Journal of pharmacological sciences最新文献

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β-Adrenoceptor blockade can augment the torsadogenic action of risperidone β-肾上腺素受体阻断可增强利培酮的致扭力作用
IF 3 3区 医学
Journal of pharmacological sciences Pub Date : 2024-07-31 DOI: 10.1016/j.jphs.2024.07.011
Ai Goto, Ryuichi Kambayashi, Hiroko Izumi-Nakaseko, Yoshinori Takei, Atsushi Sugiyama
{"title":"β-Adrenoceptor blockade can augment the torsadogenic action of risperidone","authors":"Ai Goto,&nbsp;Ryuichi Kambayashi,&nbsp;Hiroko Izumi-Nakaseko,&nbsp;Yoshinori Takei,&nbsp;Atsushi Sugiyama","doi":"10.1016/j.jphs.2024.07.011","DOIUrl":"10.1016/j.jphs.2024.07.011","url":null,"abstract":"<div><p>Risperidone is a second-generation antipsychotic for treating schizophrenia and bipolar disorder. It can potently inhibit I<sub>Kr</sub>, but is classified into conditional risk for torsade de pointes (TdP) by CredibleMeds®. Our previous studies using chronic atrioventricular block dogs showed that risperidone alone did not induce TdP, and that <em>dl</em>-sotalol (β-adrenoceptor blockade plus I<sub>Kr</sub> inhibition) induced TdP three times more frequently than <em>d</em>-sotalol (I<sub>Kr</sub> inhibition alone). Since risperidone can block α<sub>1</sub>-adrenoceptor and decrease blood pressure, the resulting reflex-mediated increase of sympathetic tone on β-adrenoceptor might protect the heart from its I<sub>Kr</sub> inhibition-associated TdP. To validate this hypothesis, risperidone was administered to chronic atrioventricular block dogs after β-adrenoceptor blocker atenolol infusion with monitoring J-T<sub>peak</sub> and T<sub>peak</sub>-T<sub>end</sub>, which are proarrhythmic surrogate markers of \"substrate\" and \"trigger\" toward TdP, respectively. Atenolol alone induced TdP in 1 out of 5 dogs; moreover, an additional infusion of risperidone induced TdP in 3 out of 4 dogs. Risperidone prolonged QT interval, J-T<sub>peak</sub> and T<sub>peak</sub>-T<sub>end</sub> in animals that induced TdP. These findings indicate that β-adrenoceptor blockade can diminish repolarization reserve to augment risperidone’s torsadogenic potential, thus advising caution when using β-adrenoceptor blockers in patients with I<sub>Kr</sub> inhibition-linked labile repolarization.</p></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"156 2","pages":"Pages 134-141"},"PeriodicalIF":3.0,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1347861324000562/pdfft?md5=6a6c58e055f64890f94f471ec0a9accb&pid=1-s2.0-S1347861324000562-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141963379","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
Neohesperidin exerts antidepressant-like effect via the mechanistic target of rapamycin complex 1 in the medial prefrontal cortex in male mice 新橙皮甙通过雷帕霉素复合体1在雄性小鼠内侧前额叶皮层的机制靶点发挥抗抑郁样作用
IF 3 3区 医学
Journal of pharmacological sciences Pub Date : 2024-07-30 DOI: 10.1016/j.jphs.2024.07.010
Satoshi Deyama, Shun Aoki, Rinako Sugie, Katsuyuki Kaneda
{"title":"Neohesperidin exerts antidepressant-like effect via the mechanistic target of rapamycin complex 1 in the medial prefrontal cortex in male mice","authors":"Satoshi Deyama,&nbsp;Shun Aoki,&nbsp;Rinako Sugie,&nbsp;Katsuyuki Kaneda","doi":"10.1016/j.jphs.2024.07.010","DOIUrl":"10.1016/j.jphs.2024.07.010","url":null,"abstract":"<div><p>Neohesperidin, a citrus flavonoid, shows potential for activating the mechanistic target of rapamycin complex 1 (mTORC1). Here, the antidepressant-like effect of neohesperidin was examined in male ICR mice (naïve mice and mice treated repeatedly with prednisolone, a synthetic glucocorticoid, which induces depression-like behavior). Oral neohesperidin administration exerted an antidepressant-like effect in the forced swim test 1 h post-treatment, in naïve mice; this effect was no longer observed at 24 h. Neohesperidin also reversed prednisolone-induced depression-like behavior. This effect was blocked by infusing rapamycin, an mTORC1 inhibitor, into the medial prefrontal cortex. Neohesperidin may rapidly produce an antidepressant-like effect.