453 results on '"Matsunaga, Naoya"'
Search Results
152. Circadian clock-controlled the expression of dopamine receptor DRD2 in caudate-putamen of mice
- Author
-
Ikeda, Eriko, primary, Matsunaga, Naoya, additional, Hayashi, Akane, additional, Koyanagi, Satoru, additional, and Ohdo, Shigehiro, additional
- Published
- 2010
- Full Text
- View/download PDF
153. Dosing Time Based on Molecular Mechanism of Biological Clock of Hepatic Drug Metabolic Enzyme
- Author
-
MATSUNAGA, Naoya, primary
- Published
- 2009
- Full Text
- View/download PDF
154. Circadian Clock-Controlled Intestinal Expression of the Multidrug-Resistance Gene mdr1a in Mice
- Author
-
Murakami, Yuichi, primary, Higashi, Yuko, additional, Matsunaga, Naoya, additional, Koyanagi, Satoru, additional, and Ohdo, Shigehiro, additional
- Published
- 2008
- Full Text
- View/download PDF
155. The molecular mechanism regulating 24-hour rhythm ofCYP2E1expression in the mouse liver
- Author
-
Matsunaga, Naoya, primary, Ikeda, Misaki, additional, Takiguchi, Takako, additional, Koyanagi, Satoru, additional, and Ohdo, Shigehiro, additional
- Published
- 2008
- Full Text
- View/download PDF
156. Molecular basis for rhythmic expression of CYP3A4 in serum-shocked HepG2 cells
- Author
-
Takiguchi, Takako, primary, Tomita, Miho, additional, Matsunaga, Naoya, additional, Nakagawa, Hiroo, additional, Koyanagi, Satoru, additional, and Ohdo, Shigehiro, additional
- Published
- 2007
- Full Text
- View/download PDF
157. TRANSIENT INHIBITION OF CYP3A IN RATS BY STAR FRUIT JUICE
- Author
-
Hidaka, Muneaki, primary, Okumura, Manabu, additional, Ogikubo, Tetsuya, additional, Kai, Hirofumi, additional, Fujita, Ken-Ichi, additional, Iwakiri, Tomomi, additional, Yamasaki, Keishi, additional, Setoguchi, Nao, additional, Matsunaga, Naoya, additional, and Arimori, Kazuhiko, additional
- Published
- 2005
- Full Text
- View/download PDF
158. Effect of Haloperidol on mPer1 Gene Expression in Mouse Suprachiasmatic Nuclei
- Author
-
Viyoch, Jarupa, primary, Matsunaga, Naoya, additional, Yoshida, Miyako, additional, To, Hideto, additional, Higuchi, Shun, additional, and Ohdo, Shigehiro, additional
- Published
- 2005
- Full Text
- View/download PDF
159. Influence of Feeding Schedule on 24-h Rhythm of Hepatotoxicity Induced by Acetaminophen in Mice
- Author
-
Matsunaga, Naoya, primary, Nakamura, Naomi, additional, Yoneda, Noriyo, additional, Qin, Tian, additional, Terazono, Hideyuki, additional, To, Hideto, additional, Higuchi, Shun, additional, and Ohdo, Shigehiro, additional
- Published
- 2004
- Full Text
- View/download PDF
160. Influence of Dosing Schedule on Toxicity and Antitumor Effects of a Combination of Adriamycin and Docetaxel in Mice
- Author
-
To, Hideto, primary, Shin, Mikiko, additional, Tabuchi, Mayumi, additional, Sakaguchi, Hiromi, additional, Takeuchi, Ayako, additional, Matsunaga, Naoya, additional, Higuchi, Shun, additional, and Ohdo, Shigehiro, additional
- Published
- 2004
- Full Text
- View/download PDF
161. Rinsho yakuri/Japanese Journal of Clinical Pharmacology and Therapeutics
- Author
-
MATSUNAGA, NAOYA, primary
- Published
- 2003
- Full Text
- View/download PDF
162. Modulation of Peroxisome Proliferator-Activated Receptor-αActivity by Bile Acids Causes Circadian Changes in the Intestinal Expression of Octn1/Slc22a4in Mice
- Author
-
Wada, Erika, Koyanagi, Satoru, Kusunose, Naoki, Akamine, Takahiro, Masui, Hiroaki, Hashimoto, Hana, Matsunaga, Naoya, and Ohdo, Shigehiro
- Abstract
In addition to their digestive actions, bile acids modulate gene expression by altering the activity of peroxisome proliferator-activated receptor-α(PPARα). The modulatory effects of bile acids have been shown to affect the expression of genes responsible for lipid metabolism as well as membrane transporters. Bile acids are secreted in response to food intake and accumulate in intestinal epithelial cells. In the present study, we identified soluble carrier protein family 22 member 4 (Slc22a4), encoding organic cation transporter novel type-1 (Octn1), as a PPARα-regulated gene and its intestinal expression exhibited circadian oscillations in a bile acid–dependent manner. Nocturnally active mice mainly consumed their food around the early dark phase, during which bile acids accumulated in intestinal epithelial cells. PPARαactivated the intestinal expression of Slc22a4mRNA during the light period, and protein levels of Octn1 peaked before the start of the dark phase. The bile acids that accumulated in intestinal epithelial cells suppressed the PPARα-mediated transactivation of Slc22a4in the dark phase. The time-dependent suppression of PPARα-mediated transactivation by bile acids regulated oscillations in the intestinal expression of Octn1/Slc22a4during the daily feeding cycle. The results of a pharmacokinetic analysis also revealed that oscillations in the expression of Octn1 caused dosing time-dependent differences in the intestinal absorption of gabapentin (2-[1-(aminomethyl)cyclohexyl]acetic acid). These results suggest a molecular clock–independent mechanism by which bile acid–regulated PPARαactivity governs the circadian expression of intestinal organic cation transporters. This mechanism could also account for interindividual variations in the pharmacokinetics of drugs that are substrates of Octn1.
- Published
- 2015
- Full Text
- View/download PDF
163. Ozagrel hydrochloride, a selective thromboxane A2 synthase inhibitor, alleviates liver injury induced by acetaminophen overdose in mice.
- Author
-
Tomishima, Yoshiro, Ishitsuka, Yoichi, Matsunaga, Naoya, Nagatome, Minako, Furusho, Hirokazu, Irikura, Mitsuru, Ohdo, Shigehiro, and Irie, Tetsumi
- Subjects
LIVER injuries ,THROMBOXANES ,LABORATORY mice ,ACETAMINOPHEN ,HEPATOTOXICOLOGY ,ALANINE aminotransferase ,HISTOPATHOLOGY ,LIVER cells ,PHYSIOLOGY - Abstract
Background: Overdosed acetaminophen (paracetamol, N-acetyl-p-aminophenol; APAP) causes severe liver injury. We examined the effects of ozagrel, a selective thromboxane A
2 (TXA2 ) synthase inhibitor, on liver injury induced by APAP overdose in mice. Methods: Hepatotoxicity was induced to ICR male mice by an intraperitoneal injection with APAP (330 mg/kg). The effects of ozagrel (200 mg/kg) treatment 30 min after the APAP injection were evaluated with mortality, serum alanine aminotransferase (ALT) levels and hepatic changes, including histopathology, DNA fragmentation, mRNA expression and total glutathione contents. The impact of ozagrel (0.001-1 mg/mL) on cytochrome P450 2E1 (CYP2E1) activity in mouse hepatic microsome was examined. RLC-16 cells, a rat hepatocytes cell line, were exposed to 0.25 mM N-acetyl-p-benzoquinone imine (NAPQI), a hepatotoxic metabolite of APAP. In this model, the cytoprotective effects of ozagrel (1-100 muM) were evaluated by the WST-1 cell viability assay. Results: Ozagel treatment significantly attenuated higher mortality, elevated serum alanine aminotransferase levels, excessive hepatic centrilobular necrosis, hemorrhaging and DNA fragmentation, as well as increase in plasma 2,3-dinor thromboxane B2 levels induced by APAP injection. Ozagrel also inhibited the hepatic expression of cell death-related mRNAs induced by APAP, such as jun oncogene, FBJ osteosarcoma oncogene (fos) and C/EBP homologous protein (chop), but did not suppress B-cell lymphoma 2-like protein11 (bim) expression and hepatic total glutathione depletion. These results show ozagrel can inhibit not all hepatic changes but can reduce the hepatic necrosis. Ozagrel had little impact on CYP2E1 activity involving the NAPQI production. In addition, ozagrel significantly attenuated cell injury induced by NAPQI in RLC-16. Conclusions: We demonstrate that the TXA2 synthase inhibitor, ozagrel, dramatically alleviates liver injury induced by APAP in mice, and suggest that it is a promising therapeutic candidate for the treatment of APAP-induced liver injury. [ABSTRACT FROM AUTHOR]- Published
- 2013
- Full Text
- View/download PDF
164. IL-6 Receptor Is a Possible Target against Growth of Metastasized Lung Tumor Cells in the Brain.
- Author
-
Noda, Mami, Yamakawa, Yukiko, Matsunaga, Naoya, Naoe, Satoko, Jodoi, Taishi, Yamafuji, Megumi, Akimoto, Nozomi, Teramoto, Norihiro, Fujita, Kyota, Ohdo, Shigehiro, and Iguchi, Haruo
- Subjects
BRAIN tumor treatment ,TREATMENT of lung tumors ,SQUAMOUS cell carcinoma ,CANCER cell growth ,INTERLEUKIN-6 receptors ,ANIMAL models in research ,GENE expression ,ASTROCYTES - Abstract
In the animal model of brain metastasis using human lung squamous cell carcinoma-derived cells (HARA-B) inoculated into the left ventricle of the heart of nude mice, metastasized tumor cells and brain resident cells interact with each other. Among them, tumor cells and astrocytes have been reported to stimulate each other, releasing soluble factors from both sides, subsequently promoting tumor growth significantly. Among the receptors for soluble factors released from astrocytes, only IL-6 receptor (IL-6R) on tumor cells was up-regulated during the activation with astrocytes. Application of monoclonal antibody against human IL-6R (tocilizumab) to the activated HARA-B cells, the growth of HARA-B cells stimulated by the conditioned medium of HARA-B/astrocytes was significantly inhibited. Injecting tocilizumab to animal models of brain metastasis starting at three weeks of inoculation of HARA-B cells, two times a week for three weeks, significantly inhibited the size of the metastasized tumor foci. The up-regulated expression of IL-6R on metastasized lung tumor cells was also observed in the tissue from postmortem patients. These results suggest that IL-6R on metastasized lung tumor cells would be a therapeutic target to inhibit the growth of the metastasized lung tumor cells in the brain. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
