Fundamental & Clinical Pharmacology最新文献_第9页

Involvement of different K+ channel subtypes in hydrogen sulfide-induced vasorelaxation of human internal mammary artery 不同 K+ 通道亚型参与硫化氢诱导的人乳内动脉血管舒张作用

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2024-09-09 DOI: 10.1111/fcp.13036

Marija Marinko, Ivan Stojanovic, Predrag Milojevic, Dragoslav Nenezic, Vladimir Kanjuh, Qin Yang, Guo-Wei He, Aleksandra Novakovic

Background

Changes in K⁺ channel expression/function are associated with disruption of vascular reactivity in several pathological conditions, including hypertension, diabetes, and atherosclerosis. Gasotransmitters achieve part of their effects in the organism by regulating ion channels, especially K⁺ channels. Their involvement in hydrogen sulfide (H₂S)-mediated vasorelaxation is still unclear, and data about human vessels are limited.

Objective

To determine the role of K⁺ channel subtypes in the vasorelaxant mechanism of H₂S donor, sodium-hydrosulfide (NaHS), on isolated human internal mammary artery (HIMA).

Results

NaHS (1 × 10⁻⁶–3 × 10⁻³ mol/L) induced a concentration-dependent relaxation of HIMA pre-contracted by phenylephrine and high K⁺. Among K⁺ channel blockers, iberiotoxin, glibenclamide, 4-aminopyridine (4-AP), and margatoxin significantly inhibited NaHS-induced relaxation of phenylephrine-contracted HIMA (P < 0.01), whereas in the presence of apamin/1-[(2-chlorophenyl) diphenylmethyl]-1H-pyrazole (TRAM-34) combination, the HIMA relaxation was partially reduced (P < 0.05). The effect of NaHS was antagonized by NO pathway inhibitors, L-NAME and KT5823, and by cyclo-oxygenase inhibitor, indomethacin (P < 0.01). Under conditions of blocked NO/prostacyclin synthesis and release, apamin/TRAM-34 and glibenclamide caused further decrease in NaHS-induced vasorelaxation (P < 0.01), while iberiotoxin, 4-AP, and margatoxin were without additional effect (P > 0.05). In the presence of nifedipine, NaHS induced partial relaxation of HIMA (P < 0.01).

Conclusion

Our results demonstrated that H₂S donor, NaHS, induced concentration-dependent relaxation of isolated HIMA. Vasorelaxant mechanisms of H₂S included direct or indirect opening of different K⁺ channel subtypes, K_ATP, BK_Ca, SK_Ca/IK_Ca, and K_V (subtype K_V1.3), in addition to NO pathway activation and interference with extracellular Ca²⁺ influx.

背景：在高血压、糖尿病和动脉粥样硬化等多种病理情况下，K+通道表达/功能的变化与血管反应性的破坏有关。气体递质通过调节离子通道，尤其是 K+ 通道，对机体产生部分影响。它们在硫化氢（H2S）介导的血管舒张中的参与尚不清楚，有关人体血管的数据也很有限：目的：确定 K+ 通道亚型在硫化氢供体钠-硫化氢（NaHS）对离体人乳内动脉（HIMA）的血管舒张机制中的作用：结果：NaHS（1 × 10-6-3 × 10-3 mol/L）可诱导苯肾上腺素和高 K+预收缩的 HIMA 产生浓度依赖性松弛。在 K+ 通道阻滞剂中，依比妥毒素、格列本脲、4-氨基吡啶（4-AP）和玛咖托辛能显著抑制 NaHS 诱导的苯肾上腺素收缩 HIMA 的松弛（P 0.05）。在硝苯地平存在的情况下，NaHS 可诱导 HIMA 部分松弛（P 结论：在硝苯地平存在的情况下，NaHS 可诱导 HIMA 部分松弛：我们的研究结果表明，H2S 供体 NaHS 可诱导离体 HIMA 的浓度依赖性松弛。H2S 的血管舒张机制包括直接或间接打开不同的 K+ 通道亚型：KATP、BKCa、SKCa/IKCa 和 KV（亚型 KV1.3），此外还有 NO 通路激活和干扰细胞外 Ca2+ 流入。

{"title":"Involvement of different K+ channel subtypes in hydrogen sulfide-induced vasorelaxation of human internal mammary artery","authors":"Marija Marinko, Ivan Stojanovic, Predrag Milojevic, Dragoslav Nenezic, Vladimir Kanjuh, Qin Yang, Guo-Wei He, Aleksandra Novakovic","doi":"10.1111/fcp.13036","DOIUrl":"10.1111/fcp.13036","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Changes in K<sup>+</sup> channel expression/function are associated with disruption of vascular reactivity in several pathological conditions, including hypertension, diabetes, and atherosclerosis. Gasotransmitters achieve part of their effects in the organism by regulating ion channels, especially K<sup>+</sup> channels. Their involvement in hydrogen sulfide (H<sub>2</sub>S)-mediated vasorelaxation is still unclear, and data about human vessels are limited.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>To determine the role of K<sup>+</sup> channel subtypes in the vasorelaxant mechanism of H<sub>2</sub>S donor, sodium-hydrosulfide (NaHS), on isolated human internal mammary artery (HIMA).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>NaHS (1 × 10<sup>−6</sup>–3 × 10<sup>−3</sup> mol/L) induced a concentration-dependent relaxation of HIMA pre-contracted by phenylephrine and high K<sup>+</sup>. Among K<sup>+</sup> channel blockers, iberiotoxin, glibenclamide, 4-aminopyridine (4-AP), and margatoxin significantly inhibited NaHS-induced relaxation of phenylephrine-contracted HIMA (<i>P</i> < 0.01), whereas in the presence of apamin/1-[(2-chlorophenyl) diphenylmethyl]-1H-pyrazole (TRAM-34) combination, the HIMA relaxation was partially reduced (<i>P</i> < 0.05). The effect of NaHS was antagonized by NO pathway inhibitors, L-NAME and KT5823, and by cyclo-oxygenase inhibitor, indomethacin (<i>P</i> < 0.01). Under conditions of blocked NO/prostacyclin synthesis and release, apamin/TRAM-34 and glibenclamide caused further decrease in NaHS-induced vasorelaxation (<i>P</i> < 0.01), while iberiotoxin, 4-AP, and margatoxin were without additional effect (<i>P</i> > 0.05). In the presence of nifedipine, NaHS induced partial relaxation of HIMA (<i>P</i> < 0.01).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our results demonstrated that H<sub>2</sub>S donor, NaHS, induced concentration-dependent relaxation of isolated HIMA. Vasorelaxant mechanisms of H<sub>2</sub>S included direct or indirect opening of different K<sup>+</sup> channel subtypes, K<sub>ATP</sub>, BK<sub>Ca</sub>, SK<sub>Ca</sub>/IK<sub>Ca</sub>, and K<sub>V</sub> (subtype K<sub>V</sub>1.3), in addition to NO pathway activation and interference with extracellular Ca<sup>2+</sup> influx.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 6","pages":"1155-1167"},"PeriodicalIF":2.1,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142153742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Acetazolamide suppresses the progression of hepatocellular carcinoma induced by diethylnitrosamine in Wistar albino rats 乙酰唑胺可抑制二乙亚硝胺诱导的 Wistar 白化大鼠肝细胞癌的发展。

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2024-08-20 DOI: 10.1111/fcp.13032

Yomna M. Tamim, Mohamed L. Soliman, Moataz M. Sayed, Muhammad S. Abdul-Rasheed, Ahmed A. Nagy, Ahmed M. Abdellah, Ahmed H. Osman, Amel F. M. Ismail

