Biochemical pharmacology最新文献_第3页

EP3 promotes macrophage M1-polarization to play a critical role in diabetic renal injury EP3促进巨噬细胞m1极化在糖尿病肾损伤中发挥关键作用。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-05-01 Epub Date: 2026-02-07 DOI: 10.1016/j.bcp.2026.117775

Xijian Chen , Jiahui Ge , Gang Yu , Yu Fan , Jianye Yang , Bingli Wu , Yineng Xu , Dong He , Zhengpeng Zeng , Cheng Peng , Anhong Cai , Bin Wang , Xinya Shi , Junneng Zhang , Xiaodi Wang , Xiyu Jiang , Bin Liu , Yingbi Zhou

Diabetic kidney disease - remains a challenge clinically. Prostaglandins (PGs), many of which activate E-prostanoid receptor-3 (EP3), have been found to increase in dietetic kidneys; however, how this influences diabetic renal injury through EP3 has not been clearly elucidated. In this study, diabetes was induced in mice with global or myeloid cell-selective Ep3 deficiency (Ep3^-/-) and their respective controls by a high-fat diet and streptozocin administration. We showed that myeloid cell-selective Ep3^-/- attenuated renal impairments in diabetic mice similarly as global Ep3^-/-. In accompanying with an increase in PG production and upregulation of Ep3, increased number of M1 macrophages, inflammation, and multiple forms of regulated cell death (RCD; namely apoptosis, necroptosis, and pyroptosis) were detected in diabetic kidneys. However, all the above-mentioned abnormalities were hardly observed in mice with myeloid cell-selective Ep3^-/-. In vitro experiments further revealed that Ep3^-/- or EP3 antagonism decreased not only macrophage M1-polarization sensitive to Rho kinase inhibition but also the production of PGE₂ in such cells of mice and/or humans. Thus, EP3, whose activation may implicate a self-amplification process, is critically involved in diabetic renal injury via promoting Rho kinase-dependent macrophage M1-polarization to mediate inflammation that may further cause the occurrence of multiple types of RCD, delineating the receptor a promising therapeutic target for diabetic renal injury and diseases with similar mechanisms.

糖尿病肾病（DKD）在临床上仍然是一个挑战。前列腺素（pg），其中许多激活e -前列腺素受体-3 (EP3)，已被发现在饮食性肾脏中增加；然而，这是如何通过EP3影响糖尿病肾损伤的尚不清楚。在这项研究中，通过高脂肪饮食和链脲佐菌素给药，在具有全局或髓细胞选择性Ep3缺陷（Ep3-/-）的小鼠及其相应的对照组中诱导糖尿病。我们发现髓系细胞选择性Ep3-/-与全局Ep3-/-相似，可以减轻糖尿病小鼠的肾损伤。在糖尿病肾脏中，随着PG生成的增加和Ep3的上调，M1巨噬细胞数量增加、炎症和多种形式的细胞死亡（RCD，即凋亡、坏死和焦亡）被检测到。然而，在骨髓细胞选择性Ep3-/-小鼠中几乎没有观察到上述所有异常。体外实验进一步表明，Ep3-/-或Ep3拮抗剂不仅可以降低小鼠和/或人巨噬细胞对Rho激酶抑制敏感的m1极化，还可以降低巨噬细胞中PGE2的产生。因此，EP3的激活可能涉及自我扩增过程，通过促进Rho激酶依赖性巨噬细胞m1极化介导炎症，从而介导多种类型RCD的发生，从而在糖尿病肾损伤中发挥重要作用，这表明EP3受体是糖尿病肾损伤和类似机制疾病的有希望的治疗靶点。

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引用次数: 0

CCR2/CCR5 antagonism with cenicriviroc relieves neuropathic pain induced by sciatic nerve injury and delays morphine tolerance in mice CCR2/CCR5拮抗剂cenicriviroc可减轻小鼠坐骨神经损伤引起的神经性疼痛并延缓吗啡耐受性。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-05-01 Epub Date: 2026-02-06 DOI: 10.1016/j.bcp.2026.117773

