Journal of pharmacological sciences最新文献

Rehmannioside A promotes the osteoblastic differentiation of MC3T3-E1 cells via the PI3K/AKT signaling pathway and inhibits glucocorticoid-induced bone loss in vivo 地黄甙 A 通过 PI3K/AKT 信号通路促进 MC3T3-E1 细胞的成骨细胞分化并抑制糖皮质激素诱导的体内骨质流失

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2024-11-06 DOI: 10.1016/j.jphs.2024.11.001

Haisheng Huang , Fang Ji , Guobin Qi , Yuting Cao , Xuecheng He , Hao Wang , Zengxin Jiang

Glucocorticoid-induced osteoporosis (GIOP) is a widespread disease characterized by low bone density. There remains a lack of effective means for osteoporosis. Rehmannioside A (ReA), an iridoid glycoside, exhibits various pharmacological activities. This study aimed to explore the role and mechanism of ReA in osteogenic differentiation of osteoblasts. Cell viability, reactive oxygen species (ROS) generation, and cell apoptosis were assessed using corresponding assay kits. Real-time quantitative polymerase chain reaction, Western blotting, and alkaline phosphatase (ALP) staining were performed to evaluate the osteogenic differentiation of MC3T3-E1 cells. Alizarin red S staining was used to assess the mineralization of MC3T3-E1 cells. Protein expression associated with the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway was analyzed using Western blotting. Micro-computed tomography, histopathological, and immunohistochemical analyses were performed to determine the therapeutic effect of ReA on GIOP in vivo.The results showed that ReA promoted the osteogenic differentiation of MC3T3-E1 cells by regulating the PI3K/AKT signaling pathway and protected mice against glucocorticoid-induced bone loss by promoting osteoblast-mediated bone formation in vivo. The findings of the current study revealed that ReA is a potential therapeutic agent for osteoporosis.

糖皮质激素诱导的骨质疏松症（GIOP）是一种以骨密度低为特征的广泛疾病。目前仍缺乏治疗骨质疏松症的有效方法。Rehmannioside A（ReA）是一种鸢尾甙，具有多种药理活性。本研究旨在探索 ReA 在成骨细胞成骨分化中的作用和机制。使用相应的检测试剂盒对细胞活力、活性氧（ROS）生成和细胞凋亡进行了评估。对 MC3T3-E1 细胞的成骨分化进行了实时定量聚合酶链反应、Western 印迹和碱性磷酸酶（ALP）染色。茜素红 S 染色用于评估 MC3T3-E1 细胞的矿化情况。用Western印迹法分析了与磷脂酰肌醇3-激酶/蛋白激酶B（PI3K/AKT）信号通路相关的蛋白质表达。结果显示，ReA 通过调节 PI3K/AKT 信号通路促进 MC3T3-E1 细胞的成骨分化，并通过促进成骨细胞介导的体内骨形成保护小鼠免受糖皮质激素诱导的骨质流失。目前的研究结果表明，ReA 是一种潜在的骨质疏松症治疗药物。

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引用次数: 0

Targeting TMEM16A ion channels suppresses airway hyperreactivity, inflammation, and remodeling in an experimental Guinea pig asthma model 在实验性几内亚猪哮喘模型中，靶向 TMEM16A 离子通道可抑制气道过度反应、炎症和重塑

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2024-10-28 DOI: 10.1016/j.jphs.2024.10.004

Jozef Mažerik , Eduard Gondáš , Matúš Dohál , Lukáš Smieško , Marta Jošková , Soňa Fraňová , Martina Šutovská

