Oxaliplatin-induced peripheral neuropathy (OIPN) is a dose-limiting toxicity with limited countermeasures. Basic research has revealed that omeprazole, a proton pump inhibitor (PPI), exerts preventive effects against OIPN. In this study, we evaluated whether other PPIs exert similar effects via in vitro and in vivo experiments. Notably, esomeprazole, lansoprazole, and rabeprazole, classified as PPIs, prevented oxaliplatin-induced cultured F11 neuronal cell damage, and repeated PPI administration prevented mechanical allodynia in rats. However, vonoprazan, a potassium ion-competitive acid blocker, did not exert such effects. Overall, our results highlight the class effects of PPIs against OIPN.
{"title":"Class effects of proton pump inhibitors in preventing oxaliplatin-induced peripheral neurotoxicity","authors":"Yusuke Mori , Keisuke Mine , Takehiro Kawashiri , Yusuke Koura , Mami Ueda , Risa Kaneko , Shunsuke Fujita , Akito Tsuruta , Satoru Koyanagi , Daisuke Kobayashi","doi":"10.1016/j.jphs.2025.09.010","DOIUrl":"10.1016/j.jphs.2025.09.010","url":null,"abstract":"<div><div>Oxaliplatin-induced peripheral neuropathy (OIPN) is a dose-limiting toxicity with limited countermeasures. Basic research has revealed that omeprazole, a proton pump inhibitor (PPI), exerts preventive effects against OIPN. In this study, we evaluated whether other PPIs exert similar effects via <em>in vitro</em> and <em>in vivo</em> experiments. Notably, esomeprazole, lansoprazole, and rabeprazole, classified as PPIs, prevented oxaliplatin-induced cultured F11 neuronal cell damage, and repeated PPI administration prevented mechanical allodynia in rats. However, vonoprazan, a potassium ion-competitive acid blocker, did not exert such effects. Overall, our results highlight the class effects of PPIs against OIPN.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"159 4","pages":"Pages 279-282"},"PeriodicalIF":2.9,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145221985","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}
Duchenne muscular dystrophy (DMD) is a severe X-linked genetic disorder caused by mutations in the dystrophin gene. Although the C57BL/10 background mdx mouse (B10-mdx) model is widely used for DMD research, it presents milder symptoms than observed in human patients. In contrast, the DBA/2N-mdx model exhibits more severe pathology, making it a promising model for evaluating disease mechanisms and therapies. In this study, we employed a 24-h behavioral monitoring system to investigate spontaneous locomotor activity and gait characteristics in DBA/2N-mdx mice. We observed significantly reduced movement and shorter active periods during the dark (active) phase at 4 and 8 weeks of age in DBA/2N-mdx mice compared to controls. Subsequent gait analysis revealed shorter walking distances, slower speeds, and reduced body extension during straight walking. These findings suggest that the DBA/2N-mdx mouse model exhibits distinct behavioral abnormalities that parallel DMD symptoms in humans. Our noninvasive, continuous monitoring approach provides an innovative method for assessing motor impairments and may facilitate more accurate preclinical assessments of potential therapies for DMD.
