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Small molecule metabolites:discovery of biomarkers and therapeutic targets

Signal Transduction and Targeted Therapy 2023年第4期8卷 1684-1720页

作者： Shi Qiu Ying Cai Hong Yao Chunsheng Lin Yiqiang Xie Songqi Tang Aihua Zhang International Advanced Functional Omics Platform Scientific Experiment CenterHainan General Hospital(Hainan Affiliated Hospital of Hainan Medical University)College of Chinese MedicineHainan Medical UniversityXueyuan Road 3Haikou 571199China Graduate School Heilongjiang University of Chinese MedicineHarbin 150040China First Affiliated Hospital Harbin Medical UniversityHarbin 150081China Second Affiliated Hospital Heilongjiang University of Chinese MedicineHarbin 150001China

Metabolic abnormalities lead to the dysfunction of metabolic pathways and metabolite accumulation or deficiency which is wellrecognizedhallmarks of diseases. Metabolite signatures that have close proximity to subject’s phenotypic informative dimension,are useful for predicting diagnosis and prognosis of diseases as well as monitoring treatments. The lack of early biomarkers couldlead to poor diagnosis and serious outcomes. Therefore, noninvasive diagnosis and monitoring methods with high specificity andselectivity are desperately needed. Small molecule metabolites-based metabolomics has become a specialized tool for metabolicbiomarker and pathway analysis, for revealing possible mechanisms of human various diseases and deciphering therapeuticpotentials. It could help identify functional biomarkers related to phenotypic variation and delineate biochemical pathwayschanges as early indicators of pathological dysfunction and damage prior to disease development. Recently, scientists haveestablished a large number of metabolic profiles to reveal the underlying mechanisms and metabolic networks for therapeutictarget exploration in biomedicine. This review summarized the metabolic analysis on the potential value of small-moleculecandidate metabolites as biomarkers with clinical events, which may lead to better diagnosis, prognosis, drug screening andtreatment. We also discuss challenges that need to be addressed to fuel the next wave of breakthroughs.

关键词： diagnosis therapeutic Small

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Cellular rejuvenation:molecular mechanisms and potential therapeutic interventions for diseases

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Signal Transduction and Targeted Therapy 2023年第4期8卷 1571-1609页

作者： Shuaifei Ji Mingchen Xiong Huating Chen Yiqiong Liu Laixian Zhou Yiyue Hong Mengyang Wang Chunming Wang Xiaobing Fu Xiaoyan Sun Research Center for Tissue Repair and Regeneration Affiliated to Medical Innovation Research Department and 4th Medical Center PLA General Hospital and PLA Medical CollegePLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin InjuryRepair and RegenerationResearch Unit of Trauma CareTissue Repair and RegenerationChinese Academy of Medical Sciences2019RU051Beijing 100048P.R.China State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical SciencesUniversity of MacaoTaipa999078 Macao SARChina

The ageing process is a systemic decline from cellular dysfunction to organ degeneration,with more predisposition to deteriorated disorders.Rejuvenation refers to giving aged cells or organisms more youthful characteristics through various techniques,such as cellular reprogramming and epigenetic regulation.The great leaps in cellular rejuvenation prove that ageing is not a one-way street,and many rejuvenative interventions have emerged to delay and even reverse the ageing process.Defining the mechanism by which roadblocks and signaling inputs influence complex ageing programs is essential for understanding and developing rejuvenative strategies.Here,we discuss the intrinsic and extrinsic factors that counteract cell rejuvenation,and the targeted cells and core mechanisms involved in this process.Then,we critically summarize the latest advances in state-of-art strategies of cellular rejuvenation.Various rejuvenation methods also provide insights for treating specific ageing-related diseases,including cellular reprogramming,the removal of senescence cells(SCs)and suppression of senescence-associated secretory phenotype(SASP),metabolic manipulation,stem cells-associated therapy,dietary restriction,immune rejuvenation and heterochronic transplantation,etc.The potential applications of rejuvenation therapy also extend to cancer treatment.Finally,we analyze in detail the therapeutic opportunities and challenges of rejuvenation technology.Deciphering rejuvenation interventions will provide further insights into anti-ageing and ageing-related disease treatment in clinical settings.