Hepatocellular carcinoma (HCC) continues to be the most prevalent type of liver cancer worldwide. Diethylnitrosamine (DEN)-induced HCC is an extensively used hepatic cancer model in experimental animals. Acetazolamide (AZA) is a carbonic anhydrase enzyme inhibitor. This study aimed to assess the therapeutic mechanism of AZA against DEN-induced HCC. Thirty male Wistar albino rats were divided equally into three groups. Group I (C): control group, Group II (HCC): DEN-induced HCC, and Group III (HCC/AZA): AZA-treated HCC. Verification of the HCC induced by DEN was confirmed by elevated liver enzymes' activities, and increased α-fetoprotein (AFP) levels, as well as distinct liver architecture changes. On the other hand, the AZA-treated HCC group experienced decreases in the activities of serum liver enzymes and AFP levels, as well as, regulated liver architecture. Additionally, it downregulated p-p38 MAPK/p-JNK1/JNK2/p-C-Jun/p-NF-κB p65 protein expressions. Moreover, it ameliorated autophagy by controlling the expression of the p-AMPK/p-mTOR1/LC3 I/II proteins. Furthermore, it downregulated the relative gene expressions of carbonic anhydrase-IX (CAIX) and hexokinase-II (HKII). Histopathological examination of AZA-treated HCC liver tissues supported these findings. Conclusion: AZA provides a new dimension in ameliorating experimentally induced HCC through regulation of hepatic biomarkers, antioxidant status, inflammatory markers, and autophagy, mediated by amelioration of CAIX and HKII gene expressions.

肝细胞癌（HCC）仍然是全球最常见的肝癌类型。二乙基亚硝胺（DEN）诱导的 HCC 是一种广泛用于实验动物的肝癌模型。乙酰唑胺（AZA）是一种碳酸酐酶抑制剂。本研究旨在评估AZA对DEN诱导的HCC的治疗机制。将 30 只雄性 Wistar 白化大鼠平均分为三组。第一组（C）：对照组；第二组（HCC）：DEN 诱导的 HCC；第三组（C）：DEN 诱导的 HCC：第三组（HCC/AZA）：AZA治疗的HCC。肝酶活性升高、α-胎儿蛋白（AFP）水平升高以及明显的肝脏结构变化证实了DEN诱导的HCC。另一方面，经 AZA 处理的 HCC 组血清肝酶活性和 AFP 水平下降，肝脏结构也得到调节。此外，它还能降低 p-p38 MAPK/p-JNK1/JNK2/p-C-Jun/p-NF-κB p65 蛋白的表达。此外，它还通过控制 p-AMPK/p-mTOR1/LC3 I/II 蛋白的表达来改善自噬。此外，它还下调了碳酸酐酶-IX（CAIX）和己糖激酶-II（HKII）的相对基因表达。经 AZA 处理的 HCC 肝组织的组织病理学检查证实了这些发现。结论AZA 通过调节肝脏生物标志物、抗氧化状态、炎症标志物和自噬，在改善 CAIX 和 HKII 基因表达的介导下，为改善实验诱导的 HCC 提供了一个新的维度。

{"title":"Acetazolamide suppresses the progression of hepatocellular carcinoma induced by diethylnitrosamine in Wistar albino rats","authors":"Yomna M. Tamim, Mohamed L. Soliman, Moataz M. Sayed, Muhammad S. Abdul-Rasheed, Ahmed A. Nagy, Ahmed M. Abdellah, Ahmed H. Osman, Amel F. M. Ismail","doi":"10.1111/fcp.13032","DOIUrl":"10.1111/fcp.13032","url":null,"abstract":"<p>Hepatocellular carcinoma (HCC) continues to be the most prevalent type of liver cancer worldwide. Diethylnitrosamine (DEN)-induced HCC is an extensively used hepatic cancer model in experimental animals. Acetazolamide (AZA) is a carbonic anhydrase enzyme inhibitor. This study aimed to assess the therapeutic mechanism of AZA against DEN-induced HCC. Thirty male <i>Wistar</i> albino rats were divided equally into three groups. Group I (C): control group, Group II (HCC): DEN-induced HCC, and Group III (HCC/AZA): AZA-treated HCC. Verification of the HCC induced by DEN was confirmed by elevated liver enzymes' activities, and increased α-fetoprotein (AFP) levels, as well as distinct liver architecture changes. On the other hand, the AZA-treated HCC group experienced decreases in the activities of serum liver enzymes and AFP levels, as well as, regulated liver architecture. Additionally, it downregulated p-p38 MAPK/p-JNK1/JNK2/p-C-Jun/p-NF-κB p65 protein expressions. Moreover, it ameliorated autophagy by controlling the expression of the p-AMPK/p-mTOR1/LC3 I/II proteins. Furthermore, it downregulated the relative gene expressions of carbonic anhydrase-IX (CAIX) and hexokinase-II (HKII). Histopathological examination of AZA-treated HCC liver tissues supported these findings. Conclusion: AZA provides a new dimension in ameliorating experimentally induced HCC through regulation of hepatic biomarkers, antioxidant status, inflammatory markers, and autophagy, mediated by amelioration of CAIX and HKII gene expressions.</p>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 6","pages":"1045-1058"},"PeriodicalIF":2.1,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142008665","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Preclinical evidence of the anti-inflammatory effect and toxicological safety of aryl-cyclohexanone in vivo 关于芳基环己酮的抗炎作用和体内毒理学安全性的临床前证据。

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2024-08-18 DOI: 10.1111/fcp.13035

Tainá Larissa Lubschinski, Luiz Antonio Escorteganha Pollo, Paula Giarola Fragoso de Oliveira, Luigi Arruda Nardino, Eduarda Talita Bramorski Mohr, Ziliani da Silva Buss, Louis Pergaud Sandjo, Maique Weber Biavatti, Felipe Perozzo Daltoé, Eduardo Monguilhott Dalmarco

Background

Respiratory distress syndrome is a complex inflammatory condition defined by the presence of acute hypoxemia and cellular infiltration with diffuse alveolar injury following a tissue injury, such as acute lung injury. The inflammatory process involved in this pathology is a defense mechanism of the body against infectious agents and/or tissue injuries. However, when the condition is not reversed, it becomes a significant cause of tissue damage, sometimes leading to loss of function of the affected organ. Therefore, it is essential to understand the mechanisms underlying inflammation, as well as the development of new therapeutic agents that reduce inflammatory damage in these cases. Aryl-cyclohexanone derivatives have previously shown significant anti-inflammatory activity linked to an immunomodulatory capacity in vitro and may be good candidates for therapies in which inflammation plays a central role.

Methods

Was evaluated the anti-inflammatory capacity of a synthesized molecule aryl-cyclohexanone in the murine model of lipopolysaccharide (LPS)-induced acute lung injury. The assessment of acute oral toxicity follows the Organization for Economic Co-operation and Development (OECD) guideline 423.

Results

The results demonstrated that the studied molecule protects against LPS-induced inflammation. We observed a decrease in the migration of total and differential leukocytes to the bronchoalveolar lavage fluid (BALF), in addition to a reduction in exudation, myeloperoxidase (MPO) activity, nitric oxide metabolites, and the secretion of pro-inflammatory cytokines (alpha tumor necrosis factors [TNF-α], interleukin-6 [IL-6], interferon-gamma [IFN-γ], and monocyte chemoattractant protein-1 [MCP-1]). Finally, aryl cyclohexanone did not show signs of acute oral toxicity (OECD 423).

Conclusions

The results prove our hypothesis that aryl-cyclohexanone is a promising molecule for developing a new, safe anti-inflammatory drug.

