Journal of pharmacological sciences最新文献_第9页

Analyses of the onset mechanisms of cardio-stimulatory action by aciclovir 阿昔洛韦对心脏刺激作用的起效机制分析

IF 3.5 3区医学

Journal of pharmacological sciences Pub Date : 2024-02-08 DOI: 10.1016/j.jphs.2024.02.005

Ai Goto , Ryuichi Kambayashi , Koki Chiba , Makoto Shinozaki , Kiryu Moritani , Hiroko Izumi-Nakaseko , Yoshinori Takei , Akira Hirasawa , Atsushi Sugiyama

{"title":"Analyses of the onset mechanisms of cardio-stimulatory action by aciclovir","authors":"Ai Goto , Ryuichi Kambayashi , Koki Chiba , Makoto Shinozaki , Kiryu Moritani , Hiroko Izumi-Nakaseko , Yoshinori Takei , Akira Hirasawa , Atsushi Sugiyama","doi":"10.1016/j.jphs.2024.02.005","DOIUrl":"10.1016/j.jphs.2024.02.005","url":null,"abstract":"<div>Cardio-stimulatory actions of aciclovir have been considered to primarily depend on the sympathetically-mediated reflex resulting from its hypotensive effect. To further clarify onset mechanisms of the cardio-stimulatory actions, we initially studied them using isoflurane-anesthetized dogs under thorough β1-adrenoceptor blockade with atenolol (1 mg/kg, i.v.) (n = 4). Aciclovir (20 mg/kg/10 min, i.v.) decreased mean arterial blood pressure by 10 mmHg, whereas it increased heart rate by 10 bpm and maximum upstroke velocity of ventricular pressure by 928 mmHg/s, and shortened AH interval by 2 ms, indicating that cardio-stimulatory actions were not totally abolished by β1-adrenoceptor blockade. Then, unknown mechanisms of cardio-stimulatory action were explored. Since aciclovir has a similar chemical structure to theophylline, in silico molecular docking simulation was performed, indicating aciclovir as well as theophylline possesses strong likelihood of interactions with phosphodiesterase 1A, 1C and 3A. Indeed, aciclovir inhibited phosphodiesterase 1A derived from the bovine heart (n = 4), moreover it exerted positive chronotropic action on the atrial tissue preparation of rats along with an increase of tissue cyclic AMP concentration (n = 4). These results indicate that cardio-stimulatory actions of aciclovir could result from not only hypotension-induced, reflex-mediated increase of sympathetic tone but also its inhibitory effects on phosphodiesterase in the heart.</div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"154 4","pages":"Pages 294-300"},"PeriodicalIF":3.5,"publicationDate":"2024-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1347861324000148/pdfft?md5=1ad5852b68e34577972680fdb6f76f61&pid=1-s2.0-S1347861324000148-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139827629","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}

引用次数: 0

Presynaptic inhibition of excitatory synaptic transmission from the calcitonin gene-related peptide-containing parabrachial neurons to the central amygdala in mice – unexpected influence of systemic inflammation thereon 小鼠从含降钙素基因相关肽的杏仁核旁神经元到中央杏仁核的兴奋性突触传递的突触前抑制--全身炎症对此的意外影响

IF 3.5 3区医学

Journal of pharmacological sciences Pub Date : 2024-02-05 DOI: 10.1016/j.jphs.2024.02.004

