Journal of pharmacological sciences最新文献

Therapeutic effects of fingolimod through sphingosine-1-phosphate signaling in pulmonary arterial hypertension 芬戈莫德通过鞘氨醇-1-磷酸信号传导治疗肺动脉高压的作用

IF 2.9 3区医学

Journal of pharmacological sciences Pub Date : 2026-04-01 Epub Date: 2026-02-03 DOI: 10.1016/j.jphs.2026.02.002

Moe Fujiwara , Aya Yamamura , Rubii Kondo , Yoshiaki Suzuki , Hisao Yamamura

{"title":"Therapeutic effects of fingolimod through sphingosine-1-phosphate signaling in pulmonary arterial hypertension","authors":"Moe Fujiwara , Aya Yamamura , Rubii Kondo , Yoshiaki Suzuki , Hisao Yamamura","doi":"10.1016/j.jphs.2026.02.002","DOIUrl":"10.1016/j.jphs.2026.02.002","url":null,"abstract":"<div><div>Pulmonary arterial hypertension (PAH) is a progressive and life-threatening disease characterized by pulmonary vascular remodeling. This remodeling is primarily caused by abnormal proliferation of pulmonary arterial smooth muscle cells (PASMCs), facilitated by perivascular inflammatory macrophages. Fingolimod, an immunosuppressive drug approved for multiple sclerosis, modulates sphingosine-1-phosphate (S1P) signaling. In the present study, the effects of fingolimod on the excessive proliferation of PASMCs from patients with idiopathic PAH (IPAH), the viability of human monocyte-derived macrophages, and pulmonary vascular remodeling and survival in monocrotaline (MCT)-induced PAH rats were examined. Fingolimod inhibited the abnormal proliferation of IPAH-PASMCs (IC<sub>50</sub> = 3.8 μM) and reduced the viability of CD163-positive macrophages. S1P receptor 3, predominantly expressed in PASMCs, was upregulated in IPAH-PASMCs and in pulmonary arterial smooth muscle tissues from MCT-PAH rats. Administration of fingolimod (1 mg/kg/day) decreased perivascular accumulation of CD163-positive macrophages, lowered right ventricular systolic pressure, and attenuated pulmonary vascular remodeling in MCT-PAH rats. Kaplan-Meier survival analysis demonstrated that fingolimod prolonged survival. Collectively, these findings indicate that fingolimod ameliorates pulmonary vascular remodeling by inhibiting abnormal PASMC proliferation and CD163-positive macrophage viability, thereby improving survival in experimental PAH rats. Targeting the S1P signaling pathway with fingolimod may represent a promising repositioning strategy for PAH therapy.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"160 4","pages":"Pages 191-198"},"PeriodicalIF":2.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146192707","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}

引用次数: 0

Sodium-glucose Co-transporter 2 (SGLT2) inhibitor dapagliflozin acutely activates cardiomyocyte HIF-1α signaling via succinate, a signaling metabolite 钠-葡萄糖共转运蛋白2 （SGLT2）抑制剂达格列净通过信号代谢物琥珀酸盐急性激活心肌细胞HIF-1α信号

IF 2.9 3区医学

Journal of pharmacological sciences Pub Date : 2026-04-01 Epub Date: 2026-02-04 DOI: 10.1016/j.jphs.2026.01.008

Tatsuyuki Sato , Takayuki Isagawa , Yuki Sugiura , Daigo Sawaki , Yu Nakagama , Takahiro Kuchimaru , Shun Minatsuki , Shigeru Sato , Kazutoshi Ono , Ariunbold Chuluun-Erdene , Hiroaki Semba , Masamichi Ito , Toshinaru Kawakami , Ryohei Tanaka , Masaya Sakamoto , Masataka Asagiri , Hiroshi Harada , Christian Stockmann , Tomo Yonezawa , Yasushi Hirota , Norihiko Takeda

