Biochemical pharmacology最新文献_第2页

ITFG2 as a NEDD4-2 inhibitor: Preserving calcium homeostasis to prevent myocardial ischemic injury ITFG2 作为一种 NEDD4-2 抑制剂：保护钙稳态以防止心肌缺血损伤

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2024-10-28 DOI: 10.1016/j.bcp.2024.116597

This study aimed to investigate the role of ITFG2, a protein highly expressed in cardiac tissues, in myocardial ischemic injury and its potential interactions with NEDD4-2. An in vivo myocardial infarction (MI) model was induced in mice via left anterior descending artery ligation, and ITFG2 expression was modulated using adeno-associated virus AAV9 vectors. Echocardiography was used to assess cardiac function, and primary mouse cardiomyocytes were cultured and subjected to hypoxia. ITFG2 expression was found to be significantly reduced following MI and in hypoxia-treated neonatal cardiomyocytes. Overexpression of ITFG2 improved cardiac contractility, reduced apoptosis, and stabilized calcium levels by inhibiting NEDD4-2-mediated ubiquitination of SERCA2a. Conversely, ITFG2 knockdown exacerbated calcium overload and cardiac dysfunction. Mechanistically, ITFG2 binds to NEDD4-2, decreasing its interaction with SERCA2a and preventing SERCA2a degradation. These findings suggest that ITFG2 acts as a critical inhibitor of NEDD4-2, preserving SERCA2a function and maintaining calcium homeostasis in cardiomyocytes under ischemic conditions. Therefore, ITFG2 may represent a potential therapeutic target for preventing myocardial ischemic injury and improving outcomes in MI patients.

本研究旨在探讨在心脏组织中高表达的 ITFG2 蛋白在心肌缺血损伤中的作用及其与 NEDD4-2 的潜在相互作用。通过左前降支动脉结扎诱导小鼠体内心肌梗死（MI）模型，并使用腺相关病毒 AAV9 载体调节 ITFG2 的表达。用超声心动图评估心脏功能，培养小鼠原代心肌细胞并使其处于缺氧状态。研究发现，在心肌梗死后和缺氧处理的新生儿心肌细胞中，ITFG2的表达明显减少。过表达 ITFG2 可改善心脏收缩能力，减少细胞凋亡，并通过抑制 NEDD4-2 介导的 SERCA2a 泛素化稳定钙离子水平。相反，敲除 ITFG2 会加重钙超载和心脏功能障碍。从机理上讲，ITFG2 与 NEDD4-2 结合，减少了 NEDD4-2 与 SERCA2a 的相互作用，阻止了 SERCA2a 的降解。这些研究结果表明，ITFG2 是 NEDD4-2 的关键抑制剂，能在缺血条件下保护 SERCA2a 的功能并维持心肌细胞的钙稳态。因此，ITFG2 可能是预防心肌缺血损伤和改善心肌梗死患者预后的潜在治疗靶点。

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引用次数: 0

Caveolin-1 ameliorates hepatic injury in non-alcoholic fatty liver disease by inhibiting ferroptosis via the NOX4/ROS/GPX4 pathway Caveolin-1通过NOX4/ROS/GPX4途径抑制铁跃迁，从而改善非酒精性脂肪肝的肝损伤。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2024-10-26 DOI: 10.1016/j.bcp.2024.116594

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease globally, with a complex and contentious pathogenesis. Caveolin-1 (CAV1) is an important regulator of liver function and can mitigate liver injury by scavenging reactive oxygen species (ROS). Evidence suggests that NOX4 is a source of ROS production, that oxidative stress and ferroptosis are closely related, and that both are involved in the onset and progression of NAFLD. However, whether CAV1 attenuates liver injury in NAFLD caused by high-fat diet via the NOX4/ROS/GPX4 pathway remains unclear. An in vivo fatty liver model was established by feeding mice with a high-fat diet for 16 weeks. In addition, an in vitro fatty liver model was established by incubating AML-12 cells with free fatty acids for 24 h using an in vitro culture method. In our study, it was observed that a high-fat diet induces mitochondrial damage and worsens oxidative stress in NAFLD. This diet also hinders GPX4 expression, leading to an escalation of ferroptosis and lipid accumulation. To counteract these effects, intraperitoneal administration of CSD peptide in mice attenuated the high-fat diet-induced liver mitochondrial damage and ferroptosis. Likewise, overexpression of CAV1 resulted in an increase in GPX4 expression and a reduction in levels of ROS-mediated iron metamorphosis, thus mitigating the progression of the disease. However, the effects of CAV1 on GPX4-mediated ferroptosis and lipid deposition could be reversed by CAV1 small interfering RNA (SiRNA). Finally, NOX4 inhibitor (GLX351322) treatment increased CAV1 siRNA-mediated GPX4 expression and decreased the level of ROS-mediated ferroptosis. These findings suggest a potential mechanism underlying the protective role of CAV1 against high-fat diet-induced hepatotoxicity in NAFLD, shedding new light on the interplay between CAV1, GPX4, and ferroptosis in liver pathology.