{"title":"Uncovering motor impairments in duchenne muscular dystrophy: 24-hour automated behavioral analysis of DBA/2N-mdx mice","authors":"Misato Kida , Yui Kobayashi , Takamasa Numano , Masahiko Yasuda , Seinosuke Sakai , Takashi Minato , Takuya Kishi , Masahiro Fukuda , Keisuke Omori , Taichi Yamamoto , Takahisa Murata","doi":"10.1016/j.jphs.2025.09.011","DOIUrl":"10.1016/j.jphs.2025.09.011","url":null,"abstract":"<div><div>Duchenne muscular dystrophy (DMD) is a severe X-linked genetic disorder caused by mutations in the dystrophin gene. Although the C57BL/10 background mdx mouse (B10-mdx) model is widely used for DMD research, it presents milder symptoms than observed in human patients. In contrast, the DBA/2N-mdx model exhibits more severe pathology, making it a promising model for evaluating disease mechanisms and therapies. In this study, we employed a 24-h behavioral monitoring system to investigate spontaneous locomotor activity and gait characteristics in DBA/2N-mdx mice. We observed significantly reduced movement and shorter active periods during the dark (active) phase at 4 and 8 weeks of age in DBA/2N-mdx mice compared to controls. Subsequent gait analysis revealed shorter walking distances, slower speeds, and reduced body extension during straight walking. These findings suggest that the DBA/2N-mdx mouse model exhibits distinct behavioral abnormalities that parallel DMD symptoms in humans. Our noninvasive, continuous monitoring approach provides an innovative method for assessing motor impairments and may facilitate more accurate preclinical assessments of potential therapies for DMD.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"159 4","pages":"Pages 283-291"},"PeriodicalIF":2.9,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145269341","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 : 2025-09-25DOI: 10.1016/j.jphs.2025.09.009
Li-King Yang , Leticia B. Sy , Ju-Fang Liu , Tsung-Ming Chang , Ji-Fan Lin , Chi-Jen Chang
Cisplatin is a commonly used chemotherapy drug that can effectively treat a variety of cancers, but it often causes severe side effects, including nephrotoxicity, ototoxicity, and gastrointestinal toxicity, which significantly affects patients' quality of life. Lutein is a natural carotenoid known for its potent antioxidant properties. Recent literature supports the beneficial effects of lutein supplements in conditions such as retinal degeneration, cardiovascular disease, and liver damage, emphasizing its broad anti-inflammatory capabilities. However, the mechanism by which cisplatin causes intestinal inflammation and the protective effect of lutein against this remain unknown. Here, we investigated the potential protective effect of lutein against cisplatin-induced intestinal epithelial injury. Our results proved that cisplatin significantly decreased cell viability, enhanced ROS generation, and activated inflammatory signaling pathways involving p38, ERK, and NF-κB in IEC-6 cells. Pretreatment with lutein markedly suppressed ROS production, reduced p38 and ERK phosphorylation, prevented NF-κB activation, and consequently attenuated inflammatory cytokine expression. These findings establish lutein as a promising dietary strategy to reduce cisplatin-induced intestinal inflammation, supporting its therapeutic potential for improving chemotherapy tolerance.
{"title":"Lutein reduces cisplatin-induced intestinal inflammation by inhibiting ROS-mediated MAPK/NF-κB pathways","authors":"Li-King Yang , Leticia B. Sy , Ju-Fang Liu , Tsung-Ming Chang , Ji-Fan Lin , Chi-Jen Chang","doi":"10.1016/j.jphs.2025.09.009","DOIUrl":"10.1016/j.jphs.2025.09.009","url":null,"abstract":"<div><div>Cisplatin is a commonly used chemotherapy drug that can effectively treat a variety of cancers, but it often causes severe side effects, including nephrotoxicity, ototoxicity, and gastrointestinal toxicity, which significantly affects patients' quality of life. Lutein is a natural carotenoid known for its potent antioxidant properties. Recent literature supports the beneficial effects of lutein supplements in conditions such as retinal degeneration, cardiovascular disease, and liver damage, emphasizing its broad anti-inflammatory capabilities. However, the mechanism by which cisplatin causes intestinal inflammation and the protective effect of lutein against this remain unknown. Here, we investigated the potential protective effect of lutein against cisplatin-induced intestinal epithelial injury. Our results proved that cisplatin significantly decreased cell viability, enhanced ROS generation, and activated inflammatory signaling pathways involving p38, ERK, and NF-κB in IEC-6 cells. Pretreatment with lutein markedly suppressed ROS production, reduced p38 and ERK phosphorylation, prevented NF-κB activation, and consequently attenuated inflammatory cytokine expression. These findings establish lutein as a promising dietary strategy to reduce cisplatin-induced intestinal inflammation, supporting its therapeutic potential for improving chemotherapy tolerance.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"159 4","pages":"Pages 292-300"},"PeriodicalIF":2.9,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145269340","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 : 2025-09-20DOI: 10.1016/j.jphs.2025.09.008
Jun Horizono , Keito Mizumoto , Mary Ann Suico , Shota Kaseda , Yuya Sannomiya , Haruki Tsuhako , Aimi Owaki , Ryoichi Sato , Masahiro Shiraga , Riko Kato , Ryo Kumabe , Tsuyoshi Shuto , Hirofumi Kai
Sodium-glucose co-transporter 2 inhibitors (SGLT2i) and angiotensin receptor blockers (ARBs) each have renoprotective effects in chronic kidney diseases, including Alport syndrome. Here, we investigated the combination of SGLT2i dapagliflozin and ARBs with different antiproteinuric strength - losartan (weak) and olmesartan (strong) - in Col4a5 G5X Alport mice. Dapagliflozin enhanced the renoprotective effect of losartan but not of olmesartan. Olmesartan alone suppressed the decline in renal function and prolonged survival similarly to losartan plus dapagliflozin. These findings suggest that the add-on effectiveness of dapagliflozin varies depending on the ARB, and that their combination needs careful evaluation for maximum benefit.
