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Upregulation of ATF4 mediates the cellular adaptation to pharmacologic inhibition of amino acid transporter LAT1 in pancreatic ductal adenocarcinoma cells J. Pharmacol. Sci. (IF 3.5) Pub Date : 2024-03-13 Yu Ma, Suguru Okuda, Hiroki Okanishi, Minhui Xu, Chunhuan Jin, Hitoshi Endou, Ryuichi Ohgaki, Yoshikatsu Kanai
L-type amino acid transporter 1 (LAT1) is recognized as a promising target for cancer therapy; however, the cellular adaptive response to its pharmacological inhibition remains largely unexplored. This study examined the adaptive response to LAT1 inhibition using nanvuranlat, a high-affinity LAT1 inhibitor. Proteomic analysis revealed the activation of a stress-induced transcription factor ATF4 following
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Gallic acid ameliorates endometrial hyperplasia through the inhibition of the PI3K/AKT pathway and the down-regulation of cyclin D1 expression J. Pharmacol. Sci. (IF 3.5) Pub Date : 2024-03-05 Caijie Zheng, Yi Wang, Beilei Bi, Wencheng Zhou, Xinran Cao, Chenyang Zhang, Wentian Lu, Yang Sun, Jiao Qu, Wen Lv
Gallic acid (GA) is an organic compound with phenolic properties that occurs naturally and can be found in Guizhi Fuling capsules, showcasing a wide range of biological functionalities. The objective of this study was to examine the influence of GA on endometrial hyperplasia (EH) and elucidate its underlying mechanism. Initially, the induction of EH was achieved by administering estradiol to mice via
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Drug combination of topical ripasudil and brimonidine enhances neuroprotection in a mouse model of optic nerve injury J. Pharmacol. Sci. (IF 3.5) Pub Date : 2024-02-29 Kazuhiko Namekata, Takahiko Noro, Euido Nishijima, Akiko Sotozono, Xiaoli Guo, Chikako Harada, Youichi Shinozaki, Yoshinori Mitamura, Tadashi Nakano, Takayuki Harada
To determine whether combination of topical ripasudil and brimonidine has more effective neuroprotection on retinal ganglion cells (RGCs) following injury to axons composing the optic nerve. Topical ripasudil, brimonidine, or mixture of both drugs were administered to adult mice after optic nerve injury (ONI). The influence of drug conditions on RGC health were evaluated by the quantifications of surviving
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Icariin alleviates diabetic renal interstitial fibrosis aggravation by inhibiting miR-320a-3p targeting BMP6 J. Pharmacol. Sci. (IF 3.5) Pub Date : 2024-02-27 Kaiwei Wang, Mengjun Hou, Chen Qiao, Yalei Duan, Rongpin Tao, Xiniao Wang, Kang Xiao, Shuo Liu, Hanzhen Zhao, Jiali Wang, Zhirong Jia, Xuansheng Ding
Diabetic nephropathy is a common complication of diabetes, accumulating evidence underscores the pivotal role of tubulointerstitial fibrosis in the progression of diabetic nephropathy. However, the underlying mechanisms remain incompletely understood. Although the mechanisms in diabetic nephropathy fibrosis have been the focus of many studies, only limited information is currently available concerning
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Laminar-selective spinal astrocyte population capable of converting tactile information into nociceptive in rats J. Pharmacol. Sci. (IF 3.5) Pub Date : 2024-02-27 Daichi Sueto, Akihisa Onishi, Eriko I, Yu Yoshikawa, Makoto Tsuda
We previously identified a spinal astrocyte population that expresses hairy and enhancer of split 5 () and is selectively present in superficial laminae in mice. However, it was unclear whether such astrocyte heterogeneity is commonly observed across species. Using adeno-associated viral (AAV) vectors incorporating a rat promotor (AAV-Hes5P), we found that AAV-Hes5P-captured astrocytes were selectively
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Identification of tumor-suppressive miRNAs that target amino acid transporter LAT1 and exhibit anti-proliferative effects on cholangiocarcinoma cells J. Pharmacol. Sci. (IF 3.5) Pub Date : 2024-02-24 Xingming Liu, Kou Nishikubo, Ryuichi Ohgaki, Hiroki Okanishi, Suguru Okuda, Minhui Xu, Yoshikatsu Kanai
Amino acid transporter LAT1 is highly upregulated in various cancer types, including cholangiocarcinoma (CHOL), and contributes to the rapid proliferation of cancer cells and disease progression. However, the molecular mechanisms underlying the pathological upregulation of LAT1 remain largely unknown. This study pursued the possibility of miRNA-mediated regulation of the LAT1 expression in CHOL cells
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Effects of D-allose on ATP production and cell viability in neonatal rat cardiomyocytes J. Pharmacol. Sci. (IF 3.5) Pub Date : 2024-02-15 Xi Chen, Asadur Rahman, Steeve Akumwami, Asahiro Morishita, Kento Kitada, Yasumasa Ikeda, Masafumi Funamoto, Akira Nishiyama
