Journal of pharmacological sciences最新文献

英文中文

Astaxanthin suppress ferroptosis through the Akt1-FoxO3a signaling pathway to alleviates brain injury after intracerebral hemorrhage 虾青素通过Akt1-FoxO3a信号通路抑制铁下垂，减轻脑出血后脑损伤

IF 2.9 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-12-01 Epub Date: 2025-10-17 DOI: 10.1016/j.jphs.2025.10.002

Jianwen Zhang , Qiuwei Hua , Lun Gao , Shangwen Yang , Minghui Lu , Qiang Cai

Intracerebral hemorrhage is the second most common subtype of stroke, characterized by high mortality and disability rates. To date, the mechanism of brain injury caused by intracerebral hemorrhage remains unclear, and there are no effective treatments to delay the progression of brain injury after intracerebral hemorrhage. Increasing evidence suggests that oxidative stress plays a crucial role in secondary injury induced by intracerebral hemorrhage, and ferroptosis plays a dominant role in the pathogenesis of brain injury after intracerebral hemorrhage.

In this study, we demonstrated in an in vitro hemin-induced PC12 cell model that astaxanthin improved cell viability, inhibited oxidative stress after intracerebral hemorrhage, and suppressed ferroptosis by upregulating the expression of glutathione peroxidase 4 and solute carrier family 7a member 11. In an in vivo autologous blood injection intracerebral hemorrhage rat model, we confirmed that astaxanthin could resist oxidative stress, ferroptosis, and further inflammatory responses by upregulating the expression of glutathione peroxidase 4 and solute carrier family 7a member 11 through the Akt1-FoxO3a pathway to protect against brain injury after intracerebral hemorrhage.

脑出血是中风的第二大常见亚型，其特点是高死亡率和致残率。迄今为止，脑出血引起脑损伤的机制尚不清楚，也没有有效的治疗方法来延缓脑出血后脑损伤的进展。越来越多的证据表明，氧化应激在脑出血继发性损伤中起着至关重要的作用，而铁下垂在脑出血后脑损伤的发病机制中起主导作用。在本研究中，我们在体外血红素诱导的PC12细胞模型中证明虾青素通过上调谷胱甘肽过氧化物酶4和溶质载体家族7a成员11的表达，提高细胞活力，抑制脑出血后氧化应激，抑制铁凋亡。在体内自体血液注射脑出血大鼠模型中，我们证实虾青素通过Akt1-FoxO3a通路上调谷胱甘肽过氧化物酶4和溶质载体家族7a成员11的表达，从而抵抗氧化应激、铁凋亡和进一步的炎症反应，保护脑出血后的脑损伤。

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引用次数: 0

Effects of nicotine- and tar-free smoke extracts from combustible cigarettes and heated tobacco products on the function of neutrophil-like HL-60 cells 可燃香烟和加热烟草制品中不含尼古丁和焦油的烟雾提取物对嗜中性粒细胞样HL-60细胞功能的影响

IF 2.9 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-12-01 Epub Date: 2025-10-27 DOI: 10.1016/j.jphs.2025.10.004

Yuichi Mazaki , Soichi Miwa , Ryosuke Shinkai , Takahiro Horinouchi

Impaired neutrophil function is thought to increase infection risk associated with smoking. We examined the effects of nicotine- and tar-free cigarette smoke extracts (CSEs) from combustible cigarettes (CCs) and heated tobacco products (HTPs) on neutrophil-like HL-60 cells. HTP-derived CSEs exhibited lower cytotoxicity and milder impairment of neutrophil functions, including chemotaxis, reactive oxygen species production, phagocytosis, and neutrophil extracellular trap formation, than those of CC-derived CSEs. However, at higher concentrations, HTP-derived CSEs markedly impaired the cell viability and function. These results indicate that HTP emissions impair neutrophil functions at high concentrations, highlighting the need for cautious health risk evaluation.