Anna Piotrowska , Joanna Starnowska-Sokół , Katarzyna Ciapała , Justyna Barut , Agata Ciechanowska , Klaudia Kwiatkowski , Ewelina Rojewska , Katarzyna Pawlik , Grzegorz Kreiner , Joanna Mika

The neuroimmune system is known to be pathologically activated after nerve injury and prolonged exposure to opioids. Whereas previous studies have predominantly focused on the involvement of individual chemokine receptors in this phenomenon, dual CCR2/CCR5 blockade with cenicriviroc represents a novel therapeutic strategy towards greater efficacy in alleviating hypersensitivity. In this study, the expression of opioid (MOR, DOR) and chemokine (CCR2, CCR5) receptors in the spinal cord was assessed by immunohistochemistry after chronic constriction injury (CCI) of the sciatic nerve. Analgesic effects of cenicriviroc were evaluated following intraperitoneal administration of cenicriviroc in behavioral tests (von Frey, cold plate) after single (both sexes) and repeated treatment (alone or with morphine in males). Motor coordination and spontaneous locomotor activity were also tested. Spinal protein levels (p-MOR^S363, p-DOR^S363, CCR2, CCR5, IBA1, GFAP) were analyzed by Western blot. Immunostaining showed that CCR5 and MOR were expressed exclusively by neurons, whereas CCR2 colocalized with neurons, astrocytes, microglia, and/or macrophages, and DOR with neurons and astrocytes. A single intraperitoneal cenicriviroc administration alleviated hypersensitivity in CCI-subjected mice. Unlike morphine, cenicriviroc did not induce tolerance over 16 days of repeated treatment. Moreover, cenicriviroc attenuated nerve injury-induced upregulation of IBA1 at all examined time points and reduced GFAP expression at day 16, which was accompanied by a decrease in CCR2 levels. Cenicriviroc exerts sustained analgesia by simultaneously blocking CCR2 and CCR5 - particularly CCR2 signaling in neurons and glia - which appears to be key to its efficacy. These findings highlight cenicriviroc as a promising, translational candidate for neuropathic pain therapy.

神经免疫系统在神经损伤和长期暴露于阿片类药物后被病理激活。尽管先前的研究主要集中在个体趋化因子受体参与这一现象，但用cenicriviroc双重阻断CCR2/CCR5代表了一种新的治疗策略，可以更有效地缓解超敏反应。本研究采用免疫组化方法检测坐骨神经慢性收缩损伤（CCI）后脊髓内阿片样物质（MOR、DOR）和趋化因子（CCR2、CCR5）受体的表达。在单次（两性）和重复治疗（男性单独或与吗啡联合）后，腹腔注射cenicriviroc进行行为测试（von Frey，冷板），评估其镇痛效果。运动协调和自发运动活动也进行了测试。Western blot检测脊髓蛋白水平（p-MOR^S363, p-DOR^S363, CCR2, CCR5, IBA1， GFAP）。免疫染色显示CCR5和MOR仅在神经元中表达，而CCR2与神经元、星形胶质细胞、小胶质细胞和/或巨噬细胞共定位，DOR与神经元和星形胶质细胞共定位。单次腹腔注射维罗韦可减轻cci小鼠的超敏反应。与吗啡不同，cenicriviroc在16天的重复治疗中没有诱导耐受性。此外，cenicriviroc在所有检测时间点减弱了神经损伤诱导的IBA1上调，并在第16天降低了GFAP表达，同时伴有CCR2水平的降低。Cenicriviroc通过同时阻断CCR2和CCR5（尤其是神经元和神经胶质中的CCR2信号传导）发挥持续的镇痛作用，这似乎是其疗效的关键。这些发现突出了cenicriviroc作为一种有前途的、可转化的神经性疼痛治疗候选药物。