165. The molecular mechanism regulating 24-hour rhythm of CYP2E1 expression in the mouse liver.
- Author
-
Matsunaga, Naoya, Ikeda, Misaki, Takiguchi, Takako, Koyanagi, Satoru, and Ohdo, Shigehiro
- Published
- 2008
- Full Text
- View/download PDF
166. Chronopharmacology of immune-related diseases.
- Author
-
Ohdo, Shigehiro, Koyanagi, Satoru, and Matsunaga, Naoya
- Subjects
- *
CLOCK genes , *SYMPTOMS , *MOLECULAR clock , *IMMUNE checkpoint proteins , *SUPRACHIASMATIC nucleus , *MYOCARDIAL infarction - Abstract
Clock genes, circadian pacemaker resides in the paired suprachiasmatic nuclei (SCN), control various circadian rhythms in many biological processes such as physiology and behavior. Clock gene regulates many diseases such as cancer, immunological dysfunction, metabolic syndrome and sleep disorders etc. Chronotherapy is especially relevant, when the risk and/or intensity of the symptoms of disease vary predicably over time as exemplified by allergic rhinitis, arthritis, asthma, myocardial infarction, congestive heart failure, stroke, and peptic ulcer disease. Dosing time influences the effectiveness and toxicity of many drugs. The pharmacodynamics of medications as well as pharmacokinetics influences chronopharmacological phenomena. To escape from host immunity in the tumor microenvironment, cancer cells have acquired several pathways. Immune checkpoint therapy targeting programmed death 1 (PD-1) and its ligand (PD-L1) interaction had been approved for the treatment of patients with several types of cancers. Circadian expression of PD-1 is identified on tumor associated macrophages (TAMs), which is rationale for selecting the most appropriate time of day for administration of PD-1/PD-L1 inhibitors. The therapies for chronic kidney disease (CKD) are urgently needed because of a global health problem. The mechanism of the cardiac complications in mice with CKD had been related the GRP68 in circulating monocytes and serum accumulation of retinol. Development of a strategy to suppress retinol accumulation will be useful to prevent the cardiac complications of CKD. Therefore, we introduce an overview of the dosing time-dependent changes in therapeutic outcome and safety of drug for immune-related diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
167. Inhibition of dynamin‐related protein 1‐filamin interaction improves systemic glucose metabolism.
- Author
-
Kato, Yuri, Ariyoshi, Kohei, Nohara, Yasunobu, Matsunaga, Naoya, Shimauchi, Tsukasa, Shindo, Naoya, Nishimura, Akiyuki, Mi, Xinya, Kim, Sang Geon, Ide, Tomomi, Kawanishi, Eiji, Ojida, Akio, Nakashima, Naoki, Mori, Yasuo, and Nishida, Motohiro
- Subjects
- *
OXYGEN consumption , *GLUCOSE metabolism , *PROTEIN-protein interactions , *TYPE 2 diabetes , *HYPERGLYCEMIA , *DIABETES complications - Abstract
Background and purpose Experimental Approach Key Results Conclusion and implications Maintaining mitochondrial quality is attracting attention as a new strategy to treat diabetes and diabetic complications. We previously reported that mitochondrial hyperfission by forming a protein complex between dynamin‐related protein (Drp) 1 and filamin, mediates chronic heart failure and cilnidipine, initially developed as an L/N‐type Ca2+ channel blocker, improves heart failure by inhibiting Drp1‐filamin protein complex. We investigated whether cilnidipine improves hyperglycaemia of various diabetic mice models.Retrospective analysis focusing on haemoglobin A1c (HbA1c) was performed in hypertensive and hyperglycaemic patients taking cilnidipine and amlodipine. After developing diabetic mice by streptozotocin (STZ) treatment, an osmotic pump including drug was implanted intraperitoneally, followed by weekly measurements of blood glucose levels. Mitochondrial morphology was analysed by electron microscopy. A Ca2+ channel‐insensitive cilnidipine derivative (1,4‐dihydropyridine [DHP]) was synthesized and its pharmacological effect was evaluated using obese (
ob/ob ) mice fed with high‐fat diet (HFD).In patients, cilnidipine was superior to amlodipine in HbA1c lowering effect. Cilnidipine treatment improved systemic hyperglycaemia and mitochondrial morphological abnormalities in STZ‐exposed mice, without lowering blood pressure. Cilnidipine failed to improve hyperglycaemia ofob/ob mice, with suppressing insulin secretion. 1,4‐DHP improved hyperglycaemia and mitochondria abnormality inob/ob mice fed HFD. 1,4‐DHP and cilnidipine improved basal oxygen consumption rate of HepG2 cells cultured under 25 mM glucose.Inhibition of Drp1‐filamin protein complex formation becomes a new strategy for type 2 diabetes treatment. [ABSTRACT FROM AUTHOR]- Published
- 2024
- Full Text
- View/download PDF
168. Time-Dependent Interaction between Differentiated Embryo Chondrocyte-2 and CCAAT/Enhancer-Binding Protein α Underlies the Circadian Expression of CYP2D6 in Serum-Shocked HepG2 Cells
- Author
-
Matsunaga, Naoya, Inoue, Miki, Kusunose, Naoki, Kakimoto, Keisuke, Hamamura, Kengo, Hanada, Yuichi, Toi, Ayumi, Yoshiyama, Yuji, Sato, Fuyuki, Fujimoto, Katsumi, Koyanagi, Satoru, and Ohdo, Shigehiro
- Abstract
Differentiated embryo chondrocyte-2 (DEC2), also known as bHLHE41 or Sharp1, is a pleiotropic transcription repressor that controls the expression of genes involved in cellular differentiation, hypoxia responses, apoptosis, and circadian rhythm regulation. Although a previous study demonstrated that DEC2 participates in the circadian control of hepatic metabolism by regulating the expression of cytochrome P450, the molecular mechanism is not fully understood. We reported previously that brief exposure of HepG2 cells to 50% serum resulted in 24-h oscillation in the expression of CYP3A4 as well as circadian clock genes. In this study, we found that the expression of CYP2D6, a major drug-metabolizing enzyme in humans, also exhibited a significant oscillation in serum-shocked HepG2 cells. DEC2 interacted with CCAAT/enhancer-binding protein (C/EBPα), accompanied by formation of a complex with histone deacetylase-1, which suppressed the transcriptional activity of C/EBPα to induce the expression of CYP2D6. The oscillation in the protein levels of DEC2 in serum-shocked HepG2 cells was nearly antiphase to that in the mRNA levels of CYP2D6. Transfection of cells with small interfering RNA against DEC2 decreased the amplitude of CYP2D6 mRNA oscillation in serum-shocked cells. These results suggest that DEC2 periodically represses the promoter activity of CYP2D6, resulting in its circadian expression in serum-shocked cells. DEC2 seems to constitute a molecular link through which output components from the circadian clock are associated with the time-dependent expression of hepatic drug-metabolizing enzyme.
- Published
- 2012
169. Glucocorticoid-dependent expression of O(6)-methylguanine-DNA methyltransferase gene modulates dacarbazine-induced hepatotoxicity in mice.
- Author
-
Horiguchi, Michiko, Kim, Jahye, Matsunaga, Naoya, Kaji, Hiroaki, Egawa, Takashi, Makino, Kazutaka, Koyanagi, Satoru, and Ohdo, Shigehiro
- Abstract
O(6)-methylguanine-DNA methyltransferase (MGMT) plays a crucial role in the defense against the alkylating agent-induced cytotoxic lesion O(6)-alkylguanine in DNA. Although a significant circadian variation in MGMT activity has been found in the liver of mice, the exact mechanism of the variation remains poorly understood. In this study, we present evidence that glucocorticoids were required for the 24-h oscillation of MGMT expression in mouse liver. The exposure of mouse hepatic cells (Hepa1-6) to dexamethasone (DEX) significantly increased the mRNA levels of MGMT in a dose-dependent manner. The DEX-induced increase in MGMT expression was reversed by concomitant treatment with RU486 [11beta-[p-(dimethylamino) phenyl]-17beta-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one], a glucocorticoid receptor antagonist. The mRNA levels of MGMT and its enzymatic activity in the liver of mice showed significant 24-h oscillations, which were not observed in adrenalectomized mice. A single administration of DEX to adrenalectomized mice significantly increased the mRNA levels of MGMT in the liver. These findings suggest that the 24-h oscillation in the hepatic expression of MGMT is caused by the endogenous rhythm of glucocorticoid secretion. Dacarbazine (DTIC), a potent O(6)-guanine-alkylating agent, causes serious hepatotoxicity accompanied by hepatocellular necrosis and hepatic vein thrombosis. DTIC-induced hepatotoxicity in mice was attenuated by administering the drug at the time of day when MGMT expression was abundant. The present findings suggest that glucocorticoid-regulated oscillation in the hepatic MGMT expression is the underlying cause of dosing time-dependent changes in DTIC-induced hepatotoxicity.
- Published
- 2010
- Full Text
- View/download PDF
170. TRANSIENT INHIBITION OF CYP3A IN RATS BY STAR FRUIT JUICE
- Author
-
Hidaka, Muneaki, Okumura, Manabu, Ogikubo, Tetsuya, Kai, Hirofumi, Fujita, Ken-Ichi, Iwakiri, Tomomi, Yamasaki, Keishi, Setoguchi, Nao, Matsunaga, Naoya, and Arimori, Kazuhiko
- Abstract
Star fruit juice is a potent in vitro inhibitor of CYP3A; however, few reports are available on the inhibition of CYP3A activities by star fruit juice in vivo. Therefore, in this study, we investigated the CYP3A-mediated star fruit-drug interaction in vivo. The effect of star fruit juice on carbamazepine pharmacokinetics was examined in rats. In comparison with water, the area under the concentration-time curve (AUC) of carbamazepine was approximately 1.3-fold greater when star fruit juice (2 ml) was orally administered 1 h before the oral administration of carbamazepine (50 mg/kg). In contrast, the elimination half-life of carbamazepine and the AUC ratio of carbamazepine 10,11-epoxide to carbamazepine were not altered by the administration of star fruit juice. These results suggest that star fruit juice impairs the function of enteric CYP3A, but not of hepatic CYP3A. In addition, we evaluated the time course of recovery of CYP3A activity that was reduced after the treatment with star fruit juice. The inhibition by star fruit juice was recovered within approximately 24 h. These data suggest that the effect of star fruit juice is mainly reversible and transient. Thus, we discovered that star fruit juice alters the carbamazepine pharmacokinetics in rats.