Asthma is a chronic inflammatory disease characterized by airway hyperresponsiveness, inflammation, and remodeling. Calcium (Ca²⁺)-activated chloride (Cl⁻) channels, such as TMEM16A, are inferred to be involved in asthma. Therefore, the present study investigated the therapeutic potential of TMEM16A inhibition in a guinea pig model of ovalbumin (OVA)-induced allergic asthma. Guinea pigs were treated with a specific blocker, CaCCinh-A01 (10 μM), administered via inhalation. A significant reduction in cough reflex sensitivity and specific airway resistance was observed in animals treated with CaCCinh-A01, highlighting its potential to improve airway function. Despite a reduction in ciliary beating frequency (CBF), CaCCinh-A01 reduced airway mucus viscosity by decreasing the production of mucin-5AC (MUC5AC). The nonspecific reduction in the Th1/Th2 cytokine spectrum following CaCCinh-A01 treatment indicated the suppression of airway inflammation. Additionally, markers associated with airway remodeling were diminished, suggesting that CaCCinh-A01 may counteract structural changes in airway tissues. Therefore, inhibition appears to mitigate the pathological aspects of asthma, including airway hyperresponsiveness, inflammation, and remodeling. However, further studies are required to comprehensively evaluate the potential of TMEM16A as a therapeutic target for asthma.

哮喘是一种以气道高反应性、炎症和重塑为特征的慢性炎症性疾病。据推断，钙（Ca2+）激活的氯离子（Cl-）通道（如 TMEM16A）与哮喘有关。因此，本研究在卵清蛋白（OVA）诱发过敏性哮喘的豚鼠模型中研究了抑制 TMEM16A 的治疗潜力。豚鼠通过吸入特异性阻断剂 CaCCinh-A01 （10 μM）进行治疗。在接受 CaCCinh-A01 治疗的动物身上观察到咳嗽反射敏感性和特定气道阻力明显降低，凸显了其改善气道功能的潜力。尽管纤毛跳动频率（CBF）降低了，但 CaCCinh-A01 通过减少粘蛋白-5AC（MUC5AC）的产生降低了气道粘液粘度。CaCCinh-A01 治疗后 Th1/Th2 细胞因子谱的非特异性减少表明气道炎症受到了抑制。此外，与气道重塑相关的标记物也有所减少，这表明 CaCCinh-A01 可能会抵消气道组织的结构变化。因此，抑制剂似乎能减轻哮喘的病理方面，包括气道高反应性、炎症和重塑。然而，要全面评估 TMEM16A 作为哮喘治疗靶点的潜力，还需要进一步的研究。

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引用次数: 0

Glucosylceramide synthase inhibitor ameliorates chronic inflammatory pain 葡萄糖酰胺合成酶抑制剂可改善慢性炎症性疼痛

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2024-10-15 DOI: 10.1016/j.jphs.2024.10.003

Shun Watanabe , Misa Oyama , Takashi Iwai , Mitsuo Tanabe

Gangliosides play pivotal roles in neuronal tissue processes, such as axonal elongation, synaptic transmission, and neuronal degeneration. Several studies have shown that mice injected with gangliosides synthesized from glucosylceramide exhibit mechanical allodynia. Thus, we hypothesized that glucosylceramide synthase inhibitors affect nociceptive behavior. We investigated the analgesic effect of intrathecal glucosylceramide inhibition on bilateral allodynia caused by prolonged unilateral hind paw inflammation in mice. Repeated administration of a glucosylceramide inhibitor reduced mechanical allodynia in both inflamed and non-inflamed hind paws. These results suggested that ganglioside reduction is critical for analgesia during inflammatory pain.

神经节苷脂在轴突伸长、突触传递和神经元变性等神经元组织过程中发挥着关键作用。多项研究表明，注射了由葡萄糖基甘油酰胺合成的神经节苷脂的小鼠会出现机械异感。因此，我们假设葡萄糖苷甘油酰胺合成酶抑制剂会影响痛觉行为。我们研究了鞘内葡萄糖酰甘油酰胺抑制剂对小鼠单侧后爪长时间发炎引起的双侧异动症的镇痛效果。重复给药葡萄糖苷酸甘油三酯抑制剂可减少发炎和未发炎后爪的机械异感。这些结果表明，神经节苷脂的减少对炎症性疼痛的镇痛至关重要。