Naoko Sato , Yukari Takahashi , Yae K. Sugimura , Fusao Kato

{"title":"Presynaptic inhibition of excitatory synaptic transmission from the calcitonin gene-related peptide-containing parabrachial neurons to the central amygdala in mice – unexpected influence of systemic inflammation thereon","authors":"Naoko Sato , Yukari Takahashi , Yae K. Sugimura , Fusao Kato","doi":"10.1016/j.jphs.2024.02.004","DOIUrl":"https://doi.org/10.1016/j.jphs.2024.02.004","url":null,"abstract":"<div>The monosynaptic connection from the lateral parabrachial nucleus (LPB) to the central amygdala (CeA) serves as a fundamental pathway for transmitting nociceptive signals to the brain. The LPB receives nociceptive information from the dorsal horn and spinal trigeminal nucleus and sends it to the “nociceptive” CeA, which modulates pain-associated emotions and nociceptive sensitivity. To elucidate the role of densely expressed mu-opioid receptors (MORs) within this pathway, we investigated the effects of exogenously applied opioids on LPB-CeA synaptic transmission, employing optogenetics in mice expressing channelrhodopsin-2 in LPB neurons with calcitonin gene-related peptide (CGRP). A MOR agonist ([D-Ala2,N–Me-Phe4,Glycinol5]-enkephalin, DAMGO) significantly reduced the amplitude of light-evoked excitatory postsynaptic currents (leEPSCs), in a manner negatively correlated with an increase in the paired-pulse ratio. An antagonist of MORs significantly attenuated these effects. Notably, this antagonist significantly increased leEPSC amplitude when applied alone, an effect further amplified in mice subjected to lipopolysaccharide injection 2 h before brain isolation, yet not observed at the 24-h mark. We conclude that opioids could shut off the ascending nociceptive signal at the LPB-CeA synapse through presynaptic mechanisms. Moreover, this gating process might be modulated by endogenous opioids, and the innate immune system influences this modulation.</div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"154 4","pages":"Pages 264-273"},"PeriodicalIF":3.5,"publicationDate":"2024-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1347861324000136/pdfft?md5=fc87a4c71512f61d7cec4f5c1a2ac6d4&pid=1-s2.0-S1347861324000136-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139748420","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}

引用次数: 0

Platelet-activating factor contracts guinea pig esophageal muscularis mucosae by stimulating extracellular Ca2+ influx through diltiazem-insensitive Ca2+ channels 血小板活化因子通过地尔硫卓不敏感的 Ca2+ 通道刺激细胞外 Ca2+ 流入，从而收缩豚鼠食管粘膜肌肉

IF 3.5 3区医学

Journal of pharmacological sciences Pub Date : 2024-02-05 DOI: 10.1016/j.jphs.2024.01.009

Keisuke Obara , Aina Ichimura , Taichi Arai , Mako Fujiwara , Miho Otake , Nana Yamada , Kento Yoshioka , Taichi Kusakabe , Keisuke Takahashi , Keisuke Kato , Yoshio Tanaka

{"title":"Platelet-activating factor contracts guinea pig esophageal muscularis mucosae by stimulating extracellular Ca2+ influx through diltiazem-insensitive Ca2+ channels","authors":"Keisuke Obara , Aina Ichimura , Taichi Arai , Mako Fujiwara , Miho Otake , Nana Yamada , Kento Yoshioka , Taichi Kusakabe , Keisuke Takahashi , Keisuke Kato , Yoshio Tanaka","doi":"10.1016/j.jphs.2024.01.009","DOIUrl":"https://doi.org/10.1016/j.jphs.2024.01.009","url":null,"abstract":"<div>Platelet-activating factor (PAF) is expected to increase esophageal motility. However, to the best of our knowledge, this has not been examined. Thus, we investigated the contractile effects of PAF on guinea pig (GP) esophageal muscularis mucosae (EMM) and the extracellular Ca2+ influx pathways responsible. PAF (10−9–10−6 M) contracted EMM in a concentration-dependent manner. PAF (10−6 M)-induced contractions were almost completely suppressed by apafant (a PAF receptor antagonist, 3 × 10−5 M). In EMM strips, PAF receptor and PAF-synthesizing/degrading enzyme mRNAs were detected. PAF (10−6 M)-induced contractions were abolished by extracellular Ca2+ removal but were not affected by diltiazem [a voltage-dependent Ca2+ channel (VDCC) inhibitor, 10−5 M]. PAF (10−6 M)-induced contractions in the presence of diltiazem were significantly suppressed by LOE-908 [a receptor-operated Ca2+ channel (ROCC) inhibitor, 3 × 10−5 M], SKF-96365 [an ROCC and store-operated Ca2+ channel (SOCC) inhibitor, 3 × 10−5 M], and LOE-908 plus SKF-96365. Among the tested ROCC/SOCC-related mRNAs, Trpc3, Trpc6, and Trpv4/Orai1, Orai3, and Stim2 were abundantly expressed in EMM strips. These results indicate that PAF potently induces GP EMM contractions that are dependent on extracellular Ca2+ influx through ROCCs/SOCCs, and VDCCs are unlikely to be involved.</div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"154 4","pages":"Pages 256-263"},"PeriodicalIF":3.5,"publicationDate":"2024-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1347861324000094/pdfft?md5=abf88f3ac524d84e9f0a80a8b52c3068&pid=1-s2.0-S1347861324000094-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139748419","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}

