Journal of pharmacological sciences最新文献_第3页

Inorganic sulfides prevent osimertinib-induced mitochondrial dysfunction in human iPS cell-derived cardiomyocytes 无机硫化物可预防奥西美替尼诱导的人类 iPS 细胞衍生心肌细胞线粒体功能障碍

IF 3 3区医学

Journal of pharmacological sciences Pub Date : 2024-07-23 DOI: 10.1016/j.jphs.2024.07.007

Moe Kondo , Yuya Nakamura , Yuri Kato , Akiyuki Nishimura , Mitsuhiro Fukata , Shohei Moriyama , Tomoya Ito , Keitaro Umezawa , Yasuteru Urano , Takaaki Akaike , Koichi Akashi , Yasunari Kanda , Motohiro Nishida

{"title":"Inorganic sulfides prevent osimertinib-induced mitochondrial dysfunction in human iPS cell-derived cardiomyocytes","authors":"Moe Kondo , Yuya Nakamura , Yuri Kato , Akiyuki Nishimura , Mitsuhiro Fukata , Shohei Moriyama , Tomoya Ito , Keitaro Umezawa , Yasuteru Urano , Takaaki Akaike , Koichi Akashi , Yasunari Kanda , Motohiro Nishida","doi":"10.1016/j.jphs.2024.07.007","DOIUrl":"10.1016/j.jphs.2024.07.007","url":null,"abstract":"<div><p>Despite the widespread recognition of the global concern regarding the onset of cardiovascular diseases in a significant number of patients following cancer treatment, definitive strategies for prevention and treatment remain elusive. In this study, we established systems to evaluate the influence of anti-cancer drugs on the quality control of mitochondria, pivotal for energy metabolism, using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Osimertinib, an epidermal growth factor receptor tyrosine kinase inhibitor used for treatment in lung cancer, reportedly increases the risk of cardiovascular disease. However, its underlying mechanism is largely unknown. Here, we found that the treatment of hiPSC-CMs with osimertinib and doxorubicin, but not trastuzumab and cisplatin, revealed a concentration-dependent impairment of respiratory function accompanied by mitochondrial fission. We previously reported the significant role of sulfur metabolism in maintaining mitochondrial quality in the heart. Co-treatment with various inorganic sulfur donors (Na<sub>2</sub>S, Na<sub>2</sub>S<sub>2</sub>, Na<sub>2</sub>S<sub>3</sub>) alongside anti-cancer drugs demonstrated that Na<sub>2</sub>S attenuated the cardiotoxicity of osimertinib but not doxorubicin. Osimertinib decreased intracellular reduced sulfur levels, while Na<sub>2</sub>S treatment suppressed the sulfur leakage, suggesting its potential in mitigating osimertinib-induced cardiotoxicity. These results imply the prospect of inorganic sulfides, such as Na<sub>2</sub>S, as a seed for precision pharmacotherapy to alleviate osimertinib's cardiotoxic effects.</p></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"156 2","pages":"Pages 69-76"},"PeriodicalIF":3.0,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1347861324000525/pdfft?md5=c0c8dd83d8cf944214165065772b20a2&pid=1-s2.0-S1347861324000525-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141771006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Activation of α7 nicotinic receptors attenuated hyperalgesia and anxiety induced by palatable obesogenic diet withdrawal 激活α7烟碱受体可减轻厌食性肥胖饮食戒断引起的痛觉过度和焦虑症

IF 3 3区医学

Journal of pharmacological sciences Pub Date : 2024-07-22 DOI: 10.1016/j.jphs.2024.07.006

Shakir D. AlSharari , Alaa A. Alameen , Fawzeyah S. Aldafiri , Yousif S. Ali , Musaad A. Alshammari , Youssef Sari , M.I. Damaj