- Published
- 2006
171. Age-Related Effects on MSC Immunomodulation, Macrophage Polarization, Apoptosis, and Bone Regeneration Correlate with IL-38 Expression.
- Author
-
Zhang, Jiewen, Akiyama, Kentaro, Mun, Aung Ye, Tagashira, Ryuji, Zou, Tingling, Matsunaga, Naoya, Kohno, Teisaku, and Kuboki, Takuo
- Subjects
- *
BONE regeneration , *GENE expression , *IMMUNOREGULATION , *MESENCHYMAL stem cells , *MACROPHAGES - Abstract
Mesenchymal stem cells (MSCs) are known to promote tissue regeneration and suppress excessive inflammation caused by infection or trauma. Reported evidence indicates that various factors influence the expression of MSCs' endogenous immunomodulatory properties. However, the detailed interactions of MSCs with macrophages, which are key cells involved in tissue repair, and their regulatory mechanisms are not completely understood. We herein investigated how age-related immunomodulatory impairment of MSCs alters the interaction of MSCs with macrophages during bone healing using young (5-week old) and aged (50-week old) mice. To clarify the relationship between inflammatory macrophages (M1) and MSCs, their spatiotemporal localization at the bone healing site was investigated by immunostaining, and possible regulatory mechanisms were analyzed in vitro co-cultures. Histomorphometric analysis revealed an accumulation of M1 and a decrease in MSC number at the healing site in aged mice, which showed a delayed bone healing. In in vitro co-cultures, MSCs induced M1 apoptosis through cell-to-cell contact but suppressed the gene expression of pro-inflammatory cytokines by soluble factors secreted in the culture supernatant. Interestingly, interleukin 38 (Il-38) expression was up-regulated in M1 after co-culture with MSCs. IL-38 suppressed the gene expression of inflammatory cytokines in M1 and promoted the expression of genes associated with M1 polarization to anti-inflammatory macrophages (M2). IL-38 also had an inhibitory effect on M1 apoptosis. These results suggest that MSCs may induce M1 apoptosis, suppress inflammatory cytokine production by M1, and induce their polarization toward M2. Nevertheless, in aged conditions, the decreased number and immunomodulatory function of MSCs could be associated with a delayed M1 clearance (i.e., apoptosis and/or polarization) and consequent delayed resolution of the inflammatory phase. Furthermore, M1-derived IL-38 may be associated with immunoregulation in the tissue regeneration site. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
172. Hematopoietic Prostaglandin D Synthase Is Increased in Mast Cells and Pericytes in Autopsy Myocardial Specimens from Patients with Duchenne Muscular Dystrophy.
- Author
-
Hamamura, Kengo, Yoshida, Yuya, Oyama, Kosuke, Li, Junhao, Kawano, Shimpei, Inoue, Kimiko, Toyooka, Keiko, Yamadera, Misaki, Matsunaga, Naoya, Matsumura, Tsuyoshi, and Aritake, Kosuke
- Subjects
- *
CYCLOOXYGENASES , *DUCHENNE muscular dystrophy , *MAST cells , *AUTOPSY , *PERICYTES , *MYELOID cells - Abstract
The leading cause of death for patients with Duchenne muscular dystrophy (DMD), a progressive muscle disease, is heart failure. Prostaglandin (PG) D2, a physiologically active fatty acid, is synthesized from the precursor PGH2 by hematopoietic prostaglandin D synthase (HPGDS). Using a DMD animal model (mdx mice), we previously found that HPGDS expression is increased not only in injured muscle but also in the heart. Moreover, HPGDS inhibitors can slow the progression of muscle injury and cardiomyopathy. However, the location of HPGDS in the heart is still unknown. Thus, this study investigated HPGDS expression in autopsy myocardial samples from DMD patients. We confirmed the presence of fibrosis, a characteristic phenotype of DMD, in the autopsy myocardial sections. Additionally, HPGDS was expressed in mast cells, pericytes, and myeloid cells of the myocardial specimens but not in the myocardium. Compared with the non-DMD group, the DMD group showed increased HPGDS expression in mast cells and pericytes. Our findings confirm the possibility of using HPGDS inhibitor therapy to suppress PGD2 production to treat skeletal muscle disorders and cardiomyopathy. It thus provides significant insights for developing therapeutic drugs for DMD. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
173. Prostaglandin F2α Affects the Cycle of Clock Gene Expression and Mouse Behavior.
- Author
-
Tsurudome, Yuya, Yoshida, Yuya, Hamamura, Kengo, Ogino, Takashi, Yasukochi, Sai, Yasuo, Shinobu, Iwamoto, Ayaka, Yoshihara, Tatsuya, Inazumi, Tomoaki, Tsuchiya, Soken, Takeo, Toru, Nakagata, Naomi, Higuchi, Shigekazu, Sugimoto, Yukihiko, Tsuruta, Akito, Koyanagi, Satoru, Matsunaga, Naoya, and Ohdo, Shigehiro
- Subjects
- *
CIRCADIAN rhythms , *MOLECULAR clock , *CLOCK genes , *GENE expression , *PROSTAGLANDINS , *SUPRACHIASMATIC nucleus , *PROSTAGLANDIN receptors - Abstract
Prostaglandins are bioactive compounds, and the activation of their receptors affects the expression of clock genes. However, the prostaglandin F receptor (Ptgfr) has no known relationship with biological rhythms. Here, we first measured the locomotor period lengths of Ptgfr-KO (B6.129-Ptgfrtm1Sna) mice and found that they were longer under constant dark conditions (DD) than those of wild-type (C57BL/6J) mice. We then investigated the clock gene patterns within the suprachiasmatic nucleus in Ptgfr-KO mice under DD and observed a decrease in the expression of the clock gene cryptochrome 1 (Cry1), which is related to the circadian cycle. Moreover, the expression of Cry1, Cry2, and Period2 (Per2) mRNA were significantly altered in the mouse liver in Ptgfr-KO mice under DD. In the wild-type mouse, the plasma prostaglandin F2α (PGF2α) levels showed a circadian rhythm under a 12 h cycle of light–dark conditions. In addition, in vitro experiments showed that the addition of PTGFR agonists altered the amplitude of Per2::luc activity, and this alteration differed with the timing of the agonist addition. These results lead us to hypothesize that the plasma rhythm of PGF2α is important for driving clock genes, thus suggesting the involvement of PGF2α- and Ptgfr-targeting drugs in the biological clock cycle. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
174. Oral administration of vancomycin alleviates heart failure triggered by chronic kidney disease.
- Author
-
Fukuoka, Kohei, Yoshida, Yuya, Sotono, Kurumi, Nishikawa, Naoki, Hamamura, Kengo, Oyama, Kosuke, Tsuruta, Akito, Mayanagi, Kota, Koyanagi, Satoru, Matsunaga, Naoya, and Ohdo, Shigehiro
- Subjects
- *
CHRONIC kidney failure , *ORAL drug administration , *HEART , *HEART failure , *BRAIN natriuretic factor , *GUT microbiome , *WEIGHT loss - Abstract
Chronic kidney disease (CKD) induces an imbalance in the intestinal microbiota, affecting various physiological functions and leading to cardiovascular inflammation and fibrosis. However, the cardiotoxic impact of intestinal microbiota-derived uremic substances in advanced renal dysfunction remains unexplored. Therefore, we developed a 5/6 nephrectomy (5/6Nx) mouse model to investigate the intestinal microbiota and the effects of administering vancomycin (VCM) on the microbiota and the cardiac pathology associated with CKD. Despite VCM administration after the development of irreversible glomerulosclerosis and tubulointerstitial fibrosis, blood indoxyl sulfate and phenyl sulfate levels, which are intestinal bacteria-derived uremic substances, brain natriuretic peptide levels, and the fibrotic area in the heart were decreased. Moreover, VCM administration prevented 5/6Nx-induced weight loss and prolonged survival time. Our findings suggest that VCM-induced changes in the intestinal microbiota composition ameliorate heart failure and improve survival rates by reducing intestinal microbiota-derived cardiotoxic substances despite advanced renal dysfunction. This highlights the potential of using the intestinal microbiota as a target to prevent and treat cardiovascular conditions associated with CKD. [Display omitted] • Despite nephrectomized 5/6 kidney, oral administring VCM substantially decreased indoxyl sulfate and phenyl sulfate in mice. • VCM administration led to decreased brain natriuretic peptide levels and fibrosis in the heart. • VCM also prevented 5/6Nx-induced weight loss and improved survival rates. • The potential of VCM-induced changes in the intestinal microbiota composition to ameliorate heart failure and enhance survival rates. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
175. The scaffold protein PDZK1 governs diurnal localization of CNT2 on the plasma membrane in mouse intestinal epithelial cells.