中性粒细胞功能受损被认为会增加与吸烟有关的感染风险。我们研究了从可燃香烟（CCs）和加热烟草制品（HTPs）中提取的不含尼古丁和不含焦油的香烟烟雾提取物（ses）对中性粒细胞样HL-60细胞的影响。与cc衍生的CSEs相比，htp衍生的CSEs表现出较低的细胞毒性和较轻的中性粒细胞功能损害，包括趋化性、活性氧产生、吞噬作用和中性粒细胞胞外陷阱形成。然而，在较高浓度下，htp衍生的CSEs明显损害细胞活力和功能。这些结果表明，HTP排放在高浓度下损害中性粒细胞功能，强调需要谨慎的健康风险评估。

引用次数: 0

Effects of imeglimin on mitochondrial functions and ischemic brain damage in young and aging rats 依米霉素对幼龄和衰老大鼠线粒体功能及缺血性脑损伤的影响

IF 2.9 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-12-01 Epub Date: 2025-10-10 DOI: 10.1016/j.jphs.2025.10.001

Evelina Paskeviciene, Kristina Skemiene, Katryna Pampuscenko, Silvija Jankeviciute, Vilmante Borutaite

Imeglimin, a novel oral antidiabetic drug, has been suggested to affect mitochondrial functions in some types of cells and tissues, however, it has never been investigated whether aging has an impact on its pharmacological effects in the brain. In this study, we investigated whether imeglimin directly affects functions of brain mitochondria and whether its intraperitoneal injection protects against ischemic brain injury in young, middle-aged and aged Wistar rats. We found that direct addition of imeglimin to mitochondria isolated from young and middle-aged rat brains suppressed oxidative phosphorylation and activities of mitochondrial Complexes I and IV. The opposite, stimulating effect on Complex II activity was observed within the same groups. Injection of imeglimin 24 h before simulated brain ischemia in vitro reduced infarct size only in young and middle-aged rat groups. In the aged rat group, imeglimin did not reduce cerebral infarct size nor directly modulate mitochondrial respiration and activities of the complexes. In conclusion, we provided novel evidence on potential effects of imeglimin in the brain by demonstrating a direct stimulating effect on mitochondrial Complex II activity and age-dependent protective effects against brain injury under in vitro simulated ischemia.

一种新型口服降糖药伊米明被认为可以影响某些类型细胞和组织的线粒体功能，然而，从未研究过衰老是否会影响其在大脑中的药理作用。在本研究中，我们研究了伊米明是否直接影响脑线粒体功能，以及其腹腔注射是否对中青年Wistar大鼠缺血性脑损伤有保护作用。我们发现，在从中青年大鼠脑中分离的线粒体中直接添加imimimin，可以抑制线粒体复合物I和IV的氧化磷酸化和活性。在同一组中，对复合物II的活性有相反的刺激作用。体外模拟脑缺血前24小时注射依米明，仅在中青年大鼠组中减少梗死面积。在老龄大鼠组中，依米霉素没有减少脑梗死面积，也没有直接调节线粒体呼吸和复合物的活性。总之，我们通过在体外模拟缺血下直接刺激线粒体复合体II活性和年龄依赖性脑损伤保护作用，为伊米霉素在脑中的潜在作用提供了新的证据。

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引用次数: 0

Class effects of proton pump inhibitors in preventing oxaliplatin-induced peripheral neurotoxicity 质子泵抑制剂在预防奥沙利铂诱导的周围神经毒性中的一类作用

IF 2.9 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-12-01 Epub Date: 2025-09-29 DOI: 10.1016/j.jphs.2025.09.010

Yusuke Mori , Keisuke Mine , Takehiro Kawashiri , Yusuke Koura , Mami Ueda , Risa Kaneko , Shunsuke Fujita , Akito Tsuruta , Satoru Koyanagi , Daisuke Kobayashi