引用次数: 0

Analgesic effect of Keishinieppiittokajutsubu on low barometric pressure-induced pain response in arthritic model rats Keishinieppiittokajutsubu 对低气压引起的关节炎模型大鼠疼痛反应的镇痛效果

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2024-10-09 DOI: 10.1016/j.jphs.2024.10.002

Yuki Kurauchi , Kana Inoue , Tomoka Kawakami , Manami Ueda , Tomoko Yamaguchi , Junji Akaki , Masahiko Komorisono , Hiroshi Katsuki

Rheumatoid arthritis (RA) is a disease that causes inflammation of joints, resulting in pain and swelling. Reduced barometric pressure induces painful symptom of RA, but there is no appropriate animal model and pharmacological evaluation. Keishinieppiittokajutsubu (KNEIJB), a Kampo medicine used to treat RA; however, its mechanism of action is not clear. Here, we found that KNEIJB suppressed the low barometric pressure (LP)-induced pain response in CFA-induced arthritic model rats. Furthermore, we found that KNEIJB reduced plasma IL-6 levels. These results suggest that KNEIJB might be beneficial in the treatment of RA or some other arthralgia induced by LP.

类风湿性关节炎（RA）是一种引起关节炎症的疾病，会导致疼痛和肿胀。气压降低会诱发类风湿关节炎的疼痛症状，但目前还没有合适的动物模型和药理评估。Keishinieppiittokajutsubu（KNEIJB）是一种用于治疗 RA 的康波药物，但其作用机制尚不清楚。在这里，我们发现 KNEIJB 可抑制低气压（LP）诱导的 CFA 关节炎模型大鼠的疼痛反应。此外，我们还发现 KNEIJB 降低了血浆 IL-6 的水平。这些结果表明，KNEIJB可能有益于治疗由低气压诱发的RA或其他关节痛。

引用次数: 0

TND1128, a 5-deazaflavin derivative with auto-redox ability, facilitates polarization of mitochondrial membrane potential (ΔΨm) and on-demand ATP synthesis in mice brain slices TND1128是一种具有自动氧化还原能力的5-去氮黄素衍生物，可促进小鼠脑切片线粒体膜电位（ΔΨm）的极化和按需合成 ATP

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2024-10-09 DOI: 10.1016/j.jphs.2024.10.001

Nanae Takahashi , Tomohisa Nagamatsu , Norio Akaike , Yoshihisa Kudo

TND1128, a 5-deazaflavin derivative, is a drug with self-redox ability. We examined the effect of TND1128 on the level of mitochondrial membrane potential (ΔΨ_m), which is the most critical motive power for the biosynthesis of ATP. We prepared brain slices from mice pretreated with TND1128 (0.1–10 mg/kg, intraperitoneally) and detected ΔΨ_m level with JC-1, a fluorescence ΔΨ_m indicator. We further examined the depolarization of ΔΨ_m under 5-min exposure to 25 mM KCl-ACSF (25K-ACSF), which activated neuronal voltage-dependent Ca²⁺ channels. We evaluated the effect of TND1128 by using the inverse number of the ΔΨ_m value as the ATP synthesis index (ASI). The level of ΔΨ_m increased significantly by 24-h pretreatment with TND1128 (10 mg/kg), and significantly higher depolarization of the ΔΨ_m was observed with 25K-ACSF exposure than in non-treated control. We found a significant decrease in 25K-ACSF induced [Ca²⁺]_c and [Ca²⁺]_m levels in the TND1128-pretreated preparations. We confirmed the dose and time-dependent facilitatory effects of TND1128 on the ASI. This study suggested that TND1128 could be incorporated into the TCA cycle and electron transfer chains to facilitate the polarization of ΔΨ_m and activate on-demand ATP synthesis. TND1128 might rescue neurons in various brain diseases caused by energy defects. (198)

