Journal of pharmacological sciences最新文献_第2页

Oral administration of undenatured type II collagen significantly inhibits arthritis-associated pain signal in a mouse model of collagen antibody-induced arthritis and meniscus removal 在胶原抗体诱导的关节炎和半月板切除小鼠模型中，口服未变性的II型胶原可显著抑制关节炎相关的疼痛信号

IF 3 3区医学

Journal of pharmacological sciences Pub Date : 2025-06-12 DOI: 10.1016/j.jphs.2025.06.001

Ibuki Yasuda , Mao Kaneki , Chiharu Ohira , Mana Ichikawa , Eiji Iwazaki , Hirohito Tsuruwaka , Tomoki Fukuyama

引用次数: 0

Novel PDE9 inhibitors, KR39526 and KR39582, attenuate cardiac hypertrophy and fibrosis induced by pressure overload 新型PDE9抑制剂KR39526和KR39582可减轻压力过载引起的心脏肥大和纤维化

IF 3 3区医学

Journal of pharmacological sciences Pub Date : 2025-05-30 DOI: 10.1016/j.jphs.2025.05.015

Jeong Hyun Lee , Hyunjin Park , Seung Hyeong Lee , Su Ah Kim , Jun Young Choi , Chae Jo Lim , Ju-Young Shin , Byung Ho Lee , Kwang-Seok Oh

{"title":"Novel PDE9 inhibitors, KR39526 and KR39582, attenuate cardiac hypertrophy and fibrosis induced by pressure overload","authors":"Jeong Hyun Lee , Hyunjin Park , Seung Hyeong Lee , Su Ah Kim , Jun Young Choi , Chae Jo Lim , Ju-Young Shin , Byung Ho Lee , Kwang-Seok Oh","doi":"10.1016/j.jphs.2025.05.015","DOIUrl":"10.1016/j.jphs.2025.05.015","url":null,"abstract":"<div><div>The natriuretic peptide and cyclic guanosine monophosphate (cGMP) cascade are promising therapeutic target for heart failure. This study evaluated the pharmacological properties and cardioprotective effects of novel phosphodiesterase 9 (PDE9) inhibitors, KR39526 and KR39582, <em>in vitro</em> and <em>in vivo</em>. The potency and selectivity of these compounds were assessed through PDE9 inhibitory activity and subfamily selectivity assays. Functional analyses in cardiomyocytes included calcium mobilization, cellular hypertrophy, and protein expression. The cardioprotective efficacy was investigated using a mouse model of pressure-overload-induced cardiac hypertrophy. KR39526 and KR39582 demonstrated potent PDE9A inhibitory activities (IC<sub>50</sub>: 5 ± 2 nM and 0.4 ± 0.1 nM, respectively) with high selectivity. This inhibition led to concentration-dependent calcium influx through maintaining intracellular cGMP levels and significantly suppressed phenylephrine-induced cardiomyocyte hypertrophy. Oral administration (50 mg·kg-1) of these compounds markedly attenuated cardiac hypertrophy and myocardial fibrosis induced by pressure overload. These results suggest that KR39526 and KR39582, as potent and selective PDE9A inhibitors, have strong potential for exerting anti-hypertrophic and anti-fibrotic effects in heart failure. These compounds can serve as valuable pharmacological tools to elucidate the roles of PDE9A signaling in heart failure pathophysiology and hold significant promise as potential therapeutic agents.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"158 4","pages":"Pages 353-362"},"PeriodicalIF":3.0,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144212507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Additive effects of mirabegron on muscarinic receptor binding and on relaxation of cholinergic detrusor muscle contraction by antimuscarinics mirabegron对毒蕈碱受体结合和抗毒蕈碱剂对胆碱能逼尿肌收缩松弛的加性作用

IF 3 3区医学

Journal of pharmacological sciences Pub Date : 2025-05-27 DOI: 10.1016/j.jphs.2025.05.018

Shizuo Yamada , Masae Mochizuki , Kana Maruyama-Fumoto , Satomi Kagota , Kazumasa Shinozuka

