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1.
Nihon Yakurigaku Zasshi ; 159(2): 101-106, 2024.
Article in Japanese | MEDLINE | ID: mdl-38432917

ABSTRACT

Sepsis is defined as the body's overwhelming and life-threatening response to infection that can lead to tissue damage, organ failure, and death. Since bacterial infection is one of the main causes of sepsis, appropriate antimicrobial therapy remains the cornerstone of sepsis and septic shock management. However, since sepsis is a multifaceted chaos involving inflammation and anti-inflammation disbalance leading to the unregulated widespread release of inflammatory mediators, cytokines, and pathogen-related molecules leading to system-wide organ dysfunction, the whole body control to prevent the progression of organ dysfunction is needed. In sepsis and septic shock, pathogen-associated molecular patterns (PAMPs), such as bacterial exotoxins, cause direct cellular damage and/or trigger an immune response in the host. PAMPs are recognized by pattern recognizing receptors (PRRs) expressed on immune-reactive cells. PRRs are also activated by host nuclear, mitochondrial, and cytosolic proteins, known as damage-associated molecular patterns (DAMPs) that are released from cells during sepsis. Thus, most PRRs respond to PAMPs or DAMPs by triggering activation of transcriptional factors, NF-κB, AP1, and STAT-3. On the other hand, sepsis leads to immune (lymphocytes and macrophages) and nonimmune (endothelial and epithelial cells) cell death. Apoptosis has been the major focus of research on cell death in sepsis, but autophagy, necrosis, necroptosis, pyroptosis, NETosis, and ferroptosis may also play an important role in this critical situation. The recent development in our understanding regarding the cellular pathogenesis of sepsis will help in developing new treatment of sepsis.


Subject(s)
Sepsis , Shock, Septic , Humans , Multiple Organ Failure/etiology , Pathogen-Associated Molecular Pattern Molecules , Apoptosis , Alarmins
2.
Heliyon ; 9(10): e21008, 2023 Oct.
Article in English | MEDLINE | ID: mdl-37876479

ABSTRACT

Introduction: Pulmonary artery smooth muscle cells (PASMCs) play an important role in the sequence of events leading to the formation of pulmonary hypertension (PH). However, little is known about the direct effects of high pressure on the function and intercellular signaling pathways of PASMCs. The aim of this study was to evaluate the effect of pressure stress that simulates PH on interleukin (IL)-1ß- or angiotensin II-induced cyclooxygenase-2 (COX-2) expression in cultured human PASMCs. Methods: Either 20 or 60 mmHg atmospheric pressure was applied to PASMCs by a pressure-loading apparatus. Protein expression and phosphorylation were analyzed by western blotting. mRNA expression was analyzed by quantitative real-time reverse transcription-polymerase chain reaction. Results: IL-1ß-induced COX-2 protein expression peaked at 6 h in non-pressurized cells, whereas COX-2 expression was delayed, peaking at 12 h, in 20 and 60 mmHg pressurized cells. Both pressures also delayed the time to peak COX-2 mRNA expression induced by IL-1ß. In addition, pressure stress delayed the time to peak mitogen-activated protein kinase (MAPK) phosphorylation induced by IL-1ß. In contrast, angiotensin II-induced transient COX-2 mRNA expression and MAPK phosphorylation were not affected by pressure stress. Conclusion: These results suggest that pressure stress delays IL-1ß-induced COX-2 expression via the delayed activation of MAPKs in PASMCs, and the effects of pressure stress differ according to the bioactive substance being stimulated. Our results demonstrate that the application of pressure stress to PASMCs directly alters cell function, which may provide a basic insight into our understanding of the pathogenesis of PH.