引用次数: 0

Characterization of cardiovascular profile of anti-influenza drug peramivir: A reverse-translational study using the isoflurane-anesthetized dog 抗流感药物帕拉米韦的心血管特征：利用异氟醚麻醉狗进行的逆转录研究

IF 3.5 3区医学

Journal of pharmacological sciences Pub Date : 2024-02-02 DOI: 10.1016/j.jphs.2024.02.002

Ryuichi Kambayashi, Ai Goto, Hiroko Izumi-Nakaseko, Yoshinori Takei, Atsushi Sugiyama

{"title":"Characterization of cardiovascular profile of anti-influenza drug peramivir: A reverse-translational study using the isoflurane-anesthetized dog","authors":"Ryuichi Kambayashi, Ai Goto, Hiroko Izumi-Nakaseko, Yoshinori Takei, Atsushi Sugiyama","doi":"10.1016/j.jphs.2024.02.002","DOIUrl":"10.1016/j.jphs.2024.02.002","url":null,"abstract":"<div>An injectable anti-influenza drug peramivir has been reported to induce QT-interval prolongation in some phase III studies, although its thorough QT/QTc study was negative. We investigated the discrepancy among those clinical studies using isoflurane-anesthetized beagle dogs (n = 4). Peramivir in doses of 1 mg/kg/10 min (sub-therapeutic dose) followed by 10 mg/kg/10 min (clinically-relevant dose) was intravenously administered. Peramivir prolonged QT interval/QTcV and Tpeak-Tend, and tended to delay ventricular repolarization in a reverse-frequency dependent manner, indicating IKr inhibition in vivo. Meanwhile, peramivir did not alter P-wave duration, PR interval or QRS width, indicating a lack of impact on cardiac conduction via Na+ or Ca2+ channel inhibition in vivo. Peramivir prolonged Tpeak-Tend and tended to prolong terminal repolarization period, which would develop substrates for initiating and maintaining spiral reentry, respectively. Meanwhile, peramivir did not prolong J-Tpeakc, which could not induce early afterdepolarization, a trigger inducing torsade de pointes. Thus, our results support that clinical dose exposure of peramivir can delay the ventricular repolarization in influenza patients. Peramivir has only a small potential to induce torsade de pointes in patients with the intact hearts, but caution should be paid on its use for patients formerly having the trigger for torsade de pointes.</div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"154 3","pages":"Pages 218-224"},"PeriodicalIF":3.5,"publicationDate":"2024-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1347861324000112/pdfft?md5=81b7b603299d32dfc39fa0d2a6caf2e6&pid=1-s2.0-S1347861324000112-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139679479","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}

引用次数: 0

JTT-654, an 11-beta hydroxysteroid dehydrogenase type 1 inhibitor, improves hypertension and diabetic kidney injury by suppressing angiotensinogen production JTT-654 是一种 11-beta 类羟基类固醇脱氢酶 1 型抑制剂，可通过抑制血管紧张素原的生成来改善高血压和糖尿病肾损伤

