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药学学报（英文版）
药学学报（英文版）

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药学学报（英文版）/Journal Acta Pharmaceutica Sinica BCSCDCSTPCD北大核心SCI
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    Cardiac resident macrophages:Spatiotemporal distribution,development,physiological functions,and their translational potential on cardiac diseases

    Jing JinYurou WangYueqin LiuSubrata Chakrabarti...
    1483-1493页
    查看更多>>摘要：Cardiac resident macrophages(CRMs)are the main population of cardiac immune cells.The role of these cells in regeneration,functional remodeling,and repair after cardiac injury is always the focus of research.However,in recent years,their dynamic changes and contributions in physiological states have a significant attention.CRMs have specific phenotypes and functions in different cardiac chambers or locations of the heart and at different stages.They further show specific differentiation and development processes.The present review will summarize the new progress about the spatiotem-poral distribution,potential developmental regulation,and their roles in cardiac development and aging as well as the translational potential of CRMs on cardiac diseases.Of course,the research tools for CRMs,their respective advantages and disadvantages,and key issues on CRMs will further be discussed.
      原文链接:
    • NETL
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    Strategies that regulate LSD1 for novel therapeutics

    Meng LiMengge DaiBing ChengShaotong Li...
    1494-1507页
    查看更多>>摘要：Histone methylation plays crucial roles in regulating chromatin structure and gene transcrip-tion in epigenetic modifications.Lysine-specific demethylase 1(LSD1),the first identified histone de-methylase,is universally overexpressed in various diseases.LSD1 dysregulation is closely associated with cancer,viral infections,and neurodegenerative diseases,etc.,making it a promising therapeutic target.Several LSD1 inhibitors and two small-molecule degraders(UM171 and BEA-17)have entered the clinical stage.LSD1 can remove methyl groups from histone 3 at lysine 4 or lysine 9(H3K4 or H3K9),resulting in either transcription repression or activation.While the roles of LSD1 in transcrip-tional regulation are well-established,studies have revealed that LSD1 can also be dynamically regulated by other factors.For example,the expression or activity of LSD1 can be regulated by many proteins that form transcriptional corepressor complexes with LSD1.Moreover,some post-transcriptional modifica-tions and cellular metabolites can also regulate LSD1 expression or its demethylase activity.Therefore,in this review,we will systematically summarize how proteins involved in the transcriptional corepressor complex,various post-translational modifications,and metabolites act as regulatory factors for LSD1 ac-tivity.
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    Macrophage senescence in health and diseases

    Longling WangWenxiang HongHong ZhuQiaojun He...
    1508-1524页
    查看更多>>摘要：Macrophage senescence,manifested by the special form of durable cell cycle arrest and chronic low-grade inflammation like senescence-associated secretory phenotype,has long been consid-ered harmful.Persistent senescence of macrophages may lead to maladaptation,immune dysfunction,and finally the development of age-related diseases,infections,autoimmune diseases,and malignancies.However,it is a ubiquitous,multi-factorial,and dynamic complex phenomenon that also plays roles in remodeled processes,including wound repair and embryogenesis.In this review,we summarize some general molecular changes and several specific biomarkers during macrophage senescence,which may bring new sight to recognize senescent macrophages in different conditions.Also,we take an in-depth look at the functional changes in senescent macrophages,including metabolism,autophagy,polarization,phagocytosis,antigen presentation,and infiltration or recruitment.Furthermore,some degenerations and diseases associated with senescent macrophages as well as the mechanisms or relevant genetic regulations of senescent macrophages are integrated,not only emphasizing the possibility of regulating macrophage senescence to benefit age-associated diseases but also has an implication on the finding of potential tar-gets or drugs clinically.
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    Nano-formulated delivery of active ingredients from traditional Chinese herbal medicines for cancer immunotherapy

