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Zhou M, Li TS, Abe H, Akashi H, Suzuki R, Bando Y. Expression levels of K ATP channel subunits and morphological changes in the mouse liver after exposure to radiation. World J Exp Med 2024; 14:90374. [PMID: 38948415 PMCID: PMC11212743 DOI: 10.5493/wjem.v14.i2.90374] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 01/28/2024] [Accepted: 03/27/2024] [Indexed: 06/19/2024] Open
Abstract
BACKGROUND ATP sensitive K+ (KATP) channels are ubiquitously distributed in various of cells and tissues, including the liver. They play a role in the pathogenesis of myocardial and liver ischemia. AIM To evaluate the radiation-induced changes in the expression of KATP channel subunits in the mouse liver to understand the potential role of KATP channels in radiation injury. METHODS Adult C57BL/6 mice were randomly exposed to γ-rays at 0 Gy (control, n = 2), 0.2 Gy (n = 6), 1 Gy (n = 6), or 5 Gy (n = 6). The livers were removed 3 and 24 h after radiation exposure. Hematoxylin and eosin staining was used for morphological observation; immunohistochemical staining was applied to determine the expression of KATP channel subunits in the liver tissue. RESULTS Compared with the control group, the livers exposed to 0.2 Gy γ-ray showed an initial increase in the expression of Kir6.1 at 3 h, followed by recovery at 24 h after exposure. Exposure to a high dose of 5.0 Gy resulted in decreased expression of Kir6.1 and increased expression of SUR2B at 24 h. However, the expression of Kir6.2, SUR1, or SUR2A had no remarkable changes at 3 and 24 h after exposure to any of these doses. CONCLUSION The expression levels of Kir6.1 and SUR2B in mouse liver changed differently in response to different radiation doses, suggesting a potential role for them in radiation-induced liver injury.
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Affiliation(s)
- Ming Zhou
- Department of Anatomy, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Tao-Sheng Li
- Department of Stem Cell Biology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki 852-8523, Japan
| | - Hiroshi Abe
- Sendai Old Age Refresh Station, A Long-term Care Health Facility, Sendai 981-1105, Japan
| | - Hideo Akashi
- Department of Anatomy, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Ryoji Suzuki
- Department of Anatomy, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Yoshio Bando
- Department of Anatomy, Akita University Graduate School of Medicine, Akita 010-8543, Japan
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Zou S, Shimizu T, Kurabayashi A, Yamamoto M, Shimizu S, Higashi Y, Shimizu N, Karashima T, Saito M. Protective effects of hydrogen sulfide pretreatment on cyclophosphamide-induced bladder dysfunction in rats via suppression of bladder afferent nerves. Nitric Oxide 2022; 127:54-63. [PMID: 35918055 DOI: 10.1016/j.niox.2022.07.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 07/13/2022] [Accepted: 07/15/2022] [Indexed: 11/17/2022]
Abstract
Cyclophosphamide (CYP), a broad-spectrum anticancer drug, causes serious side effects, such as haemorrhagic cystitis (HC). Hydrogen sulfide (H2S), an endogenous gasotransmitter, has physiological properties, including anti-inflammation, anti-oxidation, and neuromodulation. In this study, we investigated the effects of NaHS (H2S donor) pretreatment on bladder dysfunction in CYP-treated rats. Male Wistar rats were intraperitoneally pretreated with NaHS (3 or 10 μmol/kg) or vehicle once daily for 7 days before cystometry, and CYP (150 mg/kg) or saline was intraperitoneally administered 2 days before cystometry. After cystometry, the bladder tissues were collected for haematoxylin and eosin staining. In some rats, capsaicin (CAP), which can desensitise CAP-sensitive afferent nerves, was subcutaneously injected at 125 mg/kg 4 days before cystometry. CYP reduced intercontraction intervals (ICI) and bladder compliance (Comp) and increased the number of non-voiding contractions (NVCs) compared with the saline-treated control group. NaHS pretreatment dose-dependently improved the CYP-induced these changes. In bladder tissues, CYP increased histological scores of neutrophil infiltration, haemorrhage, and oedema, while NaHS had no effect on these CYP-induced changes. CAP showed a tendency to suppress CYP-induced changes in ICI. NaHS-induced improvement in CYP-induced changes in urodynamic parameters were not detected in CAP-treated rats. These findings suggest that NaHS pretreatment prevented bladder dysfunction in CYP-treated rats by suppressing CAP-sensitive bladder afferent nerves, but not by suppressing bladder inflammation. Therefore, H2S represents a new candidate as a protective drug for bladder dysfunction induced by HC, a side effect of CYP chemotherapy.