IF 3.5 3区医学

Journal of pharmacological sciences Pub Date : 2024-02-02 DOI: 10.1016/j.jphs.2024.02.001

Shiro Heitaku, Tomohiko Sasase, Tomohiro Sotani, Mimi Maki, Takashi Kawai, Hisayo Morinaga, Jun Nishiu

{"title":"JTT-654, an 11-beta hydroxysteroid dehydrogenase type 1 inhibitor, improves hypertension and diabetic kidney injury by suppressing angiotensinogen production","authors":"Shiro Heitaku, Tomohiko Sasase, Tomohiro Sotani, Mimi Maki, Takashi Kawai, Hisayo Morinaga, Jun Nishiu","doi":"10.1016/j.jphs.2024.02.001","DOIUrl":"10.1016/j.jphs.2024.02.001","url":null,"abstract":"<div>11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) plays an important role in regulating the expression of glucocorticoid actions in target tissues. Overexpression of 11β-HSD1 in mouse adipose tissue causes a metabolic syndrome-like phenotype, leading to hypertension. Although, many 11β-HSD1 inhibitors have been studied, few have shown a clear ameliorative effect against hypertension. We investigated whether JTT-654, a novel 11β-HSD1 inhibitor, ameliorated hypertension and elucidated the underlying mechanisms. JTT-654 showed inhibitory effects on angiotensinogen production in cortisone-treated 3T3-L1 adipocytes and in a rat model. JTT-654 improved hypertension not only in cortisone-treated rats and spontaneously hypertensive rats (SHR), but also in SHR/NDmcr-cp rats. In the SHR study, JTT-654 and losartan showed the same degree of antihypertensive efficacy. In addition, JTT-654 ameliorated diabetic nephropathy by suppressing renal angiotensinogen production in SHR/NDmcr-cp rats. These effects of JTT-654 were independent of its insulin-sensitizing effects, and similar effects were not observed for pioglitazone, an insulin sensitizer. Moreover, JTT-654 did not affect normotension or hypothalamus-pituitary-adrenal (HPA) axis function in normal Sprague-Dawley rats. Our results indicate that JTT-654 ameliorates hypertension and diabetic nephropathy by inhibiting 11β-HSD1 in the adipose tissue, liver, and kidney.</div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"154 4","pages":"Pages 246-255"},"PeriodicalIF":3.5,"publicationDate":"2024-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1347861324000100/pdfft?md5=4e3cefc35b67be376843d00f844aa38b&pid=1-s2.0-S1347861324000100-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139665067","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}

引用次数: 0

Inhibition of amino acid transporter LAT1 in cancer cells suppresses G0/G1-S transition by downregulating cyclin D1 via p38 MAPK activation 抑制癌细胞中的氨基酸转运体 LAT1，通过 p38 MAPK 激活下调细胞周期蛋白 D1，从而抑制 G0/G1-S 转变

IF 3.5 3区医学

Journal of pharmacological sciences Pub Date : 2024-01-30 DOI: 10.1016/j.jphs.2024.01.007

Xinyu Zhou , Ryuichi Ohgaki , Chunhuan Jin , Minhui Xu , Hiroki Okanishi , Hitoshi Endou , Yoshikatsu Kanai