背景：呼吸窘迫综合征是一种复杂的炎症，表现为急性低氧血症和细胞浸润，以及组织损伤（如急性肺损伤）后的弥漫性肺泡损伤。这种病理变化所涉及的炎症过程是机体对感染性病原体和/或组织损伤的一种防御机制。然而，如果病情得不到逆转，就会成为组织损伤的重要原因，有时甚至会导致受影响器官功能的丧失。因此，了解炎症的内在机制以及开发新的治疗药物以减少这些情况下的炎症损伤至关重要。芳基环己酮衍生物曾在体外显示出与免疫调节能力相关的显著抗炎活性，可能是炎症起核心作用的疗法的良好候选物：方法：在脂多糖（LPS）诱导的急性肺损伤小鼠模型中，评估了合成分子芳基环己酮的抗炎能力。对急性口服毒性的评估遵循了经济合作与发展组织（OECD）准则 423：结果表明，所研究的分子对 LPS 诱导的炎症有保护作用。除了减少渗出、髓过氧化物酶（MPO）活性、一氧化氮代谢物和髓过氧化物酶活性外，我们还观察到支气管肺泡灌洗液（BALF）中白细胞总数和差异性迁移的减少、一氧化氮代谢物，以及促炎细胞因子（α 肿瘤坏死因子 [TNF-α]、白细胞介素-6 [IL-6]、γ 干扰素 [IFN-γ] 和单核细胞趋化蛋白-1 [MCP-1]）的分泌。最后，芳基环己酮未显示出急性口服毒性迹象（OECD 423）：这些结果证明了我们的假设，即芳基环己酮是一种很有希望开发出新型安全消炎药的分子。

{"title":"Preclinical evidence of the anti-inflammatory effect and toxicological safety of aryl-cyclohexanone in vivo","authors":"Tainá Larissa Lubschinski, Luiz Antonio Escorteganha Pollo, Paula Giarola Fragoso de Oliveira, Luigi Arruda Nardino, Eduarda Talita Bramorski Mohr, Ziliani da Silva Buss, Louis Pergaud Sandjo, Maique Weber Biavatti, Felipe Perozzo Daltoé, Eduardo Monguilhott Dalmarco","doi":"10.1111/fcp.13035","DOIUrl":"10.1111/fcp.13035","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Respiratory distress syndrome is a complex inflammatory condition defined by the presence of acute hypoxemia and cellular infiltration with diffuse alveolar injury following a tissue injury, such as acute lung injury. The inflammatory process involved in this pathology is a defense mechanism of the body against infectious agents and/or tissue injuries. However, when the condition is not reversed, it becomes a significant cause of tissue damage, sometimes leading to loss of function of the affected organ. Therefore, it is essential to understand the mechanisms underlying inflammation, as well as the development of new therapeutic agents that reduce inflammatory damage in these cases. Aryl-cyclohexanone derivatives have previously shown significant anti-inflammatory activity linked to an immunomodulatory capacity in vitro and may be good candidates for therapies in which inflammation plays a central role.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Was evaluated the anti-inflammatory capacity of a synthesized molecule aryl-cyclohexanone in the murine model of lipopolysaccharide (LPS)-induced acute lung injury. The assessment of acute oral toxicity follows the Organization for Economic Co-operation and Development (OECD) guideline 423.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The results demonstrated that the studied molecule protects against LPS-induced inflammation. We observed a decrease in the migration of total and differential leukocytes to the bronchoalveolar lavage fluid (BALF), in addition to a reduction in exudation, myeloperoxidase (MPO) activity, nitric oxide metabolites, and the secretion of pro-inflammatory cytokines (alpha tumor necrosis factors [TNF-α], interleukin-6 [IL-6], interferon-gamma [IFN-γ], and monocyte chemoattractant protein-1 [MCP-1]). Finally, aryl cyclohexanone did not show signs of acute oral toxicity (OECD 423).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The results prove our hypothesis that aryl-cyclohexanone is a promising molecule for developing a new, safe anti-inflammatory drug.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 6","pages":"1103-1115"},"PeriodicalIF":2.1,"publicationDate":"2024-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141999762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Exploring the therapeutic potential of Modafinil in mitigating renal ischemia–reperfusion injury in rats 探索莫达非尼缓解大鼠肾缺血再灌注损伤的治疗潜力

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2024-08-13 DOI: 10.1111/fcp.13034

Fatemeh Asli, Sepideh Poshtdar, Ahmad Reza Dehpour, Razieh Mohammad Jafari

Background

Renal ischemia reperfusion injury (IRI) is a post-ischemic event, which can lead to subsequent acute kidney injury (AKI), transplant failure, renal dysfunction and fibrosis via heightened oxidative stress and production of inflammatory cytokines and chemokines.

Objective

This study aims to assess the effect of Modafinil, a wake-promoting agent with previously proven anti-inflammatory and anti-oxidative properties, on ameliorating renal IRI.

Methods

A total of 30 male Wistar rats were divided into five groups: Sham-operated group, ischemia reperfusion (I/R) control group and Modafinil pre-treated groups (at different doses of 50, 100 and 150 mg/kg). IRI was induced by means of bilaterally clamping the renal arteries for 45 min, followed by 24 h of reperfusion.

Results

Tissue pathological assessments demonstrated a reduction of glomerular, vascular and interstitial injury at doses of 50 and 100 mg/kg of Modafinil. The biochemical studies showed a significant decrease in tissue pro-inflammatory factors, including tumor necrosis factor alpha (TNF-α), Interleukin-18 (IL-18) and lactate dehydrogenase (LDH). Moreover, an elevation was observed in levels of super oxide dismutase (SOD) and catalase, indicating the reduction of oxidative stress. Furthermore, the levels of creatinine (Cr), urea and neutrophil gelatinase-associated lipocalin (NGAL) were declined, indicating the improvement in renal function at effective doses of Modafinil (50 and 100 mg/kg) compared to the I/R control group without Modafinil pre-treatment.

Conclusion

Our findings suggest that Modafinil holds promise as an effective therapeutic agent to address the clinical challenges associated with kidney IRI reducing the need for hospitalization and potentially alleviating related morbidities.

背景：肾缺血再灌注损伤（IRI）是一种缺血后事件，可通过加剧氧化应激和产生炎性细胞因子和趋化因子，导致随后的急性肾损伤（AKI）、移植失败、肾功能障碍和纤维化：本研究旨在评估莫达非尼对改善肾脏 IRI 的影响：方法：将 30 只雄性 Wistar 大鼠分为五组：方法：将 30 只雄性 Wistar 大鼠分为五组：假手术组、缺血再灌注（I/R）对照组和莫达非尼预处理组（50、100 和 150 毫克/千克的不同剂量）。诱导缺血再灌注的方法是双侧夹闭肾动脉45分钟，然后再灌注24小时：结果：组织病理学评估显示，莫达非尼剂量为 50 和 100 毫克/千克时，肾小球、血管和间质损伤有所减轻。生化研究显示，组织促炎因子，包括肿瘤坏死因子α（TNF-α）、白细胞介素-18（IL-18）和乳酸脱氢酶（LDH）明显减少。此外，还观察到超氧化物歧化酶（SOD）和过氧化氢酶水平升高，表明氧化应激减少。此外，肌酐（Cr）、尿素和中性粒细胞明胶酶相关脂联素（NGAL）的水平也有所下降，这表明与未经莫达非尼预处理的I/R对照组相比，有效剂量的莫达非尼（50和100毫克/千克）可改善肾功能：我们的研究结果表明，莫达非尼有望成为一种有效的治疗药物，以应对与肾脏IRI相关的临床挑战，减少住院治疗的需求，并有可能减轻相关的发病率。

