Biochemical pharmacology最新文献_第7页

The myocardial ischemic cascade network and multi-target synergistic interventions: From molecular mechanisms to therapeutic innovations 心肌缺血级联网络和多靶点协同干预：从分子机制到治疗创新

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-14 DOI: 10.1016/j.bcp.2026.117704

Lei Qi , Jia Yi , Yuntian Shen , Haiyan Jiang , Xinlei Yao , Bingqian Chen , Hualin Sun

Myocardial ischemic injury involves a multi-layered pathological cascade driven by interconnected energy metabolism disorders, calcium overload, oxidative stress, mitochondrial dysfunction, and inflammatory responses. Ischemia-hypoxia impairs mitochondrial oxidative phosphorylation, causing ATP depletion, acidosis, and calcium overload. Reperfusion exacerbates injury through ROS burst, mPTP opening, and NLRP3 inflammasome activation, leading to pro-inflammatory cytokine release. Sustained endoplasmic reticulum stress promotes apoptosis via the PERK/CHOP pathway, forming a vicious cycle with oxidative stress and inflammation. These processes collectively trigger diverse programmed cell death modalities—apoptosis, pyroptosis, ferroptosis, necroptosis, and cuproptosis—while microcirculatory disturbances cause the “no-reflow” phenomenon, culminating in irreversible damage. Therapeutic strategies are shifting from revascularization to multi-target interventions. Reperfusion injury is mitigated by ischemic conditioning (IPoC, RIC) via RISK/SAFE pathways and ALDH2-SIRT3 axis activation. Cell death is targeted using ferroptosis inhibitors (e.g., Liproxstatin-1), NLRP3/caspase-1 blockers, and autophagy regulators (e.g., Astragaloside IV). Mitochondrial/metabolic therapies include mitochondrial-targeted drugs (e.g., CsA@PLGA-PEG-SS31), metabolic modulators (Trimetazidine), and neuroendocrine agents (ARNI, SGLT2 inhibitors). Regenerative approaches employ stem cells/exosomes, gene therapy, and tissue engineering via paracrine signaling. Precision medicine integrates multi-omics and AI for risk stratification, while biomimetic nanocarriers enhance drug delivery. Future therapies should co-target the “energy-death-inflammation” network to advance myocardial ischemia treatment toward systemic repair and improved clinical outcomes.

心肌缺血损伤涉及一个多层次的病理级联反应，由相互关联的能量代谢紊乱、钙超载、氧化应激、线粒体功能障碍和炎症反应驱动。缺血-缺氧损害线粒体氧化磷酸化，引起ATP耗竭、酸中毒和钙超载。再灌注通过ROS爆发、mPTP开放和NLRP3炎性体激活加剧损伤，导致促炎细胞因子释放。持续的内质网应激通过PERK/CHOP途径促进细胞凋亡，与氧化应激和炎症形成恶性循环。这些过程共同引发不同的程序性细胞死亡模式——凋亡、焦亡、铁亡、坏死亡和铜亡——而微循环紊乱导致“无回流”现象，最终导致不可逆的损伤。治疗策略正从血运重建术转向多靶点干预。缺血调节（IPoC， RIC）通过RISK/SAFE通路和ALDH2-SIRT3轴激活减轻再灌注损伤。细胞死亡的目标是使用铁凋亡抑制剂（如利普司他汀-1）、NLRP3/caspase-1阻滞剂和自噬调节剂（如黄芪甲苷IV）。线粒体/代谢治疗包括线粒体靶向药物（例如CsA@PLGA-PEG-SS31）、代谢调节剂（曲美他嗪）和神经内分泌药物（ARNI、SGLT2抑制剂）。再生方法采用干细胞/外泌体、基因治疗和通过旁分泌信号传导的组织工程。精准医学结合多组学和人工智能进行风险分层，仿生纳米载体增强药物传递。未来的治疗应共同靶向“能量-死亡-炎症”网络，以推进心肌缺血治疗走向全身修复和改善临床结果。

{"title":"The myocardial ischemic cascade network and multi-target synergistic interventions: From molecular mechanisms to therapeutic innovations","authors":"Lei Qi , Jia Yi , Yuntian Shen , Haiyan Jiang , Xinlei Yao , Bingqian Chen , Hualin Sun","doi":"10.1016/j.bcp.2026.117704","DOIUrl":"10.1016/j.bcp.2026.117704","url":null,"abstract":"<div><div>Myocardial ischemic injury involves a multi-layered pathological cascade driven by interconnected energy metabolism disorders, calcium overload, oxidative stress, mitochondrial dysfunction, and inflammatory responses. Ischemia-hypoxia impairs mitochondrial oxidative phosphorylation, causing ATP depletion, acidosis, and calcium overload. Reperfusion exacerbates injury through ROS burst, mPTP opening, and NLRP3 inflammasome activation, leading to pro-inflammatory cytokine release. Sustained endoplasmic reticulum stress promotes apoptosis via the PERK/CHOP pathway, forming a vicious cycle with oxidative stress and inflammation. These processes collectively trigger diverse programmed cell death modalities—apoptosis, pyroptosis, ferroptosis, necroptosis, and cuproptosis—while microcirculatory disturbances cause the “no-reflow” phenomenon, culminating in irreversible damage. Therapeutic strategies are shifting from revascularization to multi-target interventions. Reperfusion injury is mitigated by ischemic conditioning (IPoC, RIC) via RISK/SAFE pathways and ALDH2-SIRT3 axis activation. Cell death is targeted using ferroptosis inhibitors (e.g., Liproxstatin-1), NLRP3/caspase-1 blockers, and autophagy regulators (e.g., Astragaloside IV). Mitochondrial/metabolic therapies include mitochondrial-targeted drugs (e.g., CsA@PLGA-PEG-SS31), metabolic modulators (Trimetazidine), and neuroendocrine agents (ARNI, SGLT2 inhibitors). Regenerative approaches employ stem cells/exosomes, gene therapy, and tissue engineering via paracrine signaling. Precision medicine integrates multi-omics and AI for risk stratification, while biomimetic nanocarriers enhance drug delivery. Future therapies should co-target the “energy-death-inflammation” network to advance myocardial ischemia treatment toward systemic repair and improved clinical outcomes.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"246 ","pages":"Article 117704"},"PeriodicalIF":5.6,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145975607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