</p></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"156 2","pages":"Pages 82-85"},"PeriodicalIF":3.0,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1347861324000550/pdfft?md5=e3920db2afd0c414595dc68e6f9a3abc&pid=1-s2.0-S1347861324000550-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141885295","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
Opposite regulation by L-DOPA receptor GPR143 of the long and short forms of the dopamine D2 receptors 左旋多巴受体 GPR143 对多巴胺 D2 受体长短型的相反调节作用
IF 3 3区 医学
Journal of pharmacological sciences Pub Date : 2024-07-30 DOI: 10.1016/j.jphs.2024.07.009
Rei Tajika , Daiki Masukawa , Masami Arai , Hiroyuki Nawa , Yoshio Goshima
{"title":"Opposite regulation by L-DOPA receptor GPR143 of the long and short forms of the dopamine D2 receptors","authors":"Rei Tajika ,&nbsp;Daiki Masukawa ,&nbsp;Masami Arai ,&nbsp;Hiroyuki Nawa ,&nbsp;Yoshio Goshima","doi":"10.1016/j.jphs.2024.07.009","DOIUrl":"10.1016/j.jphs.2024.07.009","url":null,"abstract":"<div><p>Dopamine (DA) D2 receptors (D2Rs) have 2 isoforms, a long form (D2L) and a short form (D2S). D2L is predominantly postsynaptic in the striatal medium spiny neurons and cholinergic interneurons. D2S is principally presynaptic autoreceptors in the nigrostriatal DA neurons. Recently, we demonstrated that L-3,4-dihydroxyphenylalanine (L-DOPA) augments D2L function through the coupling between D2L and GPR143, a receptor of L-DOPA that was originally identified as the gene product of ocular albinism 1. Here we show that GPR143 modifies the functions of D2L and D2S in an opposite manner. Haloperidol-induced catalepsy was attenuated in DA neuron-specific <em>Gpr143 gene</em>-deficient (<em>Dat-cre;Gpr143</em><sup><em>flox/y</em></sup>) mice, compared with wild-type (<em>Wt</em>) mice. Haloperidol increased in vivo DA release from the dorsolateral striatum, and this increase was augmented in <em>Gpr143</em><sup><em>-/y</em></sup> mice compared with <em>Wt</em> mice. A D2R agonist quinpirole-induced increase in the phosphorylation of GSK3β(pGSK3β(S9)) was enhanced in Chinese hamster ovary (CHO) cells coexpressing D2L and GPR143 compared with cells expressing D2L alone, while it was suppressed in cells coexpressing D2S and GPR143 compared with D2S alone, suggesting that GPR143 differentially modifies D2R functions depending on its isoforms of D2L and D2S.</p></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"156 2","pages":"Pages 77-81"},"PeriodicalIF":3.0,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1347861324000549/pdfft?md5=0fada20c7d5bb425a552b2ffd56ab094&pid=1-s2.0-S1347861324000549-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141885296","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
Galantamine suppresses α-synuclein aggregation by inducing autophagy via the activation of α7 nicotinic acetylcholine receptors 加兰他敏通过激活α7烟碱乙酰胆碱受体诱导自噬抑制α-突触核蛋白聚集
IF 3 3区 医学
Journal of pharmacological sciences Pub Date : 2024-07-30 DOI: 10.1016/j.jphs.2024.07.008
Sora Nozaki , Masanori Hijioka , Xiaopeng Wen , Natsumi Iwashita , Junya Namba , Yoshiaki Nomura , Aoi Nakanishi , Soichiro Kitazawa , Ryo Honda , Yuji O. Kamatari , Ryo Kitahara , Kenji Suzuki , Masatoshi Inden , Yoshihisa Kitamura
