies as a transformative paradigm for liver regeneration and improved patient care.
基金supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project of China(2024ZD0529500/2024ZD0529504,2024ZD0529500/2024ZD0529505)National Natural Science Foundation of China(82470109,92159302)+3 种基金Science and Technology Project of Sichuan(2022ZDZX0018)1.3.5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(ZYYC23027)1.3.5 projects for Artificial Intelligence,West China Hospital,Sichuan University(ZYAI24016)1.3.5 Project of State Key Laboratory of Respiratory Health and Multimorbidity,West China Hospital,Sichuan University(RHM24208).
文摘Early screening,diagnosis,and treatment of lung cancer are pivotal in clinical practice since the tumor stage remains the most dominant factor that affects patient survival.Previous initiatives have tried to develop new tools for decision-making of lung cancer.In this study,we proposed the China Protocol,a complete workflow of lung cancer tailored to the Chinese population,which is implemented by steps including early screening by evaluation of risk factors and three-dimensional thin-layer image reconstruction technique for low-dose computed tomography(Tre-LDCT),accurate diagnosis via artificial intelligence(Al)and novel biomarkers,and individualized treatment through non-invasive molecule visualization strategies.The application of this protocol has improved the early diagnosis and 5-year survival rates of lung cancer in China.The proportion of early-stage(stage I)lung cancer has increased from 46.3%to 65.6%,along with a 5-year survival rate of 90.4%.Moreover,especially for stage IA1 lung cancer,the diagnosis rate has improved from 16%to 27.9%;meanwhile,the 5-year survival rate of this group achieved 97.5%.Thus,here we defined stage IA1 lung cancer,which cohort benefits significantly from early diagnosis and treatment,as the"ultra-early stage lung cancer",aiming to provide an intuitive description for more precise management and survival improvement.In the future,we will promote our findings to multicenter remote areas through medical alliances and mobile health services with the desire to move forward the diagnosis and treatment of lung cancer.
基金supported by the National Key Research and Development Project of China(2023YFC3402100)the National Natural Science Foundation of China(81821002 and 82130082,82341004)1:3.5 project for disciplines of excellence,West China Hospital,Sichuan University(ZYGD22007).
文摘Redox signaling acts as a critical mediator in the dynamic interactions between organisms and their external environment,profoundly influencing both the onset and progression of various diseases.Under physiological conditions,oxidative free radicals generated by the mitochondrial oxidative respiratory chain,endoplasmic reticulum,and NADPH oxidases can be effectively neutralized by NRF2-mediated antioxidant responses.These responses elevate the synthesis of superoxide dismutase(SOD),catalase,as well as key molecules like nicotinamide adenine dinucleotide phosphate(NADPH)and glutathione(GSH),thereby maintaining cellular redox homeostasis.Disruption of this finely tuned equilibrium is closely linked to the pathogenesis of a wide range of diseases.Recent advances have broadened our understanding of the molecular mechanisms underpinning this dysregulation,highlighting the pivotal roles of genomic instability,epigenetic modifications,protein degradation,and metabolic reprogramming.These findings provide a foundation for exploring redox regulation as a mechanistic basis for improving therapeutic strategies.While antioxidant-based therapies have shown early promise in conditions where oxidative stress plays a primary pathological role,their effcacy in diseases characterized by complex,multifactorial etiologies remains controversial.A deeper,context-specific understanding of redox signaling,particularly the roles of redox-sensitive proteins,is critical for designing targeted therapies aimed at re-establishing redox balance.Emerging small molecule inhibitors that target specific cysteine residues in redox-sensitive proteins have demonstrated promising preclinical outcomes,setting the stage for forthcoming clinical trials.In this review,we summarize our current understanding of the intricate relationship between oxidative stress and disease pathogenesis and also discuss how these insights can be leveraged to optimize therapeutic strategies in clinical practice.