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引用次数: 0

Mutant NPM1-regulated estrogen signaling promotes leukemia cell survival by upregulating HGF and represents a therapeutic vulnerability 突变的npm1调节的雌激素信号通过上调HGF促进白血病细胞存活，并代表一种治疗脆弱性

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-05-01 Epub Date: 2026-02-10 DOI: 10.1016/j.bcp.2026.117796

Jing Yang , Jun Ren , Tinglu Tao , Meixi Peng , Wen Zhao , Qiaoling Xiao , Nan Wu , Xinyi Chen , Zihao Yuan , Yi Zu , Wei Cheng , Ling Zhang

Acute myeloid leukemia (AML) with mutated nucleophosmin 1 (NPM1) presents therapeutic challenge and exhibits a striking female predominance in clinical. However, the contribution of gender-specific factors, such as sex hormones to the pathogenesis and therapeutic implications in NPM1-mutated AML remains elusive. In the present study, we found that NPM1-mutated AML showed female bias, particularly among the young, pre-menopausal age (20–49 years) group, and that female exhibited inferior overall survival compared to males. Subsequently, 17β-estradiol (E2), the primary circulating estrogen in pre-menopausal females, was shown to facilitate the proliferation of NPM1-mutated leukemia cells. Importantly, ovariectomy (OVX) alleviated the leukemia burden, while reintroduction of exogenous E2 accelerated disease progression in leukemia mouse models. Mechanistically, leukemia cells exhibited an estrogen receptor α (ERα)-dominant/ERβ-low expression signature, which was maintained through NPM1 mutant-induced ubiquitination-dependent degradation of ERβ. The diminished ERβ level allowed ERα to act as the primary responder of E2, evidenced by the nuclear translocation of ERα following E2 treatment. Transcriptomic analysis identified hepatocyte growth factor (HGF) as the potential target of E2 signaling, and E2-mediated ERα activation transcriptionally upregulated HGF, thus promoting leukemia cell proliferation. Therapeutically, blockade of the E2/ER pathway using selective ER degrader fulvestrant inhibited the growth of NPM1-mutated AML cells, and its combination with chemotherapy drug cytarabine induced synergistic anti-leukemia effects in vitro and in vivo. Collectively, these data demonstrated the oncogenic role of E2/ERα signaling in NPM1-mutated leukemia and suggested that targeting E2/ERα signaling combined with standard chemotherapy may represent a promising regimen for female patients.

核磷蛋白1 （NPM1）突变的急性髓性白血病（AML）提出了治疗挑战，在临床中表现出惊人的女性优势。然而，性别特异性因素，如性激素对npm1突变AML的发病机制和治疗意义的贡献仍然难以捉摸。在本研究中，我们发现npm1突变的AML表现出女性偏见，特别是在年轻，绝经前年龄（20-49岁）组中，女性表现出低于男性的总生存率。随后，17β-雌二醇（E2），绝经前女性的主要循环雌激素，被证明可以促进npm1突变的白血病细胞的增殖。重要的是，卵巢切除术（OVX）减轻了白血病的负担，而重新引入外源性E2加速了白血病小鼠模型的疾病进展。在机制上，白血病细胞表现出雌激素受体α (ERα)显性/ERβ低表达的特征，这一特征通过NPM1突变诱导的ERβ泛素化依赖性降解来维持。ERβ水平的降低使ERα成为E2的主要应答者，E2治疗后ERα的核易位证明了这一点。转录组学分析发现，肝细胞生长因子（HGF）是E2信号的潜在靶点，E2介导的ERα激活通过转录上调HGF，从而促进白血病细胞增殖。在治疗上，使用选择性ER降解剂氟维司汀阻断E2/ER通路抑制npm1突变的AML细胞的生长，并与化疗药物阿糖胞苷联合在体外和体内诱导协同抗白血病作用。总的来说，这些数据证明了E2/ERα信号在npm1突变白血病中的致癌作用，并表明针对E2/ERα信号联合标准化疗可能是女性患者的一种有希望的方案。

