European journal of pharmacology最新文献_第8页

Modulation of SIRT6 related signaling pathways of p-AKT/mTOR and NRF2/HO-1 by memantine contributes to curbing the progression of tamoxifen/HFD-induced MASH in rats 美金刚对SIRT6相关的p-AKT/mTOR和NRF2/HO-1信号通路的调控有助于抑制他莫昔芬/高密度脂蛋白胆固醇诱导的大鼠MASH的进展

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-10-21 DOI: 10.1016/j.ejphar.2024.177069

Yousra M. Ezz-Eldin , Mohamed Gamal El-Din Ewees , Marwa M. Khalaf , Amany A. Azouz

Metabolic dysfunction-associated steatohepatitis (MASH) is a chronic liver disorder marked by hepatic fat accumulation and inflammatory infiltrates which may evolve to cirrhosis. Clinical studies have demonstrated the higher risk of MASH development after tamoxifen (TAM) therapy, especially in obese patients. Therefore, we aimed to evaluate MASH induction by TAM combined with high fat diet (HFD) and the potential interference of memantine (MEMA) with MASH progression via modulation of SIRT6 and its related signaling pathways. MASH was induced in female Wistar rats by co-administration of TAM (25 mg/kg/day, p.o.) and HFD for 5 weeks. Liver function biomarkers, tissue triglyceride and cholesterol, MASH scoring, SIRT6 with its related signals, and lipid synthesis/oxidation markers were estimated. By comparison to MASH group, MEMA improved liver function indices (ALT, AST, ALP, albumin) and reduced the progression of MASH, evidenced by decreased accumulation of lipids in hepatic tissue, improved histological features, and reduced MASH scoring. MEMA enhanced hepatic SIRT6 and downregulated p-AKT/mTOR signaling, that subsequently reduced expressions of the lipid synthesis biomarkers (SREBP1c, SCD), while elevating the lipid oxidation markers (PPAR-α, CPT1). Moreover, MEMA enhanced NRF2/HO-1 signaling, with subsequently improved antioxidant defense and pro-inflammatory/anti-inflammatory cytokines balance. Analysis of SIRT6 correlations with p-AKT/mTOR, NRF2/HO-1, SREBP1c, and PPAR-α further confirmed our results. Consequently, we conclude that MEMA could interfere with MASH progression, at least in part, via enhanced SIRT6 expression and modulation of its related p-AKT/mTOR and NRF2/HO-1 signaling pathways, eventually reducing liver steatosis and inflammation. That could be a promising therapeutic modality for curbing MASH progression.

代谢功能障碍相关性脂肪性肝炎（MASH）是一种以肝脏脂肪堆积和炎症浸润为特征的慢性肝脏疾病，可演变为肝硬化。临床研究表明，他莫昔芬（TAM）治疗后发生 MASH 的风险较高，尤其是肥胖患者。因此，我们旨在评估他莫昔芬联合高脂饮食（HFD）诱导 MASH 的情况，以及美金刚（MEMA）通过调节 SIRT6 及其相关信号通路对 MASH 进展的潜在干扰。在雌性 Wistar 大鼠体内同时给予 TAM（25 毫克/千克/天，p.o.）和高脂饮食 5 周，诱导 MASH。对肝功能生物标志物、组织甘油三酯和胆固醇、MASH评分、SIRT6及其相关信号和脂质合成/氧化标志物进行了评估。与 MASH 组相比，MEMA 改善了肝功能指标（谷丙转氨酶、谷草转氨酶、谷草转氨酶、白蛋白），并降低了 MASH 的进展，这表现在肝组织中脂类积聚减少、组织学特征改善和 MASH 评分降低。MEMA 增强了肝脏 SIRT6，下调了 p-AKT/mTOR 信号转导，从而降低了脂质合成生物标志物（SREBP1c、CPT1）的表达，同时提高了脂质氧化标志物（PPAR-α、SCD）的表达。此外，MEMA 还增强了 NRF2/HO-1 信号传导，从而改善了抗氧化防御和促炎/抗炎细胞因子的平衡。SIRT6与p-AKT/mTOR、NRF2/HO-1、SREBP1c和PPAR-α的相关性分析进一步证实了我们的研究结果。因此，我们得出结论：MEMA 可通过增强 SIRT6 的表达和调节其相关的 p-AKT/mTOR 和 NRF2/HO-1 信号通路，最终减轻肝脏脂肪变性和炎症，至少部分地干扰 MASH 的进展。这可能是一种很有前景的遏制MASH进展的治疗方法。

{"title":"Modulation of SIRT6 related signaling pathways of p-AKT/mTOR and NRF2/HO-1 by memantine contributes to curbing the progression of tamoxifen/HFD-induced MASH in rats","authors":"Yousra M. Ezz-Eldin , Mohamed Gamal El-Din Ewees , Marwa M. Khalaf , Amany A. Azouz","doi":"10.1016/j.ejphar.2024.177069","DOIUrl":"10.1016/j.ejphar.2024.177069","url":null,"abstract":"<div><div>Metabolic dysfunction-associated steatohepatitis (MASH) is a chronic liver disorder marked by hepatic fat accumulation and inflammatory infiltrates which may evolve to cirrhosis. Clinical studies have demonstrated the higher risk of MASH development after tamoxifen (TAM) therapy, especially in obese patients. Therefore, we aimed to evaluate MASH induction by TAM combined with high fat diet (HFD) and the potential interference of memantine (MEMA) with MASH progression via modulation of SIRT6 and its related signaling pathways. MASH was induced in female Wistar rats by co-administration of TAM (25 mg/kg/day, <em>p.o.</em>) and HFD for 5 weeks. Liver function biomarkers, tissue triglyceride and cholesterol, MASH scoring, SIRT6 with its related signals, and lipid synthesis/oxidation markers were estimated. By comparison to MASH group, MEMA improved liver function indices (ALT, AST, ALP, albumin) and reduced the progression of MASH, evidenced by decreased accumulation of lipids in hepatic tissue, improved histological features, and reduced MASH scoring. MEMA enhanced hepatic SIRT6 and downregulated p-AKT/mTOR signaling, that subsequently reduced expressions of the lipid synthesis biomarkers (SREBP1c, SCD), while elevating the lipid oxidation markers (PPAR-α, CPT1). Moreover, MEMA enhanced NRF2/HO-1 signaling, with subsequently improved antioxidant defense and pro-inflammatory/anti-inflammatory cytokines balance. Analysis of SIRT6 correlations with p-AKT/mTOR, NRF2/HO-1, SREBP1c, and PPAR-α further confirmed our results. Consequently, we conclude that MEMA could interfere with MASH progression, at least in part, via enhanced SIRT6 expression and modulation of its related p-AKT/mTOR and NRF2/HO-1 signaling pathways, eventually reducing liver steatosis and inflammation. That could be a promising therapeutic modality for curbing MASH progression.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"984 ","pages":"Article 177069"},"PeriodicalIF":4.2,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Spatheliachromen mitigates methylglyoxal-induced myotube atrophy by activating Nrf2, inhibiting ubiquitin-mediated protein degradation, and restoring mitochondrial function 鞘氨醇通过激活 Nrf2、抑制泛素介导的蛋白质降解和恢复线粒体功能，减轻甲基乙二醛诱导的肌管萎缩。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-10-21 DOI: 10.1016/j.ejphar.2024.177070

Yu-Fan Chuang , Lin Cheng , Wan-Hsuan Chang , Szu-Yin Yu , Hung-Te Hsu , Li-Mei An , Chia-Hung Yen , Fang-Rong Chang , Yi-Ching Lo

Background

Methylglyoxal (MGO) is a potent precursor of glycative stress that leads to oxidative stress and muscle atrophy in diabetes. Spatheliachromen (FPATM-20), derived from Ficus pumila var. awkeotsang, exhibited potential antioxidant activity.