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Affiliation(s)
- Suo Zou
- Department of Pharmacology, Kochi Medical School, Kochi University, Nankoku, Kochi, 783-8505, Japan
| | - Takahiro Shimizu
- Department of Pharmacology, Kochi Medical School, Kochi University, Nankoku, Kochi, 783-8505, Japan.
| | - Atsushi Kurabayashi
- Department of Pathology, Kochi Medical School, Kochi University, Nankoku, Kochi, 783-8505, Japan
| | - Masaki Yamamoto
- Department of Pediatrics, Kochi Medical School, Kochi University, Nankoku, Kochi, 783-8505, Japan
| | - Shogo Shimizu
- Department of Pharmacology, Kochi Medical School, Kochi University, Nankoku, Kochi, 783-8505, Japan
| | - Youichirou Higashi
- Department of Pharmacology, Kochi Medical School, Kochi University, Nankoku, Kochi, 783-8505, Japan
| | - Nobutaka Shimizu
- Department of Pelvic Floor Center, Kochi Medical School, Kochi University, Nankoku, Kochi, 783-8505, Japan
| | - Takashi Karashima
- Department of Urology, Kochi Medical School, Kochi University, Nankoku, Kochi, 783-8505, Japan
| | - Motoaki Saito
- Department of Pharmacology, Kochi Medical School, Kochi University, Nankoku, Kochi, 783-8505, Japan
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Elfakhrany A, Abo-Elsoud RAEA, Abd El Kareem HM, Samaka RM, Elfiky SR. Autophagy and Oxidative Balance Mediate the Effect of Carvedilol and Glibenclamide in a Rat Model of Renal Ischemia-Reperfusion Injury. Open Access Maced J Med Sci 2022. [DOI: 10.3889/oamjms.2022.10125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
BACKGROUND: Reactive oxygen species and cytokines are the main players in the development of renal ischemia-reperfusion (I/R) injury.
AIM: The current study aimed to evaluate the effects of carvedilol and/or glibenclamide and the interaction between autophagy and oxidative stress.
METHODS: 50 male rats were divided into five groups: Control, IR injury (IRI), carvedilol pretreated, glibenclamide pretreated, and combined carvedilol and glibenclamide pretreated. Measurements of renal blood flow (RBF), creatinine clearance, serum blood urea nitrogen (BUN), histopathological, and immunohistochemical evaluation of autophagy marker Becl-1 in the rat kidney were performed. Beclin-1and light chain 3 (LC3) Mrna expression was detected by real time polymerase chain reaction.
RESULTS: IRI was associated with significant increases in BUN, tumor necrosis factor-alpha, nuclear factor κB, and histo (H) score value of Becl-1. However, there was a significant decrease in RBF, creatinine clearance, and glutathione peroxidase compared to the control group. There was significant increase in Beclin-1 and LC3 mRNA gene expression in carvedilol, glibenclamide, and combined treatment groups as compared to IRI and control groups. Combination of carvedilol and glibenclamide significantly restored IRI changes when compared with the other pretreated groups.
CONCLUSION: This study suggests that carvedilol and glibenclamide are promising reno-protective drugs to reduce renal injury induced by I/R through their antioxidant and autophagy stimulation.