3.
Yakugaku Zasshi ; 143(7): 599-606, 2023.
Article in Japanese | MEDLINE | ID: mdl-37394455

ABSTRACT

The nausea and vomiting that occur as a result of oral iron administration for the treatment of iron-deficiency anemia (IDA) can cause significant physical and emotional stress in patients. Because iron is absorbed from the intestine as ferrous iron, the most widely used treatment for IDA is oral ferrous agents. However, ferrous forms are more toxic than ferric forms because ferrous forms readily generate free radicals. A randomized, double-blind, active-controlled, multicenter non-inferiority study conducted in Japan showed that ferric citrate hydrate (FC) was just as effective as sodium ferrous citrate (SF) in the treatment of IDA, with a lower incidence of adverse reactions such as nausea and vomiting compared with SF. Animal studies have shown that chemotherapy-induced nausea and vomiting (CINV) involves the release of 5-hydroxytryptamine from enterochromaffin cells by free radicals, and that some chemotherapeutic agents cause hyperplasia of these cells. Enterochromaffin cells also contain substance P, which is known to be also closely related to CINV. We found that administration of SF to rats causes hyperplasia of enterochromaffin cells in the small intestine, whereas FC has no effect on enterochromaffin cells. Oral iron agents may induce nausea and vomiting via the effect of ferrous iron on reactive oxygen species production in the intestine and subsequent enterochromaffin cell hyperplasia. Further research to elucidate the detailed mechanism of enterochromaffin cell hyperplasia induced by ferrous iron preparations is needed to develop a treatment for iron deficiency anemia that causes less gastrointestinal damage.


Subject(s)
Anemia, Iron-Deficiency , Iron , Animals , Rats , Anemia, Iron-Deficiency/drug therapy , Ferric Compounds/adverse effects , Hyperplasia/drug therapy , Iron/adverse effects , Nausea/chemically induced , Nausea/drug therapy , Vomiting/chemically induced , Vomiting/drug therapy
4.
J Pharmacol Sci ; 152(2): 90-102, 2023 Jun.
Article in English | MEDLINE | ID: mdl-37169484

ABSTRACT

We aimed to clarify the effect of nafamostat mesilate (nafamostat) on intestinal mucositis as well as the potentiation of intestinal 5-hydroxytryptamine (5-HT) dynamics induced by methotrexate, an anti-cancer drug, in rats. Rats received intraperitoneal methotrexate at 12.5 mg/kg/day for 4 days. In addition, 1, 3, or 10 mg/kg/day of nafamostat was given subcutaneously for 4 days. Ninety-six hours after the first administration of methotrexate, jejunal tissues were collected for analysis. The results showed that 1 mg/kg, but not 3 or 10 mg/kg, of nafamostat significantly ameliorated the methotrexate-induced body weight loss. Moreover, 1 mg/kg of nafamostat significantly improved methotrexate-induced mucositis, including villus atrophy. Nafamostat (1 mg/kg) significantly inhibited the methotrexate-induced mRNA expression of pro-inflammatory cytokines and cyclooxygenase-2, as well as methotrexate-induced 5-HT content and tryptophan hydroxylase (TPH) activity. In addition, it tended to inhibit the number of anti-TPH antibody-positive cells and significantly inhibited the number of anti-substance P antibody-positive cells. These findings suggest that low-dose nafamostat ameliorates tissue injury and 5-HT and substance P synthesis in methotrexate-induced mucositis. Nafamostat may be a novel therapeutic strategy for the prevention and treatment of mucositis as well as 5-HT- and/or substance P-related adverse effects in cancer chemotherapy.


Subject(s)
Methotrexate , Mucositis , Rats , Animals , Methotrexate/adverse effects , Serotonin/metabolism , Mucositis/chemically induced , Intestines , Guanidines/pharmacology
5.
Pharmacology ; 107(11-12): 574-583, 2022.
Article in English | MEDLINE | ID: mdl-36007495

ABSTRACT

INTRODUCTION: The most detrimental factor preventing the use of oral iron in the treatment of iron deficiency anemia is gastrointestinal side effects accompanied by nausea and vomiting. Anorexia is a known secondary effect of nausea and vomiting. The important gastrointestinal signaling molecule 5-hydroxytryptamine (5-HT) is critically involved in not only physiological function but also nausea and vomiting. The present study was designed to compare the effects of the administration of sodium ferrous citrate (SF) and ferric citrate hydrate (FC) to rats on anorexia and hyperplasia of enterochromaffin cells, which mainly synthesize and store 5-HT. METHODS: Rats received either SF (3 or 30 mg/kg/day) or FC (30 mg/kg/day) orally for 4 days. Food and water intakes were measured every 24 h during the study. At 96 h after the first administration of the oral iron preparation, the duodenal and jejunal tissues were collected for analysis. Enterochromaffin cells were detected by immunohistochemical analysis. RESULTS: Administration of 3 mg/kg SF had no effect on anorexia but led to increased hyperplasia of enterochromaffin cells in the duodenum (p < 0.1). Administration of 30 mg/kg SF significantly decreased food and water intakes and significantly increased hyperplasia of enterochromaffin cells in the duodenum and jejunum. Alternatively, administration of 30 mg/kg FC had no significant effect on food and water intakes or hyperplasia of enterochromaffin cells. CONCLUSION: The lower impact on the hyperplasia of enterochromaffin cells of FC compared to SF may contribute to the maintenance of rats' physical condition.


