查看更多>>摘要：Cancer immunotherapy,exemplified by the remarkable clinical benefits of the immune checkpoint blockade and chimeric antigen receptor T-cell therapy,is revolutionizing cancer therapy.They induce long-term tumor regression and overall survival benefit in many types of cancer.With the advances in our knowledge about the tumor immune microenvironment,remarkable progress has been made in the development of small-molecule drugs for immunotherapy.Small molecules targeting PRR-associated pathways,immune checkpoints,oncogenic signaling,metabolic pathways,cytokine/che-mokine signaling,and immune-related kinases have been extensively investigated.Monotherapy of small-molecule immunotherapeutic drugs and their combinations with other antitumor modalities are under active clinical investigations to overcome immune tolerance and circumvent immune checkpoint inhibitor resistance.Here,we review the latest development of small-molecule agents for cancer immunotherapy by targeting defined pathways and highlighting their progress in recent clinical investigations.
查看更多>>摘要：Cancer reprogramming is an important facilitator of cancer development and survival,with tumor cells exhibiting a preference for aerobic glycolysis beyond oxidative phosphorylation,even under sufficient oxygen supply condition.This metabolic alteration,known as the Warburg effect,serves as a significant indicator of malignant tumor transformation.The Warburg effect primarily impacts cancer occurrence by influencing the aerobic glycolysis pathway in cancer cells.Key enzymes involved in this process include glucose transporters(GLUTs),HKs,PFKs,LDHs,and PKM2.Moreover,the expression of transcriptional regulatory factors and proteins,such as FOXM1,p53,NF-κB,HIF1α,and c-Myc,can also influence cancer progression.Furthermore,lncRNAs,miRNAs,and circular RNAs play a vital role in directly regulating the Warburg effect.Additionally,gene mutations,tumor microenvironment remodeling,and immune system interactions are closely associated with the Warburg effect.Notably,the development of drugs targeting the Warburg effect has exhibited promising potential in tumor treatment.This comprehensive review presents novel directions and approaches for the early diagnosis and treatment of cancer patients by conducting in-depth research and summarizing the bright prospects of targeting the Warburg effect in cancer.
查看更多>>摘要：Liver fibrosis,characterized by scar tissue formation,can ultimately result in liver failure.It's a major cause of morbidity and mortality globally,often associated with chronic liver diseases like hep-atitis or alcoholic and non-alcoholic fatty liver diseases.However,current treatment options are limited,highlighting the urgent need for the development of new therapies.As a reversible regulatory mechanism,epigenetic modification is implicated in many biological processes,including liver fibrosis.Exploring the epigenetic mechanisms involved in liver fibrosis could provide valuable insights into developing new treatments for chronic liver diseases,although the current evidence is still controversial.This review pro-vides a comprehensive summary of the regulatory mechanisms and critical targets of epigenetic modifi-cations,including DNA methylation,histone modification,and RNA modification,in liver fibrotic diseases.The potential cooperation of different epigenetic modifications in promoting fibrogenesis was also highlighted.Finally,available agonists or inhibitors regulating these epigenetic mechanisms and their potential application in preventing liver fibrosis were discussed.In summary,elucidating specific drug-gable epigenetic targets and developing more selective and specific candidate medicines may represent a promising approach with bright prospects for the treatment of chronic liver diseases.
查看更多>>摘要：Synthetic chemistry plays an indispensable role in drug discovery,contributing to hit compounds identification,lead compounds optimization,candidate drugs preparation,and so on.As Nobel Prize laureate James Black emphasized,"the most fruitful basis for the discovery of a new drug is to start with an old drug"1.Late-stage modification or functionalization of drugs,natural products and bioactive compounds have garnered significant interest due to its ability to introduce diverse ele-ments into bioactive compounds promptly.Such modifications alter the chemical space and physio-chemical properties of these compounds,ultimately influencing their potency and druggability.To enrich a toolbox of chemical modification methods for drug discovery,this review focuses on the incorporation of halogen,oxygen,and nitrogen—the ubiquitous elements in pharmacophore compo-nents of the marketed drugs—through late-stage modification in recent two decades,and discusses the state and challenges faced in these fields.We also emphasize that increasing cooperation between chemists and pharmacists may be conducive to the rapid discovery of new activities of the functiona-lized molecules.Ultimately,we hope this review would serve as a valuable resource,facilitating the application of late-stage modification in the construction of novel molecules and inspiring innovative concepts for designing and building new drugs.
查看更多>>摘要：Cancer remains one of the diseases with the highest incidence and mortality globally.Con-ventional treatment modalities have demonstrated threatening drawbacks including invasiveness,non-controllability,and development of resistance for some,including chemotherapy,radiation,and surgery.Sono-photodynamic combinatorial therapy(SPDT)has been developed as an alternative treatment mo-dality which offers a non-invasive and controllable therapeutic approach.SPDT combines the mechanism of action of sonodynamic therapy(SDT),which uses ultrasound,and photodynamic therapy(PDT),which uses light,to activate a sensitizer and initiate cancer eradication.The use of phthalocyanines(Pcs)as sensitizers for SPDT is gaining interest owing to their ability to induce intracellular oxidative stress and initiate toxicity under SDT and PDT.This review discusses some of the structural prerequisites of Pcs which may influence their overall SPDT activities in cancer therapy.
