TMEM16A channels mediate Ca2+-activated Cl− (ClCa) currents in vascular smooth muscle cells (VSMCs), and their activity is influenced by cytoskeletal dynamics. The present study examined the functional role of microtubules in TMEM16A regulation. Treatment with microtubule polymerization inhibitors, colchicine and nocodazole, reduced plasma membrane localization of TMEM16A protein and TMEM16A-mediated ClCa currents. Similar effects were observed in TMEM16A-expressing HEK293 cells, with IC50 values of 3.0 μM for colchicine and 0.6 μM for nocodazole. In contrast, acute application had no significant effect. These findings indicate that microtubules are required for maintaining the expression and functional activity of TMEM16A channels in VSMCs.
{"title":"Microtubule-dependent regulation of TMEM16A-mediated Ca2+-activated Cl− currents in vascular smooth muscle cells","authors":"Ryosuke Hemmi , Akane Suzukawa , Moe Fujiwara , Rubii Kondo , Yoshiaki Suzuki , Aya Yamamura , Hisao Yamamura","doi":"10.1016/j.jphs.2025.09.001","DOIUrl":"10.1016/j.jphs.2025.09.001","url":null,"abstract":"<div><div>TMEM16A channels mediate Ca<sup>2+</sup>-activated Cl<sup>−</sup> (Cl<sub>Ca</sub>) currents in vascular smooth muscle cells (VSMCs), and their activity is influenced by cytoskeletal dynamics. The present study examined the functional role of microtubules in TMEM16A regulation. Treatment with microtubule polymerization inhibitors, colchicine and nocodazole, reduced plasma membrane localization of TMEM16A protein and TMEM16A-mediated Cl<sub>Ca</sub> currents. Similar effects were observed in TMEM16A-expressing HEK293 cells, with IC<sub>50</sub> values of 3.0 μM for colchicine and 0.6 μM for nocodazole. In contrast, acute application had no significant effect. These findings indicate that microtubules are required for maintaining the expression and functional activity of TMEM16A channels in VSMCs.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"159 3","pages":"Pages 202-207"},"PeriodicalIF":2.9,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145026571","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}
GPR35 is involved in the pathogenesis of colitis. However, because GPR35 is expressed in colonic epithelial and inflammatory/immune cells, its precise protective mechanisms remain unclear. We investigated the role of GPR35 in colitis, especially its relation to epithelial barrier function and inflammatory/immune responses.
Methods
We performed GPR35 knockout (KO) in a dextran sodium sulfate (DSS)-induced murine colitis model and elucidated the role of GPR35 through various experiments, including histological analysis, intestinal permeability, immunohistochemical staining, RT-qPCR, and western blotting.
Results
GPR35KO mice exhibited significantly exacerbated DSS-induced colitis, accompanied by upregulation of cytokines, compared with wild-type (WT) mice. An investigation using bone marrow (BM)-chimeric mice revealed that GPR35KO, which is expressed in both hematopoietic and non-hematopoietic cells, contributed to this exacerbation. GPR35KO mice showed significantly increased intestinal permeability compared with WT mice under normal conditions. Although no differences were observed in goblet cell number or epithelial proliferation between WT and GPR35KO mice, the expression levels of intercellular junction proteins were significantly lower in the normal colons of GPR35KO mice. Lipopolysaccharide-stimulated cytokine expression was significantly enhanced in BM-derived macrophages obtained from GPR35KO mice compared with WT mice.
Conclusions
GPR35 contributes to colonic protection by regulating epithelial barrier function and inflammatory/immune responses.