LIFR antagonism reverses epithelial pro-CAF programs in pancreatic ductal adenocarcinoma LIFR拮抗剂逆转胰腺导管腺癌上皮前caf程序。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-14 DOI: 10.1016/j.bcp.2026.117707

Cristina Di Giorgio , Maria Rosaria Sette , Benedetta Sensini , Eleonora Giannelli , Ginevra Lachi , Silvia Marchianò , Francesca Paniconi , Carmen Massa , Ginevra Urbani , Rosa De Gregorio , Valentina Sepe , Maria Chiara Monti , Federica Moraca , Bruno Catalanotti , Fabio Cartaginese , Eleonora Distrutti , Angela Zampella , Michele Biagioli , Stefano Fiorucci

Extracellular matrix remodelling that occurs in pancreatic ductal adenocarcinoma (PDAC) is considered a promoting factor of cancer growth, immune evasion and therapeutic resistance. Cancer-associated fibroblasts (CAFs) that constitute the dominant stromal population, arise primarily from activated pancreatic stellate cells and display remarkable functional heterogeneity, encompassing inflammatory iCAFs and contractile myCAFs. Although epithelial-stromal communication is central to PDAC biology, the upstream mechanisms that prime tumour cells toward CAF-Activating cells remain incompletely defined. The leukaemia inhibitory factor (LIF), a pleiotropic cytokine of the IL-6 family, is highly expressed in PDAC and has been implicated in tumour progression. However, the role of LIF and LIF receptor (LIFR):gp130 complex in promoting CAF activation is poorly defined. Here, we combined human PDAC transcriptomics, immunofluorescence and epithelial-stromal co-culture assays to define LIF-driven pro-CAF programs and evaluate their pharmacological reversibility. In PDAC cancer cells, MIAPaCa-2 cells, LIF induced a coordinated transcriptional network encompassing inflammatory mediators, paracrine fibroblast-activating signals and ECM/mechanotransductive modules, while repressing stromal-inhibitory genes. These signatures were recapitulated in PDAC tissues, where LIF expression directly correlated with CAF markers and with stromal remodelling genes. On this background, we have developed a novel steroidal LIFR antagonist, LRI310, and evaluate its effects on LIF:LIFR axis. Exposure of PDCA cell lines to LRI310 suppresses STAT3 activation and counteracts effects of LIF on proliferation and CAF-inducing transcriptional programs. Collectively, these findings identify LIF as an important epithelial driver of CAF-oriented transcriptional programs in PDAC and support the development of LIFR antagonism as a promising strategy to modulate the desmoplastic microenvironment.

发生在胰腺导管腺癌（PDAC）的细胞外基质重构被认为是促进肿瘤生长、免疫逃避和治疗抵抗的因素。癌相关成纤维细胞（CAFs）构成了主要的基质群体，主要来自活化的胰腺星状细胞，并显示出显著的功能异质性，包括炎症性icaf和收缩性myCAFs。尽管上皮间质通讯是PDAC生物学的核心，但将肿瘤细胞引向cafa激活细胞的上游机制仍未完全确定。白血病抑制因子（LIF）是IL-6家族的一种多效性细胞因子，在PDAC中高度表达，并与肿瘤进展有关。然而，LIF和LIF受体（LIFR）：gp130复合物在促进CAF激活中的作用尚不明确。在这里，我们结合了人类PDAC转录组学，免疫荧光和上皮-基质共培养分析来定义lifd驱动的前caf程序并评估其药理学可逆性。在PDAC癌细胞、MIAPaCa-2细胞中，LIF诱导了一个协调的转录网络，包括炎症介质、旁分泌成纤维细胞激活信号和ECM/机械转导模块，同时抑制基质抑制基因。这些特征在PDAC组织中重现，其中LIF表达与CAF标记物和基质重塑基因直接相关。在此背景下，我们开发了一种新的甾体LIFR拮抗剂LRI310，并评估了其对LIFR轴的作用。暴露于LRI310的PDCA细胞系可抑制STAT3的激活，并抵消LIF对增殖和ca诱导转录程序的影响。总的来说，这些发现确定了LIFR是PDAC中ca导向转录程序的重要上皮驱动因素，并支持LIFR拮抗剂作为调节结缔组织微环境的有前途的策略的发展。