{"title":"Activation of α7 nicotinic receptors attenuated hyperalgesia and anxiety induced by palatable obesogenic diet withdrawal","authors":"Shakir D. AlSharari , Alaa A. Alameen , Fawzeyah S. Aldafiri , Yousif S. Ali , Musaad A. Alshammari , Youssef Sari , M.I. Damaj","doi":"10.1016/j.jphs.2024.07.006","DOIUrl":"10.1016/j.jphs.2024.07.006","url":null,"abstract":"<div><p>Consumption of palatable food (PF) can alleviate anxiety, and pain in humans. Contrary, spontaneous withdrawal of long-term PF intake produces anxiogenic-like behavior and abnormal pain sensation, causing challenges to weight-loss diet and anti-obesity agents. Thus, we examined α7-nicotinic acetylcholine receptors (α7nAChR) involvement since it plays essential role in nociception and psychological behaviors.</p></div><div><h3>Methods</h3><p>Adult male C57BL/6 mice were placed on a Standard Chow (SC) alone or with PF on intermittent or continuous regimen for 6 weeks. Then, mice were replaced with normal SC (spontaneous withdrawal). Body weight, food intake, and calories intake with and without the obesogenic diet were measured throughout the study. During PF withdrawal, anxiety-like behaviors and pain sensitivity were measured with PNU-282987 (α7nAChR agonist) administration.</p></div><div><h3>Results</h3><p>Six weeks of SC + PF-intermittent and continuous paradigms produced a significant weight gain. PF withdrawal displayed hyperalgesia and anxiety-like behaviors. During withdrawal, PNU-282987 significantly attenuated hyperalgesia and anxiety-like behaviors.</p></div><div><h3>Conclusion</h3><p>The present study shows that a PF can increase food intake and body weight. Also, enhanced pain sensitivity and anxiety-like behavior were observed during PF withdrawal. α7nAChR activation attenuated anxiolytic-like behavior and hyperalgesia in PF abstinent mice. These data suggest potential therapeutic effects of targeting α7 nAChRs for obesity-withdrawal symptoms in obese subjects.</p></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"156 2","pages":"Pages 86-101"},"PeriodicalIF":3.0,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1347861324000513/pdfft?md5=1b339559c66649a1de2d81eae2eadd91&pid=1-s2.0-S1347861324000513-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141771007","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The role of ZEB1 in mediating the protective effects of metformin on skeletal muscle atrophy ZEB1 在介导二甲双胍对骨骼肌萎缩的保护作用中的作用

IF 3 3区医学

Journal of pharmacological sciences Pub Date : 2024-07-18 DOI: 10.1016/j.jphs.2024.07.004

Peiyu Jia , Ji Che , Xiaoting Xie , Qi Han , Yantao Ma , Yong Guo , Yongjun Zheng

{"title":"The role of ZEB1 in mediating the protective effects of metformin on skeletal muscle atrophy","authors":"Peiyu Jia , Ji Che , Xiaoting Xie , Qi Han , Yantao Ma , Yong Guo , Yongjun Zheng","doi":"10.1016/j.jphs.2024.07.004","DOIUrl":"10.1016/j.jphs.2024.07.004","url":null,"abstract":"<div><p>Metformin is an important antidiabetic drug that has the potential to reduce skeletal muscle atrophy and promote the differentiation of muscle cells. However, the exact molecular mechanism underlying these functions remains unclear. Previous studies revealed that the transcription factor zinc finger E-box-binding homeobox 1 (ZEB1), which participates in tumor progression, inhibits muscle atrophy. Therefore, we hypothesized that the protective effect of metformin might be related to ZEB1. We investigated the positive effect of metformin on IL-1β-induced skeletal muscle atrophy by regulating ZEB1 <em>in vitro</em> and <em>in vivo</em>. Compared with the normal cell differentiation group, the metformin-treated group presented increased myotube diameters and reduced expression levels of atrophy-marker proteins. Moreover, muscle cell differentiation was hindered, when we artificially interfered with ZEB1 expression in mouse skeletal myoblast (C2C12) cells via ZEB1-specific small interfering RNA (si-ZEB1). In response to inflammatory stimulation, metformin treatment increased the expression levels of ZEB1 and three differentiation proteins, MHC, MyoD, and myogenin, whereas si-ZEB1 partially counteracted these effects. Moreover, marked atrophy was induced in a mouse model via the administration of lipopolysaccharide (LPS) to the skeletal muscles of the lower limbs. Over a 4-week period of intragastric administration, metformin treatment ameliorated muscle atrophy and increased the expression levels of ZEB1. Metformin treatment partially alleviated muscle atrophy and stimulated differentiation. Overall, our findings may provide a better understanding of the mechanism underlying the effects of metformin treatment on skeletal muscle atrophy and suggest the potential of metformin as a therapeutic drug.</p></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"156 2","pages":"Pages 57-68"},"PeriodicalIF":3.0,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1347861324000495/pdfft?md5=a5ee22fb27dee55ffcead570eff1fba2&pid=1-s2.0-S1347861324000495-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141771008","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