非酒精性脂肪肝（NAFLD）是全球发病率最高的慢性肝病，其发病机制复杂且存在争议。Caveolin-1（CAV1）是肝功能的重要调节因子，可通过清除活性氧（ROS）减轻肝损伤。有证据表明，NOX4 是产生 ROS 的一个来源，氧化应激和铁变态反应密切相关，两者都参与了非酒精性脂肪肝的发生和发展。然而，CAV1是否通过NOX4/ROS/GPX4途径减轻高脂饮食引起的非酒精性脂肪肝的肝损伤仍不清楚。通过给小鼠喂食高脂肪饮食 16 周，建立了体内脂肪肝模型。此外，我们还采用体外培养法，将 AML-12 细胞与游离脂肪酸孵育 24 小时，建立了体外脂肪肝模型。在我们的研究中观察到，高脂饮食会诱导线粒体损伤，加重非酒精性脂肪肝的氧化应激。这种饮食还阻碍了 GPX4 的表达，导致铁变态反应和脂质积累的升级。为了抵消这些影响，给小鼠腹腔注射 CSD 肽可减轻高脂饮食引起的肝线粒体损伤和铁蛋白沉积。同样，过量表达 CAV1 可增加 GPX4 的表达，降低 ROS 介导的铁蜕变水平，从而缓解疾病的进展。然而，CAV1 对 GPX4 介导的铁蜕变和脂质沉积的影响可被 CAV1 小干扰 RNA（SiRNA）逆转。最后，NOX4 抑制剂（GLX351322）可增加 CAV1 siRNA 介导的 GPX4 表达，并降低 ROS 介导的铁蛋白沉积水平。这些发现提示了CAV1在非酒精性脂肪肝中对高脂饮食诱导的肝毒性的保护作用的潜在机制，为CAV1、GPX4和铁蛋白沉积在肝脏病理学中的相互作用提供了新的线索。

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引用次数: 0

Novel strategies to overcome chemoresistance in human glioblastoma 克服人类胶质母细胞瘤化疗抗药性的新策略。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2024-10-24 DOI: 10.1016/j.bcp.2024.116588

Temozolomide (TMZ) is currently the first-line chemotherapeutic agent for the treatment of glioblastoma multiforme (GBM). However, the inherent heterogeneity of GBM often results in suboptimal outcomes, particularly due to varying degrees of resistance to TMZ. Over the past several decades, O⁶-methylguanine-DNA methyltransferase (MGMT)-mediated DNA repair pathway has been extensively investigated as a target to overcome TMZ resistance. Nonetheless, the combination of small molecule covalent MGMT inhibitors with TMZ and other chemotherapeutic agents has frequently led to adverse clinical effects. Recently, additional mechanisms contributing to TMZ resistance have been identified, including epidermal growth factor receptor (EGFR) mutations, overactivation of intracellular signalling pathways, energy metabolism reprogramming or survival autophagy, and changes in tumor microenvironment (TME). These findings suggest that novel therapeutic strategies targeting these mechanisms hold promise for overcoming TMZ resistance in GBM patients. In this review, we summarize the latest advancements in understanding the mechanisms underlying intrinsic and acquired TMZ resistance. Additionally, we compile various small-molecule compounds with potential to mitigate chemoresistance in GBM. These mechanism-based compounds may enhance the sensitivity of GBM to TMZ and related chemotherapeutic agents, thereby improving overall survival rates in clinical practice.