{"title":"LIFR antagonism reverses epithelial pro-CAF programs in pancreatic ductal adenocarcinoma","authors":"Cristina Di Giorgio , Maria Rosaria Sette , Benedetta Sensini , Eleonora Giannelli , Ginevra Lachi , Silvia Marchianò , Francesca Paniconi , Carmen Massa , Ginevra Urbani , Rosa De Gregorio , Valentina Sepe , Maria Chiara Monti , Federica Moraca , Bruno Catalanotti , Fabio Cartaginese , Eleonora Distrutti , Angela Zampella , Michele Biagioli , Stefano Fiorucci","doi":"10.1016/j.bcp.2026.117707","DOIUrl":"10.1016/j.bcp.2026.117707","url":null,"abstract":"<div><div>Extracellular matrix remodelling that occurs in pancreatic ductal adenocarcinoma (PDAC) is considered a promoting factor of cancer growth, immune evasion and therapeutic resistance. Cancer-associated fibroblasts (CAFs) that constitute the dominant stromal population, arise primarily from activated pancreatic stellate cells and display remarkable functional heterogeneity, encompassing inflammatory iCAFs and contractile myCAFs. Although epithelial-stromal communication is central to PDAC biology, the upstream mechanisms that prime tumour cells toward CAF-Activating cells remain incompletely defined. The leukaemia inhibitory factor (LIF), a pleiotropic cytokine of the IL-6 family, is highly expressed in PDAC and has been implicated in tumour progression. However, the role of LIF and LIF receptor (LIFR):gp130 complex in promoting CAF activation is poorly defined. Here, we combined human PDAC transcriptomics, immunofluorescence and epithelial-stromal co-culture assays to define LIF-driven pro-CAF programs and evaluate their pharmacological reversibility. In PDAC cancer cells, MIAPaCa-2 cells, LIF induced a coordinated transcriptional network encompassing inflammatory mediators, paracrine fibroblast-activating signals and ECM/mechanotransductive modules, while repressing stromal-inhibitory genes. These signatures were recapitulated in PDAC tissues, where LIF expression directly correlated with CAF markers and with stromal remodelling genes. On this background, we have developed a novel steroidal LIFR antagonist, LRI310, and evaluate its effects on LIF:LIFR axis. Exposure of PDCA cell lines to LRI310 suppresses STAT3 activation and counteracts effects of LIF on proliferation and CAF-inducing transcriptional programs. Collectively, these findings identify LIF as an important epithelial driver of CAF-oriented transcriptional programs in PDAC and support the development of LIFR antagonism as a promising strategy to modulate the desmoplastic microenvironment.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"246 ","pages":"Article 117707"},"PeriodicalIF":5.6,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145987825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Inhibition of Ca2+-activated chloride channels by the NSAID meclofenamate for anti-diarrhea 非甾体抗炎药甲氯芬酯抗腹泻对Ca2+激活的氯离子通道的抑制作用。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-14 DOI: 10.1016/j.bcp.2026.117710

Qinqin Li , Huan Shi , Ping Zhou , Xiangyu Li , Yani Liu , KeWei Wang

Dysfunctional calcium-activated chloride channels (CaCCs) are implicated in many pathological phenotypes and diseases. The CaCC ANO1/TMEM16A robustly expressed in epithelial cells plays an essential role in regulation of Cl^- secretion and intestinal motility. In this study, we investigated the effects of a nonsteroidal anti-inflammatory drug (NSAID) meclofenamate on ANO1 channel and dextran sulfate sodium (DSS)-induced diarrhea in mice. Meclofenamate inhibits CaCC ANO1 channel in a concentration-dependent manner with an IC₅₀ of 16.2 ± 2.7 μM. Meclofenamate also reduces single-channel open probability without altering the channel conductance. Molecular docking and site-directed mutagenesis demonstrate that residues R515, R535 and E654 are important for meclofenamate-mediated ANO1 inhibition. Selectivity evaluation demonstrates that meclofenamate also inhibits other CaCCs, including ANO2, ANO6 and Bestrophin-1 with IC₅₀ values ranging from approximately 10 to 20 μM. Further in vivo experiments show that meclofenamate dose-dependently reduces intestinal peristalsis and diarrhea induced by DSS in mice. Altogether, our findings reveal a novel role of meclofenamate in inhibiting CaCC currents and alleviating DSS-induced acute diarrhea, thus holding repurposing potential for therapy of diarrhea or gastrointestinal dysfunction.

功能失调的钙活化氯离子通道（CaCCs）与许多病理表型和疾病有关。在上皮细胞中强烈表达的cac ANO1/TMEM16A在调节Cl-分泌和肠蠕动中起重要作用。在这项研究中，我们研究了非甾体抗炎药（NSAID）甲氯芬酯对ANO1通道和葡聚糖硫酸钠（DSS）诱导的小鼠腹泻的影响。甲氯芬酯抑制CaCC ANO1通道呈浓度依赖性，IC50为16.2 ± 2.7 μM。在不改变通道电导的情况下，甲氯芬酯也能降低单通道打开概率。分子对接和定点诱变表明，残基R515、R535和E654对甲氯芬酸介导的ANO1抑制很重要。选择性评价表明，甲氯芬酯还能抑制其他CaCCs，包括ANO2、ANO6和Bestrophin-1， IC50值约为10 ~ 20 μM。进一步的体内实验表明，甲氯芬酯能剂量依赖性地减少DSS引起的小鼠肠道蠕动和腹泻。总之，我们的研究结果揭示了甲氯芬酯在抑制CaCC电流和减轻dss诱导的急性腹泻方面的新作用，从而具有治疗腹泻或胃肠道功能障碍的潜力。

