Journal of pharmacological sciences最新文献_第5页

Subacute intranasal oxytocin improves neurological recovery after ischemic stroke 亚急性鼻内催产素促进缺血性脑卒中后神经系统恢复

IF 2.9 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-08-22 DOI: 10.1016/j.jphs.2025.08.006

Yusuke Morishita , Youichirou Higashi , Daichi Tani , Mio Togo , Takahiro Shimizu , Mikiya Fujieda , Motoaki Saito

Oxytocin (OXT) is a neuropeptide known for its anti-inflammatory and neuroprotective properties; however, its role in post-stroke recovery remains poorly defined. In this study, we investigated whether intranasal OXT administration during the subacute phase of stroke improves neurological outcomes and modulates microglial responses. Male mice underwent permanent middle cerebral artery occlusion and received intranasal OXT (300 ng/g) or saline on days 3 and 5 post-stroke. Neurological function was assessed using the modified neurological severity score; infarct volume was evaluated through hematoxylin-eosin (HE) staining, and survival rates were monitored until day 7. Immunofluorescence was used to assess microglial polarization in the peri-infarct region. OXT-treated mice showed significantly greater functional improvement and higher survival rates than saline-treated controls. Infarct volume was significantly reduced, and microglial polarization was altered by OXT, with a decrease in pro-inflammatory M1-type markers and an increase in anti-inflammatory M2-type markers. These findings demonstrate that OXT promotes neurological recovery through anti-inflammatory and neuroprotective mechanisms. Given its feasibility as a non-invasive delivery method, intranasal OXT may offer a promising therapeutic approach to enhance post-stroke neurorepair.

催产素（OXT）是一种神经肽，以其抗炎和神经保护特性而闻名；然而，其在中风后恢复中的作用仍不明确。在这项研究中，我们调查了在中风亚急性期鼻内给予OXT是否能改善神经预后并调节小胶质细胞反应。雄性小鼠在脑卒中后第3天和第5天接受永久性大脑中动脉闭塞，并鼻内注射OXT （300 ng/g）或生理盐水。采用改良的神经功能严重程度评分评估神经功能；通过苏木精-伊红（HE）染色评估梗死体积，并监测生存率至第7天。免疫荧光法用于评估梗死周围区域的小胶质细胞极化。与盐水处理的对照组相比，oxt处理的小鼠表现出更大的功能改善和更高的存活率。OXT显著减少梗死体积，改变小胶质细胞极化，促炎m1型标记物减少，抗炎m2型标记物增加。这些发现表明，OXT通过抗炎和神经保护机制促进神经恢复。鉴于其作为非侵入性给药方法的可行性，鼻内OXT可能为增强脑卒中后神经修复提供一种有希望的治疗方法。

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引用次数: 0

Sulfasalazine disrupts the interaction between TNFα and TNFR1 thus inhibiting NF-kB signaling activation to promote bone fracture healing 磺胺吡啶破坏TNFα和TNFR1之间的相互作用，从而抑制NF-kB信号激活，促进骨折愈合

IF 2.9 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-08-21 DOI: 10.1016/j.jphs.2025.08.005

Jingwei Liu , Cheng Qiu , Xiaoxiong Wang , Ziqian Xiang , Junyuan Sun , Mingzheng Chang , Qingliang Ma , Yan Zhuang , Yunpeng Zhao , Qiang Yang , Lianlei Wang , Xinyu Liu

Fracture is a common type of traumas and alternative therapies to boost bone fracture healing is necessary. The aim of this study is to elucidate the role of sulfasalazine in bone fracture healing by using MC3T3-E1 cells in vitro and murine femoral fracture model in vivo. Western blotting, flow cytometry, RNA sequencing, Calcein AM/PI staining, Alizarin-Red-S staining, ALP activity assay, transmission electron microscope, histological staining, immunohistochemistry, immunofluorescence and Surface plasmon resonance analysis were performed in this study. Sulfasalazine failed to elicit ferroptosis in osteoblasts within acceptable dose manner while promoted osteogenic differentiation. Furthermore, sulfasalazine was identified to inhibit inflammation by declination of inflammatory biomarkers. Besides, TNFα was verified as a potential downstream target for sulfasalazine and the adverse effect of TNFα on osteogenic differentiation could be largely salvaged by sulfasalazine due to direct binding between these two molecules. RNA-seq further implied decreased transcription of genes related to NF-κB pathway. Murine study showed sulfasalazine promotes fracture healing as evidenced by increased bone remodeling both histologically and radiologically. Overall, sulfasalazine accelerates osteogenic differentiation and promotes bone healing by direct binding to and thus inhibiting TNFα, which subsequently suppresses NF-κB signaling. Therefore, sulfasalazine shows a promising outcome for the treatment of bone fracture.