Subject(s)
Enterochromaffin Cells , Serotonin , Rats , Animals , Hyperplasia , Anorexia , Iron , Intestine, Small , Vomiting , Nausea , Water
6.
J Pharmacol Sci ; 148(3): 281-285, 2022 Mar.
Article in English | MEDLINE | ID: mdl-35177206

ABSTRACT

This study aimed to elucidate the role of nitric oxide (NO) in intestinal stem cells in methotrexate-induced ileal mucositis in rats. Methotrexate induced the mRNA expressions of the Wnt/ß-catenin target genes Wnt3a, Sox9, and Lgr5 and the Wnt-antagonist gene sFRP-1 and the protein expressions of Lgr5 and sFRP-1. Methotrexate also induced Lgr5+ cells and lysozyme+ cells. A non-selective NO inhibitor inhibited the methotrexate induction of Wnt/ß-catenin target genes and Lgr5+ cells but enhanced that of sFRP-1 expression. Thus, methotrexate mediates the integrity of intestinal stem cells partly through NO-dependent Wnt/ß-catenin signaling and may enhance tolerability to methotrexate-induced injury.


Subject(s)
Ileum , Intestines/cytology , Intestines/drug effects , Methotrexate/adverse effects , Mucositis/genetics , Mucositis/pathology , Nitric Oxide/physiology , Signal Transduction/drug effects , Signal Transduction/genetics , Stem Cells/drug effects , Stem Cells/pathology , Wnt Proteins/metabolism , beta Catenin/metabolism , Animals , Gene Expression/drug effects , Male , Mucositis/chemically induced , Nitric Oxide/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats, Wistar
7.
J Pharmacol Sci ; 148(3): 337-341, 2022 Mar.
Article in English | MEDLINE | ID: mdl-35177214

ABSTRACT

The stimulation of α2-adrenoceptors caused a transient increase of intracellular calcium concentration ([Ca2+]i) monitored by ratiometry using Fura-2 in epithelial cells including enterochromaffin cells in isolated mouse ileal crypts, while stimulation of α1-and ß-adrenoceptors had no effect. The effect of noradrenaline was suppressed by α2-adrenoceptor antagonists, but not by α1-and ß-adrenoceptor antagonists, and partially suppressed by Ni2+ and nicardipine, but not by ω-conotoxin and ω-agatoxin. These results suggest that noradrenaline causes an increase of [Ca2+]i by the influx of extracellular Ca2+ through certain Ca2+ channels via α2-adrenoceptors in epithelial cells of mouse ileal crypts.


Subject(s)
Calcium/metabolism , Epithelial Cells/metabolism , Ileum/cytology , Norepinephrine/pharmacology , Receptors, Adrenergic, alpha-2/drug effects , Animals , Calcium Channels/metabolism , Cells, Cultured , Ileum/metabolism , Mice , Receptors, Adrenergic, alpha-2/metabolism
8.
Biochem Pharmacol ; 197: 114909, 2022 03.
Article in English | MEDLINE | ID: mdl-35021044

ABSTRACT

Vascular endothelial cells are major participants in and regulators of immune responses and inflammation. Vascular endotheliitis is regarded as a host immune-inflammatory response of the endothelium forming the inner surface of blood vessels in association with a direct consequence of infectious pathogen invasion. Vascular endotheliitis and consequent endothelial dysfunction can be a principle determinant of microvascular failure, which would favor impaired perfusion, tissue hypoxia, and subsequent organ failure. Emerging evidence suggests the role of vascular endotheliitis in the pathogenesis of coronavirus disease 2019 (COVID-19) and its related complications. Thus, once initiated, vascular endotheliitis and resultant cytokine storm cause systemic hyperinflammation and a thrombotic phenomenon in COVID-19, leading to acute respiratory distress syndrome and widespread organ damage. Vascular endotheliitis also appears to be a contributory factor to vasculopathy and coagulopathy in sepsis that is defined as life-threatening organ dysfunction due to a dysregulated response of the host to infection. Therefore, protecting endothelial cells and reversing vascular endotheliitis may be a leading therapeutic goal for these diseases associated with vascular endotheliitis. In this review, we outline the etiological and pathogenic importance of vascular endotheliitis in infection-related inflammatory diseases, including COVID-19, and possible mechanisms leading to vascular endotheliitis. We also discuss pharmacological agents which may be now considered as potential endotheliitis-based treatment modalities for those diseases.