- Author
-
Jaballah, Nour, Tsurudome, Yuya, Murakami, Chiho, Matsunaga, Naoya, Ushijima, Kentaro, Koyanagi, Satoru, and Ohdo, Shigehiro
- Subjects
- *
CIRCADIAN rhythms , *SCAFFOLD proteins , *EPITHELIAL cells , *CELL membranes , *BIOLOGICAL systems , *INTESTINES , *MOLECULAR clock , *CLOCK genes - Abstract
Diurnal oscillations in the expression of several types of cell surface transporters have been demonstrated in the intestinal epithelial cells, which are mainly generated at transcriptional or degradation processes. Concentrative nucleoside transporter-2 (CNT2) is expressed at the apical site of intestinal epithelial cells and contributes to the uptake of nucleosides and their analogs from the intestinal lumen into the epithelial cells. In this study, we demonstrated that the localization of CNT2 protein in the plasma membrane of mouse intestinal epithelial cells exhibited a diurnal oscillation without changing its protein level in the whole cell. The scaffold protein PDZK1 interacted with CNT2 and stabilized its plasmalemmal localization. The expression of PDZK1 was under the control of molecular components of the circadian clock. Temporal accumulation of PDZK1 protein in intestinal epithelial cells enhanced the plasmalemmal localization of CNT2 at certain times of the day. The temporal increase in CNT2 protein levels at the plasma membrane also facilitated the uptake of adenosine into the intestinal epithelial cells. These results suggest a novel molecular mechanism for the diurnal localization of cell surface transporters and extend our understanding of the biological clock system that generates apparent physiological rhythms. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
176. Hericenone C attenuates the second phase of formalin-induced nociceptive behavior by suppressing the accumulation of CD11c-positive cells in the paw epidermis via phosphorylated P65.
- Author
-
Li, Junhao, Hamamura, Kengo, Yoshida, Yuya, Kawano, Shimpei, Uchinomiya, Shohei, Xie, Jiahongyi, Scuteri, Damiana, Fukuoka, Kohei, Zaitsu, Orion, Tsurusaki, Fumiaki, Terada, Yuma, Tsukamoto, Ryotaro, Nishi, Takumi, Fukuda, Taiki, Oyama, Kosuke, Bagetta, Giacinto, Ojida, Akio, Shimizu, Kuniyoshi, Ohdo, Shigehiro, and Matsunaga, Naoya
- Subjects
- *
HERICIUM erinaceus , *EPIDERMIS , *METABOLITES , *FOOT , *CELL analysis , *CELLULAR signal transduction - Abstract
Hericenone C is one of the most abundant secondary metabolites derived from Hericium erinaceus , under investigation for medicinal properties. Here, we report that Hericenone C inhibits the second phase of formalin-induced nociceptive behavior in mice. As the second phase is involved in inflammation, in a mechanistic analysis on cultured cells targeting NF-κB response element (NRE): luciferase (Luc)-expressing cells, lipopolysaccharide (LPS)-induced NRE::Luc luciferase activity was found to be significantly inhibited by Hericenone C. Phosphorylation of p65, which is involved in the inflammatory responses of the NF-κB signaling pathway, was also induced by LPS and significantly reduced by Hericenone C. Additionally, in mice, the number of CD11c-positive cells increased in the paw during the peak of the second phase of the formalin test, which decreased upon Hericenone C intake. Our findings confirm the possibility of Hericenone C as a novel therapeutic target for pain-associated inflammation. [Display omitted] • Hericenone C attenuates the second phase of formalin-induced nociceptive behavior in mice. • Inhibition of P65 activation by Hericenone C in NRE::Luc-expressing cells. • Hericenone C suppresses formalin-induced inflammation in RAW264.7 cells. • Hericenone C inhibits P65 activation of CD11b/CD11c-positive cells in the paw of formalin-treated mice. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
177. Circadian rhythms in CYP2A5 expression underlie the time-dependent effect of tegafur on breast cancer.
- Author
-
Yoshida, Yuya, Fukuda, Taiki, Tanihara, Tomohito, Nishikawa, Naoki, Iwasa, Serina, Adachi, Satoka, Zaitsu, Orion, Terada, Yuma, Tsukamoto, Ryotaro, Shimoshikiryo, Hideki, Fukuoka, Kohei, Tsurusaki, Fumiaki, Hamamura, Kengo, Oyama, Kosuke, Tsuruta, Akito, Koyanagi, Satoru, Matsunaga, Naoya, and Ohdo, Shigehiro
- Subjects
- *
CIRCADIAN rhythms , *BREAST cancer , *MEDICAL protocols , *CANCER cells , *FLUOROURACIL , *PRODRUGS - Abstract
The chemotherapeutic agent tegafur, a prodrug that prolongs the half-life of fluorouracil (5-FU), exerts antitumor effects against various cancers. Since tegafur is metabolized to 5-FU by CYP2A6 in the liver, the expression of CYP2A6 determines the effect of tegafur. Here, we report that the expression rhythm of Cyp2a5 , a homolog of human CYP2A6 , in female mice causes dosing time-dependent differences in tegafur metabolism. In the livers of female mice, CYP2A5 expression showed a circadian rhythm, peaking during the dark period. This rhythm is regulated by RORA, a core clock component, and abrogation of the CYP2A5 activity abolished the time-dependent difference in the rate of tegafur metabolism in female mice. Furthermore, administration of tegafur to mice transplanted with 4T1 breast cancer cells during the dark period suppressed increases in tumor size compared to female mice treated during the light period. Our findings reveal a novel relationship between 5-FU prodrugs and circadian clock machinery, potentially influencing antitumor effects, and contributing to the development of time-aware chemotherapy regimens for breast cancer. • Tegafur is a prodrug that is metabolized in the body to 5-fluorouracil by CYP2A6. • CYP2A5 function in the liver of BALB/c female mice exhibits circadian variation. • Antitumor effect of tegafur on female mice implanted with 4T1 cells is influenced by administration time. • Tegafur treatment protocols for breast cancer should consider the timing of administration to maximize effect. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
178. Corrigendum to "Sulfasalazine alleviates neuropathic pain hypersensitivity in mice through inhibition of SGK-1 in the spinal cord" [Biochem. Pharmacol. 185 (2021) 114411].
- Author
-
Yasukochi, Sai, Kusunose, Naoki, Matsunaga, Naoya, Koyanagi, Satoru, and Ohdo, Shigehiro
- Subjects
- *
NEURALGIA , *SPINAL cord , *MICE - Published
- 2021
- Full Text
- View/download PDF
179. Diurnal expression of MRP4 in bone marrow cells underlies the dosing-time dependent changes in the oxaliplatin-induced myelotoxicity.
- Author
-
Kato, Mizuki, Tsurudome, Yuya, Kanemitsu, Takumi, Yasukochi, Sai, Kanado, Yuki, Ogino, Takashi, Matsunaga, Naoya, Koyanagi, Satoru, and Ohdo, Shigehiro
- Subjects
- *
OXALIPLATIN , *MYELOSUPPRESSION , *BONE marrow cells , *XENOBIOTICS , *MULTIDRUG resistance , *PROTEINS - Abstract
The expression and function of some xenobiotic transporters varies according to the time of day, causing the dosing time-dependent changes in drug disposition and toxicity. Multidrug resistance-associated protein-4 (MRP4), an ATP-binding cassette (ABC) efflux transporter encoded by the Abcc4 gene, is highly expressed in bone marrow cells (BMCs) and protects them against xenobiotics, including chemotherapeutic drugs. In this study, we demonstrated that MRP4 was responsible for the extrusion of oxaliplatin (L-OHP), a platinum (Pt)-based chemotherapeutic drug, from BMCs of mice, and that the efflux transporter expression exhibited significant diurnal variation. Therefore, we investigated the relevance of the diurnal expression of MRP4 in BMCs for L-OHP-induced myelotoxicity in mice maintained under standardized light/dark cycle conditions. After intravenous injection of L-OHP, the Pt content in BMCs varied according to the injection time. Lower Pt accumulation in BMCs was detected in mice after injection of L-OHP at the mid-dark phase, during which the expression levels of MRP4 increased. Consistent with these observations, the myelotoxic effects of L-OHP were attenuated when mice were injected with L-OHP during the dark phase. This dosing schedule also alleviated the L-OHP-induced reduction of the peripheral white blood cell count. The present results suggest that the myelotoxicity of L-OHP is attenuated by optimizing the dosing schedule. Diurnal expression of MRP4 in BMCs is associated with the dosing time-dependent changes in L-OHP-induced myelotoxicity. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
180. Contribution of the clock gene DEC2 to VEGF mRNA upregulation by modulation of HIF1α protein levels in hypoxic MIO-M1 cells, a human cell line of retinal glial (Müller) cells.
- Author
-
Kusunose, Naoki, Akamine, Takahiro, Kobayashi, Yoshiyuki, Yoshida, Shigeo, Kimoto, Kenichi, Yasukochi, Sai, Matsunaga, Naoya, Koyanagi, Satoru, Ohdo, Shigehiro, and Kubota, Toshiaki
- Subjects
- *
CLOCK genes , *VASCULAR endothelial growth factors , *HYPOXIA-inducible factor 1 , *GENE expression , *MESSENGER RNA , *RETINAL ganglion cells - Abstract
Purpose: Clock genes are components of the molecular clock. Their malfunction is thought to increase the risk of numerous diseases, including cancer. Vascular endothelial growth factor (VEGF) has a pivotal role in angiogenesis, and its expression levels are controlled by clock genes in tumor cells. Ophthalmic diseases such as age-related macular degeneration, proliferative diabetic retinopathy, and neovascular glaucoma are also associated with abnormal angiogenesis followed by upregulation of VEGF in the eye. In the present study, we aimed to uncover the relationship between clock genes and VEGF in the eye.Study design: Laboratory investigationMethods: Oxygen-induced retinopathy (OIR) mice were prepared to mimic hypoxic conditions in the eye. Deferoxamine (DFO) was used to mimic hypoxic conditions in human Müller cell line MIO-M1 cells. Expression levels of mRNA and protein were quantified by quantitative reverse transcription polymerase chain reaction and Western blot analysis, respectively.Results: In the retinas of OIR mice, the expression levels of Vegf and the clock gene Dec2 increased transiently, and their temporal profiles were correlated. Knockdown of DEC2 resulted in a significant (26.7%) reduction of VEGF expression in MIO-M1 cells under hypoxia-mimicking conditions induced by DFO (P <.05). Levels of HIF1α protein were also reduced significantly, by 60.2%, in MIO-M1 cells treated with siRNA against the DEC2 gene (P <.05). Moreover, HIF1α levels showed a significant (2.5-fold) increase in MIO-M1 cells overexpressing DEC2 (P <.05).Conclusion: DEC2 could upregulate retinal VEGF gene expression through modulation of HIF1α levels under hypoxic conditions. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
181. Modulation of cell physiology by bispecific nanobodies enabling changes in the intracellular localization of organelle proteins.