骨折是一种常见的创伤类型，促进骨折愈合的替代疗法是必要的。本研究的目的是通过体外培养MC3T3-E1细胞和小鼠股骨骨折模型来阐明磺胺氮嗪在骨折愈合中的作用。Western blotting、流式细胞术、RNA测序、Calcein AM/PI染色、茜素红- s染色、ALP活性测定、透射电镜、组织学染色、免疫组织化学、免疫荧光和表面等离子体共振分析。在可接受的剂量范围内，柳氮磺胺吡啶不能诱导成骨细胞铁下垂，但能促进成骨分化。此外，磺胺吡啶通过降低炎症生物标志物来抑制炎症。此外，tnf - α被证实是磺胺氮嗪的潜在下游靶点，由于tnf - α与磺胺氮嗪之间的直接结合，tnf - α对成骨分化的不利影响可以在很大程度上被磺胺氮嗪挽救。RNA-seq进一步提示NF-κB通路相关基因的转录减少。小鼠研究表明，柳氮磺胺吡啶促进骨折愈合，这在组织学和放射学上都证明了骨重塑的增加。总体而言，磺胺氮嗪通过直接结合并抑制TNFα，从而抑制NF-κB信号传导，从而加速成骨分化并促进骨愈合。因此，柳氮磺胺吡啶显示出治疗骨折的良好结果。

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引用次数: 0

Protocatechuic aldehyde restrains NLRP3 inflammasome activation to alleviate inflammatory response in sepsis 原儿茶醛抑制NLRP3炎性体激活以减轻脓毒症的炎症反应

IF 2.9 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-08-21 DOI: 10.1016/j.jphs.2025.08.003

Yu-fei Li , Ao Sun , Yang Miao , Hong-xia Wang , Lin-lin Zhang

Sepsis, a life-threatening organ dysfunction syndrome triggered by infection, is characterized by complex pathophysiology involving dysregulated inflammation, coagulation abnormalities, and mitochondrial dysfunction. Excessive activation of the NLRP3 inflammasome plays a pivotal role in sepsis progression. This study investigated the therapeutic effects and underlying mechanisms of protocatechuic aldehyde (PCA) in sepsis. Seventy-five potential PCA targets for sepsis were identified, with KEGG enrichment highlighting involvement in inflammatory and apoptotic pathways. PPI network analysis pinpointed TNF, IL-6, and IL-1β as key inflammatory targets. PCA dose-dependently suppressed IL-1β and TNF-α release in LPS/ATP-stimulated macrophages, reduced ASC speck formation and NLRP3-ASC interaction, and decreased mt-ROS production and TXNIP-NLRP3 co-localization. PCA also preserved mitochondrial network integrity by interacting with mitochondrial dynamics proteins DRP1 and MFN2, improving mitochondrial membrane potential and morphology. In LPS-induced septic mice, PCA significantly reduced serum IL-1β and TNF-α levels, improved survival rates, and downregulated NLRP3, pro-IL-1β, and cleaved-IL-1β expression in peritoneal macrophages. PCA alleviates inflammatory responses and organ damage in septic mice by inhibiting the mt-ROS/TXNIP/NLRP3 signaling axis and maintaining mitochondrial function, offering a promising natural therapeutic candidate for sepsis.