Subject(s)
COVID-19/pathology , Endothelial Cells/pathology , Endothelium, Vascular/pathology , Vascular Diseases/pathology , COVID-19/complications , COVID-19/immunology , Endothelial Cells/drug effects , Endothelial Cells/immunology , Endothelium, Vascular/drug effects , Endothelium, Vascular/immunology , Glucocorticoids/pharmacology , Glucocorticoids/therapeutic use , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , Sepsis/drug therapy , Sepsis/etiology , Sepsis/immunology , Sepsis/pathology , Vascular Diseases/drug therapy , Vascular Diseases/etiology , Vascular Diseases/immunology , COVID-19 Drug Treatment
9.
J Pharmacol Sci ; 147(3): 251-259, 2021 Nov.
Article in English | MEDLINE | ID: mdl-34507634

ABSTRACT

The effects of cyclophosphamide on 5-hydroxytryptamine (5-HT) synthesis in the intestinal tissue of rats were investigated. Rats received 120 mg/kg cyclophosphamide intraperitoneally as a single administration, and kaolin and food intake was measured by an automatic monitoring apparatus. Ileal tissues were collected at either 24 or 72 h after administration. Cyclophosphamide caused a significant increase in kaolin intake at the acute and the delayed phases and was associated with a decrease in food intake, and body weight. Cyclophosphamide had no significant effect on intestinal mucosal morphology, or inducible nitric oxide synthase and cyclooxygenase-2 expression in the intestine. Cyclophosphamide significantly increased tryptophan hydroxylase 1 (TPH1) mRNA expression, number of anti-TPH antibody-positive cells, and 5-HT content in the intestine. Cyclophosphamide also significantly increased the expression of Tac1 mRNA, encoding preprotachykinin-1, which is a preprotein of substance P, and the number of anti-substance P antibody-positive cells in the intestine. Cyclophosphamide significantly increased Lgr5, Bmi1, and Atoh1 mRNA levels, which are markers for the proliferation and differentiation of stem cells. This study demonstrated that cyclophosphamide induced pica in rats, and potentiated 5-HT synthesis associated with hyperplasia of substance P-containing enterochromaffin cells without causing severe intestinal injury.


Subject(s)
Antineoplastic Agents, Alkylating/adverse effects , Cyclophosphamide/adverse effects , Enterochromaffin Cells/pathology , Intestines/metabolism , Pica/chemically induced , Serotonin/biosynthesis , Animals , Body Weight/drug effects , Cyclophosphamide/administration & dosage , Eating/drug effects , Hyperplasia/metabolism , Infusions, Parenteral , Kaolin/administration & dosage , Male , Rats, Wistar , Substance P/metabolism , Tryptophan Hydroxylase/metabolism
10.
Biol Pharm Bull ; 44(6): 853-860, 2021.
Article in English | MEDLINE | ID: mdl-34078818

ABSTRACT

Elevated mechanical stress on blood vessels associated with hypertension has a direct effect on the function of vascular endothelial cells and vascular smooth muscle cells (VSMCs). In the present study, we have identified the effect of pulsatile pressure stress on cyclooxygenase-2 (COX-2) expression induced by interleukin (IL)-1ß in cultured rat VSMCs. VSMCs were isolated from aortic media of Wistar rats and cultured. Pulsatile pressure applied to VSMCs was repeatedly given between either 80 and 160 mmHg, which simulates systolic hypertension, or 80 and 120 mmHg, which simulates normal blood pressure, at a frequency of 4 cycles per min using our original apparatus. Pressure loading that simulates systolic hypertension reduced IL-1ß-induced COX-2 expression. The pressure also inhibited the rapid and transient phosphorylation of extracellular signal-regulated kinase (ERK) induced by IL-1ß. IL-1ß-induced COX-2 expression was significantly inhibited by a specific conventional protein kinase C (PKC) inhibitor. Pressure loading that simulates systolic hypertension also reduced phorbol myristate 13-acetate (PMA) (a PKC activator)-induced COX-2 expression and the rapid and transient phosphorylation of ERK. Pressure loading that simulates normal blood pressure had no effect on IL-1ß- and PMA-induced COX-2 expression. The present study shows that pressure stress between 80 and 160 mmHg, which simulates systolic hypertension reduces IL-1ß-induced COX-2 expression by affecting a mechanism involving PKC and ERK signaling pathways. Downregulation of COX-2 expression in VSMCs by abnormal pressure stress may further worsen local vascular injury associated with hypertension.