{"title":"Additive effects of mirabegron on muscarinic receptor binding and on relaxation of cholinergic detrusor muscle contraction by antimuscarinics","authors":"Shizuo Yamada , Masae Mochizuki , Kana Maruyama-Fumoto , Satomi Kagota , Kazumasa Shinozuka","doi":"10.1016/j.jphs.2025.05.018","DOIUrl":"10.1016/j.jphs.2025.05.018","url":null,"abstract":"<div><div>Mirabegron is the first selective β<sub>3</sub>-adrenoceptor agonist, to be developed as an alternative to antimuscarinic therapy for patients with overactive bladder (OAB). This agent exerts off-target effects on muscarinic receptors. Its combination with solifenacin results in a higher incidence of anticholinergic effects, such as dry mouth, than solifenacin alone. The present study investigated whether the combination of mirabegron and antimuscarinics exerted additive effects on muscarinic receptors and cholinergic contraction in rat tissues. Muscarinic receptor binding activity and inhibitory effect on carbachol-induced contraction in rat tissues were evaluated by radioreceptor assays using [N-methyl-<sup>3</sup>H]scopolamine chloride (3HNMS) and the organ-bath procedure, respectively. The muscarinic receptor binding activities of solifenacin and imidafenacin in the rat brain increased when administered in combination with mirabegron. Moreover, the inhibitory effects of solifenacin and imidafenacin on carbachol-induced contractions in rat isolated bladder strips were increased by mirabegron, particularly at lower concentrations of solifenacin and imidafenacin. This is the first study to suggest that mirabegron in combination with antimuscarinics exerts additive effects for muscarinic receptor binding and inhibitory effects on cholinergic contractions in bladder strips. The results obtained also showed that these additive effects may contribute to enhanced therapeutic effects on OAB, but also cholinergic adverse effects.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"158 4","pages":"Pages 363-367"},"PeriodicalIF":3.0,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144279414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

HIF-1α stabilization in osteoclasts induces the expression of aerobic glycolysis-related proteins GLUT1, LDHA, and MCT4 破骨细胞中HIF-1α的稳定诱导了有氧糖酵解相关蛋白GLUT1、LDHA和MCT4的表达

IF 3 3区医学

Journal of pharmacological sciences Pub Date : 2025-05-26 DOI: 10.1016/j.jphs.2025.05.017

Tsuyoshi Nishioku, Sae Nakao, Rumi Anzai, Sami Hiramatsu, Akiko Momono, Miyu Moriyama, Mamiko Nakao, Ayaka Terazono

{"title":"HIF-1α stabilization in osteoclasts induces the expression of aerobic glycolysis-related proteins GLUT1, LDHA, and MCT4","authors":"Tsuyoshi Nishioku, Sae Nakao, Rumi Anzai, Sami Hiramatsu, Akiko Momono, Miyu Moriyama, Mamiko Nakao, Ayaka Terazono","doi":"10.1016/j.jphs.2025.05.017","DOIUrl":"10.1016/j.jphs.2025.05.017","url":null,"abstract":"<div><div>Hypoxia-inducible factor (HIF)-1α is a master transcription factor regulating hypoxic adaptation and activates the transcription of genes involved in various steps of energy metabolism. However, some subsets of cancer cells exhibit high HIF-1α levels regardless of the oxygen concentration. Even under normoxic and normoglycemic conditions, HIF-1α regulates basal expression of its target genes. Osteoclasts are giant multinucleated cells derived from the monocyte/macrophage lineage and are specialized in bone resorption. Excessive osteoclast resorbing activities is involved in destructive bone diseases. There are few data regarding how HIF-1α affects osteoclast differentiation. In this study, we investigated whether echinomycin, a HIF-1α inhibitor, reduced the expression of proteins of aerobic glycolysis, such as glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA), and monocarboxylate transporter 4 (MCT4), and whether HIF-1α stabilization is involved in osteoclast differentiation. HIF-1α was stabilized earlier than the upregulation of GLUT1, LDHA, and MCT4 expression during osteoclast differentiation. Echinomycin inhibited GLUT1, LDHA, and MCT4 expression. It also inhibited osteoclast differentiation and suppressed osteoclast bone-resorbing activity. We propose that HIF-1α inhibition suppresses excessive osteoclast differentiation and may represent a novel therapeutic strategy for controlling excessive bone resorption in osteoporosis and rheumatoid arthritis.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"158 4","pages":"Pages 336-342"},"PeriodicalIF":3.0,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144178600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Inhibitory effects of schisandrin A on contractions induced by spasmogenic candidates in porcine coronary arteries 五味子素A对猪冠状动脉痉挛候选物引起的收缩的抑制作用

