Lysophosphatidic acid receptor 1 (LPA1) plays a pivotal role in the pathophysiology of various diseases, especially chronic pain. In this study, we assessed the biochemical properties of Compound A, a novel LPA1 antagonist and its beneficial effects in the fibromyalgia (FM)-like pain model. Compound A was found to be a high-affinity and selective LPA1 antagonist and have high brain penetrability. Repeated oral administrations of Compound A reversed the hyperalgesia as late as 9 days after the treatments, suggesting this compound has a curative effect in the FM model.
{"title":"A novel lysophosphatidic acid receptor 1 antagonist with high brain penetrability has a curative effect in the empathic pain-related fibromyalgia model","authors":"Hiroyuki Neyama , Naoki Dozono , Yasuka Sahara , Kenji Nishikawa , Hiroshi Ueda","doi":"10.1016/j.jphs.2025.03.012","DOIUrl":"10.1016/j.jphs.2025.03.012","url":null,"abstract":"<div><div>Lysophosphatidic acid receptor 1 (LPA<sub>1</sub>) plays a pivotal role in the pathophysiology of various diseases, especially chronic pain. In this study, we assessed the biochemical properties of Compound A, a novel LPA<sub>1</sub> antagonist and its beneficial effects in the fibromyalgia (FM)-like pain model. Compound A was found to be a high-affinity and selective LPA<sub>1</sub> antagonist and have high brain penetrability. Repeated oral administrations of Compound A reversed the hyperalgesia as late as 9 days after the treatments, suggesting this compound has a curative effect in the FM model.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"158 2","pages":"Pages 139-142"},"PeriodicalIF":3.0,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143825549","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 : 2025-04-08DOI: 10.1016/j.jphs.2025.04.001
Hailin Zhang , Baoyuan Zhou , Jixing Liu , Bo Tang , Zongzhi Xie , Jianxiong Li
Rosamultin (Rosa), a natural small-molecule compound, is known for its protective activity against hypoxia-induced injury, but its role in cerebral ischemic stroke injury remains unclear. To assess Rosa's effects on cerebral ischemic stroke, the intraluminal filament method was used to construct the middle cerebral artery occlusion and reperfusion (MCAO) in vivo model with 1 h occlusion and 48 h reperfusion. In addition, an oxygen-glucose deprivation and reoxygenation (OGD/R) in vitro model was constructed using HT22 cells. The protective role and underlying mechanism of Rosa on cell injury was also determined in vivo and in vitro. Rosa notably inhibited neurological deficits and diminished infarct volume and neuronal apoptosis in mice exposed to MCAO. Rosa also exerted neuroprotection in the OGD/R model by improving cell viability, decreasing apoptosis, and enhancing the p-Akt and p-mTOR levels. However, LY294002, a PI3K inhibitor, restored the beneficial influences of Rosa after OGD/R. Moreover, Rosa treatment inhibited autophagy levels, and LY294002 partially restored the inhibition of autophagy levels caused by Rosa in the OGD/R model. In addition, Rosa enhanced the p-Akt and p-mTOR levels and inhibited autophagy levels in mice after MCAO. Rosa could attenuate autophagy via activating the PI3K/Akt/mTOR axis, thereby alleviating cerebral ischemia stroke injury.