l-DOPA receptor GPR143 inhibits neurite outgrowth via L-type calcium channels in PC12 cells l-DOPA 受体 GPR143 通过 PC12 细胞中的 L 型钙通道抑制神经元生长

IF 3 3区医学

Journal of pharmacological sciences Pub Date : 2024-07-06 DOI: 10.1016/j.jphs.2024.07.003

Miyu Inoue, Daiki Masukawa, Yoshio Goshima

引用次数: 0

Polyphyllin VII as a potential medication for targeting epithelial mesenchymal transitionin in thyroid cancer 聚卟啉 VII 是一种针对甲状腺癌上皮间质转化蛋白的潜在药物

IF 3 3区医学

Journal of pharmacological sciences Pub Date : 2024-07-06 DOI: 10.1016/j.jphs.2024.07.002

Qingqing Yu , Jinglin Chen , Chen Zhong , Le Yu , Yunhe Zhu , Xueyan Xi , Boyu Du

{"title":"Polyphyllin VII as a potential medication for targeting epithelial mesenchymal transitionin in thyroid cancer","authors":"Qingqing Yu , Jinglin Chen , Chen Zhong , Le Yu , Yunhe Zhu , Xueyan Xi , Boyu Du","doi":"10.1016/j.jphs.2024.07.002","DOIUrl":"10.1016/j.jphs.2024.07.002","url":null,"abstract":"<div><p>The need for novel anti-thyroid cancer (TC) medications is urgent due to the rising incidence and metastatic rates of malignant TC. In this study, we investigated the effect of Polyphyllin VII (PPVII) to TC cells, and explored their potential mechanism. B-CPAP and TPC-1 cells, were used to analyze the antitumor activity of PPVII by quantifying cell growth and metastasis as well as to study the effect on epithelial mesenchymal transition (EMT). The results showed that PPVII dramatically reduced the capacity of B-CPAP and TPC-1 cells to proliferate and migrate in a dose-response manner. Following PPVII treatment of TC cells, the expression levels of E-cadherin progressively increased and were higher than the control group, while the expression levels of EMT-related genes Vimentin, N-cadherin, Slug, Zeb-1, and Foxe1 gradually declined and were lower than the control group. It was proposed that PPVII might prevent TC from undergoing EMT. The Foxe1 gene was shown to be significantly expressed in TC, and a statistically significant variation in Foxe1 expression was observed across clinical stages of the disease, according to a bioinformatics database study. There was a strong link between the expression of the Foxe1 gene and the EMT-related gene. In the meantime, TC cells' expression of Foxe1 can be inhibited by PPVII. In conclusion, our results showed that PPVII may as a potential medication for targeting EMT in thyroid cancer.</p></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"156 2","pages":"Pages 49-56"},"PeriodicalIF":3.0,"publicationDate":"2024-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1347861324000471/pdfft?md5=d3fe5cae10081903a715d4c4842c8aef&pid=1-s2.0-S1347861324000471-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141714129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Combined antiallodynic effects of Neurotropin®–tramadol and Neurotropin®–mirogabalin in rats with L5-spinal nerve ligation 神经妥宾®-曲马多和神经妥宾®-米罗卡宾对脊神经L5结扎大鼠的联合镇痛作用