IF 3 3区医学

Journal of pharmacological sciences Pub Date : 2025-05-24 DOI: 10.1016/j.jphs.2025.05.016

Qianghaodi Hong, Naho Takazakura, Hideaki Ozawa, Sakika Ichihara, Kento Yoshioka, Keisuke Obara, Yoshio Tanaka

{"title":"Inhibitory effects of schisandrin A on contractions induced by spasmogenic candidates in porcine coronary arteries","authors":"Qianghaodi Hong, Naho Takazakura, Hideaki Ozawa, Sakika Ichihara, Kento Yoshioka, Keisuke Obara, Yoshio Tanaka","doi":"10.1016/j.jphs.2025.05.016","DOIUrl":"10.1016/j.jphs.2025.05.016","url":null,"abstract":"<div><div>The inhibitory effects and underlying mechanisms of schisandrin A (SA) on contractions induced by spasmogenic candidates and related chemicals were investigated in porcine coronary arteries (PCAs). SA (10<sup>−5</sup>–10<sup>−4</sup> M) inhibited contractions induced by acetylcholine, histamine, serotonin, U46619 (thromboxane A<sub>2</sub> mimetic), prostaglandin F<sub>2α</sub>, and endothelin-1 in a concentration-dependent manner. The inhibition of acetylcholine-induced contractions by SA was stronger than that by diltiazem, although both SA and diltiazem ultimately achieved similar levels of inhibition against other contractions. SA also inhibited high-KCl-induced contractions in PCAs and suppressed high-KCl-induced increases in intracellular Ca<sup>2+</sup> concentrations in A7r5 cells. However, SA (10<sup>−4</sup> M) did not inhibit SKF-96365-sensitive phenylephrine-induced contractions, despite potently inhibiting high-KCl-induced contraction in the guinea pig thoracic aorta. SA did not strongly inhibit NaF-induced contractions in Ca<sup>2+</sup>-free solution containing 0.2 mM EGTA. Furthermore, SA inhibited muscarinic receptor binding in mouse cerebral cortex and inhibited carbachol-induced increases in intracellular Ca<sup>2+</sup> concentrations in 293T cells expressing muscarinic M<sub>3</sub> receptors. These findings indicate that SA inhibits coronary artery contractions induced by spasmogens primarily through the inhibition of L-type Ca<sup>2+</sup> channels (LCCs) and exerts an anticholinergic and LCC inhibitory effect on acetylcholine-induced contractions.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"158 4","pages":"Pages 343-352"},"PeriodicalIF":3.0,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144184402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Targeting CD38 to alleviate brain endothelial cell dysfunction and cognitive impairment in vascular dementia 靶向CD38缓解血管性痴呆患者脑内皮细胞功能障碍和认知障碍

IF 3 3区医学

Journal of pharmacological sciences Pub Date : 2025-05-21 DOI: 10.1016/j.jphs.2025.05.013

Mingjing Yu , Zhi Qi , Jiaxin Zhang , Ziyi Zhang , Jieli Chen , Tao Yan , Zhili Chen