脓毒症是一种由感染引发的危及生命的器官功能障碍综合征，其特点是复杂的病理生理，包括炎症失调、凝血异常和线粒体功能障碍。NLRP3炎性小体的过度激活在脓毒症的进展中起关键作用。本研究探讨了原儿茶醛（PCA）对脓毒症的治疗作用及其机制。鉴定出75个潜在的脓毒症PCA靶点，其中KEGG富集突出了炎症和凋亡途径的参与。PPI网络分析确定TNF， IL-6和IL-1β是关键的炎症靶点。PCA剂量依赖性地抑制LPS/ atp刺激的巨噬细胞IL-1β和TNF-α释放，减少ASC斑点形成和NLRP3-ASC相互作用，减少mt-ROS产生和TXNIP-NLRP3共定位。PCA还通过与线粒体动力学蛋白DRP1和MFN2相互作用，改善线粒体膜电位和形态，从而保持线粒体网络的完整性。在lps诱导的脓毒症小鼠中，PCA显著降低血清IL-1β和TNF-α水平，提高存活率，下调腹腔巨噬细胞中NLRP3、pro-IL-1β和cleaved-IL-1β的表达。PCA通过抑制mt-ROS/TXNIP/NLRP3信号轴和维持线粒体功能，减轻脓毒症小鼠的炎症反应和器官损伤，为脓毒症提供了一种有前景的天然治疗候选药物。

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引用次数: 0

(2R,6R)-hydroxynorketamine reverses mechanical and thermal pain hypersensitivity produced by the chemotherapeutic agent oxaliplatin in rats （2R,6R）-羟诺氯胺酮逆转大鼠化疗药物奥沙利铂产生的机械和热痛超敏反应

IF 2.9 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-08-20 DOI: 10.1016/j.jphs.2025.08.004

Maria Campanile , Kaitlin Castell , Justin O. Pampalone , Bruno Carabelli , Irwin Lucki , Caroline A. Browne

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating side effect of a number of anticancer drugs, like oxaliplatin, leading to chronic sensory hypersensitivity and neuropathic pain. This study investigated the efficacy of (2R,6R)-hydroxynorketamine ((2R,6R)-HNK), a metabolite of ketamine, in a rat model of CIPN induced by oxaliplatin. Rats treated with oxaliplatin developed long-lasting mechanical and thermal hypersensitivity, as assessed by the Von Frey test and the hot plate test, respectively. A single injection of (2R,6R)-HNK (30 mg/kg, s.c.) significantly reversed both mechanical and thermal hypersensitivity for up to 24 h. Furthermore, repeated treatment with (2R,6R)-HNK (30 mg/kg/day) for 7 days produced sustained analgesia on mechanical hypersensitivity that persisted up to 14 days after treatment cessation. In comparison, repeated duloxetine (15 mg/kg/day, s.c.) showed only a short-lasting reduction of thermal hypersensitivity and no effect on mechanical hypersensitivity. Locomotor activity was not affected by (2R,6R)-HNK treatment, although duloxetine caused a transient decrease. This is the first demonstration that (2R,6R)-HNK produced analgesia in a rat model of CIPN. The persistence of analgesia with repeated treatment and sustained effects following treatment cessation suggests that (2R,6R)-HNK may represent a promising new therapeutic strategy for the rapid and sustained relief of pain associated with CIPN.

化疗引起的周围神经病变（CIPN）是许多抗癌药物（如奥沙利铂）的常见和衰弱的副作用，导致慢性感觉超敏反应和神经性疼痛。本研究探讨氯胺酮代谢物(2R,6R)-羟诺氯胺酮（(2R,6R)-HNK）在奥沙利铂诱导的大鼠CIPN模型中的作用。Von Frey试验和热板试验分别评估了奥沙利铂治疗大鼠出现持久的机械和热超敏反应。单次注射(2R,6R)-HNK （30 mg/kg, s.c）可显著逆转机械和热超敏反应长达24小时。此外，(2R,6R)-HNK （30 mg/kg/天）重复治疗7天，对机械超敏反应产生持续镇痛，持续到治疗停止后14天。相比之下，重复使用度洛西汀（15mg /kg/天，s.c）仅能短期减轻热过敏，对机械过敏没有影响。运动活动不受(2R,6R)-HNK治疗的影响，尽管度洛西汀引起短暂性下降。这是首次证明(2R,6R)-HNK在大鼠CIPN模型中产生镇痛作用。反复治疗后镇痛的持续性和停止治疗后的持续效果表明(2R,6R)-HNK可能是一种有希望的快速和持续缓解CIPN相关疼痛的新治疗策略。

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引用次数: 0

Theanine boosts frontal theta and hippocampal beta and gamma oscillations for familiarity in object recognition 茶氨酸促进额叶θ波和海马β波和γ波的振荡，以熟悉物体识别

IF 2.9 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-08-13 DOI: 10.1016/j.jphs.2025.08.002