Oxaliplatin-induced peripheral neuropathy (OIPN) is a dose-limiting toxicity with limited countermeasures. Basic research has revealed that omeprazole, a proton pump inhibitor (PPI), exerts preventive effects against OIPN. In this study, we evaluated whether other PPIs exert similar effects via in vitro and in vivo experiments. Notably, esomeprazole, lansoprazole, and rabeprazole, classified as PPIs, prevented oxaliplatin-induced cultured F11 neuronal cell damage, and repeated PPI administration prevented mechanical allodynia in rats. However, vonoprazan, a potassium ion-competitive acid blocker, did not exert such effects. Overall, our results highlight the class effects of PPIs against OIPN.

奥沙利铂诱导的周围神经病变（OIPN）是一种剂量限制性毒性，应对措施有限。基础研究表明，质子泵抑制剂奥美拉唑对OIPN具有预防作用。在这项研究中，我们通过体外和体内实验评估了其他PPIs是否具有类似的作用。值得注意的是，被归类为PPI的埃索美拉唑、兰索拉唑和雷贝拉唑可预防奥沙利铂诱导的培养F11神经元细胞损伤，反复给药可预防大鼠机械异常性疼痛。然而，vonoprazan，一种钾离子竞争酸阻滞剂，没有发挥这样的作用。总的来说，我们的结果强调了ppi对OIPN的类效应。

引用次数: 0

Lutein reduces cisplatin-induced intestinal inflammation by inhibiting ROS-mediated MAPK/NF-κB pathways 叶黄素通过抑制ros介导的MAPK/NF-κB通路减少顺铂诱导的肠道炎症

IF 2.9 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-12-01 Epub Date: 2025-09-25 DOI: 10.1016/j.jphs.2025.09.009

Li-King Yang , Leticia B. Sy , Ju-Fang Liu , Tsung-Ming Chang , Ji-Fan Lin , Chi-Jen Chang

Cisplatin is a commonly used chemotherapy drug that can effectively treat a variety of cancers, but it often causes severe side effects, including nephrotoxicity, ototoxicity, and gastrointestinal toxicity, which significantly affects patients' quality of life. Lutein is a natural carotenoid known for its potent antioxidant properties. Recent literature supports the beneficial effects of lutein supplements in conditions such as retinal degeneration, cardiovascular disease, and liver damage, emphasizing its broad anti-inflammatory capabilities. However, the mechanism by which cisplatin causes intestinal inflammation and the protective effect of lutein against this remain unknown. Here, we investigated the potential protective effect of lutein against cisplatin-induced intestinal epithelial injury. Our results proved that cisplatin significantly decreased cell viability, enhanced ROS generation, and activated inflammatory signaling pathways involving p38, ERK, and NF-κB in IEC-6 cells. Pretreatment with lutein markedly suppressed ROS production, reduced p38 and ERK phosphorylation, prevented NF-κB activation, and consequently attenuated inflammatory cytokine expression. These findings establish lutein as a promising dietary strategy to reduce cisplatin-induced intestinal inflammation, supporting its therapeutic potential for improving chemotherapy tolerance.

顺铂是常用的化疗药物，可有效治疗多种癌症，但常产生严重的副作用，包括肾毒性、耳毒性、胃肠道毒性等，严重影响患者的生活质量。叶黄素是一种天然的类胡萝卜素，以其强大的抗氧化特性而闻名。最近的文献支持叶黄素补充剂对视网膜变性、心血管疾病和肝损伤等疾病的有益作用，强调其广泛的抗炎能力。然而，顺铂引起肠道炎症的机制以及叶黄素对肠道炎症的保护作用尚不清楚。在这里，我们研究了叶黄素对顺铂诱导的肠上皮损伤的潜在保护作用。我们的研究结果证明，顺铂显著降低了IEC-6细胞的细胞活力，增强了ROS的产生，激活了包括p38、ERK和NF-κB在内的炎症信号通路。叶黄素预处理可显著抑制ROS生成，降低p38和ERK磷酸化，阻止NF-κB活化，从而减弱炎症细胞因子的表达。这些发现表明叶黄素是一种很有前景的饮食策略，可以减少顺铂诱导的肠道炎症，支持其改善化疗耐受性的治疗潜力。