{"title":"Dapagliflozin with losartan but not olmesartan has an add-on protective effect in experimental Alport syndrome","authors":"Jun Horizono , Keito Mizumoto , Mary Ann Suico , Shota Kaseda , Yuya Sannomiya , Haruki Tsuhako , Aimi Owaki , Ryoichi Sato , Masahiro Shiraga , Riko Kato , Ryo Kumabe , Tsuyoshi Shuto , Hirofumi Kai","doi":"10.1016/j.jphs.2025.09.008","DOIUrl":"10.1016/j.jphs.2025.09.008","url":null,"abstract":"<div><div>Sodium-glucose co-transporter 2 inhibitors (SGLT2i) and angiotensin receptor blockers (ARBs) each have renoprotective effects in chronic kidney diseases, including Alport syndrome. Here, we investigated the combination of SGLT2i dapagliflozin and ARBs with different antiproteinuric strength - losartan (weak) and olmesartan (strong) - in <em>Col4a5</em> G5X Alport mice. Dapagliflozin enhanced the renoprotective effect of losartan but not of olmesartan. Olmesartan alone suppressed the decline in renal function and prolonged survival similarly to losartan plus dapagliflozin. These findings suggest that the add-on effectiveness of dapagliflozin varies depending on the ARB, and that their combination needs careful evaluation for maximum benefit.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"159 4","pages":"Pages 252-255"},"PeriodicalIF":2.9,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145120421","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}
Prostate cancer is the second most common cancer in men. Although androgen deprivation therapy is initially effective, resistance inevitably develops. Most patients eventually progress to castration-resistant prostate cancer, a stage with limited treatment options and poor prognosis. Rho kinases (ROCK1 and ROCK2) have been implicated in cancer progression, but their therapeutic targeting remains limited. This study examined the pathological roles of ROCK1 and ROCK2 in epithelial-mesenchymal transition (EMT) and proliferation of prostate cancer cells. ROCK1 expression was comparable between human prostate epithelial cells (PrECs) and androgen-independent prostate cancer cells, PC-3 and DU145. In contrast, ROCK2 expression was higher in PC-3 cells than in PrECs and DU145 cells. EMT marker analysis revealed that PC-3 cells exhibited decreased E-cadherin and increased N-cadherin and Snail expression. ROCK2 knockdown reversed this EMT phenotype, reducing cell proliferation, migration, 3D tumor spheroid formation, and spheroid cell viability. Similar inhibitory effects were observed by the ROCK2-selective blocker KD025 (IC50 = 422 nM). Furthermore, ROCK2 deficiency attenuated the tumor growth of PC-3 cells in a xenograft mouse model. These findings indicate that ROCK2 promotes EMT process and tumor progression in PC-3 cells. Targeting ROCK2 may represent a promising therapeutic strategy for androgen-independent prostate cancer.