2-Deoxy--glucose (2DG) induces anticancer effects through glycolytic inhibition but it may raise the risk of arrhythmia. The rare monosaccharide -allose also has anticancer properties, but its cardiac effects are unknown. We examined the effects of -allose on adenosine triphosphate (ATP) production in neonatal rat cardiomyocytes. We showed that 25 mM -allose selectively reduced glycolytic ATP, but
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Chronic stress alters lipid mediator profiles associated with immune-related gene expressions and cell compositions in mouse bone marrow and spleen J. Pharmacol. Sci. (IF 3.5) Pub Date : 2024-02-15 Io Horikawa, Hirotaka Nagai, Masayuki Taniguchi, Guowei Chen, Masakazu Shinohara, Tomohide Suzuki, Shinichi Ishii, Yoshio Katayama, Shiho Kitaoka, Tomoyuki Furuyashiki
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
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Seihaito, a Kampo medicine, attenuates IL-13-induced mucus production and goblet cell metaplasia J. Pharmacol. Sci. (IF 3.5) Pub Date : 2024-02-13 Tomoki Sekiya, Kazuhito Murakami, Yoichiro Isohama
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
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LPS priming-induced immune tolerance mitigates LPS-stimulated microglial activation and social avoidance behaviors in mice J. Pharmacol. Sci. (IF 3.5) Pub Date : 2024-02-10 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
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-E in microglial cells. In addition, LPS tolerance downregulated the expression of suppressor of cytokine signaling 3, and inducible nitric oxide
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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 J. Pharmacol. Sci. (IF 3.5) Pub Date : 2024-02-09 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
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,
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Analyses of the onset mechanisms of cardio-stimulatory action by aciclovir J. Pharmacol. Sci. (IF 3.5) Pub Date : 2024-02-08 Ai Goto, Ryuichi Kambayashi, Koki Chiba, Makoto Shinozaki, Kiryu Moritani, Hiroko Izumi-Nakaseko, Yoshinori Takei, Akira Hirasawa, Atsushi Sugiyama
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 β-adrenoceptor blockade with atenolol (1 mg/kg, i.v.) (n = 4). Aciclovir (20 mg/kg/10 min, i.v
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Platelet-activating factor contracts guinea pig esophageal muscularis mucosae by stimulating extracellular Ca2+ influx through diltiazem-insensitive Ca2+ channels J. Pharmacol. Sci. (IF 3.5) Pub Date : 2024-02-05 Keisuke Obara, Aina Ichimura, Taichi Arai, Mako Fujiwara, Miho Otake, Nana Yamada, Kento Yoshioka, Taichi Kusakabe, Keisuke Takahashi, Keisuke Kato, Yoshio Tanaka
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 Ca influx pathways responsible. PAF (10–10 M) contracted EMM in a concentration-dependent manner. PAF (10 M)-induced contractions
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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 J. Pharmacol. Sci. (IF 3.5) Pub Date : 2024-02-05 Naoko Sato, Yukari Takahashi, Yae K. Sugimura, Fusao Kato
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
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Inhibition of amino acid transporter LAT1 in cancer cells suppresses G0/G1-S transition by downregulating cyclin D1 via p38 MAPK activation J. Pharmacol. Sci. (IF 3.5) Pub Date : 2024-01-30 Xinyu Zhou, Ryuichi Ohgaki, Chunhuan Jin, Minhui Xu, Hiroki Okanishi, Hitoshi Endou, Yoshikatsu Kanai
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
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Characterization of cardiovascular profile of anti-influenza drug peramivir: A reverse-translational study using the isoflurane-anesthetized dog J. Pharmacol. Sci. (IF 3.5) Pub Date : 2024-02-02 Ryuichi Kambayashi, Ai Goto, Hiroko Izumi-Nakaseko, Yoshinori Takei, Atsushi Sugiyama
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
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JTT-654, an 11-beta hydroxysteroid dehydrogenase type 1 inhibitor, improves hypertension and diabetic kidney injury by suppressing angiotensinogen production J. Pharmacol. Sci. (IF 3.5) Pub Date : 2024-02-02 Shiro Heitaku, Tomohiko Sasase, Tomohiro Sotani, Mimi Maki, Takashi Kawai, Hisayo Morinaga, Jun Nishiu
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
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Sulconazole induces pyroptosis promoted by interferon-γ in monocyte/macrophage lineage cells J. Pharmacol. Sci. (IF 3.5) Pub Date : 2024-01-24 Shiori Miyawaki, Atsushi Sawamoto, Satoshi Okuyama, Mitsunari Nakajima