{"title":"Inhibition of amino acid transporter LAT1 in cancer cells suppresses G0/G1-S transition by downregulating cyclin D1 via p38 MAPK activation","authors":"Xinyu Zhou , Ryuichi Ohgaki , Chunhuan Jin , Minhui Xu , Hiroki Okanishi , Hitoshi Endou , Yoshikatsu Kanai","doi":"10.1016/j.jphs.2024.01.007","DOIUrl":"10.1016/j.jphs.2024.01.007","url":null,"abstract":"<div>L-type amino acid transporter 1 (LAT1, SLC7A5) is upregulated in various cancers and associated with disease progression. Nanvuranlat (Nanv; JPH203, KYT-0353), a selective LAT1 inhibitor, suppresses the uptake of large neutral amino acids required for rapid growth and proliferation of cancer cells. Previous studies have suggested that the inhibition of LAT1 by Nanv induces the cell cycle arrest at G0/G1 phase, although the underlying mechanisms remain unclear. Using pancreatic cancer cells arrested at the restriction check point (R) by serum deprivation, we found that the Nanv drastically suppresses the G0/G1-S transition after release. This blockade of the cell cycle progression was accompanied by a sustained activation of p38 mitogen-activated protein kinase (MAPK) and subsequent phosphorylation-dependent proteasomal degradation of cyclin D1. Isoform-specific knockdown of p38 MAPK revealed the predominant contribution of p38α. Proteasome inhibitors restored the cyclin D1 amount and released the cell cycle arrest caused by Nanv. The increased phosphorylation of p38 MAPK and the decrease of cyclin D1 were recapitulated in xenograft tumor models treated with Nanv. This study contributes to delineating the pharmacological activities of LAT1 inhibitors as anti-cancer agents and provides significant insights into the molecular basis of the amino acid-dependent cell cycle checkpoint at G0/G1 phase.</div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"154 3","pages":"Pages 182-191"},"PeriodicalIF":3.5,"publicationDate":"2024-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1347861324000070/pdfft?md5=2f3d063a5999027f0f35bd1486d145ea&pid=1-s2.0-S1347861324000070-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139645596","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}

引用次数: 0

Loss of the sustained antidepressant-like effect of (2R,6R)-hydroxynorketamine in NMDA receptor GluN2D subunit knockout mice NMDA受体GluN2D亚基敲除小鼠体内(2R,6R)-羟基炔诺酮乙胺持续抗抑郁样作用的丧失

IF 3.5 3区医学

Journal of pharmacological sciences Pub Date : 2024-01-26 DOI: 10.1016/j.jphs.2024.01.008

Aimi Yamagishi , Yuiko Ikekubo , Masayoshi Mishina , Kazutaka Ikeda , Soichiro Ide

{"title":"Loss of the sustained antidepressant-like effect of (2R,6R)-hydroxynorketamine in NMDA receptor GluN2D subunit knockout mice","authors":"Aimi Yamagishi , Yuiko Ikekubo , Masayoshi Mishina , Kazutaka Ikeda , Soichiro Ide","doi":"10.1016/j.jphs.2024.01.008","DOIUrl":"10.1016/j.jphs.2024.01.008","url":null,"abstract":"<div>Ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, has attracted attention for its acute and sustained antidepressant effects in patients with depression. Hydroxynorketamine (HNK), a metabolite of ketamine, exerts antidepressant effects without exerting ketamine's side effects and has attracted much attention in recent years. However, the detailed pharmacological mechanism of action of HNK remains unclear. We previously showed that the GluN2D NMDA receptor subunit is important for sustained antidepressant-like effects of (R)-ketamine. Therefore, we investigated whether the GluN2D subunit is involved in antidepressant-like effects of (2R,6R)-HNK and (2S,6S)-HNK. Treatment with (2R,6R)-HNK but not (2S,6S)-HNK exerted acute and sustained antidepressant-like effects in the tail-suspension test in wildtype mice. Interestingly, sustained antidepressant-like effects of (2R,6R)-HNK were abolished in GluN2D-knockout mice, whereas acute antidepressant-like effects were maintained in GluN2D-knockout mice. When expression levels of GluN2A and GluN2B subunits were evaluated, a decrease in GluN2B protein expression in the nucleus accumbens was found in stressed wildtype mice but not in stressed GluN2D-knockout mice. These results suggest that the GluN2D subunit and possibly the GluN2B subunit are involved in the sustained antidepressant-like effect of (2R,6R)-HNK.</div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"154 3","pages":"Pages 203-208"},"PeriodicalIF":3.5,"publicationDate":"2024-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1347861324000082/pdfft?md5=00ea33238b3934dd3830799218515da1&pid=1-s2.0-S1347861324000082-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139589450","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}

