Journal of pharmacological sciences最新文献

Ameliorative effects of Kir4.1 channel inhibitors on lipopolysaccharide-induced cognitive impairment via BDNF/TrkB signaling pathway Kir4.1通道抑制剂通过BDNF/TrkB信号通路改善脂多糖诱导的认知功能障碍

IF 3 3区医学

Journal of pharmacological sciences Pub Date : 2025-07-15 DOI: 10.1016/j.jphs.2025.07.002

Yuto Ishizaki , Saki Shimizu , Ayana Kusaka, Akane Yoshida, Naofumi Kunisawa, Yukihiro Ohno

{"title":"Ameliorative effects of Kir4.1 channel inhibitors on lipopolysaccharide-induced cognitive impairment via BDNF/TrkB signaling pathway","authors":"Yuto Ishizaki , Saki Shimizu , Ayana Kusaka, Akane Yoshida, Naofumi Kunisawa, Yukihiro Ohno","doi":"10.1016/j.jphs.2025.07.002","DOIUrl":"10.1016/j.jphs.2025.07.002","url":null,"abstract":"<div><div>Inwardly rectifying potassium 4.1 (Kir4.1) channels are predominantly expressed in astrocytes and considered to be involved in the pathogenesis of brain diseases, including depression and epilepsy. In the present study, we evaluated the effects of Kir4.1 channel inhibitors, VU0134992 and quinacrine, on lipopolysaccharide (LPS)-induced cognitive impairment to clarify the role of Kir4.1 channels in controlling cognitive functions. Male BALB/c mice were treated with LPS, with or without Kir4.1 channel inhibitors, for 7 days. Animals were then subjected to novel object recognition (NOR) and rota-rod tests. Immunohistochemical analyses of glia fibrillary acid protein (GFAP) and neuronal nuclei (NeuN) were also performed. Treatment of LPS clearly showed cognitive impairment in the NOR test, which accompanied elevated GFAP- and reduced NeuN-immunoreactivity in hippocampal CA1 and CA3 regions. VU0134992 and quinacrine significantly ameliorated LPS-induced cognitive impairment without affecting rota-rod performance. In addition, both Kir4.1 channel inhibitors suppressed LPS-induced astrocyte activation and attenuated neuronal damage in CA1 and CA3 regions. Furthermore, combined treatments of ANA-12, a TrkB receptor antagonist, with VU0134992 suppressed the ameliorative effects of VU0134992 on cognitive impairment and hippocampal neuronal damage. These results suggest that blockade of astrocytic Kir4.1 channels ameliorates neuroinflammatory cognitive impairment via BDNF/TrkB signaling pathway.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"159 2","pages":"Pages 64-73"},"PeriodicalIF":3.0,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144662538","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

Early temporal suppression of SPARC inhibits oxidative stress, inflammation, and fibrosis in the chronic phase after renal ischemia/reperfusion 早期时间抑制SPARC可抑制肾缺血/再灌注后慢性期的氧化应激、炎症和纤维化

IF 3 3区医学

Journal of pharmacological sciences Pub Date : 2025-07-14 DOI: 10.1016/j.jphs.2025.07.003

Hiroe Toba , Denan Jin , Shinji Takai

{"title":"Early temporal suppression of SPARC inhibits oxidative stress, inflammation, and fibrosis in the chronic phase after renal ischemia/reperfusion","authors":"Hiroe Toba , Denan Jin , Shinji Takai","doi":"10.1016/j.jphs.2025.07.003","DOIUrl":"10.1016/j.jphs.2025.07.003","url":null,"abstract":"<div><div>Acute kidney injury is associated with not only high morbidity in the acute phase but also the development of chronic kidney disease (CKD). Recently, we found that suppression of secreted protein acidic and rich in cysteine (SPARC) exhibits renoprotective effects in acute ischemia/reperfusion (I/R) injury. The present study investigated the hypothesis that temporal suppression of SPARC in the early stages of I/R-injury might lead to the prevention of renal injury in the chronic phase. The left renal pedicle of male BALB/c mice was occluded for 45 min after right uninephrectomy and subsequently reperfused for 28 days. Small interfering RNA (siRNA) targeting SPARC was injected intravenously 1 day before and 3 days after I/R. Histological assessment revealed that SPARC knockdown by siRNA attenuated tubular injury, tubulointerstitial fibrosis, and the overexpression of 4-hydroxynonenal, a marker of lipid peroxidation. I/R-induced overexpression of a major source of superoxide NADPH oxidase, tumor necrosis factor-α, and matrix metalloproteinase-9 was suppressed by siRNA targeting SPARC. Treatment with siRNA targeting SPARC reduced the expression of a disintegrin and metalloproteinase with thrombospondin type 1 motif (ADAMTS1), which colocalizes with SPARC. In conclusion, SPARC might be a potential therapeutic target for preventing CKD development following acute I/R injury.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"159 2","pages":"Pages 57-63"},"PeriodicalIF":3.0,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144662537","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