- Author
-
Tsuruta, Akito, Kanetani, Daiki, Shiiba, Yuki, Inoki, Takuto, Yoshida, Yuya, Matsunaga, Naoya, Koyanagi, Satoru, and Ohdo, Shigehiro
- Subjects
- *
CELL physiology , *BISPECIFIC antibodies , *IMMUNOGLOBULINS , *IMMOBILIZED proteins , *ORGANELLES , *PROTEINS , *NUCLEAR membranes - Abstract
[Display omitted] Proteins localize to their respective organelles in cells. This localization is changed by activation or repression in response to signal transduction. Therefore, the appropriate intracellular localization of proteins is important for their functions to be exerted. However, difficulties are associated with controlling the localization of endogenous proteins. In the present study, we developed a conceptually new method of controlling the intracellular localization of endogenous proteins using bispecific nanobodies (BiNbs). BiNbs recognize proteins expressed in the inner membrane, cytoskeleton, nucleus, and peroxisomes, but not in mitochondria or endoplasmic reticulum. BiNbs designed to recognize β-CATENIN and the intrinsic cytosolic protein VIMENTIN (3 × Flag β-CAT-VIM BiNbs) decreased the β-CATENIN-mediated transactivation of target genes by preventing its nuclear localization. Furthermore, 3 × Flag β-CAT-VIM BiNbs suppressed the proliferation and invasion of the VIMENTIN-expressing breast cancer cell line MDA-MB-231, but not MDA-MB-468, in which the expression of VIMENTIN was defective. The present results revealed that changes in the intracellular localization of specific proteins by BiNbs modulated the physiology and functions of cells. The development of BiNbs to recognize proteins specifically expressed in target cells may be a useful approach for eliciting cell-selective effects. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
182. Epigenetic repression of de novo cysteine synthetases induces intra-cellular accumulation of cysteine in hepatocarcinoma by up-regulating the cystine uptake transporter xCT.
- Author
-
Yamauchi T, Okano Y, Terada D, Yasukochi S, Tsuruta A, Tsurudome Y, Ushijima K, Matsunaga N, Koyanagi S, and Ohdo S
- Abstract
Background: The metabolic reprogramming of amino acids is critical for cancer cell growth and survival. Notably, intracellular accumulation of cysteine is often observed in various cancers, suggesting its potential role in alleviating the oxidative stress associated with rapid proliferation. The liver is the primary organ for cysteine biosynthesis, but much remains unknown about the metabolic alterations of cysteine and their mechanisms in hepatocellular carcinoma cells., Methods: RNA-seq data from patients with hepatocarcinoma were analyzed using the TNMplot database. The underlying mechanism of the oncogenic alteration of cysteine metabolism was studied in mice implanted with BNL 1ME A.7 R.1 hepatocarcinoma., Results: Database analysis of patients with hepatocellular carcinoma revealed that the expression of enzymes involved in de novo cysteine synthesis was down-regulated accompanying with increased expression of the cystine uptake transporter xCT. Similar alterations in gene expression have also been observed in a syngeneic mouse model of hepatocarcinoma. The enhanced expression of DNA methyltransferase in murine hepatocarcinoma cells caused methylation of the upstream regions of cysteine synthesis genes, thereby repressing their expression. Conversely, suppression of de novo cysteine synthesis in healthy liver cells induced xCT expression by up-regulating the oxidative-stress response factor NRF2, indicating that reduced de novo cysteine synthesis repulsively increases cystine uptake via enhanced xCT expression, leading to intracellular cysteine accumulation. Furthermore, the pharmacological inhibition of xCT activity decreased intracellular cysteine levels and suppressed hepatocarcinoma tumor growth in mice., Conclusions: Our findings indicate an underlying mechanism of the oncogenic alteration of cysteine metabolism in hepatocarcinoma and highlight the efficacy of alteration of cysteine metabolism as a viable therapeutic target in cancer., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
183. Macrophages modulate mesenchymal stem cell function via tumor necrosis factor alpha in tooth extraction model.
- Author
-
Mun AY, Akiyama K, Wang Z, Zhang J, Kitagawa W, Kohno T, Tagashira R, Ishibashi K, Matsunaga N, Zou T, Ono M, and Kuboki T
- Abstract
Mesenchymal stem cells (MSCs) and macrophages collaboratively contribute to bone regeneration after injury. However, detailed mechanisms underlying the interaction between MSCs and inflammatory macrophages (M1) remain unclear. A macrophage-depleted tooth extraction model was generated in 5-wk-old female C57BL/6J mice using clodronate liposome (12.5 mg/kg/mouse, intraperitoneally) or saline injection (control) before maxillary first molar extraction. Mice were sacrificed on days 1, 3, 5, 7, and 10 after tooth extraction ( n = 4). Regenerated bone volume evaluation of tooth extraction socket (TES) and histochemical analysis of CD80
+ M1, CD206+ M2 (anti-inflammatory macrophages), PDGFRα+ MSC, and TNF-α+ cells were performed. In vitro, isolated MSCs with or without TNF-α stimulation (10 ng/mL, 24 h, n = 3) were bulk RNA-sequenced (RNA-Seq) to identify TNF-α stimulation-specific MSC transcriptomes. Day 7 micro-CT and HE staining revealed significantly lower mean bone volume (clodronate vs control: 0.01 mm3 vs 0.02 mm3 , p <.0001) and mean percentage of regenerated bone area per total TES in clodronate group (41.97% vs 54.03%, p <.0001). Clodronate group showed significant reduction in mean number of CD80+ , TNF-α+ , PDGFRα+ , and CD80+ TNF-α+ cells on day 5 (306.5 vs 558.8, p <.0001; 280.5 vs 543.8, p <.0001; 365.0 vs 633.0, p <.0001, 29.0 vs 42.5, p <.0001), while these cells recovered significantly on day 7 (493.3 vs 396.0, p =.0004; 479.3 vs 384.5, p =.0008; 593.0 vs 473.0, p =.0010, 41.0 vs 32.5, p =.0003). RNA-Seq analysis showed that 15 genes (|log2FC| > 5.0, log2TPM > 5) after TNF-α stimulation were candidates for regulating MSC's immunomodulatory capacity. In vivo, Clec4e and Gbp6 are involved in inflammation and bone formation. Clec4e , Gbp6 , and Cxcl10 knockdown increased osteogenic differentiation of MSCs in vitro. Temporal reduction followed by apparent recovery of TNF-α-producing M1 macrophages and MSCs after temporal macrophage depletion suggests that TNF-α activated MSCs during TES healing. In vitro mimicking the effect of TNF-α on MSCs indicated that there are 15 candidate MSC genes for regulation of immunomodulatory capacity., Competing Interests: The authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)- Published
- 2024
- Full Text
- View/download PDF
184. Inhibition of G protein-coupled receptor 68 using homoharringtonine attenuates chronic kidney disease-associated cardiac impairment.
- Author
-
Yoshida Y, Fukuoka K, Sakugawa M, Kurogi M, Hamamura K, Hamasaki K, Tsurusaki F, Sotono K, Nishi T, Fukuda T, Kumamoto T, Oyama K, Ogino T, Tsuruta A, Mayanagi K, Yamashita T, Fuchino H, Kawahara N, Yoshimatsu K, Kawakami H, Koyanagi S, Matsunaga N, and Ohdo S
- Subjects
- Animals, Mice, Cytokines metabolism, Fibrosis, Heart Diseases drug therapy, Heart Diseases etiology, Mice, Inbred C57BL, Homoharringtonine pharmacology, Homoharringtonine therapeutic use, Plant Extracts pharmacology, Plant Extracts therapeutic use, Receptors, G-Protein-Coupled drug effects, Receptors, G-Protein-Coupled metabolism, Renal Insufficiency, Chronic drug therapy, Renal Insufficiency, Chronic metabolism, Renal Insufficiency, Chronic pathology, Renal Insufficiency, Chronic complications
- Abstract
Chronic kidney disease (CKD) induces cardiac inflammation and fibrosis and reduces survival. We previously demonstrated that G protein-coupled receptor 68 (GPR68) promotes cardiac inflammation and fibrosis in mice with 5/6 nephrectomy (5/6Nx) and patients with CKD. However, no method of GPR68 inhibition has been found that has potential for therapeutic application. Here, we report that Cephalotaxus harringtonia var. nana extract and homoharringtonine ameliorate cardiac inflammation and fibrosis under CKD by suppressing GPR68 function. Reagents that inhibit the function of GPR68 were explored by high-throughput screening using a medicinal plant extract library (8,008 species), and we identified an extract from Cephalotaxus harringtonia var. nana as a GPR68 inhibitor that suppresses inflammatory cytokine production in a GPR68 expression-dependent manner. Consumption of the extract inhibited inflammatory cytokine expression and cardiac fibrosis and improved the decreased survival attributable to 5/6Nx. Additionally, homoharringtonine, a cephalotaxane compound characteristic of C. harringtonia, inhibited inflammatory cytokine production. Homoharringtonine administration in drinking water alleviated cardiac fibrosis and improved heart failure and survival in 5/6Nx mice. A previously unknown effect of C. harringtonia extract and homoharringtonine was revealed in which GPR68-dependent inflammation and cardiac dysfunction were suppressed. Utilizing these compounds could represent a new strategy for treating GPR68-associated diseases, including CKD., Competing Interests: Declaration of competing interest All authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. All the authors have read and approved the submission for publication., (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
185. Cholecystokinin receptor type A are involved in the circadian rhythm of the mouse retina.
- Author
-
Yamakawa Y, Tsurudome Y, Tamada M, Tsuchimochi Y, Umeda Y, Yoshida Y, Kobayashi D, Kawashiri T, Kubota T, Matsunaga N, and Shimazoe T
- Abstract
The retina is the only organ projecting external light to the suprachiasmatic nucleus. Cholecystokinin receptor type A (Cckar/ Cckar ) is one of the essential factors for light reception in retinal cells. As there was a lack of literature on the matter, we aimed to elucidate the cause of the time-dependent phase change in clock gene expression. We found that Cckar mRNA expression in retinal cells exhibited diurnal variations. The rhythm of expression of the clock gene Per1 / Per2 in retinal cells was altered in Cckar
-/- mice. The light sensitivity of retinal cells was evaluated in wild-type mice, which showed c-Fos was activated in the ganglion cell layer more than in the inner granular layer. This increase in the number of c-Fos-positive cells was suppressed by lorglumide, a Cckar antagonist. Treatment of rat retina primary cells with lorglumide suppressed Per2 transcription, which was altered in a time-dependent manner relative to the Per2 expression. Light irradiation studies in Cckar-/- mice did not exhibit an increase in Period expression in the suprachiasmatic nucleus. These results indicate that Cckar is among the factors that regulate the cycle of clock genes on the retina. Cckar knockout attenuates the light responsiveness of suprachiasmatic nucleus and reduces the expression amplitude of Period genes in the retina. Thus, Cckar may contribute to entrainment of the light environment and maintenance of the expression cycle of Period gene, which is one of the core clock genes., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier Ltd.)- Published
- 2024
- Full Text
- View/download PDF
186. Suppression of neuropathic pain in the circadian clock-deficient Per2 m/m mice involves up-regulation of endocannabinoid system.