TND1128是一种5-去氮黄素衍生物，是一种具有自我氧化还原能力的药物。我们研究了 TND1128 对线粒体膜电位（ΔΨm）水平的影响，线粒体膜电位是生物合成 ATP 的最关键动力。我们制备了用 TND1128（0.1-10 mg/kg，腹腔注射）预处理的小鼠脑片，并用荧光ΔΨm 指示剂 JC-1 检测ΔΨm 水平。我们进一步检测了ΔΨm在暴露于25 mM KCl-ACSF（25K-ACSF）5分钟后的去极化情况，KCl-ACSF可激活神经元电压依赖性Ca2+通道。我们用ΔΨm值的倒数作为ATP合成指数（ASI）来评估TND1128的效果。用TND1128（10 mg/kg）预处理24小时后，ΔΨm的水平明显升高，并且观察到暴露于25K-ACSF的ΔΨm的去极化程度明显高于未处理的对照组。我们发现，在 TND1128 预处理的制备物中，25K-ACSF 诱导的[Ca2+]c 和[Ca2+]m 水平明显下降。我们证实了 TND1128 对 ASI 的促进作用具有剂量和时间依赖性。这项研究表明，TND1128可被纳入TCA循环和电子传递链，以促进ΔΨm的极化并激活按需ATP合成。TND1128 可能会挽救因能量缺陷导致的各种脑部疾病中的神经元。(198)

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引用次数: 0

Involvement of Cav3.2 T-type Ca2+ channels and cystathionine-β-synthase in colitis-related visceral hypersensitivity in mice Cav3.2 T 型 Ca2+ 通道和胱硫醚-β-合成酶参与小鼠结肠炎相关的内脏超敏反应

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2024-09-21 DOI: 10.1016/j.jphs.2024.09.003

Maho Tsubota , Yuriko Iba , Tsukasa Hatakeyama , Myu Honda , Yoshihito Kasanami , Fumiko Sekiguchi , Atsushi Kawase , Takuya Okada , Naoki Toyooka , Atsufumi Kawabata

We tested the hypothesis that Ca_v3.2 T-type Ca²⁺ channels, which can be rebooted by sulfides from Zn²⁺ inhibition under physiological conditions, and sulfide-generating enzymes including cystathionine-β-synthase (CBS) would participate in the colitis-related visceral pain in mice treated with 2,4,6-trinitrobenzene sulfonic acid (TNBS). The visceral hypersensitivity following TNBS-induced colitis was abolished by an inhibitor or genetic deletion of Ca_v3.2 and by a CBS inhibitor, and accompanied by CBS upregulation in the colon. Our data thus suggest that the enhanced activity of Ca_v3.2 brought about by sulfides generated by upregulated CBS is involved in the colitis-related visceral hypersensitivity.

我们假设，在生理条件下，Cav3.2 T 型 Ca2+ 通道可通过 Zn2+ 抑制硫化物而重新启动，而硫化物生成酶包括胱硫醚-β-合成酶（CBS）将参与 2,4,6-三硝基苯磺酸（TNBS）治疗小鼠结肠炎相关的内脏疼痛。Cav3.2抑制剂或基因缺失以及CBS抑制剂均可消除TNBS诱导的结肠炎引起的内脏超敏反应，同时结肠中的CBS也会上调。因此，我们的数据表明，CBS 上调产生的硫化物导致的 Cav3.2 活性增强参与了结肠炎相关的内脏超敏反应。

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引用次数: 0

Role of CD34 in calcification of human aortic valve interstitial cells from patients with aortic valve stenosis CD34 在主动脉瓣狭窄患者主动脉瓣间质细胞钙化中的作用

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2024-09-12 DOI: 10.1016/j.jphs.2024.09.002

Shihu Men , Zaiqiang Yu , Xu Liu , Kazuyuki Daitoku , Mayuki Tachizaki , Shogo Kawaguchi , Tadaatsu Imaizumi , Masahito Minakawa , Kazuhiko Seya