IF 3 3区医学

Journal of pharmacological sciences Pub Date : 2024-07-02 DOI: 10.1016/j.jphs.2024.07.001

Yukihiro Yoshimoto, Hisashi Okai, Hiroyoshi Namba, Kazuki Taguchi, Yoshiya Yamauchi, Jun Wakita, Ryohei Okazaki

{"title":"Combined antiallodynic effects of Neurotropin®–tramadol and Neurotropin®–mirogabalin in rats with L5-spinal nerve ligation","authors":"Yukihiro Yoshimoto, Hisashi Okai, Hiroyoshi Namba, Kazuki Taguchi, Yoshiya Yamauchi, Jun Wakita, Ryohei Okazaki","doi":"10.1016/j.jphs.2024.07.001","DOIUrl":"https://doi.org/10.1016/j.jphs.2024.07.001","url":null,"abstract":"<div><p>We aimed to examine the efficacy of combination therapies of Neurotropin® with tramadol and Neurotropin with mirogabalin for neuropathic pain management. A neuropathic pain model (L5 spinal nerve ligation model: L5-SNL) using male Wistar rats was generated through tight ligation of the left fifth lumbar nerve using silk sutures. Mechanical allodynia was assessed using the 50% paw withdrawal threshold. The combined antiallodynic effects were evaluated using isobolographic analyses. Small intestinal transit was evaluated using the charcoal meal test, and motor coordination using the rota-rod test. Neurotropin (50–200 NU/kg, p.o.), tramadol (7.5–60 mg/kg, p.o.), and mirogabalin (3–30 mg/kg, p.o.) showed a dose-dependent antiallodynic effect in L5-SNL rats. The combined antiallodynic effects of Neurotropin and tramadol were additive or synergistic, whereas those of Neurotropin and mirogabalin were additive. Neurotropin (100–400 NU/kg, p.o.) did not affect the small intestinal transit, whereas tramadol (30–100 mg/kg, p.o.) significantly inhibited it. Neurotropin (100–400 NU/kg, p.o.) did not affect the walking time, whereas mirogabalin (10–100 mg/kg, p.o.) significantly decreased it. Neurotropin dose-dependently ameliorated mechanical allodynia in rats, and combination therapy with Neurotropin–tramadol or Neurotropin–mirogabalin may alleviate neuropathic pain without aggravating the adverse effects of tramadol and mirogabalin.</p></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"156 1","pages":"Pages 30-37"},"PeriodicalIF":3.0,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S134786132400046X/pdfft?md5=1f42974a74708cb6655b49c70f8527d9&pid=1-s2.0-S134786132400046X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141542596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Alteration of reactivity in isolated mesenteric artery from Zucker fatty diabetes mellitus rats 扎克脂肪糖尿病大鼠离体肠系膜动脉反应性的改变

IF 3 3区医学

Journal of pharmacological sciences Pub Date : 2024-06-27 DOI: 10.1016/j.jphs.2024.06.006

Kosuke Otani, Naofumi Uemura, Hiroshi Funada, Tomoko Kodama, Muneyoshi Okada, Hideyuki Yamawaki

