Accurate assessment of animal behavior is limited by manual video observation. Here, we demonstrate that deep learning-based analysis of multi-site electromyograms enables classification of behavioral states. Electromyograms were recorded from five muscles in the limbs and neck of mice alongside video monitoring to establish ground-truth labels (i.e., walking, grooming, rearing). A custom convolutional neural network was trained on electromyogram segments. Our model achieved robust classification accuracy, demonstrating the effective detection of behavioral patterns. Our electromyogram-based model provides an objective, automated, and scalable framework for behavioral classification, which can be seamlessly integrated with video monitoring workflows.
{"title":"Deep learning deciphers behavioral states from muscle activation patterns","authors":"Honoka Kuroyanagi , Yuji Ikegaya , Nobuyoshi Matsumoto","doi":"10.1016/j.jphs.2026.01.007","DOIUrl":"10.1016/j.jphs.2026.01.007","url":null,"abstract":"<div><div>Accurate assessment of animal behavior is limited by manual video observation. Here, we demonstrate that deep learning-based analysis of multi-site electromyograms enables classification of behavioral states. Electromyograms were recorded from five muscles in the limbs and neck of mice alongside video monitoring to establish ground-truth labels (<em>i.e.</em>, walking, grooming, rearing). A custom convolutional neural network was trained on electromyogram segments. Our model achieved robust classification accuracy, demonstrating the effective detection of behavioral patterns. Our electromyogram-based model provides an objective, automated, and scalable framework for behavioral classification, which can be seamlessly integrated with video monitoring workflows.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"160 3","pages":"Pages 187-190"},"PeriodicalIF":2.9,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146079882","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 : 2026-01-16DOI: 10.1016/j.jphs.2026.01.005
Aimi Owaki , Shota Kaseda , Shunsuke Tanigawa , Koichiro Miike , Yuya Sannomiya , Haruki Tsuhako , Ryoichi Sato , Keito Mizumoto , Jun Horizono , Ryo Kumabe , Midori Tokuyasu , Yukio Fujiwara , Toru Takeo , Kimi Araki , Bernard Davenport , Rachel Lennon , Tsuyoshi Shuto , Ryuichi Nishinakamura , Mary Ann Suico , Hirofumi Kai
Alport syndrome is a progressive kidney disease caused by pathogenic variants in genes encoding type IV collagen, a major structural component of the glomerular basement membrane (GBM). Abnormal GBM architecture impairs filtration and triggers inflammation, fibrosis, and eventual kidney failure. Because disease progression is irreversible, identifying early molecular changes is essential for understanding disease onset. We performed glomerular single-cell RNA sequencing (scRNA-seq) in a Col4a5 G5X Alport mouse model at 5 weeks of age, prior to detectable proteinuria or GBM/podocyte abnormalities (pre-onset), and at 8 weeks, when mild proteinuria and structural defects emerged. Despite the early stage, scRNA-seq revealed widespread transcriptional alterations, most prominently in podocytes. Among genes upregulated at both time points, we identified Tumor Necrosis Factor Superfamily Member 15 (Tnfsf15), previously associated with kidney disease susceptibility but with unclear function. To determine its role in Alport syndrome, we generated Tnfsf15-deficient Alport mice. Tnfsf15 homozygous knockout mice exhibited increased proteinuria and exacerbated glomerular injury compared with Tnfsf15(+/+) Alport mice during early disease. These findings support a protective role for Tnfsf15 in the early stages of Alport syndrome, mitigating proteinuria and limiting glomerular injury.