TPNA10168, an Nrf2 activator, attenuates LPS-induced inflammation in microglia through modulation of MAPK and NF-κB pathways TPNA10168是一种Nrf2激活剂，通过调节MAPK和NF-κB通路，减轻lps诱导的小胶质细胞炎症

IF 3 3区医学

Journal of pharmacological sciences Pub Date : 2025-07-03 DOI: 10.1016/j.jphs.2025.07.001

Yasuhiko Izumi , Eri Koide , Fumika Kobayashi , Saori Ikawa , Midai Takayama , Kouya Yamaki , Norihiko Takeda , Takahiro Yamada , Masafumi Ueda , Toshiaki Kume , Yutaka Koyama

{"title":"TPNA10168, an Nrf2 activator, attenuates LPS-induced inflammation in microglia through modulation of MAPK and NF-κB pathways","authors":"Yasuhiko Izumi , Eri Koide , Fumika Kobayashi , Saori Ikawa , Midai Takayama , Kouya Yamaki , Norihiko Takeda , Takahiro Yamada , Masafumi Ueda , Toshiaki Kume , Yutaka Koyama","doi":"10.1016/j.jphs.2025.07.001","DOIUrl":"10.1016/j.jphs.2025.07.001","url":null,"abstract":"<div><div>The nuclear factor erythroid 2-related factor 2 (Nrf2)–antioxidant response element (ARE) pathway is a major cellular defense mechanism against oxidative stress through the induction of antioxidant proteins. Chemical inducers of Nrf2 often exhibit anti-inflammatory properties. TPNA10168, originally identified as an Nrf2–ARE activator, has previously been shown to attenuate interferon-γ-induced inflammatory responses in BV-2 microglial cells in an Nrf2-independent manner. However, its anti-inflammatory effects on primary microglia remain unclear. In this study, TPNA10168 significantly suppressed the lipopolysaccharide (LPS)-induced expression of inflammatory genes, including tumor necrosis factor-α, interleukin (IL)-1β, and IL-6, in primary microglia. The anti-inflammatory effects of TPNA10168 persisted even after Nrf2 knockdown. Mechanistic analysis revealed that TPNA10168 inhibited LPS-induced phosphorylation of extracellular signal-regulated kinase, p38 mitogen-activated protein kinase, and nuclear factor-κB (NF-κB) p65 without affecting NF-κB nuclear translocation. These findings indicate that TPNA10168 attenuates microglial activation by inhibiting proinflammatory signaling pathways, in part through Nrf2-independent pathways, and is a promising compound for modulating neuroinflammation.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"159 1","pages":"Pages 35-43"},"PeriodicalIF":3.0,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144572445","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

Formalizing and expanding our ethical framework: Introducing the comprehensive ethical guidelines for the Journal of Pharmacological Sciences 规范和扩展我们的伦理框架：为《药理学杂志》介绍全面的伦理准则

IF 3 3区医学

Journal of pharmacological sciences Pub Date : 2025-06-26 DOI: 10.1016/j.jphs.2025.06.007

Junko Kurokawa , Yuji Ikegaya , Tomoyuki Furuyashiki , Naohiko Anzai , Shuhei Tomita , Yasunari Kanda

引用次数: 0

SMTP-44D prevents negative symptoms of diabetic neuropathy by inhibiting sciatic nerve apoptosis SMTP-44D通过抑制坐骨神经凋亡来预防糖尿病神经病变的阴性症状

IF 3 3区医学

Journal of pharmacological sciences Pub Date : 2025-06-26 DOI: 10.1016/j.jphs.2025.06.006