替莫唑胺（TMZ）是目前治疗多形性胶质母细胞瘤（GBM）的一线化疗药物。然而，GBM固有的异质性往往导致疗效不理想，特别是对TMZ产生不同程度的耐药性。在过去的几十年中，O6-甲基鸟嘌呤-DNA 甲基转移酶（MGMT）介导的 DNA 修复通路作为克服 TMZ 耐药性的靶点已被广泛研究。然而，小分子共价 MGMT 抑制剂与 TMZ 及其他化疗药物的联合应用常常导致不良的临床效果。最近，人们发现了导致TMZ耐药的其他机制，包括表皮生长因子受体（EGFR）突变、细胞内信号通路的过度激活、能量代谢重编程或生存自噬以及肿瘤微环境（TME）的变化。这些发现表明，针对这些机制的新型治疗策略有望克服 GBM 患者的 TMZ 耐药性。在这篇综述中，我们总结了在了解 TMZ 内在和获得性耐药机制方面的最新进展。此外，我们还汇编了各种有可能减轻 GBM 化疗耐药性的小分子化合物。这些基于机制的化合物可能会提高 GBM 对 TMZ 和相关化疗药物的敏感性，从而提高临床实践中的总生存率。

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引用次数: 0

MNAM enhances Blautia abundance and modulates Th17/Treg balance to alleviate diabetes in T2DM mice MNAM 可提高 Blautia 的丰度并调节 Th17/Treg 的平衡，从而缓解 T2DM 小鼠的糖尿病。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2024-10-23 DOI: 10.1016/j.bcp.2024.116593

This study investigated the therapeutic effects of N¹-Methylnicotinamide (MNAM), a metabolic derivative, on T2DM mice induced by a high-fat diet and streptozotocin (STZ), focusing on its impact on the gut microbiome and immune modulation. MNAM significantly reduced hyperglycemia and enhanced insulin secretion, effects that were dependent on the presence of gut microbiota. It also mitigated STZ-induced weight loss and improved islet cell morphology, reducing islet cell mortality and increasing insulin (INS) levels. Flow cytometry analysis showed a decrease in T helper 17 cells (Th17) and an increase in Treg cells after MNAM treatment, corresponding to the upregulation of Treg markers [interleukin (IL)-10, forkhead box P3 (FOXP3)] and downregulation of Th17 markers [IL17A, RAR-related orphan receptor gamma (RORγt)]. Additionally, MNAM raised anti-inflammatory IL-10 levels while reducing pro-inflammatory cytokines [IL-17α, tumor necrosis factor (TNF-α), IL-6]. Microbiome analysis revealed decreased diversity and increased Blautia abundance post-MNAM administration. Treatment with Blautia not only reversed diabetes indicators but also modulated the Th17/Treg balance and reduced inflammation, with its metabolite sodium acetate mimicking these effects through the G protein-coupled receptor 43 (GPR43) pathway. These findings suggest that MNAM’s mitigation of diabetes operates through modulation of the gut microbiota and immune regulation, highlighting Blautia and its metabolite as potential therapeutic agents and providing a theoretical foundation for novel treatment strategies in T2DM.

本研究探讨了代谢衍生物 N1-甲基烟酰胺（MNAM）对高脂饮食和链脲佐菌素（STZ）诱导的 T2DM 小鼠的治疗效果，重点关注其对肠道微生物群和免疫调节的影响。MNAM 能明显降低高血糖，增强胰岛素分泌，这些效果取决于肠道微生物群的存在。它还减轻了 STZ 引起的体重减轻，改善了胰岛细胞形态，降低了胰岛细胞死亡率，提高了胰岛素（INS）水平。流式细胞术分析表明，MNAM治疗后T辅助17细胞（Th17）减少，Treg细胞增加，这与Treg标志物[白细胞介素（IL）-10、叉头盒P3（FOXP3）]上调和Th17标志物[IL17A、RAR相关孤儿受体γ（RORγt）]下调相对应。此外，MNAM 提高了抗炎 IL-10 水平，同时降低了促炎细胞因子 [IL-17α、肿瘤坏死因子 (TNF-α) 和 IL-6]。微生物组分析表明，服用 MNAM 后，微生物组的多样性减少，布劳菌丰度增加。使用布劳菌治疗不仅能逆转糖尿病指标，还能调节Th17/Treg平衡并减少炎症，其代谢产物醋酸钠通过G蛋白偶联受体43（GPR43）途径模拟这些效应。这些研究结果表明，MNAM 通过调节肠道微生物群和免疫调节来缓解糖尿病，突出了布劳提亚及其代谢物作为潜在治疗药物的作用，并为 T2DM 的新型治疗策略提供了理论基础。