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
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Loss of the sustained antidepressant-like effect of (2R,6R)-hydroxynorketamine in NMDA receptor GluN2D subunit knockout mice J. Pharmacol. Sci. (IF 3.5) Pub Date : 2024-01-26 Aimi Yamagishi, Yuiko Ikekubo, Masayoshi Mishina, Kazutaka Ikeda, Soichiro Ide
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
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The inhibitory effect of DIF-3 on polyinosinic–polycytidylic acid-induced innate immunity activation in human cerebral microvascular endothelial cells J. Pharmacol. Sci. (IF 3.5) Pub Date : 2024-01-17 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
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
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Therapeutic effects of the alkaline extract of leaves of Sasa sp. and elucidation of its mechanism in acute kidney injury J. Pharmacol. Sci. (IF 3.5) Pub Date : 2024-01-11 Mizuki Sano, Yutaro Koseki, Keita Shibata, Tomohiro Fujisawa, Koji Nobe
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
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Neuronal activation of nucleus accumbens by local methamphetamine administration induces cognitive impairment through microglial inflammation in mice J. Pharmacol. Sci. (IF 3.5) Pub Date : 2024-01-09 Yuka Kusui, Naotaka Izuo, Reika Tokuhara, Takashi Asano, Atsumi Nitta
More than half of methamphetamine (METH) users present with cognitive impairment, making it difficult for them to reintegrate into society. However, the mechanisms of METH-induced cognitive impairment remain unclear. METH causes neuronal hyperactivation in the nucleus accumbens (NAc) by aberrantly releasing dopamine, which triggers dependence. In this study, to clarify the involvement of hyperactivation
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2,5-Dimethyl-celecoxib induces early termination of inflammatory responses by transient macrophage accumulation and inhibits the progression of cardiac remodeling in a mouse model of cryoinjury-induced myocardial infarction J. Pharmacol. Sci. (IF 3.5) Pub Date : 2024-01-03 Takehiro Kishigami, Shin Ishikane, Masaki Arioka, Kazunobu Igawa, Yosuke Nishimura, Fumi Takahashi-Yanaga
In our previous study, we reported that 2, 5-dimethyl-celecoxib (DM-C), a derivative of celecoxib, prevents cardiac remodeling in different mouse models of heart failure, including myocardial infarction (MI). The inflammatory response after MI affects the progression of cardiac remodeling, wherein the immune cells, mainly macrophages, play crucial roles. Therefore, we evaluated the effect of DM-C on
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Blockade of vasoactive intestinal peptide receptor 2 (VIPR2) signaling suppresses cyclin D1-dependent cell-cycle progression in MCF-7 cells J. Pharmacol. Sci. (IF 3.5) Pub Date : 2024-01-05 Satoshi Asano, Ami Ono, Kaede Baba, Teru Uehara, Kotaro Sakamoto, Atsuko Hayata-Takano, Takanobu Nakazawa, Souichi Yanamoto, Kotaro Tanimoto, Hitoshi Hashimoto, Yukio Ago
Vasoactive intestinal peptide (VIP) receptor 2 (VIPR2) is a G protein-coupled receptor that binds to Gαs, Gαi, and Gαq proteins to regulate various downstream signaling molecules, such as protein kinase A (PKA), phosphatidylinositol 3-kinase (PI3K), and phospholipase C. In this study, we examined the role of VIPR2 in cell cycle progression. KS-133, a newly developed VIPR2-selective antagonist peptide
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The role of P2Y6 receptor in the pathogenesis of cardiovascular and inflammatory diseases J. Pharmacol. Sci. (IF 3.5) Pub Date : 2024-01-05 Kazuhiro Nishiyama
The purinergic receptor P2Y6 receptor (P2Y6R) is a member of the G protein-coupled receptors (GPCR) family. P2Y6R is widely expressed in various cell types and plays a critical role in physiological processes, where it is activated by extracellular uridine diphosphate (UDP) and mobilizes Ca2+ via the Gαq/11 protein pathway. We have recently discovered the pathophysiological role of P2Y6R in cardiovascular
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Attenuation of protein arginine dimethylation via S-nitrosylation of protein arginine methyltransferase 1 J. Pharmacol. Sci. (IF 3.5) Pub Date : 2023-12-28 Rikako Taniguchi, Yuto Moriya, Naoshi Dohmae, Takehiro Suzuki, Kengo Nakahara, Sho Kubota, Nobumasa Takasugi, Takashi Uehara
Upregulation of nitric oxide (NO) production contributes to the pathogenesis of numerous diseases via S-nitrosylation, a post-translational modification of proteins. This process occurs due to the oxidative reaction between NO and a cysteine thiol group; however, the extent of this reaction remains unknown. S-Nitrosylation of PRMT1, a major asymmetric arginine methyltransferase of histones and numerous