- Author
-
Yamakawa W, Yasukochi S, Tsurudome Y, Kusunose N, Yamaguchi Y, Tsuruta A, Matsunaga N, Ushijima K, Koyanagi S, and Ohdo S
- Abstract
Neuropathic pain often results from injuries and diseases that affect the somatosensory system. Disruption of the circadian clock has been implicated in the exacerbation of the neuropathic pain state. However, in this study, we report that mice deficient in a core clock component Period2 ( Per2
m/m mice) fail to develop tactile pain hypersensitivity even following peripheral nerve injury. Similar to male wild-type mice, partial sciatic nerve ligation (PSL)- Per2m/m male mice showed activation of glial cells in the dorsal horn of the spinal cord and increased expression of pain-related genes. Interestingly, α1D-adrenergic receptor (α1D-AR) expression was up-regulated in the spinal cord of Per2m/m mice, leading to increased production of 2-arachidonoylglycerol (2-AG), an endocannabinoid receptor ligand. This increase in 2-AG suppressed the PSL-induced tactile pain hypersensitivity. Furthermore, intraspinal dorsal horn injection of adeno-associated viral vectors expressing α1D-AR also attenuated pain hypersensitivity in PSL-wild-type male mice by increasing 2-AG production. Our findings reveal an uncovered role of the circadian clock in neuropathic pain disorders and suggest a link between α1D-AR signaling and the endocannabinoid system., (© The Author(s) 2024. Published by Oxford University Press on behalf of National Academy of Sciences.)- Published
- 2024
- Full Text
- View/download PDF
187. Time-Dependent Differences in Vancomycin Sensitivity of Macrophages Underlie Vancomycin-Induced Acute Kidney Injury.
- Author
-
Yoshida Y, Fukuda T, Fukuoka K, Nagayama T, Tanihara T, Nishikawa N, Otsuki K, Terada Y, Hamamura K, Oyama K, Tsuruta A, Mayanagi K, Koyanagi S, Matsunaga N, and Ohdo S
- Subjects
- Mice, Animals, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents metabolism, Kidney, Macrophages, Vancomycin pharmacology, Vancomycin metabolism, Acute Kidney Injury chemically induced, Acute Kidney Injury metabolism
- Abstract
Although vancomycin (VCM)-frequently used to treat drug-resistant bacterial infections-often induces acute kidney injury (AKI), discontinuation of the drug is the only effective treatment; therefore, analysis of effective avoidance methods is urgently needed. Here, we report the differences in the induction of AKI by VCM in 1/2-nephrectomized mice depending on the time of administration. Despite the lack of difference in the accumulation of VCM in the kidney between the light (ZT2) and dark (ZT14) phases, the expression of AKI markers due to VCM was observed only in the ZT2 treatment. Genomic analysis of the kidney suggested that the time of administration was involved in VCM-induced changes in monocyte and macrophage activity, and VCM had time-dependent effects on renal macrophage abundance, ATP activity, and interleukin (IL)-1 β expression. Furthermore, the depletion of macrophages with clodronate abolished the induction of IL-1 β and AKI marker expression by VCM administration at ZT2. This study provides evidence of the need for time-dependent pharmacodynamic considerations in the prevention of VCM-induced AKI as well as the potential for macrophage-targeted AKI therapy. SIGNIFICANCE STATEMENT: There is a time of administration at which vancomycin (VCM)-induced renal injury is more and less likely to occur, and macrophages are involved in this difference. Therefore, there is a need for time-dependent pharmacodynamic considerations in the prevention of VCM-induced acute kidney injury as well as the potential for macrophage-targeted acute kidney injury therapy., (Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.)
- Published
- 2024
- Full Text
- View/download PDF
188. Implications of biological clocks in pharmacology and pharmacokinetics of antitumor drugs.
- Author
-
Ohdo S, Koyanagi S, and Matsunaga N
- Subjects
- Animals, Biological Clocks genetics, Chronotherapy, Homeostasis, Mammals, Circadian Rhythm genetics, Antineoplastic Agents pharmacology
- Abstract
Mammalians' circadian pacemaker resides in the paired suprachiasmatic nuclei (SCN). SCN control biological rhythms such as the sleep-wake rhythm and homeostatic functions of steroid hormones and their receptors. Alterations in these biological rhythms are implicated in the outcomes of pathogenic conditions such as depression, diabetes, and cancer. Chronotherapy is about optimizing treatment to combat risks and intensity of the disease symptoms that vary depending on the time of day. Thus, conditions/diseases such as allergic rhinitis, arthritis, asthma, myocardial infarction, congestive heart failure, stroke, and peptic ulcer disease, prone to manifest severe symptoms depending on the time of day, would be benefited from chronotherapy. Monitoring rhythm, overcoming rhythm disruption, and manipulating the rhythms from the viewpoints of underlying molecular clocks are essential to enhanced chronopharmacotherapy. New drugs focused on molecular clocks are being developed to improve therapeutics. In this review, we provide a critical summary of literature reports concerning (a) the rationale/mechanisms for time-dependent dosing differences in therapeutic outcomes and safety of antitumor drugs, (b) the molecular pathways underlying biological rhythms, and (c) the possibility of pharmacotherapy based on the intra- and inter-individual variabilities from the viewpoints of the clock genes., (Copyright © 2023 Elsevier B.V. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
189. Population Pharmacokinetic Analysis of Drug-Drug Interactions Between Perampanel and Carbamazepine Using Enzyme Induction Model in Epileptic Patients.
- Author
-
Fujita Y, Murai M, Muraki S, Suetsugu K, Tsuchiya Y, Hirota T, Matsunaga N, and Ieiri I
- Subjects
- Humans, Retrospective Studies, Enzyme Induction, Benzodiazepines therapeutic use, Drug Interactions, Carbamazepine therapeutic use, Epilepsy drug therapy
- Abstract
Background: Perampanel (PER) is an oral antiepileptic drug and its concomitant use with carbamazepine (CBZ) leads to decreased PER concentrations. However, the magnitude of its influence may vary, depending on the dynamics of the enzyme induction properties of CBZ. This study aimed to develop a population pharmacokinetic (PPK) model considering the dynamics of enzyme induction and evaluate the effect of CBZ on PER pharmacokinetics., Methods: We retrospectively collected data on patient background, laboratory tests, and prescribed drugs from electronic medical records. We developed 2 PPK models incorporating the effect of CBZ-mediated enzyme induction to describe time-concentration profiles of PER using the following different approaches: (1) treating the concomitant use of CBZ as a categorical covariate (empirical PPK model) and (2) incorporating the time-course of changes in the amount of enzyme by CBZ-mediated induction (semimechanistic PPK model). The bias and precision of the predictions were investigated by calculating the mean error, mean absolute error, and root mean squared error., Results: A total of 133 PER concentrations from 64 patients were available for PPK modelling. PPK analyses showed that the co-administration of CBZ increased the clearance of PER. Goodness-of-fit plots indicated a favorable description of the observed data and low bias. The mean error, mean absolute error, and root mean square error values based on the semimechanistic model were smaller than those obtained using the empirical PPK model for predicting PER concentrations in patients with CBZ., Conclusions: We developed 2 PPK models to describe PER pharmacokinetics based on different approaches, using electronic medical record data. Our PPK models support the use of PER in clinical practice., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
190. Inhibition of Tumor-Derived C-C Motif Chemokine Ligand 2 Expression Attenuates Tactile Allodynia in NCTC 2472 Fibrosarcoma-Inoculated Mice.
- Author
-
Taniguchi M, Yasukochi S, Yamakawa W, Tsurudome Y, Tsuruta A, Horiguchi M, Ushijima K, Yamashita T, Shindo N, Ojida A, Matsunaga N, Koyanagi S, and Ohdo S
- Subjects
- Animals, Mice, Chemokine CCL2 metabolism, Chemokine CCL2 therapeutic use, Delayed-Action Preparations, Hyperalgesia drug therapy, Hyperalgesia etiology, Hyperalgesia metabolism, Ligands, Fibrosarcoma complications, Fibrosarcoma drug therapy, Neuralgia drug therapy
- Abstract
Neuropathic pain associated with cancers is caused by tumor growth compressing and damaging nerves, which would also be enhanced by inflammatory factors through sensitizing nociceptor neurons. A troublesome hallmark symptom of neuropathic pain is hypersensitivity to innocuous stimuli, a condition known as "tactile allodynia", which is often refractory to NSAIDs and opioids. The involvement of chemokine CCL2 (monocyte chemoattractant protein-1) in cancer-evoked neuropathic pain is well established, but opinions remain divided as to whether CCL2 is involved in the production of tactile allodynia with tumor growth. In this study, we constructed Ccl2 knockout NCTC 2472 ( Ccl2 -KO NCTC) fibrosarcoma cells and conducted pain behavioral test using Ccl2 -KO NCTC-implanted mice. Implantation of naïve NCTC cells around the sciatic nerves of mice produced tactile allodynia in the inoculated paw. Although the growth of Ccl2 KO NCTC-formed tumors was comparable to that of naïve NCTC-formed tumors, Ccl2 -KO NCTC-bearing mice failed to show tactile pain hypersensitivity, suggesting the involvement of CCL2 in cancer-induced allodynia. Subcutaneous administration of controlled-release nanoparticles containing the CCL2 expression inhibitor NS-3-008 (1-benzyl-3-hexylguanidine) significantly attenuated tactile allodynia in naïve NCTC-bearing mice accompanied by a reduction of CCL2 content in tumor masses. Our present findings suggest that inhibition of CCL2 expression in cancer cells is a useful strategy to attenuate tactile allodynia induced by tumor growth. Development of a controlled-release system of CCL2 expression inhibitor may be a preventative option for the treatment of cancer-evoked neuropathic pain. SIGNIFICANCE STATEMENT: The blockade of chemokine/receptor signaling, particularly for C-C motif chemokine ligand 2 (CCL2) and its high-affinity receptor C-C chemokine receptor type 2 (CCR2), has been implicated to attenuate cancer-induced inflammatory and nociceptive pain. This study demonstrated that continuous inhibition of CCL2 production from cancer cells also prevents the development of tactile allodynia associated with tumor growth. Development of a controlled-release system of CCL2 expression inhibitor may be a preventative option for management of cancer-evoked tactile allodynia., (Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.)