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引用次数: 0

Increased hydrogen sulfide turnover serves a cytoprotective role during the development of replicative senescence 在复制衰老的发展过程中，硫化氢周转的增加起到了细胞保护的作用。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2024-10-23 DOI: 10.1016/j.bcp.2024.116595

The mammalian gasotransmitter hydrogen sulfide (H₂S) is produced by enzymes such as cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), 3-mercaptopyruvate sulfurtransferase (3-MST). Prior studies suggest that H₂S may have cytoprotective and anti-aging effects. This project explores the regulation and role of endogenous H₂S in a murine model of replicative senescence. H₂S and polysulfide levels in RAW 264.7 murine macrophages (control cells: passage 5–10; senescent cells: passage 30–40) were measured using fluorescent probes. The expression of H₂S-related enzymes and the activity of senescence marker beta-galactosidase (SA-β-Gal) were also analyzed. CBS, CSE, and 3-MST were inhibited using selective pharmacological inhibitors. Senescence led to a moderate upregulation of CBS and in a significant increase in CSE and 3-MST. H₂S degradation enzymes were also elevated in senescence. Inhibition of H₂S-producing enzymes reduced H₂S levels but increased polysulfides. Inhibition of H₂S production during senescence suppressed cell proliferation, and elevated SA-β-Gal and p21 levels. Comparing young and old mice spleens revealed downregulation of CBS and ETHE1 and upregulation of rhodanese and SUOX in older mice. The results demonstrate that increased reactive sulfur turnover occurs in senescent macrophages and that reactive sulfur species support cell proliferation and regulate cellular senescence.

哺乳动物的气体递质硫化氢（H2S）是由胱硫醚β-合成酶（CBS）、胱硫醚γ-赖氨酸酶（CSE）、3-巯基丙酮酸硫基转移酶（3-MST）等酶产生的。先前的研究表明，H2S 可能具有细胞保护和抗衰老作用。本项目探讨了内源性 H2S 在小鼠复制性衰老模型中的调节和作用。使用荧光探针测量了 RAW 264.7 小鼠巨噬细胞（对照细胞：5-10 期；衰老细胞：30-40 期）中的 H2S 和多硫化物水平。此外，还分析了 H2S 相关酶的表达和衰老标记物 beta-半乳糖苷酶（SA-β-Gal）的活性。使用选择性药理抑制剂抑制了 CBS、CSE 和 3-MST。衰老导致 CBS 中度上调，CSE 和 3-MST 显著增加。在衰老过程中，H2S 降解酶也会升高。抑制产生 H2S 的酶会降低 H2S 水平，但会增加多硫化物。抑制衰老期的 H2S 生成可抑制细胞增殖，并提高 SA-β-Gal 和 p21 的水平。比较年轻小鼠和老年小鼠的脾脏发现，老年小鼠的 CBS 和 ETHE1 下调，而红丹和 SUOX 上调。研究结果表明，衰老的巨噬细胞中活性硫周转增加，活性硫支持细胞增殖并调节细胞衰老。

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引用次数: 0

Therapeutic targeting of Wnt antagonists by small molecules for treatment of osteoporosis 利用小分子 Wnt 拮抗剂治疗骨质疏松症。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2024-10-22 DOI: 10.1016/j.bcp.2024.116587