{"title":"Protective role of early Tnfsf15 upregulation in limiting glomerular injury and proteinuria in experimental Alport Syndrome","authors":"Aimi Owaki , Shota Kaseda , Shunsuke Tanigawa , Koichiro Miike , Yuya Sannomiya , Haruki Tsuhako , Ryoichi Sato , Keito Mizumoto , Jun Horizono , Ryo Kumabe , Midori Tokuyasu , Yukio Fujiwara , Toru Takeo , Kimi Araki , Bernard Davenport , Rachel Lennon , Tsuyoshi Shuto , Ryuichi Nishinakamura , Mary Ann Suico , Hirofumi Kai","doi":"10.1016/j.jphs.2026.01.005","DOIUrl":"10.1016/j.jphs.2026.01.005","url":null,"abstract":"<div><div>Alport syndrome is a progressive kidney disease caused by pathogenic variants in genes encoding type IV collagen, a major structural component of the glomerular basement membrane (GBM). Abnormal GBM architecture impairs filtration and triggers inflammation, fibrosis, and eventual kidney failure. Because disease progression is irreversible, identifying early molecular changes is essential for understanding disease onset. We performed glomerular single-cell RNA sequencing (scRNA-seq) in a <em>Col4a5 G5X</em> Alport mouse model at 5 weeks of age, prior to detectable proteinuria or GBM/podocyte abnormalities (pre-onset), and at 8 weeks, when mild proteinuria and structural defects emerged. Despite the early stage, scRNA-seq revealed widespread transcriptional alterations, most prominently in podocytes. Among genes upregulated at both time points, we identified Tumor Necrosis Factor Superfamily Member 15 (Tnfsf15), previously associated with kidney disease susceptibility but with unclear function. To determine its role in Alport syndrome, we generated Tnfsf15-deficient Alport mice. Tnfsf15 homozygous knockout mice exhibited increased proteinuria and exacerbated glomerular injury compared with Tnfsf15(+/+) Alport mice during early disease. These findings support a protective role for Tnfsf15 in the early stages of Alport syndrome, mitigating proteinuria and limiting glomerular injury.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"160 3","pages":"Pages 158-166"},"PeriodicalIF":2.9,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146035918","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}
Ischemia-reperfusion (I/R) following reperfusion therapy for ischemic heart disease is a driver of adverse cardiac remodeling and eventual heart failure. We investigated the therapeutic potential of 2,5-dimethylelcelecoxib (DM-C) to prevent cardiac remodeling in a mouse model of cardiac I/R injury. Male C57BL/6 mice were subjected to 30 min of left anterior descending coronary artery ligation followed by reperfusion. Immediately upon awakening, mice received a single oral administration of either vehicle or 150 mg/kg DM-C. This was followed by dietary administration of vehicle or 1000 ppm DM-C. Post-reperfusion administration of DM-C significantly attenuated cardiac remodeling, as demonstrated by improved left ventricular function and reduced cardiac fibrosis and hypertrophy. Mechanistically, DM-C transiently increased the accumulation of CD68-positive macrophages in the injured myocardium, potentially facilitating resolution of inflammation. DM-C also suppressed α-smooth muscle actin-expressing myofibroblast accumulation and downregulated extracellular matrix components. While DM-C treatment tended to mitigate I/R-induced mitochondrial structural destruction and dysfunction, it did not directly improve mitochondrial function in in vitro hypoxia-reoxygenation model. These findings suggest that DM-C suppresses post-I/R cardiac remodeling and dysfunction by modulating inflammatory and fibrotic responses and indirectly supporting mitochondrial integrity, underscoring its potential as a therapeutic agent for I/R injury-induced heart failure.
{"title":"Postoperative administration of 2,5-dimethylcelecoxib attenuates ischemia-reperfusion injury-induced cardiac dysfunction","authors":"Shin Ishikane , Takehiro Kishigami , Eigo Ikushima , Masaki Arioka , Kazunobu Igawa , Fumi Takahashi-Yanaga","doi":"10.1016/j.jphs.2026.01.004","DOIUrl":"10.1016/j.jphs.2026.01.004","url":null,"abstract":"<div><div>Ischemia-reperfusion (I/R) following reperfusion therapy for ischemic heart disease is a driver of adverse cardiac remodeling and eventual heart failure. We investigated the therapeutic potential of 2,5-dimethylelcelecoxib (DM-C) to prevent cardiac remodeling in a mouse model of cardiac I/R injury. Male C57BL/6 mice were subjected to 30 min of left anterior descending coronary artery ligation followed by reperfusion. Immediately upon awakening, mice received a single oral administration of either vehicle or 150 mg/kg DM-C. This was followed by dietary administration of vehicle or 1000 ppm DM-C. Post-reperfusion administration of DM-C significantly attenuated cardiac remodeling, as demonstrated by improved left ventricular function