{"title":"Exploring the therapeutic potential of Modafinil in mitigating renal ischemia–reperfusion injury in rats","authors":"Fatemeh Asli, Sepideh Poshtdar, Ahmad Reza Dehpour, Razieh Mohammad Jafari","doi":"10.1111/fcp.13034","DOIUrl":"10.1111/fcp.13034","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Renal ischemia reperfusion injury (IRI) is a post-ischemic event, which can lead to subsequent acute kidney injury (AKI), transplant failure, renal dysfunction and fibrosis via heightened oxidative stress and production of inflammatory cytokines and chemokines.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>This study aims to assess the effect of Modafinil, a wake-promoting agent with previously proven anti-inflammatory and anti-oxidative properties, on ameliorating renal IRI.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A total of 30 male Wistar rats were divided into five groups: Sham-operated group, ischemia reperfusion (I/R) control group and Modafinil pre-treated groups (at different doses of 50, 100 and 150 mg/kg). IRI was induced by means of bilaterally clamping the renal arteries for 45 min, followed by 24 h of reperfusion.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Tissue pathological assessments demonstrated a reduction of glomerular, vascular and interstitial injury at doses of 50 and 100 mg/kg of Modafinil. The biochemical studies showed a significant decrease in tissue pro-inflammatory factors, including tumor necrosis factor alpha (TNF-α), Interleukin-18 (IL-18) and lactate dehydrogenase (LDH). Moreover, an elevation was observed in levels of super oxide dismutase (SOD) and catalase, indicating the reduction of oxidative stress. Furthermore, the levels of creatinine (Cr), urea and neutrophil gelatinase-associated lipocalin (NGAL) were declined, indicating the improvement in renal function at effective doses of Modafinil (50 and 100 mg/kg) compared to the I/R control group without Modafinil pre-treatment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our findings suggest that Modafinil holds promise as an effective therapeutic agent to address the clinical challenges associated with kidney IRI reducing the need for hospitalization and potentially alleviating related morbidities.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 6","pages":"1168-1177"},"PeriodicalIF":2.1,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975517","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Alamandin and especially melatonin attenuate pulmonary arterial hypertension induced by monocrotalin 阿拉曼丁，尤其是褪黑素可减轻单核细胞增多症诱发的肺动脉高压。

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2024-08-11 DOI: 10.1111/fcp.13033

Seyhan Ayik, Mehmet Gunata, Onural Ozhan, Azibe Yildiz, Nigar Vardi, Emre Sonmez, Necip Ermis, Nilay Ates, Ertugrul Kilic, Samir Abbas Ali Noma, Ahmet Ulu, Seyfullah Taha Inan, Haci Ahmet Acet, Hakan Parlakpinar

Background

Despite the available treatments, pulmonary arterial hypertension (PAH) prognosis is poor.

Objectives

We aimed to investigate the effects of the alamandine (ALA), melatonin (MEL), and ALA + MEL in PAH.

Methods

The rats were randomly divided into Control (n = 10), monocrotaline (MCT) (n = 12), ALA (n = 12), MEL (n = 12), and ALA + MEL (n = 12) groups. PAH was induced by MCT. The ALA, MEL, and ALA + MEL groups received 50 μg/kg/day ALA, 10 mg/kg/day MEL, and ALA + MEL, respectively, for 35 days. Echocardiographic and hemodynamic measurements and tissue analyses (morphometric, histopathological, ELISA, and western blot) were performed.

Results

Monotherapies, especially MEL, reduced the right ventricular (RV) systolic pressure. Only MEL increased the pulmonary artery acceleration time. MCT increased the RV/left ventricle (LV) + interventricular septum (IVS) ratio. While ALA and ALA + MEL slightly decreased the RV/(LV + IVS), MEL significantly restored it. MCT increased the tunica intima-media (TIM) thickness, PCNA and α-SMA of pulmonary arterioles, histopathological score (HS) (inflammatory infiltration etc.) of the lung, and RV. All treatments reduced the TIM thickness (especially MEL), PCNA, and α-SMA. All treatments significantly decreased the HS of the lung; however, MEL and ALA + MEL produced greater benefits. All treatments attenuated the HS of RV. MCT caused a significant increase in lung lysyl oxidase (LOX) activity. All treatments restored the LOX; however, MEL and ALA + MEL provided greater improvement. While lung Nrf-2 was increased in MCT-treated rats, MEL reduced it.

Conclusion

ALA, MEL, and ALA + MEL attenuate PAH and protect RV via antiproliferative, anti-remodeling, antihypertrophic, anti-inflammatory, and free radical scavenging (only MEL) capabilities. Overall, MEL produced the best outcomes.

背景：尽管有治疗方法，但肺动脉高压（PAH）的预后很差：尽管有多种治疗方法，但肺动脉高压（PAH）的预后很差：我们旨在研究阿拉曼定（ALA）、褪黑素（MEL）以及 ALA + MEL 对 PAH 的影响：方法：将大鼠随机分为对照组（n = 10）、一缩醛（MCT）组（n = 12）、ALA 组（n = 12）、MEL 组（n = 12）和 ALA + MEL 组（n = 12）。MCT诱导PAH。ALA组、MEL组和ALA + MEL组分别接受50微克/千克/天的ALA、10毫克/千克/天的MEL和ALA + MEL，共35天。进行了超声心动图和血液动力学测量以及组织分析（形态计量学、组织病理学、ELISA和Western印迹）：结果：单一疗法，尤其是 MEL，降低了右心室收缩压。只有 MEL 增加了肺动脉加速时间。MCT 增加了 RV/ 左心室（LV）+ 室间隔（IVS）比率。虽然 ALA 和 ALA + MEL 稍微降低了 RV/（LV + IVS），但 MEL 显著恢复了这一比率。MCT 增加了肺动脉内膜厚度、PCNA 和 α-SMA、肺组织病理学评分（HS）（炎症浸润等）和 RV。所有治疗方法都能减少 TIM 厚度（尤其是 MEL）、PCNA 和 α-SMA。所有治疗方法都能明显降低肺的HS，但MEL和ALA + MEL的疗效更好。所有治疗方法都减轻了 RV 的 HS。MCT 导致肺溶酶体氧化酶（LOX）活性明显增加。所有治疗方法都能恢复 LOX，但 MEL 和 ALA + MEL 的改善效果更好。MCT 处理的大鼠肺部 Nrf-2 增加，而 MEL 则减少：结论：ALA、MEL 和 ALA + MEL 可通过抗增殖、抗重塑、抗肥大、抗炎和清除自由基（仅 MEL）的能力减轻 PAH 并保护 RV。总体而言，MEL 的效果最好。