Wnt signaling is one of the key regulators of bone development and homeostasis. Wnt signaling regulates key biological events, including stem cell fate and osteoblast and osteoclast activity, leading to the maintenance of bone mass and strength. Wnt ligands are secreted glycoproteins that bind to Frizzled (FZD) receptors and their coreceptors, lipoprotein receptor-related proteins-5/6 (LRP5/6). Binding of Wnts to FZD triggers canonical (β-catenin-dependent) and noncanonical (β-catenin-independent) pathways. In canonical Wnt signaling, stabilized β-catenin translocates to the nucleus, where it promotes osteoblast differentiation by activating target genes, including Runx2 and Osterix. The negative regulators of Wnt or so-called Wnt antagonists, including CXXC5, sFRP, sclerostin, DKK1, and Notum, compete for Fzd binding, attenuating Wnt signaling. The critical roles of Wnt signaling in bone homeostasis have been established by various bone diseases caused by mutations in Wnt signaling pathways. Loss-of-function mutations in the LRP5 gene cause osteoporosis-pseudoglioma syndrome, whereas gain-of-function mutations are linked to osteopetrosis characterized by high bone density. Sclerosteosis and Van Buchem disease are caused by mutations affecting the SOST gene, which encodes sclerostin, a natural inhibitor of Wnt signalling. Loss-of-function mutations in SOST result in excessive bone growth, markedly increased bone density, and other skeletal abnormalities due to uncontrolled Wnt activity. Considering the clinical relevance of Wnt signaling, targeting Wnt inhibitors is being intensely pursued using small molecules that act by inhibiting endogenous Wnt agonists. We used a computational biology approach to review current data on pharmacophores of Wnt antagonists, assessing their potential as therapeutic candidates for postmenopausal osteoporosis.

Wnt 信号是骨骼发育和平衡的关键调节因子之一。Wnt 信号调节包括干细胞命运、成骨细胞和破骨细胞活性在内的关键生物事件，从而维持骨量和骨强度。Wnt 配体是分泌型糖蛋白，可与 Frizzled（FZD）受体及其核心受体脂蛋白受体相关蛋白-5/6（LRP5/6）结合。Wnts 与 FZD 结合会触发规范（依赖于 β-catenin）和非规范（不依赖于 β-catenin）途径。在典型的 Wnt 信号传导过程中，稳定的 β-catenin 转移到细胞核，通过激活包括 Runx2 和 Osterix 在内的靶基因促进成骨细胞分化。Wnt 的负调控因子或所谓的 Wnt 拮抗剂（包括 CXXC5、sFRP、sclerostin、DKK1 和 Notum）会竞争 Fzd 的结合，从而削弱 Wnt 信号的传递。由 Wnt 信号通路突变引起的各种骨病证实了 Wnt 信号在骨稳态中的关键作用。LRP5 基因的功能缺失突变导致骨质疏松症-假性胶质瘤综合征，而功能增益突变则与以高骨密度为特征的骨化症有关。硬骨病和 Van Buchem 病是由影响 SOST 基因的突变引起的，SOST 基因编码硬骨素，是 Wnt 信号的天然抑制剂。SOST 基因的功能缺失突变会导致骨质过度生长、骨密度明显增加，以及因 Wnt 活性失控而引起的其他骨骼异常。考虑到 Wnt 信号的临床相关性，人们正在利用通过抑制内源性 Wnt 激动剂起作用的小分子来研究靶向 Wnt 抑制剂。我们采用计算生物学方法回顾了目前有关 Wnt 拮抗剂药理的数据，评估了它们作为绝经后骨质疏松症候选疗法的潜力。

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引用次数: 0

Ponatinib exacerbate renal injury in systemic lupus erythematosus mouse model through PDGFR-PI3K/AKT pathway 泊纳替尼通过PDGFR-PI3K/AKT通路加剧系统性红斑狼疮小鼠模型的肾损伤

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2024-10-19 DOI: 10.1016/j.bcp.2024.116578

Lupus nephritis (LN) is a common clinical complication of systemic lupus erythematosus (SLE). Proliferative lupus nephritis represents the gravest form of LN, and since effective drugs for its treatment are still lacking, tyrosine kinase inhibitors (TKIs) find extensive clinical utility due to their notable impact on suppressing cell proliferation and may serve as potential drugs for LN treatment. However, previous studies on the effects of TKI on LN have been controversial. Ponatinib, a third-generation TKI, lacks studies on its role in LN. This study aimed to investigate the impact of the ponatinib on LN. MRL/lpr mice were evaluated for renal function, autoimmune markers and histopathological changes after oral administration of ponatinib. RNA-seq analysis was performed to explore the molecular pathways involved in ponatinib-induced kidney injury. Ponatinib uniquely exacerbated renal damage in MRL/lpr mice, evidenced by a decline in renal function and acute pathological changes, without affecting lupus-related autoimmune markers. Differential expressed genes analysis and functional enrichment implicate ponatinib-induced renal damage in MRL/lpr mice associated with adiponectin. Furthermore, we verified ponatinib signaling the PI3K/AKT pathway through PDGFRα, potentially influencing high molecular weight adiponectin (HMW ADIPOQ) expression and exacerbating renal damage. In conclusion, this study demonstrates that ponatinib can up-regulate HMW ADIPOQ expression via the PI3K/AKT pathway by inhibiting PDGFRα phosphorylation, highlighting the potential nephrotoxic effects of ponatinib in lupus-prone mice, and underscoring the importance of monitoring renal function in systemic autoimmune diseases patients receiving ponatinib.

