Journal of pharmacological sciences最新文献

{"title":"Centrally administered prostaglandin E2 suppresses the micturition reflex in rats","authors":"Takahiro Shimizu ,&nbsp;Nobutaka Shimizu ,&nbsp;Shun Tsubouchi ,&nbsp;Mio Togo ,&nbsp;Youichirou Higashi ,&nbsp;Motoaki Saito","doi":"10.1016/j.jphs.2025.05.005","DOIUrl":"10.1016/j.jphs.2025.05.005","url":null,"abstract":"<div><div>Prostaglandin E₂ (PGE₂) facilitates the micturition reflex at the lower urinary tract and spinal cord levels. However, the roles of brain PGE₂ in reflex regulation remain unclear. Therefore, we aimed to investigate the effects of intracerebroventricularly administered PGE₂ on the micturition reflex. We further investigated whether the PGE₂-induced responses were dependent on the sympathetic nervous system (SNS) and identified the brain E-prostanoid receptor subtypes (EP₁–EP₄) involved in PGE₂-induced effects. Intracerebroventricularly administered PGE₂ (0.1, 0.3, or 1 nmol/rat) dose-dependently increased the intercontraction intervals (ICI) and threshold pressure required to induce micturition (TP) without altering maximal voiding pressure in urethane-anesthetized (0.8 g/kg, ip) male rats. PGE₂ (1 nmol/rat) significantly increased the mean blood pressure; 6-hydroxydopamine-induced chemical sympathectomy ameliorated this increase. In contrast, chemical sympathectomy had no significant effect on the PGE₂-induced increases in ICI and TP. Intracerebroventricularly pretreated SC51322 (EP₁ receptor antagonist, 100 nmol/rat) and PF04418948 (EP₂ receptor antagonist, 100 nmol/rat), but not L-798106 (EP₃ receptor antagonist, 100 nmol/rat) or L-161982 (EP₄ receptor antagonist, 100 nmol/rat), significantly attenuated the PGE₂ (1 nmol/rat)-induced changes in ICI and TP. These results suggest that centrally administered PGE₂ suppresses the rat micturition reflex through brain EP₁ and EP₂ receptors, independent of SNS activation.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"158 3","pages":"Pages 231-237"},"PeriodicalIF":3.0,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143931633","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}

{"title":"Early neuromyelitis optica antibody-induced molecular changes in aquaporin 4 and associated proteins at astrocyte endfeet in murine brain tissues","authors":"Yumi Yoshikawa ,&nbsp;Masaki Tomioka ,&nbsp;Yoichiro Abe ,&nbsp;Masato Yasui ,&nbsp;Mutsuo Nuriya","doi":"10.1016/j.jphs.2025.05.007","DOIUrl":"10.1016/j.jphs.2025.05.007","url":null,"abstract":"<div><div>Neuromyelitis optica spectrum disorder (NMOSD) is characterized by the production of autoantibodies against aquaporin 4 (AQP4). Because NMOSD progressively causes irreversible and severe neurological damages, understanding the initial molecular changes induced by anti-AQP4 antibody binding is crucial for designing early interventions. However, knowledge about the effects of the antibodies before AQP4 loss in brain tissues is limited. Using acutely prepared mouse brain slices, we aimed to investigate the initial molecular impact of NMO model antibodies on AQP4 and its associated proteins. We employed two different types of NMO model antibodies, E5415A and E5415B; E5415A recognizes both M1 and M23 isoforms, whereas E5415B exclusively binds to M23. We found that E5415A but not E5415B disrupted the uniform perivascular localization of AQP4, leading to fragmentation. We further addressed the impact of these changes on AQP4-associated proteins and found that strong colocalizations between AQP4 and dystrophin-glycoprotein complex (DGC) components were preserved, even after AQP4 localization pattern became fragmented. Thus, our study reveals the initial molecular changes in the AQP4 channel at the astrocytic endfeet in response to NMO model antibodies and highlights the early pathological events occurring in NMOSD.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"158 3","pages":"Pages 212-218"},"PeriodicalIF":3.0,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143929572","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}