{"title":"Protective role of orphan G protein-coupled receptor GPR35 in the pathogenesis of colitis through regulating epithelial barrier function and immune responses","authors":"Koga Tokuyama , Hiroyuki Yasuda , Michiko Saito , Shusaku Hayashi , Shinichi Kato","doi":"10.1016/j.jphs.2025.08.009","DOIUrl":"10.1016/j.jphs.2025.08.009","url":null,"abstract":"<div><h3>Background and objective</h3><div>GPR35 is involved in the pathogenesis of colitis. However, because GPR35 is expressed in colonic epithelial and inflammatory/immune cells, its precise protective mechanisms remain unclear. We investigated the role of GPR35 in colitis, especially its relation to epithelial barrier function and inflammatory/immune responses.</div></div><div><h3>Methods</h3><div>We performed GPR35 knockout (KO) in a dextran sodium sulfate (DSS)-induced murine colitis model and elucidated the role of GPR35 through various experiments, including histological analysis, intestinal permeability, immunohistochemical staining, RT-qPCR, and western blotting.</div></div><div><h3>Results</h3><div>GPR35KO mice exhibited significantly exacerbated DSS-induced colitis, accompanied by upregulation of cytokines, compared with wild-type (WT) mice. An investigation using bone marrow (BM)-chimeric mice revealed that GPR35KO, which is expressed in both hematopoietic and non-hematopoietic cells, contributed to this exacerbation. GPR35KO mice showed significantly increased intestinal permeability compared with WT mice under normal conditions. Although no differences were observed in goblet cell number or epithelial proliferation between WT and GPR35KO mice, the expression levels of intercellular junction proteins were significantly lower in the normal colons of GPR35KO mice. Lipopolysaccharide-stimulated cytokine expression was significantly enhanced in BM-derived macrophages obtained from GPR35KO mice compared with WT mice.</div></div><div><h3>Conclusions</h3><div>GPR35 contributes to colonic protection by regulating epithelial barrier function and inflammatory/immune responses.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"159 3","pages":"Pages 191-201"},"PeriodicalIF":2.9,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145026570","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}
Pub Date : 2025-08-25DOI: 10.1016/j.jphs.2025.08.008
Tsugunobu Andoh
This study investigated whether tachykinin NK1 receptor antagonist aprepitant (APT) inhibits oxaliplatin (OXP)-induced cutaneous mast cell migration in mice. OXP-induced mast cell migration was inhibited by repeated oral administration of APT. OXP increased the expression of monocyte chemotactic protein-1 (MCP-1), stem cell factor (SCF), and interleukin-3 (IL-3), but not platelet-derived endothelial cell growth factor in the plantar skin. APT inhibited OXP-induced MCP-1, but not IL-3, expression. The expression of SCF tended to be inhibited by APT. These results suggest that APT attenuates OXP-induced cutaneous mast cell migration mainly by inhibiting the expression of MCP-1 and SCF.
{"title":"Aprepitant attenuates cutaneous mast cell migration in oxaliplatin-treated mice","authors":"Tsugunobu Andoh","doi":"10.1016/j.jphs.2025.08.008","DOIUrl":"10.1016/j.jphs.2025.08.008","url":null,"abstract":"<div><div>This study investigated whether tachykinin NK1 receptor antagonist aprepitant (APT) inhibits oxaliplatin (OXP)-induced cutaneous mast cell migration in mice. OXP-induced mast cell migration was inhibited by repeated oral administration of APT. OXP increased the expression of monocyte chemotactic protein-1 (MCP-1), stem cell factor (SCF), and interleukin-3 (IL-3), but not platelet-derived endothelial cell growth factor in the plantar skin. APT inhibited OXP-induced MCP-1, but not IL-3, expression. The expression of SCF tended to be inhibited by APT. These results suggest that APT attenuates OXP-induced cutaneous mast cell migration mainly by inhibiting the expression of MCP-1 and SCF.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"159 3","pages":"Pages 159-162"},"PeriodicalIF":2.9,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144903647","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}
The development of targeted anti-epilepsy drugs is crucial, as 30 % of patients with epilepsy are resistant to current therapeutics. Transient receptor potential vanilloid 1 (TRPV1) channel antagonists have been demonstrated to suppress drug-induced epileptiform discharges (EDs) and seizures (ESs). Here, we investigated the correlation between the anti-epileptiform efficacy of AMG9810 and extracellular glutamate levels. The somatosensory cortices of male C57BL/6N mice were intracortically injected with penicillin G (PG: 200 IU, 1 μL/10 min), a seizure inducer that inhibits the GABAA receptor. The mice were intracortically injected with AMG9810 (3 μM, 1 μL/10 min) either before or after PG administration. EDs, ESs, and glutamate levels were subsequently evaluated. The results of each experiment were compared between the vehicle and AMG9810-injected groups. AMG9810 injected after PG reduced glutamate levels and ED power, and there was a positive correlation between AMG9810 efficacy and these parameters. Injecting AMG9810 before PG injection decreased the increase in glutamate levels and development of EDs and ESs, with positive correlations observed among the three parameters. These findings suggest that TRPV1 antagonists suppress the development of EDs and ESs by decreasing extracellular glutamate levels, indicating that TRPV1 channels may represent a promising treatment option for epilepsy.