Subject(s)
Cyclooxygenase 2/metabolism , Hypertension/metabolism , Interleukin-1beta , Myocytes, Smooth Muscle/metabolism , Stress, Mechanical , Animals , Blood Pressure , Cells, Cultured , Cyclooxygenase 2/genetics , Extracellular Signal-Regulated MAP Kinases/metabolism , Muscle, Smooth, Vascular/cytology , Myocytes, Smooth Muscle/physiology , Phosphorylation , Rats, Wistar , Tetradecanoylphorbol Acetate
11.
Biomed Res ; 41(5): 253-257, 2020.
Article in English | MEDLINE | ID: mdl-33071261

ABSTRACT

Administration of cisplatin and methotrexate significantly increased 5-hydroxytryptamine (5-HT) release from intestinal tissues isolated at 72 h after administration in rats. Daily administration with nafamostat mesilate, a potent serine protease inhibitor, significantly inhibited the release of 5-HT induced by methotrexate, but not by cisplatin, in a dose-dependent manner. When applied to isolated ileal tissues in vitro, nafamostat mesilate also significantly inhibited the release of 5-HT induced by methotrexate, but not by cisplatin, in a concentration-dependent manner. These results suggest that serine proteases are involved in the mechanism of the methotrexate-induced release of 5-HT from the rat small intestine.


Subject(s)
Benzamidines/pharmacology , Guanidines/pharmacology , Ileum/drug effects , Serotonin/metabolism , Animals , Cisplatin/administration & dosage , Disease Models, Animal , Intestine, Small/drug effects , Male , Methotrexate/administration & dosage , Rats , Rats, Wistar , Serine Proteinase Inhibitors/pharmacology
12.
Pharmacology ; 105(11-12): 723-728, 2020.
Article in English | MEDLINE | ID: mdl-32694256

ABSTRACT

This study aimed to investigate whether the consecutive administration of methotrexate affects 5-hydroxytryptamine (5-HT) synthesis in the rat small intestine. Rats received methotrexate at a dose of 12.5 mg/kg intraperitoneally on 4 consecutive days. NG-nitro-L-arginine methyl ester (L-NAME) was given subcutaneously to inhibit nitric oxide (NO) synthase. Methotrexate moderately altered 5-HT synthesis, whereas the combined administration of methotrexate and L-NAME significantly changed 5-HT synthesis in the rat ileal tissue. These results suggest that endogenous NO has an antagonistic role in the induction of 5-HT synthesis in rats following the consecutive administration of methotrexate.


Subject(s)
Enzyme Inhibitors/pharmacology , Intestine, Small/drug effects , Intestine, Small/metabolism , Methotrexate/pharmacology , Nitric Oxide/metabolism , Serotonin/biosynthesis , Animals , Drug Administration Schedule , Enzyme Inhibitors/administration & dosage , Injections, Intraperitoneal , Intestinal Diseases/chemically induced , Intestine, Small/pathology , Male , Methotrexate/administration & dosage , NG-Nitroarginine Methyl Ester/administration & dosage , NG-Nitroarginine Methyl Ester/pharmacology , Nitric Oxide Synthase/antagonists & inhibitors , RNA, Messenger/metabolism , Rats , Rats, Wistar , Substance P/drug effects , Substance P/metabolism , Tachykinins/drug effects , Tachykinins/genetics , Tachykinins/metabolism , Tryptophan Hydroxylase/drug effects , Tryptophan Hydroxylase/genetics , Tryptophan Hydroxylase/metabolism
13.
J Pharmacol Sci ; 143(1): 30-38, 2020 May.
Article in English | MEDLINE | ID: mdl-32151540

ABSTRACT

The role of nitric oxide (NO) on intestinal mucosal injury induced by single or consecutive administration of methotrexate was investigated in a rodent model. Rats received methotrexate intraperitoneally either as a single administration (50 mg/kg) or as a consecutive administration (12.5 mg/kg/day) for 4 days. NG-nitro-l-arginine methyl ester (L-NAME) was given subcutaneously to inhibit NO synthase (NOS). Ninety-six hours after the first administration of methotrexate, ileal tissues were collected for analysis. Consecutive administration of methotrexate led to decreased body weight and reduced intake of food and water, which were further worsened by L-NAME. Although a slight mucosal injury resulted from single administration of methotrexate, L-NAME had almost no effect. Consecutive administration of methotrexate caused a significant mucosal injury, which was further worsened by L-NAME. Consecutive, but not single, administration of methotrexate induced mRNA expression of inflammatory cytokines in ileal tissue. Consecutive administration of methotrexate significantly induced constitutive NOS expression in ileal tissue. These results suggest that consecutive administration, rather than single administration, of methotrexate aggravates mucosal injury. Potentiation of constitutive NOS expression by consecutive administration might be one of the main reason to antagonize the intestinal mucosal injury as well as lead to a reduction in rat quality of life.