{"title":"A selective eukaryotic elongation factor 2 kinase inhibitor, A484954 lowered blood glucose in Zucker fatty diabetes mellitus rat","authors":"Ko Adachi,&nbsp;Tomoko Kodama,&nbsp;Kosuke Otani,&nbsp;Keito Sano,&nbsp;Asuka Sugiyama,&nbsp;Muneyoshi Okada,&nbsp;Hideyuki Yamawaki","doi":"10.1016/j.jphs.2025.05.006","DOIUrl":"10.1016/j.jphs.2025.05.006","url":null,"abstract":"<div><div>Eukaryotic elongation factor 2 kinase (eEF2K) is a protein kinase, regulating peptide translation. Zucker fatty diabetes mellitus (ZFDM) rat is a recently developed obesity and type 2 diabetes animal model with a missense mutation (<em>fa</em>) in leptin receptor gene (<em>Lepr</em>). ZFDM-<em>Lepr</em>^{<em>fa/fa</em>} rats (Homo) develop obesity and type 2 diabetes, while ZFDM-<em>Lepr</em>^{<em>fa/+</em>} rats (Hetero) are normal. The aim of this study was to determine effects of A484954 on glucose metabolism in ZFDM rats. A484954 (2.5 mg/kg) or carboxymethyl cellulose (CMC; 0.5 %), a vehicle was injected intraperitoneally for 15 days in 17–19-week-old rats. Compared with Hetero CMC, in Homo CMC; 1) blood and urine glucose levels were significantly elevated, 2) Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) was significantly elevated, 3) mRNA expression of sodium-glucose cotransporter (SGLT)2 in kidney tended to be elevated, while that of glucose transporter (GLUT)4 in vastus lateralis muscle decreased. Compared with Homo CMC, in Homo A484954; 1) blood glucose was significantly reduced, while urine glucose did not change, 2) HOMA-IR tended to decrease, 3) mRNA expression of SGLT2 in the kidney and GLUT4 in the muscle did not change. This study demonstrates for the first time that A484954 induces hypoglycemic effects in Homo partly via preventing insulin resistance.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"158 3","pages":"Pages 270-275"},"PeriodicalIF":3.0,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143935791","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}

{"title":"Ginkgolide B inhibits ferroptosis in PC12 cells and ameliorates the oxidative stress in spinal cord injury through activating Nrf2 signaling pathway","authors":"Wei She ,&nbsp;Wenji Ma ,&nbsp;Tongtong Zhang ,&nbsp;Xunian Wu ,&nbsp;Jianfu Li ,&nbsp;Xingyong Li","doi":"10.1016/j.jphs.2025.05.004","DOIUrl":"10.1016/j.jphs.2025.05.004","url":null,"abstract":"<div><div>Spinal cord injury (SCI) commonly leads to loss of motor and sensory function and results in huge socioeconomic burden, and it triggers numerous secondary pathological events, including oxidative stress and ferroptosis. This study investigates the therapeutic potential of Ginkgolide B (GB), a neuroprotective compound derived from <em>Ginkgo biloba</em>, in mitigating SCI by targeting on ferroptosis. By using Erastin-induced ferroptosis in PC12 cells and a rat contusion SCI model, the present study demonstrated that GB significantly improved locomotor recovery, reduced neuronal loss, and attenuated histopathological damage. Mechanistically, GB suppressed ferroptosis markers, including elevated iron content, lipid peroxidation, and ACSL4, while restoring the expression of GPX4 and xCT. Crucially, GB enhanced nuclear translocation of Nrf2, upregulating downstream antioxidants and ferroptosis-related genes (HO-1 and NQO1). Notably, the functions of GB were abolished after utilization of Nrf2 signaling inhibitor ML385 which revealed the role of GB on recovery of SCI was highly related to the activation of Nrf2 signaling. These findings reveal that GB alleviates SCI by inhibiting ferroptosis through Nrf2 activation, positioning it as a promising therapeutic agent. This study elucidates a novel mechanism linking Nrf2 signaling to ferroptosis suppression in SCI and provides a translational framework for repurposing GB in SCI treatment.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"158 3","pages":"Pages 199-206"},"PeriodicalIF":3.0,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143906313","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}

