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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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    Fenofibrate-promoted hepatomegaly and liver regeneration are PPARα-dependent and partially related to the YAP pathway

    Shicheng FanYue GaoPengfei ZhaoGuomin Xie...
    2992-3008页
    查看更多>>摘要：Fenofibrate,a peroxisome proliferator-activated receptor α(PPARα)agonist,is widely prescribed for hyperlipidemia management.Recent studies also showed that it has therapeutic potential in various liver diseases.However,its effects on hepatomegaly and liver regeneration and the involved mechanisms remain unclear.Here,the study showed that fenofibrate significantly promoted liver enlargement and regeneration post-partial hepatectomy in mice,which was dependent on hepatocyte-expressed PPARα.Yes-associated protein(YAP)is pivotal in manipulating liver growth and regeneration.We further identified that fenofibrate activated YAP signaling by suppressing its K48-linked ubiquitina-tion,promoting its K63-linked ubiquitination,and enhancing the interaction and transcriptional activity of the YAP-TEAD complex.Pharmacological inhibition of YAP-TEAD interaction using verteporfin or suppression of YAP using AAV Yap shRNA in mice significantly attenuated fenofibrate-induced hepatomegaly.Other factors,such as MYC,KRT23,RAS,and RHOA,might also participate in fenofibrate-promoted hepatomegaly and liver regeneration.These studies demonstrate that fenofibrate-promoted liver enlargement and regeneration are PPARα-dependent and partially through activating the YAP signaling,with clinical implications of fenofibrate as a novel therapeutic agent for promoting liver regeneration.
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    Exosomes derived from tumor adjacent fibroblasts efficiently target pancreatic tumors

    Saini SetuaShabia ShabirPoornima ShajiAna Martinez Bulnes...
    3009-3026页
    查看更多>>摘要：The application of extracellular vesicles,particularly exosomes(EXs),is rapidly expanding in the field of medicine,owing to their remarkable properties as natural carriers of biological cargo.This study investigates utilization of exosomes derived from stromal cells of tumor adjacent normal tissues(NAF-EXs)for personalized medicine,which can be derived at the time of diagnosis by endoscopic ul-trasound.Herein,we show that exosomes(EXs)derived from NAFs demonstrate differential bio-physical characteristics,efficient cellular internalization,drug loading efficiency,pancreatic tumor targeting and delivery of payloads.NAF-derived EXs(NAF-EXs)were used for loading ormeloxifene(ORM),a potent anti-cancer and desmoplasia inhibitor as a model drug.We found that ORM maintains normal fibroblast cell phenotype and renders them incompatible to be triggered for a CAF-like phenotype,which may be due to regulation of Ca2+influx in fibroblast cells.NAF-EXs-ORM effectively blocked oncogenic signaling pathways involved in desmoplasia and epithelial mesenchymal transition(EMT)and repressed tumor growth in xenograft mouse model.In conclusion,our data suggests preferential tropism of NAF-EXs for PDAC tumors,thus imply feasibility of developing a novel personalized med-icine for PDAC patients using autologous NAF-EXs for improved therapeutic outcome of anti-cancer drugs.Additionally,it provides the opportunity of utilizing this biological scaffold for effective therapeu-tics in combination with standard therapeutic regimen.
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    ASF1A-dependent P300-mediated histone H3 lysine 18 lactylation promotes atherosclerosis by regulating EndMT