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Arni S, Maeyashiki T, Latshang T, Opitz I, Inci I. Ex Vivo Lung Perfusion with K(ATP) Channel Modulators Antagonize Ischemia Reperfusion Injury. Cells 2021; 10:cells10092296. [PMID: 34571948 PMCID: PMC8472464 DOI: 10.3390/cells10092296] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 08/25/2021] [Accepted: 09/02/2021] [Indexed: 11/18/2022] Open
Abstract
Ex vivo lung perfusion (EVLP) has been implemented to increase the number of donor lungs available for transplantation. The use of K(ATP) channel modulators during EVLP experiments may protect against lung ischemia-reperfusion injury and may inhibit the formation of reactive oxygen species. In a rat model of donation after circulatory death with 2 h warm ischemic time, we evaluated rat lungs for a 4-hour time in EVLP containing either mitochondrial-specific or plasma membrane and/or sarcolemmal-specific forms of K(ATP) channel modulators. Lung physiological data were recorded, and metabolic parameters were assessed. When compared to the control group, in the EVLP performed with diazoxide or 5-hydroxydecanoic acid (5-HD) we recorded significantly lower pulmonary vascular resistance and only in the diazoxide group recorded significant lung weight loss. In the perfusate of the 5-HD group, interleukin-1β and interleukin-1α were significantly lower when compared to the control group. Perfusate levels of calcium ions were significantly higher in both 5-HD and cromakalim groups, whereas the levels of calcium, potassium, chlorine and lactate were reduced in the diazoxide group, although not significantly when compared to the control. The use of a diazoxide mitochondrial-specific K(ATP) channel opener during EVLP improved lung physiological and metabolic parameters and reduced edema.
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Affiliation(s)
- Stephan Arni
- Department of Thoracic Surgery, University Hospital Zürich, 8091 Zürich, Switzerland; (S.A.); (T.M.); (I.O.)
| | - Tatsuo Maeyashiki
- Department of Thoracic Surgery, University Hospital Zürich, 8091 Zürich, Switzerland; (S.A.); (T.M.); (I.O.)
| | - Tsogyal Latshang
- Department of Pneumology, Kantonsspital Graubünden, 7000 Chur, Switzerland;
| | - Isabelle Opitz
- Department of Thoracic Surgery, University Hospital Zürich, 8091 Zürich, Switzerland; (S.A.); (T.M.); (I.O.)
| | - Ilhan Inci
- Department of Thoracic Surgery, University Hospital Zürich, 8091 Zürich, Switzerland; (S.A.); (T.M.); (I.O.)
- Correspondence: ; Tel.: +41-(0)-44-255-85-43
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Tanriverdi HI, Şenel U, Gevrek F, Akbaş A. Protective effect of famotidine on ischemia-reperfusion injury following testicular torsion in rats. J Pediatr Urol 2021; 17:167.e1-167.e7. [PMID: 33046373 DOI: 10.1016/j.jpurol.2020.09.019] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 08/05/2020] [Accepted: 09/14/2020] [Indexed: 10/23/2022]
Abstract
INTRODUCTION In testicular torsion, testicular blood flow is impaired, resulting in ischemic changes. Torsion must be corrected urgently with surgical treatment. Detorsioning and restoration of blood supply to the testis cause reperfusion injury. OBJECTIVE In this experimental study, we aimed to investigate the effect of famotidine on ischemia-reperfusion injury in a rat model of testicular torsion. STUDY DESIGN The rats were randomly divided into three groups; Group I (control, no torsion) (n = 8), Group II (torsion + detorsion) (n = 8), Group III (torsion + detorsion + famotidine) (n = 8). Levels of oxidative stress markers, such as malondialdehyde (MDA) and nitric oxide (NO), and antioxidants, such as superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), were measured for biochemical analysis. Testicular tissues were assessed by Johnsen Scoring for spermatogenic evaluation. Tissues were also examined with TUNEL staining to determine the extent of apoptosis. RESULTS Average MDA level was higher in Group II than Groups I and III. The difference was only significant between Group I and II (p = 0.03). Average NO level was significantly higher in Group II than Groups I and III (p = 0.03; p = 0.04; respectively). Conversely, average SOD level was lower in Group II than Groups I and III. The difference was only significant between Group II and III (p < 0.001). Average GSH-Px level was lower in Group II than Groups I and III, but the differences were not significant (p = 0.37; p = 0.35; respectively). The average Johnsen score in Group II was significantly lower than the scores in Groups I and III (p < 0.001; p < 0.001; respectively). The apoptotic index of Group II was significantly higher than those of Groups I and III (p < 0.001; p < 0.001; respectively). DISCUSSION Famotidine prevented increases in oxidative stress markers and reductions of antioxidants during ischemia-reperfusion injury in our study. Spermatogenesis was less affected and DNA injury was reduced in rats treated with famotidine. The antioxidant characteristics of famotidine and its protective effects have been shown in our study. CONCLUSION Famotidine may prevent oxidative tissue injury during ischemia-reperfusion.