Purpose

This study aimed to evaluate the potential impact and underlying mechanisms of FPATM-20 on MGO-induced myotube atrophy and mitochondrial dysfunction in mouse skeletal C2C12 myotubes.

Methods

Atrophic and antioxidant factors were evaluated using immunofluorescence, enzyme-linked immunosorbent assay, and western blotting. Mitochondrial function was assessed using the ATP assay and Seahorse Cell Mito Stress Test. The glycogen content was determined using periodic acid-Schiff staining. Molecular docking was performed to determine the interaction between FPATM-20 and Keap1.

Results

In myotubes treated with MGO, FPATM-20 activated the Nrf2 pathway, reduced ROS levels, enhanced antioxidant defense, and increased glycogen content. FPATM-20 improved myotube viability and size, upregulated myosin heavy chain (MyHC) expression, modulated ubiquitin-proteasome molecules (nuclear FoxO3a, atrogin-1, MuRF-1, and p62/SQSTM1), and inhibited apoptosis (Bax/Bcl-2 ratio and cleaved caspase 3). Moreover, FPATM-20 restored mitochondrial function, including mitochondrial membrane potential, mitochondrial oxygen consumption rate, and mitochondrial biogenesis pathway (nuclear PGC-1α/TFAM/FNDC5). The inhibition of Nrf2 with ML385 reversed the effects of FPATM-20 on MGO. Furthermore, molecular docking confirmed the binding of FPATM-20 to Keap1, a suppressor of Nrf2, showing the crucial role of Nrf2 in protective effects.

Conclusions

FPATM-20 protects myotubes from MGO toxicity by activating the Nrf2 antioxidant defense, reducing protein degradation and apoptosis, and enhancing mitochondrial function. Thus, FPATM-20 may be a novel agent for preventing skeletal muscle atrophy.

背景：甲基乙二酸（MGO）是糖应激的一种强效前体物，会导致糖尿病患者的氧化应激和肌肉萎缩。目的：本研究旨在评估 FPATM-20 对 MGO 诱导的小鼠骨骼肌 C2C12 肌细胞萎缩和线粒体功能障碍的潜在影响及其内在机制：方法：使用免疫荧光、酶联免疫吸附试验和免疫印迹法评估萎缩和抗氧化因子。线粒体功能采用 ATP 试验和海马细胞线粒体应激试验进行评估。糖原含量采用周期性酸-Schiff染色法测定。进行分子对接以确定 FPATM-20 与 Keap1 之间的相互作用：结果：在经 MGO 处理的肌管中，FPATM-20 激活了 Nrf2 通路，降低了 ROS 水平，增强了抗氧化防御能力，并提高了糖原含量。FPATM-20提高了肌管的活力和尺寸，上调了肌球蛋白重链（MyHC）的表达，调节了泛素-蛋白酶体分子（核FoxO3a、atrogin-1、MuRF-1和p62/SQSTM1），抑制了细胞凋亡（Bax/Bcl-2比率和裂解的caspase 3）。此外，FPATM-20 还能恢复线粒体功能，包括线粒体膜电位、线粒体耗氧率和线粒体生物生成途径（核 PGC-1α/TFAM/FNDC5）。用 ML385 抑制 Nrf2 可以逆转 FPATM-20 对 MGO 的影响。此外，分子对接证实了FPATM-20与Nrf2的抑制因子Keap1的结合，显示了Nrf2在保护作用中的关键作用：结论：FPATM-20通过激活Nrf2抗氧化防御、减少蛋白质降解和凋亡以及增强线粒体功能来保护肌管免受MGO毒性的伤害。因此，FPATM-20 可能是一种预防骨骼肌萎缩的新型药物。

{"title":"Spatheliachromen mitigates methylglyoxal-induced myotube atrophy by activating Nrf2, inhibiting ubiquitin-mediated protein degradation, and restoring mitochondrial function","authors":"Yu-Fan Chuang , Lin Cheng , Wan-Hsuan Chang , Szu-Yin Yu , Hung-Te Hsu , Li-Mei An , Chia-Hung Yen , Fang-Rong Chang , Yi-Ching Lo","doi":"10.1016/j.ejphar.2024.177070","DOIUrl":"10.1016/j.ejphar.2024.177070","url":null,"abstract":"<div><h3>Background</h3><div>Methylglyoxal (MGO) is a potent precursor of glycative stress that leads to oxidative stress and muscle atrophy in diabetes. Spatheliachromen (FPATM-20), derived from <em>Ficus pumila</em> var. <em>awkeotsang</em>, exhibited potential antioxidant activity.</div></div><div><h3>Purpose</h3><div>This study aimed to evaluate the potential impact and underlying mechanisms of FPATM-20 on MGO-induced myotube atrophy and mitochondrial dysfunction in mouse skeletal C2C12 myotubes.</div></div><div><h3>Methods</h3><div>Atrophic and antioxidant factors were evaluated using immunofluorescence, enzyme-linked immunosorbent assay, and western blotting. Mitochondrial function was assessed using the ATP assay and Seahorse Cell Mito Stress Test. The glycogen content was determined using periodic acid-Schiff staining. Molecular docking was performed to determine the interaction between FPATM-20 and Keap1.</div></div><div><h3>Results</h3><div>In myotubes treated with MGO, FPATM-20 activated the Nrf2 pathway, reduced ROS levels, enhanced antioxidant defense, and increased glycogen content. FPATM-20 improved myotube viability and size, upregulated myosin heavy chain (MyHC) expression, modulated ubiquitin-proteasome molecules (nuclear FoxO3a, atrogin-1, MuRF-1, and p62/SQSTM1), and inhibited apoptosis (Bax/Bcl-2 ratio and cleaved caspase 3). Moreover, FPATM-20 restored mitochondrial function, including mitochondrial membrane potential, mitochondrial oxygen consumption rate, and mitochondrial biogenesis pathway (nuclear PGC-1α/TFAM/FNDC5). The inhibition of Nrf2 with ML385 reversed the effects of FPATM-20 on MGO. Furthermore, molecular docking confirmed the binding of FPATM-20 to Keap1, a suppressor of Nrf2, showing the crucial role of Nrf2 in protective effects.</div></div><div><h3>Conclusions</h3><div>FPATM-20 protects myotubes from MGO toxicity by activating the Nrf2 antioxidant defense, reducing protein degradation and apoptosis, and enhancing mitochondrial function. Thus, FPATM-20 may be a novel agent for preventing skeletal muscle atrophy.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"984 ","pages":"Article 177070"},"PeriodicalIF":4.2,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Antidepressant-like and antistress effects of the ACTH(4–10) synthetic analogs Semax and Melanotan II on male rats in a model of chronic unpredictable stress ACTH(4-10) 合成类似物 Semax 和 Melanotan II 在慢性不可预测压力模型中对雄性大鼠的抗抑郁和抗抑郁作用