    Mengdie DongYunjia ZhangMinghong ChenYongkang Tan...
    3027-3048页
    查看更多>>摘要：Endothelial-to-mesenchymal transition(EndMT)is a key driver of atherosclerosis.Aerobic glycolysis is increased in the endothelium of atheroprone areas,accompanied by elevated lactate levels.Histone lactylation,mediated by lactate,can regulate gene expression and participate in disease regula-tion.However,whether histone lactylation is involved in atherosclerosis remains unknown.Here,we report that lipid peroxidation could lead to EndMT-induced atherosclerosis by increasing lactate-dependent histone H3 lysine 18 lactylation(H3K181a)in vitro and in vivo,as well as in atherosclerotic patients'arteries.Mechanistically,the histone chaperone ASF1A was first identified as a cofactor of P300,which precisely regulated the enrichment of H3K181a at the promoter of SNAI1,thereby activating SNAI1 transcription and promoting EndMT.We found that deletion of ASF1A inhibited EndMT and improved endothelial dysfunction.Functional analysis based on ApoeKOAsf1aECKO mice in the athero-sclerosis model confirmed the involvement of H3K181a in atherosclerosis and found that endothelium-specific ASF1A deficiency inhibited EndMT and alleviated atherosclerosis development.Inhibition of glycolysis by pharmacologic inhibition and advanced PROTAC attenuated H3K181a,SNAI1 transcription,and EndMT-induced atherosclerosis.This study illustrates precise crosstalk between metabolism and epi-genetics via H3K181a by the P300/ASF1A molecular complex during EndMT-induced atherogenesis,which provides emerging therapies for atherosclerosis.
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    PIM1-HDAC2 axis modulates intestinal homeostasis through epigenetic modification

    Jianming YangYawen XiaoNingning ZhaoGeng Pei...
    3049-3067页
    查看更多>>摘要：The mucosal barrier is crucial for intestinal homeostasis,and goblet cells are essential for maintaining the mucosal barrier integrity.The proviral integration site for Moloney murine leukemia virus-1(PIM1)kinase regulates multiple cellular functions,but its role in intestinal homeostasis during colitis is unknown.Here,we demonstrate that PIM1 is prominently elevated in the colonic epithelia of both ulcerative colitis patients and murine models,in the presence of intestinal microbiota.Epithelial PIM1 leads to decreased goblet cells,thus impairing resistance to colitis and colitis-associated colorectal cancer(CAC)in mice.Mechanistically,PIM1 modulates goblet cell differentiation through the Wnt and Notch signaling pathways.Interestingly,PIM1 interacts with histone deacetylase 2(HDAC2)and down-regulates its level via phosphorylation,thereby altering the epigenetic profiles of Wnt signaling pathway genes.Collectively,these findings investigate the unknown function of the PIM1-HDAC2 axis in goblet cell differentiation and ulcerative colitis/CAC pathogenesis,which points to the potential for PIM1-targeted therapies of ulcerative colitis and CAC.
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    Gut commensal metabolite rhamnose promotes macrophages phagocytosis by activating SLC12A4 and protects against sepsis in mice

    Dongping LiRongjuan WeiXianglong ZhangShenhai Gong...
    3068-3085页
    查看更多>>摘要：Sepsis progression is significantly associated with the disruption of gut eubiosis.However,the modulatory mechanisms of gut microbiota operating during sepsis are still unclear.Herein,we investigated how gut commensals impact sepsis development in a pre-clinical model.Cecal ligation and puncture(CLP)surgery was used to establish polymicrobial sepsis in mice.Mice depleted of gut microbiota by an antibiotic cocktail(ABX)exhibited a significantly higher level of mortality than controls.As determined by metabolomics analysis,ABX treatment has depleted many metabolites,and subsequent supplementation with L-rhamnose(rhamnose,Rha),a bacterial carbohydrate metabolite,exerted profound immunomodulatory properties with a significant enhancement in macrophage phagocytosis,which in turn improved organ damage and mortality.Mechanistically,rhamnose binds directly to and activates the solute carrier family 12(potassium-chloride symporter),member 4(SLC12A4)in macrophages and promotes phagocytosis by activating the small G-proteins,Ras-related C3 botulinum toxin substrate1(Rac1)and cell division control protein 42 homolog(Cdc42).Interestingly,rhamnose has enhanced the phagocytosis capacity of macrophages from sepsis patients.In conclusion,by identifying SLC12A4 as the host interacting protein,we disclosed that the gut commensal metabolite rhamnose is a functional molecular that could promote the phagocytosis capacity of macrophages and protect the host against sepsis.
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    Deep simulated annealing for the discovery of novel dental anesthetics with local anesthesia and anti-inflammatory properties