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引用次数: 0

Uncovering motor impairments in duchenne muscular dystrophy: 24-hour automated behavioral analysis of DBA/2N-mdx mice 揭示杜氏肌营养不良症的运动损伤：DBA/2N-mdx小鼠的24小时自动行为分析

IF 2.9 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-12-01 Epub Date: 2025-09-29 DOI: 10.1016/j.jphs.2025.09.011

Misato Kida , Yui Kobayashi , Takamasa Numano , Masahiko Yasuda , Seinosuke Sakai , Takashi Minato , Takuya Kishi , Masahiro Fukuda , Keisuke Omori , Taichi Yamamoto , Takahisa Murata

Duchenne muscular dystrophy (DMD) is a severe X-linked genetic disorder caused by mutations in the dystrophin gene. Although the C57BL/10 background mdx mouse (B10-mdx) model is widely used for DMD research, it presents milder symptoms than observed in human patients. In contrast, the DBA/2N-mdx model exhibits more severe pathology, making it a promising model for evaluating disease mechanisms and therapies. In this study, we employed a 24-h behavioral monitoring system to investigate spontaneous locomotor activity and gait characteristics in DBA/2N-mdx mice. We observed significantly reduced movement and shorter active periods during the dark (active) phase at 4 and 8 weeks of age in DBA/2N-mdx mice compared to controls. Subsequent gait analysis revealed shorter walking distances, slower speeds, and reduced body extension during straight walking. These findings suggest that the DBA/2N-mdx mouse model exhibits distinct behavioral abnormalities that parallel DMD symptoms in humans. Our noninvasive, continuous monitoring approach provides an innovative method for assessing motor impairments and may facilitate more accurate preclinical assessments of potential therapies for DMD.

杜氏肌营养不良症（DMD）是一种由肌营养不良蛋白基因突变引起的严重的x连锁遗传疾病。虽然C57BL/10背景mdx小鼠（B10-mdx）模型被广泛用于DMD研究，但它的症状比在人类患者中观察到的要轻。相比之下，DBA/2N-mdx模型表现出更严重的病理，使其成为评估疾病机制和治疗的有希望的模型。在这项研究中，我们采用24小时行为监测系统来研究DBA/2N-mdx小鼠的自发运动活动和步态特征。我们观察到，与对照组相比，DBA/2N-mdx小鼠在4周龄和8周龄的黑暗（活动）期运动明显减少，活动时间缩短。随后的步态分析显示，直线行走时行走距离缩短，速度减慢，身体伸展减少。这些发现表明DBA/2N-mdx小鼠模型表现出与人类DMD症状相似的明显行为异常。我们的无创、连续监测方法提供了一种评估运动损伤的创新方法，并可能促进对DMD潜在治疗方法的更准确的临床前评估。

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引用次数: 0

Rho kinase 2 promotes epithelial-mesenchymal transition and proliferation in human prostate cancer PC-3 cells Rho激酶2促进人前列腺癌PC-3细胞上皮间质转化和增殖

IF 2.9 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-12-01 Epub Date: 2025-09-20 DOI: 10.1016/j.jphs.2025.09.007

Alamgir Hossain , Aya Yamamura , Md Junayed Nayeem , Sivasundaram Karnan , Rie Takahashi , Hisaki Hayashi , Motohiko Sato