基金supported by the National Key Research and Development Program of China(2021YFA1301900 to H.D.)the National Natural Science Foundation of China(31900039 and 32170029 to X.T.,32000844 to S.C.,81971974 and 82372297 to H.D.)+1 种基金the 1.3.5 Project for Disciplines Excellence of West China Hospital,Sichuan University(ZYYC23014 to H.D.)the Sichuan Provincial Natural Science Foundation Outstanding Young Scientist Fund Project(2024NSFJQ0002 to H.D.).
文摘Outer membrane(OM)lipoproteins serve vital roles in Gram-negative bacteria,contributing to their pathogenicity and drug resistance.For these lipoproteins to function,they must be transported from the inner membrane(IM),where they are assembled,to the OM by the ABC transporter LolCDE.We have previously captured structural snapshots of LolCDE in multiple states,revealing its dynamic conformational changes.However,the exact mechanism by which LolCDE recognizes and transfers lipoprotein between domains remains unclear.Here,we characterized the E.coli LolCDE complex bound with endogenous lipoprotein or ATP to explore the molecular features governing its substrate binding and transport functions.We found that the N-terminal unstructured linker of lipoprotein is critical for efficient binding by LolCDE;it must be sufficiently long to keep the lipoprotein’s main body outside the complex while allowing the triacyl chains to bind within the central cavity.Mutagenic assays identified key residues that mediate allosteric communication between the cytoplasmic and transmembrane domains and in the periplasmic domain to form a lipoprotein transport pathway at the LolC-LolE interface.This study provides insights into the OM lipoprotein relocation process mediated by LolCDE,with significant implications for antimicrobial drug development.
基金jointly sponsored by Sichuan Science and Tech-nology Program(2024NSFSC0002 and MZGC20240011)“1.3.5”Project for Disciplines of Excellence,West China Hospital,Sichuan University(ZYGD23037)+1 种基金the Frontiers Medical Center,Tianfu Jincheng Laboratory Foundation(TFJC2023010002)the National Natural Science Foundation of China(Grant No.32171351).
文摘Uncontrolled hemorrhage remains the leading cause of death in clinical and emergency care,posing a major threat to human life.To achieve effective bleeding control,many hemostatic materials have emerged.Among them,nature-derived biopolymers occupy an important position due to the excellent inherent biocompatibility,biodegradability and bioactivity.Additionally,sponges have been widely used in clinical and daily life because of their rapid blood absorption.Therefore,we provide the overview focusing on the latest advances and smart designs of biopolymer-based hemostatic sponge.Starting from the component,the applications of polysaccharide and polypeptide in hemostasis are systematically introduced,and the unique bioactivities such as antibacterial,antioxidant and immunomodulation are also concerned.From the perspective of sponge structure,different preparation processes can obtain unique physical properties and structures,which will affect the material properties such as hemostasis,antibacterial and tissue repair.Notably,as development frontier,the multifunctions of hemostatic materials is summarized,mainly including enhanced coagulation,antibacterial,avoiding tumor recurrence,promoting tissue repair,and hemorrhage monitoring.Finally,the challenges facing the development of biopolymer-based hemostatic sponges are emphasized,and future directions for in vivo biosafety,emerging materials,multiple application scenarios and translational research are proposed.
基金supported by the National Key R&D Program of China(no.2022YFA1303200)the National Natural Science Foundation of China(nos.82073221,32201216,and 31870826)+2 种基金the Science and Technology Project of Sichuan Province(nos.2024YFFK0099,2023NSFSC1525,and 2021YFS0134)the National Clinical Research Center for Geriatrics at West China Hospital(no.Z2024JC002)the West China Hospital 135 project(nos.ZYYC23013 and ZYYC23025).