Various osteogenic factors are involved in ectopic human aortic valve calcification; however, the key cell species involved in calcification remains unclear. In a previous study, we reported that mesenchymal stem (CD73, 90, 105) and endothelial (VEGFR2) cell markers are positive in almost all human aortic valve interstitial cells (HAVICs) obtained from a patient with calcified aortic valve stenosis (CAVS). Further, CD34-negative HAVICs are highly sensitive to calcification stimulations. Here, we aimed to pathophysiologically clarify the role of CD34 in HAVICs obtained from individual patients with severe CAVS. A DNA microarray between CD34-positive and CD34-negative HAVICs, separated by fluorescence-activated cell sorting, indicated that tenascin X (TNX) mRNA expression significantly decreased in CD34-negative cells. Furthermore, the inflammatory cytokines, tumor necrosis factor (TNF)-α and interleukin (IL)-1β significantly downregulated CD34 expression in HAVICs. TGF-β, a key cytokine of endothelial-mesenchymal transition, did not affect HAVIC calcification. CD34 overexpression strongly inhibited TNF-α- and IL-1β-induced calcification and maintained TNX mRNA expression. These results suggest one possibility that CD34 is an inhibitory regulator of valve calcification. Furthermore, TNF-α- and IL-1β-induced CD34 downregulation in HAVICs contributes to HAVIC calcification by downregulating TNX protein expression.

各种成骨因子参与了异位人类主动脉瓣钙化；然而，参与钙化的关键细胞种类仍不清楚。在之前的一项研究中，我们报道了间充质干细胞（CD73、90、105）和内皮细胞（VEGFR2）标记在从一名主动脉瓣狭窄（CAVS）患者体内获得的几乎所有人类主动脉瓣间质细胞（HAVICs）中均呈阳性。此外，CD34 阴性的 HAVIC 对钙化刺激高度敏感。在此，我们旨在从病理生理学角度阐明 CD34 在重度 CAVS 患者 HAVICs 中的作用。通过荧光激活细胞分拣技术分离出的 CD34 阳性和 CD34 阴性 HAVICs 的 DNA 微阵列显示，CD34 阴性细胞中的腱鞘蛋白 X (TNX) mRNA 表达量明显下降。此外，炎性细胞因子、肿瘤坏死因子（TNF）-α 和白细胞介素（IL）-1β 能显著下调 CD34 在 HAVICs 中的表达。内皮-间质转化的关键细胞因子 TGF-β 并不影响 HAVIC 的钙化。CD34 的过表达强烈抑制了 TNF-α 和 IL-1β 诱导的钙化，并维持了 TNX mRNA 的表达。这些结果表明，CD34可能是瓣膜钙化的抑制性调节因子。此外，TNF-α和IL-1β诱导的CD34在HAVIC中的下调通过下调TNX蛋白的表达而促进了HAVIC的钙化。

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引用次数: 0

Evaluation of inhibitory actions of antidepressants on muscarinic receptors assessed by a binding assay in the mouse cerebral neocortex 通过小鼠大脑新皮层结合试验评估抗抑郁药对毒蕈碱受体的抑制作用

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2024-09-11 DOI: 10.1016/j.jphs.2024.09.001

Keisuke Obara, Yuki Usami, Risa Okamoto, Kento Yoshioka, Yoshio Tanaka

We investigated the inhibitory effects of 32 antidepressants on [³H]N-methylscopolamine ([³H]NMS)-specific binding in the mouse cerebral neocortex to determine which antidepressants should be recommended for patients with Alzheimer's disease (AD). Of those tested, nine antidepressants (10⁻⁴ M) exhibited less inhibitory effect on [³H]NMS-specific binding (<35%): tianeptine (a tricyclic); trazodone (a serotonin 5-HT_2A blocker); sulpiride (a dopamine D₂ blocker); fluvoxamine (a selective serotonin reuptake inhibitor (RI)); milnacipran, levomilnacipran, venlafaxine, and desvenlafaxine (serotonin and noradrenaline RIs); and bupropion (a noradrenaline and dopamine RI). Therefore, these antidepressants show little anticholinergic effect in the brain and are recommended for use in patients with AD.