Kisa Watanabe , Kinjiro Takeda , Takeshi Nagahiro , Sena Iijima , Yuji Ikegaya , Nobuyoshi Matsumoto

Object recognition memory encourages animals to distinguish between new and known objects, supported by neural activity in the hippocampus, prefrontal cortex, and perirhinal cortex. Theanine, a non-proteinogenic amino acid derivative from green tea leaves, enhances object recognition memory in rats through facilitated neurogenesis. Although the cellular mechanism for the theanine-enhanced object recognition memory has been elucidated to some extent, physiological evidence still remains unclear. To tackle this issue, we chronically fed mice with theanine (or tap water) for three weeks, implanted electrodes into the hippocampus and frontal cortex, both of which are responsible for object recognition memory. We then recorded the local field potentials from the two regions during the novel object recognition task, evaluated the memory performance, and broke down the neural signals in the hippocampus and frontal cortex into delta, theta, beta, low gamma, and high gamma frequency bands. The memory performance of theanine-treated mice was higher than that of vehicle-treated mice. We also found that theta oscillations in the frontal cortex and beta and low gamma oscillations in the hippocampus in theanine-treated mice were simultaneously enhanced for familiar objects. These results shed light on the new physiological underpinnings of object recognition memory enhanced by exogenous substances.

物体识别记忆鼓励动物区分新的和已知的物体，这是由海马体、前额叶皮层和鼻周围皮层的神经活动支持的。茶氨酸是一种从绿茶中提取的非蛋白质氨基酸，通过促进神经发生来增强大鼠的物体识别记忆。虽然茶氨酸增强物体识别记忆的细胞机制已在一定程度上得到阐明，但生理证据仍不清楚。为了解决这个问题，我们长期给老鼠喂食茶氨酸（或自来水）三周，在海马和额叶皮层植入电极，这两个区域都负责物体识别记忆。然后，我们记录了在新物体识别任务中两个区域的局部场电位，评估了记忆表现，并将海马和额叶皮层的神经信号分解为δ、θ、β、低伽马和高伽马频段。茶氨酸处理小鼠的记忆能力明显高于灌胃小鼠。我们还发现，在茶氨酸治疗的小鼠中，额叶皮层的θ波振荡和海马体的β波和低伽马波振荡在熟悉的物体面前同时增强。这些结果揭示了外源性物质增强物体识别记忆的新生理基础。

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引用次数: 0

Lactucin alleviates lipid accumulation via AMPK-mediated autophagy and fatty acid β-oxidation in FFA-induced HepG2 cells 乳酸素通过ampk介导的自噬和脂肪酸β-氧化在ffa诱导的HepG2细胞中减轻脂质积累

IF 2.9 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-08-08 DOI: 10.1016/j.jphs.2025.08.001

Xiaoyan Ma , Yilizere Aibaidula , Chunzi Zhang , Shuwen Qi , Tuxia Pang , Juan Zhang , Wenhui Hou , Xiaoli Ma

Lactucin is a natural sesquiterpene lactone isolated from Cichorium glandulosum Boiss. et Huet (CG) has unique biological and pharmaceutical properties. This study was designed to investigate the mechanisms by which Lactucin inhibits lipid accumulation in free fatty acid (FFA)-treated HepG2 cells. We demonstrated that Lactucin exerts a protective effect against hepatic steatosis in vitro. In FFA-induced HepG2 cells, Lactucin effectively ameliorated lipid accumulation, oxidative stress, and mitochondrial dysfunction. Mechanistically, we showed that activation of AMP-activated protein kinase (AMPK) and hormone-sensitive lipase (HSL) by Lactucin promoted lipolysis and further enhanced fatty acid β-oxidation (FAβO) by increasing the activity of FAβO-related enzymes, thereby contributing to the reduction of lipid accumulation. Moreover, Lactucin activated autophagy and modulated the AMPK/mammalian target of rapamycin (mTOR) signaling pathway. Notably, we found that Lactucin-induced autophagy played a significant role in decreasing lipid droplet accumulation, suggesting it may be a key underlying mechanism. These findings, for the first time, provide new insights into the pharmaceutical mechanism of Lactucin in protecting against nonalcoholic fatty liver disease (NAFLD).