Prostate cancer is the second most common cancer in men. Although androgen deprivation therapy is initially effective, resistance inevitably develops. Most patients eventually progress to castration-resistant prostate cancer, a stage with limited treatment options and poor prognosis. Rho kinases (ROCK1 and ROCK2) have been implicated in cancer progression, but their therapeutic targeting remains limited. This study examined the pathological roles of ROCK1 and ROCK2 in epithelial-mesenchymal transition (EMT) and proliferation of prostate cancer cells. ROCK1 expression was comparable between human prostate epithelial cells (PrECs) and androgen-independent prostate cancer cells, PC-3 and DU145. In contrast, ROCK2 expression was higher in PC-3 cells than in PrECs and DU145 cells. EMT marker analysis revealed that PC-3 cells exhibited decreased E-cadherin and increased N-cadherin and Snail expression. ROCK2 knockdown reversed this EMT phenotype, reducing cell proliferation, migration, 3D tumor spheroid formation, and spheroid cell viability. Similar inhibitory effects were observed by the ROCK2-selective blocker KD025 (IC₅₀ = 422 nM). Furthermore, ROCK2 deficiency attenuated the tumor growth of PC-3 cells in a xenograft mouse model. These findings indicate that ROCK2 promotes EMT process and tumor progression in PC-3 cells. Targeting ROCK2 may represent a promising therapeutic strategy for androgen-independent prostate cancer.

前列腺癌是男性中第二常见的癌症。虽然雄激素剥夺疗法最初是有效的，但不可避免地会产生耐药性。大多数患者最终发展为去势抵抗性前列腺癌，这一阶段的治疗选择有限，预后较差。Rho激酶（ROCK1和ROCK2）与癌症进展有关，但其治疗靶点仍然有限。本研究探讨了ROCK1和ROCK2在前列腺癌细胞上皮-间质转化（epithelial-mesenchymal transition， EMT）和增殖中的病理作用。ROCK1的表达在人前列腺上皮细胞（PrECs）和雄激素非依赖性前列腺癌细胞PC-3和DU145之间具有可同性。ROCK2在PC-3细胞中的表达高于PrECs和DU145细胞。EMT标记分析显示PC-3细胞E-cadherin表达减少，N-cadherin和Snail表达增加。ROCK2敲低逆转了这种EMT表型，减少了细胞增殖、迁移、3D肿瘤球状体形成和球状细胞活力。rock2选择性阻断剂KD025也有类似的抑制作用（IC50 = 422 nM）。此外，在异种移植小鼠模型中，ROCK2缺乏可减弱PC-3细胞的肿瘤生长。这些发现表明ROCK2促进了PC-3细胞的EMT过程和肿瘤进展。靶向ROCK2可能是治疗雄激素非依赖性前列腺癌的一种有希望的治疗策略。

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引用次数: 0

Rosiridin reduces Idiopathic Pulmonary Fibrosis by inhibiting the STAT3/NFκB/SMAD3 signaling pathways 罗西瑞定通过抑制STAT3/NFκB/SMAD3信号通路减少特发性肺纤维化

IF 2.9 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-12-01 Epub Date: 2025-09-19 DOI: 10.1016/j.jphs.2025.09.004

Yuyao Li , Huili Qi , Haoyue Xu , Xuehai Jia , Wenyan Chen , Ruoliu Pan , Xinhui Pan , Hangyu Wang , Dahong Yao , Ke Zhang , Jinhui Wang

Idiopathic pulmonary fibrosis is a progressive, highly lethal disease with limited treatment options. It is characterized by fibroblast-to-myofibroblast transformation, excessive ECM proliferation and collagen deposition, leading to the destruction of normal lung architecture and function. As a constituent of Rhodiola rosea L., rosiridin is a monomer with significant structural compatibility, conferring strong therapeutic potential. This bioactive compound mitigates oxidative stress-driven pathology and reverses its resultant damage in various diseases. However, its potential protective effects against bleomycin-induced IPF and the underlying mechanisms remain unclear. This study aimed to investigate the role and mechanism of rosiridin in IPF. Rosiridin attenuated TGF-β1-induced oxidative stress and inflammatory responses in lung epithelial cells and suppressed apoptosis associated with pulmonary fibrosis. Hematoxylin and eosin (HE) staining and Masson's trichrome staining showed that rosiridin improved pathological lung changes, reduced oxidative stress, and alleviated pulmonary fibrosis in a dose-dependent manner. Transcriptomic analysis revealed that rosiridin inhibited JAK protein activation, reduced the transformation of fibroblasts into myofibroblasts, and suppressed the secretion of proinflammatory and profibrotic cytokines. These findings suggest that rosiridin mitigates pulmonary fibrosis through modulation of the STAT3/NF-κB/SMAD3 signaling pathways. Rosiridin may represent a promising therapeutic candidate for the treatment of IPF.