    Yihang HaoHaofan WangXianggen LiuWenrui Gai...
    3086-3109页
    查看更多>>摘要：Multifunctional therapeutics have emerged as a solution to the constraints imposed by drugs with singular or insufficient therapeutic effects.The primary challenge is to integrate diverse pharmaco-phores within a single-molecule framework.To address this,we introduced DeepSA,a novel edit-based generative framework that utilizes deep simulated annealing for the modification of articaine,a well-known local anesthetic.DeepSA integrates deep neural networks into metaheuristics,effectively constraining molecular space during compound generation.This framework employs a sophisticated objective function that accounts for scaffold preservation,anti-inflammatory properties,and covalent constraints.Through a sequence of local editing to navigate the molecular space,DeepSA successfully identified AT-17,a derivative exhibiting potent analgesic properties and significant anti-inflammatory activity in various animal models.Mechanistic insights into AT-17 revealed its dual mode of action:selective inhibition of Nav1.7 and 1.8 channels,contributing to its prolonged local anesthetic effects,and suppression of inflammatory mediators via modulation of the NLRP3 inflammasome pathway.These findings not only highlight the efficacy of AT-17 as a multifunctional drug candidate but also highlight the potential of DeepSA in facilitating AI-enhanced drug discovery,particularly within stringent chemical constraints.
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    Design and optimization of piperidine-substituted thiophene[3,2-d]pyrimidine-based HIV-1 NNRTIs with improved drug resistance and pharmacokinetic profiles

    Yanying SunZhenzhen ZhouZhongling ShiFabao Zhao...
    3110-3124页
    查看更多>>摘要：HIV-1 reverse transcriptase(RT)has received great attention as an attractive therapeutic target for acquired immune deficiency syndrome(AIDS),but the inevitable drug resistance and side ef-fects have always been major challenges faced by non-nucleoside reverse transcriptase inhibitors(NNRTIs).This work aimed to identify novel chemotypes of anti-HIV-1 agents with improved drug-resistance profiles,reduced toxicity,and excellent druggability.A series of diarylpyrimidine(DAPY)de-rivatives were prepared via structural modifications of the leads K-5a2 and 25a.Among them,15a with dimethylphosphine oxide moiety showed the most prominent antiviral potency against all of the tested viral panel,being 1.6-fold(WT,EC50=1.75 nmol/L),3.0-fold(L100I,EC50=2.84 nmol/L),2.4-fold(K103N,EC50=1.27 nmol/L),3.3-fold(Y181C,EC50=5.38 nmol/L),2.9-fold(Y188L,EC50=7.96 nmol/L),2.5-fold(E138K,EC50=4.28 nmol/L),4.8-fold(F227L/V106A,EC50=3.76 nmol/L)and 5.3-fold(RES056,EC50=15.8 nmol/L)more effective than that of the marketed drug ETR.Molecular docking results illustrated the detailed interactions formed by compound 15a and WT,F227L/V106A,and RES056 RT.Moreover,15a·HCl carried outstanding pharmacokinetic(t1/2=1.32 h,F=40.8％)and safety profiles(LD50＞2000 mg/kg),which demonstrated that 15a HCl is a potential anti-HIV-1 drug candidate.
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    Glycnsisitin A:A promising bicyclic peptide against heart failure that facilitates TFRC-mediated uptake of iron in cardiomyocytes