lacucin是一种天然的倍半萜内酯，从菊苣中分离得到。et Huet （CG）具有独特的生物学和药学特性。本研究旨在探讨乳酸蛋白抑制游离脂肪酸（FFA）处理的HepG2细胞脂质积累的机制。我们证明了乳酸蛋白在体外对肝脂肪变性有保护作用。在ffa诱导的HepG2细胞中，lacucin有效地改善了脂质积累、氧化应激和线粒体功能障碍。在机制上，我们发现乳酸蛋白激活amp激活的蛋白激酶（AMPK）和激素敏感脂肪酶（HSL）促进脂肪分解，并通过增加FAβO相关酶的活性进一步增强脂肪酸β氧化（FAβO），从而有助于减少脂质积累。此外，lacucin激活自噬并调节AMPK/哺乳动物雷帕霉素靶蛋白（mTOR）信号通路。值得注意的是，我们发现乳酸素诱导的自噬在减少脂滴积累中起着重要作用，这可能是一个关键的潜在机制。这些发现首次为乳黄素预防非酒精性脂肪性肝病（NAFLD）的药物机制提供了新的见解。

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引用次数: 0

Direct effects of cigarette smoke extract from heated tobacco products on cardiomyocyte: Comparison with combustible cigarettes 加热烟草制品烟气提取物对心肌细胞的直接影响：与可燃香烟的比较

IF 2.9 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-07-24 DOI: 10.1016/j.jphs.2025.07.007

Jumpei Yasuda , Takuya Notomi , Takahiro Horinouchi , Tomoe Y. Nakamura

Smoking of combustible cigarettes is a risk factor for cardiovascular disease. Heated tobacco products (HTPs) have recently increased in use due to their perceived lower toxicity compared with combustible cigarettes, yet their direct effects on cardiomyocytes remain unclear. In the present study, we compared the effects of nicotine- and tar-free cigarette smoke extracts (CSE) from two HTPs (‘HTP-1’ and ‘HTP-2’) and a combustible reference cigarette (RF) on cultured neonatal rat ventricular myocyte. All CSEs reduced cell viability and the spontaneous beating rate, with toxicity ranked as RF > HTP-2 > HTP-1. HTP-2 and RF also induced intracellular Ca²⁺-overload, contractile dysfunction, and mitochondrial reactive oxygen species production, whereas HTP-1 did not. Mitochondrial respiration and ATP production were suppressed by all CSEs, while glycolysis was upregulated only by HTP-2 and RF, indicating different metabolic alterations. Acrolein, a shared toxicant in all products, also reduced cell viability, suggesting its involvement in CSE-induced cardiotoxicity. In summary, we revealed that HTPs, like combustible cigarettes, exhibit direct cardiomyocyte toxicity, but the underlying mechanisms appear to differ between different cigarette products with regard to abnormal Ca²⁺ regulation and metabolic inhibition. These findings raise concern regarding the cardiac safety of HTPs.

吸可燃香烟是患心血管疾病的一个危险因素。与可燃香烟相比，加热烟草制品（HTPs）的毒性较低，因此最近使用量有所增加，但其对心肌细胞的直接影响尚不清楚。在本研究中，我们比较了两种HTPs（“HTP-1”和“HTP-2”）中不含尼古丁和不含焦油的香烟烟雾提取物（CSE）和可燃参比香烟（RF）对培养的新生大鼠心室肌细胞的影响。所有CSEs均降低细胞活力和自发跳动率，毒性等级为RF >；HTP-2祝辞HTP-1。HTP-2和RF也诱导细胞内Ca2+超载、收缩功能障碍和线粒体活性氧产生，而HTP-1则没有。所有CSEs均抑制线粒体呼吸和ATP产生，而糖酵解仅被HTP-2和RF上调，表明不同的代谢改变。丙烯醛是所有产品中共有的一种有毒物质，它也降低了细胞活力，表明它参与了cse诱导的心脏毒性。总之，我们发现HTPs，像可燃香烟一样，表现出直接的心肌细胞毒性，但关于异常Ca2+调节和代谢抑制，不同香烟产品之间的潜在机制似乎不同。这些发现引起了人们对htp心脏安全性的关注。

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引用次数: 0

Therapeutic potential of SMTP-27 in attenuating diabetic nephropathy with anti-inflammatory activity SMTP-27抗炎治疗糖尿病肾病的潜力

IF 2.9 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-07-24 DOI: 10.1016/j.jphs.2025.07.006