{"title":"Sodium-glucose Co-transporter 2 (SGLT2) inhibitor dapagliflozin acutely activates cardiomyocyte HIF-1α signaling via succinate, a signaling metabolite","authors":"Tatsuyuki Sato , Takayuki Isagawa , Yuki Sugiura , Daigo Sawaki , Yu Nakagama , Takahiro Kuchimaru , Shun Minatsuki , Shigeru Sato , Kazutoshi Ono , Ariunbold Chuluun-Erdene , Hiroaki Semba , Masamichi Ito , Toshinaru Kawakami , Ryohei Tanaka , Masaya Sakamoto , Masataka Asagiri , Hiroshi Harada , Christian Stockmann , Tomo Yonezawa , Yasushi Hirota , Norihiko Takeda","doi":"10.1016/j.jphs.2026.01.008","DOIUrl":"10.1016/j.jphs.2026.01.008","url":null,"abstract":"<div><div>SGLT2 inhibitors are widely used to treat patients with chronic heart failure, and several studies have shown that the efficacy of SGLT2 inhibitors also extends to acute heart failure. However, the mechanisms remain unknown. Here, using knockout mice and pharmacological approaches, we show that short-term SGLT2 inhibitor treatment activates hypoxia-inducible factor-1α (HIF-1α) signaling in cardiomyocytes, and further pharmacological studies raised the possibility that this effect is mediated by ketone body-derived succinate. One week of Dapagliflozin administration upregulated the expression of HIF-1α target genes, and the effect was abolished in cardiomyocyte-specific HIF-1α knockout mice. Metabolome analysis and enzyme-based assays revealed that, following one week of short-term Dapagliflozin treatment, ketone body levels in the heart increased, leading to an accumulation of succinate, which may act as a signaling metabolite that stabilizes HIF-1α. Administration of pimozide, which is a succinyl-CoA:3-ketoacid CoA transferase (SCOT) inhibitor that inhibits ketone body metabolism, abolished dapagliflozin-elicited activation of HIF-1α signaling. These results, although not conclusive, can be plausibly explained if short-term Dapagliflozin treatment activates HIF-1α signaling in cardiomyocytes via ketone body-derived succinate. Our study raises the possibility that HIF-1α plays a role in the effects of SGLT2 inhibitors and highlights HIF-1α as a speculative target for future studies.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"160 4","pages":"Pages 221-231"},"PeriodicalIF":2.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146192423","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}

引用次数: 0

Ferulic acid activates Nrf2/HO-1 signaling axis to ameliorate neuronal Golgi stress by SKP2 阿魏酸激活Nrf2/HO-1信号轴，通过SKP2改善神经元高尔基应激

IF 2.9 3区医学

Journal of pharmacological sciences Pub Date : 2026-04-01 Epub Date: 2026-01-29 DOI: 10.1016/j.jphs.2026.01.006

Qinghua Dong , Chao Liu , Aiguo Li , Xinwei Zhao , Xiaohui Qin , Wencong Xu , Gangjian Tang

{"title":"Ferulic acid activates Nrf2/HO-1 signaling axis to ameliorate neuronal Golgi stress by SKP2","authors":"Qinghua Dong , Chao Liu , Aiguo Li , Xinwei Zhao , Xiaohui Qin , Wencong Xu , Gangjian Tang","doi":"10.1016/j.jphs.2026.01.006","DOIUrl":"10.1016/j.jphs.2026.01.006","url":null,"abstract":"<div><h3>Background</h3><div>Traumatic brain injury (TBI) ranks among the top contributors to neurological impairments worldwide, with Golgi stress implicated in neuronal injury. This study investigated the neuroprotective effects of ferulic acid (FA) in TBI by regulating Golgi stress.</div></div><div><h3>Methods</h3><div>HT-22 and NSC34 cells were exposed to H<sub>2</sub>O<sub>2</sub> to induce a neuronal injury model. Protein expression were evaluated via Western blot and immunofluorescence. Cell viability and apoptosis were quantified using CCK-8 assay and TUNEL staining, respectively. The interactions between Src, SKP2, and Nrf2 were detected by Co-IP assay.</div></div><div><h3>Results</h3><div>FA treatment reduced LDH release, as well as repressed Golgi stress and apoptosis by H<sub>2</sub>O<sub>2</sub>-induced in HT-22 and NSC34 cells. Mechanistically, FA inhibited Src-mediated phosphorylation of SKP2 at Y131, preventing SKP2-mediated Nrf2 ubiquitination and degradation. Moreover, FA activated the antioxidative Nrf2/HO-1 pathway, alleviating H<sub>2</sub>O<sub>2</sub>-induced Golgi stress and neuronal injury.</div></div><div><h3>Conclusion</h3><div>FA reduced neuronal Golgi stress in H<sub>2</sub>O<sub>2</sub>-treated neuronal cells by restoring the Nrf2/HO-1 signaling through inhibiting Src-mediated SKP2 phosphorylation. These findings indicate that FA is a potential neuroprotective agent.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"160 4","pages":"Pages 209-220"},"PeriodicalIF":2.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146192434","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}

引用次数: 0

Protective effects of a highly water-soluble rutin on cognitive dysfunction in mice 高水溶性芦丁对小鼠认知功能障碍的保护作用

IF 2.9 3区医学

Journal of pharmacological sciences Pub Date : 2026-04-01 Epub Date: 2026-02-03 DOI: 10.1016/j.jphs.2026.02.001

Honoka Fujimori , Takuya Ohba , Yoshiki Kuse , Shinsuke Nakamura , Hiroaki Kida , Takeshi Okada , Naoto Yamaguchi , Hideaki Hara , Masamitsu Shimazawa