- Published
- 2023
- Full Text
- View/download PDF
191. Expanding the Chemistry of Dihaloacetamides as Tunable Electrophiles for Reversible Covalent Targeting of Cysteines.
- Author
-
Yamane D, Tetsukawa R, Zenmyo N, Tabata K, Yoshida Y, Matsunaga N, Shindo N, and Ojida A
- Subjects
- Humans, Cysteine chemistry, Mutation, Protein Kinase Inhibitors pharmacology, Sulfhydryl Compounds, ErbB Receptors
- Abstract
The choice of an appropriate electrophile is crucial in the design of targeted covalent inhibitors (TCIs). In this report, we systematically investigated the glutathione (GSH) reactivity of various haloacetamides and the aqueous stability of their thiol adducts. Our findings revealed that dihaloacetamides cover a broad range of GSH reactivity depending on the combination of the halogen atoms and the structure of the amine scaffold. Among the dihaloacetamides, dichloroacetamide (DCA) exhibited slightly lower GSH reactivity than chlorofluoroacetamide (CFA). The DCA-thiol adduct is readily hydrolyzed under aqueous conditions, but it can stably exist in the solvent-sequestered binding pocket of the protein. These reactivity profiles of DCA were successfully exploited in the design of TCIs targeting noncatalytic cysteines of KRAS
G12C and EGFRL858R/T790M . These inhibitors exhibited strong antiproliferative activities against cancer cells. Our findings provide valuable insights for designing dihaloacetamide-based reversible covalent inhibitors.- Published
- 2023
- Full Text
- View/download PDF
192. Fluorescence-Based Detection of Fatty Acid β-Oxidation in Cells and Tissues Using Quinone Methide-Releasing Probes.
- Author
-
Uchinomiya S, Nagaura T, Weber M, Matsuo Y, Zenmyo N, Yoshida Y, Tsuruta A, Koyanagi S, Ohdo S, Matsunaga N, and Ojida A
- Subjects
- Mice, Animals, Oxidation-Reduction, Fluorescence, Hepatocytes metabolism, Fatty Acids metabolism
- Abstract
Detection of metabolic activity enables us to reveal the inherent metabolic state of cells and elucidate mechanisms underlying cellular homeostasis and growth. However, a fluorescence approach for the study of metabolic pathways is still largely unexplored. Herein, we have developed a new chemical probe for the fluorescence-based detection of fatty acid β-oxidation (FAO), a key process in lipid catabolism, in cells and tissues. This probe serves as a substrate of FAO and forms a reactive quinone methide (QM) as a result of metabolic reactions. The liberated QM is covalently captured by intracellular proteins, and subsequent bio-orthogonal ligation with a fluorophore enables fluorescence analysis. This reaction-based sensing allowed us to detect FAO activity in cells at a desired emission wavelength using diverse analytical techniques including fluorescence imaging, in-gel fluorescence activity-based protein profiling (ABPP), and fluorescence-activated cell sorting (FACS). The probe was able to detect changes in FAO activity induced by chemical modulators in cultured cells. The probe was further employed for fluorescence imaging of FAO in mouse liver tissues and revealed the metabolic heterogeneity of FAO activity in hepatocytes by the combination of FACS and gene expression analysis, highlighting the utility of our probe as a chemical tool for fatty acid metabolism research.
- Published
- 2023
- Full Text
- View/download PDF
193. Discovery of Chlorofluoroacetamide-Based Covalent Inhibitors for Severe Acute Respiratory Syndrome Coronavirus 2 3CL Protease.
- Author
-
Hirose Y, Shindo N, Mori M, Onitsuka S, Isogai H, Hamada R, Hiramoto T, Ochi J, Takahashi D, Ueda T, Caaveiro JMM, Yoshida Y, Ohdo S, Matsunaga N, Toba S, Sasaki M, Orba Y, Sawa H, Sato A, Kawanishi E, and Ojida A
- Subjects
- Humans, Coronavirus 3C Proteases, Peptide Hydrolases, Protease Inhibitors pharmacology, Protease Inhibitors therapeutic use, Protease Inhibitors chemistry, Cysteine, Cysteine Endopeptidases chemistry, Antiviral Agents pharmacology, Antiviral Agents therapeutic use, Antiviral Agents chemistry, Peptides chemistry, SARS-CoV-2, COVID-19 Drug Treatment
- Abstract
The coronavirus disease 2019 (COVID-19) pandemic has necessitated the development of antiviral agents against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). 3C-like protease (3CL
pro ) is a promising target for COVID-19 treatment. Here, we report a new class of covalent inhibitors of 3CLpro that possess chlorofluoroacetamide (CFA) as a cysteine-reactive warhead. Based on an aza-peptide scaffold, we synthesized a series of CFA derivatives in enantiopure form and evaluated their biochemical efficiency. The data revealed that 8a ( YH-6 ) with the R configuration at the CFA unit strongly blocks SARS-CoV-2 replication in infected cells, and its potency is comparable to that of nirmatrelvir. X-ray structural analysis showed that YH-6 formed a covalent bond with Cys145 at the catalytic center of 3CLpro . The strong antiviral activity and favorable pharmacokinetic properties of YH-6 suggest its potential as a lead compound for the treatment of COVID-19.- Published
- 2022
- Full Text
- View/download PDF
194. RNA editing enzyme ADAR1 controls miR-381-3p-mediated expression of multidrug resistance protein MRP4 via regulation of circRNA in human renal cells.
- Author
-
Omata Y, Okawa M, Haraguchi M, Tsuruta A, Matsunaga N, Koyanagi S, and Ohdo S
- Subjects
- Adenosine metabolism, Adenosine Deaminase genetics, Drug Resistance, Multiple, Humans, Inosine genetics, Kidney metabolism, Multidrug Resistance-Associated Proteins genetics, Multidrug Resistance-Associated Proteins metabolism, RNA, Circular genetics, RNA-Binding Proteins genetics, Adenosine Deaminase metabolism, MicroRNAs genetics, MicroRNAs metabolism, RNA Editing, RNA-Binding Proteins metabolism
- Abstract
Multidrug resistance-associated protein 4 (MRP4), a member of the C subfamily of ATP-binding cassette transporters, is highly expressed in the kidneys of mammals and is responsible for renal elimination of numerous drugs. Adenosine deaminase acting on RNA 1 (ADAR1) has been reported to regulate gene expression by catalyzing adenosine-to-inosine RNA editing reactions; however, potential roles of ADAR1 in the regulation of MRP4 expression have not been investigated. In this study, we found that downregulation of ADAR1 increased the expression of MRP4 in human renal cells at the posttranscriptional level. Luciferase reporter assays and microarray analysis revealed that downregulation of ADAR1 reduced the levels of microRNA miR-381-3p, which led to the corresponding upregulation of MPR4 expression. Circular RNAs (circRNAs) are a type of closed-loop endogenous noncoding RNAs that play an essential role in gene expression by acting as miRNA sponges. We demonstrate that ADAR1 repressed the biogenesis of circRNA circHIPK3 through its adenosine-to-inosine RNA editing activity, which altered the secondary structure of the precursor of circHIPK3. Furthermore, in silico analysis suggested that circHIPK3 acts as a sponge of miR-381-3p. Indeed, we found overexpression of circHIPK3 induced the expression of MRP4 through its interference with miR-381-3p. Taken together, our study provides novel insights into regulation of the expression of xenobiotic transporters through circRNA expression by the RNA editing enzyme ADAR1., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
195. Alteration of circadian machinery in monocytes underlies chronic kidney disease-associated cardiac inflammation and fibrosis.
- Author
-
Yoshida Y, Matsunaga N, Nakao T, Hamamura K, Kondo H, Ide T, Tsutsui H, Tsuruta A, Kurogi M, Nakaya M, Kurose H, Koyanagi S, and Ohdo S
- Subjects
- ARNTL Transcription Factors metabolism, Animals, CLOCK Proteins metabolism, Cells, Cultured, Circadian Rhythm genetics, Cytokines biosynthesis, Fibrosis pathology, Hypertension genetics, Hypertension pathology, Inflammation genetics, Inflammation pathology, Male, Mice, Mice, Inbred C57BL, Mice, Inbred ICR, Mice, Transgenic, Receptors, G-Protein-Coupled metabolism, CLOCK Proteins genetics, Circadian Clocks genetics, Circadian Rhythm physiology, Heart Diseases pathology, Monocytes metabolism, Renal Insufficiency, Chronic pathology
- Abstract
Dysfunction of the circadian clock has been implicated in the pathogenesis of cardiovascular disease. The CLOCK protein is a core molecular component of the circadian oscillator, so that mice with a mutated Clock gene (Clk/Clk) exhibit abnormal rhythms in numerous physiological processes. However, here we report that chronic kidney disease (CKD)-induced cardiac inflammation and fibrosis are attenuated in Clk/Clk mice even though they have high blood pressure and increased serum angiotensin II levels. A search for the underlying cause of the attenuation of heart disorder in Clk/Clk mice with 5/6 nephrectomy (5/6Nx) led to identification of the monocytic expression of G protein-coupled receptor 68 (GPR68) as a risk factor of CKD-induced inflammation and fibrosis of heart. 5/6Nx induces the expression of GPR68 in circulating monocytes via altered CLOCK activation by increasing serum levels of retinol and its binding protein (RBP4). The high-GPR68-expressing monocytes have increased potential for producing inflammatory cytokines, and their cardiac infiltration under CKD conditions exacerbates inflammation and fibrosis of heart. Serum retinol and RBP4 levels in CKD patients are also sufficient to induce the expression of GPR68 in human monocytes. Our present study reveals an uncovered role of monocytic clock genes in CKD-induced heart failure.