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Farrerol suppresses osteoclast differentiation and postmenopausal osteoporosis by inhibiting the nuclear factor kappa B signaling pathway J. Pharmacol. Sci. (IF 3.5) Pub Date : 2023-12-29 Wei Lu, Guobin Qi, Xiuying Yang, Defang Li, Weibin Chen, Qingmin Zeng, Zengxin Jiang
Excessive bone resorption caused by upregulated osteoclast activity is a key factor in osteoporosis pathogenesis. Farrerol is a typical natural flavanone and exhibits various pharmacological actions. However, the role and mechanism of action of farrerol in osteoclast differentiation regulation remain unclear. This study aimed to evaluate the effects and mechanism of farrerol on the inhibition of osteoclastogenesis
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Taurine deficiency associated with dilated cardiomyopathy and aging J. Pharmacol. Sci. (IF 3.5) Pub Date : 2023-12-28 Takashi Ito, Shigeru Murakami
Taurine (2-aminoethanesulfonic acid) is a free amino acid found ubiquitously and abundantly in mammalian tissues. Taurine content in the heart is approximately 20 mM, which is approximately 100 times higher than plasma concentration. The high intracellular concentration of taurine is maintained by the taurine transporter (TauT; Slc6a6). Taurine plays various roles, including the regulation of intracellular
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Mechanism of cytotoxicity induced by the cigarette smoke extract (CSE) of heated tobacco products in vascular smooth muscle cells: A comparative study of the cytotoxic effects of CSE and the ferroptosis inducer, erastin J. Pharmacol. Sci. (IF 3.5) Pub Date : 2023-12-27 Takahiro Horinouchi, Yuichi Mazaki, Soichi Miwa
Heated tobacco products (HTPs) are marketed worldwide as less harmful alternatives to combustible cigarettes; however, their cytotoxic mechanisms in vascular smooth muscle cells are poorly understood. Ferroptosis is defined as iron-dependent cell death caused by the accumulation of lipid peroxidation products. In this study, the cytotoxic effects of nicotine- and tar-free cigarette smoke extracts (CSE)
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Supersulfide prevents cigarette smoke extract-induced mitochondria hyperfission and cardiomyocyte early senescence by inhibiting Drp1-filamin complex formation J. Pharmacol. Sci. (IF 3.5) Pub Date : 2023-12-27 Akiyuki Nishimura, Liuchenzi Zhou, Yuri Kato, Xinya Mi, Tomoya Ito, Yuko Ibuki, Yasunari Kanda, Motohiro Nishida
Smoking is one of the most serious risk factors for cardiovascular diseases. Although cigarette mainstream and sidestream smoke are significant contributors to increased cardiovascular mortality and morbidity, the underlying mechanism is still unclear. Here, we report that exposure of rat neonatal cardiomyocytes to cigarette smoke extract (CSE) induces mitochondrial hyperfission-mediated myocardial
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CU06-1004 alleviates oxidative stress and inflammation on folic acid-induced acute kidney injury in mice J. Pharmacol. Sci. (IF 3.5) Pub Date : 2023-12-23 Cho-Rong Bae, Yeomyeong Kim, Young-Guen Kwon
Purpose Acute kidney injury (AKI) is characterized by reduced renal function, oxidative stress, inflammation, and renal fibrosis. CU06-1004, an endothelial cell dysfunction blocker, exhibits anti-inflammatory effects by reducing vascular permeability in pathological conditions. However, the potential effects of CU06-1004 on AKI have not been investigated. We investigated the renoprotective effect of
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Protective effect and regulatory mechanism of salidroside on skin inflammation induced by imiquimod in psoriasis mice J. Pharmacol. Sci. (IF 3.5) Pub Date : 2023-12-21 Zhenxing Su, Yunqin Kang
Salidroside (SAL) is a glucoside of tyrosol commonly existing in the roots of Rhodiola rosea. This study unveils the protective effect of SAL on skin inflammation in imiquimod (IMQ)-induced psoriasis. The mouse model of psoriasis was established by local application of IMQ, and SAL efficacy was evaluated through PASI scoring, H&E staining, and skin tissue pathology observation. The HaCaT cell model
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Impaired monoamine neural system in the mPFC of SHRSP/Ezo as an animal model of attention-deficit/hyperactivity disorder J. Pharmacol. Sci. (IF 3.5) Pub Date : 2023-12-19 Naoya Suzuki, Sachiko Hiraide, Hiroki Shikanai, Takeru Isshiki, Taku Yamaguchi, Takeshi Izumi, Kenji Iizuka