{"title":"Rosamultin attenuates cerebral ischemia/reperfusion injury by inhibiting autophagy via the PI3K/Akt/mTOR pathway","authors":"Hailin Zhang , Baoyuan Zhou , Jixing Liu , Bo Tang , Zongzhi Xie , Jianxiong Li","doi":"10.1016/j.jphs.2025.04.001","DOIUrl":"10.1016/j.jphs.2025.04.001","url":null,"abstract":"<div><div>Rosamultin (Rosa), a natural small-molecule compound, is known for its protective activity against hypoxia-induced injury, but its role in cerebral ischemic stroke injury remains unclear. To assess Rosa's effects on cerebral ischemic stroke, the intraluminal filament method was used to construct the middle cerebral artery occlusion and reperfusion (MCAO) in vivo model with 1 h occlusion and 48 h reperfusion. In addition, an oxygen-glucose deprivation and reoxygenation (OGD/R) in vitro model was constructed using HT22 cells. The protective role and underlying mechanism of Rosa on cell injury was also determined in vivo and in vitro. Rosa notably inhibited neurological deficits and diminished infarct volume and neuronal apoptosis in mice exposed to MCAO. Rosa also exerted neuroprotection in the OGD/R model by improving cell viability, decreasing apoptosis, and enhancing the p-Akt and p-mTOR levels. However, <span>LY294002</span>, a PI3K inhibitor, restored the beneficial influences of Rosa after OGD/R. Moreover, Rosa treatment inhibited autophagy levels, and <span>LY294002</span> partially restored the inhibition of autophagy levels caused by Rosa in the OGD/R model. In addition, Rosa enhanced the p-Akt and p-mTOR levels and inhibited autophagy levels in mice after MCAO. Rosa could attenuate autophagy via activating the PI3K/Akt/mTOR axis, thereby alleviating cerebral ischemia stroke injury.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"158 3","pages":"Pages 182-192"},"PeriodicalIF":3.0,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143864011","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 : 2025-04-08DOI: 10.1016/j.jphs.2025.04.003
Jinwen Yao , Xu Wang , Dexi Zhao
Background and objective
Ischemic stroke is a disease with high incidence. Astaxanthin is a functional foods with protective effects against ischemic stroke. However, the integral mechanism of astaxanthin protect ischemic stroke is not clear. The aim of this study was to investigate the mechanism of astaxanthin protect ischemic stroke by integrated network analysis.
Methods
Middle cerebral artery occlusion model was used to establish ischemic stroke model, and ischemic stroke models were treated with 25, 45, 65 mg/kg astaxanthin for 7 days. The rats were killed 24 h after successful modeling. Integrated network analysis, molecular docking, molecular dynamics (MD) simulation, and Western blot were used to explore the astaxanthin and potential proteins related to inflammation and cell death.
Results
The results of integrated network analysis indicate that astaxanthin may protect ischemic stroke through Toll like receptor signaling pathway and apoptosis pathway. The main targets involved MMP9, IL1B, IL10, Bcl2 and among others. astaxanthin has a low binding score and compact complex with PARP1, AIF, Bax, IL10, MMP9, Bcl2. In addition, astaxanthin has reduced inflammation and cell death-related proteins such as PARP1, AIF, Bax, TLR4, MMP9, IL1β and increased anti-inflammation and anti-cell death-related proteins by Bcl2 and IL10.
Conclusions
Astaxanthin can improve anti-inflammatory, anti-cell death ability after ischemic stroke. Our study provides a theoretical basis for the subsequent experimental and clinical application of astaxanthin in the treatment of ischemic stroke.
{"title":"Clarifying the mechanism of astaxanthin in the treatment of inflammation in ischemic stroke using integrated network analysis","authors":"Jinwen Yao , Xu Wang , Dexi Zhao","doi":"10.1016/j.jphs.2025.04.003","DOIUrl":"10.1016/j.jphs.2025.04.003","url":null,"abstract":"<div><h3>Background and objective</h3><div>Ischemic stroke is a disease with high incidence. Astaxanthin is a functional foods with protective effects against ischemic stroke. However, the integral mechanism of astaxanthin protect ischemic stroke is not clear. The aim of this study was to investigate the mechanism of astaxanthin protect ischemic stroke by integrated network analysis.</div></div><div><h3>Methods</h3><div>Middle cerebral artery occlusion model was used to establish ischemic stroke model, and ischemic stroke models were treated with 25, 45, 65 mg/kg astaxanthin for 7 days. The rats were killed 24 h after successful modeling. Integrated network analysis, molecular docking, molecular dynamics (MD) simulation, and Western blot were used to explore the astaxanthin and potential proteins related to inflammation and cell death.</div></div><div><h3>Results</h3><div>The results of integrated network analysis indicate that astaxanthin may protect ischemic stroke through Toll like receptor signaling pathway and apoptosis pathway. The main targets involved MMP9, IL1B, IL10, Bcl2 and among others. astaxanthin has a low binding score and compact complex with PARP1, AIF, Bax, IL10, MMP9, Bcl2. In addition, astaxanthin has reduced inflammation and cell death-related proteins such as PARP1, AIF, Bax, TLR4, MMP9, IL1β and increased anti-inflammation and anti-cell death-related proteins by Bcl2 and IL10.</div></div><div><h3>Conclusions</h3><div>Astaxanthin can improve anti-inflammatory, anti-cell death ability after ischemic stroke. Our study provides a theoretical basis for the subsequent experimental and clinical application of astaxanthin in the treatment of ischemic stroke.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"158 3","pages":"Pages 155-165"},"PeriodicalIF":3.0,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143864070","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 : 2025-04-07DOI: 10.1016/j.jphs.2025.04.002
Yao Zhang , Bing Yang , Miao Tan, Jinchuan Tan
Objectives
To investigate the therapeutic potential and renal protective mechanisms of hirsutine in diabetic kidney disease (DKD).