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-10-21 DOI: 10.1016/j.ejphar.2024.177068

Ludmila S. Inozemtseva , Ksenia A. Yatsenko , Natalya Yu Glazova , Andrey A. Kamensky , Nikolai F. Myasoedov , Natalia G. Levitskaya , Igor A. Grivennikov , Oleg V. Dolotov

Current antidepressant therapy shows substantial limitations, and there is an urgent need for the development of new treatment strategies for depression. Stressful events and hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis play an important role in the pathogenesis of depression. HPA axis activity is self-regulated by negative feedback at several levels including adrenocorticotropic hormone (ACTH)-mediated feedback. Here, we investigated whether noncorticotropic synthetic analogs of the ACTH(4–10) fragment, ACTH(4–7)-Pro-Gly-Pro (Semax) and Ac-Nle4-cyclo[Asp5-His6-D-Phe7-Arg8-Trp9-Lys10]ACTH(4–10)-NH2 (Melanotan II (MTII), a potent agonist of melanocortin receptors), have potential antidepressant activity in a chronic unpredictable stress (CUS) rat model of depression. Stressed and control male adult Sprague-Dawley rats received daily intraperitoneal injections of saline or a low dose (60 nmol/kg of body weight (BW)) of Semax or MTII. Rats were monitored for BW and hedonic status, as measured in the sucrose preference test. We found that chronic treatment with Semax and MTII reversed or substantially attenuated CUS-induced anhedonia, BW gain suppression, adrenal hypertrophy and a decrease in the hippocampal levels of BDNF. In the forced swim test, no effects of the CUS procedure or peptides on the duration of rat immobility were detected. Our findings show that in the CUS paradigm, systemically administered ACTH(4–10) analogs Semax and MTII exert antidepressant-like effects on anhedonia and hippocampal BDNF levels, and attenuate markers of chronic stress load, at least in male rats. The results support the argument that ACTH(4–10) analogs and other noncorticotropic melanocortins may have promising therapeutic potential for the treatment and prevention of depression and other stress-related pathologies.

目前的抗抑郁疗法存在很大的局限性，因此迫切需要开发新的抑郁症治疗策略。压力事件和下丘脑-垂体-肾上腺（HPA）轴的过度活跃在抑郁症的发病机制中起着重要作用。HPA轴的活动在多个水平上通过负反馈进行自我调节，包括促肾上腺皮质激素（ACTH）介导的反馈。在此，我们研究了促肾上腺皮质激素（ACTH）（4-10）片段的非促皮质合成类似物--促肾上腺皮质激素（4-7）-Pro-Gly-Pro（Semax）和Ac-Nle4-cyclo[Asp5-His6-D-Phe7-Arg8-Trp9-Lys10]ACTH（4-10）-NH2（Melanotan II（MTII），一种黑皮素受体的强效激动剂）--在慢性不可预测应激（CUS）抑郁大鼠模型中是否具有潜在的抗抑郁活性。应激大鼠和对照组雄性成年 Sprague-Dawley 大鼠每天腹腔注射生理盐水或低剂量（每公斤体重 60 nmol）的 Semax 或 MTII。通过蔗糖偏好测试，对大鼠的体重和享乐状态进行监测。我们发现，Semax 和 MTII 的长期治疗可逆转或大大减轻 CUS 引起的失神、体重增加抑制、肾上腺肥大和海马 BDNF 水平的下降。在强迫游泳试验中，没有发现 CUS 程序或肽对大鼠静止不动的持续时间有任何影响。我们的研究结果表明，在CUS范例中，全身给药的促肾上腺皮质激素（4-10）类似物Semax和MTII对失神和海马BDNF水平具有类似抗抑郁的作用，并能减轻慢性压力负荷的标记物，至少在雄性大鼠中是如此。这些结果证明，促肾上腺皮质激素（4-10）类似物和其他非促皮质素类黑色素皮质激素在治疗和预防抑郁症及其他压力相关病症方面具有广阔的治疗潜力。

{"title":"Antidepressant-like and antistress effects of the ACTH(4–10) synthetic analogs Semax and Melanotan II on male rats in a model of chronic unpredictable stress","authors":"Ludmila S. Inozemtseva , Ksenia A. Yatsenko , Natalya Yu Glazova , Andrey A. Kamensky , Nikolai F. Myasoedov , Natalia G. Levitskaya , Igor A. Grivennikov , Oleg V. Dolotov","doi":"10.1016/j.ejphar.2024.177068","DOIUrl":"10.1016/j.ejphar.2024.177068","url":null,"abstract":"<div><div>Current antidepressant therapy shows substantial limitations, and there is an urgent need for the development of new treatment strategies for depression. Stressful events and hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis play an important role in the pathogenesis of depression. HPA axis activity is self-regulated by negative feedback at several levels including adrenocorticotropic hormone (ACTH)-mediated feedback. Here, we investigated whether noncorticotropic synthetic analogs of the ACTH(4–10) fragment, ACTH(4–7)-Pro-Gly-Pro (Semax) and Ac-Nle4-<em>cyclo</em>[Asp5-His6-D-Phe7-Arg8-Trp9-Lys10]ACTH(4–10)-NH2 (Melanotan II (MTII), a potent agonist of melanocortin receptors), have potential antidepressant activity in a chronic unpredictable stress (CUS) rat model of depression. Stressed and control male adult Sprague-Dawley rats received daily intraperitoneal injections of saline or a low dose (60 nmol/kg of body weight (BW)) of Semax or MTII. Rats were monitored for BW and hedonic status, as measured in the sucrose preference test. We found that chronic treatment with Semax and MTII reversed or substantially attenuated CUS-induced anhedonia, BW gain suppression, adrenal hypertrophy and a decrease in the hippocampal levels of BDNF. In the forced swim test, no effects of the CUS procedure or peptides on the duration of rat immobility were detected. Our findings show that in the CUS paradigm, systemically administered ACTH(4–10) analogs Semax and MTII exert antidepressant-like effects on anhedonia and hippocampal BDNF levels, and attenuate markers of chronic stress load, at least in male rats. The results support the argument that ACTH(4–10) analogs and other noncorticotropic melanocortins may have promising therapeutic potential for the treatment and prevention of depression and other stress-related pathologies.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"984 ","pages":"Article 177068"},"PeriodicalIF":4.2,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142497544","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

New insights on pharmacological and therapeutic potentials of trimetazidine beyond anti-anginal drug: A comprehensive review 关于曲美他嗪超越抗心绞痛药物的药理和治疗潜力的新见解：全面综述。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-10-19 DOI: 10.1016/j.ejphar.2024.177062

Dhirendra Singh , Joy Oladimeji-Salami , Abidemi James Akindele

Trimetazidine (TMZ) is a beneficial and well-tolerable anti-anginal drug which has protective action towards ischemia and reperfusion injury. TMZ performs its anti-ischemic effect by modifying cardiac metabolism without shifting the hemodynamic functions, so it represents an outstanding complementary perspective to the general angina treatment. TMZ possesses a positive impact on the inflammatory profile, and also endothelial function furthermore displays various benefits through minimising the number, as well as the intensity of angina strikes and ameliorating the clinical indication and symptoms of myocardium ischemia. It is administrated as monotherapy along with a combination of different antianginal drugs. Apart from anti-angina action, in recent years TMZ has shown various pharmacological activities such as neuroprotective, renal protective, hepato-protective, cardio-protective effects, and other beneficial pharmacological activities. We select to write the present review article to cover the different pharmacological and therapeutic potentials of TMZ.