Attention-deficit/hyperactivity disorder (ADHD) is the most common childhood-onset psychiatric disorder. We investigated the effects of systemic administration of monoamine reuptake inhibitors on long-term potentiation (LTP) formation and monoamine release in the medial prefrontal cortex (mPFC) of the stroke-prone spontaneously hypertensive rat (SHRSP)/Ezo, an animal model of ADHD, and its genetic
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Investigation into the usefulness of cynomolgus monkeys with spontaneously elevated intraocular pressure as a model for glaucoma treatment research J. Pharmacol. Sci. (IF 3.5) Pub Date : 2023-12-17 Tomoaki Araki, Masamitsu Shimazawa, Shinsuke Nakamura, Wataru Otsu, Yosuke Numata, Megumi Sakata, Koji Kabayama, Hideshi Tsusaki, Hideaki Hara
Many glaucoma treatments focus on lowering intraocular pressure (IOP), with novel drugs continuing to be developed. One widely used model involves raising IOP by applying a laser to the trabecular iris angle (TIA) of cynomolgus monkeys to damage the trabecular meshwork. This model, however, presents challenges such as varying IOP values, potential trabecular meshwork damage, and risk of animal distress
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Long-lasting anti-despair and anti-anhedonia effects of (S)-norketamine in social isolation-reared mice J. Pharmacol. Sci. (IF 3.5) Pub Date : 2023-12-14 Rei Yokoyama, Momoko Higuchi, Wataru Tanabe, Shinji Tsukada, Hisato Igarashi, Kaoru Seiriki, Takanobu Nakazawa, Atsushi Kasai, Yukio Ago, Hitoshi Hashimoto
Alternatives to ketamine without psychotomimetic properties for the treatment of depression have attracted much attention. Here, we examined the anti-despair and anti-anhedonia effects of the ketamine metabolites (S)-norketamine ((S)-NK), (R)-NK, (2S,6S)-hydroxynorketamine, and (2R,6R)-hydroxynorketamine in a mouse model of depression induced by social isolation. All ketamine metabolites examined had
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Goreisan regulates cerebral blood flow according to barometric pressure fluctuations in female C57BL/6J mice J. Pharmacol. Sci. (IF 3.5) Pub Date : 2023-12-07 Yuki Kurauchi, Sumika Ryu, Risako Tanaka, Makito Haruta, Kiyotaka Sasagawa, Takahiro Seki, Jun Ohta, Hiroshi Katsuki
Goreisan is a Kampo medicine used to treat headaches associated with climate change. Here, by using an implantable complementary metal-oxide-semiconductor (CMOS) device, we evaluated the effects of Goreisan and loxoprofen on cerebral blood flow (CBF) dynamics associated with barometric pressure fluctuations in freely moving mice. In the vehicle group, decreasing barometric pressure increased CBF that
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Transient receptor potential melastatin 2 is involved in trinitrobenzene sulfonic acid-induced acute and chronic colitis-associated fibrosis progression in mice J. Pharmacol. Sci. (IF 3.5) Pub Date : 2023-11-30 Tomohiro Nakamoto, Kenjiro Matsumoto, Hiroyuki Yasuda, Yasuo Mori, Shinichi Kato
Crohn's disease, a chronic and recurrent gastrointestinal disease, frequently causes intestinal fibrosis. Transient receptor potential melastatin 2 (TRPM2), a non-selective cation channel, is activated by reactive oxygen species. This study investigated the role of TRPM2 in acute colitis and chronic colitis-associated fibrosis progression. Acute colitis and chronic colitis-associated fibrosis were
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An ADAM17 selective inhibitor promotes glucose uptake by activating AMPK J. Pharmacol. Sci. (IF 3.5) Pub Date : 2023-12-01 Tsugumasa Toma, Nobukazu Miyakawa, Mika Tateishi, Mikio Todaka, Tatsuya Kondo, Mikako Fujita, Masami Otsuka, Eiichi Araki, Hiroshi Tateishi
AMPK activation promotes glucose and lipid metabolism. Here, we found that our previously reported ADAM17 inhibitor SN-4 activates AMPK and promotes membrane translocation and sugar uptake of GLUT4. AMPK inhibitor dorsomorphin reversed this effect of SN-4, confirming that the effect is mediated by AMPK activation. In addition, SN-4 inhibited lipid accumulation in HepG2 under high glucose conditions
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Simultaneous XIAP and cIAP1/2 inhibition by a dimeric SMAC mimetic AZD5582 induces apoptosis in multiple myeloma J. Pharmacol. Sci. (IF 3.5) Pub Date : 2023-11-23 Shohei Kikuchi, Yusuke Sugama, Kohichi Takada, Yusuke Kamihara, Akinori Wada, Yohei Arihara, Hajime Nakamura, Tsutomu Sato
Overexpression of inhibitor of apoptosis (IAP) proteins is associated with poor prognosis. In multiple myeloma (MM), the IAP inhibitors (IAPi), LCL161, have been evaluated in preclinical and clinical settings but are not fully effective. Among IAPs, XIAP has the strongest anti-apoptotic function with direct binding activity to caspases and cIAP1 and cIAP2 are positive regulator of NF-κB signaling.