{"title":"Rho kinase 2 promotes epithelial-mesenchymal transition and proliferation in human prostate cancer PC-3 cells","authors":"Alamgir Hossain , Aya Yamamura , Md Junayed Nayeem , Sivasundaram Karnan , Rie Takahashi , Hisaki Hayashi , Motohiko Sato","doi":"10.1016/j.jphs.2025.09.007","DOIUrl":"10.1016/j.jphs.2025.09.007","url":null,"abstract":"<div><div>Prostate cancer is the second most common cancer in men. Although androgen deprivation therapy is initially effective, resistance inevitably develops. Most patients eventually progress to castration-resistant prostate cancer, a stage with limited treatment options and poor prognosis. Rho kinases (ROCK1 and ROCK2) have been implicated in cancer progression, but their therapeutic targeting remains limited. This study examined the pathological roles of ROCK1 and ROCK2 in epithelial-mesenchymal transition (EMT) and proliferation of prostate cancer cells. ROCK1 expression was comparable between human prostate epithelial cells (PrECs) and androgen-independent prostate cancer cells, PC-3 and DU145. In contrast, ROCK2 expression was higher in PC-3 cells than in PrECs and DU145 cells. EMT marker analysis revealed that PC-3 cells exhibited decreased E-cadherin and increased N-cadherin and Snail expression. ROCK2 knockdown reversed this EMT phenotype, reducing cell proliferation, migration, 3D tumor spheroid formation, and spheroid cell viability. Similar inhibitory effects were observed by the ROCK2-selective blocker KD025 (IC<sub>50</sub> = 422 nM). Furthermore, ROCK2 deficiency attenuated the tumor growth of PC-3 cells in a xenograft mouse model. These findings indicate that ROCK2 promotes EMT process and tumor progression in PC-3 cells. Targeting ROCK2 may represent a promising therapeutic strategy for androgen-independent prostate cancer.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"159 4","pages":"Pages 229-241"},"PeriodicalIF":2.9,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145108613","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 : 2025-09-20DOI: 10.1016/j.jphs.2025.09.006
Haruki Tsuhako , Mary Ann Suico , Haruka Kojima , Saki Takahashi , Shunsuke Tanigawa , Misato Kamura , Ryoichi Sato , Riko Kato , Aimi Owaki , Ryuichi Nishinakamura , Tsuyoshi Shuto , Hirofumi Kai
Nephrin is crucial for the formation of the glomerular slit diaphragm, which is the final filtration barrier in the kidney. A mutation in the NPHS1 gene that codes for nephrin causes congenital nephrotic syndrome of the Finnish type (CNF). Most missense mutations render nephrin non-functional due to the defective nephrin trafficking to the cell membrane. Pharmacological approaches that induce the expression of nephrin on the cell membrane are feasible, but therapeutic development is hampered by the lack of a high-throughput screening (HTS) system. Here, we developed a nanoluciferase HiBiT-based HTS platform to quantify the cell membrane expression of a nephrin mutant. This evaluation system reflected the previously reported results of various nephrin mutant localization. Using this system, we screened and identified 10 compounds that promoted the expression of the nephrin E725D mutant on the cell membrane. Moreover, the phosphorylation and N-glycosylation of nephrin, which are modifications that indicate its cell surface localization, correlated with the luminescence values of HiBiT-Nephrin in the compound screening. Consequently, this HiBiT-Nephrin evaluation system could be a new platform for predicting the pathogenicity of variants and searching for therapeutic agents for CNF.