- Published
- 2021
- Full Text
- View/download PDF
196. Circadian clock component PERIOD2 regulates diurnal expression of Na + /H + exchanger regulatory factor-1 and its scaffolding function.
- Author
-
Tsurudome Y, Koyanagi S, Kanemitsu T, Katamune C, Oda M, Kanado Y, Kato M, Morita A, Tahara Y, Matsunaga N, Shibata S, and Ohdo S
- Subjects
- Animals, Cell Line, Tumor, Cell Membrane metabolism, Cells, Cultured, Fatty Acid Transport Proteins genetics, Fatty Acid Transport Proteins metabolism, Gene Expression Regulation, Liver cytology, Liver metabolism, Mice, Mice, Knockout, NIH 3T3 Cells, Period Circadian Proteins metabolism, Phosphoproteins metabolism, Sodium-Hydrogen Exchangers metabolism, Circadian Clocks genetics, Circadian Rhythm genetics, Period Circadian Proteins genetics, Phosphoproteins genetics, Sodium-Hydrogen Exchangers genetics
- Abstract
A number of diverse cell-surface proteins are anchored to the cytoskeleton via scaffold proteins. Na
+ /H+ exchanger regulatory factor-1 (NHERF1), encoded by the Slc9a3r1 gene, functions as a scaffold protein, which is implicated in the regulation of membrane expression of various cell-surface proteins. Here, we demonstrate that the circadian clock component PERIOD2 (PER2) modulates transcription of the mouse Slc9a3r1 gene, generating diurnal accumulation of NHERF1 in the mouse liver. Basal expression of Slc9a3r1 was dependent on transcriptional activation by p65/p50. PER2 bound to p65 protein and prevented p65/p50-mediated transactivation of Slc9a3r1. The time-dependent interaction between PER2 and p65 underlay diurnal oscillation in the hepatic expression of Slc9a3r1/NHERF1. The results of immunoprecipitation experiments and liquid chromatography-mass spectrometry analysis of mouse liver revealed that NHERF1 time-dependently interacted with fatty acid transport protein-5 (FATP5). Temporary accumulation of NHERF1 protein stabilized plasmalemmal localization of FATP5, thereby enhancing hepatic uptake of fatty acids at certain times of the day. Our results suggest an unacknowledged role for PER2 in regulating the diurnal expression of NHERF1 in mouse liver. This machinery also contributed to diurnal changes in the ability of hepatic cells to uptake fatty acids.- Published
- 2018
- Full Text
- View/download PDF
197. Optimizing the dosing schedule of l-asparaginase improves its anti-tumor activity in breast tumor-bearing mice.
- Author
-
Shiromizu S, Kusunose N, Matsunaga N, Koyanagi S, and Ohdo S
- Subjects
- Animals, Asparagine metabolism, Breast Neoplasms metabolism, Breast Neoplasms pathology, Cell Line, Tumor, Disease Models, Animal, Drug Administration Schedule, Female, Humans, Infusions, Intravenous, Mice, Inbred BALB C, Neoplasm Transplantation, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma metabolism, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Antineoplastic Agents administration & dosage, Asparaginase administration & dosage, Breast Neoplasms drug therapy, Drug Chronotherapy
- Abstract
Proliferation of acute lymphoblastic leukemic cells is nutritionally dependent on the external supply of asparagine. l-asparaginase, an enzyme hydrolyzing l-asparagine in blood, is used for treatment of acute lymphoblastic leukemic and other related blood cancers. Although previous studies demonstrated that l-asparaginase suppresses the proliferation of cultured solid tumor cells, it remains unclear whether this enzyme prevents the growth of solid tumors in vivo. In this study, we demonstrated the importance of optimizing dosing schedules for the anti-tumor activity of l-asparaginase in 4T1 breast tumor-bearing mice. Cultures of several types of murine solid tumor cells were dependent on the external supply of asparagine. Among them, we selected murine 4T1 breast cancer cells and implanted them into BALB/c female mice kept under standardized light/dark cycle conditions. The growth of 4T1 tumor cells implanted in mice was significantly suppressed by intravenous administration of l-asparaginase during the light phase, whereas its administration during the dark phase failed to show significant anti-tumor activity. Decreases in plasma asparagine levels due to the administration of l-asparaginase were closely related to the dosing time-dependency of its anti-tumor effects. These results suggest that the anti-tumor efficacy of l-asparaginase in breast tumor-bearing mice is improved by optimizing the dosing schedule., (Copyright © 2018 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
198. Dietary supplementation with essence of chicken enhances daily oscillations in plasma glucocorticoid levels and behavioral adaptation to the phase-shifted environmental light-dark cycle in mice.
- Author
-
Dilixiati A, Koyanagi S, Kusunose N, Matsunaga N, and Ohdo S
- Subjects
- Adrenal Glands metabolism, Animals, Chickens, Chronobiology Disorders diet therapy, Chronobiology Disorders prevention & control, Glucocorticoids biosynthesis, Humans, Male, Mice, Inbred C57BL, Mice, Inbred ICR, Phosphoproteins metabolism, Biological Clocks physiology, Circadian Rhythm physiology, Dietary Supplements, Environment, Glucocorticoids blood, Meat Products, Photoperiod
- Abstract
Maintenance of circadian rhythms is essential to many aspects of human health, including metabolism and neurological and psychiatric well-being. Chronic disruption of circadian clock function is implicated in increasing the risk of metabolic syndrome, cardiovascular events and development of cancers. However, there are little approaches to reinforce the function of circadian clock for prevention of these diseases. Essence of Chicken (EC) is a nutritional supplement that is traditionally made by extracting water soluble substances derived from cooking the whole chicken. In this study, we found that dietary supplementation with EC enhanced circadian oscillation of glucocorticoid secretion in mice, and this was accompanied by enhancement of circadian oscillation in the adrenal expression of steroidogenic acute regulatory (StAR) protein that mediates the rate-limiting step of glucocorticoid synthesis. Furthermore, EC facilitated re-entrainment of behavioral rhythm in mice when phase of the light-dark cycle was suddenly advanced. These results suggest that intake of EC has enhancement effect on circadian clock function in mice, which may contribute to sustain health and also offer new preventive strategies against circadian-related diseases., (Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
199. Modulation of peroxisome proliferator-activated receptor-α activity by bile acids causes circadian changes in the intestinal expression of Octn1/Slc22a4 in mice.
- Author
-
Wada E, Koyanagi S, Kusunose N, Akamine T, Masui H, Hashimoto H, Matsunaga N, and Ohdo S
- Subjects
- Animals, Caco-2 Cells, Circadian Rhythm drug effects, Humans, Intestinal Mucosa drug effects, Male, Mice, Mice, Inbred ICR, Mice, Knockout, Organic Cation Transport Proteins, Symporters, Bile Acids and Salts pharmacology, Carrier Proteins biosynthesis, Circadian Rhythm physiology, Gene Expression Regulation, Intestinal Mucosa metabolism, Membrane Proteins biosynthesis, PPAR alpha metabolism
- Abstract
In addition to their digestive actions, bile acids modulate gene expression by altering the activity of peroxisome proliferator-activated receptor-α (PPARα). The modulatory effects of bile acids have been shown to affect the expression of genes responsible for lipid metabolism as well as membrane transporters. Bile acids are secreted in response to food intake and accumulate in intestinal epithelial cells. In the present study, we identified soluble carrier protein family 22 member 4 (Slc22a4), encoding organic cation transporter novel type-1 (Octn1), as a PPARα-regulated gene and its intestinal expression exhibited circadian oscillations in a bile acid-dependent manner. Nocturnally active mice mainly consumed their food around the early dark phase, during which bile acids accumulated in intestinal epithelial cells. PPARα activated the intestinal expression of Slc22a4 mRNA during the light period, and protein levels of Octn1 peaked before the start of the dark phase. The bile acids that accumulated in intestinal epithelial cells suppressed the PPARα-mediated transactivation of Slc22a4 in the dark phase. The time-dependent suppression of PPARα-mediated transactivation by bile acids regulated oscillations in the intestinal expression of Octn1/Slc22a4 during the daily feeding cycle. The results of a pharmacokinetic analysis also revealed that oscillations in the expression of Octn1 caused dosing time-dependent differences in the intestinal absorption of gabapentin (2-[1-(aminomethyl)cyclohexyl]acetic acid). These results suggest a molecular clock-independent mechanism by which bile acid-regulated PPARα activity governs the circadian expression of intestinal organic cation transporters. This mechanism could also account for interindividual variations in the pharmacokinetics of drugs that are substrates of Octn1., (Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.)
- Published
- 2015
- Full Text
- View/download PDF
200. [Chrono-drug delivery system based on the circadian rhythm of transferrin receptor].
- Author
-
Matsunaga N, Okazaki F, Koyanagi S, and Ohdo S
- Subjects
- Animals, Drug Delivery Systems, Humans, Iron metabolism, Neoplasms metabolism, Receptors, Transferrin genetics, Transferrin metabolism, Circadian Rhythm physiology, Receptors, Transferrin metabolism
- Abstract
Transferrin receptor 1(TfR1) is a key cell surface molecule that regulates the uptake of iron-bound transferrin. TfR1 expression is higher in tumor cells than in normal cells. Thus, intracellular targeting using iron-saturated Tf as a ligand for TfR-mediated endocytosis has attracted attention. TfR1 in colon cancer-bearing mice exhibits a 24-hour rhythm in mRNA and protein levels. The clock-controlled gene c-MYC rhythmically activate the transcription of the TfR1 gene. In addition, the cyclical accumulation of TfR1 causes dosing time-dependent changes in the intratumoral delivery of drug by receptor-mediated endocytosis. Identification of the circadian properties of molecules that are targeted by ligand-directed DDS may aid the choice of the most appropriate time of day for their administration.
- Published
- 2013
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.