{"title":"Inhibition of Ca2+-activated chloride channels by the NSAID meclofenamate for anti-diarrhea","authors":"Qinqin Li , Huan Shi , Ping Zhou , Xiangyu Li , Yani Liu , KeWei Wang","doi":"10.1016/j.bcp.2026.117710","DOIUrl":"10.1016/j.bcp.2026.117710","url":null,"abstract":"<div><div>Dysfunctional calcium-activated chloride channels (CaCCs) are implicated in many pathological phenotypes and diseases. The CaCC ANO1/TMEM16A robustly expressed in epithelial cells plays an essential role in regulation of Cl<sup>-</sup> secretion and intestinal motility. In this study, we investigated the effects of a nonsteroidal anti-inflammatory drug (NSAID) meclofenamate on ANO1 channel and dextran sulfate sodium (DSS)-induced diarrhea in mice. Meclofenamate inhibits CaCC ANO1 channel in a concentration-dependent manner with an IC<sub>50</sub> of 16.2 ± 2.7 μM. Meclofenamate also reduces single-channel open probability without altering the channel conductance. Molecular docking and site-directed mutagenesis demonstrate that residues R515, R535 and E654 are important for meclofenamate-mediated ANO1 inhibition. Selectivity evaluation demonstrates that meclofenamate also inhibits other CaCCs, including ANO2, ANO6 and Bestrophin-1 with IC<sub>50</sub> values ranging from approximately 10 to 20 μM. Further <em>in vivo</em> experiments show that meclofenamate dose-dependently reduces intestinal peristalsis and diarrhea induced by DSS in mice. Altogether, our findings reveal a novel role of meclofenamate in inhibiting CaCC currents and alleviating DSS-induced acute diarrhea, thus holding repurposing potential for therapy of diarrhea or gastrointestinal dysfunction.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"246 ","pages":"Article 117710"},"PeriodicalIF":5.6,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145987822","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

DNMT1 knockdown mitigates sepsis-induced myocardial dysfunction by preventing TFAM-mediated mitochondrial DNA cytosolic escape and subsequent cGAS-STING to regulate macrophage M2 polarization DNMT1敲低可通过阻止tfam介导的线粒体DNA胞质逃逸和随后的cGAS-STING调节巨噬细胞M2极化，减轻败血症诱导的心肌功能障碍。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-14 DOI: 10.1016/j.bcp.2026.117709

Min Li , Yang Liu , Kuo Qu , Yu Zhang , Hailing Yang

Sepsis-induced myocardial dysfunction (SIMD) is a prevalent complication of sepsis and correlates with high mortality. The study investigated the effect of inhibiting DNA methyltransferase 1 (DNMT1) on SIMD and its potential mechanism. In this study, an SIMD mouse model was established using lipopolysaccharide (LPS). Two weeks before modeling, mice were intraperitoneally injected with the DNMT1 inhibitor decitabine or Vehicle. Pretreatment with the DNMT1 inhibitor decitabine in SIMD mice improved survival, cardiac function, and reduced cardiomyocyte apoptosis. In LPS-stimulated RAW264.7 macrophages, DNMT1 knockdown promoted M2 polarization while suppressing M1 polarization, and reduced apoptosis in cardiomyocytes cultured with conditioned media. Mechanistically, DNMT1 depletion upregulated mitochondrial transcription factor A (TFAM) by reducing DNA methylation modification, which alleviated mitochondrial dysfunction and limited mitochondrial DNA (mtDNA) release into the cytosol. This subsequently inactivated the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. TFAM downregulation reversed the improvement in mitochondrial function achieved by DNMT1 knockdown, while cGAS upregulation averted DNMT1 knockdown-inhibited mtDNA cytosolic escape-mediated cGAS-STING. In vivo validation confirmed this mechanism. Collectively, DNMT1 regulates mitochondrial dysfunction and cytosolic mtDNA release by modulating TFAM promoter DNA methylation, thereby activating the cGAS-STING pathway, further influencing macrophage polarization and cardiomyocyte apoptosis, and ultimately exacerbating SIMD.

脓毒症引起的心肌功能障碍（SIMD）是脓毒症的常见并发症，与高死亡率相关。本研究探讨了抑制DNA甲基转移酶1 （DNMT1）对SIMD的影响及其潜在机制。本研究采用脂多糖（LPS）建立SIMD小鼠模型。造模前2周，小鼠腹腔注射DNMT1抑制剂地西他滨或Vehicle。DNMT1抑制剂地西他滨预处理SIMD小鼠可改善生存、心功能并减少心肌细胞凋亡。在lps刺激的RAW264.7巨噬细胞中，DNMT1敲低促进M2极化，抑制M1极化，减少条件培养基培养的心肌细胞凋亡。从机制上说，DNMT1缺失通过减少DNA甲基化修饰来上调线粒体转录因子A (TFAM)，从而减轻线粒体功能障碍，限制线粒体DNA （mtDNA）释放到细胞质中。这随后使干扰素基因环GMP-AMP合成酶刺激因子（cGAS-STING）通路失活。TFAM下调逆转了DNMT1敲低实现的线粒体功能改善，而cGAS上调避免了DNMT1敲低抑制mtDNA胞质逃逸介导的cGAS- sting。体内验证证实了这一机制。综上所述，DNMT1通过调节TFAM启动子DNA甲基化调节线粒体功能障碍和胞质mtDNA释放，从而激活cGAS-STING通路，进而影响巨噬细胞极化和心肌细胞凋亡，最终加重SIMD。