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引用次数: 0

Modulation of thrombin-induced human platelet activation and oxidative stress by polyamines 多胺调节凝血酶诱导的人血小板活化和氧化应激。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-05-01 Epub Date: 2026-01-31 DOI: 10.1016/j.bcp.2026.117767

Maria Grazia Signorello

The effects of three polyamines, spermine, spermidine, and putrescine, on thrombin-induced platelet activation and function were investigated. Our findings demonstrate that polyamines significantly influence platelet activity, with spermine exhibiting the most pronounced effects. Polyamines dose-dependently were able to inhibit platelet aggregation and CD62P exposure induced by thrombin, as well as the rise in intracellular calcium concentration, indicating the involvement of polyamines in platelet activation signaling pathways. Beyond their effects on platelet function, polyamines show potent antioxidant activity. In thrombin-stimulated platelets, polyamines, and spermine in particular, inhibit reactive oxygen species and superoxide anion production, as well as the consequent lipid peroxidation, demonstrating a protective effect against oxidative stress. Furthermore, polyamines restored mitochondrial function by improving oxidative phosphorylation efficiency. Polyamines can restore the oxygen consumption rate and ATP production, indicating a role in maintaining cellular energy homeostasis under pro-thrombotic conditions. These findings suggest that polyamines, particularly spermine, could have an interesting therapeutic role since they can modulate platelet activation, oxidative stress, and oxidative phosphorylation efficiency. The restoration of platelet function through treatment with polyamines could have a protective effect against a pro-thrombotic state, which is involved in venous and arterial thrombosis, which contributes to cardiovascular diseases.

研究了精胺、亚精胺和腐胺三种多胺对凝血素诱导的血小板活化和功能的影响。我们的研究结果表明，多胺显著影响血小板活性，精胺表现出最显著的影响。多胺能够剂量依赖性地抑制凝血酶诱导的血小板聚集和CD62P暴露，以及细胞内钙浓度升高，提示多胺参与血小板激活信号通路。除了对血小板功能的影响外，多胺还显示出强大的抗氧化活性。在凝血酶刺激的血小板中，多胺，特别是精胺，抑制活性氧和超氧阴离子的产生，以及随之而来的脂质过氧化，显示出对氧化应激的保护作用。此外，多胺通过提高氧化磷酸化效率来恢复线粒体功能。多胺可以恢复氧气消耗速率和ATP的产生，表明在促血栓条件下维持细胞能量稳态的作用。这些发现表明，多胺，特别是精胺，可能具有有趣的治疗作用，因为它们可以调节血小板活化、氧化应激和氧化磷酸化效率。通过多胺治疗恢复血小板功能可能对血栓形成前状态具有保护作用，血栓形成参与静脉和动脉血栓形成，从而导致心血管疾病。

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引用次数: 0

TBG096 stimulates hair regeneration through IGF-1R-mediated angiogenesis TBG096通过igf - 1r介导的血管生成刺激头发再生。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-05-01 Epub Date: 2026-01-29 DOI: 10.1016/j.bcp.2026.117764

Majid Manzoor , Danni Chen , Ting Jiang, Jiahui Lin, Jiayuan Zeng, Lan Xiang, Jianhua Qi

Current pharmacological treatments for alopecia mainly aim to prevent further hair loss. However, efforts to identify therapeutic agents capable of reactivating the hair cycle have limited success. Herein, we identify that TBG096, a novel natural product-derived molecule with anti-aging properties promotes hair growth. In particular, we investigated hair regeneration effects of topical and oral TBG096 treatments across various models, including female and male rats, naturally aged and dihydrotestosterone (DHT)-induced alopecia model mice. TBG096 facilitated the transition of hair follicles from the telogen to the anagen phase, enhancing hair growth rate in a dose-dependent manner. Mechanistically, TBG096 directly binds and activates insulin-like growth factor 1 receptor (IGF-1R) that in turn activates downstream phosphatidylinositol 3-kinase /protein Kinase B (PI3K/AKT) signaling pathway. IGF-1R/PI3K/AKT activation increased angiogenesis in the dermal papilla to promote hair follicle proliferation and differentiation. Conversely, inhibition of IGF-1R impaired TBG096 mediated angiogenesis and hair regrowth. In addition, TBG096 also reduced DHT levels, increased keratin 15 (k15) expression and regulated growth factors like IGF-1 and epidermal growth factor (EGF), suggesting a restoration of normal follicular function. This is the first study to comprehensively demonstrate that TBG096 effectively promotes hair regeneration independent of age, gender, or application method, making it a promising candidate for treating androgenic alopecia and age-related hair loss.