我们研究了32种抗抑郁药对小鼠大脑新皮层中[3H]N-甲基东莨菪碱（[3H]NMS）特异性结合的抑制作用，以确定哪些抗抑郁药应推荐给阿尔茨海默病患者（AD）。在接受测试的药物中，有九种抗抑郁药（10-4 M）对[3H]NMS特异性结合的抑制作用较小（35%）：噻奈普汀（一种三环类药物）；曲唑酮（一种血清素 5-HT2A 阻断剂）；舒必利（一种多巴胺 D2 阻断剂）；氟伏沙明（一种选择性血清素再摄取抑制剂 (RI)）；米那西普兰、左米那西普兰、文拉法辛和去文拉法辛（血清素和去甲肾上腺素 RI）；以及安非他酮（一种去甲肾上腺素和多巴胺 RI）。因此，这些抗抑郁药对大脑的抗胆碱能作用很小，建议用于注意力缺失症患者。

引用次数: 0

Emodin alleviates lung injury via the miR-217-5p/Sirt1 axis in rats with severe acute pancreatitis 大黄素通过 miR-217-5p/Sirt1 轴减轻重症急性胰腺炎大鼠的肺损伤

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2024-08-30 DOI: 10.1016/j.jphs.2024.08.007

Zhihang Zhang , Yalan Luo , Xijing Zhuang , Haifeng Gao , Qi Yang , Hailong Chen

Acute lung injury (ALI) is closely related to high mortality in severe acute pancreatitis (SAP). This study unveils the therapeutic effect and mechanism of miR-217-5p on SAP-associated ALI. The miR-217-5p RNA expression was significantly up-regulated in lipopolysaccharide (LPS)-stimulated primary rat alveolar epithelial type II cells (AEC II) and sodium taurocholate-treated pancreas and lung in SAP rats. miR-217 inhibition protected AEC II from LPS-induced damage by inhibiting apoptosis and reducing the TNF-α, IL-6, and ROS levels. miR-217 inhibition suppressed apoptosis and alleviated mitochondrial damage through mitochondria-mediated apoptotic pathway in vitro. Sirt1 is a direct target of miR-217-5p. Dual-luciferase reporter assay confirmed the binding of miR-217-5p to Sirt1 mRNA 3′-UTR. The rescue experiment identified that the anti-apoptotic, anti-inflammatory, and anti-oxidative effects of miR-217 inhibition were mediated by Sirt1 in vitro. Emodin (EMO) protected AEC II from LPS-induced damage and alleviated pancreatic and lung tissue injuries. EMO exerted similar effects as miR-217 inhibition in vitro and in vivo. The effects of EMO were abolished by miR-217 overexpression. In conclusion, miR-217-5p inhibition exerts protective effects on SAP-ALI in vitro and in vivo by repressing apoptosis, inflammation, and oxidative stress through Sirt1 activation. EMO protects against lung injuries in SAP-associated ALI rats through miR-217-5p/Sirt1 axis.

急性肺损伤（ALI）与重症急性胰腺炎（SAP）的高死亡率密切相关。本研究揭示了 miR-217-5p 对 SAP 相关 ALI 的治疗作用和机制。在脂多糖（LPS）刺激的原代大鼠肺泡上皮 II 型细胞（AEC II）和牛磺胆酸钠处理的 SAP 大鼠胰腺和肺中，miR-217-5p RNA 表达明显上调。抑制 miR-217 可抑制细胞凋亡，降低 TNF-α、IL-6 和 ROS 水平，从而保护 AEC II 免受 LPS 诱导的损伤。Sirt1 是 miR-217-5p 的直接靶标。双荧光素酶报告实验证实了 miR-217-5p 与 Sirt1 mRNA 3′-UTR 的结合。拯救实验表明，体外抑制 miR-217 的抗凋亡、抗炎和抗氧化作用是由 Sirt1 介导的。大黄素（EMO）能保护 AEC II 免受 LPS 诱导的损伤，并减轻胰腺和肺组织损伤。在体外和体内，EMO 发挥了与抑制 miR-217 相似的作用。过表达 miR-217 会取消 EMO 的作用。总之，miR-217-5p抑制通过激活Sirt1抑制细胞凋亡、炎症和氧化应激，从而在体外和体内对SAP-ALI产生保护作用。EMO通过miR-217-5p/Sirt1轴保护SAP相关ALI大鼠免受肺损伤。