{"title":"Unravelling the effects of specific ingredients of kamishoyosan in reducing aggressive biting behavior in chronically isolated mice to inanimate objects","authors":"Kento Igarashi ,&nbsp;Satoshi Kuchiiwa ,&nbsp;Toshiko Kuchiiwa ,&nbsp;Tomoaki Sato","doi":"10.1016/j.jphs.2025.05.001","DOIUrl":"10.1016/j.jphs.2025.05.001","url":null,"abstract":"<div><div>Kamishoyosan (KSS) is a well-known traditional Japanese herbal medicine used to treat psychiatric symptoms, such as irritation. We previously reported that KSS decreases mouse aggressive biting behavior (ABB) to inanimate objects using the Aggression Response Meter, however, it was not revealed which ingredient of KSS is effective. In this study, we used real-time reverse transcriptase (RT) PCR to investigate the mRNA expression of 5-HT-related genes in SH-SY5Y cells cultured in a medium containing the ten individual herbal medicines in KSS. The cells treated with shakuyaku showed increase of tryptophan hydroxylase mRNA expression, whereas those cultured in a medium containing botanpi showed decreased monoamine oxidase A and B mRNA levels. We investigated the ABB of mice administered with <em>Paeonia lactiflora</em> (shakuyaku) or <em>Paeonia suffruticosa</em> (botanpi). We also examined the gene expression in cells treated with paeoniflorin (PF), a main active component in shakuyaku, and the ABB of PF-treated mice. We found that shakuyaku or PF administration reduced ABB in male and female mice, whereas botanpi treatment mitigated ABB only in males. WAY-100635, a 5-HT1A receptor antagonist, abolished ABB-reducing effect of shakuyaku and botanpi. These results suggest that shakuyaku and botanpi are activate ingredient to reduce ABB through activation on serotoninergic neurotransmission.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"158 3","pages":"Pages 259-269"},"PeriodicalIF":3.0,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143936647","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}

{"title":"Pedunculoside regulates the differentiation of neural stem cells into neurons via the PI3K/AKT/GSK-3β pathway","authors":"Ruichen Jiang ,&nbsp;Yuming Wang ,&nbsp;Yanzhu Shen ,&nbsp;Jiancheng Tang ,&nbsp;Xiangsheng Tang ,&nbsp;Haoning Ma ,&nbsp;Ping Yi","doi":"10.1016/j.jphs.2025.05.002","DOIUrl":"10.1016/j.jphs.2025.05.002","url":null,"abstract":"<div><div>The aging population has increased neurodegenerative diseases, yet current therapies mostly relieve symptoms rather than halt disease progression. Neural stem cells (NSCs) are crucial in nervous system development and repair, and research on their proliferation and differentiation regulation is vital. This study aimed to explore the effect of pedunculoside (PE) on primary NSCs and its mechanism. NSCs from pregnant rats (E13 - E14) were cultured and studied using CCK - 8, EDU incorporation, immunofluorescence, Western blot, and molecular docking. Results showed PE significantly promoted NSC proliferation at 10 μM and 20 μM dose - dependently. It also enhanced neuronal differentiation, with increased TUJ - 1 and decreased GFAP. Molecular docking and Western blot revealed PE binds to PI3K, activates the PI3K/AKT/GSK-3β pathway, and promotes protein phosphorylation. The PI3K inhibitor experiment confirmed PE's effect on NSC differentiation is mediated by this pathway. This study provides evidence for PE's role in NSC research and advances nervous system disease treatment research.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"158 3","pages":"Pages 276-282"},"PeriodicalIF":3.0,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143948132","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}

{"title":"A novel role of celecoxib in the inhibition of calcium-activated chloride channel ANO1","authors":"Ping Zhou ,&nbsp;Qinqin Li ,&nbsp;Xiangyu Li ,&nbsp;Yani Liu","doi":"10.1016/j.jphs.2025.05.003","DOIUrl":"10.1016/j.jphs.2025.05.003","url":null,"abstract":"<div><div>Celecoxib, a non-steroidal anti-inflammatory drug, is widely used in the clinic for its analgesic and anti-inflammatory effects by inhibiting COX-2. Celecoxib also modulates many ion channels including Nav1.5, Kv7 and Kv2.1 channels. Here we show a novel role of celecoxib in inhibiting calcium-activated chloride channel ANO1 that is involved in pain sensation. Celecoxib results in a concentration-dependent inhibition of ANO1 current with an IC₅₀ value of 20.3 ± 1.9 μM, and the residue P701 in the S7 is important for celecoxib-mediated ANO1 inhibition. These results suggest that ANO1 inhibition may contribute to celecoxib's analgesic and anti-inflammatory effects.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"158 3","pages":"Pages 207-211"},"PeriodicalIF":3.0,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143912560","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}

{"title":"Erratum to \"A novel lysophosphatidic acid receptor 1 antagonist with high brain penetrability has a curative effect in the empathic pain-related fibromyalgia model\" [J Pharmacol Sci (2025) 139-142].","authors":"Hiroyuki Neyama, Naoki Dozono, Yasuka Sahara, Kenji Nishikawa, Hiroshi Ueda","doi":"10.1016/j.jphs.2025.04.009","DOIUrl":"https://doi.org/10.1016/j.jphs.2025.04.009","url":null,"abstract":"","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143968514","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}