查看更多>>摘要：Despite advances in understanding the development and progression of cancer in recent years,there remains a lack of comprehensive characterization of the cancer glycoproteome.Glycopro-teins play an important role in medicine and are involved in various human disease conditions including cancer.Glycan-moieties participate in fundamental cancer processes like cell signaling,invasion,angio-genesis,and metastasis.Aberrant N-glycosylation significantly impacts cancer processes and targeted therapies in clinic.Therefore,understanding N-glycosylation in a tumor is essential for comprehending disease progression and discovering anti-cancer targets and biomarkers for therapy monitoring and diag-nosis.This review presents the fundamental process of protein N-glycosylation and summarizes glycosyl-ation changes in tumor cells,including increased terminal sialylation,N-glycan branching,and core-fucosylation.Also,the role of N-glycosylation in tumor signaling pathways,migration,and metabolism are discussed.Glycoproteins and glycopeptides as potential biomarkers for early detection of cancer based on site specificity have been introduced.Collectively,understanding and exploring the cancer gly-coproteome,along with its role in medicine,implication in cancer and other human diseases,highlights the significance of N-glycosylation in tumor processes,necessitating further research for potential anti-cancer targets and biomarkers.
查看更多>>摘要：Conventional photodynamic therapy(PDT)approaches face challenges including limited light penetration,low uptake of photosensitizers by tumors,and lack of oxygen in tumor microenviron-ments.One promising solution is to internally generate light,photosensitizers,and oxygen.This can be accomplished through endogenous production,such as using bioluminescence as an endogenous light source,synthesizing genetically encodable photosensitizers in situ,and modifying cells genetically to ex-press catalase enzymes.Furthermore,these strategies have been reinforced by the recent rapid advance-ments in synthetic biology.In this review,we summarize and discuss the approaches to overcome PDT obstacles by means of endogenous production of excitation light,photosensitizers,and oxygen.We envi-sion that as synthetic biology advances,genetically engineered cells could act as precise and targeted"living factories"to produce PDT components,leading to enhanced performance of PDT.
查看更多>>摘要：Cancer,a complex and heterogeneous disease,arises from genomic instability.Currently,DNA damage-based cancer treatments,including radiotherapy and chemotherapy,are employed in clin-ical practice.However,the efficacy and safety of these therapies are constrained by various factors,limiting their ability to meet current clinical demands.Metal nanoparticles present promising avenues for enhancing each critical aspect of DNA damage-based cancer therapy.Their customizable physico-chemical properties enable the development of targeted and personalized treatment platforms.In this re-view,we delve into the design principles and optimization strategies of metal nanoparticles.We shed light on the limitations of DNA damage-based therapy while highlighting the diverse strategies made possible by metal nanoparticles.These encompass targeted drug delivery,inhibition of DNA repair mechanisms,induction of cell death,and the cascading immune response.Moreover,we explore the pivotal role of physicochemical factors such as nanoparticle size,stimuli-responsiveness,and surface modification in shaping metal nanoparticle platforms.Finally,we present insights into the challenges and future direc-tions of metal nanoparticles in advancing DNA damage-based cancer therapy,paving the way for novel treatment paradigms.
查看更多>>摘要：Aside from antibodies,peptides show great potential as immune checkpoint inhibitors(ICIs)due to several advantages,such as better tumor penetration and lower cost.Lymphocyte-activation gene 3(LAG-3)is an immune checkpoint which can induce T cell dysfunction through interaction with its soluble ligand fibrinogen like protein-l(FGL1).Here,we found that LAG-3 expression was higher than programmed cell death protein 1(PD-1)in multiple human cancers by TCGA databases,and successfully identified a LAG-3 binding peptide LFP-6 by phage display bio-panning,which specifically blocks the interaction of LAG-3/FGL1 but not LAG-3/MHC-Ⅱ.Subsequently,D-amino acids were introduced to substitute the N-and C-terminus of LFP-6 to obtain the proteolysis-resistant peptide LFP-D1,which restores T cell function in vitro and inhibits tumor growth in vivo.Further,a bispecific peptide LFOP targeting both PD-1/PD-L1 and LAG-3/FGL1 was designed by conjugating LFP-D1 with PD-1/PD-L1 blocking peptide OPBP-1(8-12),which activates T cell with enhanced proliferation and IFN-γproduction.More importantly,LFOP combined with radiotherapy significantly improve the T cell infiltration in tumor and elevate systemic antitumor immune response.In conclusion,we developed a novel peptide blocking LAG-3/FGL1 which can restore T cell function,and the bispecific peptide syner-gizes with radiotherapy to further enhance the antitumor immune response.
查看更多>>摘要：Aging increases the risks of various diseases and the vulnerability to death.Cellular senes-cence is a hallmark of aging that contributes greatly to aging and aging-related diseases.This study demonstrates that extracellular vesicles from human urine-derived stem cells(USC-EVs)efficiently inhibit cellular senescence in vitro and in vivo.The intravenous injection of USC-EVs improves cognitive function,increases physical fitness and bone quality,and alleviates aging-related structural changes in different organs of senescence-accelerated mice and natural aging mice.The anti-aging effects of USC-EVs are not obviously affected by the USC donors'ages,genders,or health status.Proteomic analysis reveals that USC-EVs are enriched with plasminogen activator urokinase(PLAU)and tissue in-hibitor of metalloproteinases 1(TIMP1).These two proteins contribute importantly to the anti-senescent effects of USC-EVs associated with the inhibition of matrix metalloproteinases,cyclin-dependent kinase inhibitor 2A(P16INK4a),and cyclin-dependent kinase inhibitor 1A(P21cip1).These findings suggest a great potential of autologous USC-EVs as a promising anti-aging agent by transferring PLAU and TIMP1 proteins.
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