{"title":"Alteration of reactivity in isolated mesenteric artery from Zucker fatty diabetes mellitus rats","authors":"Kosuke Otani, Naofumi Uemura, Hiroshi Funada, Tomoko Kodama, Muneyoshi Okada, Hideyuki Yamawaki","doi":"10.1016/j.jphs.2024.06.006","DOIUrl":"https://doi.org/10.1016/j.jphs.2024.06.006","url":null,"abstract":"<div><p>Obesity and diabetes are major risk factors for cardiovascular diseases. Zucker fatty diabetes mellitus (ZFDM) rats are novel animal model of obesity and type 2 diabetes. We have recently reported that blood pressure in ZFDM-<em>Lepr</em><sup>fa/fa</sup> (Homo) rats was normal, while blood adrenaline level and heart rate were lower than those in control ZFDM-<em>Lepr</em><sup>fa/+</sup> (Hetero) rats. Here, we compared the reactivity in isolated mesenteric artery between Hetero and Homo rats. Contraction induced by phenylephrine was increased, while relaxation induced by isoprenaline was decreased in Homo rats at 21–23 weeks old compared with those in Hetero rats. The mRNA expression for α<sub>1A</sub> but not β<sub>2</sub> adrenoreceptor in Homo rats was increased. Nitric oxide (NO)-mediated relaxation induced by acetylcholine was decreased, while the mRNA expression for endothelial NO synthase (eNOS) was rather increased in mesenteric artery from Homo rats. These findings for the first time revealed that in Homo rats with reduced plasma adrenaline, blood pressure could be maintained by enhancing vascular contractility induced by adrenaline through the increased α<sub>1</sub> adrenoceptor expression and the attenuated β<sub>2</sub> adrenoceptor signaling. Additionally, NO-mediated endothelium-dependent relaxation is impaired perhaps due to eNOS dysfunction, which might also contribute to maintain the blood pressure in Homo rats.</p></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"156 1","pages":"Pages 38-44"},"PeriodicalIF":3.0,"publicationDate":"2024-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1347861324000458/pdfft?md5=540649ac368aa19ed70b6770807da17e&pid=1-s2.0-S1347861324000458-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141542563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Characterization of remodeling processes in the atria of atrioventricular block dogs: Utility as an early-stage atrial fibrillation model 房室传导阻滞犬心房重塑过程的特征：作为早期心房颤动模型的实用性

IF 3 3区医学

Journal of pharmacological sciences Pub Date : 2024-06-27 DOI: 10.1016/j.jphs.2024.06.004

Ryuichi Kambayashi , Ai Goto , Akira Takahara , Hiroyuki Saito , Hiroko Izumi-Nakaseko , Yoshinori Takei , Yasuki Akie , Masaaki Hori , Atsushi Sugiyama

{"title":"Characterization of remodeling processes in the atria of atrioventricular block dogs: Utility as an early-stage atrial fibrillation model","authors":"Ryuichi Kambayashi , Ai Goto , Akira Takahara , Hiroyuki Saito , Hiroko Izumi-Nakaseko , Yoshinori Takei , Yasuki Akie , Masaaki Hori , Atsushi Sugiyama","doi":"10.1016/j.jphs.2024.06.004","DOIUrl":"https://doi.org/10.1016/j.jphs.2024.06.004","url":null,"abstract":"<div><p>To characterize utility of atrioventricular block (AVB) dogs as atrial fibrillation (AF) model, we studied remodeling processes occurring in their atria in acute (<2 weeks) and chronic (>4 weeks) phases. Fifty beagle dogs were used. Holter electrocardiogram demonstrated that paroxysmal AF occurred immediately after the production of AVB, of which duration tended to be prolonged in chronic phase. Electrophysiological analysis showed that inter-atrial conduction time and duration of burst pacing-induced AF increased in the chronic phase compared with those in the acute phase, but that atrial effective refractory period was hardly altered. Echocardiographic study revealed that diameters of left atrium, right pulmonary vein and inferior vena cava increased similarly in the acute and chronic phases. Histological evaluation indicated that hypertrophy and fibrosis in atrial tissue increased in the chronic phase. Electropharmacological characterization showed that i.v. pilsicainide effectively suppressed burst pacing-induced AF with increasing atrial conduction time and refractoriness of AVB dogs in chronic phase, but that i.v. amiodarone did not exert such electrophysiological effects. Taken together, AVB dogs in chronic phase appear to possess such pathophysiology as developed in the atria of early-stage AF patients, and therefore they can be used to evaluate drug candidates against early-stage AF.</p></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"156 1","pages":"Pages 19-29"},"PeriodicalIF":3.0,"publicationDate":"2024-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1347861324000434/pdfft?md5=8c223283ccc67452e3221247a8a58908&pid=1-s2.0-S1347861324000434-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141542565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Contribution of MLKL to the development of doxorubicin-induced cardiomyopathy and its amelioration by rapamycin MLKL对多柔比星诱发的心肌病发展的贡献以及雷帕霉素对其的改善作用