Methods
A DKD model was induced in Sprague-Dawley rats using a high-fat diet (HFD) and streptozotocin (STZ). High glucose (HG)-stimulated HK-2 cells served as an in vitro model. Reactive oxygen species (ROS) levels in kidney tissues were measured using dihydroethidium (DHE) staining. ELISA was performed to measure MDA, SOD, and GSH in both rat tissues and HK-2 cells. Western blot and immunofluorescence analyses evaluated renal fibrosis, the Nrf2 signaling pathway, and autophagy-related proteins (Beclin 1, LC3I/II, P62).
Results
Hirsutine treatment significantly improved metabolic and renal parameters in rats, enhancing renal function and reducing fibrosis, as shown by lower levels of Vimentin, Collagen-IV, and α-SMA. It alleviated oxidative stress, indicated by reduced ROS and MDA levels and increased SOD and GSH activity. Additionally, hirsutine enhanced autophagy, reflected by higher Beclin 1 and LC3I/II levels and decreased P62 expression. By disrupting the Keap1-Nrf2 interaction, hirsutine increased Nrf2 levels and upregulated antioxidative enzymes like NQO1, SOD-2, and HO-1.
Conclusion
Hirsutine exhibited renoprotective effects in DKD by modulating the Keap1/Nrf2 pathway, mitigating oxidative stress and promoting autophagy, making it a promising candidate for treatment.
{"title":"Hirsutine attenuated oxidative stress and autophagy in diabetic kidney disease through Keap1/Nrf2 pathway","authors":"Yao Zhang , Bing Yang , Miao Tan, Jinchuan Tan","doi":"10.1016/j.jphs.2025.04.002","DOIUrl":"10.1016/j.jphs.2025.04.002","url":null,"abstract":"<div><h3>Objectives</h3><div>To investigate the therapeutic potential and renal protective mechanisms of hirsutine in diabetic kidney disease (DKD).</div></div><div><h3>Methods</h3><div>A DKD model was induced in Sprague-Dawley rats using a high-fat diet (HFD) and streptozotocin (STZ). High glucose (HG)-stimulated HK-2 cells served as an <em>in vitro</em> model. Reactive oxygen species (ROS) levels in kidney tissues were measured using dihydroethidium (DHE) staining. ELISA was performed to measure MDA, SOD, and GSH in both rat tissues and HK-2 cells. Western blot and immunofluorescence analyses evaluated renal fibrosis, the Nrf2 signaling pathway, and autophagy-related proteins (Beclin 1, LC3I/II, P62).</div></div><div><h3>Results</h3><div>Hirsutine treatment significantly improved metabolic and renal parameters in rats, enhancing renal function and reducing fibrosis, as shown by lower levels of Vimentin, Collagen-IV, and α-SMA. It alleviated oxidative stress, indicated by reduced ROS and MDA levels and increased SOD and GSH activity. Additionally, hirsutine enhanced autophagy, reflected by higher Beclin 1 and LC3I/II levels and decreased P62 expression. By disrupting the Keap1-Nrf2 interaction, hirsutine increased Nrf2 levels and upregulated antioxidative enzymes like NQO1, SOD-2, and HO-1.</div></div><div><h3>Conclusion</h3><div>Hirsutine exhibited renoprotective effects in DKD by modulating the Keap1/Nrf2 pathway, mitigating oxidative stress and promoting autophagy, making it a promising candidate for treatment.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"158 2","pages":"Pages 143-153"},"PeriodicalIF":3.0,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143828878","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 is an animal's ability to discriminate between novel and familiar items and is supported by neural activities in not only the perirhinal cortex but also the hippocampus and prefrontal cortex. Since we previously demonstrated that ramelteon enhanced object recognition memory in mice, we sought neural correlates of the memory improvement. We recorded neural activity in the hippocampus and prefrontal cortex of mice while they performed a novel object recognition task. We found that theta oscillations in the hippocampus were enhanced when ramelteon-treated mice explored both novel and familiar objects. Moreover, we showed high coherence in phases at low gamma frequencies between the hippocampus and prefrontal cortex. We assume that theta enhancement is indicative of increased cholinergic activity by melatonin receptor activation. High coherence of low gamma oscillations between the hippocampal and prefrontal network in ramelteon-treated mice sampling novel objects suggests better cognitive operations for discrimination between novelty and familiarity. The current study sheds light upon physiological consequences of melatonin receptor activation, further contributing improved cognitive functions.