关键词： therapeutic mechanisms potential

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Dental stem cell-derived extracellular vesicles as promising therapeutic agents in the treatment of diseases

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International Journal of Oral Science 2022年第1期14卷 31-39页

作者： Ye Li Xu Duan Yinxue Chen Bingyun Liu Gang Chen The State Key Laboratory Breeding Base of Basic Science of Stomatology(Hubei-MOST)&Key Laboratory of Oral Biomedicine Ministry of Education School and Hospital of StomatologyWuhan UniversityWuhanChina Department of Oral and Maxillofacial Surgery School and Hospital of StomatologyWuhan UniversityWuhanChina Frontier Science Center for Immunology and Metabolism Wuhan UniversityWuhanChina

Dental stem cells(DSCs), an important source of mesenchymal stem cells(MSCs), can be easily obtained by minimally invasive procedures and have been used for the treatment of various diseases. Classic paradigm attributed the mechanism of their therapeutic action to direct cell differentiation after targeted migration, while contemporary insights into indirect paracrine effect opened new avenues for the mystery of their actual low engraftment and differentiation ability in vivo. As critical paracrine effectors, DSC-derived extracellular vesicles(DSC-EVs) are being increasingly linked to the positive effects of DSCs by an evolving body of in vivo studies. Carrying bioactive contents and presenting therapeutic potential in certain diseases, DSC-EVs have been introduced as promising treatments. Here, we systematically review the latest in vivo evidence that supports the therapeutic effects of DSC-EVs with mechanistic studies. In addition, current challenges and future directions for the clinical translation of DSC-EVs are also highlighted to call for more attentions to the(Ⅰ) distinguishing features of DSC-EVs compared with other types of MSC-EVs,(Ⅱ)heterogeneity among different subtypes of DSC-derived EVs,(Ⅲ) action modes of DSC-EVs,(Ⅳ) standardization for eligible DSC-EVs and(Ⅴ) safety guarantee for the clinical application of DSC-EVs. The present review would provide valuable insights into the emerging opportunities of DSC-EVs in future clinical applications.

关键词： therapeutic treatment insight

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Exploration and functionalization of M1-macrophage extracellular vesicles for effective accumulation in glioblastoma and strong synergistic therapeutic effects

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Signal Transduction and Targeted Therapy 2022年第4期7卷 1271-1286页

作者： Xiaojun Wang Hui Ding Zongyang Li Yaonan Peng Hui Tan Changlong Wang Guodong Huang Weiping Li Guanghui Ma Wei Wei Shenzhen Key Laboratory of Neurosurgery Department of NeurosurgeryShenzhen Second People’s HospitalShenzhen University 1st Affiliated HospitalGuangdong 518035P.R.China State Key Laboratory of Biochemical Engineering Institute of Process EngineeringChinese Academy of SciencesBeijing 100190P.R.China Department of Ophthalmology Beijing Chaoyang HospitalCapital Medical UniversityBeijing 100020P.R.China Department of Otolaryngology and Institute of Translational Medicine Shenzhen Second People’s Hospitalthe First Affiliated Hospital of Shenzhen University Health Science CenterShenzhenGuangdong 518110P.R.China Department of Neurosurgery Jinling HospitalJiangsuNanjing 210000P.R.China School of Chemical Engineering University of Chinese Academy of SciencesBeijing 100049P.R.China