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Affiliation(s)
- Halil Ibrahim Tanriverdi
- Pediatric Surgery, Manisa Celal Bayar University Medical School, Department of Pediatric Surgery, Manisa, Turkey.
| | - Ufuk Şenel
- Pediatric Surgery, Gaziosmanpasa University Medical School, Department of Pediatric Surgery, Tokat, Turkey.
| | - Fikret Gevrek
- Histology and Embriology, Gaziosmanpasa University Medical School, Department of Histology and Embriology, Tokat, Turkey.
| | - Ali Akbaş
- Biochemistry, Balıkesir University Medical School, Department of Biochemistry, Balıkesir, Turkey.
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Shimizu S, Nagao Y, Shimizu T, Higashi Y, Karashima T, Saito M. Therapeutic effects of losartan on prostatic hyperplasia in spontaneously hypertensive rats. Life Sci 2020; 266:118924. [PMID: 33352172 DOI: 10.1016/j.lfs.2020.118924] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 12/04/2020] [Accepted: 12/12/2020] [Indexed: 11/30/2022]
Abstract
AIMS We investigated the therapeutic effects of losartan, an angiotensin II type 1 receptor blocker, on prostatic hyperplasia in spontaneously hypertensive rats (SHRs). MAIN METHODS Male SHRs (age, 36 weeks) were perorally treated with losartan (3 or 10 mg·kg-1) or vehicle once daily for 18 weeks. Age-matched Wistar Kyoto rats (WKYs) were used as vehicle-treated controls (n = 8). The effects of losartan were evaluated by analyzing prostate weight, blood pressure, and prostatic blood flow. The tissue malondialdehyde (MDA), interleukin-6 (IL-6), and basic fibroblast growth factor (bFGF) levels were measured. Histological analysis for the ventral prostate involved hematoxylin and eosin staining and TdT-mediated dUTP nick-end labeling (TUNEL) assay. KEY FINDINGS Compared to the vehicle-treated WKYs, the vehicle-treated SHRs had significantly higher prostate weight, prostate weight/body weight ratio (PBR), blood pressure, glandular epithelial area, and tissue MDA, IL-6, and bFGF levels in the ventral prostate and lower prostatic blood flow. Treatment with losartan caused significant recovery of blood flow and decreased PBR and glandular epithelial area as well as tissue MDA, IL-6, and bFGF levels in the SHR ventral prostate without affecting blood pressure. High-dose losartan significantly decreased blood pressure and increased TUNEL-positive cells in the ventral prostate in SHRs. SIGNIFICANCE Chronic losartan treatment could ameliorate prostatic hyperplasia via recovery of reduced prostatic blood flow and induction of apoptosis in the ventral prostate in SHRs. Losartan might have therapeutic effects on not only hypertension but also prostatic hyperplasia in humans.
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Affiliation(s)
- Shogo Shimizu
- Department of Pharmacology, Kochi Medical School, Kochi University, Nankoku, Japan
| | - Yoshiki Nagao
- Department of Pediatrics, Kochi Medical School, Kochi University, Nankoku, Japan
| | - Takahiro Shimizu
- Department of Pharmacology, Kochi Medical School, Kochi University, Nankoku, Japan
| | - Youichirou Higashi
- Department of Pharmacology, Kochi Medical School, Kochi University, Nankoku, Japan
| | - Takashi Karashima
- Department of Urology, Kochi Medical School, Kochi University, Nankoku, Japan
| | - Motoaki Saito
- Department of Pharmacology, Kochi Medical School, Kochi University, Nankoku, Japan.