曲美他嗪（TMZ）是一种有益且可耐受的抗心绞痛药物，对缺血和再灌注损伤具有保护作用。TMZ 通过改变心脏新陈代谢来发挥抗缺血作用，而不会改变血液动力学功能，因此是一般心绞痛治疗的出色补充药物。TMZ 对炎症概况和血管内皮功能有积极影响，并通过减少心绞痛发作的次数和强度以及改善心肌缺血的临床症状和体征而显示出各种益处。它可作为单一疗法与不同的抗心绞痛药物联合使用。除抗心绞痛作用外，近年来 TMZ 还显示出多种药理活性，如神经保护作用、肾脏保护作用、肝脏保护作用、心脏保护作用以及其他有益的药理活性。我们选择撰写这篇综述文章来介绍 TMZ 的不同药理和治疗潜力。

{"title":"New insights on pharmacological and therapeutic potentials of trimetazidine beyond anti-anginal drug: A comprehensive review","authors":"Dhirendra Singh , Joy Oladimeji-Salami , Abidemi James Akindele","doi":"10.1016/j.ejphar.2024.177062","DOIUrl":"10.1016/j.ejphar.2024.177062","url":null,"abstract":"<div><div>Trimetazidine (TMZ) is a beneficial and well-tolerable anti-anginal drug which has protective action towards ischemia and reperfusion injury. TMZ performs its anti-ischemic effect by modifying cardiac metabolism without shifting the hemodynamic functions, so it represents an outstanding complementary perspective to the general angina treatment. TMZ possesses a positive impact on the inflammatory profile, and also endothelial function furthermore displays various benefits through minimising the number, as well as the intensity of angina strikes and ameliorating the clinical indication and symptoms of myocardium ischemia. It is administrated as monotherapy along with a combination of different antianginal drugs. Apart from anti-angina action, in recent years TMZ has shown various pharmacological activities such as neuroprotective, renal protective, hepato-protective, cardio-protective effects, and other beneficial pharmacological activities. We select to write the present review article to cover the different pharmacological and therapeutic potentials of TMZ.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"985 ","pages":"Article 177062"},"PeriodicalIF":4.2,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Therapeutic potency of marine collagen/pectin scaffolds - Fabrication, characterization and evaluation 海洋胶原蛋白/pectin 支架的治疗功效--制作、表征和评估。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-10-19 DOI: 10.1016/j.ejphar.2024.177066

Weslen Vedakumari Sathyaraj , Yovan Raja Pravin , Lokesh Prabakaran , Anbalagan Gokulnath , Jayavardhini Bhoopathy , Selvarajan Rajendran

Skin is an important vital organ that must be given proper care and protection from external damage and harmful microbes. If injured, it must be treated with an ideal wound dressing material with potent hemostatic and non-toxic properties. In the present study, fish collagen (FC) was extracted from the fins and tails of Black pomfret (Parastromateus niger). The isolated fish collagen was homogenized with pectin (P) and freeze dried to obtain fish collagen/pectin (FC/P) scaffolds. Scanning electron microscopic analysis showed the porous nature of scaffolds with intermittent holes. UV–Visible and Fourier infrared spectroscopic analyses demonstrated the physicochemical properties of FC/P scaffolds. Hemolytic assay performed using human blood demonstrated the percentage of hemolysis as 0.5 %. In vitro blood clotting assay carried out to determine the hemostatic behaviour displayed the formation of blood clot within 60 s in the presence of FC/P scaffolds. 95 % of cells were viable with the highest concentration of FC/P scaffold used for MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay. Scratch wound assay demonstrated complete closure of wound in FC/P scaffold treated cells after 48 h of treatment. Chick embryo chorioallantoic membrane (CAM) assay showed the development of new blood vessels within 6 h of incubation with the FC/P scaffolds, thereby proving their angiogenic potency. These results indicate the potential use of FC/P scaffolds as effective biomaterials for tissue regenerative applications.

皮肤是一个重要的生命器官，必须给予适当的护理和保护，使其免受外部损伤和有害微生物的侵害。如果皮肤受伤，必须使用止血效果好且无毒的理想伤口敷料进行处理。本研究从黑鲳（Parastromateus niger）的鳍和尾中提取了鱼胶原蛋白（FC）。分离出的鱼胶原蛋白与果胶（P）均质后冷冻干燥，得到鱼胶原蛋白/果胶（FC/P）支架。扫描电子显微镜分析表明，支架具有间歇性多孔性质。紫外可见光谱和傅立叶红外光谱分析证明了 FC/P 支架的理化性质。利用人体血液进行的溶血试验表明，溶血率为 0.5%。为确定止血性能而进行的体外凝血试验显示，在 FC/P 材料支架存在的 60 秒内，血凝块就会形成。在 MTT（3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide）试验中使用最高浓度的 FC/P 支架，95% 的细胞都能存活。划痕伤口试验表明，经 FC/P 支架处理的细胞在 48 小时后伤口完全闭合。雏鸡胚胎绒毛膜（CAM）试验表明，FC/P 支架在孵育 6 小时内就能发育出新的血管，从而证明了其血管生成功效。这些结果表明，FC/P 支架可作为有效的生物材料用于组织再生应用。

{"title":"Therapeutic potency of marine collagen/pectin scaffolds - Fabrication, characterization and evaluation","authors":"Weslen Vedakumari Sathyaraj , Yovan Raja Pravin , Lokesh Prabakaran , Anbalagan Gokulnath , Jayavardhini Bhoopathy , Selvarajan Rajendran","doi":"10.1016/j.ejphar.2024.177066","DOIUrl":"10.1016/j.ejphar.2024.177066","url":null,"abstract":"<div><div>Skin is an important vital organ that must be given proper care and protection from external damage and harmful microbes. If injured, it must be treated with an ideal wound dressing material with potent hemostatic and non-toxic properties. In the present study, fish collagen (FC) was extracted from the fins and tails of Black pomfret (<em>Parastromateus niger)</em>. The isolated fish collagen was homogenized with pectin (P) and freeze dried to obtain fish collagen/pectin (FC/P) scaffolds. Scanning electron microscopic analysis showed the porous nature of scaffolds with intermittent holes. UV–Visible and Fourier infrared spectroscopic analyses demonstrated the physicochemical properties of FC/P scaffolds. Hemolytic assay performed using human blood demonstrated the percentage of hemolysis as 0.5 %. <em>In vitro</em> blood clotting assay carried out to determine the hemostatic behaviour displayed the formation of blood clot within 60 s in the presence of FC/P scaffolds. 95 % of cells were viable with the highest concentration of FC/P scaffold used for MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay. Scratch wound assay demonstrated complete closure of wound in FC/P scaffold treated cells after 48 h of treatment. Chick embryo chorioallantoic membrane (CAM) assay showed the development of new blood vessels within 6 h of incubation with the FC/P scaffolds, thereby proving their angiogenic potency. These results indicate the potential use of FC/P scaffolds as effective biomaterials for tissue regenerative applications.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"984 ","pages":"Article 177066"},"PeriodicalIF":4.2,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Isoechinulin B, a natural product from Antarctic fungus, attenuates acute liver injury by inhibiting excessive cell adhesion Isoechinulin B 是一种来自南极真菌的天然产物，可通过抑制细胞过度粘附来减轻急性肝损伤。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-10-19 DOI: 10.1016/j.ejphar.2024.177065