and reduced cardiac fibrosis and hypertrophy. Mechanistically, DM-C transiently increased the accumulation of CD68-positive macrophages in the injured myocardium, potentially facilitating resolution of inflammation. DM-C also suppressed α-smooth muscle actin-expressing myofibroblast accumulation and downregulated extracellular matrix components. While DM-C treatment tended to mitigate I/R-induced mitochondrial structural destruction and dysfunction, it did not directly improve mitochondrial function in <em>in vitro</em> hypoxia-reoxygenation model. These findings suggest that DM-C suppresses post-I/R cardiac remodeling and dysfunction by modulating inflammatory and fibrotic responses and indirectly supporting mitochondrial integrity, underscoring its potential as a therapeutic agent for I/R injury-induced heart failure.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"160 3","pages":"Pages 176-186"},"PeriodicalIF":2.9,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146036300","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}
Tacrolimus, a topical calcineurin inhibitor, is used to treat atopic dermatitis (AD). AD is classically T helper type (Th) 2-driven, but Th17 cells are implicated in chronic AD, yet its efficacy against Th17-dependent pathology remains unclear. We investigated the effects of tacrolimus using a murine model of Th17-mediated allergic skin inflammation. In CD4+ T cells from DO11.10/Rag2−/− mice, which express ovalbumin (OVA)-specific T cell receptor, tacrolimus differentially suppressed stimulation-induced cytokine expression by Th2 cells. At similar concentrations, tacrolimus suppressed Il21, but not Il17a or Il22, expression in Th17 cells. Subcutaneous OVA challenge elicited ear thickening in BALB/c mice after adoptive transfer of Th2 or Th17 cells, with a stronger response in Th17-transferred mice, but less than OVA-immunized controls. Topical tacrolimus reduced Th17-mediated ear swelling, corroborated by histopathology. In Th2-transferred mice, tacrolimus tended to reduce early skin thickening (day 3) but did not affect late responses (day 7). In Th17-transferred mice, tacrolimus significantly reduced allergen-specific T-cell accumulation in OVA-injected skin and tended to reduce Il21 expression, whereas Th2-cell accumulation and cytokine expression were unaffected. Tacrolimus exerts stronger inhibitory effects on Th17- than Th2-driven responses in this model, suggesting that suppression of Th17 pathways may contribute to its therapeutic benefit in AD.
{"title":"Tacrolimus attenuates Th17 cell-mediated allergic skin inflammation in mice","authors":"Fatemeh Beygom Mirkatouli , Yukiko Tao , Uyanga Enkhbaatar , Ryoken Yamanaka , Kento Miura , Norimasa Yamasaki , Sawako Ogata , Naohisa Hosomi , Akio Mori , Tomoharu Yasuda , Masaya Matsuda , Yuya Sannomiya , Takeshi Nabe , Tomofumi Numata , Kazumitsu Sugiura , Noriko Kitamura , Minoru Gotoh , Osamu Kaminuma","doi":"10.1016/j.jphs.2026.01.003","DOIUrl":"10.1016/j.jphs.2026.01.003","url":null,"abstract":"<div><div>Tacrolimus, a topical calcineurin inhibitor, is used to treat atopic dermatitis (AD). AD is classically T helper type (Th) 2-driven, but Th17 cells are implicated in chronic AD, yet its efficacy against Th17-dependent pathology remains unclear. We investigated the effects of tacrolimus using a murine model of Th17-mediated allergic skin inflammation. In CD4<sup>+</sup> T cells from DO11.10/Rag2<sup>−/−</sup> mice, which express ovalbumin (OVA)-specific T cell receptor, tacrolimus differentially suppressed stimulation-induced cytokine expression by Th2 cells. At similar concentrations, tacrolimus suppressed <em>Il21,</em> but not <em>Il17a</em> or <em>Il22</em>, expression in Th17 cells. Subcutaneous OVA challenge elicited ear thickening in BALB/c mice after adoptive transfer of Th2 or Th17 cells, with a stronger response in Th17-transferred mice, but less than OVA-immunized controls. Topical tacrolimus reduced Th17-mediated ear swelling, corroborated by histopathology. In Th2-transferred mice, tacrolimus tended to reduce early skin thickening (day 3) but did not affect late responses (day 7). In Th17-transferred mice, tacrolimus significantly reduced allergen-specific T-cell accumulation in OVA-injected skin and tended to reduce <em>Il21</em> expression, whereas Th2-cell accumulation and cytokine expression were unaffected. Tacrolimus exerts stronger inhibitory effects on Th17- than Th2-driven responses in this model, suggesting that suppression of Th17 pathways may contribute to its therapeutic benefit in AD.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"160 3","pages":"Pages 152-157"},"PeriodicalIF":2.9,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145982078","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}