{"title":"TRPV1 antagonist AMG9810 suppresses focal epileptiform discharges and seizures by decreasing extracellular glutamate concentrations in mice","authors":"Hiroshi Moriyama , Hirochika Imoto , Sadahiro Nomura , Naomasa Mori , Yuichi Maruta , Natsumi Fujii , Shunsuke Fujitsuku , Hideyuki Ishihara","doi":"10.1016/j.jphs.2025.08.007","DOIUrl":"10.1016/j.jphs.2025.08.007","url":null,"abstract":"<div><div>The development of targeted anti-epilepsy drugs is crucial, as 30 % of patients with epilepsy are resistant to current therapeutics. Transient receptor potential vanilloid 1 (TRPV1) channel antagonists have been demonstrated to suppress drug-induced epileptiform discharges (EDs) and seizures (ESs). Here, we investigated the correlation between the anti-epileptiform efficacy of AMG9810 and extracellular glutamate levels. The somatosensory cortices of male C57BL/6N mice were intracortically injected with penicillin G (PG: 200 IU, 1 μL/10 min), a seizure inducer that inhibits the GABA<sub>A</sub> receptor. The mice were intracortically injected with AMG9810 (3 μM, 1 μL/10 min) either before or after PG administration. EDs, ESs, and glutamate levels were subsequently evaluated. The results of each experiment were compared between the vehicle and AMG9810-injected groups. AMG9810 injected after PG reduced glutamate levels and ED power, and there was a positive correlation between AMG9810 efficacy and these parameters. Injecting AMG9810 before PG injection decreased the increase in glutamate levels and development of EDs and ESs, with positive correlations observed among the three parameters. These findings suggest that TRPV1 antagonists suppress the development of EDs and ESs by decreasing extracellular glutamate levels, indicating that TRPV1 channels may represent a promising treatment option for epilepsy.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"159 3","pages":"Pages 163-171"},"PeriodicalIF":2.9,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144903646","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}
Oxytocin (OXT) is a neuropeptide known for its anti-inflammatory and neuroprotective properties; however, its role in post-stroke recovery remains poorly defined. In this study, we investigated whether intranasal OXT administration during the subacute phase of stroke improves neurological outcomes and modulates microglial responses. Male mice underwent permanent middle cerebral artery occlusion and received intranasal OXT (300 ng/g) or saline on days 3 and 5 post-stroke. Neurological function was assessed using the modified neurological severity score; infarct volume was evaluated through hematoxylin-eosin (HE) staining, and survival rates were monitored until day 7. Immunofluorescence was used to assess microglial polarization in the peri-infarct region. OXT-treated mice showed significantly greater functional improvement and higher survival rates than saline-treated controls. Infarct volume was significantly reduced, and microglial polarization was altered by OXT, with a decrease in pro-inflammatory M1-type markers and an increase in anti-inflammatory M2-type markers. These findings demonstrate that OXT promotes neurological recovery through anti-inflammatory and neuroprotective mechanisms. Given its feasibility as a non-invasive delivery method, intranasal OXT may offer a promising therapeutic approach to enhance post-stroke neurorepair.