Han Sun , Xu Pang , Jian-Rui Li , Hu Li , Mei Tang , Tao Zhang , Li-Yan Yu , Zong-Gen Peng

Abnormal cell adhesion between leukocytes and endothelial cells is closely associated with the development of numerous inflammation-related diseases, with adhesion molecules playing a crucial role. The disruption of cell adhesion directly or indirectly inhibits excessive cell adhesion and thus produces a therapeutic effect. However, there are only a few clinically available antagonists of cell adhesion. One of the biggest challenges is the development of novel and efficient cell adhesion inhibitors. Recently, the anti-inflammatory pharmacological activity of natural products of microbial origin has also received increasing attention. Here, we obtained a potential cell adhesion inhibitor isoechinulin B, an indole diketopiperazine derivative, from the Antarctic fungus Aspergillus sp. CPCC 401072, which is active against cell adhesion. Isoechinulin B decreased the expression of vascular endothelial adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) by inhibiting the activation of the NF-κB signaling pathway, thereby inhibiting cell adhesion between leukocytes and endothelial cells to reduce macrophage infiltration in the liver and significantly attenuate lipopolysaccharide-induced acute liver injury in mice.

Conclusion

Isoechinulin B is a novel cell adhesion inhibitor derived from fungi found in extreme environments.

白细胞与内皮细胞之间异常的细胞粘附与多种炎症相关疾病的发生密切相关，而粘附分子在其中扮演着至关重要的角色。破坏细胞粘附力可以直接或间接抑制细胞的过度粘附，从而产生治疗效果。然而，目前临床上可用的细胞粘附拮抗剂寥寥无几。最大的挑战之一就是开发新型高效的细胞粘附抑制剂。最近，微生物来源的天然产物的抗炎药理活性也受到越来越多的关注。在这里，我们从南极真菌 Aspergillus sp. CPCC 401072 中获得了一种潜在的细胞粘附抑制剂异胆苷 B，它是一种吲哚二酮哌嗪衍生物，具有抗细胞粘附的活性。Isoechinulin B通过抑制NF-κB信号通路的激活，降低血管内皮粘附分子1（VCAM-1）和细胞间粘附分子1（ICAM-1）的表达，从而抑制白细胞和内皮细胞之间的细胞粘附，减少巨噬细胞在肝脏中的浸润，显著减轻脂多糖诱导的小鼠急性肝损伤。结论：Isoechinulin B是从极端环境中发现的真菌中提取的一种新型细胞粘附抑制剂。

{"title":"Isoechinulin B, a natural product from Antarctic fungus, attenuates acute liver injury by inhibiting excessive cell adhesion","authors":"Han Sun , Xu Pang , Jian-Rui Li , Hu Li , Mei Tang , Tao Zhang , Li-Yan Yu , Zong-Gen Peng","doi":"10.1016/j.ejphar.2024.177065","DOIUrl":"10.1016/j.ejphar.2024.177065","url":null,"abstract":"<div><div>Abnormal cell adhesion between leukocytes and endothelial cells is closely associated with the development of numerous inflammation-related diseases, with adhesion molecules playing a crucial role. The disruption of cell adhesion directly or indirectly inhibits excessive cell adhesion and thus produces a therapeutic effect. However, there are only a few clinically available antagonists of cell adhesion. One of the biggest challenges is the development of novel and efficient cell adhesion inhibitors. Recently, the anti-inflammatory pharmacological activity of natural products of microbial origin has also received increasing attention. Here, we obtained a potential cell adhesion inhibitor isoechinulin B, an indole diketopiperazine derivative, from the Antarctic fungus <em>Aspergillus</em> sp. CPCC 401072, which is active against cell adhesion. Isoechinulin B decreased the expression of vascular endothelial adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) by inhibiting the activation of the NF-κB signaling pathway, thereby inhibiting cell adhesion between leukocytes and endothelial cells to reduce macrophage infiltration in the liver and significantly attenuate lipopolysaccharide-induced acute liver injury in mice.</div></div><div><h3>Conclusion</h3><div>Isoechinulin B is a novel cell adhesion inhibitor derived from fungi found in extreme environments.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"984 ","pages":"Article 177065"},"PeriodicalIF":4.2,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

N-(4-methoxyphenyl) quinoline-8-sulfonamide reduces the inflammatory response of fibroblast-like synoviocytes by targeting receptor (calcitonin) activity modifying protein 1 in rheumatoid arthritis N-（4-甲氧基苯基）喹啉-8-磺酰胺通过靶向受体（降钙素）活性修饰蛋白 1 减轻类风湿性关节炎成纤维细胞样滑膜细胞的炎症反应。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-10-19 DOI: 10.1016/j.ejphar.2024.177064

Ying-Li Yang , Ning Yao , Shang-Qing Ge , Biao Song , Han Xu , Zeng Li , Xiao-Feng Li , Jun Li

Background

Rheumatoid arthritis (RA) is characterized by chronic inflammation of the synovium of joints. Fibroblast-like synoviocytes (FLS) play an important role in RA pathogenesis. We aimed to investigate the effect of N-(4-methoxyphenyl) quinoline-8-sulfonamide (QS-3g) on the inflammatory response of FLS and explore the potential underlying mechanisms.

Methods

We screened and found that QS-3g exhibits the best anti-inflammatory response against FLS using the CCK8 assay. To investigate the therapeutic effects of QS-3g on K/BxN STA mice, we used H&E staining, immunofluorescence, immunohistochemistry, micro-CT, and other techniques. Additional investigations, including RNA-seq, molecular docking, and CETSA, revealed that QS-3g binds to RAMP1.

Results

Among a series of 8-quinoline sulfonyl amide derivatives, QS-3g reduced the inflammatory response in TNF-α stimulated FLS, such as the release of interleukin (IL)-1β and IL-6. H&E staining and micro-CT showed that QS-3g inhibited synovial hypertrophy, inflammatory cell infiltration, and bone destruction. RNA-seq and CETSA analyses revealed the targeted inhibition of RAMP1 by QS-3g. Inhibition of RAMP1 expression could reduce IL-6 and IL-1β levels. Compared with RAMP1-si, combined administration of QS-3g and RAMP1-si reduced the TNF-α-induced inflammation in TNF-α stimulated FLS without statistically significant differences. Finally, the results of in vitro experiments showed that QS-3g could restore the balance of Gαi/Gαs by inhibiting Gαi and activating Gαs and up-regulate the expression of cAMP protein, thus inhibiting the RAMP1-mediated inflammatory response in FLS.

Conclusion

QS-3g could inhibit RAMP1 activity and mediate the Gαs/Gαi–cAMP pathway to reduce FLS inflammatory response. Therefore, QS-3g may serve as a novel anti-inflammatory compound for treating RA.