Hypertensive disorders of pregnancy (HDPs) are serious complications that pose significant risks to both maternal and fetal health. In HDP, placental circulatory impairment is generally attributed to defective differentiation and invasion of the human extravillous trophoblasts (EVTs). Our previous RNA-seq analysis of placentas from early-onset HDP patients revealed decreased expression of dihydroorotate dehydrogenase (DHODH), a mitochondrial enzyme involved in pyrimidine biosynthesis. DHODH inhibition is hypothesized to induce mitochondrial dysfunction. In this study, we investigated whether DHODH inhibition affects mitochondrial homeostasis and invasive capacity in EVT cell line. Selective DHODH inhibitors resulted in decreased mitochondrial membrane potential, upregulation of mitochondrial degradation factors, and mitochondrial fragmentation. Inhibition of DHODH or mitochondrial complexes I, II, and IV led to impaired cell invasion, accompanied by an increase in SA-β-gal-positive senescent cells. Treatment with quercetin or riboflavin, enhancers of mitochondrial ATP functions, partially restored invasive capacity and reduced senescent cell accumulation under mitochondrial stress conditions. Thus, DHODH inhibition in EVTs induces cellular senescence and diminished capacity for invasion. Mitochondrial activators such as quercetin and riboflavin may hold therapeutic promise for ameliorating the pathology of HDPs.
{"title":"DHODH inhibition impairs mitochondrial function and extravillous trophoblast invasion: Protective roles of quercetin and riboflavin","authors":"Kanoko Yoshida, Kazuya Kusama, Kana Kanazawa, Yu Kawaguchi, Atsuya Tsuru, Mikihiro Yoshie, Kazuhiro Tamura","doi":"10.1016/j.jphs.2026.01.001","DOIUrl":"10.1016/j.jphs.2026.01.001","url":null,"abstract":"<div><div>Hypertensive disorders of pregnancy (HDPs) are serious complications that pose significant risks to both maternal and fetal health. In HDP, placental circulatory impairment is generally attributed to defective differentiation and invasion of the human extravillous trophoblasts (EVTs). Our previous RNA-seq analysis of placentas from early-onset HDP patients revealed decreased expression of dihydroorotate dehydrogenase (DHODH), a mitochondrial enzyme involved in pyrimidine biosynthesis. DHODH inhibition is hypothesized to induce mitochondrial dysfunction. In this study, we investigated whether DHODH inhibition affects mitochondrial homeostasis and invasive capacity in EVT cell line. Selective DHODH inhibitors resulted in decreased mitochondrial membrane potential, upregulation of mitochondrial degradation factors, and mitochondrial fragmentation. Inhibition of DHODH or mitochondrial complexes I, II, and IV led to impaired cell invasion, accompanied by an increase in SA-β-gal-positive senescent cells. Treatment with quercetin or riboflavin, enhancers of mitochondrial ATP functions, partially restored invasive capacity and reduced senescent cell accumulation under mitochondrial stress conditions. Thus, DHODH inhibition in EVTs induces cellular senescence and diminished capacity for invasion. Mitochondrial activators such as quercetin and riboflavin may hold therapeutic promise for ameliorating the pathology of HDPs.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"160 3","pages":"Pages 143-151"},"PeriodicalIF":2.9,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145957726","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}
Intracerebral hemorrhage (ICH) is a devastating type of stroke with high mortality and limited treatment options. Brain tissue injury featured by neuroinflammation and axonal damage plays a pivotal role in poor outcome. S-allyl-l-cysteine, a garlic-derived amino acid derivative, possesses antioxidant and anti-inflammatory properties and has been shown to afford neuroprotection in ischemic stroke models. In the present study, ICH was induced in male ICR mice by collagenase injection into the striatum. When S-allyl-l-cysteine (300 or 600 mg/kg) was administered intraperitoneally at 1 h before and 3, 27, and 51 h after ICH induction, the compound alleviated ICH-induced motor deficits as revealed by limb-placing and beam-walking tests in a dose-dependent manner. At 600 mg/kg, S-allyl-l-cysteine significantly suppressed hematoma-associated microglial/macrophage activation and neuronal loss, reduced axonal fragmentation in the internal capsule and decreased brain lesion volume, while having no effect on several other events such as astrocyte activation, nitrosative stress, or hemorrhage volume. S-allyl-l-cysteine also tended to inhibit neutrophil infiltration but did not alter expression of IL-6 and CXCL2 mRNAs. Overall, S-allyl-l-cysteine ameliorated prognosis of ICH, and the underlying mechanisms may involve suppression of microglial/macrophage activation and neuronal loss, attenuation of axonal injury, and reduction of brain lesion volume.