文摘Oxidative stress plays a crucial role in organ aging and related diseases, yet the endogenous regulators involved remain largelyunknown. This work highlights the importance of metabolic homeostasis in protecting against oxidative stress in the large intestine.By developing a low-input and user-friendly pipeline for the simultaneous profiling of five distinct cysteine (Cys) states, includingfree SH, total Cys oxidation (Sto), sulfenic acid (SOH), S-nitrosylation (SNO), and S-glutathionylation (SSG), we shed light on Cysredox modification stoichiometries and signaling with regional resolution in the aging gut of monkeys. Notably, the proteinsmodified by SOH and SSG were associated primarily with cell adhesion. In contrast, SNO-modified proteins were involved inimmunity. Interestingly, we observed that the Sto levels ranged from 0.97% to 99.88%, exhibiting two distinct peaks and increasingwith age. Crosstalk analysis revealed numerous age-related metabolites potentially involved in modulating oxidative stress and Cysmodifications. Notably, we elucidated the role of fumarate in alleviating intestinal oxidative stress in a dextran sulfate sodium (DSS)-induced colitis mouse model. Our findings showed that fumarate treatment promotes the recovery of several cell types, signalingpathways, and genes involved in oxidative stress regulation. Calorie restriction (CR) is a known strategy for alleviating oxidativestress. Two-month CR intervention led to the recovery of many antioxidative metabolites and reshaped the Cys redoxome. Thiswork decodes the complexities of redoxomics during the gut aging of non-human primates and identifies key metabolic regulatorsof oxidative stress and redox signaling.
基金funded by National Natural Science Foundation of China(Grant Nos.:82373336,and 82303238,Sichuan Science and Technology Department,China(Grant Nos.:2024NSFSC1945,and 2023NSFSC0667)The Third People's Hospital of Chengdu Clinical Research Program,China(Program Nos.:CSY-YN-01-2023-013,CSY-YN-01-2023-005,and CSY-YN-03-2024-003)+1 种基金Sichuan University“From 0 to 1”Innovative Research Project,China(Project No.:2023SCUH0024)Health Commission of Chengdu,China(Grant No.:2024291).
文摘CD8^(+)T cell-based immune-therapeutics,including immune checkpoint inhibitors and adoptive cell therapies(tumor-infiltrating lymphocytes(TILs),T cell receptor-engineered T cells(TCR-T),chimeric antigen receptor T cells(CAR-T)),have achieved significant successes and prolonged patient survival to varying extents and even achieved cure in some cases.However,immunotherapy resistance and tumor insusceptibility frequently occur,leading to treatment failure.Recent evidences have highlighted the ponderance of tumor cells metabolic reprogramming in establishing an immunosuppressive milieu through the secretion of harmful metabolites,immune-inhibitory cytokines,and alteration of gene expression,which suppress the activity of immune cells,particularly CD8^(+)T cells to evade immune surveillance.Therefore,targeting tumor cell metabolic adaptations to reshape the immune microenvironment holds promise as an immunomodulatory strategy to facilitate immunotherapy.Here,we summarize recent advances in the crosstalk between immunotherapy and tumor reprogramming,focusing on the regulatory mechanisms underlying tumor cell glucose metabolism,amino acid metabolism,and lipid metabolism in influencing CD8^(+)T cells to provide promising metabolic targets or combinational strategies for immunotherapy.
基金This review was supported by the National Natural Science Foundation of China(82073318)Sichuan Science and Technology Program(2019YFS0003,China)the Support Program of Science&Technology Department of Sichuan Provincial(2023YFSY0046 and 2022NSFSC1365,China).
文摘Bispecific antibody‒drug conjugates(BsADCs)represent an innovative therapeutic category amalgamating the merits of antibody‒drug conjugates(ADCs)and bispecific antibodies(BsAbs).Positioned as the next-generation ADC approach,BsADCs hold promise for ameliorating extant clinical challenges associated with ADCs,particularly pertaining to issues such as poor internalization,off-target toxicity,and drug resistance.Presently,ten BsADCs are undergoing clinical trials,and initial findings underscore the imperative for ongoing refinement.This review initially delves into specific design considerations for BsADCs,encompassing target selection,antibody formats,and the linker–payload complex.Subsequent sections delineate the extant progress and challenges encountered by BsADCs,illustrated through pertinent case studies.The amalgamation of BsAbs with ADCs offers a prospective solution to prevailing clinical limitations of ADCs.Nevertheless,the symbiotic interplay among BsAb,linker,and payload necessitates further optimizations and coordination beyond a simplistic“1+1”to effectively surmount the extant challenges facing the BsADC domain.