{"title":"Establishing a nanoluciferase-based assay as a high-throughput screening platform for therapeutics in congenital nephrotic syndrome","authors":"Haruki Tsuhako , Mary Ann Suico , Haruka Kojima , Saki Takahashi , Shunsuke Tanigawa , Misato Kamura , Ryoichi Sato , Riko Kato , Aimi Owaki , Ryuichi Nishinakamura , Tsuyoshi Shuto , Hirofumi Kai","doi":"10.1016/j.jphs.2025.09.006","DOIUrl":"10.1016/j.jphs.2025.09.006","url":null,"abstract":"<div><div>Nephrin is crucial for the formation of the glomerular slit diaphragm, which is the final filtration barrier in the kidney. A mutation in the <em>NPHS1</em> gene that codes for nephrin causes congenital nephrotic syndrome of the Finnish type (CNF). Most missense mutations render nephrin non-functional due to the defective nephrin trafficking to the cell membrane. Pharmacological approaches that induce the expression of nephrin on the cell membrane are feasible, but therapeutic development is hampered by the lack of a high-throughput screening (HTS) system. Here, we developed a nanoluciferase HiBiT-based HTS platform to quantify the cell membrane expression of a nephrin mutant. This evaluation system reflected the previously reported results of various nephrin mutant localization. Using this system, we screened and identified 10 compounds that promoted the expression of the nephrin E725D mutant on the cell membrane. Moreover, the phosphorylation and N-glycosylation of nephrin, which are modifications that indicate its cell surface localization, correlated with the luminescence values of HiBiT-Nephrin in the compound screening. Consequently, this HiBiT-Nephrin evaluation system could be a new platform for predicting the pathogenicity of variants and searching for therapeutic agents for CNF.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"159 4","pages":"Pages 219-228"},"PeriodicalIF":2.9,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145108615","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 : 2025-09-19DOI: 10.1016/j.jphs.2025.09.004
Yuyao Li , Huili Qi , Haoyue Xu , Xuehai Jia , Wenyan Chen , Ruoliu Pan , Xinhui Pan , Hangyu Wang , Dahong Yao , Ke Zhang , Jinhui Wang
Idiopathic pulmonary fibrosis is a progressive, highly lethal disease with limited treatment options. It is characterized by fibroblast-to-myofibroblast transformation, excessive ECM proliferation and collagen deposition, leading to the destruction of normal lung architecture and function. As a constituent of Rhodiola rosea L., rosiridin is a monomer with significant structural compatibility, conferring strong therapeutic potential. This bioactive compound mitigates oxidative stress-driven pathology and reverses its resultant damage in various diseases. However, its potential protective effects against bleomycin-induced IPF and the underlying mechanisms remain unclear. This study aimed to investigate the role and mechanism of rosiridin in IPF. Rosiridin attenuated TGF-β1-induced oxidative stress and inflammatory responses in lung epithelial cells and suppressed apoptosis associated with pulmonary fibrosis. Hematoxylin and eosin (HE) staining and Masson's trichrome staining showed that rosiridin improved pathological lung changes, reduced oxidative stress, and alleviated pulmonary fibrosis in a dose-dependent manner. Transcriptomic analysis revealed that rosiridin inhibited JAK protein activation, reduced the transformation of fibroblasts into myofibroblasts, and suppressed the secretion of proinflammatory and profibrotic cytokines. These findings suggest that rosiridin mitigates pulmonary fibrosis through modulation of the STAT3/NF-κB/SMAD3 signaling pathways. Rosiridin may represent a promising therapeutic candidate for the treatment of IPF.