    Qi ShangWandong LiuFaith LeslieJiapei Yang...
    1525-1541页
    查看更多>>摘要：Cancer immunotherapy has garnered promise in tumor progression,invasion,and metastasis through establishing durable and memorable immunological activity.However,low response rates,adverse side effects,and high costs compromise the additional benefits for patients treated with current chemical and biological agents.Chinese herbal medicines(CHMs)are a potential treasure trove of nat-ural medicines and are gaining momentum in cancer immunomodulation with multi-component,multi-target,and multi-pathway characteristics.The active ingredient extracted from CHMs benefit generalized patients through modulating immune response mechanisms.Additionally,the introduction of nanotech-nology has greatly improved the pharmacological qualities of active ingredients through increasing the hydrophilicity,stability,permeability,and targeting characteristics,further enhancing anti-cancer immu-nity.In this review,we summarize the mechanism of active ingredients for cancer immunomodulation,highlight nano-formulated deliveries of active ingredients for cancer immunotherapy,and provide in-sights into the future applications in the emerging field of nano-formulated active ingredients of CHMs.
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    Emerging non-antibody-drug conjugates(non-ADCs)therapeutics of toxins for cancer treatment

    Xiaolan XuJiaming ZhangTao WangJing Li...
    1542-1559页
    查看更多>>摘要：The non-selective cytotoxicity of toxins limits the clinical relevance of the toxins.In recent years,toxins have been widely used as warheads for antibody-drug conjugates(ADCs)due to their effi-cient killing activity against various cancer cells.Although ADCs confer certain targeting properties to the toxins,low drug loading capacity,possible immunogenicity,and other drawbacks also limit the po-tential application of ADCs.Recently,non-ADC delivery strategies for toxins have been extensively investigated.To further understand the application of toxins in anti-tumor,this paper provided an over-view of prodrugs,nanodrug delivery systems,and biomimetic drug delivery systems.In addition,toxins and their combination strategies with other therapies were discussed.Finally,the prospect and challenge of toxins in cancer treatment were also summarized.
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    The emerging tumor microbe microenvironment:From delineation to multidisciplinary approach-based interventions

    Yu FuJia LiWenyun CaiYulan Huang...
    1560-1591页
    查看更多>>摘要：Intratumoral microbiota has become research hotspots,and emerges as a non-negligent new component of tumor microenvironments(TME),due to its powerful influence on tumor initiation,metas-tasis,immunosurveillance and prognosis despite in low-biomass.The accumulations of microbes,and their related components and metabolites within tumor tissues,endow TME with additional pluralistic features which are distinct from the conventional one.Therefore,it's definitely necessary to comprehen-sively delineate the sophisticated landscapes of tumor microbe microenvironment,as well as their func-tions and related underlying mechanisms.Herein,in this review,we focused on the fields of tumor microbe microenvironment,including the heterogeneity of intratumor microbiota in different types of tu-mors,the controversial roles of intratumoral microbiota,the basic features of tumor microbe microenvi-ronment(i.e.,pathogen-associated molecular patterns(PAMPs),typical microbial metabolites,autophagy,inflammation,multi-faceted immunomodulation and chemoresistance),as well as the multi-disciplinary approach-based intervention of tumor microbiome for cancer therapy by applying wild-type or engineered live microbes,microbiota metabolites,antibiotics,synthetic biology and rationally de-signed biomaterials.We hope our work will provide valuable insight to deeply understand the interplay of cancer-immune-microbial,and facilitate the development of microbes-based tumor-specific treatments.
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    Construction and characterization of a humanized SLCO1B1 rat model with its application in evaluating the uptake of different statins

    Yuanjin ZhangJunze HuangShengbo HuangJie Liu...
    1592-1604页
    查看更多>>摘要：Organic anion-transporting polypeptides 1B1(OATP1B1)plays a crucial role in the transport of statins.However,there are too few animal models related to OATP1B1,especially humanized animal models.In this study,the human SLCO1B1 cDNA was inserted into the second exon of the rat Slcolb2 gene using CRISPR/Cas9 technology.Pharmacokinetic characteristics of statins were conducted in wild-type(WT),humanized OATP1B1(hOATP1B1),and OATP1B2 knockout(OATP1B2 KO)rats,respec-tively.The results showed that human OATP1B1 was successfully expressed in rat liver and exhibited transport function.Furthermore,the pharmacokinetic results revealed that OATP1B1 exhibited varying uptake levels of pivastatin,rosuvastatin,and fluvastatin,leading to different levels of exposure within the body.These results were consistent with those obtained from in vitro experiments using overexpressed cell lines.In conclusion,we established a novel humanized SLCO1B1 transgenic rat model to assess the role of human OATP1B1 in the uptake of different statins.The different uptake mediated by OATP1B1 may be an important reason for the different efficacy of statins.The hOATP1B1 rat is a promising model for improving the prediction of human drug transport.
      原文链接:
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    FGF4 protects the liver from immune-mediated injury by activating CaMKKβ-PINK1 signal pathway to inhibit hepatocellular apoptosis