{"title":"DNMT1 knockdown mitigates sepsis-induced myocardial dysfunction by preventing TFAM-mediated mitochondrial DNA cytosolic escape and subsequent cGAS-STING to regulate macrophage M2 polarization","authors":"Min Li , Yang Liu , Kuo Qu , Yu Zhang , Hailing Yang","doi":"10.1016/j.bcp.2026.117709","DOIUrl":"10.1016/j.bcp.2026.117709","url":null,"abstract":"<div><div>Sepsis-induced myocardial dysfunction (SIMD) is a prevalent complication of sepsis and correlates with high mortality. The study investigated the effect of inhibiting DNA methyltransferase 1 (DNMT1) on SIMD and its potential mechanism. In this study, an SIMD mouse model was established using lipopolysaccharide (LPS). Two weeks before modeling, mice were intraperitoneally injected with the DNMT1 inhibitor decitabine or Vehicle. Pretreatment with the DNMT1 inhibitor decitabine in SIMD mice improved survival, cardiac function, and reduced cardiomyocyte apoptosis. In LPS-stimulated RAW264.7 macrophages, DNMT1 knockdown promoted M2 polarization while suppressing M1 polarization, and reduced apoptosis in cardiomyocytes cultured with conditioned media. Mechanistically, DNMT1 depletion upregulated mitochondrial transcription factor A (TFAM) by reducing DNA methylation modification, which alleviated mitochondrial dysfunction and limited mitochondrial DNA (mtDNA) release into the cytosol. This subsequently inactivated the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. TFAM downregulation reversed the improvement in mitochondrial function achieved by DNMT1 knockdown, while cGAS upregulation averted DNMT1 knockdown-inhibited mtDNA cytosolic escape-mediated cGAS-STING. <em>In vivo</em> validation confirmed this mechanism. Collectively, DNMT1 regulates mitochondrial dysfunction and cytosolic mtDNA release by modulating TFAM promoter DNA methylation, thereby activating the cGAS-STING pathway, further influencing macrophage polarization and cardiomyocyte apoptosis, and ultimately exacerbating SIMD.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"246 ","pages":"Article 117709"},"PeriodicalIF":5.6,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145987871","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Optical control of H1 receptor signaling with a BODIPY-photocaged antihistamine bodipy光笼抗组胺药对H1受体信号的光学控制。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-13 DOI: 10.1016/j.bcp.2026.117705

Ivana Josimovic , Yang Zheng , Zhiyong Wang, Tiffany van der Meer, Maikel Wijtmans, Henry F. Vischer, Rob Leurs

Photopharmacology strives for light-dependent regulation of the activity of drug molecules, as a mean for precise control of drug targets on demand and the promise of reduced systemic side effects. Photocaging makes use of photoremovable protecting groups (PPGs), which can be introduced at key positions to inactivate drug ligands. Photocaged ligands can release active drug molecules following light-mediated uncaging with spatiotemporal precision. Here, a boron-dipyrromethene (BODIPY)-based PPG is used to inactivate desloratadine, which is a clinically used histamine H₁ receptor (H₁R) antagonist for the treatment of allergic disorders. The photocaged desloratadine analogue 1 (VUF25549) displays more than 290-fold lower H₁R affinity compared to desloratadine. Irradiation of 1 with 560 nm light results in photo-uncaging and the release of the parent drug desloratadine, resulting in optical modulation of histamine-induced H₁R signaling. The presented BODIPY-based photocaging of desloratadine offers a powerful new tool for the precise optical control of H₁R function.

光药理学致力于药物分子活性的光依赖性调节，作为一种精确控制药物靶点的手段，并有望减少全身副作用。光笼化利用了可光移保护基团（PPGs），它可以在关键位置引入以灭活药物配体。光笼化配体在光介导解封后释放出具有时空精度的活性药物分子。在这里，以硼-二吡咯甲基（BODIPY）为基础的PPG用于灭活地氯雷他定，地氯雷他定是一种临床使用的组胺H1受体（H1R）拮抗剂，用于治疗过敏性疾病。光笼化地氯雷他定类似物1 （VUF25549）显示比地氯雷他定低290倍以上的H1R亲和力。用560 nm光照射1导致光脱壳和母体药物地氯雷他定的释放，导致组胺诱导的H1R信号的光调制。所提出的基于bodip的地氯雷他定的光捕获为精确光学控制H1R功能提供了一种强有力的新工具。

{"title":"Optical control of H1 receptor signaling with a BODIPY-photocaged antihistamine","authors":"Ivana Josimovic , Yang Zheng , Zhiyong Wang, Tiffany van der Meer, Maikel Wijtmans, Henry F. Vischer, Rob Leurs","doi":"10.1016/j.bcp.2026.117705","DOIUrl":"10.1016/j.bcp.2026.117705","url":null,"abstract":"<div><div>Photopharmacology strives for light-dependent regulation of the activity of drug molecules, as a mean for precise control of drug targets on demand and the promise of reduced systemic side effects. Photocaging makes use of photoremovable protecting groups (PPGs), which can be introduced at key positions to inactivate drug ligands. Photocaged ligands can release active drug molecules following light-mediated uncaging with spatiotemporal precision. Here, a boron-dipyrromethene (BODIPY)-based PPG is used to inactivate desloratadine, which is a clinically used histamine H<sub>1</sub> receptor (H<sub>1</sub>R) antagonist for the treatment of allergic disorders. The photocaged desloratadine analogue <strong>1</strong> (VUF25549) displays more than 290-fold lower H<sub>1</sub>R affinity compared to desloratadine. Irradiation of <strong>1</strong> with 560 nm light results in photo-uncaging and the release of the parent drug desloratadine, resulting in optical modulation of histamine-induced H<sub>1</sub>R signaling. The presented BODIPY-based photocaging of desloratadine offers a powerful new tool for the precise optical control of H<sub>1</sub>R function.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"246 ","pages":"Article 117705"},"PeriodicalIF":5.6,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145987869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Valine availability controls oncogenic cell-cycle progression through translation of D-type cyclins 缬氨酸的有效性通过翻译d型细胞周期蛋白来控制致癌细胞周期的进程。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-13 DOI: 10.1016/j.bcp.2026.117706

