Journal of pharmacological sciences最新文献_第10页

Chronic stress alters lipid mediator profiles associated with immune-related gene expressions and cell compositions in mouse bone marrow and spleen 慢性应激改变了小鼠骨髓和脾脏中与免疫相关基因表达和细胞组成有关的脂质介质谱系

IF 3.5 3区医学

Journal of pharmacological sciences Pub Date : 2024-02-15 DOI: 10.1016/j.jphs.2024.02.010

Io Horikawa , Hirotaka Nagai , Masayuki Taniguchi , Guowei Chen , Masakazu Shinohara , Tomohide Suzuki , Shinichi Ishii , Yoshio Katayama , Shiho Kitaoka , Tomoyuki Furuyashiki

{"title":"Chronic stress alters lipid mediator profiles associated with immune-related gene expressions and cell compositions in mouse bone marrow and spleen","authors":"Io Horikawa , Hirotaka Nagai , Masayuki Taniguchi , Guowei Chen , Masakazu Shinohara , Tomohide Suzuki , Shinichi Ishii , Yoshio Katayama , Shiho Kitaoka , Tomoyuki Furuyashiki","doi":"10.1016/j.jphs.2024.02.010","DOIUrl":"10.1016/j.jphs.2024.02.010","url":null,"abstract":"<div>Despite the importance of lipid mediators in stress and depression and their link to inflammation, the influence of stress on these mediators and their role in inflammation is not fully understood. This study used RNA-seq, LC-MS/MS, and flow cytometry analyses in a mouse model subjected to chronic social defeat stress to explore the effects of acute and chronic stress on lipid mediators, gene expression, and cell population in the bone marrow and spleen. In the bone marrow, chronic stress induced a sustained transition from lymphoid to myeloid cells, accompanied by corresponding changes in gene expression. This change was associated with decreased levels of 15-deoxy-d12,14-prostaglandin J2, a lipid mediator that inhibits inflammation. In the spleen, chronic stress also induced a lymphoid-to-myeloid transition, albeit transiently, alongside gene expression changes indicative of extramedullary hematopoiesis. These changes were linked to lower levels of 12-HEPE and resolvins, both critical for inhibiting and resolving inflammation. Our findings highlight the significant role of anti-inflammatory and pro-resolving lipid mediators in the immune responses induced by chronic stress in the bone marrow and spleen. This study paves the way for understanding how these lipid mediators contribute to the immune mechanisms of stress and depression.</div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"154 4","pages":"Pages 279-293"},"PeriodicalIF":3.5,"publicationDate":"2024-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1347861324000215/pdfft?md5=d0923d053b1625bac5010259dd286bd9&pid=1-s2.0-S1347861324000215-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139833182","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

Seihaito, a Kampo medicine, attenuates IL-13-induced mucus production and goblet cell metaplasia Seihaito 是一种堪布药，可减少 IL-13 诱导的粘液分泌和上皮细胞增生

IF 3.5 3区医学

Journal of pharmacological sciences Pub Date : 2024-02-13 DOI: 10.1016/j.jphs.2024.02.008

Tomoki Sekiya, Kazuhito Murakami, Yoichiro Isohama

{"title":"Seihaito, a Kampo medicine, attenuates IL-13-induced mucus production and goblet cell metaplasia","authors":"Tomoki Sekiya, Kazuhito Murakami, Yoichiro Isohama","doi":"10.1016/j.jphs.2024.02.008","DOIUrl":"10.1016/j.jphs.2024.02.008","url":null,"abstract":"<div>Goblet cell hyperplasia and increased mucus production are features of airway diseases, including asthma, and excess airway mucus often worsens these conditions. Even steroids are not uniformly effective in mucus production in severe asthma, and new therapeutic options are needed. Seihaito is a Japanese traditional medicine that is used clinically as an antitussive and expectorant. In the present study, we examined the effect of Seihaito on goblet cell differentiation and mucus production. In in vitro studies, using air–liquid interface culture of guinea-pig tracheal epithelial cells, Seihaito inhibited IL-13-induced proliferation of goblet cells and MUC5AC, a major component of mucus production. Seihaito suppressed goblet cell-specific gene expression, without changing ciliary cell-specific genes, suggesting that it inhibits goblet cell differentiation. In addition, Seihaito suppressed MUC5AC expression in cells transfected with SPDEF, a transcription factor activated by IL-13. Furthermore, Seihaito attenuated in vivo goblet cell proliferation and MUC5AC mRNA expression in IL-13-treated mouse lungs. Collectively, these findings demonstrated that Seihaito has an inhibitory effect on goblet cell differentiation and mucus production, which is at least partly due to the inhibition of SPDEF.</div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"155 2","pages":"Pages 21-28"},"PeriodicalIF":3.5,"publicationDate":"2024-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1347861324000197/pdfft?md5=582d82ecef1c0bf646e122f4d4b17aff&pid=1-s2.0-S1347861324000197-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139889843","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

LPS priming-induced immune tolerance mitigates LPS-stimulated microglial activation and social avoidance behaviors in mice LPS 引物诱导的免疫耐受可减轻 LPS 刺激的小鼠微胶质细胞活化和社交回避行为

IF 3.5 3区医学

Journal of pharmacological sciences Pub Date : 2024-02-10 DOI: 10.1016/j.jphs.2024.02.006

