查看更多>>摘要：Protein tyrosine phosphorylation is a post-translational modification that regulates protein structure to modulate demic organisms'homeostasis and function.This physiological process is regulated by two enzyme families,protein tyrosine kinases(PTKs)and protein tyrosine phosphatases(PTPs).As an important regulator of protein function,PTPs are indispensable for maintaining cell intrinsic physiology in different systems,as well as liver physiological and pathological processes.Dysregulation of PTPs has been implicated in multiple liver-related diseases,including chronic liver diseases(CLDs),hepatocellular carcinoma(HCC),and liver injury,and several PTPs are being studied as drug therapeutic targets.There-fore,given the regulatory role of PTPs in diverse liver diseases,a collated review of their function and mechanism is necessary.Moreover,based on the current research status of targeted therapy,we empha-size the inclusion of several PTP members that are clinically significant in the development and progres-sion of liver diseases.As an emerging breakthrough direction in the treatment of liver diseases,this review summarizes the research status of PTP-targeting compounds in liver diseases to illustrate their po-tential in clinical treatment.Overall,this review aims to support the development of novel PTP-based treatment pathways for liver diseases.
查看更多>>摘要：Progranulin(PGRN),a multifunctional growth factor-like protein expressed by a variety of cell types,serves an important function in the physiologic and pathologic processes of fibrotic diseases,including wound healing and the inflammatory response.PGRN was discovered to inhibit pro-inflammation effect by competing with tumor necrosis factor-alpha(TNF-α)binding to TNF receptors.Notably,excessive tissue repair in the development of inflammation causes tissue fibrosis.Previous investigations have indicated the significance of PGRN in regulating inflammatory responses.Recently,multiple studies have shown that PGRN was linked to fibrogenesis,and was considered to monitor the formation of fibrosis in multiple organs,including liver,cardiovascular,lung and skin.This paper is a comprehensive review summarizing our current knowledge of PGRN,from its discovery to the role in fibrosis.This is followed by an in-depth look at the characteristics of PGRN,consisting of its structure,basic function and intracellular signaling.Finally,we will discuss the potential of PGRN in the diagnosis and treatment of fibrosis.
查看更多>>摘要：Mitophagy,essential for mitochondrial health,selectively degrades damaged mitochondria.It is intricately linked to the cGAS-STING pathway,which is crucial for innate immunity.This pathway responds to mitochondrial DNA and is associated with cellular stress response.Our review explores the molecular details and regulatory mechanisms of mitophagy and the cGAS-STING pathway.We criti-cally evaluate the literature demonstrating how dysfunctional mitophagy leads to neuroinflammatory con-ditions,primarily through the accumulation of damaged mitochondria,which activates the cGAS-STING pathway.This activation prompts the production of pro-inflammatory cytokines,exacerbating neuroinflammation.This review emphasizes the interaction between mitophagy and the cGAS-STING pathways.Effective mitophagy may suppress the cGAS-STING pathway,offering protection against neuroinflammation.Conversely,impaired mitophagy may activate the cGAS-STING pathway,leading to chronic neuroinflammation.Additionally,we explored how this interaction influences neurodegenera-tive disorders,suggesting a common mechanism underlying these diseases.In conclusion,there is a need for additional targeted research to unravel the complexities of mitophagy-cGAS-STING interactions and their role in neurodegeneration.This review highlights potential therapies targeting these pathways,potentially leading to new treatments for neuroinflammatory and neurodegenerative conditions.This syn-thesis enhances our understanding of the cellular and molecular foundations of neuroinflammation and opens new therapeutic avenues for neurodegenerative disease research.
查看更多>>摘要：Drug discovery is a sophisticated process that incorporates scientific innovations and cutting-edge technologies.Compared to traditional bioactivity-based screening methods,encoding and display technologies for combinatorial libraries have recently advanced from proof-of-principle experiments to promising tools for pharmaceutical hit discovery due to their high screening efficiency,throughput,and resource minimization.This review systematically summarizes the development history,typology,and prospective applications of encoding and displayed technologies,including phage display,ribosomal display,mRNA display,yeast cell display,one-bead one-compound,DNA-encoded,peptide nucleic acid-encoded,and new peptide-encoded technologies,and examples of preclinical and clinical translation.We discuss the progress of novel targeted therapeutic agents,covering a spectrum from small-molecule inhibitors and nonpeptidic macrocycles to linear,monocyclic,and bicyclic peptides,in addition to antibodies.We also address the pending challenges and future prospects of drug discovery,including the size of screening libraries,advantages and disadvantages of the technology,clinical translational potential,and market space.This review is intended to establish a comprehensive high-throughput drug discovery strategy for scientific researchers and clinical drug developers.
查看更多>>摘要：Bile acids(BAs)are synthesized by the host liver from cholesterol and are delivered to the intes-tine,where they undergo further metabolism by gut microbes and circulate between the liver and intestines through various transporters.They serve to emulsify dietary lipids and act as signaling molecules,regulating the host's metabolism and immune homeostasis through specific receptors.Therefore,disruptions in BA meta-bolism,transport,and signaling are closely associated with cholestasis,metabolic disorders,autoimmune dis-eases,and others.Botanical triterpenoids and steroids share structural similarities with BAs,and they have been found to modulate BA metabolism,transport,and signaling,potentially exerting pharmacological ortoxi-cological effects.Here,we have updated the research progress on BA,with a particular emphasis on new-found microbial BAs.Additionally,the latest advancements in targeting BA metabolism and signaling for disease treatment are highlighted.Subsequently,the roles of botanical triterpenoids in BA metabolism,transport,and signaling are examined,analyzing their potential pharmacological,toxicological,or drug interaction effects through these mechanisms.Finally,a research paradigm is proposed that utilizes the gut microbiota as a link to interpret the role of these important natural products in BA signaling.