{"title":"Galantamine suppresses α-synuclein aggregation by inducing autophagy via the activation of α7 nicotinic acetylcholine receptors","authors":"Sora Nozaki ,&nbsp;Masanori Hijioka ,&nbsp;Xiaopeng Wen ,&nbsp;Natsumi Iwashita ,&nbsp;Junya Namba ,&nbsp;Yoshiaki Nomura ,&nbsp;Aoi Nakanishi ,&nbsp;Soichiro Kitazawa ,&nbsp;Ryo Honda ,&nbsp;Yuji O. Kamatari ,&nbsp;Ryo Kitahara ,&nbsp;Kenji Suzuki ,&nbsp;Masatoshi Inden ,&nbsp;Yoshihisa Kitamura","doi":"10.1016/j.jphs.2024.07.008","DOIUrl":"10.1016/j.jphs.2024.07.008","url":null,"abstract":"<div><p>Synucleinopathies, including Parkinson's disease and dementia with Lewy bodies, are neurodegenerative disorders characterized by the aberrant accumulation of α-synuclein (α-syn). Although no treatment is effective for synucleinopathies, the suppression of α-syn aggregation may contribute to the development of numerous novel therapeutic targets. Recent research revealed that nicotinic acetylcholine (nACh) receptor activation has neuroprotective effects and promotes the degradation of amyloid protein by activating autophagy. In an <em>in vitro</em> human-derived cell line model, we demonstrated that galantamine, the nAChR allosteric potentiating ligand, significantly reduced the cell number of SH-SY5Y cells with intracellular Lewy body-like aggregates by enhancing the sensitivity of α<sub>7</sub>-nAChR. In addition, galantamine promoted autophagic flux, and prevented the formation of Lewy body-resembled aggregates. In an <em>in vivo</em> synucleinopathy mouse model, the propagation of α-syn aggregation in the cerebral cortex was inhibited by galantamine administration for 90 days. These results suggest that α<sub>7</sub>-nAChR is expected to be a novel therapeutic target, and galantamine is a potential agent for synucleinopathies.</p></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"156 2","pages":"Pages 102-114"},"PeriodicalIF":3.0,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1347861324000537/pdfft?md5=aa744b27678a643ecef9a42546b74b7a&pid=1-s2.0-S1347861324000537-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141885299","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
Glucocorticoid-induced acute diuresis in rats in relation to the reduced renal expression of sodium-dependent cotransporter genes 糖皮质激素诱导的大鼠急性利尿与依赖钠的共转运体基因的肾表达减少有关
IF 3 3区 医学
Journal of pharmacological sciences Pub Date : 2024-07-25 DOI: 10.1016/j.jphs.2024.07.005
Peiyan Zhao , Yoshiki Higashijima , Hiroko Sonoda , Rio Morinaga , Keito Uema , Akane Oguchi , Toshiyuki Matsuzaki , Masahiro Ikeda
{"title":"Glucocorticoid-induced acute diuresis in rats in relation to the reduced renal expression of sodium-dependent cotransporter genes","authors":"Peiyan Zhao ,&nbsp;Yoshiki Higashijima ,&nbsp;Hiroko Sonoda ,&nbsp;Rio Morinaga ,&nbsp;Keito Uema ,&nbsp;Akane Oguchi ,&nbsp;Toshiyuki Matsuzaki ,&nbsp;Masahiro Ikeda","doi":"10.1016/j.jphs.2024.07.005","DOIUrl":"10.1016/j.jphs.2024.07.005","url":null,"abstract":"<div><p>Although several studies have shown that glucocorticoids exert diuretic effects in animals and humans, the underlying mechanism responsible for the acute diuretic effect remains obscure. Here we examined the mechanism in terms of gene-expression. We observed that glucocorticoids, including dexamethasone (Dex) and prednisolone (PSL), acutely induced diuresis in rats in a dose-dependent manner. Free water clearance values were negative after Dex or PSL treatment, similar to those observed after treatment with osmotic diuretics (furosemide and acetazolamide). Dex significantly increased the urinary excretion of sodium, potassium, chloride, glucose, and