Glioblastoma multiforme(GBM)is a highly aggressive brain tumor with an extremely low survival rate.New and effective approaches for treatment are therefore urgently needed.Here,we successfully developed M1-like macrophage-derived extracellular vesicles(M1EVs)that overcome multiple challenges via guidance from two macrophage-related observations in clinical specimens from GBM patients:enrichment of M2 macrophages in GBM;and origination of a majority of infiltrating macrophage from peripheral blood.To maximize the synergistic effect,we further functionalized the membranes of M1EVs with two hydrophobic agents(the chemical excitation source CPPO(C)and the photosensitizer Ce6(C))and loaded the hydrophilic hypoxiaactivated prodrug AQ4N(A)into the inner core of the M1EVs.After intravenous injection,the inherent nature of M1-derived extracellular vesicles CCA-M1EVs allowed for blood-brain barrier penetration,and modulated the immunosuppressive tumor microenvironment via M2-to-M1 polarization,which increased hydrogen peroxide(H_(2)O_(2))levels.Furthermore,the reaction between H_(2)O_(2) and CPPO produced chemical energy,which could be used for Ce6 activation to generate large amounts of reactive oxygen species to achieve chemiexcited photodynamic therapy(CDT).As this reaction consumed oxygen,the aggravation of tumor hypoxia also led to the conversion of non-toxic AQ4N into toxic AQ4 for chemotherapy.Therefore,CCA-M1EVs achieved synergistic immunomodulation,CDT,and hypoxia-activated chemotherapy in GBM to exert a potent therapeutic effect.Finally,we demonstrated the excellent effect of CCA-M1EVs against GBM in cell-derived xenograft and patient-derived xenograft models,underscoring the strong potential of our highly flexible M1EVs system to support multi-modal therapies for difficult-to-treat GBM.

关键词： therapeutic chemotherapy synergistic

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Expanding horizons in overcoming therapeutic resistance in castration-resistant prostate cancer:targeting the androgen receptor-regulated tumor immune microenvironment

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癌症生物学与医学:英文版 2023年第8期20卷 568-574页

作者： Bisheng Cheng Hai Huang Department of Urology Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou 510120China

Castration-resistant prostate cancer(CRPC)poses a major treatment challenge,because disease progression occurs despite androgen deprivation therapy(ADT)1.Overcoming therapeutic resistance in CRPC remains a critical unmet need in clinical practice.The androgen receptor(AR)signaling pathway plays a critical role in prostate cancer development and progression,and is also involved in regulating the tumor immune microenvironment(TIME).

关键词： therapeutic cancer resistance

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Pathogenesis of allergic diseases and implications for therapeutic interventions

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Signal Transduction and Targeted Therapy 2023年第4期8卷 1784-1813页

作者： Ji Wang Yumei Zhou Honglei Zhang Linhan Hu Juntong Liu Lei Wang Tianyi Wang Haiyun Zhang Linpeng Cong Qi Wang National Institute of TCM constitution and Preventive Medicine School of Chinese MedicineBeijing University of Chinese MedicineBeijing 100029P.R.China National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 1000210China

Allergic diseases such as allergic rhinitis (AR), allergic asthma (AAS), atopic dermatitis (AD), food allergy (FA), and eczema aresystemic diseases caused by an impaired immune system. Accompanied by high recurrence rates, the steadily rising incidence ratesof these diseases are attracting increasing attention. The pathogenesis of allergic diseases is complex and involves many factors,including maternal-fetal environment, living environment, genetics, epigenetics, and the body’s immune status. The pathogenesisof allergic diseases exhibits a marked heterogeneity, with phenotype and endotype defining visible features and associatedmolecular mechanisms, respectively. With the rapid development of immunology, molecular biology, and biotechnology, manynew biological drugs have been designed for the treatment of allergic diseases, including anti-immunoglobulin E (IgE), antiinterleukin(IL)-5, and anti-thymic stromal lymphopoietin (TSLP)/IL-4, to control symptoms. For doctors and scientists, it is becomingmore and more important to understand the influencing factors, pathogenesis, and treatment progress of allergic diseases. Thisreview aimed to assess the epidemiology, pathogenesis, and therapeutic interventions of allergic diseases, including AR, AAS, AD,and FA. We hope to help doctors and scientists understand allergic diseases systematically.