Tomoaki Yamauchi , Runa Fukuzaki , Yumi Takahata , Yumi Okano , Kouki Suzuki , Akito Tsuruta , Shigehiro Ohdo , Satoru Koyanagi

Although rapid proliferation of cancer cells imposes a heightened demand for specific amino acids, the mechanistic links between amino acid availability and cell cycle regulation remain poorly defined. Valine, a branched-chain amino acid, is traditionally recognized for its role in protein synthesis and energy metabolism, but its direct influence on malignant cell growth has not been established. Here, we identify intracellular valine as a critical regulator of oncogenic cell cycle progression. Across murine hepatocarcinoma, breast cancer, renal cancer, colorectal adenocarcinoma, valine deprivation triggered G₀/G₁ phase arrest and potently suppressed their proliferation. Mechanistically, valine depletion upregulated eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), which repressed cyclin D1 and D2 translation by sequestering eukaryotic translation initiation factor 4E (eIF4E). Concurrently, valine deprivation induced Sestrin2 expression and inhibited mammalian target of rapamycin (mTOR) activity, converging to attenuate mRNA translation. These findings uncover a previously unrecognized role of valine as a direct molecular controller of the cancer cell cycle, acting through translational repression of D-type cyclins. Targeting exogenous valine supply, in combination with cell cycle–directed therapies, may offer a promising strategy to suppress the growth of malignant tumors.

尽管癌细胞的快速增殖增加了对特定氨基酸的需求，但氨基酸可用性和细胞周期调节之间的机制联系仍然不清楚。缬氨酸是一种支链氨基酸，传统上认为它在蛋白质合成和能量代谢中起作用，但它对恶性细胞生长的直接影响尚未确定。在这里，我们确定细胞内缬氨酸是致癌细胞周期进程的关键调节剂。在小鼠肝癌、乳腺癌、肾癌、结直肠腺癌中，缬氨酸剥夺可触发G0/G1期阻滞并有效抑制其增殖。从机制上讲，缬氨酸缺失上调真核翻译起始因子4E结合蛋白1 (4E- bp1)，该蛋白通过隔离真核翻译起始因子4E （eIF4E）抑制cyclin D1和D2的翻译。同时，缬氨酸剥夺诱导了Sestrin2的表达，抑制了哺乳动物雷帕霉素靶蛋白（mTOR）的活性，从而减弱mRNA的翻译。这些发现揭示了先前未被认识到的缬氨酸作为癌细胞周期的直接分子控制器的作用，通过d型细胞周期蛋白的翻译抑制起作用。靶向外源性缬氨酸供应，结合细胞周期导向疗法，可能为抑制恶性肿瘤的生长提供一种有希望的策略。

{"title":"Valine availability controls oncogenic cell-cycle progression through translation of D-type cyclins","authors":"Tomoaki Yamauchi , Runa Fukuzaki , Yumi Takahata , Yumi Okano , Kouki Suzuki , Akito Tsuruta , Shigehiro Ohdo , Satoru Koyanagi","doi":"10.1016/j.bcp.2026.117706","DOIUrl":"10.1016/j.bcp.2026.117706","url":null,"abstract":"<div><div>Although rapid proliferation of cancer cells imposes a heightened demand for specific amino acids, the mechanistic links between amino acid availability and cell cycle regulation remain poorly defined. Valine, a branched-chain amino acid, is traditionally recognized for its role in protein synthesis and energy metabolism, but its direct influence on malignant cell growth has not been established. Here, we identify intracellular valine as a critical regulator of oncogenic cell cycle progression. Across murine hepatocarcinoma, breast cancer, renal cancer, colorectal adenocarcinoma, valine deprivation triggered G<sub>0</sub>/G<sub>1</sub> phase arrest and potently suppressed their proliferation. Mechanistically, valine depletion upregulated eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), which repressed cyclin D1 and D2 translation by sequestering eukaryotic translation initiation factor 4E (eIF4E). Concurrently, valine deprivation induced Sestrin2 expression and inhibited mammalian target of rapamycin (mTOR) activity, converging to attenuate mRNA translation. These findings uncover a previously unrecognized role of valine as a direct molecular controller of the cancer cell cycle, acting through translational repression of D-type cyclins. Targeting exogenous valine supply, in combination with cell cycle–directed therapies, may offer a promising strategy to suppress the growth of malignant tumors.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"246 ","pages":"Article 117706"},"PeriodicalIF":5.6,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145987823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Modulating UNC-51-like kinase 1 (ULK1) to treat diseases: A perspective from autophagic initiator to druggable target 调节unc -51样激酶1 （ULK1）治疗疾病：从自噬启动物到可药物靶点的视角

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-11 DOI: 10.1016/j.bcp.2026.117692

