Journal of pharmacological sciences最新文献_第4页

Medial prefrontal cortex inputs to the dorsomedial striatum regulate motivation for wheel running in male mice 内侧前额叶皮层对背内侧纹状体的输入调节雄性小鼠滚轮跑的动机

IF 3 3区医学

Journal of pharmacological sciences Pub Date : 2025-06-17 DOI: 10.1016/j.jphs.2025.06.004

Kazuhei Niitani , Ryoma Nishida , Yu Ogura , Naoya Nishitani, Satoshi Deyama, Katsuyuki Kaneda

{"title":"Medial prefrontal cortex inputs to the dorsomedial striatum regulate motivation for wheel running in male mice","authors":"Kazuhei Niitani , Ryoma Nishida , Yu Ogura , Naoya Nishitani, Satoshi Deyama, Katsuyuki Kaneda","doi":"10.1016/j.jphs.2025.06.004","DOIUrl":"10.1016/j.jphs.2025.06.004","url":null,"abstract":"<div><div>Wheel running is rewarding for rodents, and thus they exhibit strong willingness to engage in it and desire for it, i.e., motivation. Although neural activity in the dorsomedial striatum (DM-Str) has been suggested to be involved in motivation for wheel running, the causal relationship between neural activity and motivation remains unknown. Here, we investigated the role of neural activity in the DM-Str and the mechanisms regulating this activity in motivation for wheel running. Fiber photometry recordings with GCaMP sensors revealed that DM-Str neural activity transiently increased at the initiation of running on running wheels (RWs), whereas it decreased during running. Intra-DM-Str injection of the GABA<sub>A</sub> receptor agonist muscimol or the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist NBQX reduced the number of RW rotations. In the open field test, neither muscimol nor NBQX injection into the DM-Str affected locomotor activity. Additionally, selective chemogenetic inhibition of projections from the medial prefrontal cortex (mPFC) to the DM-Str reduced RW rotation numbers without altering locomotor activity. Together, our findings suggest that DM-Str neural activity, enhanced by glutamatergic projection from the mPFC, plays a critical role in regulating motivation for wheel running.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"159 1","pages":"Pages 1-7"},"PeriodicalIF":3.0,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144331446","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

Down-regulation of TNF-α/RIPK/Caspase-8 axis by combined infliximab and umbelliferone prevents unilateral ureter ligation-induced interstitial renal fibrosis 英夫利昔单抗联合umbelliferone下调TNF-α/RIPK/Caspase-8轴可预防单侧输尿管结扎引起的间质性肾纤维化

IF 3 3区医学

Journal of pharmacological sciences Pub Date : 2025-06-16 DOI: 10.1016/j.jphs.2025.06.003

Maha Habash , Zainab H. Almansour , Rasha K. Al-Akeel , Mohammad Bani Ismail , Duaa Althumairy , Hamad Abu Zahra , Tarek Hamdy Abd-Elhamid , Osama M. Ghogar , Mahmoud M. Ali , Mostafa K. Abd El-Aziz , Elham I. Sharab , Heba F. Khader , Amany Refaat Mahmoud , Fares E.M. Ali

{"title":"Down-regulation of TNF-α/RIPK/Caspase-8 axis by combined infliximab and umbelliferone prevents unilateral ureter ligation-induced interstitial renal fibrosis","authors":"Maha Habash , Zainab H. Almansour , Rasha K. Al-Akeel , Mohammad Bani Ismail , Duaa Althumairy , Hamad Abu Zahra , Tarek Hamdy Abd-Elhamid , Osama M. Ghogar , Mahmoud M. Ali , Mostafa K. Abd El-Aziz , Elham I. Sharab , Heba F. Khader , Amany Refaat Mahmoud , Fares E.M. Ali","doi":"10.1016/j.jphs.2025.06.003","DOIUrl":"10.1016/j.jphs.2025.06.003","url":null,"abstract":"<div><div>Obstructive nephropathy is a chronic condition that causes progressive kidney damage due to inflammation, oxidative stress, necroptosis, and fibrosis. The present study aimed to evaluate the potential chemopreventive effect of infliximab (TNF-α inhibitor) or umbelliferone (UMB, a natural antioxidant) individually and together to treat unilateral ureter ligation (UUL)-induced interstitial renal fibrosis in rats. The therapeutic effects were assessed through renal function biomarkers, histopathology, fibrosis, inflammation, oxidative stress, and necroptosis. UUL-induced renal injury led to increased serum biomarkers (urea, creatinine, uric acid), inflammation markers (TNF-α, NF-κB, IKK), oxidative stress (elevated NADPH oxidase and MDA, reduced Nrf2/HO-1, GSH, SOD), and necroptosis (upregulated RIPK1/RIPK3/p-RIPK3/MLKL/caspase-8), with substantial collagen deposition and fibrosis. Treatment with infliximab and UMB showed preventive effects by suppressing TNF-α signaling, reducing oxidative stress, and boosting antioxidant defense. Combined therapy provided superior results by downregulating TNF-α/RIPK/Caspase-8 pathways, enhancing Nrf2/HO-1 activity, reducing fibrosis, and restoring renal structure and function. Computational docking confirmed the ability of UMB to interact with TNF-α and RIPK3/MLKL binding sites. In conclusion, the combination of infliximab and UMB offers a promising multi-targeted approach to treat obstructive nephropathy and related chronic kidney diseases and highlights its potential to modulate key pathways involved in kidney fibrosis.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"159 1","pages":"Pages 8-20"},"PeriodicalIF":3.0,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144331447","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

Automated analysis of mouse rearing using deep learning 利用深度学习对老鼠饲养进行自动分析

IF 3 3区医学

Journal of pharmacological sciences Pub Date : 2025-06-13 DOI: 10.1016/j.jphs.2025.06.002

Naoaki Sakamoto , Masahiro Fukuda , Yusuke Miyazaki , Keisuke Omori , Koji Kobayashi , Takahisa Murata

引用次数: 0

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}

引用次数: 0

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