关键词： allergic diseases therapeutic

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Signaling pathways in Parkinson’s disease:molecular mechanisms and therapeutic interventions

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Signal Transduction and Targeted Therapy 2023年第3期8卷 1094-1111页

作者： Xu Dong-Chen Chen Yong Xu Yang ShenTu Chen-Yu Peng Li-Hua College of Pharmaceutical Sciences Zhejiang University310058 HangzhouP.R.China State Key Laboratory of Quality Research in Chinese Medicine Macao University of Science and TechnologyMacaoP.R.China

Parkinson’s disease(PD)is the second most common neurodegenerative disease worldwide,and its treatment remains a big challenge.The pathogenesis of PD may be related to environmental and genetic factors,and exposure to toxins and gene mutations may be the beginning of brain lesions.The identified mechanisms of PD includeα-synuclein aggregation,oxidative stress,ferroptosis,mitochondrial dysfunction,neuroinflammation,and gut dysbiosis.The interactions among these molecular mechanisms complicate the pathogenesis of PD and pose great challenges to drug development.At the same time,the diagnosis and detection of PD are also one of obstacles to the treatment of PD due to its long latency and complex mechanism.Most conventional therapeutic interventions for PD possess limited effects and have serious side effects,heightening the need to develop novel treatments for this disease.In this review,we systematically summarized the pathogenesis,especially the molecular mechanisms of PD,the classical research models,clinical diagnostic criteria,and the reported drug therapy strategies,as well as the newly reported drug candidates in clinical trials.We also shed light on the components derived from medicinal plants that are newly identified for their effects in PD treatment,with the expectation to provide the summary and outlook for developing the next generation of drugs and preparations for PD therapy.

关键词： therapeutic mechanisms summarized

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Epigenetic and post-translational modifications in autophagy:biological functions and therapeutic targets

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Signal Transduction and Targeted Therapy 2023年第2期8卷 581-603页

作者： Feng Shu Han Xiao Qiu-Nuo Li Xiao-Shuai Ren Zhi-Gang Liu Bo-Wen Hu Hong-Sheng Wang Hao Wang Guan-Min Jiang Department of Clinical Laboratory The Fifth Affiliated Hospital of Sun Yat-sen UniversityZhuhaiGuangdongChina Cancer Center Affiliated Dongguan HospitalSouthern Medical UniversityDongguanGuangdongChina Department of Urology The Fifth Affiliated Hospital of Sun Yat-sen UniversityZhuhaiGuangdongChina Guangdong Key Laboratory of Chiral Molecule and Drug Discovery School of Pharmaceutical SciencesSun Yat-sen UniversityGuangzhouGuangdongChina Department of Clinical Laboratory The First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhuiChina

Autophagy is a conserved lysosomal degradation pathway where cellular components are dynamically degraded and re-processed to maintain physical homeostasis.However,the physiological effect of autophagy appears to be multifaced.On the one hand,autophagy functions as a cytoprotective mechanism,protecting against multiple diseases,especially tumor,cardiovascular disorders,and neurodegenerative and infectious disease.Conversely,autophagy may also play a detrimental role via pro-survival effects on cancer cells or cell-killing effects on normal body cells.During disorder onset and progression,the expression levels of autophagy-related regulators and proteins encoded by autophagy-related genes(ATGs)are abnormally regulated,giving rise to imbalanced autophagy flux.However,the detailed mechanisms and molecular events of this process are quite complex.Epigenetic,including DNA methylation,histone modifications and miRNAs,and post-translational modifications,including ubiquitination,phosphorylation and acetylation,precisely manipulate gene expression and protein function,and are strongly correlated with the occurrence and development of multiple diseases.There is substantial evidence that autophagy-relevant regulators and machineries are subjected to epigenetic and post-translational modulation,resulting in alterations in autophagy levels,which subsequently induces disease or affects the therapeutic effectiveness to agents.In this review,we focus on the regulatory mechanisms mediated by epigenetic and post-translational modifications in disease-related autophagy to unveil potential therapeutic targets.In addition,the effect of autophagy on the therapeutic effectiveness of epigenetic drugs or drugs targeting post-translational modification have also been discussed,providing insights into the combination with autophagy activators or inhibitors in the treatment of clinical diseases.