{"title":"Ramelteon coordinates theta and gamma oscillations in the hippocampus for novel object recognition memory in mice","authors":"Kinjiro Takeda , Kisa Watanabe , Sena Iijima , Takeshi Nagahiro , Haruka Suzuki , Kano Izumo , Yuji Ikegaya , Nobuyoshi Matsumoto","doi":"10.1016/j.jphs.2025.03.013","DOIUrl":"10.1016/j.jphs.2025.03.013","url":null,"abstract":"<div><div>Object recognition memory is an animal's ability to discriminate between novel and familiar items and is supported by neural activities in not only the perirhinal cortex but also the hippocampus and prefrontal cortex. Since we previously demonstrated that ramelteon enhanced object recognition memory in mice, we sought neural correlates of the memory improvement. We recorded neural activity in the hippocampus and prefrontal cortex of mice while they performed a novel object recognition task. We found that theta oscillations in the hippocampus were enhanced when ramelteon-treated mice explored both novel and familiar objects. Moreover, we showed high coherence in phases at low gamma frequencies between the hippocampus and prefrontal cortex. We assume that theta enhancement is indicative of increased cholinergic activity by melatonin receptor activation. High coherence of low gamma oscillations between the hippocampal and prefrontal network in ramelteon-treated mice sampling novel objects suggests better cognitive operations for discrimination between novelty and familiarity. The current study sheds light upon physiological consequences of melatonin receptor activation, further contributing improved cognitive functions.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"158 2","pages":"Pages 121-130"},"PeriodicalIF":3.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143792004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-31DOI: 10.1016/j.jphs.2025.03.014
Yuji Odagaki , Masakazu Kinoshita , Makoto Honda , J. Javier Meana , Luis F. Callado , Jesús A. García-Sevilla , Miklós Palkovits , Dasiel Oscar Borroto-Escuela , Kjell Fuxe
Functional activation of heterotrimeric guanine nucleotide-binding proteins (G-proteins) via G-protein-coupled receptors (GPCRs) has been extensively explored using guanosine-5′-O-(3-[35S]thio)triphosphate ([35S]GTPγS) binding assay. However, the conventional method is primarily applicable to Gi/o family without discrimination among G-protein subtypes. Therefore, this study aims to reestablish a novel method termed “[35S]GTPγS binding/immunoprecipitation assay” by identifying a most suitable anti-Gαi-3 antibody instead of the previously utilized, now withdrawn antibody. In the initial screening of commercially available anti-Gαi-3 antibodies, two were identified and one was selected for further investigations based on efficacy with adenosine—the most potent agonist in our previous research. After optimizing experimental conditions with rat and postmortem human brain membranes, the stimulatory effects of various agonists were evaluated. Some agonists, including nociceptin, exhibited sufficient stimulatory effects for further pharmacological characterization. Nociceptin increased [35S]GTPγS binding to Gαi-3 in a concentration-dependent manner, response that was insensitive to naloxone but potently inhibited using (±)-J-113397. The method described in this study provides a valuable strategy for determining the intrinsic efficacy of ligands at various GPCRs. This includes nociceptin/orphanin FQ opioid peptide (NOP) receptor selectively coupled to Gαi-3, providing insights into the pharmacological concept of “functional selectivity.”