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Identification of a novel enzyme and the regulation of key enzymes in mammalian taurine synthesis J. Pharmacol. Sci. (IF 3.5) Pub Date : 2023-11-21 Teruo Miyazaki
Taurine has many pharmacological roles on various tissues. The maintenance of abundant taurine content in the mammalian body through endogenous synthesis, in addition to exogenous intake, is the essential factor for morphological and functional maintenances in most tissues. The synthesis of taurine from sulfur-containing amino acids is influenced by various factors. Previous literature findings indicate
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Development of multifunctional pyrrole-imidazole polyamides that increase hepatocyte growth factor and suppress transforming growth factor-β1 J. Pharmacol. Sci. (IF 3.5) Pub Date : 2023-11-19 Lan Chen, Noboru Fukuda, Takahiro Ueno, Masanori Abe, Taro Matsumoto
Purpose The DNA recognition peptide compounds pyrrole-imidazole (PI) polyamides bind to the minor groove and can block the binding of transcription factors to target sequences. To develop more PI polyamides as potential treatments for fibrotic diseases, including chronic renal failure, we developed multifunctional PI polyamides that increase hepatocyte growth factor (HGF) and decrease transforming
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Catalpol ameliorates dexamethasone-induced osteoporosis by promoting osteogenic differentiation of bone marrow mesenchymal stem cells via the activation of PKD1 promoter J. Pharmacol. Sci. (IF 3.5) Pub Date : 2023-10-17 Lei Xu, Gang Xu, Na Sun, Jialin Yao, Changyuan Wang, Wanhao Zhang, Kang Tian, Mozhen Liu, Huijun Sun
Objective To investigate the effects of CA on glucocorticoid-induced osteoporosis (GIOP) and lucubrate the underlying mechanism of CA via the activation of polycystic kidney disease-1(PKD1) in bone marrow mesenchymal stem cells (BMSCs). Methods In vivo, a GIOP model in mice treated with dexamethasone (Dex) was established. Biomechanical, micro-CT, immunofluorescence staining of OCN, ALP and PKD1 and
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CA9 and PRELID2; hypoxia-responsive potential therapeutic targets for pancreatic ductal adenocarcinoma as per bioinformatics analyses J. Pharmacol. Sci. (IF 3.5) Pub Date : 2023-10-17 Masaki Imanishi, Takahisa Inoue, Keijo Fukushima, Ryosuke Yamashita, Ryo Nakayama, Masataka Nojima, Kosuke Kondo, Yoshiki Gomi, Honoka Tsunematsu, Kohei Goto, Licht Miyamoto, Masafumi Funamoto, Masaya Denda, Keisuke Ishizawa, Akira Otaka, Hiromichi Fujino, Yasumasa Ikeda, Koichiro Tsuchiya
A strong hypoxic environment has been observed in pancreatic ductal adenocarcinoma (PDAC) cells, which contributes to drug resistance, tumor progression, and metastasis. Therefore, we performed bioinformatics analyses to investigate potential targets for the treatment of PDAC. To identify potential genes as effective PDAC treatment targets, we selected all genes whose expression level was related to
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Imeglimin profoundly affects the circadian clock in mouse embryonic fibroblasts J. Pharmacol. Sci. (IF 3.5) Pub Date : 2023-10-13 Kotomi Miura, Jun-ichi Morishige, Jotaro Abe, Pingping Xu, Yifan Shi, Zheng Jing, Naoto Nagata, Ryo Miyazaki, Naoki Sakane, Michihiro Mieda, Masanori Ono, Yoshiko Maida, Tomoko Fujiwara, Hiroshi Fujiwara, Hitoshi Ando
Objective Imeglimin is a novel antidiabetic drug structurally related to metformin. Metformin has been shown to modulate the circadian clock in rat fibroblasts. Accordingly, in the present study, we aimed to determine whether imeglimin can impact the circadian oscillator in mouse embryonic fibroblasts (MEFs). Methods MEFs carrying a Bmal1-Emerald luciferase (Bmal1-ELuc) reporter were exposed to imeglimin
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Therapeutic effect of allicin in a mouse model of intracerebral hemorrhage J. Pharmacol. Sci. (IF 3.5) Pub Date : 2023-10-02 Yara Atef, Keita Kinoshita, Yusei Ichihara, Keisuke Ushida, Yuma Hirata, Yuki Kurauchi, Takahiro Seki, Hiroshi Katsuki
Natural compounds with sulfur moiety produce various biological actions that may be beneficial for the therapies of several devastative disorders of the central nervous system. Here we investigated potential therapeutic effect of allicin, an organosulfur compound derived from garlic, in a mouse model of intracerebral hemorrhage (ICH) based on intrastriatal collagenase injection. Daily intraperitoneal
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Regulatory action of PGRMC1 on cyclic AMP-mediated COX2 expression in human endometrial cells J. Pharmacol. Sci. (IF 3.5) Pub Date : 2023-09-27 Atsuya Tsuru, Mikihiro Yoshie, Ryota Negishi, Toko Mukoyama, Ryo Yonekawa, Junya Kojima, Mana Azumi, Kazuya Kusama, Hirotaka Nishi, Kazuhiro Tamura