Xinyi Qi , Xiangyu Fu , Huiping Wang , Leilei Fu

UNC-51-like kinase 1 (ULK1), a serine/threonine kinase, serves as the master initiator of autophagy. By integrating upstream signaling pathways such as AMPK/mTOR, ULK1 orchestrates autophagosome formation while also participating in non-canonical functions including energy metabolism and immune regulation. In this review, we systematically delineate the molecular structure and biological functions of ULK1, while elucidating its intricate associations with human diseases. Furthermore, we comprehensively discuss current advances in small-molecule ULK1 activators and inhibitors, with particular emphasis on their combinatorial therapeutic strategies. This synthesis provides novel perspectives for developing ULK1-targeted pharmacological interventions.

unc -51样激酶1 （ULK1）是一种丝氨酸/苏氨酸激酶，是自噬的主要启动物。通过整合上游信号通路，如AMPK/mTOR， ULK1协调自噬体的形成，同时也参与非规范功能，包括能量代谢和免疫调节。在这篇综述中，我们系统地描述了ULK1的分子结构和生物学功能，同时阐明了它与人类疾病的复杂关联。此外，我们全面讨论了小分子ULK1激活剂和抑制剂的最新进展，特别强调了它们的组合治疗策略。这种综合为开发针对ulk1的药物干预提供了新的视角。

引用次数: 0

Oxidative stress in metabolic dysfunction-associated steatohepatitis: Mechanisms and emerging therapeutic strategies 氧化应激在代谢功能障碍相关的脂肪性肝炎：机制和新兴的治疗策略。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-10 DOI: 10.1016/j.bcp.2026.117702

Yidan Chen, Hui Yu, Xinyu Kai, Runting Yin, Zhen Ouyang, Yuan Wei, Cai Zhang

Metabolic dysfunction-associated steatotic liver disease and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), affect a substantial proportion of the global population and have emerged as a major disease burden. If left untreated, MASH can progress to cirrhosis and hepatocellular carcinoma. However, effective pharmacological therapies for MASH remain limited. Accumulating evidence indicates that oxidative stress plays an important role in MASH pathogenesis by coordinating inflammatory responses and contributing to hepatocyte injury. Although previous studies have emphasized the importance of oxidative stress, a panoramic view of how oxidative stress emerges during the onset of MASH and sustains a vicious cycle of progression is still lacking. This review systematically discusses the mechanisms underlying oxidative stress-driven MASH progression, highlighting its interactions with inflammation, hepatocyte apoptosis, necroptosis, emerging ferroptosis, and mitochondria-associated membranes. Furthermore, we summarize the recent advances in investigational drugs targeting oxidative stress, encompassing key druggable targets as well as representative synthetic compounds, natural products, and biotechnology drugs. Collectively, this review aims to deepen the mechanistic understanding of oxidative stress in MASH and to provide insights into potential therapeutic strategies.

代谢功能障碍相关脂肪性肝病及其进行性形式代谢功能障碍相关脂肪性肝炎（MASH）影响着全球相当大比例的人口，并已成为一种主要的疾病负担。如果不及时治疗，MASH可发展为肝硬化和肝细胞癌。然而，有效的药物治疗MASH仍然有限。越来越多的证据表明，氧化应激通过协调炎症反应和促进肝细胞损伤在MASH发病机制中起重要作用。虽然以前的研究强调了氧化应激的重要性，但氧化应激如何在MASH发病期间出现并维持恶性循环的全景视图仍然缺乏。这篇综述系统地讨论了氧化应激驱动的MASH进展的机制，强调了它与炎症、肝细胞凋亡、坏死下垂、新出现的铁下垂和线粒体相关膜的相互作用。此外，我们总结了针对氧化应激的研究药物的最新进展，包括关键的药物靶点以及具有代表性的合成化合物、天然产物和生物技术药物。总的来说，这篇综述旨在加深对MASH氧化应激机制的理解，并为潜在的治疗策略提供见解。

{"title":"Oxidative stress in metabolic dysfunction-associated steatohepatitis: Mechanisms and emerging therapeutic strategies","authors":"Yidan Chen, Hui Yu, Xinyu Kai, Runting Yin, Zhen Ouyang, Yuan Wei, Cai Zhang","doi":"10.1016/j.bcp.2026.117702","DOIUrl":"10.1016/j.bcp.2026.117702","url":null,"abstract":"<div><div>Metabolic dysfunction-associated steatotic liver disease and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), affect a substantial proportion of the global population and have emerged as a major disease burden. If left untreated, MASH can progress to cirrhosis and hepatocellular carcinoma. However, effective pharmacological therapies for MASH remain limited. Accumulating evidence indicates that oxidative stress plays an important role in MASH pathogenesis by coordinating inflammatory responses and contributing to hepatocyte injury. Although previous studies have emphasized the importance of oxidative stress, a panoramic view of how oxidative stress emerges during the onset of MASH and sustains a vicious cycle of progression is still lacking. This review systematically discusses the mechanisms underlying oxidative stress-driven MASH progression, highlighting its interactions with inflammation, hepatocyte apoptosis, necroptosis, emerging ferroptosis, and mitochondria-associated membranes. Furthermore, we summarize the recent advances in investigational drugs targeting oxidative stress, encompassing key druggable targets as well as representative synthetic compounds, natural products, and biotechnology drugs. Collectively, this review aims to deepen the mechanistic understanding of oxidative stress in MASH and to provide insights into potential therapeutic strategies.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"246 ","pages":"Article 117702"},"PeriodicalIF":5.6,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145958597","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Targeting mitochondrial complexes for cancer therapy. 靶向线粒体复合物用于癌症治疗。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-10 DOI: 10.1016/j.bcp.2026.117695