特发性肺纤维化是一种进行性、高致命性疾病，治疗方案有限。其特点是成纤维细胞向肌成纤维细胞转化，ECM过度增殖和胶原沉积，导致正常肺结构和功能的破坏。作为红景天的组成成分，红景天苷是一种具有显著结构相容性的单体，具有很强的治疗潜力。这种生物活性化合物减轻氧化应激驱动的病理，并逆转其在各种疾病中产生的损害。然而，其对博莱霉素诱导的IPF的潜在保护作用及其潜在机制尚不清楚。本研究旨在探讨罗什瑞定在IPF中的作用及其机制。罗西瑞定可减弱TGF-β1诱导的肺上皮细胞氧化应激和炎症反应，抑制与肺纤维化相关的细胞凋亡。苏木精和伊红（HE）染色和马松三色染色显示罗西瑞定改善病理性肺改变，降低氧化应激，减轻肺纤维化呈剂量依赖性。转录组学分析显示，罗西瑞定抑制JAK蛋白活化，减少成纤维细胞向肌成纤维细胞的转化，抑制促炎和促纤维化细胞因子的分泌。这些发现表明，罗西瑞定通过调节STAT3/NF-κB/SMAD3信号通路减轻肺纤维化。罗西瑞定可能是治疗IPF的一个有希望的候选药物。

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引用次数: 0

Establishing a nanoluciferase-based assay as a high-throughput screening platform for therapeutics in congenital nephrotic syndrome 建立一种基于纳米荧光素的检测方法，作为先天性肾病综合征治疗方法的高通量筛选平台

IF 2.9 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-12-01 Epub Date: 2025-09-20 DOI: 10.1016/j.jphs.2025.09.006

Haruki Tsuhako , Mary Ann Suico , Haruka Kojima , Saki Takahashi , Shunsuke Tanigawa , Misato Kamura , Ryoichi Sato , Riko Kato , Aimi Owaki , Ryuichi Nishinakamura , Tsuyoshi Shuto , Hirofumi Kai

Nephrin is crucial for the formation of the glomerular slit diaphragm, which is the final filtration barrier in the kidney. A mutation in the NPHS1 gene that codes for nephrin causes congenital nephrotic syndrome of the Finnish type (CNF). Most missense mutations render nephrin non-functional due to the defective nephrin trafficking to the cell membrane. Pharmacological approaches that induce the expression of nephrin on the cell membrane are feasible, but therapeutic development is hampered by the lack of a high-throughput screening (HTS) system. Here, we developed a nanoluciferase HiBiT-based HTS platform to quantify the cell membrane expression of a nephrin mutant. This evaluation system reflected the previously reported results of various nephrin mutant localization. Using this system, we screened and identified 10 compounds that promoted the expression of the nephrin E725D mutant on the cell membrane. Moreover, the phosphorylation and N-glycosylation of nephrin, which are modifications that indicate its cell surface localization, correlated with the luminescence values of HiBiT-Nephrin in the compound screening. Consequently, this HiBiT-Nephrin evaluation system could be a new platform for predicting the pathogenicity of variants and searching for therapeutic agents for CNF.