目前脱发的药物治疗主要是为了防止进一步脱发。然而，鉴别能够重新激活头发周期的治疗药物的努力收效甚微。在此，我们发现TBG096是一种具有抗衰老特性的新型天然产物衍生分子，可促进头发生长。特别地，我们研究了局部和口服TBG096治疗在各种模型中的毛发再生效果，包括雌性和雄性大鼠，自然衰老和双氢睾酮（DHT）诱导的脱发模型小鼠。TBG096促进毛囊从休止期向生长期过渡，以剂量依赖性方式提高头发生长速度。在机制上，TBG096直接结合并激活胰岛素样生长因子1受体（IGF-1R），进而激活下游磷脂酰肌醇3-激酶/蛋白激酶B （PI3K/AKT）信号通路。IGF-1R/PI3K/AKT激活可增加真皮乳头血管生成，促进毛囊增殖和分化。相反，抑制IGF-1R会损害tbg介导的血管生成和头发再生。此外，TBG096还能降低DHT水平，增加角蛋白15 （Keratin 15, k15）表达，调节生长因子如IGF-1和表皮生长因子（epidermal growth factor， EGF），提示恢复正常卵泡功能。这是第一个全面证明TBG096有效促进头发再生的研究，不受年龄、性别或使用方法的影响，使其成为治疗雄激素性脱发和年龄相关性脱发的有希望的候选药物。

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引用次数: 0

An allosteric SHP2 inhibitor suppresses breast cancer-induced osteoclastogenesis and bone lysis 一种变构SHP2抑制剂抑制乳腺癌诱导的破骨细胞生成和骨溶解。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-05-01 Epub Date: 2026-02-13 DOI: 10.1016/j.bcp.2026.117810

Qinghe Liang , Wenqi Dai , Jiehuang Zheng, Yan Chen, Lishan Chen, Ziye Chen, Zhichao Huang, Jianchao Chen, Jianxin Pang, Xiaojuan Li

Inhibition of osteoclast hyperactivation represents a promising therapeutic approach for pathological bone destruction induced by breast cancer bone metastasis. Inhibitors of Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase 2 (SHP2), a protein tyrosine phosphatase (PTP) oncoprotein, show prominent antitumour activity, and eight allosteric inhibitors among them have entered clinical trials. However, the role of SHP2 in tumour-associated osteoclastogenesis remains unexplored. This study observed that SHP2 expression was increased in bone tissue with breast cancer cell metastasis. It further demonstrates that SHP099, an allosteric inhibitor of SHP2, suppresses human breast cancer MDA-MB-231 cell conditioned medium (CM)-induced osteoclast differentiation and bone resorption from 250 nM in vitro. Notably, SHP099 disrupts F-actin rings formation and downregulates osteoclast-specific genes. Mechanistically, SHP099 inhibits the phosphorylation of p38 mitogen-activated protein kinases (MAPK), c-Fos and calcium oscillation downstream of SHP2, thereby suppressing Nuclear Factor of Activated T-cells, Cytoplasmic 1 (NFATc1) nuclear translocation. In a murine model of MDA-MB-231-induced osteolytic lesions, oral administration of 10 mg/kg SHP099 reduces osteoclasts and prevents the trabecular bone loss. Our study identifies SHP2 as a druggable target for inhibiting breast cancer-induced osteoclast differentiation, positioning the specific inhibitors of SHP2 as potential drugs developed to treat tumour-induced osteolysis in the future.