基金supported by the National Natural Science Foundation of China(82341083,82100119)the Science and Technology Project of Sichuan(2020YFG0473,2022ZDZX0018)+3 种基金the Beijing Municipal Science and Technology Planning Project(Z211100003521009)Hong Kong Research Grants Council through General Research Fund(Grant 17207722)the Sichuan University from“0”to“1”Innovation Project(2023SCUH0051)the 1.3.5 Project for Disciplines Excellence of West China Hospital,Sichuan University(ZYYC23027)。
文摘Pulmonary infections pose formidable challenges in clinical settings with high mortality rates across all age groups worldwide.Accurate diagnosis and early intervention are crucial to improve patient outcomes.Artificial intelligence(AI)has the capability to mine imaging features specific to different pathogens and fuse multimodal features to reach a synergistic diagnosis,enabling more precise investigation and individualized clinical management.In this study,we successfully developed a multimodal integration(MMI)pipeline to differentiate among bacterial,fungal,and viral pneumonia and pulmonary tuberculosis based on a real-world dataset of 24,107 patients.The area under the curve(AUC)of the MMI system comprising clinical text and computed tomography(CT)image scans yielded 0.910(95%confidence interval[CI]:0.904–0.916)and 0.887(95%CI:0.867–0.909)in the internal and external testing datasets respectively,which were comparable to those of experienced physicians.Furthermore,the MMI system was utilized to rapidly differentiate between viral subtypes with a mean AUC of 0.822(95%CI:0.805–0.837)and bacterial subtypes with a mean AUC of 0.803(95%CI:0.775–0.830).Here,the MMI system harbors the potential to guide tailored medication recommendations,thus mitigating the risk of antibiotic misuse.Additionally,the integration of multimodal factors in the AI-driven system also provided an evident advantage in predicting risks of developing critical illness,contributing to more informed clinical decision-making.To revolutionize medical care,embracing multimodal AI tools in pulmonary infections will pave the way to further facilitate early intervention and precise management in the foreseeable future.
基金supported by the National Key Research and Development Program of China(2021YFA1301900,2021YFA1301203 and 2022YFC2303700 to H.D.and Z.S.)the National Natural Science Foundation of China(31900039 and 32170029 to X.T.,81971974 to H.D.,32222040 and 32070049 to Z.S.)+1 种基金the 1.3.5 Project for Disciplines Excellence of West China Hospital,Sichuan University(ZYYC20021 to H.D.)Tianjin Synthetic Biotechnology Innovation Capacity Improvement Action(TSBICIP-KJGG-008 to Z.S.).
文摘CRISPR‒Cas7-11 is a Type Ⅲ-E CRISPR-associated nuclease that functions as a potent RNA editing tool.Tetratrico-peptide repeat fused with Cas/HEF1-associated signal transducer(TPR-CHAT)acts as a regulatory protein that interacts with CRISPR RNA(crRNA)-bound Cas7-11 to form a CRISPR-guided caspase complex(Craspase).However,the precise modulation of Cas7-11’s nuclease activity by TPR-CHAT to enhance its utility requires further study.Here,we report cryo-electron microscopy(cryo-EM)structures of Desulfonema ishimotonii(Di)Cas7-11-crRNA,complexed with or without the full length or the N-terminus of TPR-CHAT.These structures unveil the molecular features of the Craspase complex.Structural analysis,combined with in vitro nuclease assay and electrophoretic mobility shift assay,reveals that DiTPR-CHAT negatively regulates the activity of DiCas7-11 by preventing target RNA from binding through the N-terminal 65 amino acids of DiTPR-CHAT(DiTPR-CHAT_(NTD)).Our work demonstrates that DiTPRCHAT_(NTD) can function as a small unit of DiCas7-11 regulator,potentially enabling safe applications to prevent overcutting and offtarget effects of the CRISPR‒Cas7-11 system.
基金supported by Natural Science Foundation of Sichuan Province,Frontiers Medical Center,Tianfu Jincheng Laboratory Foundation(TFJC2023010002)“1.3.5”Project for Disciplines of Excellence,West China Hospital,Sichuan University(ZYGD23037).