查看更多>>摘要：Chimeric antigen receptor T(CAR-T)cell therapy as a form of adoptive cell therapy(ACT)has shown significant promise in cancer treatment,demonstrated by the FDA-approved CAR-T cell ther-apies targeting CD19 or B cell maturation antigen(BCMA)for hematological malignancies,albeit with moderate outcomes in solid tumors.However,despite these advancements,the efficacy of CAR-T therapy is often compromised by T cell exhaustion,a phenomenon that impedes the persistence and effector func-tion of CAR-T cells,leading to a relapse rate of up to 75％in patients treated with CD 19 orCD22 CAR-T cells for hematological malignancies.Strategies to overcome CAR-T exhaustion employ state-of-the-art genomic engineering tools and single-cell sequencing technologies.In this review,we provide a compre-hensive understanding of the latest mechanistic insights into T cell exhaustion and their implications for the current efforts to optimize CAR-T cell therapy.These insights,combined with lessons learned from benchmarking CAR-T based products in recent clinical trials,aim to address the challenges posed by T cell exhaustion,potentially setting the stage for the development of tailored next-generation approaches to cancer treatment.
查看更多>>摘要：The advent of cancer immunotherapy has imparted a transformative impact on cancer treatment paradigms by harnessing the power of the immune system.However,the challenge of practical and precise targeting of malignant cells persists.To address this,engineered nanoparticles(NPs)have emerged as a promising solution for enhancing targeted drug delivery in immunotherapeutic interventions,owing to their small size,low immunogenicity,and ease of surface modification.This comprehensive review delves into contemporary research at the nexus of NP engineering and immunotherapy,encompassing an extensive spectrum of NP morphologies and strategies tailored toward optimizing tumor targeting and augmenting therapeutic effectiveness.Moreover,it underscores the mechanisms that NPs leverage to bypass the numerous obstacles encountered in immunotherapeutic regimens and probes into the combined potential of NPs when co-administered with both established and novel immunotherapeutic modalities.Finally,the review evaluates the existing limitations of NPs as drug delivery platforms in immunotherapy,which could shape the path for future advancements in this promising field.
查看更多>>摘要：Tumor metastasis,the apex of cancer progression,poses a formidable challenge in therapeutic endeavors.Circulating tumor cells(CTCs),resilient entities originating from primary tumors or their metastases,significantly contribute to this process by demonstrating remarkable adaptability.They survive shear stress,resist anoikis,evade immune surveillance,and thwart chemotherapy.This comprehensive review aims to elucidate the intricate landscape of CTC formation,metastatic mechanisms,and the myriad factors influencing their behavior.Integral signaling pathways,such as integrin-related signaling,cellular autophagy,epithelial-mesenchymal transition,and interactions with platelets,are examined in detail.Furthermore,we explore the realm of precision nanomedicine design,with a specific emphasis on the anoikis-platelet interface.This innovative approach strategically targets CTC survival mechanisms,offering promising avenues for combatting metastatic cancer with unprecedented precision and efficacy.The review underscores the indispensable role of the rational design of platelet-based nanomedicine in the pursuit of restraining CTC-driven metastasis.
查看更多>>摘要：Owing to their limited accuracy and narrow applicability,current antimicrobial peptide(AMP)prediction models face obstacles in industrial application.To address these limitations,we developed and improved an AMP prediction model using Comparing and Optimizing Multiple DEep Learning(COMDEL)algorithms,coupled with high-throughput AMP screening method,finally reaching an accuracy of 94.8％in test and 88％in experiment verification,surpassing other state-of-the-art models.In conjunction with COMDEL,we employed the phage-assisted evolution method to screen Sortase in vivo and developed a cell-free AMP synthesis system in vitro,ultimately increasing AMPs yields to a range of 0.5-2.1 g/L within hours.Moreover,by multi-omics analysis using COMDEL,we identified Lactobacillus plantarum as the most promising candidate for AMP generation among 35 edible probiotics.Following this,we developed a microdroplet sorting approach and successfully screened three L.plantarum mutants,each showing a twofold increase in antimicrobial ability,underscoring their substantial industrial application values.
查看更多>>摘要：Amino acid metabolic remodeling is a hallmark of cancer,driving an increased nutritional demand for amino acids.Amino acids are pivotal for energetic regulation,biosynthetic support,and ho-meostatic maintenance to stimulate cancer progression.However,the role of phenylalanine in multiple myeloma(MM)remains unknown.Here,we demonstrate that phenylalanine levels in MM patients are decreased in plasma but elevated in bone marrow(BM)cells.After the treatment,phenylalanine levels increase in plasma and decrease in BM.This suggests that changes in phenylalanine have diagnostic value and that phenylalanine in the BM microenvironment is an essential source of nutrients for MM pro-gression.The requirement for phenylalanine by MM cells exhibits a similar pattern.Inhibiting phenylal-anine utilization suppresses MM cell growth and provides a synergistic effect with Bortezomib(BTZ)treatment in vitro and murine models.Mechanistically,phenylalanine deprivation induces excessive endo-plasmic reticulum stress and leads to MM cell apoptosis through the ATF3-CHOP-DR5 pathway.Inter-ference with ATF3 significantly affects phenylalanine deprivation therapy.In conclusion,we have identified phenylalanine metabolism as a characteristic feature of MM metabolic remodeling.Phenylal-anine is necessary for MM proliferation,and its aberrant demand highlights the importance of low-phenylalanine diets as an adjuvant treatment for MM.
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