{"title":"S-allyl-l-cysteine ameliorates sensorimotor functions after intracerebral hemorrhage in mice concomitantly with prevention of axon tract fragmentation and reduction of brain lesion volume","authors":"Yuma Hirata , Keita Kinoshita , Keisuke Ushida , Shunya Tsujita , Moe Fujino , Natsuko Hitora-Imamura , Yuki Kurauchi , Hiroshi Katsuki","doi":"10.1016/j.jphs.2026.01.002","DOIUrl":"10.1016/j.jphs.2026.01.002","url":null,"abstract":"<div><div>Intracerebral hemorrhage (ICH) is a devastating type of stroke with high mortality and limited treatment options. Brain tissue injury featured by neuroinflammation and axonal damage plays a pivotal role in poor outcome. <em>S</em>-allyl-<span>l</span>-cysteine, a garlic-derived amino acid derivative, possesses antioxidant and anti-inflammatory properties and has been shown to afford neuroprotection in ischemic stroke models. In the present study, ICH was induced in male ICR mice by collagenase injection into the striatum. When <em>S</em>-allyl-<span>l</span>-cysteine (300 or 600 mg/kg) was administered intraperitoneally at 1 h before and 3, 27, and 51 h after ICH induction, the compound alleviated ICH-induced motor deficits as revealed by limb-placing and beam-walking tests in a dose-dependent manner. At 600 mg/kg, <em>S</em>-allyl-<span>l</span>-cysteine significantly suppressed hematoma-associated microglial/macrophage activation and neuronal loss, reduced axonal fragmentation in the internal capsule and decreased brain lesion volume, while having no effect on several other events such as astrocyte activation, nitrosative stress, or hemorrhage volume. <em>S</em>-allyl-<span>l</span>-cysteine also tended to inhibit neutrophil infiltration but did not alter expression of IL-6 and CXCL2 mRNAs. Overall, <em>S</em>-allyl-<span>l</span>-cysteine ameliorated prognosis of ICH, and the underlying mechanisms may involve suppression of microglial/macrophage activation and neuronal loss, attenuation of axonal injury, and reduction of brain lesion volume.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"160 3","pages":"Pages 167-175"},"PeriodicalIF":2.9,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146036301","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}
Recent studies have reported that sodium-glucose cotransporter (SGLT) 2 inhibitors ameliorate steatotic liver disease. We investigated the contribution of SGLT2 inhibitor-induced fluid loss due to glycosuria in hepatic ureagenesis for water conservation to the association between improvement of steatotic liver disease and the energy-consuming nature of hepatic ureagenesis.
General methods
ob/ob mice fed a high-fat diet without carbohydrate restriction were administered luseogliflozin, an SGLT2 inhibitor, for eight weeks.
Findings
Luseogliflozin significantly decreased the liver weight, plasma aspartate aminotransferase and alanine aminotransferase levels, and fat content in mice with enhanced glycosuria (H-GlcV group). The ratio of urinary urea excretion decreased as a substitute for increased glucose excretion in the H-GlcV group. Luseogliflozin significantly increased liver urea content and tended to increase malate dehydrogenase (MDH)-1 activity. Liver MDH-1 activity was significantly positively correlated with liver urea content, suggesting that MDH-1-induced amino acid recruitment from the tricarboxylic acid cycle to the urea cycle may contribute to enhanced ureagenesis. In addition, liver weight was significantly negatively correlated with the liver urea content.