{"title":"Alamandin and especially melatonin attenuate pulmonary arterial hypertension induced by monocrotalin","authors":"Seyhan Ayik, Mehmet Gunata, Onural Ozhan, Azibe Yildiz, Nigar Vardi, Emre Sonmez, Necip Ermis, Nilay Ates, Ertugrul Kilic, Samir Abbas Ali Noma, Ahmet Ulu, Seyfullah Taha Inan, Haci Ahmet Acet, Hakan Parlakpinar","doi":"10.1111/fcp.13033","DOIUrl":"10.1111/fcp.13033","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Despite the available treatments, pulmonary arterial hypertension (PAH) prognosis is poor.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>We aimed to investigate the effects of the alamandine (ALA), melatonin (MEL), and ALA + MEL in PAH.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The rats were randomly divided into Control (<i>n</i> = 10), monocrotaline (MCT) (<i>n</i> = 12), ALA (<i>n</i> = 12), MEL (<i>n</i> = 12), and ALA + MEL (<i>n</i> = 12) groups. PAH was induced by MCT. The ALA, MEL, and ALA + MEL groups received 50 μg/kg/day ALA, 10 mg/kg/day MEL, and ALA + MEL, respectively, for 35 days. Echocardiographic and hemodynamic measurements and tissue analyses (morphometric, histopathological, ELISA, and western blot) were performed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Monotherapies, especially MEL, reduced the right ventricular (RV) systolic pressure. Only MEL increased the pulmonary artery acceleration time. MCT increased the RV/left ventricle (LV) + interventricular septum (IVS) ratio. While ALA and ALA + MEL slightly decreased the RV/(LV + IVS), MEL significantly restored it. MCT increased the tunica intima-media (TIM) thickness, PCNA and α-SMA of pulmonary arterioles, histopathological score (HS) (inflammatory infiltration etc.) of the lung, and RV. All treatments reduced the TIM thickness (especially MEL), PCNA, and α-SMA. All treatments significantly decreased the HS of the lung; however, MEL and ALA + MEL produced greater benefits. All treatments attenuated the HS of RV. MCT caused a significant increase in lung lysyl oxidase (LOX) activity. All treatments restored the LOX; however, MEL and ALA + MEL provided greater improvement. While lung Nrf-2 was increased in MCT-treated rats, MEL reduced it.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>ALA, MEL, and ALA + MEL attenuate PAH and protect RV via antiproliferative, anti-remodeling, antihypertrophic, anti-inflammatory, and free radical scavenging (only MEL) capabilities. Overall, MEL produced the best outcomes.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 6","pages":"1143-1154"},"PeriodicalIF":2.1,"publicationDate":"2024-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141916547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Methylsulfonylmethane induces caspase-dependent apoptosis in acute myeloid leukemia cell lines 甲基磺酰基甲烷可诱导急性髓性白血病细胞系发生依赖于 Caspase 的细胞凋亡。

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2024-08-08 DOI: 10.1111/fcp.13030

Yalda Hekmatshoar, Arzu Zeynep Karabay, Tulin Ozkan, Asli Koc, Asuman Sunguroglu

Background: Acute myeloid leukemia (AML) is a heterogeneous ailment in both biological and clinical concepts. Numerous efforts have been devoted to discover natural compounds for combating cancer, which showed great potential in cancer management. Methylsulfonylmethane (MSM), an organosulfur dietary supplement, is utilized for improving various clinical conditions, particularly osteoarthritis. MSM can exert antitumor activity in a wide range of cancers. Objectives: The molecular mechanisms of action underlying antileukemic activity of MSM remain unclear. In this regard, we aimed to investigate the anticancer properties of MSM on human AML cell lines (U937 and HL60) with focus on underlying cell death mechanism. Methods: Anticancer activity of the MSM was examined employing MTT assay, Annexin V-PE/7AAD staining, caspase3/7 activity test, and real-time qPCR. Both cell lines were treated with different concentrations (50–400 mM) of MSM for 24 h. Pretreatment of the cells with a caspase inhibitor (i.e., Z-VAD-fmk) was performed for the assessment of apoptosis induction. Results: The results of MTT assay revealed that in both cell lines, the MSM markedly reduced cell viability in comparison to the control cells. Additionally, findings of Annexin V-7AAD staining revealed that MSM induced apoptosis and activated caspase 3/7 in both cell lines markedly. Real-time quantitative PCR results also supported the induction of apoptosis in AML cells. MSM altered the expression levels of various apoptotic genes (BAX, BAD, and BIM). Conclusion: Overall, our results indicated that MSM could induce apoptosis in AML cell lines in a dose-dependent manner, which therefore could be utilized as an antileukemic agent.

背景：急性髓性白血病（AML）在生物学和临床概念上都是一种异质性疾病。人们致力于发现抗癌的天然化合物，这些化合物在癌症治疗中显示出巨大的潜力。甲基磺酰基甲烷（MSM）是一种有机硫膳食补充剂，可用于改善各种临床症状，尤其是骨关节炎。MSM 可在多种癌症中发挥抗肿瘤活性：MSM 抗白血病活性的分子作用机制尚不清楚。为此，我们旨在研究 MSM 对人类急性髓细胞白血病细胞系（U937 和 HL60）的抗癌特性，并重点研究其潜在的细胞死亡机制：方法：采用 MTT 试验、Annexin V-PE/7AAD 染色、caspase3/7 活性测试和实时 qPCR 检测 MSM 的抗癌活性。用 Caspase 抑制剂（即 Z-VAD-fmk）对细胞进行预处理，以评估细胞凋亡诱导情况：MTT检测结果显示，与对照细胞相比，MSM明显降低了两种细胞系的细胞活力。此外，Annexin V-7AAD 染色结果显示，MSM 在两种细胞系中都能明显诱导细胞凋亡并激活 caspase 3/7。实时定量 PCR 结果也证实了 MSM 诱导急性髓细胞白血病细胞凋亡的作用。MSM改变了多种凋亡基因（BAX、BAD和BIM）的表达水平：总之，我们的研究结果表明，MSM 能以剂量依赖的方式诱导 AML 细胞株凋亡，因此可用作抗白血病药物。

{"title":"Methylsulfonylmethane induces caspase-dependent apoptosis in acute myeloid leukemia cell lines","authors":"Yalda Hekmatshoar, Arzu Zeynep Karabay, Tulin Ozkan, Asli Koc, Asuman Sunguroglu","doi":"10.1111/fcp.13030","DOIUrl":"10.1111/fcp.13030","url":null,"abstract":"<p>Background: Acute myeloid leukemia (AML) is a heterogeneous ailment in both biological and clinical concepts. Numerous efforts have been devoted to discover natural compounds for combating cancer, which showed great potential in cancer management. Methylsulfonylmethane (MSM), an organosulfur dietary supplement, is utilized for improving various clinical conditions, particularly osteoarthritis. MSM can exert antitumor activity in a wide range of cancers. Objectives: The molecular mechanisms of action underlying antileukemic activity of MSM remain unclear. In this regard, we aimed to investigate the anticancer properties of MSM on human AML cell lines (U937 and HL60) with focus on underlying cell death mechanism. Methods: Anticancer activity of the MSM was examined employing MTT assay, Annexin V-PE/7AAD staining, caspase3/7 activity test, and real-time qPCR. Both cell lines were treated with different concentrations (50–400 mM) of MSM for 24 h. Pretreatment of the cells with a caspase inhibitor (i.e., Z-VAD-fmk) was performed for the assessment of apoptosis induction. Results: The results of MTT assay revealed that in both cell lines, the MSM markedly reduced cell viability in comparison to the control cells. Additionally, findings of Annexin V-7AAD staining revealed that MSM induced apoptosis and activated caspase 3/7 in both cell lines markedly. Real-time quantitative PCR results also supported the induction of apoptosis in AML cells. MSM altered the expression levels of various apoptotic genes (BAX, BAD, and BIM). Conclusion: Overall, our results indicated that MSM could induce apoptosis in AML cell lines in a dose-dependent manner, which therefore could be utilized as an antileukemic agent.</p>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 6","pages":"1094-1102"},"PeriodicalIF":2.1,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141901443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Wnt/beta-catenin modulation: A promising frontier in chronic kidney disease management Wnt/beta-catenin 调节：慢性肾病治疗的一个前景广阔的领域。

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2024-08-05 DOI: 10.1111/fcp.13031

Shubhangi Saxena, Neha Dagar, Vishwadeep Shelke, Bhupendra Puri, Anil Bhanudas Gaikwad

Background

Being amongst the leading factors of death and distress, chronic kidney disease (CKD) has affected around 850 million people globally. The Wnt/β-catenin axis is vital for maintaining kidney homeostasis, from nephron generation to overall management. The β-catenin growth factor is typically not expressed in the adult kidney; however, its expression is found to increase under stress and injury conditions. It is categorised as canonical and non-canonical based on β-catenin availability, which mounts promising targets for ameliorating CKD. Hence, modulation of the Wnt/β-catenin signalling for CKD management is of utmost relevance.