利用鸟苷-5′- o -（3-[35S]硫代）三磷酸（[35S]GTPγS）结合实验，广泛探讨了异三聚体鸟嘌呤核苷酸结合蛋白（g蛋白）通过g蛋白偶联受体（gpcr）的功能激活。而传统方法主要适用于Gi/o家族，对g蛋白亚型没有区别。因此，本研究旨在通过鉴定一种最合适的抗g αi-3抗体来替代先前使用的现已退出的抗体，从而重建一种称为“[35S]GTPγS结合/免疫沉淀法”的新方法。在对市售抗g αi-3抗体的初步筛选中，确定了两种抗体，并根据与腺苷（我们之前研究中最有效的激动剂）的疗效选择了一种抗体进行进一步研究。在优化大鼠和人死后脑膜的实验条件后，评估了各种激动剂的刺激作用。一些激动剂，包括诺西西汀，表现出足够的刺激作用，可以进一步进行药理学表征。Nociceptin以浓度依赖的方式增加[35S]GTPγS与Gαi-3的结合，该反应对纳洛酮不敏感，但（±）-J-113397有效抑制。本研究中描述的方法为确定各种gpcr配体的内在功效提供了有价值的策略。这包括痛觉肽/孤啡肽FQ阿片肽（NOP）受体选择性偶联Gαi-3，为“功能选择性”的药理学概念提供见解。
{"title":"Receptor-mediated Gi-3 activation in mammalian and human brain membranes: Reestablishment method and its application to nociceptin/orphanin FQ opioid peptide (NOP) receptor/Gi-3 interaction","authors":"Yuji Odagaki , Masakazu Kinoshita , Makoto Honda , J. Javier Meana , Luis F. Callado , Jesús A. García-Sevilla , Miklós Palkovits , Dasiel Oscar Borroto-Escuela , Kjell Fuxe","doi":"10.1016/j.jphs.2025.03.014","DOIUrl":"10.1016/j.jphs.2025.03.014","url":null,"abstract":"<div><div>Functional activation of heterotrimeric guanine nucleotide-binding proteins (G-proteins) via G-protein-coupled receptors (GPCRs) has been extensively explored using guanosine-5′-<em>O</em>-(3-[<sup>35</sup>S]thio)triphosphate ([<sup>35</sup>S]GTPγS) binding assay. However, the conventional method is primarily applicable to G<sub>i/o</sub> family without discrimination among G-protein subtypes. Therefore, this study aims to reestablish a novel method termed “[<sup>35</sup>S]GTPγS binding/immunoprecipitation assay” by identifying a most suitable anti-Gα<sub>i-3</sub> antibody instead of the previously utilized, now withdrawn antibody. In the initial screening of commercially available anti-Gα<sub>i-3</sub> antibodies, two were identified and one was selected for further investigations based on efficacy with adenosine—the most potent agonist in our previous research. After optimizing experimental conditions with rat and postmortem human brain membranes, the stimulatory effects of various agonists were evaluated. Some agonists, including nociceptin, exhibited sufficient stimulatory effects for further pharmacological characterization. Nociceptin increased [<sup>35</sup>S]GTPγS binding to Gα<sub>i-3</sub> in a concentration-dependent manner, response that was insensitive to naloxone but potently inhibited using (±)-J-113397. The method described in this study provides a valuable strategy for determining the intrinsic efficacy of ligands at various GPCRs. This includes nociceptin/orphanin FQ opioid peptide (NOP) receptor selectively coupled to Gα<sub>i-3</sub>, providing insights into the pharmacological concept of “functional selectivity.”</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"158 2","pages":"Pages 131-138"},"PeriodicalIF":3.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143791936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-21DOI: 10.1016/j.jphs.2025.03.010
Hiroe Toba , Denan Jin , Shinji Takai
Secreted protein acidic and rich in cysteine (SPARC), a collagen-binding matricellular protein, is reported to facilitate inflammation and fibrosis in various tissues including the kidneys. Ischemia/reperfusion (I/R) is a major process of acute kidney injury. To investigate whether SPARC inhibition might attenuate renal I/R injury, we injected small interfering RNA (siRNA) targeting SPARC into male BALB/c mice one day before 45 min of renal ischemia followed by 72 h of reperfusion. Serum creatinine concentration, blood urea nitrogen, histological tubular damage, tubulointerstitial fibrosis, and expression of collagen I and transforming growth factor-β were increased after I/R. Expression of 4-hydroxy-2-nonenal, an oxidative stress marker, and the inflammatory cytokines monocyte chemoattractant protein-1 and tumor necrosis factor-α, were also upregulated in I/R kidneys. Overexpression of SPARC mRNA was observed after I/R, and immunohistochemistry revealed that SPARC was localized mainly in damaged tubuloepithelial cells. Additionally, a disintegrin and metalloproteinase with thrombospondin type 1 motif (ADAMTS1) expression colocalized with SPARC. Injection of siRNA targeting SPARC attenuated renal dysfunction, histological abnormalities, collagen deposition, oxidative stress, and renal inflammation. In addition, SPARC gene knockdown suppressed the I/R-induced increases in ADAMTS1 and matrix metalloproteinase-2/9 expression. In conclusion, I/R-induced SPARC could be a novel therapeutic target against acute kidney injury.