Ayaka Aoki , Keita Shibata , Ryosuke Shinouchi , Keiji Hasumi , Koji Nobe

{"title":"SMTP-44D prevents negative symptoms of diabetic neuropathy by inhibiting sciatic nerve apoptosis","authors":"Ayaka Aoki , Keita Shibata , Ryosuke Shinouchi , Keiji Hasumi , Koji Nobe","doi":"10.1016/j.jphs.2025.06.006","DOIUrl":"10.1016/j.jphs.2025.06.006","url":null,"abstract":"<div><div>Diabetic neuropathy (DN) affects more than 50 % of patients with diabetes mellitus (DM). With progression, it causes negative symptoms characterized by sensory numbness. However, no effective treatment drug has been approved for the negative symptoms of DN. In this study, <em>Stachybotrys microspora</em> triprenyl phenol-44D (SMTP-44D), previously reported to inhibit apoptosis and ameliorate axonal damage in immortalized mouse Schwann cells treated with high glucose, was evaluated in a DN mouse model. Streptozocin (STZ)-induced DM models were treated with SMTP-44D for 49 days starting 8 days after STZ administration of SMTP-44D, and effects on mechanical and thermal thresholds, blood flow, and conduction velocity were evaluated. Epoxyeicosatrienoic acid (EET)/dihydroxyeicosatrienoic acid (DHET) measurements in serum, morphological changes in the sciatic nerve, immunohistochemistry, and TUNEL staining were performed to elucidate the mechanism of action. SMTP-44D improved the 11,12-EET/DHET decrease in serum and blood flow in the sciatic nerve. It inhibited sciatic nerve apoptosis and alleviated myelin thinning, thereby preserving the conduction velocity and showing dose-dependent improvements in mechanical and thermal threshold elevation. A hypoglycemic effect with long-term administration is suggested based on the findings. In conclusion, SMTP-44D is a promising therapeutic agent against the negative symptoms of DN.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"159 1","pages":"Pages 25-34"},"PeriodicalIF":3.0,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144502405","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

Phenylalanine amide derivatives promote FLG expression via AHR activation in normal human epidermal keratinocytes 苯丙酰胺衍生物通过AHR激活在正常人表皮角质形成细胞中促进FLG表达

IF 3 3区医学

Journal of pharmacological sciences Pub Date : 2025-06-23 DOI: 10.1016/j.jphs.2025.06.005

Akiko Sumitomo , Ratklao Siriwach , Makio Higuchi , Quynh Anh Ngo , Nobuo Tanaka , Somsak Prasongtanakij , Dean Thumkeo , Shuh Narumiya

{"title":"Phenylalanine amide derivatives promote FLG expression via AHR activation in normal human epidermal keratinocytes","authors":"Akiko Sumitomo , Ratklao Siriwach , Makio Higuchi , Quynh Anh Ngo , Nobuo Tanaka , Somsak Prasongtanakij , Dean Thumkeo , Shuh Narumiya","doi":"10.1016/j.jphs.2025.06.005","DOIUrl":"10.1016/j.jphs.2025.06.005","url":null,"abstract":"<div><div>Filaggrin (FLG) is one of the major components expressed in terminally differentiated keratinocytes and critical for skin barrier functions. It is known that reduced FLG expression causes skin barrier dysfunctions and results in atopic dermatitis (AD). Restoring FLG expression therefore may serve as an effective therapeutic strategy against AD. Using normal human epidermal keratinocyte (NHEK), we identified a phenylalanine amide derivative, termed Compound 8.1, that promotes expression of <em>FLG</em> and other skin barrier-related genes in NHEKs. Gene expression profiling by microarray suggested that Compound 8.1 promotes <em>FLG</em> expression through activation of the aryl hydrocarbon receptor (AHR). Interestingly, compared to a typical AHR activator, FICZ (6-Formylindolo[3,2-<em>b</em>]carbazole), Compound 8.1 preferentially upregulated the expression of genes related to keratinocyte differentiation and skin barrier function in an AHR-dependent manner, but induced a conventional AHR target gene involved in cellular toxicity, <em>CYP1A1</em>, to a significantly lesser extent. Structure-activity relationship analysis further demonstrates that the structural modification of Compound 8.1 could dissociate induction of skin barrier-related gene expression from <em>CYP1A1</em>-dependent metabolism of xenobiotics in AHR actions. Together, our results suggest that Compound 8.1 serves as a prototype compound for developing novel AHR-activating drugs to treat skin barrier dysfunctions without toxicity.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"159 1","pages":"Pages 44-53"},"PeriodicalIF":3.0,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144588369","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

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