    Jichao ZhouYuanyuan LiuXiaoli WeiMeng Yuan...
    3125-3139页
    查看更多>>摘要：Zhigancao decoction is a traditional prescription for treating irregular pulse and palpitations in China.As the monarch drug of Zhigancao decoction,the bioactive molecules of licorice against heart diseases remain elusive.We established the HRESIMS-guided method leading to the isolation of three novel bicyclic peptides,glycnsisitins A-C(1-3),with distinctive C-C and C-O-C side-chain-to-side-chain linkages from the roots of Glycyrrhiza uralensis(Licorice).Glycnsisitin A demonstrated stronger cardioprotective activity than glycnsisitins B and C in an in vitro model of doxorubicin(DOX)-induced cardiomyocyte injury.Glycnsisitin A treatment not only reduced the mortality of heart failure(HF)mice in a dose-dependent manner but also significantly attenuated DOX-induced cardiac dysfunction and myocardial fibrosis.Gene set enrichment analysis(GSEA)of the differentially expressed genes indicated that the cardioprotective effect of glycnsisitin A was mainly attributed to its ability to maintain iron homeostasis in the myocardium.Mechanistically,glycnsisitin A interacted with transferrin and facilitated its binding to the transferrin receptor(TFRC),which caused increased uptake of iron in cardiomyocytes.These findings highlight the key role of bicyclic peptides as bioactive molecules of Zhi-gancao decoction for the treatment of HF,and glycnsisitin A constitutes a promising therapeutic agent for the treatment of HF.
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    Selectively T cell phosphorylation activation of azvudine in the thymus tissue with immune protection effect

    Ning ShengRui LiYang LiZhe Wang...
    3140-3154页
    查看更多>>摘要：Thymus is the important immune organ,responsible for T cell development and differentiation.The lower circulating T counts have been observed in patients who died from COVID-19 compared with survivors.Azvudine,also known as FNC,is a thymus-homing anti-SARS-CoV-2 drug in treating COVID-19 patients.In this study,single-cell transcriptome,prote-omics,and parallel reaction monitoring(PRM)were applied to insight into the activation process of FNC in rat and SARS-CoV-2 rhesus monkey thymus.The results indicated that thymic immune cells possess a robust metabolic capacity for cytidine-analogue drugs such as FNC.Key enzymes involved in the FNC phosphorylation process,such as Dck,Cmpk1,and Nme2,were highly expressed in CD4+T cells,CD8+T cells,and DP(CD4+CD8+)cells.Additionally,FNC could upregulate multiple phosphorylated kinases in various cell types while downregulating the phosphatases,phosphoribosyl transferases,and deaminases,respectively.The robust phosphorylation capacity of the thymus for cytidine analogue drug FNC,and the activation effect of FNC on the NAs metabolism system potentially contribute to its enrichment in the thymus and immune protection effect.This suggests that it is crucial to consider the expression level of phosphorylation kinases when evaluating NA drug properties,as an important factor during antiviral drug design.
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    Julolidinyl aza-BODIPYs as NIR-Ⅱ fluorophores for the bioimaging of nanocarriers

    Chang LiuYifan CaiZichen ZhangYi Lu...
    3155-3168页
    查看更多>>摘要：The aggregation-caused quenching(ACQ)rationale has been employed to improve the fluorescence imaging accuracy of nanocarriers by precluding free probe-derived interferences.However,its usefulness is undermined by limited penetration and low spatiotemporal resolution of NIR-Ⅰ(700-900 nm)bioimaging owing to absorption and diffraction by biological tissues and tissue-derived autofluorescence.This study aimed to develop ACQ-based NIR-Ⅱ(1000-1700 nm)probes to further improve the imaging resolution and accuracy.The strategy employed is to install highly planar and electron-rich julolidine into the 3,5-position of aza-BODIPY based on the larger substituent effects.The newly developed probes displayed remarkable photophysical properties,with intense absorption centered at approximately 850 nm and bright emission in the 950-1300 nm region.Compared with the NIR-Ⅰ counterpart P2,the NIR-Ⅱ probes demonstrated superior water sensitivity and quenching stability.ACQ1 and ACQ6 exhibited more promising ACQ effects with absolute fluorescence quenching at water fractions above 40％and higher quenching stability with less than 2.0％fluorescence reillumination in plasma after 24 h of incubation.Theoretical calculations verified that molecular planarity is more important than hydrophobicity for ACQ properties.Additionally,in vivo and ex vivo reillumination studies revealed less than 2.5％signal interference from prequenched ACQ1,in contrast to 15％for P2.
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