Objectives

The primary aim of this review is to highlight the significance of targeting Wnt/β-catenin signalling for CKD management.

Methods

The literature review regarding the role of Wnt/β-catenin signalling and therapies modulating it in CKD was conducted using PubMed, Scopus, Science Direct and Google Scholar.

Results

The current review summarises the pharmacological therapies modulating the Wnt/β-catenin axis in CKD, building upon promising preclinical studies to establish a foundation for clinical studies in the future.

Conclusion

Wnt/β-catenin signalling is the evolution's most conserved pathway, which plays a pivotal role in CKD progression. Therapies modulating Wnt/β-catenin signalling have emerged as effective means for alleviating CKD.

背景：慢性肾脏病（CKD）是导致死亡和痛苦的主要因素之一，已影响到全球约 8.5 亿人。Wnt/β-catenin 轴对维持肾脏的平衡至关重要，包括肾小球的生成和整体管理。β-catenin生长因子通常不在成人肾脏中表达，但在压力和损伤条件下，其表达会增加。根据β-catenin的可用性，可将其分为典型和非典型两类，这为改善慢性肾脏病提供了有希望的靶点。因此，调节 Wnt/β-catenin 信号对治疗 CKD 至关重要：本综述的主要目的是强调靶向 Wnt/β-catenin 信号对治疗 CKD 的重要意义：方法：使用 PubMed、Scopus、Science Direct 和 Google Scholar 对 Wnt/β-catenin 信号在 CKD 中的作用以及调节 Wnt/β-catenin 信号的疗法进行文献综述：本综述总结了在 CKD 中调节 Wnt/β-catenin 轴的药理学疗法，以前景看好的临床前研究为基础，为未来的临床研究奠定基础：结论：Wnt/β-catenin 信号是进化过程中最保守的通路，在 CKD 的进展中起着关键作用。调节 Wnt/β-catenin 信号的疗法已成为缓解 CKD 的有效手段。

{"title":"Wnt/beta-catenin modulation: A promising frontier in chronic kidney disease management","authors":"Shubhangi Saxena, Neha Dagar, Vishwadeep Shelke, Bhupendra Puri, Anil Bhanudas Gaikwad","doi":"10.1111/fcp.13031","DOIUrl":"10.1111/fcp.13031","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Being amongst the leading factors of death and distress, chronic kidney disease (CKD) has affected around 850 million people globally. The Wnt/β-catenin axis is vital for maintaining kidney homeostasis, from nephron generation to overall management. The β-catenin growth factor is typically not expressed in the adult kidney; however, its expression is found to increase under stress and injury conditions. It is categorised as canonical and non-canonical based on β-catenin availability, which mounts promising targets for ameliorating CKD. Hence, modulation of the Wnt/β-catenin signalling for CKD management is of utmost relevance.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>The primary aim of this review is to highlight the significance of targeting Wnt/β-catenin signalling for CKD management.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The literature review regarding the role of Wnt/β-catenin signalling and therapies modulating it in CKD was conducted using PubMed, Scopus, Science Direct and Google Scholar.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The current review summarises the pharmacological therapies modulating the Wnt/β-catenin axis in CKD, building upon promising preclinical studies to establish a foundation for clinical studies in the future.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Wnt/β-catenin signalling is the evolution's most conserved pathway, which plays a pivotal role in CKD progression. Therapies modulating Wnt/β-catenin signalling have emerged as effective means for alleviating CKD.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 6","pages":"1020-1030"},"PeriodicalIF":2.1,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141893247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

The therapeutic effect of NRF2 activator, ezetimibe, in cardiac cachexia NRF2 激活剂依折麦布对心脏恶病质的治疗作用

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2024-07-15 DOI: 10.1111/fcp.13029

Ruju Vashi, Mit Joshi, Bhoomika M. Patel

Introduction

Heart failure (HF) is caused by functional and structural irregularity leading to impaired ejection or filling capacity of the heart. HF leads to chronic inflammatory conditions in the heart leads to weight loss, anorexia, and muscle atrophy known as cachexia. The present study was carried out to investigate the role of Ezetimibe, an NRF2 activator, in cardiac cachexia and to develop a treatment strategy for cardiac cachexia.

Method

Balb/c mice of either sex at 6–8 weeks of age were given 2 mg/kg of doxorubicin in 0.9% sodium chloride solution intraperitoneally (i.p.) for the alternate days for the first week and then once a week for the next 4 weeks. After induction of cardiac atrophy, treatment with Ezetimibe (1.5 mg/kg, p.o) was given for the next 4 weeks.

Result

In the cardiac cachectic animals, a significant decrease in body weight, food, and water intake was observed. Cardiac cachectic animals showed a significant increase in serum glucose, total cholesterol, LDL, triglyceride, VLDL, CK-MB, LDH, and CRP levels. Cardiac atrophic index, heart weight to body weight ratios (HW/BW), right ventricular weight to heart weight ratios (RV/HW), and left ventricular weight to heart weight ratios (LV/HW), were significantly decreased in cardiac cachectic animals. The weights of the skeletal muscles such as EDL, gastrocnemius, soleus, tibialis anterior, and quadriceps muscles, and the weight of adipose tissue such as subcutaneous, visceral, perirenal, and brown adipose tissue were significantly decreased in the cardiac cachectic group relative to the normal group. Treatment with ezetimibe improves body weight, food intake, and water intake. Ezetimibe decreases serum glucose, total cholesterol, LDL, triglyceride, VLDL, CK-MB, LDH and CRP levels. Cardiac atrophic markers such as HW/BW, RV/HW, and LV/HW were improved. The weight of skeletal muscles and adipose tissue was increased after treatment with ezetimibe.

Conclusion

Our data showed that the NRF2 activator, Ezetimibe produces a beneficial effect on cardiac cachexia in the doxorubicin-induced cardiac cachexia model. Ezetimibe was successful to reduce the levels of inflammatory cytokines, ameliorate the effects on cardiac muscle wasting, lipid levels, fat tissues, and skeletal muscles.

导言心力衰竭（HF）是由于功能和结构不正常导致心脏射血或充盈能力受损而引起的。心力衰竭会导致心脏慢性炎症，引起体重下降、厌食和肌肉萎缩，即恶病质。本研究旨在探究 NRF2 激活剂依折麦布在心脏恶病质中的作用，并制定心脏恶病质的治疗策略：方法：给 6-8 周龄的 Balb/c 小鼠腹腔注射 2 毫克/千克 0.9% 氯化钠溶液中的多柔比星，第一周隔天注射一次，随后 4 周每周注射一次。诱导心脏萎缩后，在接下来的 4 周内给予依折麦布（1.5 毫克/千克，口服）治疗：结果：观察到心脏萎缩动物的体重、进食量和饮水量显著下降。心脏衰竭动物的血清葡萄糖、总胆固醇、低密度脂蛋白、甘油三酯、VLDL、CK-MB、LDH 和 CRP 水平明显升高。心脏萎缩动物的心脏萎缩指数、心脏重量与体重之比（HW/BW）、右心室重量与心脏重量之比（RV/HW）和左心室重量与心脏重量之比（LV/HW）均明显下降。相对于正常组，心脏衰竭组的骨骼肌重量（如 EDL、腓肠肌、比目鱼肌、胫骨前肌和股四头肌）以及脂肪组织重量（如皮下组织、内脏组织、肾周组织和棕色脂肪组织）均明显降低。依折麦布治疗可改善体重、食物摄入量和水摄入量。依折麦布可降低血清葡萄糖、总胆固醇、低密度脂蛋白、甘油三酯、VLDL、CK-MB、LDH 和 CRP 水平。HW/BW、RV/HW 和 LV/HW 等心脏萎缩指标均有所改善。依折麦布治疗后，骨骼肌和脂肪组织的重量增加：我们的数据显示，在多柔比星诱导的心脏恶病质模型中，NRF2激活剂依折麦布对心脏恶病质产生了有益的影响。依泽替米贝成功降低了炎性细胞因子的水平，改善了对心肌消耗、血脂水平、脂肪组织和骨骼肌的影响。