Conclusions
Our data suggest that enhanced hepatic ureagenesis as a compensatory water conservation mechanism for glycosuria-induced fluid loss may be associated with amelioration of steatotic liver disease in SGLT2 inhibitor-treated ob/ob mice.
{"title":"SGLT2 inhibitor-induced glycosuria improves steatotic liver disease in parallel with enhanced ureagenesis in ob/ob mice","authors":"Satoshi Kidoguchi , Kento Kitada , Asahiro Morishita , Yudai Tsuji , Hiroyuki Ohsaki , Daisuke Yamazaki , Takashi Morikawa , Yoshio Konishi , Hideki Kobara , Takashi Yokoo , Jens Titze , Kazuo Takahashi , Akira Nishiyama","doi":"10.1016/j.jphs.2025.12.006","DOIUrl":"10.1016/j.jphs.2025.12.006","url":null,"abstract":"<div><h3>Purpose</h3><div>Recent studies have reported that sodium-glucose cotransporter (SGLT) 2 inhibitors ameliorate steatotic liver disease. We investigated the contribution of SGLT2 inhibitor-induced fluid loss due to glycosuria in hepatic ureagenesis for water conservation to the association between improvement of steatotic liver disease and the energy-consuming nature of hepatic ureagenesis.</div></div><div><h3>General methods</h3><div><em>ob/ob</em> mice fed a high-fat diet without carbohydrate restriction were administered luseogliflozin, an SGLT2 inhibitor, for eight weeks.</div></div><div><h3>Findings</h3><div>Luseogliflozin significantly decreased the liver weight, plasma aspartate aminotransferase and alanine aminotransferase levels, and fat content in mice with enhanced glycosuria (H-GlcV group). The ratio of urinary urea excretion decreased as a substitute for increased glucose excretion in the H-GlcV group. Luseogliflozin significantly increased liver urea content and tended to increase malate dehydrogenase (MDH)-1 activity. Liver MDH-1 activity was significantly positively correlated with liver urea content, suggesting that MDH-1-induced amino acid recruitment from the tricarboxylic acid cycle to the urea cycle may contribute to enhanced ureagenesis. In addition, liver weight was significantly negatively correlated with the liver urea content.</div></div><div><h3>Conclusions</h3><div>Our data suggest that enhanced hepatic ureagenesis as a compensatory water conservation mechanism for glycosuria-induced fluid loss may be associated with amelioration of steatotic liver disease in SGLT2 inhibitor-treated <em>ob/ob</em> mice.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"160 2","pages":"Pages 122-131"},"PeriodicalIF":2.9,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145837624","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 : 2025-12-16DOI: 10.1016/j.jphs.2025.12.005
Ami Ono , Tatsunori Miyaoka , Daichi Koan , Zihao Jin , Lu Chen , Atsuko Hayata-Takano , Satoshi Asano , Rei Yokoyama , Kenji Ishimoto , Nobumasa Hino , Akihiro Harada , Takanobu Nakazawa , Hitoshi Hashimoto , James A. Waschek , Shinsaku Nakagawa , Kotaro Tanimoto , Yukio Ago
Accumulating evidence suggests that microduplications of the VIPR2 gene are strongly associated with schizophrenia. VIPR2 encodes vasoactive intestinal peptide receptor 2 (VPAC2). However, cell-type-specific actions of VPAC2 overexpression with respect to schizophrenia remain unclear. Therefore, we aimed to determine the effects of human VPAC2 overexpression in neurons on cognition-related behaviors and prefrontal cortex dendritic morphology in mice. We crossed a Tau-Cre mouse line, which targets neuronal recombinase activity, with a newly generated double transgenic mouse line containing tetracycline-responsive element-human VPAC2-IRES-mCherry and ROSA:LNL:tTA. Immunohistochemical and Western blot analyses revealed that VPAC2 was overexpressed in neurons throughout the brain. Mice that overexpressed VPAC2 showed impaired performance in the novel object recognition test. Furthermore, VPAC2-overexpressing mice exhibited significant reductions in brain weight and the length, branch number, and complexity of arborization of prefrontal cortex pyramidal neuron dendrites. RNA sequencing analysis revealed that VPAC2 overexpression may affect signaling pathways involved in regulating stem cell pluripotency, cell cycle, and actin cytoskeleton. Quantitative PCR analysis also confirmed increased expression of the X-linked lymphocyte-regulated 3B gene, which regulates dendritic morphogenesis and spine assembly. These results suggest that VPAC2 overexpression in neurons has a detrimental effect on brain development, which leads to impaired neural circuitry and cognitive function.