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引用次数: 0

Effect of antiemetics on zolbetuximab-induced gastric injury and emesis in ferrets 止吐药对唑贝妥昔单抗诱发雪貂胃损伤和呕吐的影响

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2024-08-26 DOI: 10.1016/j.jphs.2024.08.005

Fumitaka Kinugasa , Satoru Kajikawa , Jane Weng , Tohru Ugawa , Hiroshi Fushiki , Yosuke Yamanaka , Masanori Nagata , Gillian Haggerty , Shinobu Akuzawa , Taisuke Nakazawa , Hiroshi Suzuki , Taiji Sawamoto

Claudin-18 splice variant 2 (CLDN18.2), a tight junction protein, is a highly cell type–specific antigen that is expressed by differentiated gastric mucosa cells. The expression of CLDN18.2 in gastric mucosa cells may be retained upon malignant transformation and is displayed on the surface of several tumors, including gastric/gastroesophageal junction adenocarcinoma. Zolbetuximab is a genetically engineered, highly purified chimeric (mouse/human IgG1) antibody directed against CLDN18.2. Nausea and vomiting were observed as adverse events of zolbetuximab. To investigate the mechanism of nausea and vomiting in humans, we evaluated emesis (retching and vomiting) and conducted histopathologic assessment in ferrets after the administration of zolbetuximab. Emesis was frequently observed in all ferrets treated with zolbetuximab in the first hour after administration. Histopathologic assessment revealed the surface of the gastric mucosa was the primary site of emesis-associated tissue damage. The effect of antiemetics (dexamethasone, ondansetron, fosaprepitant, and olanzapine) on emesis induced by zolbetuximab was investigated. Fosaprepitant showed suppressive effects on emesis, and use of dexamethasone or concomitant use of fosaprepitant with other antiemetics tended to alleviate gastric tissue damage. The onset of emesis in humans receiving zolbetuximab may be associated with damage in the gastric mucosa, and antiemetics may mitigate gastrointestinal adverse events.

Claudin-18剪接变体2（CLDN18.2）是一种紧密连接蛋白，是一种细胞类型特异性很强的抗原，在分化的胃粘膜细胞中表达。CLDN18.2在胃黏膜细胞中的表达可能会在恶性转化时保留下来，并显示在包括胃/胃食管交界腺癌在内的多种肿瘤表面。唑贝妥昔单抗是一种针对 CLDN18.2 的基因工程高纯度嵌合（小鼠/人 IgG1）抗体。唑贝妥昔单抗的不良反应包括恶心和呕吐。为了研究人类恶心和呕吐的机理，我们对服用唑贝妥昔单抗后的雪貂进行了呕吐（反胃和呕吐）评估和组织病理学评估。所有接受唑贝妥昔单抗治疗的雪貂在用药后一小时内都经常出现呕吐现象。组织病理学评估显示，胃黏膜表面是与呕吐相关的组织损伤的主要部位。研究人员还考察了止吐药（地塞米松、昂丹司琼、福沙吡坦和奥氮平）对唑贝妥昔单抗诱导的呕吐的影响。福沙匹坦显示出抑制呕吐的作用，使用地塞米松或与其他止吐药同时使用福沙匹坦往往会减轻胃组织损伤。接受唑贝妥昔单抗治疗的患者出现呕吐可能与胃黏膜损伤有关，止吐药可减轻胃肠道不良反应。

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引用次数: 0