引用次数: 0

Sulconazole induces pyroptosis promoted by interferon-γ in monocyte/macrophage lineage cells 磺康唑在单核细胞/巨噬细胞系细胞中诱导由干扰素-γ促进的脓毒症

IF 3.5 3区医学

Journal of pharmacological sciences Pub Date : 2024-01-24 DOI: 10.1016/j.jphs.2024.01.006

Shiori Miyawaki, Atsushi Sawamoto, Satoshi Okuyama, Mitsunari Nakajima

{"title":"Sulconazole induces pyroptosis promoted by interferon-γ in monocyte/macrophage lineage cells","authors":"Shiori Miyawaki, Atsushi Sawamoto, Satoshi Okuyama, Mitsunari Nakajima","doi":"10.1016/j.jphs.2024.01.006","DOIUrl":"10.1016/j.jphs.2024.01.006","url":null,"abstract":"<div>Imidazole derivatives are commonly used as antifungal agents. Here, we aimed to investigate the functions of imidazole derivatives on macrophage lineage cells. We assessed the expression levels of inflammatory cytokines in mouse monocyte/macrophage lineage (RAW264.7) cells. All six imidazole derivatives examined, namely ketoconazole, sulconazole, isoconazole, luliconazole, clotrimazole, and bifonazole, reduced the expression levels of inflammatory cytokines, such as interleukin (IL)-6 and tumor necrosis factor-α, after induction by lipopolysaccharide (LPS) in RAW264.7 cells. These imidazole derivatives also induced cell death in RAW264.7 cells, regardless of the presence or absence of LPS. Since the cell death was characteristic in morphology, we investigated the mode of the cell death. An imidazole derivative, sulconazole, induced gasdermin D degradation together with caspase-11 activation, namely, pyroptosis in RAW264.7 cells and peritoneal macrophages. Furthermore, priming with interferon-γ promoted sulconazole-induced pyroptosis in RAW264.7 cells and macrophages and reduced the secretion of the inflammatory cytokine, IL-1β, from sulconazole-treated macrophages. Our results suggest that imidazole derivatives suppress inflammation by inducing macrophage pyroptosis, highlighting their modulatory potential for inflammatory diseases.</div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"154 3","pages":"Pages 166-174"},"PeriodicalIF":3.5,"publicationDate":"2024-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1347861324000069/pdfft?md5=02ad9073820dcbec5a07db633c872dfc&pid=1-s2.0-S1347861324000069-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139553810","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}

引用次数: 0

The inhibitory effect of DIF-3 on polyinosinic–polycytidylic acid-induced innate immunity activation in human cerebral microvascular endothelial cells DIF-3 对聚肌苷酸诱导的人脑微血管内皮细胞先天免疫激活的抑制作用

IF 3.5 3区医学

Journal of pharmacological sciences Pub Date : 2024-01-17 DOI: 10.1016/j.jphs.2024.01.005

Ryusei Araya , Shihu Men , Yoshinori Uekusa , Zaiqiang Yu , Haruhisa Kikuchi , Kazuyuki Daitoku , Masahito Minakawa , Shogo Kawaguchi , Ken-Ichi Furukawa , Yoshiteru Oshima , Tadaatsu Imaizumi , Kazuhiko Seya