Subject(s)
Gene Expression , Intestinal Diseases/etiology , Intestine, Small/metabolism , Intestine, Small/pathology , Methotrexate/administration & dosage , Methotrexate/adverse effects , Nitric Oxide/adverse effects , Nitric Oxide/metabolism , Animals , Cytokines/genetics , Cytokines/metabolism , Inflammation Mediators/metabolism , Male , Models, Animal , Nitric Oxide/genetics , RNA, Messenger/metabolism , Rats, Wistar
14.
Biol Pharm Bull ; 42(10): 1733-1740, 2019.
Article in English | MEDLINE | ID: mdl-31582661

ABSTRACT

The aim of this study was to clarify the relationship between chemotherapy-induced mucositis and endogenous glucagon-like peptide-2 (GLP-2) dynamics in the small intestine following treatment with either methotrexate or 5-fluorouracil. Rats were injected intraperitoneally with a single dose of either 50 mg/kg methotrexate or 100 mg/kg 5-fluorouracil. At 24 and 72 h after drug administration, ileal tissues and plasma were used to investigate GLP-2 dynamics. Administration of methotrexate caused moderate but not significant intestinal injury within 72 h, while administration of 5-fluorouracil caused severe injury in a time-dependent manner. Methotrexate significantly increased proglucagon mRNA expression and the number of anti-GLP-2 antibody-positive cells in the ileal tissue at 24 h after administration. Methotrexate also significantly induced GLP-2 receptor, insulin-like growth factor-1 (IGF-1), and transforming growth factor-ß2 (TGF-ß2) mRNA expression in ileal tissue. In contrast, 5-fluorouracil significantly inhibited proglucagon, GLP-2 receptor, IGF-1, and TGF-ß2 mRNA expression as well as the number of anti-GLP-2 antibody-positive cells. Methotrexate slightly increased dipeptidyl peptidase IV (DPP-4) mRNA expression, whereas 5-fluorouracil significantly increased DPP-4 mRNA expression. These results suggest that potentiation of endogenous GLP-2 dynamics by methotrexate is associated with a mechanism that preserves gastrointestinal mucosal integrity at a moderate level.


Subject(s)
Antimetabolites, Antineoplastic/pharmacology , Glucagon-Like Peptide 2/blood , Intestine, Small/drug effects , Methotrexate/pharmacology , Animals , Dipeptidyl Peptidase 4/genetics , Fluorouracil/pharmacology , Glucagon-Like Peptide-2 Receptor/genetics , Insulin-Like Growth Factor I/genetics , Insulin-Like Growth Factor I/metabolism , Intestine, Small/metabolism , Intestine, Small/pathology , Male , Rats, Wistar
15.
J Pharmacol Sci ; 141(1): 32-40, 2019 Sep.
Article in English | MEDLINE | ID: mdl-31564550

ABSTRACT

The role of nitric oxide (NO) in the changes in enterochromaffin cells and ileal 5-hydroxytryptamine (5-HT) content induced by a single i.p. administration of methotrexate was investigated in rats. Methotrexate significantly increased inducible NO synthase (iNOS) mRNA and protein expressions in the intestinal tissue at 96 h. Methotrexate also significantly caused hyperplasia of the enterochromaffin cells at 96 h; this was associated with a significant increase in 5-HT content. The methotrexate-induced hyperplasia of enterochromaffin cells and increase in 5-HT content were, however, completely suppressed by daily treatment with dexamethasone, and with NG-nitro-l-arginine methyl ester (l-NAME); this was not observed when meloxicam was administered. Histological examination showed slight but not pronounced mucosal injury, at 96 h after methotrexate administration. The methotrexate-induced decrease in body weight did not fully recover to the control level up to 96 h; however, the methotrexate-induced decrease in food/water intake slightly returned to the control level up to 96 h. l-NAME had no significant effect on methotrexate-induced body weight loss and anorexia. To conclude, the present study suggests that NO derived from methotrexate-induced iNOS plays a critical role in the mechanism of hyperplasia of enterochromaffin cells containing 5-HT in the intestinal tissue of rats.