背景：类风湿性关节炎（RA类风湿性关节炎（RA）的特征是关节滑膜的慢性炎症。成纤维细胞样滑膜细胞（FLS）在 RA 的发病机制中发挥着重要作用。我们旨在研究N-（4-甲氧基苯基）喹啉-8-磺酰胺（QS-3g）对FLS炎症反应的影响，并探索其潜在的内在机制：我们利用 CCK8 试验筛选并发现 QS-3g 对 FLS 的抗炎反应最佳。为了研究 QS-3g 对 K/BxN STA 小鼠的治疗效果，我们使用了 H&E 染色、免疫荧光、免疫组化、显微 CT 等技术。包括RNA-seq、分子对接和CETSA在内的其他研究发现，QS-3g与RAMP1结合：结果：在一系列 8-喹啉磺酰胺衍生物中，QS-3g 可降低 TNF-α 刺激的 FLS 的炎症反应，如白细胞介素（IL）-1β 和 IL-6 的释放。H&E 染色和显微 CT 显示，QS-3g 可抑制滑膜肥厚、炎症细胞浸润和骨质破坏。RNA-seq 和 CETSA 分析显示，QS-3g 对 RAMP1 有靶向抑制作用。抑制 RAMP1 的表达可降低 IL-6 和 IL-1β 的水平。与RAMP1-si相比，联合使用QS-3g和RAMP1-si可减少TNF-α刺激FLS诱发的炎症，但差异无统计学意义。最后，体外实验结果表明，QS-3g可通过抑制Gαi和激活Gαs来恢复Gαi/Gαs的平衡，并上调cAMP蛋白的表达，从而抑制RAMP1介导的FLS炎症反应：结论：QS-3g 可抑制 RAMP1 的活性，介导 Gαs/Gαi-cAMP 通路，从而减轻 FLS 的炎症反应。因此，QS-3g 可作为治疗 RA 的新型抗炎化合物。

{"title":"N-(4-methoxyphenyl) quinoline-8-sulfonamide reduces the inflammatory response of fibroblast-like synoviocytes by targeting receptor (calcitonin) activity modifying protein 1 in rheumatoid arthritis","authors":"Ying-Li Yang , Ning Yao , Shang-Qing Ge , Biao Song , Han Xu , Zeng Li , Xiao-Feng Li , Jun Li","doi":"10.1016/j.ejphar.2024.177064","DOIUrl":"10.1016/j.ejphar.2024.177064","url":null,"abstract":"<div><h3>Background</h3><div>Rheumatoid arthritis (RA) is characterized by chronic inflammation of the synovium of joints. Fibroblast-like synoviocytes (FLS) play an important role in RA pathogenesis. We aimed to investigate the effect of N-(4-methoxyphenyl) quinoline-8-sulfonamide (QS-3g) on the inflammatory response of FLS and explore the potential underlying mechanisms.</div></div><div><h3>Methods</h3><div>We screened and found that QS-3g exhibits the best anti-inflammatory response against FLS using the CCK8 assay. To investigate the therapeutic effects of QS-3g on K/BxN STA mice, we used H&E staining, immunofluorescence, immunohistochemistry, micro-CT, and other techniques. Additional investigations, including RNA-seq, molecular docking, and CETSA, revealed that QS-3g binds to RAMP1.</div></div><div><h3>Results</h3><div>Among a series of 8-quinoline sulfonyl amide derivatives, QS-3g reduced the inflammatory response in TNF-α stimulated FLS, such as the release of interleukin (IL)-1β and IL-6. H&E staining and micro-CT showed that QS-3g inhibited synovial hypertrophy, inflammatory cell infiltration, and bone destruction. RNA-seq and CETSA analyses revealed the targeted inhibition of RAMP1 by QS-3g. Inhibition of RAMP1 expression could reduce IL-6 and IL-1β levels. Compared with RAMP1-si, combined administration of QS-3g and RAMP1-si reduced the TNF-α-induced inflammation in TNF-α stimulated FLS without statistically significant differences. Finally, the results of <em>in vitro</em> experiments showed that QS-3g could restore the balance of Gαi/Gαs by inhibiting Gαi and activating Gαs and up-regulate the expression of cAMP protein, thus inhibiting the RAMP1-mediated inflammatory response in FLS.</div></div><div><h3>Conclusion</h3><div>QS-3g could inhibit RAMP1 activity and mediate the Gαs/Gαi–cAMP pathway to reduce FLS inflammatory response. Therefore, QS-3g may serve as a novel anti-inflammatory compound for treating RA.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"984 ","pages":"Article 177064"},"PeriodicalIF":4.2,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Escin ameliorates CUMS-induced depressive-like behavior via BDNF/TrkB/CREB and TLR4/MyD88/NF-κB signaling pathways in rats Escin可通过BDNF/TrkB/CREB和TLR4/MyD88/NF-κB信号通路改善CUMS诱导的大鼠抑郁样行为。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-10-18 DOI: 10.1016/j.ejphar.2024.177063

Fengjiao Liu , Yaxin Jia , Liwei Zhao , Li-na Xiao , Xizhen Cheng , Yingying Xiao , Ying Zhang , Yuling Zhang , Huimin Yu , Qiao-en Deng , Yuanyuan Zhang , Yimeng Feng , junfang Wang , Yonggang Gao , Xuan Zhang , Yunyun Geng

Major depressive disorder (MDD) is a prevalent psychiatric disorder associated with brain inflammation and neuronal damage. Derived from the Aesculus chinensis Bunge fruit, escin has shown anti-inflammatory and neuroprotective effects. However, its potential as a treatment for MDD is unclear. This study investigates the antidepressant properties of escin using in vivo experimentation. The chronic unpredictable mild stress (CUMS) model was used to analyze the potential antidepressant effects and underlying mechanisms of escin. Wistar rats were exposed to CUMS for 35 consecutive days to induce MDD. The rats were then given either escin (1, 3, and 10 mg/kg) or fluoxetine (2 mg/kg) on a daily basis. Notably, escin significantly alleviated the depressive behaviors induced by CUMS, as evaluated through a series of behavioral assessments. Moreover, escin administration reduced TNF-α, IL-1β, and IL-6 levels in the hippocampus. It also decreased serum adrenal cortical hormone (ACTH) and corticosterone (CORT) levels while increasing 5-HT and Brain-derived neurotrophic factor (BDNF) levels in the CUMS rats, as measured by the enzyme-linked immunosorbent assay (ELISA). Pathological changes in the hippocampal regions were identified through Nissl staining, and Western blotting was used to quantify the protein levels of BDNF, TrkB, CREB, TLR4, MyD88, and NF-κB. Escin mitigated neuronal injury, elevated TrkB, BDNF, and CREB, and reduced TLR4, MyD88, and NF-κB protein levels in CUMS rats. The data from this study suggest that escin holds the potential for alleviating depression-like symptoms induced by CUMS. This effect may be mediated through the modulation of two signaling pathways, BDNF/TrkB/CREB and TLR4/MyD88/NF-κB.