文摘Characterized by their pivotal roles in cell-to-cell communication,cell proliferation,and immune regulation during tissue repair,exosomes have emerged as a promising avenue for“cell-free therapy”in clinical applications.Hydrogels,possessing commendable biocompatibility,degradability,adjustability,and physical properties akin to biological tissues,have also found extensive utility in tissue engineering and regenerative repair.The synergistic combination of exosomes and hydrogels holds the potential not only to enhance the efficiency of exosomes but also to collaboratively advance the tissue repair process.This review has summarized the advancements made over the past decade in the research of hydrogel-exosome systems for regenerating various tissues including skin,bone,cartilage,nerves and tendons,with a focus on the methods for encapsulating and releasing exosomes within the hydrogels.It has also critically examined the gaps and limitations in current research,whilst proposed future directions and potential applications of this innovative approach.
基金supported by funding from the projects of the National Natural Science Foundation of China(Y.Z.,Grant No.82001496)Sichuan Science and Technology Program(Sichuan Natural Science Foundation for Youth,China,NO.2022NSFSC1281)Sichuan Medical Association Foundation(China,NO.S21006)
文摘Collagen-based biomaterials(CBB) are highly esteemed by researchers in materials science and biomedicine due to their extensive applications across various biomedical disciplines.In recent years,owing to advancements in developmental biology techniq ues,this superior biomaterial has seen increasing utilization in 3D in vitro tissue culture.Three-dimensional cell cultures,often referred to as organoids,have emerged in response to technological advancements in biomaterials and the growing need in the field of medical research.They serve as important models for simulating normal physiological activities in vivo,addressing limitations in experimental material sources,and resolving ethical issues.In this review,we discuss the material characteristics of CBBs commonly used for organoid culture,integrating aspects such as Matrigel and decellularized ECM as culture matrices.We also analyzed the development prospects and directions of various materials in the context of biology,clinical medicine,and partic ularly reproductive medicine.Currently,despite the FDA approval and clinical research incorporating numerous CBBs,existing challenges in multiple studies indicate a significant unmet need in the development of key tissue models for both medical research and clinical applications.In summary,CBBs are swiftly broadening their applicability in the realms of organoid nature and medical research,serving as a versatile and high-performing material for 3D in vitro tissue culture.
基金provided by the National Natural Science Foundation of China(82073318)the Fundamental Research Funds for the Central Universities(SCU2022D025,0082604151345,China)+1 种基金Sichuan Science and Technology Program Projects(2019YFS0003,China)to Yuxi Wangprovided by the University of Tennessee College of Pharmacy Drug Discovery Center to Wei Li。
文摘Antibody-drug conjugates(ADCs),which combine the advantages of monoclonal antibodies with precise targeting and payloads with efficient killing,show great clinical therapeutic value.The ADCs’payloads play a key role in determining the efficacy of ADC drugs and thus have attracted great attention in the field.An ideal ADC payload should possess sufficient toxicity,low immunogenicity,high stability,and modifiable functional groups.Common ADC payloads include tubulin inhibitors and DNA damaging agents,with tubulin inhibitors accounting for more than half of the ADC drugs in clinical development.However,due to clinical limitations of traditional ADC payloads,such as inadequate efficacy and the development of acquired drug resistance,novel highly efficient payloads with diverse targets and reduced side effects are being developed.This perspective summarizes the recent research advances of traditional and novel ADC payloads with main focuses on the structure-activity relationship studies,co-crystal structures,and designing strategies,and further discusses the future research directions of ADC payloads.This review also aims to provide valuable references and future directions for the development of novel ADC payloads that will have high efficacy,low toxicity,adequate stability,and abilities to overcome drug resistance.
基金funded by the National Major Scientific and Technological Special Project for“Significant New Drugs Development”(No.2018ZX09201018-013)by Natural Science Foundation Project of Sichuan(No.2022NSFSC0848)+1 种基金as well as supported by the 1.3.5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(No.ZYGD18007)The Frontiers Medical Center,Tianfu Jincheng Laboratory Foundation(TFJC202310005).