{"title":"Targeting CD38 to alleviate brain endothelial cell dysfunction and cognitive impairment in vascular dementia","authors":"Mingjing Yu , Zhi Qi , Jiaxin Zhang , Ziyi Zhang , Jieli Chen , Tao Yan , Zhili Chen","doi":"10.1016/j.jphs.2025.05.013","DOIUrl":"10.1016/j.jphs.2025.05.013","url":null,"abstract":"<div><div>Vascular dementia (VaD) is a leading cause of cognitive decline, closely associated with cerebrovascular endothelial cell (CEC) dysfunction, blood-brain barrier (BBB) disruption, and neuroinflammation. CD38, an enzyme implicated in neuroinflammation and cellular senescence, has emerged as a potential regulator of these pathological processes, yet its role in CEC dysfunction within the context of VaD remains unclear. In this study, we investigated the impact of CD38 on CEC dysfunction using a mouse model of VaD induced by bilateral common carotid artery stenosis (BCAS). Our results demonstrate that BCAS significantly reduces cerebral blood flow (CBF), increases BBB permeability, and induces cognitive deficits, all accompanied by elevated CD38 expression in CECs and heightened levels of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α). Notably, treatment with the selective CD38 inhibitor 78c (10 mg/kg, twice daily for 1 month) effectively mitigated these effects, reducing white matter damage, improving CBF, enhancing the expression of CEC tight junction proteins, and decreasing neuroinflammation and BBB disruption. In vitro experiments further revealed that 78c attenuates TNF-α-induced CD38 expression and inflammatory responses in CECs, likely through the NOX4/eNOS aixs. These findings identify CD38 as a crucial mediator of CEC dysfunction in VaD, linking chronic cerebral hypoperfusion to neurovascular damage.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"158 4","pages":"Pages 310-321"},"PeriodicalIF":3.0,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144124443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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Inhibition of CYP1B1 by miR-200b-3p increases the sensitivity of paclitaxel in hepatocellular carcinoma treatment miR-200b-3p抑制CYP1B1可增加紫杉醇治疗肝癌的敏感性

IF 3 3区医学

Journal of pharmacological sciences Pub Date : 2025-05-21 DOI: 10.1016/j.jphs.2025.05.014

Jiaqi Wang , Jiayi Wu , Haihong Hu , Lushan Yu , Xiaoli Zheng , Su Zeng

引用次数: 0

Tomatidine attenuates post-stroke cognitive impairment by reducing neuroinflammation through prevention of M1 microglial polarization via NF-κB signaling 番茄碱通过NF-κB信号传导预防M1小胶质细胞极化，减轻神经炎症，从而减轻脑卒中后认知障碍

IF 3 3区医学

Journal of pharmacological sciences Pub Date : 2025-05-15 DOI: 10.1016/j.jphs.2025.05.011

Ayami Kita, Yuka Kawade, Haruyoshi Murakami, Rei Ikeda, Ryota Araki, Takeshi Yabe

{"title":"Tomatidine attenuates post-stroke cognitive impairment by reducing neuroinflammation through prevention of M1 microglial polarization via NF-κB signaling","authors":"Ayami Kita, Yuka Kawade, Haruyoshi Murakami, Rei Ikeda, Ryota Araki, Takeshi Yabe","doi":"10.1016/j.jphs.2025.05.011","DOIUrl":"10.1016/j.jphs.2025.05.011","url":null,"abstract":"<div><div>Post-stroke cognitive impairment (PSCI) is a clinical disorder that commonly occurs after a stroke and may persist long-term in most stroke survivors. Neuroinflammation involving proinflammatory M1 microglia, an activated microglial phenotype after stroke injury, is a major risk factor for PSCI. Tomatidine is a steroidal alkaloid of immature green tomatoes that has anti-inflammatory properties. To investigate the effects of tomatidine on cognitive impairment and microglial-associated neuroinflammation after stroke, we performed behavioral experiments and analyses on activated microglia in a transient bilateral common carotid arteries occlusion (tBCCAO) mouse model. Tomatidine attenuated cognitive impairment and neurodegeneration in the CA1 and CA3 hippocampal regions and reduced microglial activation and polarization into an M1 phenotype in the hippocampus in tBCCAO mice. The direct effect of tomatidine on polarization into the M1 phenotype was examined using LPS-stimulated BV2 microglia, as an M1 microglia model. Tomatidine reduced expression of M1 microglial markers and inflammatory mediators and inhibited nuclear translocation and phosphorylation of NF-κB in LPS-treated BV2 microglia. These results suggest that tomatidine suppresses microglial polarization into an M1 phenotype via modulation of NF-κB signaling, resulting in attenuation of neuroinflammation and reduction of PSCI.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"158 4","pages":"Pages 294-302"},"PeriodicalIF":3.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144105737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Ferulic acid suppresses guinea pig ileal longitudinal smooth muscle contractions by inhibiting voltage-dependent Ca2+ channels 阿魏酸通过抑制电压依赖性Ca2+通道抑制豚鼠回肠纵向平滑肌收缩