{"title":"Subacute intranasal oxytocin improves neurological recovery after ischemic stroke","authors":"Yusuke Morishita , Youichirou Higashi , Daichi Tani , Mio Togo , Takahiro Shimizu , Mikiya Fujieda , Motoaki Saito","doi":"10.1016/j.jphs.2025.08.006","DOIUrl":"10.1016/j.jphs.2025.08.006","url":null,"abstract":"<div><div>Oxytocin (OXT) is a neuropeptide known for its anti-inflammatory and neuroprotective properties; however, its role in post-stroke recovery remains poorly defined. In this study, we investigated whether intranasal OXT administration during the subacute phase of stroke improves neurological outcomes and modulates microglial responses. Male mice underwent permanent middle cerebral artery occlusion and received intranasal OXT (300 ng/g) or saline on days 3 and 5 post-stroke. Neurological function was assessed using the modified neurological severity score; infarct volume was evaluated through hematoxylin-eosin (HE) staining, and survival rates were monitored until day 7. Immunofluorescence was used to assess microglial polarization in the peri-infarct region. OXT-treated mice showed significantly greater functional improvement and higher survival rates than saline-treated controls. Infarct volume was significantly reduced, and microglial polarization was altered by OXT, with a decrease in pro-inflammatory M1-type markers and an increase in anti-inflammatory M2-type markers. These findings demonstrate that OXT promotes neurological recovery through anti-inflammatory and neuroprotective mechanisms. Given its feasibility as a non-invasive delivery method, intranasal OXT may offer a promising therapeutic approach to enhance post-stroke neurorepair.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"159 3","pages":"Pages 151-158"},"PeriodicalIF":2.9,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144903632","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}
Pub Date : 2025-08-21DOI: 10.1016/j.jphs.2025.08.005
Jingwei Liu , Cheng Qiu , Xiaoxiong Wang , Ziqian Xiang , Junyuan Sun , Mingzheng Chang , Qingliang Ma , Yan Zhuang , Yunpeng Zhao , Qiang Yang , Lianlei Wang , Xinyu Liu
Fracture is a common type of traumas and alternative therapies to boost bone fracture healing is necessary. The aim of this study is to elucidate the role of sulfasalazine in bone fracture healing by using MC3T3-E1 cells in vitro and murine femoral fracture model in vivo. Western blotting, flow cytometry, RNA sequencing, Calcein AM/PI staining, Alizarin-Red-S staining, ALP activity assay, transmission electron microscope, histological staining, immunohistochemistry, immunofluorescence and Surface plasmon resonance analysis were performed in this study. Sulfasalazine failed to elicit ferroptosis in osteoblasts within acceptable dose manner while promoted osteogenic differentiation. Furthermore, sulfasalazine was identified to inhibit inflammation by declination of inflammatory biomarkers. Besides, TNFα was verified as a potential downstream target for sulfasalazine and the adverse effect of TNFα on osteogenic differentiation could be largely salvaged by sulfasalazine due to direct binding between these two molecules. RNA-seq further implied decreased transcription of genes related to NF-κB pathway. Murine study showed sulfasalazine promotes fracture healing as evidenced by increased bone remodeling both histologically and radiologically. Overall, sulfasalazine accelerates osteogenic differentiation and promotes bone healing by direct binding to and thus inhibiting TNFα, which subsequently suppresses NF-κB signaling. Therefore, sulfasalazine shows a promising outcome for the treatment of bone fracture.
{"title":"Sulfasalazine disrupts the interaction between TNFα and TNFR1 thus inhibiting NF-kB signaling activation to promote bone fracture healing","authors":"Jingwei Liu , Cheng Qiu , Xiaoxiong Wang , Ziqian Xiang , Junyuan Sun , Mingzheng Chang , Qingliang Ma , Yan Zhuang , Yunpeng Zhao , Qiang Yang , Lianlei Wang , Xinyu Liu","doi":"10.1016/j.jphs.2025.08.005","DOIUrl":"10.1016/j.jphs.2025.08.005","url":null,"abstract":"<div><div>Fracture is a common type of traumas and alternative therapies to boost bone fracture healing is necessary. The aim of this study is to elucidate the role of sulfasalazine in bone fracture healing by using MC3T3-E1 cells in vitro and murine femoral fracture model in vivo. Western blotting, flow cytometry, RNA sequencing, Calcein AM/PI staining, Alizarin-Red-S staining, ALP activity assay, transmission electron microscope, histological staining, immunohistochemistry, immunofluorescence and Surface plasmon resonance analysis were performed in this study. Sulfasalazine failed to elicit ferroptosis in osteoblasts within acceptable dose manner while promoted osteogenic differentiation. Furthermore, sulfasalazine was identified to inhibit inflammation by declination of inflammatory biomarkers. Besides, TNFα was verified as a potential downstream target for sulfasalazine and the adverse effect of TNFα on osteogenic differentiation could be largely salvaged by sulfasalazine due to direct binding between these two molecules. RNA-seq further implied decreased transcription of genes related to NF-κB pathway. Murine study showed sulfasalazine promotes fracture healing as evidenced by increased bone remodeling both histologically and radiologically. Overall, sulfasalazine accelerates osteogenic differentiation and promotes bone healing by direct binding to and thus inhibiting TNFα, which subsequently suppresses NF-κB signaling. Therefore, sulfasalazine shows a promising outcome for the treatment of bone fracture.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"159 3","pages":"Pages 139-150"},"PeriodicalIF":2.9,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144902645","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}