抑制破骨细胞过度活化是治疗乳腺癌骨转移引起的病理性骨破坏的一种很有前途的治疗方法。Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase 2 （SHP2）是一种蛋白酪氨酸磷酸酶（PTP）癌蛋白，其抑制剂显示出突出的抗肿瘤活性，其中8种变构抑制剂已进入临床试验。然而，SHP2在肿瘤相关破骨细胞发生中的作用仍未被探索。本研究发现，SHP2在乳腺癌细胞转移的骨组织中表达升高。进一步证明SHP2的变构抑制剂SHP099在体外抑制250 nM的人乳腺癌MDA-MB-231细胞条件培养基诱导的破骨细胞分化和骨吸收。值得注意的是，SHP099破坏f -肌动蛋白环的形成并下调破骨细胞特异性基因。机制上，SHP099抑制SHP2下游p38丝裂原活化蛋白激酶（MAPK）的磷酸化、c-Fos和钙振荡，从而抑制活化t细胞核因子细胞质1 （NFATc1）核易位。在mda - mb -231诱导的小鼠溶骨损伤模型中，口服10 mg/kg SHP099可减少破骨细胞，防止小梁骨丢失。我们的研究确定了SHP2是抑制乳腺癌诱导的破骨细胞分化的可药物靶点，将SHP2的特异性抑制剂定位为未来治疗肿瘤诱导的骨溶解的潜在药物。

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引用次数: 0

IMB5023: Dual suppression of microtubule assembly and STAT3 signaling overcomes chemoresistance and activates antitumor immunity IMB5023：微管组装和STAT3信号的双重抑制克服化疗耐药并激活抗肿瘤免疫。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-05-01 Epub Date: 2026-02-16 DOI: 10.1016/j.bcp.2026.117812

Han-Yu Hong , Wen-Jie Guo , Yu-Jing Li , Yu-Xin Lei , Jia-Nan Ni , Yi-Jia Zheng , Yan-Qun Dong , Jun-Yi Zhang , Ling-Li Gao , Jian-Hua Gong , Lin Cai , Yan-Bo Zheng

Microtubule-targeting agents constitute a cornerstone of cancer chemotherapy, yet drug resistance remains a major challenge. Signal transducer and activator of transcription-3 (STAT3) inhibition may potentiate chemosensitivity and circumvent resistance mechanisms. During a phenotypic screen of anticancer agents, a small-molecule compound IMB5023 emerged as a promising candidate. In the present work, we report its antitumor efficacy and mechanism of action. IMB5023 exhibited cytotoxicity across multiple cancer cell lines, inducing pyroptosis in gasdermin E-positive cells and apoptosis in gasdermin E-negative cells. Transcriptomic profiling revealed that IMB5023 targeted centrosome-related pathway and impaired mitotic spindle assembly. Immunofluorescence analysis revealed concentration-dependent effects: multipolar spindle formation at a low concentration (1 μM) and microtubule network disruption at a higher concentration (10 μM). Furthermore, IMB5023 suppressed STAT3 pathway in vitro and overcame multidrug resistance by downregulating drug efflux pump ATP-binding cassette sub-family G member 2 (ABCG2) and anti-apoptotic protein B-cell lymphoma-extra large (Bcl-XL). Notably, IMB5023 triggered immunogenic cell death and enhanced dendritic cell phagocytosis. In vivo, IMB5023 inhibited tumor growth by 52%. Tumor histopathology confirmed centrosome declustering and STAT3 pathway inhibition. Collectively, IMB5023 concurrently disrupts microtubules and inhibits STAT3 pathway. This dual mechanisms of action positions IMB5023 as a promising therapeutic candidate, particularly for resistant malignancies.