Human endometrial stromal cells (ESCs) undergo differentiation, known as decidualization, and endometrial epithelial cells mature around the embryo implantation stage. In the uterus, cyclooxygenase 2 (COX2), the rate-limiting enzyme that produces prostaglandin E2, is expressed in endometrial stromal and epithelial cells, and promotes decidualization of the former cells. Our recent study demonstrated
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Lactate dehydrogenase A inhibition prevents RANKL-induced osteoclastogenesis by reducing enhanced glycolysis J. Pharmacol. Sci. (IF 3.5) Pub Date : 2023-09-27 Tsuyoshi Nishioku, Rumi Anzai, Sami Hiramatsu, Ayaka Terazono, Mamiko Nakao, Miyu Moriyama
Osteoclasts are multinucleated, specializes bone-resorbing cells that are derived from the monocyte/macrophage lineage. Excessive resorbing activities of osteoclasts are involved in destructive bone diseases. The detailed mechanism of acidification at the bone adhesion surface during the bone resorption process of osteoclasts remains to be defined. During glycolysis, pyruvate proceeds to the tricarboxylic
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Characterization of spinal microglial activation in a mouse model of imiquimod-induced psoriasis J. Pharmacol. Sci. (IF 3.5) Pub Date : 2023-09-20 Fumihiro Saika, Yohji Fukazawa, Shiroh Kishioka, Norikazu Kiguchi
Although microglia are associated with chronic pain, the role of spinal microglia in the regulation of itch remains unclear. In this study, we characterized spinal microglial activation in a mouse model of imiquimod (IMQ)-induced psoriasis. Hypertrophic (activated) microglia were observed throughout the spinal cord after the topical application of IMQ. Furthermore, the mRNA expression of microglial
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The influence of OATP2B1 and atorvastatin on coproporphyrin isomers in rats J. Pharmacol. Sci. (IF 3.5) Pub Date : 2023-09-14 Jonny Kinzi, Markus Grube, Janine Hussner, Isabell Seibert, Matthias Hamburger, Henriette E. Meyer zu Schwabedissen
Coproporphyrin I (CPI) and III (CPIII) are discussed as biomarkers for organic anion transporting polypeptides (OATPs). We report on CPI and CPIII levels in wildtype, rSlco2b1-knockout, and SLCO2B1-humanized rats at baseline and after administration of atorvastatin, an inhibitor of the CPIII-specific rOATP2B1/hOATP2B1 and the CPI/CPIII-transporting rOATP1B2. OATP-inhibition by atorvastatin leads to
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Usefulness and difficulties with the thiopurine pharmacogenomic NUDT15 genotyping test: Analysis of real-world data in Japan J. Pharmacol. Sci. (IF 3.5) Pub Date : 2023-09-11 Yoichi Kakuta, Motohiro Kato, Yusuke Shimoyama, Takeo Naito, Rintaro Moroi, Masatake Kuroha, Hisashi Shiga, Yoshitaka Kinouchi, Atsushi Masamune
The usefulness of NUDT15 genotyping as a pharmacogenomic test for thiopurine has been established. The first such test developed to date, NUDT15 genotyping was approved for reimbursement in Japan in February 2019 for all indicated patients. We retrospectively examined claims data in Japan and confirmed that the proportion of patients who undergo genotyping before initiating a new thiopurine regimen
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KCa3.1 regulates cell cycle progression by modulating Ca2+ signaling in murine preosteoblasts J. Pharmacol. Sci. (IF 3.5) Pub Date : 2023-09-06 Hiroaki Kito, Reiko Kawagishi, Takusei Ryu, Kyoko Endo, Junko Kajikuri, Wayne R. Giles, Susumu Ohya
Osteoblasts synthesize and deposit essential components of the extracellular bone matrix and collagen scaffolds, leading to mineralized bone formation. Therefore, the proliferation of preosteoblasts (precursors of mature osteoblasts) helps in regulating skeletal homeostasis. This study demonstrated that the functional expression of KCa3.1, an intermediate-conductance Ca2+-activated K+ channel, is markedly
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Determination of single-molecule transport activity of OATP2B1 by measuring the number of transporter molecules using electrophysiological approach J. Pharmacol. Sci. (IF 3.5) Pub Date : 2023-09-01 Kodai Yajima, Takeshi Akiyoshi, Kazuho Sakamoto, Yoshiaki Suzuki, Takayuki Oka, Ayuko Imaoka, Hisao Yamamura, Junko Kurokawa, Hisakazu Ohtani
Transporter-mediated clearance is determined by two factors, its single-molecule clearance, and expression level. However, no reliable method has been developed to evaluate them separately. This study aimed to develop a reliable method for evaluating the single-molecule activity of membrane transporters, such as organic anion transporting polypeptide (OATP) 2B1. HEK293 cells that co-expressed large
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Compensatory role of neuregulin-1 in diabetic cardiomyopathy J. Pharmacol. Sci. (IF 3.5) Pub Date : 2023-09-01 Yoshinori Mikami, Fumiki Iwase, Daisuke Ohshima, Taichiro Tomida, Satomi Adachi-Akahane