狼疮性肾炎（LN）是系统性红斑狼疮（SLE）常见的临床并发症。增殖性狼疮性肾炎是狼疮性肾炎中最严重的一种，由于目前仍缺乏有效的治疗药物，酪氨酸激酶抑制剂（TKIs）因其在抑制细胞增殖方面的显著作用而被广泛应用于临床，并可能成为治疗狼疮性肾炎的潜在药物。然而，以往关于 TKI 对 LN 影响的研究一直存在争议。作为第三代 TKI，泊纳替尼缺乏对其在 LN 中作用的研究。本研究旨在探讨泊纳替尼对LN的影响。口服泊纳替尼后，对MRL/lpr小鼠的肾功能、自身免疫标记物和组织病理学变化进行了评估。进行了RNA-seq分析，以探索参与泊纳替尼诱导的肾损伤的分子通路。在不影响狼疮相关自身免疫标记物的情况下，泊纳替尼独特地加剧了MRL/lpr小鼠的肾损伤，表现为肾功能下降和急性病理变化。差异表达基因分析和功能富集表明，泊纳替尼诱导的MRL/lpr小鼠肾损伤与脂联素有关。此外，我们还验证了泊纳替尼通过PDGFRα向PI3K/AKT通路发出信号，可能会影响高分子量脂联素（HMW ADIPOQ）的表达并加剧肾损伤。总之，本研究表明，泊纳替尼可以通过抑制PDGFRα磷酸化，通过PI3K/AKT通路上调HMW ADIPOQ的表达，突出了泊纳替尼对狼疮易感小鼠的潜在肾毒性作用，并强调了监测接受泊纳替尼治疗的系统性自身免疫性疾病患者肾功能的重要性。

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引用次数: 0

Activation of the γ-secretase/NICD-PXR/Notch pathway induces Taxol resistance in triple-negative breast cancer 激活γ-分泌酶/NICD-PXR/Notch通路可诱导三阴性乳腺癌对紫杉醇产生抗药性。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2024-10-19 DOI: 10.1016/j.bcp.2024.116577

Triple-negative breast cancer (TNBC) is currently the only subtype lacking efficient targeted therapies. Taxol is the primary chemotherapeutic agent for TNBC. However, Taxol resistance often develops in the treatment of TNBC patients, which importantly contributes to high mortality and poor prognosis in TNBC patients. Recent preclinical studies have shown that the inhibition of Notch pathway by γ-secretase inhibitors can slow down the progression of TNBC. Our studies in bioinformatic analysis of breast cancer patients and TNBC/Taxol cells in vitro showed that there was high correlation between the activation of Notch pathway and Taxol resistance in TNBC. Increased γ-secretase activity (by the overexpression of catalytic core PSEN-1) significantly reduced Taxol sensitivity of TNBC cells, and enhanced biological characteristics of malignancy in vitro, and tumour growth in vivo. Mechanistically, increased γ-secretase activity led to the accumulation of NICD in the nucleus, promoting the interaction between NICD and PXR to activate PXR, which triggered the transcription of PXR downstream associated drug resistance genes. Furthermore, we showed that pharmacological inhibition of γ-secretase with γ-secretase inhibitors (Nirogacestat and DAPT) can reverse Taxol resistance in vivo and in vitro. Our results for the first time demonstrate that the activation of γ −secretase/NCD-PXR/Notch pathway is one of important mechanisms to cause Taxol resistance in TNBC, and the blockades of this pathway may represent a new therapeutic strategy for overcoming Taxol resistance in TNBC.