{"title":"Neuron-specific overexpression of human vasoactive intestinal peptide receptor 2 in mice causes cognitive dysfunction and abnormal dendritic morphology in the prefrontal cortex","authors":"Ami Ono , Tatsunori Miyaoka , Daichi Koan , Zihao Jin , Lu Chen , Atsuko Hayata-Takano , Satoshi Asano , Rei Yokoyama , Kenji Ishimoto , Nobumasa Hino , Akihiro Harada , Takanobu Nakazawa , Hitoshi Hashimoto , James A. Waschek , Shinsaku Nakagawa , Kotaro Tanimoto , Yukio Ago","doi":"10.1016/j.jphs.2025.12.005","DOIUrl":"10.1016/j.jphs.2025.12.005","url":null,"abstract":"<div><div>Accumulating evidence suggests that microduplications of the <em>VIPR2</em> gene are strongly associated with schizophrenia. <em>VIPR2</em> encodes vasoactive intestinal peptide receptor 2 (VPAC2). However, cell-type-specific actions of VPAC2 overexpression with respect to schizophrenia remain unclear. Therefore, we aimed to determine the effects of human VPAC2 overexpression in neurons on cognition-related behaviors and prefrontal cortex dendritic morphology in mice. We crossed a Tau-Cre mouse line, which targets neuronal recombinase activity, with a newly generated double transgenic mouse line containing tetracycline-responsive element-human VPAC2-IRES-mCherry and ROSA:LNL:tTA. Immunohistochemical and Western blot analyses revealed that VPAC2 was overexpressed in neurons throughout the brain. Mice that overexpressed VPAC2 showed impaired performance in the novel object recognition test. Furthermore, VPAC2-overexpressing mice exhibited significant reductions in brain weight and the length, branch number, and complexity of arborization of prefrontal cortex pyramidal neuron dendrites. RNA sequencing analysis revealed that VPAC2 overexpression may affect signaling pathways involved in regulating stem cell pluripotency, cell cycle, and actin cytoskeleton. Quantitative PCR analysis also confirmed increased expression of the X-linked lymphocyte-regulated 3B gene, which regulates dendritic morphogenesis and spine assembly. These results suggest that VPAC2 overexpression in neurons has a detrimental effect on brain development, which leads to impaired neural circuitry and cognitive function.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"160 2","pages":"Pages 111-121"},"PeriodicalIF":2.9,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145837570","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}
Triple-negative breast cancer (TNBC), which lacks expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2), is associated with poor prognosis. Immune checkpoint inhibitors (ICIs) have emerged as a promising therapeutic option for TNBC, but their efficacy remains limited due to resistance. In this study, we investigated whether the non-receptor tyrosine kinase Src (Src tyrosine kinase) regulates interferon-gamma (IFNγ)-induced expression of programmed death-ligand 1 (PD-L1). IFNγ stimulation of TNBC and luminal A breast cancer cell lines induced time-dependent phosphorylation of Src at its activation site (Y419). Pharmacological inhibition of Src significantly suppressed IFNγ–induced PD-L1 mRNA and protein expression, as well as activation of PD-L1–related transcription factors, suggesting transcriptional regulation. In co-culture assays with CD8+ T-cells, TNBC cells were more susceptible to T-cell–mediated cytotoxicity compared with luminal A cells, and Src inhibition further enhanced this cytotoxicity. These findings indicate that Src plays a crucial role in IFNγ–mediated PD-L1 expression and immune evasion in TNBC cell lines. Src inhibition may represent a promising combinatorial strategy to enhance antitumor immunity in TNBC cell lines.