重度抑郁症（MDD）是一种常见的精神疾病，与脑部炎症和神经元损伤有关。从 Aesculus chinensis Bunge 果实中提取的 escin 具有抗炎和保护神经的作用。然而，它作为 MDD 治疗药物的潜力尚不明确。本研究通过体内实验研究了埃斯京的抗抑郁特性。研究采用了慢性不可预知轻度应激（CUMS）模型来分析埃斯京的潜在抗抑郁作用及其内在机制。将 Wistar 大鼠连续暴露于 CUMS 35 天，以诱发 MDD。然后每天给大鼠服用埃辛（1、3 和 10 毫克/千克）或氟西汀（2 毫克/千克）。值得注意的是，通过一系列行为评估，埃斯京明显减轻了CUMS诱导的抑郁行为。此外，服用埃斯京能降低海马中 TNF-α、IL-1β 和 IL-6 的水平。通过酶联免疫吸附试验（ELISA）测定，它还降低了CUMS大鼠血清肾上腺皮质激素（ACTH）和皮质酮（CORT）的水平，同时提高了5-羟色胺和脑源性神经营养因子（BDNF）的水平。通过 Nissl 染色确定了海马区的病理变化，并用 Western 印迹法量化了 BDNF、TrkB、CREB、TLR4、MyD88 和 NF-κB 的蛋白水平。埃辛减轻了 CUMS 大鼠的神经元损伤，提高了 TrkB、BDNF 和 CREB 的水平，降低了 TLR4、MyD88 和 NF-κB 蛋白水平。这项研究的数据表明，埃斯京有可能减轻 CUMS 诱发的抑郁症状。这种作用可能是通过调节两种信号通路（BDNF/TrkB/CREB 和 TLR4/MyD88/NF-κB）来实现的。

{"title":"Escin ameliorates CUMS-induced depressive-like behavior via BDNF/TrkB/CREB and TLR4/MyD88/NF-κB signaling pathways in rats","authors":"Fengjiao Liu , Yaxin Jia , Liwei Zhao , Li-na Xiao , Xizhen Cheng , Yingying Xiao , Ying Zhang , Yuling Zhang , Huimin Yu , Qiao-en Deng , Yuanyuan Zhang , Yimeng Feng , junfang Wang , Yonggang Gao , Xuan Zhang , Yunyun Geng","doi":"10.1016/j.ejphar.2024.177063","DOIUrl":"10.1016/j.ejphar.2024.177063","url":null,"abstract":"<div><div>Major depressive disorder (MDD) is a prevalent psychiatric disorder associated with brain inflammation and neuronal damage. Derived from the <em>Aesculus chinensis Bunge</em> fruit, escin has shown anti-inflammatory and neuroprotective effects. However, its potential as a treatment for MDD is unclear. This study investigates the antidepressant properties of escin using in vivo experimentation. The chronic unpredictable mild stress (CUMS) model was used to analyze the potential antidepressant effects and underlying mechanisms of escin. Wistar rats were exposed to CUMS for 35 consecutive days to induce MDD. The rats were then given either escin (1, 3, and 10 mg/kg) or fluoxetine (2 mg/kg) on a daily basis. Notably, escin significantly alleviated the depressive behaviors induced by CUMS, as evaluated through a series of behavioral assessments. Moreover, escin administration reduced TNF-α, IL-1β, and IL-6 levels in the hippocampus. It also decreased serum adrenal cortical hormone (ACTH) and corticosterone (CORT) levels while increasing 5-HT and Brain-derived neurotrophic factor (BDNF) levels in the CUMS rats, as measured by the enzyme-linked immunosorbent assay (ELISA). Pathological changes in the hippocampal regions were identified through Nissl staining, and Western blotting was used to quantify the protein levels of BDNF, TrkB, CREB, TLR4, MyD88, and NF-κB. Escin mitigated neuronal injury, elevated TrkB, BDNF, and CREB, and reduced TLR4, MyD88, and NF-κB protein levels in CUMS rats. The data from this study suggest that escin holds the potential for alleviating depression-like symptoms induced by CUMS. This effect may be mediated through the modulation of two signaling pathways, BDNF/TrkB/CREB and TLR4/MyD88/NF-κB.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"984 ","pages":"Article 177063"},"PeriodicalIF":4.2,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461166","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Longikaurin A induces ferroptosis and inhibits glioblastoma progression through DNA methylation - Mediated GPX4 suppression 龙葵素 A 通过 DNA 甲基化介导的 GPX4 抑制作用诱导铁变态反应并抑制胶质母细胞瘤的进展。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-10-18 DOI: 10.1016/j.ejphar.2024.177061

Xiangrui Meng , Qingqing Yang , Yisu Gao , Yawei Liu , Fang Chen , Wangsen Cao , Guan Sun

Glioblastoma (GBM) is the most common primary intracranial tumor highly resistant to conventional clinical chemotherapy. Recently, the induction of ferroptosis is emerging as a putative strategy to treat various tumors. However, the identification of the effective and applicable tumor ferroptosis-inducing agents remains challenging. In this study, we showed that longikaurin A (LK-A), a natural diterpenoid isolated from the medicinal plant Isodon ternifolius with strong anti-GBM capacities, induced remarkable GBM cell ferroptosis along with suppressing the key anti-ferroptosis factor glutathione peroxidase 4 (GPX4). GPX4 promoter contains conserved CpG islands. The LK-A-induced GPX4 suppression coincided with the inhibition of ten-eleven translocation 2 (TET2), a key DNA demethylation enzyme and an increase in the hypermethylation of the GPX4 promoter. Further, LK-A promoted the GBM ferroptotic alterations and inhibited GBM progression in both subcutaneous and orthotopic xenograft mouse models, whereas GPX4 overexpression largely abrogated its anti-GBM effects both in vitro and in vivo, suggesting that LK-A inductions of the DNA methylation-incurred GPX4 suppression and ferroptosis are crucial for its anti-GBM functions. Together, our study has elaborated an important epigenetic pathway of GBM ferroptosis and uncovered a critical pharmacological property of LK-A for treating GBM patients.

胶质母细胞瘤（GBM）是最常见的原发性颅内肿瘤，对传统的临床化疗高度耐药。最近，诱导铁变态反应正在成为治疗各种肿瘤的一种可能策略。然而，确定有效且适用的肿瘤铁诱导剂仍具有挑战性。在这项研究中，我们发现从药用植物 Isodon ternifolius 中分离出来的天然二萜类化合物 Longikaurin A（LK-A）具有很强的抗 GBM 能力，它能诱导 GBM 细胞显著的铁变态反应，同时抑制关键的抗铁变态反应因子谷胱甘肽过氧化物酶 4（GPX4）。GPX4 启动子含有保守的 CpG 岛。LK-A 诱导的 GPX4 抑制作用与十-十一转位 2（TET2）（一种关键的 DNA 去甲基化酶）的抑制作用和 GPX4 启动子高甲基化的增加相吻合。此外，在皮下和正位异种移植小鼠模型中，LK-A促进了GBM的铁变态改变并抑制了GBM的进展，而GPX4的过表达在很大程度上削弱了其体外和体内的抗GBM作用，这表明LK-A诱导DNA甲基化引起的GPX4抑制和铁变态是其抗GBM功能的关键。总之，我们的研究阐述了 GBM 铁凋亡的一个重要表观遗传学途径，并发现了 LK-A 治疗 GBM 患者的一个关键药理学特性。