三阴性乳腺癌（TNBC）是目前唯一缺乏高效靶向疗法的亚型。紫杉醇是治疗 TNBC 的主要化疗药物。然而，在治疗 TNBC 患者的过程中经常会出现紫杉醇耐药性，这也是 TNBC 患者死亡率高、预后差的重要原因。最近的临床前研究表明，通过γ-分泌酶抑制剂抑制Notch通路可以延缓TNBC的进展。我们对乳腺癌患者和体外 TNBC/Taxol 细胞进行的生物信息学分析表明，Notch 通路的激活与 TNBC 的 Taxol 耐药性高度相关。γ-分泌酶活性的增加（通过催化核心 PSEN-1 的过表达）显著降低了 TNBC 细胞对 Taxol 的敏感性，增强了体外恶性肿瘤的生物学特征和体内肿瘤的生长。从机理上讲，γ-分泌酶活性的增加会导致 NICD 在细胞核中的积累，促进 NICD 与 PXR 之间的相互作用，从而激活 PXR，引发 PXR 下游相关耐药基因的转录。此外，我们还发现用γ-分泌酶抑制剂（Nirogacestat和DAPT）对γ-分泌酶进行药理抑制，可以逆转体内和体外的紫杉醇耐药性。我们的研究结果首次证明，γ-分泌酶/NCD-PXR/Notch通路的激活是导致TNBC对Taxol耐药的重要机制之一，阻断该通路可能是克服TNBC对Taxol耐药的一种新的治疗策略。

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引用次数: 0

Corrigendum to “Melatonin inhibits angiotensin II–induced atrial fibrillation through preventing degradation of Ang II Type I Receptor–Associated Protein (ATRAP)” [Biochem. Pharmacol. 202 (2022) 115146] 褪黑素通过阻止血管紧张素ⅡⅠ型受体相关蛋白（ATRAP）降解，抑制血管紧张素Ⅱ诱导的心房颤动》[《生物化学药理学》202 (2022) 115146]更正。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2024-10-19 DOI: 10.1016/j.bcp.2024.116579

引用次数: 0

SERPINA1 promotes the invasion, metastasis, and proliferation of pancreatic ductal adenocarcinoma via the PI3K/Akt/NF-κB pathway SERPINA1通过PI3K/Akt/NF-κB途径促进胰腺导管腺癌的侵袭、转移和增殖。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2024-10-18 DOI: 10.1016/j.bcp.2024.116580

Serpin peptidase inhibitor clade A member 1 (SERPINA1) is highly expressed in a variety of solid tumors. However, its role in pancreatic ductal adenocarcinoma (PDAC) remains unclear. Here, we report evidence that SERPINA1 acts as a potent oncogene to drive its extremely malignant character. We found that elevated SERPINA1 expression in primary tumors was associated with lymph node metastasis and shorter survival in PDAC patients. Mechanistic investigations revealed that overexpression of SERPINA1 induced nuclear translocation and phosphorylation of the p65 subunit through the PI3K/Akt/NF-κB pathway, thereby promoting the invasion, metastasis and proliferation of PDAC cells in vitro and in vivo. Conversely, the knockdown of SERPINA1 attenuated this signaling pathway and restored the phenotype of PDAC cells overexpressing SERPINA1. Overall, our study reveals that SERPINA1 affects the properties of PDAC through the PI3K/Akt/NF-κB pathway, and its activation confers the clinical features of epithelial-mesenchymal transition and proliferation in the disease.

血清素肽酶抑制剂 A 族成员 1（SERPINA1）在多种实体瘤中高度表达。然而，它在胰腺导管腺癌（PDAC）中的作用仍不清楚。在此，我们报告了 SERPINA1 作为一种强效致癌基因驱动胰腺导管腺癌极度恶性的证据。我们发现，原发性肿瘤中 SERPINA1 表达的升高与淋巴结转移和 PDAC 患者的生存期缩短有关。机理研究发现，SERPINA1 的过表达可通过 PI3K/Akt/NF-κB 通路诱导 p65 亚基的核转位和磷酸化，从而促进 PDAC 细胞在体外和体内的侵袭、转移和增殖。相反，敲除 SERPINA1 可减轻这一信号通路，并恢复过表达 SERPINA1 的 PDAC 细胞的表型。总之，我们的研究揭示了SERPINA1通过PI3K/Akt/NF-κB途径影响PDAC的特性，其激活赋予了该疾病上皮-间质转化和增殖的临床特征。

引用次数: 0