{"title":"Protective effects of a highly water-soluble rutin on cognitive dysfunction in mice","authors":"Honoka Fujimori , Takuya Ohba , Yoshiki Kuse , Shinsuke Nakamura , Hiroaki Kida , Takeshi Okada , Naoto Yamaguchi , Hideaki Hara , Masamitsu Shimazawa","doi":"10.1016/j.jphs.2026.02.001","DOIUrl":"10.1016/j.jphs.2026.02.001","url":null,"abstract":"<div><div>Dementia involves progressive cognitive decline, impairing daily and social activities. As no current drugs can reverse this decline, preventive strategies using functional compounds are gaining attention. Rutin, a flavonoid with neuroprotective and vascular benefits, has limited bioavailability due to poor water solubility. Although enzymatic glycosylation improves its solubility, it contains multiple compounds with differing numbers of sugar units and is not a single compound. To address this, EubioQuercetin®, a novel water-soluble rutin (wsRutin) formulation, was developed using L-arginine and ascorbic acid, without enzymatic processing. Here, we evaluated the neuroprotective effects of quercetin and isorhamnetin, the major metabolites of rutin, and compared the cognitive effects of rutin suspension and wsRutin solution in mice. Quercetin and isorhamnetin suppressed glutamate-, menadione- and H<sub>2</sub>O<sub>2</sub>-induced cell death and glutamate-induced reactive oxygen species production in HT22 mouse hippocampal cells. The oral administration of wsRutin solution significantly improved scopolamine- and MK-801-induced cognitive impairment in the novel object recognition test. wsRutin solution also enhanced the expression of brain-derived neurotrophic factor (BDNF)-related proteins in the hippocampus, including BDNF pro-peptide, p-TrkB, p-CREB, PKCα, NR1, HO-1 and NQO1. These findings suggest that wsRutin improves cognitive function via activating BDNF/TrkB signaling or antioxidant mechanism and may represent a preventive agent for dementia.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"160 4","pages":"Pages 199-208"},"PeriodicalIF":2.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146192433","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}

引用次数: 0

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 s -烯丙基-l-半胱氨酸改善小鼠脑出血后的感觉运动功能，同时预防轴突束断裂和减少脑损伤体积

IF 2.9 3区医学

Journal of pharmacological sciences Pub Date : 2026-03-01 Epub Date: 2026-01-08 DOI: 10.1016/j.jphs.2026.01.002

Yuma Hirata , Keita Kinoshita , Keisuke Ushida , Shunya Tsujita , Moe Fujino , Natsuko Hitora-Imamura , Yuki Kurauchi , Hiroshi Katsuki

{"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":"2026-03-01","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}

引用次数: 0

Protective role of early Tnfsf15 upregulation in limiting glomerular injury and proteinuria in experimental Alport Syndrome 早期Tnfsf15上调对实验性Alport综合征肾小球损伤和蛋白尿的保护作用

IF 2.9 3区医学

Journal of pharmacological sciences Pub Date : 2026-03-01 Epub Date: 2026-01-16 DOI: 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

{"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":"2026-03-01","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}

引用次数: 0

Postoperative administration of 2,5-dimethylcelecoxib attenuates ischemia-reperfusion injury-induced cardiac dysfunction 术后给予2,5-二甲基塞来昔布可减轻缺血再灌注损伤引起的心功能障碍

IF 2.9 3区医学

Journal of pharmacological sciences Pub Date : 2026-03-01 Epub Date: 2026-01-16 DOI: 10.1016/j.jphs.2026.01.004

Shin Ishikane , Takehiro Kishigami , Eigo Ikushima , Masaki Arioka , Kazunobu Igawa , Fumi Takahashi-Yanaga

{"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":"2026-03-01","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}

引用次数: 0

Deep learning deciphers behavioral states from muscle activation patterns 深度学习从肌肉激活模式中解读行为状态

IF 2.9 3区医学

Journal of pharmacological sciences Pub Date : 2026-03-01 Epub Date: 2026-01-20 DOI: 10.1016/j.jphs.2026.01.007

Honoka Kuroyanagi , Yuji Ikegaya , Nobuyoshi Matsumoto

引用次数: 0

DHODH inhibition impairs mitochondrial function and extravillous trophoblast invasion: Protective roles of quercetin and riboflavin DHODH抑制损害线粒体功能和外滋养细胞侵袭：槲皮素和核黄素的保护作用

IF 2.9 3区医学

Journal of pharmacological sciences Pub Date : 2026-03-01 Epub Date: 2026-01-09 DOI: 10.1016/j.jphs.2026.01.001

Kanoko Yoshida, Kazuya Kusama, Kana Kanazawa, Yu Kawaguchi, Atsuya Tsuru, Mikihiro Yoshie, Kazuhiro Tamura

{"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":"2026-03-01","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}

引用次数: 0

Tacrolimus attenuates Th17 cell-mediated allergic skin inflammation in mice 他克莫司减轻小鼠Th17细胞介导的过敏性皮肤炎症

IF 2.9 3区医学

Journal of pharmacological sciences Pub Date : 2026-03-01 Epub Date: 2026-01-12 DOI: 10.1016/j.jphs.2026.01.003

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

{"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":"2026-03-01","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}

引用次数: 0