Pub Date : 2025-08-21DOI: 10.1016/j.jphs.2025.08.003
Yu-fei Li , Ao Sun , Yang Miao , Hong-xia Wang , Lin-lin Zhang
Sepsis, a life-threatening organ dysfunction syndrome triggered by infection, is characterized by complex pathophysiology involving dysregulated inflammation, coagulation abnormalities, and mitochondrial dysfunction. Excessive activation of the NLRP3 inflammasome plays a pivotal role in sepsis progression. This study investigated the therapeutic effects and underlying mechanisms of protocatechuic aldehyde (PCA) in sepsis. Seventy-five potential PCA targets for sepsis were identified, with KEGG enrichment highlighting involvement in inflammatory and apoptotic pathways. PPI network analysis pinpointed TNF, IL-6, and IL-1β as key inflammatory targets. PCA dose-dependently suppressed IL-1β and TNF-α release in LPS/ATP-stimulated macrophages, reduced ASC speck formation and NLRP3-ASC interaction, and decreased mt-ROS production and TXNIP-NLRP3 co-localization. PCA also preserved mitochondrial network integrity by interacting with mitochondrial dynamics proteins DRP1 and MFN2, improving mitochondrial membrane potential and morphology. In LPS-induced septic mice, PCA significantly reduced serum IL-1β and TNF-α levels, improved survival rates, and downregulated NLRP3, pro-IL-1β, and cleaved-IL-1β expression in peritoneal macrophages. PCA alleviates inflammatory responses and organ damage in septic mice by inhibiting the mt-ROS/TXNIP/NLRP3 signaling axis and maintaining mitochondrial function, offering a promising natural therapeutic candidate for sepsis.
{"title":"Protocatechuic aldehyde restrains NLRP3 inflammasome activation to alleviate inflammatory response in sepsis","authors":"Yu-fei Li , Ao Sun , Yang Miao , Hong-xia Wang , Lin-lin Zhang","doi":"10.1016/j.jphs.2025.08.003","DOIUrl":"10.1016/j.jphs.2025.08.003","url":null,"abstract":"<div><div>Sepsis, a life-threatening organ dysfunction syndrome triggered by infection, is characterized by complex pathophysiology involving dysregulated inflammation, coagulation abnormalities, and mitochondrial dysfunction. Excessive activation of the NLRP3 inflammasome plays a pivotal role in sepsis progression. This study investigated the therapeutic effects and underlying mechanisms of protocatechuic aldehyde (PCA) in sepsis. Seventy-five potential PCA targets for sepsis were identified, with KEGG enrichment highlighting involvement in inflammatory and apoptotic pathways. PPI network analysis pinpointed TNF, IL-6, and IL-1β as key inflammatory targets. PCA dose-dependently suppressed IL-1β and TNF-α release in LPS/ATP-stimulated macrophages, reduced ASC speck formation and NLRP3-ASC interaction, and decreased mt-ROS production and TXNIP-NLRP3 co-localization. PCA also preserved mitochondrial network integrity by interacting with mitochondrial dynamics proteins DRP1 and MFN2, improving mitochondrial membrane potential and morphology. In LPS-induced septic mice, PCA significantly reduced serum IL-1β and TNF-α levels, improved survival rates, and downregulated NLRP3, pro-IL-1β, and cleaved-IL-1β expression in peritoneal macrophages. PCA alleviates inflammatory responses and organ damage in septic mice by inhibiting the mt-ROS/TXNIP/NLRP3 signaling axis and maintaining mitochondrial function, offering a promising natural therapeutic candidate for sepsis.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"159 3","pages":"Pages 172-183"},"PeriodicalIF":2.9,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144908020","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}
Pub Date : 2025-08-20DOI: 10.1016/j.jphs.2025.08.004
Maria Campanile , Kaitlin Castell , Justin O. Pampalone , Bruno Carabelli , Irwin Lucki , Caroline A. Browne
Chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating side effect of a number of anticancer drugs, like oxaliplatin, leading to chronic sensory hypersensitivity and neuropathic pain. This study investigated the efficacy of (2R,6R)-hydroxynorketamine ((2R,6R)-HNK), a metabolite of ketamine, in a rat model of CIPN induced by oxaliplatin. Rats treated with oxaliplatin developed long-lasting mechanical and thermal hypersensitivity, as assessed by the Von Frey test and the hot plate test, respectively. A single injection of (2R,6R)-HNK (30 mg/kg, s.c.) significantly reversed both mechanical and thermal hypersensitivity for up to 24 h. Furthermore, repeated treatment with (2R,6R)-HNK (30 mg/kg/day) for 7 days produced sustained analgesia on mechanical hypersensitivity that persisted up to 14 days after treatment cessation. In comparison, repeated duloxetine (15 mg/kg/day, s.c.) showed only a short-lasting reduction of thermal hypersensitivity and no effect on mechanical hypersensitivity. Locomotor activity was not affected by (2R,6R)-HNK treatment, although duloxetine caused a transient decrease. This is the first demonstration that (2R,6R)-HNK produced analgesia in a rat model of CIPN. The persistence of analgesia with repeated treatment and sustained effects following treatment cessation suggests that (2R,6R)-HNK may represent a promising new therapeutic strategy for the rapid and sustained relief of pain associated with CIPN.