微管靶向药物是癌症化疗的基石，但耐药性仍然是一个主要挑战。信号换能器和转录-3激活因子（STAT3）抑制可能增强化学敏感性和规避耐药机制。在抗癌药物的表型筛选中，一种小分子化合物IMB5023成为一种有希望的候选药物。本文报道其抗肿瘤作用及作用机制。IMB5023在多种癌细胞系中表现出细胞毒性，诱导气凝胶蛋白e阳性细胞焦亡，诱导气凝胶蛋白e阴性细胞凋亡。转录组学分析显示，IMB5023靶向着丝体相关途径并破坏有丝分裂纺锤体组装。免疫荧光分析显示了浓度依赖性效应：低浓度（1 μM）下多极纺锤体形成，高浓度（10 μM）下微管网络破坏。此外，IMB5023通过下调药物外排泵atp结合盒亚家族G成员2 （ABCG2）和抗凋亡蛋白b细胞淋巴瘤-特大型（Bcl-XL），在体外抑制STAT3通路，克服多药耐药。值得注意的是，IMB5023触发免疫原性细胞死亡和增强树突状细胞吞噬。在体内，IMB5023抑制肿瘤生长52%。肿瘤组织病理学证实中心体散簇和STAT3通路抑制。总的来说，IMB5023同时破坏微管并抑制STAT3途径。这种双重作用机制使IMB5023成为一种有希望的治疗候选者，特别是对于耐药恶性肿瘤。

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引用次数: 0

Bioinspired material design for oral targeted delivery Systems: From structural bioinspiration to functional implementation 口服靶向递送系统的仿生材料设计：从结构仿生到功能实现。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-05-01 Epub Date: 2026-01-27 DOI: 10.1016/j.bcp.2026.117747

Minhui Xu , Tao Sun , Huangbang Liang , Guangfu Feng , Qiongfang Hu , Yuanchun Du , Jun Fang

Bioinspired materials (BMs) have emerged as a pivotal research focus in drug delivery, demonstrating significant potential for oral targeted delivery systems (OTDS) in recent years. By mimicking the structural features or functional mechanisms of biological systems, these materials significantly enhance delivery efficiency and optimize drug activity, offering a novel paradigm for the rational design of OTDS. Despite significant progress, existing evaluations primarily focus on single-disease applications or specific material types, leaving a systematic summary of the transition from structural design to functional manifestation in BMs notably lacking. Meanwhile, the advantages and limitations of different preparation methods and their influence on delivery performance remain underexplored. To address these gaps, this article provides a comprehensive analysis of the design strategies and functional mechanisms of BMs in OTDS, emphasizing two key dimensions: Structural emulation and biological emulation. Additionally, it critically evaluates the advantages and limitations of various preparation methods. By synthesizing experimental evidence from diverse disease models, with a focus on colitis and cancer as representative examples, this review systematically elucidates the pivotal role of BMs in improving oral drug targeting efficiency. Moreover, it proposes strategic approaches to optimize delivery systems and discusses critical challenges and future directions in the field. This work aims to facilitate the transition toward the rational design and clinical implementation of next-generation OTDS.

近年来，生物激发材料（BMs）已成为药物递送领域的关键研究热点，在口服靶向递送系统（OTDS）方面显示出巨大的潜力。这些材料通过模拟生物系统的结构特征或功能机制，显著提高了给药效率，优化了药物活性，为OTDS的合理设计提供了新的范式。尽管取得了重大进展，但现有的评估主要集中在单一疾病的应用或特定的材料类型上，对脑转移从结构设计到功能表现的转变缺乏系统的总结。同时，不同制备方法的优缺点及其对递送性能的影响还有待进一步研究。为了解决这些问题，本文全面分析了OTDS中脑转移的设计策略和功能机制，强调了两个关键维度：结构仿真和生物仿真。此外，它批判性地评估了各种制备方法的优点和局限性。本文通过综合不同疾病模型的实验证据，以结肠炎和癌症为代表，系统阐述脑转移瘤在提高口服药物靶向效率中的关键作用。此外，它还提出了优化交付系统的战略方法，并讨论了该领域的关键挑战和未来方向。这项工作旨在促进向下一代OTDS的合理设计和临床实施过渡。