{"title":"Rosiridin reduces Idiopathic Pulmonary Fibrosis by inhibiting the STAT3/NFκB/SMAD3 signaling pathways","authors":"Yuyao Li , Huili Qi , Haoyue Xu , Xuehai Jia , Wenyan Chen , Ruoliu Pan , Xinhui Pan , Hangyu Wang , Dahong Yao , Ke Zhang , Jinhui Wang","doi":"10.1016/j.jphs.2025.09.004","DOIUrl":"10.1016/j.jphs.2025.09.004","url":null,"abstract":"<div><div>Idiopathic pulmonary fibrosis is a progressive, highly lethal disease with limited treatment options. It is characterized by fibroblast-to-myofibroblast transformation, excessive ECM proliferation and collagen deposition, leading to the destruction of normal lung architecture and function. As a constituent of <em>Rhodiola rosea</em> L., rosiridin is a monomer with significant structural compatibility, conferring strong therapeutic potential. This bioactive compound mitigates oxidative stress-driven pathology and reverses its resultant damage in various diseases. However, its potential protective effects against bleomycin-induced IPF and the underlying mechanisms remain unclear. This study aimed to investigate the role and mechanism of rosiridin in IPF. Rosiridin attenuated TGF-β1-induced oxidative stress and inflammatory responses in lung epithelial cells and suppressed apoptosis associated with pulmonary fibrosis. Hematoxylin and eosin (HE) staining and Masson's trichrome staining showed that rosiridin improved pathological lung changes, reduced oxidative stress, and alleviated pulmonary fibrosis in a dose-dependent manner. Transcriptomic analysis revealed that rosiridin inhibited JAK protein activation, reduced the transformation of fibroblasts into myofibroblasts, and suppressed the secretion of proinflammatory and profibrotic cytokines. These findings suggest that rosiridin mitigates pulmonary fibrosis through modulation of the STAT3/NF-κB/SMAD3 signaling pathways. Rosiridin may represent a promising therapeutic candidate for the treatment of IPF.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"159 4","pages":"Pages 242-251"},"PeriodicalIF":2.9,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145108614","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}
Inhibitors of histone deacetylases (HDACs) suppress retinal angiogenesis by interrupting the vascular endothelial growth factor (VEGF)-mammalian target of rapamycin complex 1 (mTORC1) pathway in proliferating endothelial cells. To investigate the underlying mechanisms, we examined the effects of valproic acid (VPA) and vorinostat on the distribution of VEGF protein and phosphorylated S6 protein, an indicator of mTORC1 activity, in the neonatal mouse retina, an experimental model of retinal angiogenesis. Newborn mice were subcutaneously injected with VPA, vorinostat, or vehicle once daily from postnatal day (P) 0 to P3. Their eyes were collected at P4. Compared to vehicle-treated mice, retinal vascularization was delayed, and the number of proliferating vascular cells was reduced in front of the retinal vasculature in VPA- and vorinostat-treated mice. In P4 mice, a single injection of VPA or vorinostat reduced VEGF expression on the retinal surface at 2 and 6 h after injection. Both drugs reduced mTORC1 activity in proliferating endothelial cells. The proteasome inhibitor, MG132, suppressed the VPA- and vorinostat-induced reduction in VEGF expression on the retinal surface. These results suggest that HDAC inhibitors suppress retinal angiogenesis by preventing endothelial cell proliferation and accelerating VEGF protein degradation in a proteasome-dependent manner.
{"title":"Histone deacetylase inhibitors suppress retinal angiogenesis by preventing endothelial cell proliferation and accelerating VEGF degradation","authors":"Akane Morita, Kanako Takahashi, Naoto Iizuka, Tsutomu Nakahara","doi":"10.1016/j.jphs.2025.09.005","DOIUrl":"10.1016/j.jphs.2025.09.005","url":null,"abstract":"<div><div>Inhibitors of histone deacetylases (HDACs) suppress retinal angiogenesis by interrupting the vascular endothelial growth factor (VEGF)-mammalian target of rapamycin complex 1 (mTORC1) pathway in proliferating endothelial cells. To investigate the underlying mechanisms, we examined the effects of valproic acid (VPA) and vorinostat on the distribution of VEGF protein and phosphorylated S6 protein, an indicator of mTORC1 activity, in the neonatal mouse retina, an experimental model of retinal angiogenesis. Newborn mice were subcutaneously injected with VPA, vorinostat, or vehicle once daily from postnatal day (P) 0 to P3. Their eyes were collected at P4. Compared to vehicle-treated mice, retinal vascularization was delayed, and the number of proliferating vascular cells was reduced in front of the retinal vasculature in VPA- and vorinostat-treated mice. In P4 mice, a single injection of VPA or vorinostat reduced VEGF expression on the retinal surface at 2 and 6 h after injection. Both drugs reduced mTORC1 activity in proliferating endothelial cells. The proteasome inhibitor, MG132, suppressed the VPA- and vorinostat-induced reduction in VEGF expression on the retinal surface. These results suggest that HDAC inhibitors suppress retinal angiogenesis by preventing endothelial cell proliferation and accelerating VEGF protein degradation in a proteasome-dependent manner.