Alaa M A Osman, Alya A Arabi

Mitochondrial Complexes I-IV in the electron transport chain (ETC) are strategic targets for cancer treatment since they provide the energy and biosynthetic demands of cancer cells. This review covers in silico, in vitro, and in vivo findings related to the inhibition of ETC complexes in order to block cancer cell survival. It covers details about bioenergetic disruption as well as innovative therapeutic strategies such as photodynamic therapy (PDT). This review, thus, serves as a guide for the development of novel small molecules and repurposed drugs for cancer treatment that target the ETC. In addition, this review shows how deep learning and AI-based nanotechnologies are being applied to predict the oxidative phosphorylation (OXPHOS) activity, identify ETC dependencies in cancer cells, and accelerate the discovery of mitochondrial complex-targeted anticancer drugs. It further explains how targeting ETC complexes can be implemented in precision medicine strategies.

电子传递链（ETC）中的线粒体复合物I-IV是癌症治疗的战略靶点，因为它们提供癌细胞的能量和生物合成需求。这篇综述涵盖了在硅，体外和体内的发现与抑制ETC复合物以阻止癌细胞存活有关。它涵盖了生物能量破坏以及创新治疗策略，如光动力疗法（PDT）的细节。因此，本文综述可为开发以ETC为靶点的新型小分子和靶向性癌症治疗药物提供指导。此外，这篇综述还展示了深度学习和基于人工智能的纳米技术如何被应用于预测氧化磷酸化（OXPHOS）活性，识别癌细胞中的ETC依赖性，以及加速发现线粒体复合物靶向抗癌药物。它进一步解释了靶向ETC复合物如何在精准医学策略中实施。

引用次数: 0

ATF4 in cardiovascular diseases: an emerging therapeutic target ATF4在心血管疾病中的作用：一个新兴的治疗靶点。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-10 DOI: 10.1016/j.bcp.2026.117703

Luning Qin , Ruolan Chen , Chao Huang , Xuezhe Wang , Qinghang Song , Zhaoqing Li , Xiaojian Xu , Zhijun Liu , Banghui Wang , Bing Li , Xian-Ming Chu

Activating transcription factor 4 (ATF4), as a core regulatory factor of the activating transcription factor (ATF)/cAMP-response element binding protein (CREB) family, governs cell fate determination through endoplasmic reticulum stress(ERS), autophagy, and redox networks. The dynamic balance of its functions is crucial for maintaining cardiovascular homeostasis; however, there remains a significant lack of systematic understanding of its regulatory mechanisms. To address the aforementioned research gap, this article systematically elucidates the dynamic regulatory network of ATF4 in cardiovascular diseases (CVDs), constructs its interaction relationship map, and highlights three critical scientific issues that urgently need to be resolved: the cell-type-specific epigenetic regulatory network of ATF4, precise intervention strategies for spatiotemporally specific ATF4 activation, and the development of tissue-targeted ATF4 modulators. Breakthroughs in these research directions are expected to provide novel therapeutic strategies for CVDs targeting the ATF4-mediated metabolic-death axis.

激活转录因子4 （ATF4）是激活转录因子(ATF)/ camp反应元件结合蛋白（CREB）家族的核心调控因子，通过内质网应激（ERS）、自噬和氧化还原网络决定细胞命运。其功能的动态平衡对维持心血管稳态至关重要；然而，对其调控机制仍然缺乏系统的认识。为了弥补上述研究空白，本文系统阐述了ATF4在心血管疾病（cvd）中的动态调控网络，构建了其相互作用关系图，并突出了ATF4细胞特异性表观遗传调控网络、ATF4时空特异性激活的精准干预策略、组织靶向ATF4调节剂的开发等三个亟待解决的关键科学问题。这些研究方向的突破有望为针对atf4介导的代谢-死亡轴的心血管疾病提供新的治疗策略。

{"title":"ATF4 in cardiovascular diseases: an emerging therapeutic target","authors":"Luning Qin , Ruolan Chen , Chao Huang , Xuezhe Wang , Qinghang Song , Zhaoqing Li , Xiaojian Xu , Zhijun Liu , Banghui Wang , Bing Li , Xian-Ming Chu","doi":"10.1016/j.bcp.2026.117703","DOIUrl":"10.1016/j.bcp.2026.117703","url":null,"abstract":"<div><div>Activating transcription factor 4 (ATF4), as a core regulatory factor of the activating transcription factor (ATF)/cAMP-response element binding protein (CREB) family, governs cell fate determination through endoplasmic reticulum stress(ERS), autophagy, and redox networks. The dynamic balance of its functions is crucial for maintaining cardiovascular homeostasis; however, there remains a significant lack of systematic understanding of its regulatory mechanisms. To address the aforementioned research gap, this article systematically elucidates the dynamic regulatory network of ATF4 in cardiovascular diseases (CVDs), constructs its interaction relationship map, and highlights three critical scientific issues that urgently need to be resolved: the cell-type-specific epigenetic regulatory network of ATF4, precise intervention strategies for spatiotemporally specific ATF4 activation, and the development of tissue-targeted ATF4 modulators. Breakthroughs in these research directions are expected to provide novel therapeutic strategies for CVDs targeting the ATF4-mediated metabolic-death axis.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"246 ","pages":"Article 117703"},"PeriodicalIF":5.6,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145958459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0