IF 3 3区医学

Journal of pharmacological sciences Pub Date : 2024-06-27 DOI: 10.1016/j.jphs.2024.06.005

Masaki Shimizu , Wataru Ohwada , Toshiyuki Yano , Hidemichi Kouzu , Tatsuya Sato , Toshifumi Ogawa , Arata Osanami , Yuki Toda , Hiroshi Nagahama , Masaya Tanno , Tetsuji Miura , Atsushi Kuno , Masato Furuhashi

{"title":"Contribution of MLKL to the development of doxorubicin-induced cardiomyopathy and its amelioration by rapamycin","authors":"Masaki Shimizu , Wataru Ohwada , Toshiyuki Yano , Hidemichi Kouzu , Tatsuya Sato , Toshifumi Ogawa , Arata Osanami , Yuki Toda , Hiroshi Nagahama , Masaya Tanno , Tetsuji Miura , Atsushi Kuno , Masato Furuhashi","doi":"10.1016/j.jphs.2024.06.005","DOIUrl":"https://doi.org/10.1016/j.jphs.2024.06.005","url":null,"abstract":"<div><p>Necroptosis, necrosis characterized by RIPK3-MLKL activation, has been proposed as a mechanism of doxorubicin (DOX)-induced cardiomyopathy. We showed that rapamycin, an mTORC1 inhibitor, attenuates cardiomyocyte necroptosis. Here we examined role of MLKL in DOX-induced myocardial damage and protective effects of rapamycin. Cardiomyopathy was induced in mice by intraperitoneal injections of DOX (10 mg/kg, every other day) and followed for 7 days. DOX-treated mice showed a significant decline in LVEF assessed by cardiac MRI (45.5 ± 5.1% vs. 65.4 ± 4.2%), reduction in overall survival rates, and increases in myocardial RIPK3 and MLKL expression compared with those in vehicle-treated mice, and those changes were prevented by administration of rapamycin (0.25 mg/kg) before DOX injection. In immunohistochemical analyses, p-MLKL signals were detected in the cardiomyocytes of DOX-treated mice, and the signals were reduced by rapamycin. <em>Mlkl</em><sup><em>+/-</em></sup> and <em>Mlkl</em><sup><em>-/-</em></sup> mice were similarly resistant to DOX-induced cardiac dysfunction, indicating that a modest reduction in MLKL level is sufficient to prevent the development of DOX-induced cardiomyopathy. However, evidence of cardiomyocyte necrosis assessed by C9 immunostaining, presence of replacement fibrosis, and electron microscopic analyses was negligible in the myocardium of DOX-treated mice. Thus, MLKL-mediated signaling contributes to DOX-induced cardiac dysfunction primarily by a necrosis-independent mechanism, which is inhibitable by rapamycin.</p></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"156 1","pages":"Pages 9-18"},"PeriodicalIF":3.0,"publicationDate":"2024-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1347861324000446/pdfft?md5=96d1d026ca9fff759593a72f659ebe9a&pid=1-s2.0-S1347861324000446-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141542564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cinnamaldehyde protects SH-SY5Y cells against advanced glycation end-products induced ectopic cell cycle re-entry 肉桂醛保护 SH-SY5Y 细胞免受高级糖化终产物诱导的异位细胞周期再进入的影响

IF 3 3区医学

Journal of pharmacological sciences Pub Date : 2024-06-17 DOI: 10.1016/j.jphs.2024.06.003

Yijing Wu , Jing Zhong , Jiaqi Wang , Hemei Li , Xiuting Chen , Xing Xia , Jinling Zhou

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