{"title":"Longikaurin A induces ferroptosis and inhibits glioblastoma progression through DNA methylation - Mediated GPX4 suppression","authors":"Xiangrui Meng , Qingqing Yang , Yisu Gao , Yawei Liu , Fang Chen , Wangsen Cao , Guan Sun","doi":"10.1016/j.ejphar.2024.177061","DOIUrl":"10.1016/j.ejphar.2024.177061","url":null,"abstract":"<div><div>Glioblastoma (GBM) is the most common primary intracranial tumor highly resistant to conventional clinical chemotherapy. Recently, the induction of ferroptosis is emerging as a putative strategy to treat various tumors. However, the identification of the effective and applicable tumor ferroptosis-inducing agents remains challenging. In this study, we showed that longikaurin A (LK-A), a natural diterpenoid isolated from the medicinal plant Isodon ternifolius with strong anti-GBM capacities, induced remarkable GBM cell ferroptosis along with suppressing the key anti-ferroptosis factor glutathione peroxidase 4 (GPX4). GPX4 promoter contains conserved CpG islands. The LK-A-induced GPX4 suppression coincided with the inhibition of ten-eleven translocation 2 (TET2), a key DNA demethylation enzyme and an increase in the hypermethylation of the GPX4 promoter. Further, LK-A promoted the GBM ferroptotic alterations and inhibited GBM progression in both subcutaneous and orthotopic xenograft mouse models, whereas GPX4 overexpression largely abrogated its anti-GBM effects both in vitro and <em>in vivo</em>, suggesting that LK-A inductions of the DNA methylation-incurred GPX4 suppression and ferroptosis are crucial for its anti-GBM functions. Together, our study has elaborated an important epigenetic pathway of GBM ferroptosis and uncovered a critical pharmacological property of LK-A for treating GBM patients.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"984 ","pages":"Article 177061"},"PeriodicalIF":4.2,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Sodium nitrite induces tolerance in the mouse aorta: Involvement of the renin-angiotensin system, nitric oxide synthase, and reactive oxygen species 亚硝酸钠诱导小鼠主动脉的耐受性：肾素-血管紧张素系统、一氧化氮合酶和活性氧的参与。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-10-18 DOI: 10.1016/j.ejphar.2024.177056

Natalia Ferreira de Araujo , Natalia Ribeiro Cabacinha Nobrega , Daniela Esteves Ferreira dos Reis Costa , Janaina Aparecida Simplicio , Naiara de Assis Rabelo Ribeiro , Carlos Renato Tirapelli , Daniella Bonaventura

Nitrites have emerged as promising therapeutic agents for cardiovascular diseases, alongside nitrates. While chronic use of organic nitrates is well recognized to lead to vascular tolerance, the tolerance associated with nitrite therapy remains incompletely understood. The aim of the present study was to investigate vascular tolerance to sodium nitrite and the underlying molecular mechanisms. Endothelium-denuded aortic rings isolated from male Balb/C mice were incubated with either the EC₅₀ (10⁻⁴ mol/L) or EC₁₀₀ (10⁻² mol/L) concentration of sodium nitrite for 15 min to induce tolerance. The EC₁₀₀ concentration of sodium nitrite induced vascular tolerance. Pre-incubation with captopril and losartan effectively reversed sodium nitrite-induced tolerance. Similarly, pre-incubation with L-NAME and L-arginine prevented sodium nitrite-induced tolerance. Increased levels of reactive oxidative species (ROS) and reduced bioavailability of nitric oxide (NO) were observed in tolerant aortas. Increased superoxide dismutase (SOD) activity and decreased catalase activity were also verified in tolerant aortas. Both captopril and L-NAME prevented the increased levels of ROS observed in tolerant aortas. Furthermore, pre-incubation with catalase effectively prevented sodium nitrite-induced tolerance. Our findings suggest that sodium nitrite induces vascular tolerance through a signaling pathway involving the renin-angiotensin system, nitric oxide synthase, and ROS. This study contributes to the understanding of the interaction between nitrites and vascular tolerance and highlights potential targets to overcome or prevent this phenomenon.

亚硝酸盐与硝酸盐一样，已成为治疗心血管疾病的有前途的药物。虽然长期使用有机硝酸盐会导致血管耐受性，但人们对亚硝酸盐疗法的耐受性仍不甚了解。本研究旨在探讨血管对亚硝酸钠的耐受性及其分子机制。用 EC50（10-4 mol/L）或 EC100（10-2 mol/L）浓度的亚硝酸钠孵育雄性 Balb/C 小鼠 15 分钟，诱导其产生耐受性。EC100 浓度的亚硝酸钠可诱导血管耐受。预孵育卡托普利和洛沙坦能有效逆转亚硝酸钠诱导的耐受性。同样，预孵育 L-NAME 和 L-精氨酸可防止亚硝酸钠诱导的耐受性。在耐受性主动脉中观察到活性氧化物（ROS）水平升高，一氧化氮（NO）的生物利用率降低。耐受性主动脉中的超氧化物歧化酶（SOD）活性增加，过氧化氢酶活性降低。卡托普利和 L-NAME 都能阻止耐受性主动脉中观察到的 ROS 水平升高。此外，预孵育过氧化氢酶可有效防止亚硝酸钠诱导的耐受性。我们的研究结果表明，亚硝酸钠通过涉及肾素-血管紧张素系统、一氧化氮合酶和 ROS 的信号途径诱导血管耐受性。这项研究有助于人们了解亚硝酸盐与血管耐受性之间的相互作用，并突出了克服或预防这种现象的潜在靶点。

{"title":"Sodium nitrite induces tolerance in the mouse aorta: Involvement of the renin-angiotensin system, nitric oxide synthase, and reactive oxygen species","authors":"Natalia Ferreira de Araujo , Natalia Ribeiro Cabacinha Nobrega , Daniela Esteves Ferreira dos Reis Costa , Janaina Aparecida Simplicio , Naiara de Assis Rabelo Ribeiro , Carlos Renato Tirapelli , Daniella Bonaventura","doi":"10.1016/j.ejphar.2024.177056","DOIUrl":"10.1016/j.ejphar.2024.177056","url":null,"abstract":"<div><div>Nitrites have emerged as promising therapeutic agents for cardiovascular diseases, alongside nitrates. While chronic use of organic nitrates is well recognized to lead to vascular tolerance, the tolerance associated with nitrite therapy remains incompletely understood. The aim of the present study was to investigate vascular tolerance to sodium nitrite and the underlying molecular mechanisms. Endothelium-denuded aortic rings isolated from male Balb/C mice were incubated with either the EC<sub>50</sub> (10<sup>−4</sup> mol/L) or EC<sub>100</sub> (10<sup>−2</sup> mol/L) concentration of sodium nitrite for 15 min to induce tolerance. The EC<sub>100</sub> concentration of sodium nitrite induced vascular tolerance. Pre-incubation with captopril and losartan effectively reversed sodium nitrite-induced tolerance. Similarly, pre-incubation with L-NAME and L-arginine prevented sodium nitrite-induced tolerance. Increased levels of reactive oxidative species (ROS) and reduced bioavailability of nitric oxide (NO) were observed in tolerant aortas. Increased superoxide dismutase (SOD) activity and decreased catalase activity were also verified in tolerant aortas. Both captopril and L-NAME prevented the increased levels of ROS observed in tolerant aortas. Furthermore, pre-incubation with catalase effectively prevented sodium nitrite-induced tolerance. Our findings suggest that sodium nitrite induces vascular tolerance through a signaling pathway involving the renin-angiotensin system, nitric oxide synthase, and ROS. This study contributes to the understanding of the interaction between nitrites and vascular tolerance and highlights potential targets to overcome or prevent this phenomenon.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"985 ","pages":"Article 177056"},"PeriodicalIF":4.2,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0