Subject(s)
Enterochromaffin Cells/metabolism , Enterochromaffin Cells/pathology , Intestine, Small/cytology , Intestine, Small/metabolism , Methotrexate/adverse effects , Nitric Oxide/physiology , Serotonin/metabolism , Animals , Body Weight/drug effects , Gene Expression , Hyperplasia/chemically induced , Male , Nitric Oxide/metabolism , Nitric Oxide Synthase Type II/metabolism , RNA, Messenger/metabolism , Rats , Rats, Wistar
16.
Cell Death Discov ; 4: 29, 2018.
Article in English | MEDLINE | ID: mdl-30131878

ABSTRACT

Docosahexaenoic acid (DHA) and their CYP-derived metabolites, epoxydocosapentaenoic acids (EDPs), are important fatty acids obtained from dietary sources. While it is known that they have significant biological effects, which can differ between cell type and disease state, our understanding of how they work remains limited. Previously, we demonstrated that DHA and 19,20-EDP triggered pronounced cytotoxicity in H9c2 cells correlating with increased ceramide production. In this study, we examine whether DHA- and 19,20-EDP-induced cell death depends on the type of metabolism (glycolysis or OXPHOS). We cultivated H9c2 cells in distinct conditions that result in either glycolytic or oxidative metabolism. Our major findings suggest that DHA and its epoxy metabolite, 19,20-EDP, trigger cytotoxic effects toward H9c2 cells with a glycolytic metabolic profile. Cell death occurred through a mechanism involving activation of a lysosomal-proteolytic degradation pathway. Importantly, accumulation of ceramide played a critical role in the susceptibility of glycolytic H9c2 cells to cytotoxicity. Furthermore, our data suggest that an alteration in the cellular metabolic profile is a major factor determining the type and magnitude of cellular toxic response. Together, the novelty of this study demonstrates that DHA and 19,20-EDP induce cell death in H9c2 cells with a glycolytic metabolicwct 2 profile through a lysosomal-proteolytic mechanism.

17.
Biomed Res ; 39(3): 141-148, 2018.
Article in English | MEDLINE | ID: mdl-29899189

ABSTRACT

Elevated mechanical stress applied to vascular walls is well known to modulate vascular remodeling and plays a part in the pathogenesis of atherosclerosis. On the other hand, docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid, has been shown to protect against several types of cardiovascular diseases including atherosclerosis and hypertension. The aim of this study was to clarify the effect of pulsatile pressure stress and DHA on angiotensin II-induced proliferation and migration in A7r5 vascular smooth muscle cells (VSMCs). Pulsatile pressure of between 80 and 160 mmHg was repeatedly applied to VSMCs at a frequency of 4 cycles per min using an apparatus that we developed. Cell proliferation and migration were evaluated using a live cell movie analyzer. Application of pulsatile pressure stress for 24 h significantly increased cell proliferation. Angiotensin II also significantly increased cell proliferation in the presence or absence of pressure stress. DHA significantly inhibited angiotensin II-induced cell proliferation regardless of the pressure load. Angiotensin II significantly induced cell migration regardless of the pulsatile pressure load. Pulsatile pressure stress alone slightly, but not significantly, induced cell migration. DHA inhibited angiotensin II-induced VSMC proliferation and migration under abnormal pressure conditions. Pressure stress tended to induce extracellular signal-regulated kinase (ERK) phosphorylation in the absence of angiotensin II, whereas it significantly induced ERK phosphorylation in the presence of angiotensin II. However, the pressure-induced ERK phosphorylation was not observed in the DHA-treated VSMCs. Our findings may contribute to the understanding of the beneficial effect of DHA on various cardiovascular disorders.


Subject(s)
Angiotensin II/pharmacology , Cell Movement/drug effects , Cell Proliferation/drug effects , Docosahexaenoic Acids/pharmacology , Muscle, Smooth, Vascular/metabolism , Myocytes, Smooth Muscle/metabolism , Pulsatile Flow , Animals , Muscle, Smooth, Vascular/cytology , Myocytes, Smooth Muscle/cytology , Rats , Stress, Mechanical
18.
Naunyn Schmiedebergs Arch Pharmacol ; 391(8): 847-858, 2018 08.
Article in English | MEDLINE | ID: mdl-29766222