{"title":"Suppressing SPARC gene with siRNA exerts therapeutic effects and inhibits MMP-2/9 and ADAMTS1 overexpression in a murine model of ischemia/reperfusion-induced acute kidney injury","authors":"Hiroe Toba , Denan Jin , Shinji Takai","doi":"10.1016/j.jphs.2025.03.010","DOIUrl":"10.1016/j.jphs.2025.03.010","url":null,"abstract":"<div><div>Secreted protein acidic and rich in cysteine (SPARC), a collagen-binding matricellular protein, is reported to facilitate inflammation and fibrosis in various tissues including the kidneys. Ischemia/reperfusion (I/R) is a major process of acute kidney injury. To investigate whether SPARC inhibition might attenuate renal I/R injury, we injected small interfering RNA (siRNA) targeting SPARC into male BALB/c mice one day before 45 min of renal ischemia followed by 72 h of reperfusion. Serum creatinine concentration, blood urea nitrogen, histological tubular damage, tubulointerstitial fibrosis, and expression of collagen I and transforming growth factor-β were increased after I/R. Expression of 4-hydroxy-2-nonenal, an oxidative stress marker, and the inflammatory cytokines monocyte chemoattractant protein-1 and tumor necrosis factor-α, were also upregulated in I/R kidneys. Overexpression of SPARC mRNA was observed after I/R, and immunohistochemistry revealed that SPARC was localized mainly in damaged tubuloepithelial cells. Additionally, a disintegrin and metalloproteinase with thrombospondin type 1 motif (ADAMTS1) expression colocalized with SPARC. Injection of siRNA targeting SPARC attenuated renal dysfunction, histological abnormalities, collagen deposition, oxidative stress, and renal inflammation. In addition, SPARC gene knockdown suppressed the I/R-induced increases in ADAMTS1 and matrix metalloproteinase-2/9 expression. In conclusion, I/R-induced SPARC could be a novel therapeutic target against acute kidney injury.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"158 2","pages":"Pages 103-112"},"PeriodicalIF":3.0,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143705001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nab-paclitaxel (nab-PTX) is transported by organic anion-transporting polypeptide (OATP)1B1 and OATP1B3. Chemotherapy-induced peripheral neuropathy (CIPN) is a representative adverse event associated with gemcitabine plus nab-PTX (GnP) in patients with pancreatic cancer. Gadoxetic acid is also transported by OATP1B1 and OATP1B3. We aimed to assess whether the enhancement effect of gadoxetic acid-enhanced magnetic resonance (MR) imaging could predict the development of CIPN for GnP. This study evaluated 27 patients with pancreatic cancer who underwent gadoxetic acid-enhanced MR imaging prior to GnP treatment. The contrast enhancement index (CEI), a measure of liver enhancement on hepato-biliary images, was measured. Plasma concentrations of paclitaxel at 0.5, 6, and 24 h after first administration were also determined in 13 patients. Sixteen of the twenty-seven patients (59.3 %) developed ≥ grade 1 CIPN during the first 8 weeks. We found a negative relationship between the CEI and area under the plasma concentration curve of PTX (r = −0.729, p = 0.003). In multivariate analysis, a CEI <1.84 and concomitant diabetes mellitus were independent predictors of CIPN development (hazard ratio, 5.37, p = 0.027; hazard ratio, 3.68, p = 0.012, respectively). Gadoxetic acid-enhanced MR imaging could be useful in predicting the development of CIPN during GnP therapy.