inorganic phosphorus. Renal microarray analysis revealed that Dex significantly altered the renal expression of genes related to transmembrane transport activity. The mRNA levels of sodium/phosphate (<em>NaPi-2a</em>/<em>Slc34a1</em>, <em>NaPi-2b/Slc34a2</em>, and <em>NaPi-2c</em>/<em>Slc34a3</em>) and sodium/glucose cotransporters (<em>Sglt2</em>/<em>Slc5a2</em>) were significantly reduced in the Dex-treated kidney, being negatively correlated with the urinary excretion of their corresponding solutes. Dex did not affect renal expression of the natriuretic peptide receptor 1 (<em>Npr1</em>) gene, or the expression, localization, and phosphorylation of aquaporin-2 (AQP2), a water channel protein. These findings suggest that the acute diuretic effects of glucocorticoids might be mediated by reduced expression of sodium-dependent cotransporter genes.</p></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"156 2","pages":"Pages 115-124"},"PeriodicalIF":3.0,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1347861324000501/pdfft?md5=24cc0b983274fa57852681e87efd3633&pid=1-s2.0-S1347861324000501-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141844691","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
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 ,&nbsp;Yuya Nakamura ,&nbsp;Yuri Kato ,&nbsp;Akiyuki Nishimura ,&nbsp;Mitsuhiro Fukata ,&nbsp;Shohei Moriyama ,&nbsp;Tomoya Ito ,&nbsp;Keitaro Umezawa ,&nbsp;Yasuteru Urano ,&nbsp;Takaaki Akaike ,&nbsp;Koichi Akashi ,&nbsp;Yasunari Kanda ,&nbsp;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 ,&nbsp;Alaa A. Alameen ,&nbsp;Fawzeyah S. Aldafiri ,&nbsp;Yousif S. Ali ,&nbsp;Musaad A. Alshammari ,&nbsp;Youssef Sari ,&nbsp;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 ,&nbsp;Ji Che ,&nbsp;Xiaoting Xie ,&nbsp;Qi Han ,&nbsp;Yantao Ma ,&nbsp;Yong Guo ,&nbsp;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
{"title":"l-DOPA receptor GPR143 inhibits neurite outgrowth via L-type calcium channels in PC12 cells","authors":"Miyu Inoue,&nbsp;Daiki Masukawa,&nbsp;Yoshio Goshima","doi":"10.1016/j.jphs.2024.07.003","DOIUrl":"https://doi.org/10.1016/j.jphs.2024.07.003","url":null,"abstract":"<div><p>The gene product of ocular albinism 1 (OA1)/G-protein-coupled receptor (GPR)143 is a receptor for L-3,4-dihydroxyphenylanine (<span>l</span>-DOPA), the most effective agent for Parkinson's disease. When overexpressed, human wild-type GPR143, but not its mutants, inhibits neurite outgrowth in PC12 cells. We investigated the downstream signaling pathway for GPR143-induced inhibition of neurite outgrowth. Nifedipine restored GPR143-induced neurite outgrowth inhibition to the level of control transfectant but did not affect outgrowth in GPR143-knockdown cells. Cilnidipine and flunarizine also suppressed the GPR143-induced inhibition, but their effects at higher concentrations still occurred even in GPR143-knockdown cells. These results suggest that GPR143 regulates neurite outgrowth via L-type calcium channel(s).</p></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"156 1","pages":"Pages 45-48"},"PeriodicalIF":3.0,"publicationDate":"2024-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1347861324000483/pdfft?md5=26879980d3366ae1e4d1359eb7017b76&pid=1-s2.0-S1347861324000483-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141595648","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
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 ,&nbsp;Jinglin Chen ,&nbsp;Chen Zhong ,&nbsp;Le Yu ,&nbsp;Yunhe Zhu ,&nbsp;Xueyan Xi ,&nbsp;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
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