ABSTRACT

We previously reported that cisplatin potentiated ileal 5-hydroxytryptamine (5-HT) metabolism and caused pathological changes with an inflammatory response in the delayed phase (72 h) after administration to rats. In the present study, we further investigated the time-dependent effect of cisplatin on ileal 5-HT metabolism and the effects of combining cisplatin and anti-inflammatory drugs on ileal tryptophan hydroxylase expression and pica (the consumption of non-nutritive materials such as kaolin). Cyclooxygenase-2 (COX-2) expression was significantly increased at 24 h after cisplatin (5 mg/kg, intraperitoneal) administration. Cisplatin significantly increased ileal 5-HT content at 48 h after administration and the number of L-tryptophan hydroxylase-expressing cells (i.e., enterochromaffin cells) in the ileal mucosa within 24 h after administration. It also caused a significant increase in the number of substance P-expressing cells. Immunohistochemical double staining revealed that most of the enterochromaffin cells contained substance P. Neither daily treatment with dexamethasone (1 mg/kg, subcutaneous) nor meloxicam (3 mg/kg, subcutaneous), a selective COX-2 inhibitor, affected the cisplatin-induced increase in the number of enterochromaffin cells. Meloxicam had no effect on cisplatin-induced pica, although dexamethasone almost completely inhibited it. This study demonstrated that cisplatin administration induced COX-2 expression and increased the number of enterochromaffin cells in the acute phase (i.e., within 24 h). However, COX-2 expression in the ileum seems to have little direct effect on the mechanism of the induction of enterochromaffin cells and pica.


Subject(s)
Antineoplastic Agents/pharmacology , Cisplatin/pharmacology , Cyclooxygenase 2/metabolism , Enterochromaffin Cells/drug effects , Ileum/drug effects , Substance P/metabolism , Animals , Anti-Inflammatory Agents/pharmacology , Behavior, Animal/drug effects , Dexamethasone/pharmacology , Enterochromaffin Cells/metabolism , Ileum/metabolism , Ileum/pathology , Kaolin , Male , Meloxicam/pharmacology , Pica/chemically induced , Pica/drug therapy , Rats, Wistar , Serotonin/metabolism , Tryptophan Hydroxylase/metabolism
20.
Biol Pharm Bull ; 40(6): 916-921, 2017.
Article in English | MEDLINE | ID: mdl-28566634

ABSTRACT

We previously reported that docosahexaenoic acid (DHA) inhibits an increase in intracellular Ca2+ concentration ([Ca2+]i) in cultured rat vascular smooth muscle cells (VSMCs) through a mechanism involving mainly voltage-dependent Ca2+ channels; however, the effect of DHA on voltage-independent pathways, such as store-operated and receptor-operated Ca2+ entry, and Ca2+ entry through Na+/Ca2+ exchanger (NCX), has not been clarified. In the present study, we investigated the effect of DHA treatment on the expression of transient receptor potential canonical (TRPC) channels, capacitative Ca2+ entry, and Ca2+ entry through NCX in rat cultured VSMCs stimulated with 5-hydroxytryptamine (5-HT). RT-PCR analysis detected TRPC1, TRPC4, and TRPC6 mRNA in cultured VSMCs. DHA treatment for 2 d slightly but significantly decreased TRPC1, but not TRPC4 and TRPC6, mRNA expression. Sarpogrelate, a selective serotonin 5-HT2A receptor inhibitor, completely inhibited the 5-HT-induced increase in [Ca2+]i in cultured VSMCs. Ca2+ influx by adding extracellular Ca2+ (1.3 mM) to the Ca2+-free condition in the presence of 5-HT was partially but significantly inhibited by sarpogrelate. DHA treatment for 2 d had no effect on Ca2+ influx when extracellular Ca2+ was added to the Ca2+-free condition in the presence of either 5-HT alone or 5-HT with sarpogrelate. KB-R7943, a selective inhibitor of reverse mode NCX, significantly suppressed the 5-HT-induced increase of [Ca2+]i. Furthermore, DHA treatment for 2 d significantly decreased NCX1 mRNA expression. These results suggest that DHA seems to have little effect on capacitative Ca2+ entry. Through decreasing NCX1 expression, DHA may suppress the 5-HT-induced increase in [Ca2+]i.


Subject(s)
Calcium/metabolism , Docosahexaenoic Acids/pharmacology , Myocytes, Smooth Muscle/drug effects , TRPC Cation Channels/genetics , Animals , Cells, Cultured , Muscle, Smooth, Vascular/cytology , Myocytes, Smooth Muscle/metabolism , Rats, Wistar , Serotonin/pharmacology , Sodium-Calcium Exchanger/genetics
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