{"title":"Gadoxetic acid-enhanced magnetic resonance imaging predicts early nab-paclitaxel-induced peripheral neuropathy during pancreatic cancer treatment: A pilot study","authors":"Yusuke Takasaki , Hironao Okubo , Yuka Fukuo , Muneo Ikemura , Hitoshi Ando , Hiroyuki Isayama","doi":"10.1016/j.jphs.2025.03.009","DOIUrl":"10.1016/j.jphs.2025.03.009","url":null,"abstract":"<div><div>Nab-paclitaxel (nab-PTX) is transported by organic anion-transporting polypeptide (OATP)1B1 and OATP1B3. Chemotherapy-induced peripheral neuropathy (CIPN) is a representative adverse event associated with gemcitabine plus nab-PTX (GnP) in patients with pancreatic cancer. Gadoxetic acid is also transported by OATP1B1 and OATP1B3. We aimed to assess whether the enhancement effect of gadoxetic acid-enhanced magnetic resonance (MR) imaging could predict the development of CIPN for GnP. This study evaluated 27 patients with pancreatic cancer who underwent gadoxetic acid-enhanced MR imaging prior to GnP treatment. The contrast enhancement index (CEI), a measure of liver enhancement on hepato-biliary images, was measured. Plasma concentrations of paclitaxel at 0.5, 6, and 24 h after first administration were also determined in 13 patients. Sixteen of the twenty-seven patients (59.3 %) developed ≥ grade 1 CIPN during the first 8 weeks. We found a negative relationship between the CEI and area under the plasma concentration curve of PTX (r = −0.729, <em>p</em> = 0.003). In multivariate analysis, a CEI <1.84 and concomitant diabetes mellitus were independent predictors of CIPN development (hazard ratio, 5.37, <em>p</em> = 0.027; hazard ratio, 3.68, <em>p</em> = 0.012, respectively). Gadoxetic acid-enhanced MR imaging could be useful in predicting the development of CIPN during GnP therapy.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"158 2","pages":"Pages 113-120"},"PeriodicalIF":3.0,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143768612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-19DOI: 10.1016/j.jphs.2025.03.011
Yoichi Sunagawa , Sonoka Iwashimizu , Masaya Ono , Saho Mochizuki , Kenshiro Iwashita , Rina Sato , Satoshi Shimizu , Masafumi Funamoto , Kana Shimizu , Toshihide Hamabe-Horiike , Yasufumi Katanasaka , Akira Murakami , Tomohiro Asakawa , Makoto Inai , Toshiyuki Kan , Maki Komiyama , Philip Hawke , Kiyoshi Mori , Yoshiki Arakawa , Koji Hasegawa , Tatsuya Morimoto
Background
The anthracycline anticancer drug doxorubicin (DOX) induces myocardial cell death and heart failure. The aim of the present study was to investigate whether nobiletin (NOB), a natural flavonoid isolated from citrus peel, has a protective effect against DOX-induced cardiotoxicity.
Methods and results
H9C2 cells were pretreated with 100 μM NOB and then treated with 1 μM DOX. An MTT assay revealed that NOB improved the decreased cell viability induced by DOX. A TUNEL assay showed that NOB treatment improved DOX-induced apoptosis in H9C2 cells. Western blotting indicated that DOX-induced increases in cleaved caspase-3 and -9 expression were significantly suppressed by NOB treatment. Motion field imaging of human iPS cell-derived cardiomyocyte sheets showed that NOB significantly suppressed a DOX-induced reduction of their contractile function. Next, to investigate the effect of NOB in vivo, DOX was intraperitoneally administered to mice. Echocardiography showed that oral administration of NOB reduced DOX-induced left ventricular systolic dysfunction, and a TUNEL assay showed that oral administration also inhibited apoptosis in the mouse heart.
Conclusions
These results indicate that NOB treatment suppressed DOX-induced cardiotoxicity by reducing apoptosis. Further study of the mechanism of this effect may lead to the development of a novel therapy for DOX-induced heart failure.