Diabetes mellitus is a prevalent risk factor for congestive heart failure. Diabetic cardiomyopathy patients present with left ventricular (LV) diastolic dysfunction at an early stage, then systolic dysfunction as the disease progresses. The mechanism underlying the development of diabetic cardiomyopathy has not yet been fully understood. This study aimed to elucidate the mechanisms by which diastolic
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Microglial depletion exacerbates axonal damage and motor dysfunction in mice with cuprizone-induced demyelination J. Pharmacol. Sci. (IF 3.5) Pub Date : 2023-08-25 Shinji Yamamoto, Kensuke Iwasa, Anzu Yamagishi, Chikara Haruta, Kei Maruyama, Keisuke Yoshikawa
The cuprizone (CPZ)-induced demyelination model, an animal model of Multiple sclerosis (MS), is characterized by demyelination and motor dysfunction due to microglial-mediated neuroinflammation. To determine the contribution of microglia to motor function during CPZ-induced demyelination, the microglia of mice in the CPZ-model were depleted using PLX3397 (PLX), an orally bioavailable selective colony
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Aggravation of lipopolysaccharide-induced depressive-like behavior in CCR4-deficient mice J. Pharmacol. Sci. (IF 3.5) Pub Date : 2023-08-24 Yuta Hara, Tatsuma Honzawa, Moeka Kitagawa, Ritsuki Sano, Kazuhiko Matsuo, Takashi Nakayama
Increasing evidence indicates that immune abnormalities are associated with the pathogenesis of depression. CCR4 is a chemokine receptor that regulates regulatory T cell (Treg) and Th17 cell migration. Here, using a lipopolysaccharide (LPS)-induced depression mouse model, we demonstrated that CCR4 deficiency exacerbated depressive-like behavior. Tregs and M2 macrophages, but not Th17 cells, were decreased
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Pharmacological study on the enhancing effects of U46619 on guinea pig urinary bladder smooth muscle contraction induced by acetylcholine and α,β-methylene ATP and the possible involvement of protein kinase C J. Pharmacol. Sci. (IF 3.5) Pub Date : 2023-08-29 Guanghan Ou, Akane Komura, Misaki Hojo, Rina Kato, Masahiro Ikeda, Miki Fujisawa, Keyue Xu, Kento Yoshioka, Keisuke Obara, Yoshio Tanaka
We examined whether U46619 (a prostanoid TP receptor agonist) could enhance the contractions of guinea pig urinary bladder smooth muscle (UBSM) in response to acetylcholine (ACh) and an ATP analog (α,β-methylene ATP (αβ-MeATP)) through stimulation of the UBSM TP receptor and whether protein kinase C (PKC) is involved. U46619 (10−7 M) markedly enhanced UBSM contractions induced by electrical field stimulation
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Pituitary adenylate cyclase-activating polypeptide deficient mice show length abnormalities of the axon initial segment J. Pharmacol. Sci. (IF 3.5) Pub Date : 2023-08-28 Misaki Iwahashi, Takeshi Yoshimura, Wakana Harigai, Kazuhiro Takuma, Hitoshi Hashimoto, Taiichi Katayama, Atsuko Hayata-Takano
We previously found that pituitary adenylate cyclase-activating polypeptide (PACAP)-deficient (PACAP−/−) mice exhibit dendritic spine morphology impairment and neurodevelopmental disorder (NDD)-like behaviors such as hyperactivity, increased novelty-seeking behavior, and deficient pre-pulse inhibition. Recent studies have indicated that rodent models of NDDs (e.g., attention-deficit hyperactivity disorder
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Behavioral changes of food allergic model mice during light and dark period J. Pharmacol. Sci. (IF 3.5) Pub Date : 2023-08-25 Yusuke Miyazaki, Koji Kobayashi, Takahisa Murata
Although an animal model of food allergy has been used to investigate its progression mechanism, most researcher could not assess its symptoms for long especially under dark environment. We assessed the behavioral changes of food allergic mice using an image analysis system to track a mouse under both light and dark environments. Mice were sensitized with intraperitoneal ovalbumin (OVA) injections
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CYP11A1 silencing suppresses HMGCR expression via cholesterol accumulation and sensitizes CRPC cell line DU-145 to atorvastatin J. Pharmacol. Sci. (IF 3.5) Pub Date : 2023-08-23 Jiro Tashiro, Akihiro Sugiura, Tomoko Warita, Nanami Irie, Danang Dwi Cahyadi, Takuro Ishikawa, Katsuhiko Warita
Statins, which are cholesterol synthesis inhibitors, are well-known therapeutics for dyslipidemia; however, some studies have anticipated their use as anticancer agents. However, epithelial cancer cells show strong resistance to statins through an increased expression of HMG-CoA reductase (HMGCR), an inhibitory target of statins. Castration-resistant prostate cancer (CRPC) cells synthesize androgens