{"title":"Nerol enhances lipid synthesis in human sebocytes via cannabinoid receptor-2-mediated MAPK signaling","authors":"Qi Zhao ,&nbsp;Zhiwei Liu ,&nbsp;Yong Wang ,&nbsp;Tan Li ,&nbsp;Juan Wang ,&nbsp;Yaozhao Li ,&nbsp;Chengliang Li ,&nbsp;Chuntao Zhai ,&nbsp;Christos C. Zouboulis ,&nbsp;Xiaolei Ding ,&nbsp;Qiang Ju ,&nbsp;Zhenlin Hu","doi":"10.1016/j.jphs.2025.04.008","DOIUrl":"10.1016/j.jphs.2025.04.008","url":null,"abstract":"<div><h3>Purpose</h3><div>Nerol, a natural monoterpene, is commonly used as a fragrance additive in perfumes and cosmetics due to its pleasant rose-like aromas. Nerol application possesses diverse pharmacological properties, including anti-microbial, antioxidant, antinociceptive and anti-inflammatory activities, but its effects on sebum production and the consequent skin barrier function remain elusive. Here, we explored the effect of nerol on the lipogenesis of sebocytes.</div></div><div><h3>Patients and methods</h3><div>Immortalized human SZ95 sebocytes were used. The intracellular lipids were quantitatively measured by western blotting or fluorescent Nile Red staining followed by fluorometric analysis, semiquantitative detection or flow cytometry. The cell proliferation and differentiation were detected with CCK8 and flow cytometry, respectively. Moreover, RT-qPCR and immunocytochemistry were used to determine the expression levels of olfactory receptor OR2W3 and cannabinoid receptor-2 (CB2) receptors in SZ95 sebocytes.The mechanism was investigated by RNA interference and Western blotting.</div></div><div><h3>Results</h3><div>Our findings revealed that nerol induced lipid production in SZ95 sebocytes, together with the upregulation of multiple genes related to lipid synthesis, including PPARγ, SREBP-1, and FAS. Nerol also induced sebocyte differentiation, as evidenced by elevated cellular granulation and upregulated differentiation marker genes. Mechanistically, the lipogenic effect of nerol was mediated via CB2, rather than OR2W3 and TRP channels. Moreover, MAPK signaling was involved in neurol's effect.</div></div><div><h3>Conclusion</h3><div>Collectively, our findings show that nerol exerts a lipogenic effect on human sebocytes in a CB2-dependent manner through the activation of MAPK pathway, suggesting the therapeutic potential of this monoterpene in controlling cutaneous disorders involving sebaceous gland dysfunction and reduced sebum production, such as atopic dermatitis, skin dryness and aging.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"158 3","pages":"Pages 219-230"},"PeriodicalIF":3.0,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143929574","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}

{"title":"Diurnal variations of neurokinin-1 receptor defines dosing time-dependent differences in antitumor effects of aprepitant in mice","authors":"Yoshihiro Seto ,&nbsp;Shun Tokeshi ,&nbsp;Daisuke Inoue ,&nbsp;Fumiyasu Okazaki ,&nbsp;Hideto To","doi":"10.1016/j.jphs.2025.04.007","DOIUrl":"10.1016/j.jphs.2025.04.007","url":null,"abstract":"<div><div>Aprepitant, a neurokinin-1 receptor (NK1R) antagonist, has the potential as a novel anticancer agent. This study explored the impact of chronotherapy on the antitumor effect of aprepitant in a mouse model of colorectal carcinoma. Aprepitant inhibited the proliferation of Colon-26 cells <em>in vitro</em> in a concentration-dependent manner and reduced the expression of cell cycle-related genes. Diurnal variations in NK1R mRNA and protein levels were observed in Colon-26 tumors, peaking at zeitgeber time (ZT) 2 and ZT 10, respectively. Administration of aprepitant at ZT 6, achieving peak plasma concentration at ZT 10, significantly reduced the tumor volume compared with administration at ZT 18. Despite the lower plasma concentrations and AUC_0–12 h in the ZT 6 group, superior antitumor effect suggests a dosing time-dependent efficacy due to variations in NK1R expression rather than its pharmacokinetics. These findings indicate that the antitumor activity of aprepitant against colorectal cancer can be enhanced by aligning its administration with NK1R expression rhythms, warranting further exploration of aprepitant chronotherapy in cancer chemotherapy.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"158 3","pages":"Pages 193-198"},"PeriodicalIF":3.0,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143879123","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}