{"title":"The inhibitory effect of DIF-3 on polyinosinic–polycytidylic acid-induced innate immunity activation in human cerebral microvascular endothelial cells","authors":"Ryusei Araya , Shihu Men , Yoshinori Uekusa , Zaiqiang Yu , Haruhisa Kikuchi , Kazuyuki Daitoku , Masahito Minakawa , Shogo Kawaguchi , Ken-Ichi Furukawa , Yoshiteru Oshima , Tadaatsu Imaizumi , Kazuhiko Seya","doi":"10.1016/j.jphs.2024.01.005","DOIUrl":"10.1016/j.jphs.2024.01.005","url":null,"abstract":"<div>For the treatment and prevention of autoinflammatory diseases, it is essential to develop the drug, regulating the innate immune system. Although differentiation-inducing factor (DIF) derivatives, extracted from the cellular slime mold, Dictyostelium discoideum, exhibit immunomodulatory effects, their effects on the regulation of innate immunity in brain are unknown. In this study, we used the human cerebral microvascular endothelial cell line, hCMEC/D3, to investigate the effects of DIF derivatives on the generation of C-X-C motif chemokine (CXCL) 10 and interferon (IFN)-β induced by polyinosinic–polycytidylic acid (poly IC). DIF-3 (1–10 μM), but not DIF-1 and DIF-2, dose-dependently inhibited the biosynthesis of not only CXCL10 but also CXCL16 and C–C motif chemokine 2 induced by poly IC. DIF-3 also strongly decreased IFN-β mRNA expression and protein release from the cells induced by poly IC through the prohibition of p65, a subtype of NF-ĸB, not interferon regulatory transcription factor 3 phosphorylation. In the docking simulation study, we confirmed that DIF-3 had a high affinity to p65. These results suggest that DIF-3 regulates the innate immune system by inhibiting TLR3/IFN-β signaling axis through the NF-ĸB phosphorylation inhibition.</div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"154 3","pages":"Pages 157-165"},"PeriodicalIF":3.5,"publicationDate":"2024-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1347861324000057/pdfft?md5=c67009b6c8242c11c621726df47b77d3&pid=1-s2.0-S1347861324000057-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139497770","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}

引用次数: 0

Therapeutic effects of the alkaline extract of leaves of Sasa sp. and elucidation of its mechanism in acute kidney injury 莎莎叶碱性提取物对急性肾损伤的治疗作用及其机制的阐明

IF 3.5 3区医学

Journal of pharmacological sciences Pub Date : 2024-01-11 DOI: 10.1016/j.jphs.2024.01.004

Mizuki Sano , Yutaro Koseki , Keita Shibata , Tomohiro Fujisawa , Koji Nobe

{"title":"Therapeutic effects of the alkaline extract of leaves of Sasa sp. and elucidation of its mechanism in acute kidney injury","authors":"Mizuki Sano , Yutaro Koseki , Keita Shibata , Tomohiro Fujisawa , Koji Nobe","doi":"10.1016/j.jphs.2024.01.004","DOIUrl":"10.1016/j.jphs.2024.01.004","url":null,"abstract":"<div>Acute kidney injury (AKI), a common complication in hospitalized patients, is associated with high morbidity and mortality rates. However, there are currently no approved or effective therapeutics for AKI. AKI is primarily caused by ischemia/reperfusion (I/R) injury, with oxidative stress from reactive oxygen species (ROS) being a major contributor. This study aimed to evaluate the efficacy of an alkaline extract of the leaves of Sasa sp. (SE) using mouse renal I/R injury and hypoxia/reoxygenation (H/R) models in NRK-52E cells. Renal function parameters were measured, and histopathological evaluations were performed to assess the efficacy of SE. In addition, to determine the mechanisms underlying the effects of SE on renal I/R injury, its effects on malondialdehyde (MDA) of oxidative stress and interleukin (IL)-6 and IL-1β of inflammatory cytokines were evaluated. SE (0.03, 0.3, and 3 g/kg) improved renal function in a dose-dependent manner. In addition, SE ameliorated tubular injury and, reduced IL-6, IL-1β and MDA. Also, SE ameliorated cell death, ROS production, and inflammatory cytokine production in H/R-exposed NRK-52E cells. SE showed antioxidant and anti-inflammatory activities in the AKI. These results indicate the potential of SE as a medicinal compound for the prevention and treatment of AKI.</div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"154 3","pages":"Pages 148-156"},"PeriodicalIF":3.5,"publicationDate":"2024-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1347861324000045/pdfft?md5=23b688b6714e82e6fa4024464d0a9195&pid=1-s2.0-S1347861324000045-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139422731","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}

引用次数: 0