{"title":"The citrus flavonoid nobiletin prevents the development of doxorubicin-induced heart failure by inhibiting apoptosis","authors":"Yoichi Sunagawa , Sonoka Iwashimizu , Masaya Ono , Saho Mochizuki , Kenshiro Iwashita , Rina Sato , Satoshi Shimizu , Masafumi Funamoto , Kana Shimizu , Toshihide Hamabe-Horiike , Yasufumi Katanasaka , Akira Murakami , Tomohiro Asakawa , Makoto Inai , Toshiyuki Kan , Maki Komiyama , Philip Hawke , Kiyoshi Mori , Yoshiki Arakawa , Koji Hasegawa , Tatsuya Morimoto","doi":"10.1016/j.jphs.2025.03.011","DOIUrl":"10.1016/j.jphs.2025.03.011","url":null,"abstract":"<div><h3>Background</h3><div>The anthracycline anticancer drug doxorubicin (DOX) induces myocardial cell death and heart failure. The aim of the present study was to investigate whether nobiletin (NOB), a natural flavonoid isolated from citrus peel, has a protective effect against DOX-induced cardiotoxicity.</div></div><div><h3>Methods and results</h3><div>H9C2 cells were pretreated with 100 μM NOB and then treated with 1 μM DOX. An MTT assay revealed that NOB improved the decreased cell viability induced by DOX. A TUNEL assay showed that NOB treatment improved DOX-induced apoptosis in H9C2 cells. Western blotting indicated that DOX-induced increases in cleaved caspase-3 and -9 expression were significantly suppressed by NOB treatment. Motion field imaging of human iPS cell-derived cardiomyocyte sheets showed that NOB significantly suppressed a DOX-induced reduction of their contractile function. Next, to investigate the effect of NOB in vivo, DOX was intraperitoneally administered to mice. Echocardiography showed that oral administration of NOB reduced DOX-induced left ventricular systolic dysfunction, and a TUNEL assay showed that oral administration also inhibited apoptosis in the mouse heart.</div></div><div><h3>Conclusions</h3><div>These results indicate that NOB treatment suppressed DOX-induced cardiotoxicity by reducing apoptosis. Further study of the mechanism of this effect may lead to the development of a novel therapy for DOX-induced heart failure.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"158 2","pages":"Pages 84-94"},"PeriodicalIF":3.0,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143683457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Curcumin mitigates memory deficits or improves memory when it is chronically administered to animals. Due to limited bioavailability of curcumin, it remains almost unknown whether acutely treated curcumin influences cognitive function and underlying neural activity. To address this question, we monitored behavior and neural activity in the hippocampus and medial prefrontal cortex of mice treated with vehicle or curcumin while they were engaged in a novel object recognition task. Object recognition memory performance in the novel object recognition task was increased in curcumin-treated mice. Moreover, delta oscillations in the hippocampus were enhanced in the curcumin-administered mice in the test trial. Altogether, acute curcumin treatment boosts delta oscillations for memory recognition possibly by neuromodulation.
{"title":"Acute curcumin administration enhances delta oscillations in the hippocampus underlying object memory improvement","authors":"Sena Iijima , Kinjiro Takeda , Takeshi Nagahiro , Kisa Watanabe , Yuji Ikegaya , Nobuyoshi Matsumoto","doi":"10.1016/j.jphs.2025.03.007","DOIUrl":"10.1016/j.jphs.2025.03.007","url":null,"abstract":"<div><div>Curcumin mitigates memory deficits or improves memory when it is chronically administered to animals. Due to limited bioavailability of curcumin, it remains almost unknown whether acutely treated curcumin influences cognitive function and underlying neural activity. To address this question, we monitored behavior and neural activity in the hippocampus and medial prefrontal cortex of mice treated with vehicle or curcumin while they were engaged in a novel object recognition task. Object recognition memory performance in the novel object recognition task was increased in curcumin-treated mice. Moreover, delta oscillations in the hippocampus were enhanced in the curcumin-administered mice in the test trial. Altogether, acute curcumin treatment boosts delta oscillations for memory recognition possibly by neuromodulation.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"158 2","pages":"Pages 95-102"},"PeriodicalIF":3.0,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143696938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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