    Zhifeng HuangTongtong PanLiang XuLu Shi...
    1605-1623页
    查看更多>>摘要：Immune-mediated liver injury(ILI)is a condition where an aberrant immune response due to various triggers causes the destruction of hepatocytes.Fibroblast growth factor 4(FGF4)was recently identified as a hepatoprotective cytokine;however,its role in ILI remains unclear.In patients with auto-immune hepatitis(type of ILI)and mouse models of concanavalin A(ConA)-or S-100-induced ILI,we observed a biphasic pattern in hepatic FGF4 expression,characterized by an initial increase followed by a return to basal levels.Hepatic FGF4 deficiency activated the mitochondria-associated intrinsic apoptotic pathway,aggravating hepatocellular apoptosis.This led to intrahepatic immune hyper-reactivity,inflammation accentuation,and subsequent liver injury in both ILI models.Conversely,administration of recombinant FGF4 reduced hepatocellular apoptosis and rectified immune imbalance,thereby mitigating liver damage.The beneficial effects of FGF4 were mediated by hepatocellular FGF receptor 4,which activated the Ca2+/calmodulin-dependent protein kinasekinase 2(CaMKKβ)and its downstream phos-phatase and tensin homologue-induced putative kinase 1(PINK1)-dependent B-cell lymphoma 2-like protein 1-isoform L(Bcl-XL)signalling axis in the mitochondria.Hence,FGF4 serves as an early response factor and plays a protective role against ILI,suggesting a therapeutic potential of FGF4 and its analogue for treating clinical immune disorder-related liver injuries.
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    Blockade of the deubiquitinating enzyme USP48 degrades oncogenic HMGA2 and inhibits colorectal cancer invasion and metastasis

    Can ChengHanhui YaoHeng LiJingwen Liu...
    1624-1643页
    查看更多>>摘要：HMGA2,a pivotal transcription factor,functions as a versatile regulator implicated in the progression of diverse aggressive malignancies.In this study,mass spectrometry was employed to iden-tify ubiquitin-specific proteases that potentially interact with HMGA2,and USP48 was identified as a deubiquitinating enzyme of HMGA2.The enforced expression of USP48 significantly increased HMGA2 protein levels by inhibiting its degradation,while the deprivation of USP48 promoted HMGA2 degradation,thereby suppressing tumor invasion and metastasis.We discovered that USP48 un-dergoes SUMOylation at lysine 258,which enhances its binding affinity to HMGA2.Through subsequent phenotypic screening of small molecules,we identified DUB-IN-2 as a remarkably potent pharmacolog-ical inhibitor of USP48.Interestingly,the small-molecule inhibitor targeting USP48 induces destabiliza-tion of HMGA2.Clinically,upregulation of USP48 or HMGA2 in cancerous tissues is indicative of poor prognosis for patients with colorectal cancer(CRC).Collectively,our study not only elucidates the reg-ulatory mechanism of DUBs involved in HMGA2 stability and validates USP48 as a potential therapeutic target for CRC,but also identifies DUB-IN-2 as a potent inhibitor of USP48 and a promising candidate for CRC treatment.
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    Engagement of N6-methyladenisine methylation of Gng4 mRNA in astrocyte dysfunction regulated by CircHECW2

    Ying BaiDi ChangHui RenMinzi Ju...
    1644-1660页
    查看更多>>摘要：The N6-methyladenosine(m6A)modification is the most prevalent modification of eukaryotic mRNAs and plays a crucial role in various physiological processes by regulating the stability or function of target mRNAs.Accumulating evidence has suggested that m6A methylation may be involved in the pathological process of major depressive disorder(MDD),a common neuropsychiatric disorder with an unclear aetiology.Here,we found that the levels of the circular RNA HECW2(circHECW2)were significantly increased in the plasma of both MDD patients and the chronic unpredictable stress(CUS)mouse model.Notably,the downregulation of circHECW2 attenuated astrocyte dysfunction and depression-like behaviors induced by CUS.Furthermore,we demonstrated that the downregulation of cir-cHECW2 increased the expression of the methylase WTAP,leading to an increase in Gng4 expression via m6A modifications.Our findings provide functional insight into the correlation between circHECW2 and m6A methylation,suggesting that circHECW2 may represent a potential target for MDD treatment.
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