Keita Shibata , Taiki Awane , Takashi Takaki , Keiji Hasumi , Koji Nobe

Diabetic nephropathy (DN) is a leading cause of chronic kidney disease (CKD), affecting nearly one-third of CKD patients. As CKD advances, it may progress to end-stage renal disease, necessitating dialysis or transplantation. Hyperglycemia-driven metabolic and hemodynamic disturbances contribute to oxidative stress, inflammation, and fibrosis. Since current treatments remain insufficient, novel therapeutic strategies are urgently needed to halt DN progression. Stachybotrys microspora triprenyl phenols (SMTPs), the focus of our research, exhibit anti-inflammatory properties and have shown therapeutic potential in various disease models. We aimed to evaluate the efficacy of SMTP-27 in a DN mouse model. DN was induced by removing the right kidney of db/db mice. The efficacy of SMTP-27 was determined by evaluating the renal function using urine and serum samples and morphological assessment of the kidney tissues. For deciphering the mechanism of action of SMTP-27, markers associated with inflammatory signaling pathways in the kidney were detected. SMTP-27 (0.03, 0.3, 3, 30 mg/kg) dose-dependently improved the renal function. In addition, it improved the mesangial matrix overproduction, podocyte injury, and renal tubule injury and exhibited anti-inflammatory activity in the kidneys of mice with DN. These results indicate the potential of SMTP-27 as a novel therapeutic strategy for DN.

糖尿病肾病（DN）是慢性肾脏疾病（CKD）的主要原因，影响近三分之一的CKD患者。随着CKD的进展，它可能发展为终末期肾脏疾病，需要透析或移植。高血糖引起的代谢和血流动力学紊乱可导致氧化应激、炎症和纤维化。由于目前的治疗仍然不足，迫切需要新的治疗策略来阻止DN的进展。小孢子Stachybotrys microspora triprenyl phenols （SMTPs）是我们研究的重点，它具有抗炎特性，并在多种疾病模型中显示出治疗潜力。我们的目的是评估SMTP-27在DN小鼠模型中的疗效。通过切除db/db小鼠右肾诱导DN。SMTP-27的疗效通过尿液、血清和肾组织形态学评估来确定。为了破译SMTP-27的作用机制，检测了肾脏中与炎症信号通路相关的标志物。SMTP-27（0.03、0.3、3、30 mg/kg）呈剂量依赖性改善肾功能。此外，它还能改善DN小鼠肾系膜基质过剩、足细胞损伤和肾小管损伤，并表现出抗炎活性。这些结果表明SMTP-27作为一种新的DN治疗策略的潜力。

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引用次数: 0

Oren-gedoku-to inhibits calcification of human aortic valve interstitial cells in vitro and aortic valve in spontaneously hypertensive rats in vivo oren - gedokuto体外抑制人主动脉瓣间质细胞钙化，体内抑制自发性高血压大鼠主动脉瓣钙化

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-07-18 DOI: 10.1016/j.jphs.2025.07.004

Zaiqiang Yu , Shihu Men , Kazuyuki Daitoku , Tadaatsu Imaizumi , Masahito Minakawa , Kazuhiko Seya

Despite being the most common adult heart valve disease in developed countries, no medicinal treatment exists for calcific aortic valve stenosis (CAS). We previously demonstrated that tumor necrosis factor (TNF)-α promotes aortic valve calcification (AVC) via the bone morphogenic protein (BMP) 2-alkaline phosphatase (ALP) pathway. In the present study, we aimed to investigate the effects of Kampo, a traditional Japanese herbal medicine, on TNF-α-induced AVC involving CAS progression. We confirmed that Oren-gedoku-to (OGT, 10–100 μg/mL) strongly and dose-relatedly inhibited HAVIC calcification induced by TNF-α (30 ng/mL). OGT significantly inhibited TNF-α-induced BMP2 expression, p65 NF-κB phosphorylation, and ALP activation in HAVICs. Notably, two crude drugs from OGT [Coptis rhizome (CR), and Phellodendron bark (PB)] exhibited inhibitory effects akin to those of OGT. Berberine, mainly contained in CR and PB, also inhibited TNF-α induced HAVIC calcification, BMP2 expression, and p65 NF-κB phosphorylation. Further, OGT significantly prevented accelerated AVC in spontaneously hypertensive rats in vivo. Our results suggest that OGT and its component, berberine, can effectively prevent AVC acceleration both in vitro and in vivo.