{"title":"The therapeutic effect of NRF2 activator, ezetimibe, in cardiac cachexia","authors":"Ruju Vashi, Mit Joshi, Bhoomika M. Patel","doi":"10.1111/fcp.13029","DOIUrl":"10.1111/fcp.13029","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>Heart failure (HF) is caused by functional and structural irregularity leading to impaired ejection or filling capacity of the heart. HF leads to chronic inflammatory conditions in the heart leads to weight loss, anorexia, and muscle atrophy known as cachexia. The present study was carried out to investigate the role of Ezetimibe, an NRF2 activator, in cardiac cachexia and to develop a treatment strategy for cardiac cachexia.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Method</h3>\u0000 \u0000 <p>Balb/c mice of either sex at 6–8 weeks of age were given 2 mg/kg of doxorubicin in 0.9% sodium chloride solution intraperitoneally (i.p.) for the alternate days for the first week and then once a week for the next 4 weeks. After induction of cardiac atrophy, treatment with Ezetimibe (1.5 mg/kg, <i>p.o</i>) was given for the next 4 weeks.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Result</h3>\u0000 \u0000 <p>In the cardiac cachectic animals, a significant decrease in body weight, food, and water intake was observed. Cardiac cachectic animals showed a significant increase in serum glucose, total cholesterol, LDL, triglyceride, VLDL, CK-MB, LDH, and CRP levels. Cardiac atrophic index, heart weight to body weight ratios (HW/BW), right ventricular weight to heart weight ratios (RV/HW), and left ventricular weight to heart weight ratios (LV/HW), were significantly decreased in cardiac cachectic animals. The weights of the skeletal muscles such as EDL, gastrocnemius, soleus, tibialis anterior, and quadriceps muscles, and the weight of adipose tissue such as subcutaneous, visceral, perirenal, and brown adipose tissue were significantly decreased in the cardiac cachectic group relative to the normal group. Treatment with ezetimibe improves body weight, food intake, and water intake. Ezetimibe decreases serum glucose, total cholesterol, LDL, triglyceride, VLDL, CK-MB, LDH and CRP levels. Cardiac atrophic markers such as HW/BW, RV/HW, and LV/HW were improved. The weight of skeletal muscles and adipose tissue was increased after treatment with ezetimibe.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our data showed that the NRF2 activator, Ezetimibe produces a beneficial effect on cardiac cachexia in the doxorubicin-induced cardiac cachexia model. Ezetimibe was successful to reduce the levels of inflammatory cytokines, ameliorate the effects on cardiac muscle wasting, lipid levels, fat tissues, and skeletal muscles.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 6","pages":"1131-1142"},"PeriodicalIF":2.1,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141619758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Bezafibrate mitigates oxidized-low density lipoprotein (ox-LDL)-induced the attachment of monocytes to endothelial cells: An implication in atherosclerosis 贝扎贝特可减轻氧化低密度脂蛋白（ox-LDL）诱导的单核细胞对内皮细胞的附着：对动脉粥样硬化的影响。

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2024-07-15 DOI: 10.1111/fcp.13025

Huijun Huang, Yan Shen

Background

Oxidized forms of low-density lipoproteins (ox-LDL)-associated endothelial dysfunction and subsequent monocyte adhesion play an important role in the development of atherosclerosis (AS). Bezafibrate (BEZ) is a peroxisome proliferator-activated receptor (pan-PPAR) agonist licensed as a hypolipidemic drug. However, the effects of BEZ on endothelial dysfunction are less reported.

Objectives

In this study, we aim to investigate the protective effects of BEZ on ox-LDL-challenged vascular endothelial cells to evaluate its potential value in treating AS.

Methods

Human aortic endothelial cells (HAECs) and THP-1 cells were used to establish an In Vitro AS model. Cell Counting Kit-8 (CCK-8) assay, Real-time PCR, Western blot analysis, and Enzyme-linked immunosorbent assay (ELISA) were used to test the data.

Results

As expected, treatment with BEZ suppressed the expression of vascular endothelial growth factor A (VEGF-A), tissue factor (TF), Interleukin 12 (IL-12), tumor necrosis factor (TNF-α), and monocyte chemoattractant protein-1 (MCP-1). BEZ was also found to inhibit ox-LDL-induced expression of the endothelial adhesion molecules vascular cellular adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) in HAECs. Correspondingly, BEZ prevented attachment of THP-1 monocytes to ox-LDL-incubated HAECs. Mechanically, BEZ was found to prevent NF-κB activation by reducing the levels of nuclear NF-κB p65 and inhibiting luciferase activity of NF-κB.

Conclusion

Our study revealed the pharmacological function of BEZ in protecting endothelial dysfunction against ox-LDL, which may provide valuable insight for the clinical application of BEZ.

背景：与氧化形式的低密度脂蛋白（ox-LDL）相关的内皮功能障碍和随后的单核细胞粘附在动脉粥样硬化（AS）的发展中起着重要作用。贝扎贝特（Bezafibrate，BEZ）是一种过氧化物酶体增殖体激活受体（pan-PPAR）激动剂，已被许可作为降血脂药物。然而，有关 BEZ 对内皮功能障碍的影响的报道较少：方法：使用人主动脉内皮细胞（HAECs）和 THP-1 细胞建立体外 AS 模型。方法：用人主动脉内皮细胞（HAECs）和THP-1细胞建立体外强直性脊柱炎模型，采用细胞计数试剂盒-8（CCK-8）检测、实时PCR、Western印迹分析和酶联免疫吸附试验（ELISA）检测数据：正如预期的那样，BEZ能抑制血管内皮生长因子A（VEGF-A）、组织因子（TF）、白细胞介素12（IL-12）、肿瘤坏死因子（TNF-α）和单核细胞趋化蛋白-1（MCP-1）的表达。研究还发现，BEZ 能抑制氧化-LDL 诱导的 HAECs 内皮粘附分子血管细胞粘附分子-1（VCAM-1）和细胞间粘附分子-1（ICAM-1）的表达。相应地，BEZ 能阻止 THP-1 单核细胞附着在氧化-LDL 诱导的 HAECs 上。通过降低核 NF-κB p65 的水平和抑制 NF-κB 的荧光素酶活性，BEZ 被发现能从机制上阻止 NF-κB 的活化：我们的研究揭示了 BEZ 保护内皮功能障碍免受 ox-LDL 影响的药理作用，这可能会为 BEZ 的临床应用提供有价值的启示。