肾素对肾小球狭缝隔膜的形成至关重要，这是肾脏的最终滤过屏障。编码肾素的NPHS1基因突变导致芬兰型先天性肾病综合征（CNF）。大多数错义突变使肾素失去功能，这是由于肾素运输到细胞膜的缺陷。诱导肾素在细胞膜上表达的药理学方法是可行的，但由于缺乏高通量筛选（HTS）系统，治疗发展受到阻碍。在这里，我们开发了一个基于纳米荧光素酶hibit的HTS平台来量化肾素突变体的细胞膜表达。该评价体系反映了先前报道的各种肾素突变定位的结果。利用该系统，我们筛选并鉴定了10种促进肾素E725D突变体在细胞膜上表达的化合物。此外，nephrin的磷酸化和n -糖基化修饰（表明其细胞表面定位）与HiBiT-Nephrin在化合物筛选中的发光值相关。因此，该HiBiT-Nephrin评价系统可作为预测变异致病性和寻找CNF治疗药物的新平台。

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引用次数: 0

Histone deacetylase inhibitors suppress retinal angiogenesis by preventing endothelial cell proliferation and accelerating VEGF degradation 组蛋白去乙酰化酶抑制剂通过阻止内皮细胞增殖和加速VEGF降解抑制视网膜血管生成

IF 2.9 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-12-01 Epub Date: 2025-09-17 DOI: 10.1016/j.jphs.2025.09.005

Akane Morita, Kanako Takahashi, Naoto Iizuka, Tsutomu Nakahara

Inhibitors of histone deacetylases (HDACs) suppress retinal angiogenesis by interrupting the vascular endothelial growth factor (VEGF)-mammalian target of rapamycin complex 1 (mTORC1) pathway in proliferating endothelial cells. To investigate the underlying mechanisms, we examined the effects of valproic acid (VPA) and vorinostat on the distribution of VEGF protein and phosphorylated S6 protein, an indicator of mTORC1 activity, in the neonatal mouse retina, an experimental model of retinal angiogenesis. Newborn mice were subcutaneously injected with VPA, vorinostat, or vehicle once daily from postnatal day (P) 0 to P3. Their eyes were collected at P4. Compared to vehicle-treated mice, retinal vascularization was delayed, and the number of proliferating vascular cells was reduced in front of the retinal vasculature in VPA- and vorinostat-treated mice. In P4 mice, a single injection of VPA or vorinostat reduced VEGF expression on the retinal surface at 2 and 6 h after injection. Both drugs reduced mTORC1 activity in proliferating endothelial cells. The proteasome inhibitor, MG132, suppressed the VPA- and vorinostat-induced reduction in VEGF expression on the retinal surface. These results suggest that HDAC inhibitors suppress retinal angiogenesis by preventing endothelial cell proliferation and accelerating VEGF protein degradation in a proteasome-dependent manner.

组蛋白去乙酰化酶（hdac）抑制剂通过阻断内皮细胞增殖中的血管内皮生长因子(VEGF)-哺乳动物雷帕霉素复合物1 （mTORC1）通路抑制视网膜血管生成。为了研究其潜在的机制，我们研究了丙戊酸（VPA）和伏立诺他对新生小鼠视网膜（视网膜血管生成的实验模型）中VEGF蛋白和磷酸化S6蛋白（mTORC1活性的指标）分布的影响。新生小鼠从出生后(P) 0至P3，每天1次皮下注射VPA、伏立诺他或对照物。他们的眼睛集中在P4。VPA-和伏立诺他处理小鼠视网膜血管化延迟，视网膜血管前增殖血管细胞数量减少。在P4小鼠中，单次注射VPA或伏立诺他可在注射后2和6小时降低视网膜表面VEGF的表达。这两种药物都降低了增殖内皮细胞中mTORC1的活性。蛋白酶体抑制剂MG132抑制VPA-和伏立诺他诱导的视网膜表面VEGF表达的降低。这些结果表明，HDAC抑制剂通过蛋白酶体依赖的方式阻止内皮细胞增殖和加速VEGF蛋白降解来抑制视网膜血管生成。

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