尽管钙化性主动脉瓣狭窄（CAS）是发达国家最常见的成人心脏瓣膜疾病，但目前尚无药物治疗方法。我们之前已经证明肿瘤坏死因子(TNF)-α通过骨形态发生蛋白（BMP） 2-碱性磷酸酶（ALP）途径促进主动脉瓣钙化（AVC）。在本研究中，我们旨在研究日本传统中草药甘布对TNF-α-诱导的AVC涉及CAS进展的影响。我们证实了orengedoku -to （OGT, 10-100 μg/mL）对TNF-α (30 ng/mL)诱导的HAVIC钙化具有强烈且剂量相关的抑制作用。OGT显著抑制TNF-α-诱导的肝纤维化患者BMP2表达、p65 NF-κB磷酸化和ALP激活。值得注意的是，从OGT中提取的两种药材[黄连（Coptis rhizome， CR）和黄柏树皮（Phellodendron bark， PB）]表现出与OGT相似的抑制作用。主要存在于CR和PB中的小檗碱还能抑制TNF-α诱导的HAVIC钙化、BMP2表达和p65 NF-κB磷酸化。此外，OGT在体内显著阻止自发性高血压大鼠AVC加速。我们的研究结果表明，OGT及其成分小檗碱在体外和体内都能有效地防止AVC加速。

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引用次数: 0

LncRNA Mir155hg contributes to hippocampal injury in status epilepticus rats through miR-155/Socs1/NF-κΒ signaling axis LncRNA Mir155hg通过miR-155/Socs1/NF-κΒ信号轴参与癫痫持续状态大鼠海马损伤

IF 2.9 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-07-17 DOI: 10.1016/j.jphs.2025.07.005

Yangmei Xie , Ming Wang , Binyuan Xu , Yiye Shao , Yinghui Chen

Background

Neuroinflammation contributes to cognitive deficits in status epilepticus (SE). The lncRNA Mir155hg has been identified as a key regulator of inflammation, but its role in SE remains unclear.

Methods

Mir155hg was knocked down using the adeno-associated virus (AAV) in the rat models of SE. Cognitive function and neuronal damage were assessed using Morris Water Maze and Nissl staining. Inflammatory cytokines (TNF-α, IL-1β) and NF-κB pathway activity were measured by Western blot. Mechanistic insights into Mir155hg-mediated NF-κB regulation were investigated via dual-luciferase assays and co-immunoprecipitation analysis.

Results

Our findings demonstrated that elevated level of Mir155hg was positively correlated with upregulation of TNF-α and IL-1β both in vivo and in vitro. Knockdown of Mir155hg reduced hippocampal inflammation and NF-κB activation. Mechanistically, Mir155hg acted as a competing endogenous RNA to sequester miR-155, thereby suppressing the expression of Socs1, an E3 ligase targeting NF-κB p65 for degradation. Co-immunoprecipitation analysis confirmed the interaction between NF-κB p65 and Socs1.

Conclusions

Mir155hg exacerbates SE-related neuroinflammation via the miR-155/Socs1/NF-κB axis. Targeting this pathway may mitigate SE-induced neuronal injury and cognitive deficits.

背景：神经炎症可导致癫痫持续状态（SE）的认知缺陷。lncRNA Mir155hg已被确定为炎症的关键调节因子，但其在SE中的作用尚不清楚。方法应用腺相关病毒（AAV）在SE大鼠模型中敲低smir155hg。采用Morris水迷宫和尼氏染色评估认知功能和神经元损伤。Western blot检测炎症因子（TNF-α、IL-1β）和NF-κB通路活性。通过双荧光素酶测定和共免疫沉淀分析，研究了mir155hg介导的NF-κB调节的机制。结果Mir155hg在体内和体外均与TNF-α和IL-1β的上调呈正相关。Mir155hg的下调降低了海马炎症和NF-κB的激活。在机制上，Mir155hg作为竞争性内源性RNA隔离miR-155，从而抑制Socs1的表达，Socs1是一种靶向NF-κB p65降解的E3连接酶。共免疫沉淀分析证实了NF-κB p65与Socs1之间的相互作用。结论smir155hg通过miR-155/Socs1/NF-κB轴加重se相关神经炎症。靶向这一途径可能减轻se诱导的神经元损伤和认知缺陷。

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