文摘Despite the remarkable success of immune checkpoint inhibitors(ICIs),primary resistance to ICIs causes only subsets of patients to achieve durable responses due to the complex tumor microenvironment(TME).Oncolytic viruses(OVs)can overcome the immunosuppressive TME and promote systemic antitumor immunity in hosts.Engineered OVs armed with ICIs would likely have improved effectiveness as a cancer therapy.According to the diverse immune cell landscapes among different types of tumors,we rationally and precisely generated three recombinant oncolytic adenoviruses(OAds):OAd-SIRPα-Fc,OAd-Siglec10-Fc and OAd-TIGIT-Fc.These viruses were designed to locally deliver SIRPα-Fc,Siglec10-Fc or TIGIT-Fc fusion proteins recognizing CD47,CD24 or CD155,respectively,in the TME to achieve enhanced antitumor effects.Our results suggested that OAd-SIRPα-Fc and OAd-Siglec10-Fc both showed outstanding efficacy in tumor suppression of macrophage-dominated tumors,while OAd-TIGIT-Fc showed the best antitumor immunity in CD8+T-cell-dominated tumors.Importantly,the recombinant OAds activated an inflammatory immune response and generated long-term antitumor memory.In addition,the combination of OAd-Siglec10-Fc with anti-PD-1 significantly enhanced the antitumor effect in a 4T1 tumor model by remodeling the TME.In summary,rationally designed OAds expressing ICIs tailored to the immune cell landscape in the TME can precisely achieve tumor-specific immunotherapy of cancer.
基金This work was supported by the National Natural Science Foundation of China(32100988 to W.Y.,31972916 to Z.S,82271190 and 32100965 to L.C.)Science and Technology Department of Sichuan Province(2020YFQ0055 to P.F.and 2022ZYD0085 to Z.S.)+1 种基金Ministry of Technology Department of China grant(2019YFA0508800 to Z.S)1.3.5 project for disciplines of excellence,West China Hospital,Sichuan University(ZYGD18027 to P.F,ZYYC20023 to Z.S).
文摘Hydroxycarboxylic acid receptor 2(HCAR2),a member of Class A G-protein-coupled receptor(GPCR)family,plays a pivotal role in anti-lipolytic and anti-inflammatory effects,establishing it as a significant therapeutic target for treating dyslipidemia and inflammatory diseases.
基金This research was supported by Ministry of Science and Technology of China(MoST 2022YFC2303700 and 2021YFA1301900)National Natural Science Foundation of China(NSFC 32222040 and 32070049)+1 种基金Tianjin Synthetic Biotechnology Innovation Capacity Improvement Action(TSBICIP-KJGG-008)the 1.3.5 Project for Disciplines Excellence of West China Hospital,Sichuan University(ZYYC21006)to Z.S.The pCAG-OSF vector plasmid was a kind gift from Prof.Jinbiao Ma at Fudan University。
文摘Respiratory syncytial virus(RSV)is a nonsegmented,negative strand RNA virus that has caused severe lower respiratory tract infections of high mortality rates in infants and the elderly,yet no effective vaccine or antiviral therapy is available.The RSV genome encodes the nucleoprotein(N)that forms helical assembly to encapsulate and protect the RNA genome from degradation,and to serve as a template for transcription and replication.Previous crystal structure revealed a decameric ring architecture of N in complex with the cellular RNA(N-RNA)of 70 nucleotides(70-nt),whereas cryo-ET reconstruction revealed a low-resolution left-handed filament,in which the crystal monomer structure was docked with the helical symmetry applied to simulate a nucleocapsid-like assembly of RSV.However,the molecular details of RSV nucleocapsid assembly remain unknown,which continue to limit our complete understanding of the critical interactions involved in the nucleocapsid and antiviral development that may target this essential process during the viral life cycle.Here we resolve the near-atomic cryo-EM structure of RSV N-RNA that represents roughly one turn of the helical assembly that unveils critical interaction interfaces of RSV nucleocapsid and may facilitate development of RSV antiviral therapy.