{"title":"Bezafibrate mitigates oxidized-low density lipoprotein (ox-LDL)-induced the attachment of monocytes to endothelial cells: An implication in atherosclerosis","authors":"Huijun Huang, Yan Shen","doi":"10.1111/fcp.13025","DOIUrl":"10.1111/fcp.13025","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Oxidized forms of low-density lipoproteins (ox-LDL)-associated endothelial dysfunction and subsequent monocyte adhesion play an important role in the development of atherosclerosis (AS). Bezafibrate (BEZ) is a peroxisome proliferator-activated receptor (pan-PPAR) agonist licensed as a hypolipidemic drug. However, the effects of BEZ on endothelial dysfunction are less reported.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>In this study, we aim to investigate the protective effects of BEZ on ox-LDL-challenged vascular endothelial cells to evaluate its potential value in treating AS.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Human aortic endothelial cells (HAECs) and THP-1 cells were used to establish an In Vitro AS model. Cell Counting Kit-8 (CCK-8) assay, Real-time PCR, Western blot analysis, and Enzyme-linked immunosorbent assay (ELISA) were used to test the data.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>As expected, treatment with BEZ suppressed the expression of vascular endothelial growth factor A (VEGF-A), tissue factor (TF), Interleukin 12 (IL-12), tumor necrosis factor (TNF-α), and monocyte chemoattractant protein-1 (MCP-1). BEZ was also found to inhibit ox-LDL-induced expression of the endothelial adhesion molecules vascular cellular adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) in HAECs. Correspondingly, BEZ prevented attachment of THP-1 monocytes to ox-LDL-incubated HAECs. Mechanically, BEZ was found to prevent NF-κB activation by reducing the levels of nuclear NF-κB p65 and inhibiting luciferase activity of NF-κB.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our study revealed the pharmacological function of BEZ in protecting endothelial dysfunction against ox-LDL, which may provide valuable insight for the clinical application of BEZ.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 5","pages":"958-966"},"PeriodicalIF":2.1,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141619727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

The protective effect of pregabalin and xanthenone on testicular ischemia/reperfusion injury in rats 普瑞巴林和香丹酮对大鼠睾丸缺血再灌注损伤的保护作用

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2024-07-08 DOI: 10.1111/fcp.13027

Maha M. Abdel-Fattah, Ahmed Mamdouh Ahmed, Rabeh Khairy Saleh, Basim Anwar Shehata Messiha, Remon Roshdy Rofaeil

Background

Torsion of the spermatic cord is a hazardous and common urologic issue. The current work evaluates the possible protective effect of pregabalin (PGB) and xanthenone (XAN) in testicular ischemia/reperfusion injury induced by testicular torsion/detorsion in rats.

Materials and methods

Seven groups of adult male Wistar albino rats were allocated randomly into seven groups, namely, sham control, torsion/detorsion (T/D), PGB 50 mg/kg, PGB 100 mg/kg, XAN 1 mg/kg, XAN 2 mg/kg, and PGB 50 mg/kg plus XAN 1 mg/kg groups. Serum cholesterol and testosterone levels were determined. Also, the levels of malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide (NO), superoxide dismutase (SOD), tumor necrosis factor-α (TNF-α), nuclear factor kappa B (NF-қB), angiotensin (Ang) II, Ang-(1–7), and angiotensin-converting enzyme2 (ACE2) were assessed in testicular tissue. Immunohistochemical analysis of heme oxygenase-1 (HO-1) and caspase-3 was performed. Finally, the histopathological examination of the testicular tissues was performed.

Results

The PGB 50 mg/kg, PGB 100 mg/kg, XAN 1 mg/kg, XAN 2 mg/kg, and PGB 50 mg/kg plus XAN 1 mg/kg groups showed a significant decrease in serum cholesterol, MDA, NO, TNF-α, NF-қB, and Ang-II levels coupled with a significant increase in both testosterone and ACE2 expression. Furthermore, all test groups showed a significant improvement in the histopathological picture with a reduction in caspase-3 and an increase in HO-1 immunoexpression in testicular tissue.

Conclusion

PGB and XAN may have promising effects on preventing testicular T/D injury through antioxidant, anti-inflammatory, and antiapoptotic actions.

背景：精索扭转是泌尿科常见的危险问题。本研究评估了普瑞巴林（PGB）和安体舒通（XAN）对大鼠睾丸扭转/离体诱导的睾丸缺血/再灌注损伤可能具有的保护作用：将7组成年雄性Wistar白化大鼠随机分为7组，即假性对照组、扭转/离体（T/D）组、PGB 50 mg/kg组、PGB 100 mg/kg组、XAN 1 mg/kg组、XAN 2 mg/kg组和PGB 50 mg/kg加XAN 1 mg/kg组。测定了血清胆固醇和睾酮水平。此外，还评估了睾丸组织中丙二醛（MDA）、还原型谷胱甘肽（GSH）、一氧化氮（NO）、超氧化物歧化酶（SOD）、肿瘤坏死因子-α（TNF-α）、核因子卡巴B（NF-қB）、血管紧张素（Ang）II、Ang-（1-7）和血管紧张素转换酶2（ACE2）的水平。对血红素加氧酶-1（HO-1）和Caspase-3进行了免疫组化分析。最后，对睾丸组织进行了组织病理学检查：结果：PGB 50 mg/kg组、PGB 100 mg/kg组、XAN 1 mg/kg组、XAN 2 mg/kg组和PGB 50 mg/kg加XAN 1 mg/kg组的血清胆固醇、MDA、NO、TNF-α、NF-қB和Ang-II水平显著下降，睾酮和ACE2的表达显著增加。此外，所有试验组的组织病理学状况都有明显改善，睾丸组织中的 Caspase-3 减少，HO-1 免疫表达增加：结论：PGB 和 XAN 可通过抗氧化、抗炎和抗细胞凋亡作用预防睾丸 T/D 损伤。

{"title":"The protective effect of pregabalin and xanthenone on testicular ischemia/reperfusion injury in rats","authors":"Maha M. Abdel-Fattah, Ahmed Mamdouh Ahmed, Rabeh Khairy Saleh, Basim Anwar Shehata Messiha, Remon Roshdy Rofaeil","doi":"10.1111/fcp.13027","DOIUrl":"10.1111/fcp.13027","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Torsion of the spermatic cord is a hazardous and common urologic issue. The current work evaluates the possible protective effect of pregabalin (PGB) and xanthenone (XAN) in testicular ischemia/reperfusion injury induced by testicular torsion/detorsion in rats.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Materials and methods</h3>\u0000 \u0000 <p>Seven groups of adult male Wistar albino rats were allocated randomly into seven groups, namely, sham control, torsion/detorsion (T/D), PGB 50 mg/kg, PGB 100 mg/kg, XAN 1 mg/kg, XAN 2 mg/kg, and PGB 50 mg/kg plus XAN 1 mg/kg groups. Serum cholesterol and testosterone levels were determined. Also, the levels of malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide (NO), superoxide dismutase (SOD), tumor necrosis factor-α (TNF-α), nuclear factor kappa B (NF-қB), angiotensin (Ang) II, Ang-(1–7), and angiotensin-converting enzyme2 (ACE2) were assessed in testicular tissue. Immunohistochemical analysis of heme oxygenase-1 (HO-1) and caspase-3 was performed. Finally, the histopathological examination of the testicular tissues was performed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The PGB 50 mg/kg, PGB 100 mg/kg, XAN 1 mg/kg, XAN 2 mg/kg, and PGB 50 mg/kg plus XAN 1 mg/kg groups showed a significant decrease in serum cholesterol, MDA, NO, TNF-α, NF-қB, and Ang-II levels coupled with a significant increase in both testosterone and ACE2 expression. Furthermore, all test groups showed a significant improvement in the histopathological picture with a reduction in caspase-3 and an increase in HO-1 immunoexpression in testicular tissue.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>PGB and XAN may have promising effects on preventing testicular T/D injury through antioxidant, anti-inflammatory, and antiapoptotic actions.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 6","pages":"1080-1093"},"PeriodicalIF":2.1,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141558636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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