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引用次数: 0

Corrigendum to “Angiotensin II upregulates KCa3.1 channels and stimulates cell proliferation in rat cardiac fibroblasts”. [Biochem. Pharmacol. 85 (2013) 1486–1494] “血管紧张素II上调KCa3.1通道并刺激大鼠心脏成纤维细胞的细胞增殖”的更正。(生物化学。药学，85 (2013)1486-1494]

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-05-01 Epub Date: 2026-02-13 DOI: 10.1016/j.bcp.2026.117782

Li-Ping Wang , Yan Wang , Li-Mei Zhao , Gui-Rong Li , Xiu-Ling Deng

引用次数: 0

Therapeutic DNAzyme targeting conserved N gene sequences of pan-coronaviruses: Dual antiviral mechanisms of RNA cleavage and immune activation 靶向泛冠状病毒保守N基因序列的治疗性DNAzyme: RNA切割和免疫激活的双重抗病毒机制

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-05-01 Epub Date: 2026-02-07 DOI: 10.1016/j.bcp.2026.117776

Jiliang Jiang , Ruitong Tang , Leran Li , Zhaohui Kou , Fangtao Xing , Xiao Liu , Yurong Fu , Zhengjun Yi

Coronaviruses frequently mutate and cross species, rendering most strain-specific drugs and antibodies less effective and leaving familial-level threats unresolved. The nucleocapsid (N) protein, with highly conserved N- and C-terminal domains, plays a central role in viral replication and immune evasion, making it an ideal target for broad-spectrum antiviral development. We designed DNAzyme targeting conserved N gene sequences from SARS-CoV and multiple SARS-CoV-2 variants, identifying N4 with strong in vitro RNA cleavage activity (K_obs = 0.053 min⁻¹, 54.56% cleavage rate) and 80% N mRNA knockdown in transfected cells. To enhance its pharmacological properties, N4 was chemically modified with FANA, generating FANA4. Compared with N4, FANA4 exhibited a sixfold increase in serum half-life (8 h to 48 h), a twofold improvement in cleavage efficiency, and > 95% cellular uptake. In N-overexpressing and virus-infected cell models, FANA4 suppressed N protein expression by 99.02% and reduced viral replication by 85%. In vivo, intranasal administration decreased lung viral load by 3-fold without observable toxicity. Transcriptomic profiling revealed ERK/MAPK pathway activation, supporting a dual antiviral mechanism of sequence-specific RNA cleavage and host immunity enhancement. These findings highlight FANA4 as a promising, broad-spectrum nucleic acid therapeutic candidate for combating current and emerging coronaviruses.

冠状病毒经常发生变异和跨物种，使大多数菌株特异性药物和抗体的效果降低，使家族级威胁得不到解决。核衣壳蛋白(N)具有高度保守的N端和c端结构域，在病毒复制和免疫逃避中起着核心作用，使其成为广谱抗病毒药物开发的理想靶点。我们设计了针对SARS-CoV和多种SARS-CoV-2变异的保守N基因序列的DNAzyme，发现N4在转染细胞中具有较强的体外RNA裂解活性（Kobs = 0.053 min-1, 54.56%的裂解率）和80%的N mRNA敲除。为了增强N4的药理作用，用FANA对其进行化学修饰，生成FANA4。与N4相比，FANA4的血清半衰期增加了6倍（8 h至48 h），裂解效率提高了2倍， > 细胞摄取率提高了95%。在N过表达和病毒感染的细胞模型中，FANA4抑制了99.02%的N蛋白表达，减少了85%的病毒复制。在体内，鼻内给药可使肺病毒载量降低3倍，无明显毒性。转录组学分析显示ERK/MAPK通路激活，支持序列特异性RNA切割和宿主免疫增强的双重抗病毒机制。这些发现突出表明，FANA4是一种有前途的广谱核酸治疗候选者，可用于对抗当前和新出现的冠状病毒。

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