Vichuda Charoensaensuk , Bor-Ren Huang , Sian-Ting Huang , Chingju Lin , Sheng-Yun Xie , Chao-Wei Chen , Yen-Chang Chen , Han-Tsung Cheng , Yu-Shu Liu , Sheng-Wei Lai , Ching-Kai Shen , Hui-Jung Lin , Liang-Yo Yang , Dah-Yuu Lu

{"title":"LPS priming-induced immune tolerance mitigates LPS-stimulated microglial activation and social avoidance behaviors in mice","authors":"Vichuda Charoensaensuk , Bor-Ren Huang , Sian-Ting Huang , Chingju Lin , Sheng-Yun Xie , Chao-Wei Chen , Yen-Chang Chen , Han-Tsung Cheng , Yu-Shu Liu , Sheng-Wei Lai , Ching-Kai Shen , Hui-Jung Lin , Liang-Yo Yang , Dah-Yuu Lu","doi":"10.1016/j.jphs.2024.02.006","DOIUrl":"https://doi.org/10.1016/j.jphs.2024.02.006","url":null,"abstract":"<div>In this study, we investigated the regulatory mechanisms underlying the effects of LPS tolerance on the inflammatory homeostasis of immune cells. LPS priming–induced immune tolerance downregulated cyclooxygenase-2, and lowered the production of prostaglandin-E2 in microglial cells. In addition, LPS tolerance downregulated the expression of suppressor of cytokine signaling 3, and inducible nitric oxide synthase/nitric oxide; suppressed the LPS-mediated induction of tumor necrosis factor-α, interleukin (IL)-6, and IL-1; and reduced reactive oxygen species production in microglial cells. LPS stimulation increased the levels of the adaptive response–related proteins heme oxygenase-1 and superoxide dismutase 2, and the levels of heme oxygenase-1 (HO-1) enhanced after LPS priming. Systemic administration of low-dose LPS (0.5 mg/kg) to mice for 4 consecutive days attenuated high-dose LPS (5 mg/kg)–induced inflammatory response, microglial activation, and proinflammatory cytokine expression. Moreover, repeated exposure to low-dose LPS suppressed the recruitment of peripheral monocytes or macrophages to brain regions and downregulated the expression of proinflammatory cytokines. Notably, LPS-induced social avoidance behaviors in mice were mitigated by immune tolerance. In conclusion, immune tolerance may reduce proinflammatory cytokine expression and reactive oxygen species production. Our findings provide insights into the effects of endotoxin tolerance on innate immune cells and social behaviors.</div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"154 4","pages":"Pages 225-235"},"PeriodicalIF":3.5,"publicationDate":"2024-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S134786132400015X/pdfft?md5=c68a625a9686dc84d90f383eda9be5f6&pid=1-s2.0-S134786132400015X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139738712","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

Activation of σ-1 receptor mitigates estrogen withdrawal-induced anxiety/depressive-like behavior in mice via restoration of GABA/glutamate signaling and neuroplasticity in the hippocampus 通过恢复 GABA/谷氨酸信号传导和海马体的神经可塑性，激活 σ-1 受体减轻雌激素戒断诱发的小鼠焦虑/抑郁样行为

IF 3.5 3区医学

Journal of pharmacological sciences Pub Date : 2024-02-09 DOI: 10.1016/j.jphs.2024.02.003

Peng Ren , Jing-Ya Wang , Hong-Lei Chen , Yue Wang , Lin-Yu Cui , Jing-Yao Duan , Wen-Zhi Guo , Yong-Qi Zhao , Yun-Feng Li

{"title":"Activation of σ-1 receptor mitigates estrogen withdrawal-induced anxiety/depressive-like behavior in mice via restoration of GABA/glutamate signaling and neuroplasticity in the hippocampus","authors":"Peng Ren , Jing-Ya Wang , Hong-Lei Chen , Yue Wang , Lin-Yu Cui , Jing-Yao Duan , Wen-Zhi Guo , Yong-Qi Zhao , Yun-Feng Li","doi":"10.1016/j.jphs.2024.02.003","DOIUrl":"https://doi.org/10.1016/j.jphs.2024.02.003","url":null,"abstract":"<div>Postpartum depression (PPD) is a significant contributor to maternal morbidity and mortality. The Sigma-1 (σ-1) receptor has received increasing attention in recent years because of its ability to link different signaling systems and exert its function in the brain through chaperone actions, especially in neuropsychiatric disorders. YL-0919, a novel σ-1 receptor agonist developed by our institute, has shown antidepressive and anxiolytic effects in a variety of animal models, but effects on PPD have not been revealed. In the present study, excitatory/inhibitory signaling in the hippocampus was reflected by GABA and glutamate and their associated excitatory-inhibitory receptor proteins, the HPA axis hormones in the hippocampus were assessed by ELISA. Finally, immunofluorescence for markers of newborn neuron were undertaken in the dentate gyri, along with dendritic spine staining and dendritic arborization tracing. YL-0919 rapidly improves anxiety and depressive-like behavior in PPD-like mice within one week, along with normalizing the excitation/inhibition signaling as well as the HPA axis activity. YL-0919 rescued the decrease in hippocampal dendritic complexity and spine density induced by estrogen withdrawal. The study results suggest that YL-0919 elicits a therapeutic effect on PPD-like mice; therefore, the σ-1 receptor may be a novel promising target for PPD treatment in the future.</div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"154 4","pages":"Pages 236-245"},"PeriodicalIF":3.5,"publicationDate":"2024-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1347861324000124/pdfft?md5=551e7d6413187bfae0882225c67467a0&pid=1-s2.0-S1347861324000124-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139738713","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

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