{"title":"Src-dependent modulation of IFNγ-induced PD-L1 expression in human breast cancer cell lines","authors":"Chihiro Hayashi , Yuto Mizuno , Yu Iida , Akane Nagasako , Michiko Endo , Wakana Fukae , Eriko Yamashita , Yoshihiro Ishikawa , Masanari Umemura","doi":"10.1016/j.jphs.2025.12.004","DOIUrl":"10.1016/j.jphs.2025.12.004","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC), which lacks expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2), is associated with poor prognosis. Immune checkpoint inhibitors (ICIs) have emerged as a promising therapeutic option for TNBC, but their efficacy remains limited due to resistance. In this study, we investigated whether the non-receptor tyrosine kinase Src (Src tyrosine kinase) regulates interferon-gamma (IFNγ)-induced expression of programmed death-ligand 1 (PD-L1). IFNγ stimulation of TNBC and luminal A breast cancer cell lines induced time-dependent phosphorylation of Src at its activation site (Y419). Pharmacological inhibition of Src significantly suppressed IFNγ–induced PD-L1 mRNA and protein expression, as well as activation of PD-L1–related transcription factors, suggesting transcriptional regulation. In co-culture assays with CD8<sup>+</sup> T-cells, TNBC cells were more susceptible to T-cell–mediated cytotoxicity compared with luminal A cells, and Src inhibition further enhanced this cytotoxicity. These findings indicate that Src plays a crucial role in IFNγ–mediated PD-L1 expression and immune evasion in TNBC cell lines. Src inhibition may represent a promising combinatorial strategy to enhance antitumor immunity in TNBC cell lines.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"160 2","pages":"Pages 132-141"},"PeriodicalIF":2.9,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145837623","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}
Magnesium (Mg) is an essential cation critical for neuronal and cardiac homeostasis, principally by modulating N-methyl-d-aspartate (NMDA) receptor function. While magnesium deficiency (MgD) is known to impair memory and autonomic function, the systemic interplay remains poorly understood.
As a preliminary step to investigating neural activity during memory tasks, this study investigated the effects of 3 weeks of MgD on neural activity patterns and cardiac function in rats. Simultaneous electrophysiological recordings from the dorsal hippocampus and medial prefrontal cortex, along with electrocardiogram and electromyogram (EMG) monitoring, revealed that MgD selectively altered neural oscillations without affecting cardiac function or sleep architecture. Notably, frequency-specific changes in local field potentials (LFPs) were most pronounced during quiet wakefulness under dark conditions. This excessive enhancement of gamma wave activity may contribute to memory impairment.
This 3-week deficiency was characterized by altered neural excitability, which could lead to cognitive impairment and partial cardiac arrhythmia.
Our findings demonstrate that spontaneous neural activity is altered even in the 3-week of MgD and support a model in which the deficiency progressively disrupts physiological regulation.
{"title":"Magnesium deficiency differentially modulates hippocampal and prefrontal oscillations and cardiac rhythms","authors":"Sora Inoue , Yuji Ikegaya , Nobuyoshi Matsumoto , Tetsuhiko Kashima","doi":"10.1016/j.jphs.2025.12.002","DOIUrl":"10.1016/j.jphs.2025.12.002","url":null,"abstract":"<div><div>Magnesium (Mg) is an essential cation critical for neuronal and cardiac homeostasis, principally by modulating <em>N</em>-methyl-d-aspartate (NMDA) receptor function. While magnesium deficiency (MgD) is known to impair memory and autonomic function, the systemic interplay remains poorly understood.</div><div>As a preliminary step to investigating neural activity during memory tasks, this study investigated the effects of 3 weeks of MgD on neural activity patterns and cardiac function in rats. Simultaneous electrophysiological recordings from the dorsal hippocampus and medial prefrontal cortex, along with electrocardiogram and electromyogram (EMG) monitoring, revealed that MgD selectively altered neural oscillations without affecting cardiac function or sleep architecture. Notably, frequency-specific changes in local field potentials (LFPs) were most pronounced during quiet wakefulness under dark conditions. This excessive enhancement of gamma wave activity may contribute to memory impairment.</div><div>This 3-week deficiency was characterized by altered neural excitability, which could lead to cognitive impairment and partial cardiac arrhythmia.</div><div>Our findings demonstrate that spontaneous neural activity is altered even in the 3-week of MgD and support a model in which the deficiency progressively disrupts physiological regulation.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"160 2","pages":"Pages 97-110"},"PeriodicalIF":2.9,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145711962","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号