{"title":"(2R,6R)-hydroxynorketamine reverses mechanical and thermal pain hypersensitivity produced by the chemotherapeutic agent oxaliplatin in rats","authors":"Maria Campanile , Kaitlin Castell , Justin O. Pampalone , Bruno Carabelli , Irwin Lucki , Caroline A. Browne","doi":"10.1016/j.jphs.2025.08.004","DOIUrl":"10.1016/j.jphs.2025.08.004","url":null,"abstract":"<div><div>Chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating side effect of a number of anticancer drugs, like oxaliplatin, leading to chronic sensory hypersensitivity and neuropathic pain. This study investigated the efficacy of (2R,6R)-hydroxynorketamine ((2R,6R)-HNK), a metabolite of ketamine, in a rat model of CIPN induced by oxaliplatin. Rats treated with oxaliplatin developed long-lasting mechanical and thermal hypersensitivity, as assessed by the Von Frey test and the hot plate test, respectively. A single injection of (2R,6R)-HNK (30 mg/kg, s.c.) significantly reversed both mechanical and thermal hypersensitivity for up to 24 h. Furthermore, repeated treatment with (2R,6R)-HNK (30 mg/kg/day) for 7 days produced sustained analgesia on mechanical hypersensitivity that persisted up to 14 days after treatment cessation. In comparison, repeated duloxetine (15 mg/kg/day, s.c.) showed only a short-lasting reduction of thermal hypersensitivity and no effect on mechanical hypersensitivity. Locomotor activity was not affected by (2R,6R)-HNK treatment, although duloxetine caused a transient decrease. This is the first demonstration that (2R,6R)-HNK produced analgesia in a rat model of CIPN. The persistence of analgesia with repeated treatment and sustained effects following treatment cessation suggests that (2R,6R)-HNK may represent a promising new therapeutic strategy for the rapid and sustained relief of pain associated with CIPN.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"159 3","pages":"Pages 184-190"},"PeriodicalIF":2.9,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144917546","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}
Object recognition memory encourages animals to distinguish between new and known objects, supported by neural activity in the hippocampus, prefrontal cortex, and perirhinal cortex. Theanine, a non-proteinogenic amino acid derivative from green tea leaves, enhances object recognition memory in rats through facilitated neurogenesis. Although the cellular mechanism for the theanine-enhanced object recognition memory has been elucidated to some extent, physiological evidence still remains unclear. To tackle this issue, we chronically fed mice with theanine (or tap water) for three weeks, implanted electrodes into the hippocampus and frontal cortex, both of which are responsible for object recognition memory. We then recorded the local field potentials from the two regions during the novel object recognition task, evaluated the memory performance, and broke down the neural signals in the hippocampus and frontal cortex into delta, theta, beta, low gamma, and high gamma frequency bands. The memory performance of theanine-treated mice was higher than that of vehicle-treated mice. We also found that theta oscillations in the frontal cortex and beta and low gamma oscillations in the hippocampus in theanine-treated mice were simultaneously enhanced for familiar objects. These results shed light on the new physiological underpinnings of object recognition memory enhanced by exogenous substances.