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"159 4","pages":"Pages 268-278"},"PeriodicalIF":2.9,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145120569","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 : 2025-09-16DOI: 10.1016/j.jphs.2025.09.002
Jingjing Shi , Caina Ma , Yuexi Liu , Chao Yang , Jinyu Wu , Xiaohong Wang
{"title":"MicroRNA-3473b regulates corticosterone-induced microglial polarization and inflammation through TREM2","authors":"Jingjing Shi , Caina Ma , Yuexi Liu , Chao Yang , Jinyu Wu , Xiaohong Wang","doi":"10.1016/j.jphs.2025.09.002","DOIUrl":"10.1016/j.jphs.2025.09.002","url":null,"abstract":"","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"159 4","pages":"Pages 209-218"},"PeriodicalIF":2.9,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145099892","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 : 2025-09-14DOI: 10.1016/j.jphs.2025.09.003
Jing Cai , Wenshuang Ji , Peng Liu , Libo Zou
The NLRP3 inflammasome is primarily expressed and activated in microglial and endothelial cells. Extensive research has been conducted on the activation of NLRP3 inflammasomes by microglial cells leading to pyroptosis. However, there have been no reports on the activation of NLRP3 inflammasomes in brain vascular endothelial cells in patients with Huntington's disease (HD) or HD animal models, leading to blood-brain barrier (BBB) disruption. We herein found that BBB leakage increased and the expression of tight junction proteins significantly decreased after transfecting the mutant Huntingtin protein (mHtt) Q74 plasmid into the mouse brain microvascular endothelial cell line bEnd.3. mHtt promoted the activation of NLRP3 by brain vascular endothelial cells, and increased the expression of the pyroptosis-related proteins. This resulted in a decrease in the expression of the NeuN in the brain of hHTT130 transgenic mice. Furthermore, by downregulating NLRP3 in Q74-transfected bEnd.3 cells or in hHTT130 mouse brain vascular endothelial cells, BBB disruption and endothelial cell pyroptosis were alleviated, the number of surviving neurons was significantly increased. In conclusion, mHtt can activate the NLRP3 inflammasome in brain microvascular endothelial cells to induce endothelial cell pyroptosis, thereby disrupting the function of the BBB, leading to neuronal damage.
{"title":"Endothelial NLRP3-mediated pyroptosis induces blood-brain barrier and neuronal damage in Huntington's disease models","authors":"Jing Cai , Wenshuang Ji , Peng Liu , Libo Zou","doi":"10.1016/j.jphs.2025.09.003","DOIUrl":"10.1016/j.jphs.2025.09.003","url":null,"abstract":"<div><div>The NLRP3 inflammasome is primarily expressed and activated in microglial and endothelial cells. Extensive research has been conducted on the activation of NLRP3 inflammasomes by microglial cells leading to pyroptosis. However, there have been no reports on the activation of NLRP3 inflammasomes in brain vascular endothelial cells in patients with Huntington's disease (HD) or HD animal models, leading to blood-brain barrier (BBB) disruption. We herein found that BBB leakage increased and the expression of tight junction proteins significantly decreased after transfecting the mutant Huntingtin protein (mHtt) Q74 plasmid into the mouse brain microvascular endothelial cell line bEnd.3. mHtt promoted the activation of NLRP3 by brain vascular endothelial cells, and increased the expression of the pyroptosis-related proteins. This resulted in a decrease in the expression of the NeuN in the brain of hHTT130 transgenic mice. Furthermore, by downregulating <em>NLRP3</em> in Q74-transfected bEnd.3 cells or in hHTT130 mouse brain vascular endothelial cells, BBB disruption and endothelial cell pyroptosis were alleviated, the number of surviving neurons was significantly increased. In conclusion, mHtt can activate the NLRP3 inflammasome in brain microvascular endothelial cells to induce endothelial cell pyroptosis, thereby disrupting the function of the BBB, leading to neuronal damage.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"159 4","pages":"Pages 256-267"},"PeriodicalIF":2.9,"publicationDate":"2025-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145120471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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