IF 3 3区医学

Journal of pharmacological sciences Pub Date : 2025-05-14 DOI: 10.1016/j.jphs.2025.05.012

Keisuke Obara , Kento Yoshioka , Aya Shimada, Sakika Ichihara, Wakaba Kinami, Futaba Makino, Naho Takazakura, Miwa Enomoto, Yoshio Tanaka

引用次数: 0

Exposure of Zinc-induced Parkinson's disease-like non-motor and motor symptoms in relation to oxidative/nitrosative stress mediated neurodegeneration in the brain of Drosophila melanogaster 暴露于锌诱导的帕金森病样非运动和运动症状与氧化/亚硝化应激介导的黑腹果蝇大脑神经变性有关

IF 3 3区医学

Journal of pharmacological sciences Pub Date : 2025-05-14 DOI: 10.1016/j.jphs.2025.05.010

Abhishek P.R. Nadiga , K.L. Krishna , Afrasim Moin , Amr Selim Abu Lila , Syed Mohd Danish Rizvi , Sahyadri M. , Suman Pathak , Shahanawaz Syed , El-Sayed Khafagy

{"title":"Exposure of Zinc-induced Parkinson's disease-like non-motor and motor symptoms in relation to oxidative/nitrosative stress mediated neurodegeneration in the brain of Drosophila melanogaster","authors":"Abhishek P.R. Nadiga , K.L. Krishna , Afrasim Moin , Amr Selim Abu Lila , Syed Mohd Danish Rizvi , Sahyadri M. , Suman Pathak , Shahanawaz Syed , El-Sayed Khafagy","doi":"10.1016/j.jphs.2025.05.010","DOIUrl":"10.1016/j.jphs.2025.05.010","url":null,"abstract":"<div><div>Parkinson's disease (PD) is the second most prevalent idiopathic neurodegenerative disorder, characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, leading to locomotor impairment. Despite extensive research, the etiology of PD remains unclear, and existing experimental models for pharmacological evaluation do not fully replicate the disease's hallmarks, necessitating the development of a cost-effective and reliable alternative. In recent past, Drosophila melanogaster has been utilized as a model organism for various neurodegenerative diseases, including PD. The present study was conceptualized to develop a reliable PD model in the Drosophila by Zinc (Zn<sup>+2</sup>).Chronic exposure to 20 mM Zn<sup>+2</sup> for 7 days exhibited non-motor and motor PD-like symptoms in adult Drosophila flies, with reduced locomotory activity, indicating motor function deficit and reduced olfactory function and courtship behavior, indicating a deficit in non-motor function. These behavioral symptoms were associated with decreased dopamine levels. Furthermore, chronic Zn<sup>+2</sup> exposure resulted in enhanced membrane lipid peroxidation and decreased endogenous antioxidants level in the Drosophila brain. These effects were primarily mediated by oxidative/nitrosative stress pathway. Thus, Zn<sup>2+</sup>-induced PD in Drosophila serves as a cost-effective model for drug discovery, facilitating the screening of potential therapeutic compounds. Additionally, this model offers a valuable platform to investigate the molecular mechanisms underlying PD pathophysiology.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"158 4","pages":"Pages 303-309"},"PeriodicalIF":3.0,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144124444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0