{"title":"Theanine boosts frontal theta and hippocampal beta and gamma oscillations for familiarity in object recognition","authors":"Kisa Watanabe , Kinjiro Takeda , Takeshi Nagahiro , Sena Iijima , Yuji Ikegaya , Nobuyoshi Matsumoto","doi":"10.1016/j.jphs.2025.08.002","DOIUrl":"10.1016/j.jphs.2025.08.002","url":null,"abstract":"<div><div>Object recognition memory encourages animals to distinguish between new and known objects, supported by neural activity in the hippocampus, prefrontal cortex, and perirhinal cortex. Theanine, a non-proteinogenic amino acid derivative from green tea leaves, enhances object recognition memory in rats through facilitated neurogenesis. Although the cellular mechanism for the theanine-enhanced object recognition memory has been elucidated to some extent, physiological evidence still remains unclear. To tackle this issue, we chronically fed mice with theanine (or tap water) for three weeks, implanted electrodes into the hippocampus and frontal cortex, both of which are responsible for object recognition memory. We then recorded the local field potentials from the two regions during the novel object recognition task, evaluated the memory performance, and broke down the neural signals in the hippocampus and frontal cortex into delta, theta, beta, low gamma, and high gamma frequency bands. The memory performance of theanine-treated mice was higher than that of vehicle-treated mice. We also found that theta oscillations in the frontal cortex and beta and low gamma oscillations in the hippocampus in theanine-treated mice were simultaneously enhanced for familiar objects. These results shed light on the new physiological underpinnings of object recognition memory enhanced by exogenous substances.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"159 3","pages":"Pages 129-138"},"PeriodicalIF":2.9,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144865014","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}
Pub Date : 2025-08-08DOI: 10.1016/j.jphs.2025.08.001
Xiaoyan Ma , Yilizere Aibaidula , Chunzi Zhang , Shuwen Qi , Tuxia Pang , Juan Zhang , Wenhui Hou , Xiaoli Ma
Lactucin is a natural sesquiterpene lactone isolated from Cichorium glandulosum Boiss. et Huet (CG) has unique biological and pharmaceutical properties. This study was designed to investigate the mechanisms by which Lactucin inhibits lipid accumulation in free fatty acid (FFA)-treated HepG2 cells. We demonstrated that Lactucin exerts a protective effect against hepatic steatosis in vitro. In FFA-induced HepG2 cells, Lactucin effectively ameliorated lipid accumulation, oxidative stress, and mitochondrial dysfunction. Mechanistically, we showed that activation of AMP-activated protein kinase (AMPK) and hormone-sensitive lipase (HSL) by Lactucin promoted lipolysis and further enhanced fatty acid β-oxidation (FAβO) by increasing the activity of FAβO-related enzymes, thereby contributing to the reduction of lipid accumulation. Moreover, Lactucin activated autophagy and modulated the AMPK/mammalian target of rapamycin (mTOR) signaling pathway. Notably, we found that Lactucin-induced autophagy played a significant role in decreasing lipid droplet accumulation, suggesting it may be a key underlying mechanism. These findings, for the first time, provide new insights into the pharmaceutical mechanism of Lactucin in protecting against nonalcoholic fatty liver disease (NAFLD).
lacucin是一种天然的倍半萜内酯，从菊苣中分离得到。et Huet （CG）具有独特的生物学和药学特性。本研究旨在探讨乳酸蛋白抑制游离脂肪酸（FFA）处理的HepG2细胞脂质积累的机制。我们证明了乳酸蛋白在体外对肝脂肪变性有保护作用。在ffa诱导的HepG2细胞中，lacucin有效地改善了脂质积累、氧化应激和线粒体功能障碍。在机制上，我们发现乳酸蛋白激活amp激活的蛋白激酶（AMPK）和激素敏感脂肪酶（HSL）促进脂肪分解，并通过增加FAβO相关酶的活性进一步增强脂肪酸β氧化（FAβO），从而有助于减少脂质积累。此外，lacucin激活自噬并调节AMPK/哺乳动物雷帕霉素靶蛋白（mTOR）信号通路。值得注意的是，我们发现乳酸素诱导的自噬在减少脂滴积累中起着重要作用，这可能是一个关键的潜在机制。这些发现首次为乳黄素预防非酒精性脂肪性肝病（NAFLD）的药物机制提供了新的见解。
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