关键词： therapeutic drugs protective

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Intratumoral microbiota:roles in cancer initiation,development and therapeutic efficacy

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Signal Transduction and Targeted Therapy 2023年第2期8卷 506-529页

作者： Li Yang Aitian Li Ying Wang Yi Zhang Biotherapy Center The First Affiliated Hospital of Zhengzhou UniversityZhengzhou450052China School of Life Sciences Zhengzhou UniversityZhengzhou450001P.R.China State Key Laboratory of Esophageal Cancer Prevention&Treatment Zhengzhou450052China

Microorganisms,including bacteria,viruses,fungi,and other eukaryotes,play critical roles in human health.An altered microbiome can be associated with complex diseases.Intratumoral microbial components are found in multiple tumor tissues and are closely correlated with cancer initiation and development and therapy efficacy.The intratumoral microbiota may contribute to promotion of the initiation and progression of cancers by DNA mutations,activating carcinogenic pathways,promoting chronic inflammation,complement system,and initiating metastasis.Moreover,the intratumoral microbiota may not only enhance antitumor immunity via mechanisms including STING signaling activation,T and NK cell activation,TLS production,and intratumoral microbiota-derived antigen presenting,but also decrease antitumor immune responses and promote cancer progression through pathways including upregulation of ROS,promoting an anti-inflammatory environment,T cell inactivation,and immunosuppression.The effect of intratumoral microbiota on antitumor immunity is dependent on microbiota composition,crosstalk between microbiota and the cancer,and status of cancers.The intratumoral microbiota may regulate cancer cell physiology and the immune response by different signaling pathways,including ROS,β-catenin,TLR,ERK,NF-κB,and STING,among others.These viewpoints may help identify the microbiota as diagnosis or prognosis evaluation of cancers,and as new therapeutic strategy and potential therapeutic targets for cancer therapy.

关键词： therapeutic immunity diagnosis

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Transcriptional co-activators: emerging roles in signaling pathways and potential therapeutic targets for diseases

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Signal Transduction and Targeted Therapy 2023年第12期8卷 5686-5726页

作者： Priyanka Dey Talukdar Urmi Chatterji Cancer Research Laboratory Department of ZoologyUniversity of Calcutta35 Ballygunge Circular RoadKolkata 700019 West BengalIndia

Specific cell states in metazoans are established by the symphony of gene expression programs that necessitate intricate synergic interactions between transcription factors and the co-activators.Deregulation of these regulatory molecules is associated with cell state transitions,which in turn is accountable for diverse maladies,including developmental disorders,metabolic disorders,and most significantly,cancer.A decade back most transcription factors,the key enablers of disease development,were historically viewed as‘undruggable’;however,in the intervening years,a wealth of literature validated that they can be targeted indirectly through transcriptional co-activators,their confederates in various physiological and molecular processes.These co-activators,along with transcription factors,have the ability to initiate and modulate transcription of diverse genes necessary for normal physiological functions,whereby,deregulation of such interactions may foster tissue-specific disease phenotype.Hence,it is essential to analyze how these co-activators modulate specific multilateral processes in coordination with other factors.The proposed review attempts to elaborate an in-depth account of the transcription co-activators,their involvement in transcription regulation,and context-specific contributions to pathophysiological conditions.This review also addresses an issue that has not been dealt with in a comprehensive manner and hopes to direct attention towards future research that will encompass patient-friendly therapeutic strategies,where drugs targeting co-activators will have enhanced benefits and reduced side effects.Additional insights into currently available therapeutic interventions and the associated constraints will eventually reveal multitudes of advanced therapeutic targets aiming for disease amelioration and good patient prognosis.

关键词： therapeutic eventually potential

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