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Mouithys-Mickalad A, Ceusters J, Charif M, El Moualij B, Schoumacher M, Plyte S, Franck T, Bettendorff L, Pirotte B, Serteyn D, de Tullio P. Modulation of mitochondrial respiration rate and calcium-induced swelling by new cromakalim analogues. Chem Biol Interact 2020; 331:109272. [PMID: 33010220 DOI: 10.1016/j.cbi.2020.109272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Revised: 09/07/2020] [Accepted: 09/28/2020] [Indexed: 10/23/2022]
Abstract
A cellular model of cardiomyocytes (H9c2 cell line) and mitochondria isolated from mouse liver were used to understand the drug action of BPDZ490 and BPDZ711, two benzopyran analogues of the reference potassium channel opener cromakalim, on mitochondrial respiratory parameters and swelling, by comparing their effects with those of the parent compound cromakalim. For these three compounds, the oxygen consumption rate (OCR) was determined by high-resolution respirometry (HRR) and their impact on adenosine triphosphate (ATP) production and calcium-induced mitochondrial swelling was investigated. Cromakalim did not modify neither the OCR of H9c2 cells and the ATP production nor the Ca-induced swelling. By contrast, the cromakalim analogue BPDZ490 (1) induced a strong increase of OCR, while the other benzopyran analogue BPDZ711 (2) caused a marked slowdown. For both compounds, 1 displayed a biphasic behavior while 2 still showed an inhibitory effect. Both compounds 1 and 2 were also found to decrease the ATP synthesis, with pronounced effect for 2, while cromakalim remained without effect. Overall, these results indicate that cromakalim, as parent molecule, does not induce per se any direct effect on mitochondrial respiratory function neither on whole cells nor on isolated mitochondria whereas both benzopyran analogues 1 and 2 display totally opposite behavior profiles, suggesting that compound 1, by increasing the maximal respiration capacity, might behave as a mild uncoupling agent and compound 2 is taken as an inhibitor of the mitochondrial electron-transfer chain.
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Affiliation(s)
- Ange Mouithys-Mickalad
- Center for Oxygen, Research & Development (CORD) & Center for Interdisciplinary Research on Medicines (CIRM), Institute of Chemistry, B6a, ULiège, Allée du six Août, 11, B-4000, Liège, Belgium.
| | - Justine Ceusters
- Center for Oxygen, Research & Development (CORD) & Center for Interdisciplinary Research on Medicines (CIRM), Institute of Chemistry, B6a, ULiège, Allée du six Août, 11, B-4000, Liège, Belgium
| | - Mounia Charif
- Centre de Recherche sur les Protéines Prions (CRPP), ULiège, Quartier Hôpital, 15, Avenue Hippocrate, B-4000, Liège, Belgium
| | - Benaïssa El Moualij
- Centre de Recherche sur les Protéines Prions (CRPP), ULiège, Quartier Hôpital, 15, Avenue Hippocrate, B-4000, Liège, Belgium
| | - Mathieu Schoumacher
- Department of Medicinal Chemistry, Center for Interdisciplinary Research on Medicines (CIRM), ULiège, Quartier Hôpital, 15, Avenue de l'Hospital, B-4000, Liège, Belgium
| | - Simon Plyte
- Merus, Closing in on Cancer, Immuno-Oncology, Yalelaan 62, 3584 CM, Utrecht, the Netherlands
| | - Thierry Franck
- Center for Oxygen, Research & Development (CORD) & Center for Interdisciplinary Research on Medicines (CIRM), Institute of Chemistry, B6a, ULiège, Allée du six Août, 11, B-4000, Liège, Belgium; Department of Clinical Sciences, Faculty of Veterinary Medicine, Quartier Vallée 2, 5A-5D, Avenue de Cureghem, ULiège, B-4000, Liège, Belgium
| | - Lucien Bettendorff
- Laboratory of Neurophysiology, GIGA-neurosciences, ULiège, Quartier Hôpital, 15, Avenue Hippocrate, B-4000, Liège, Belgium
| | - Bernard Pirotte
- Center for Oxygen, Research & Development (CORD) & Center for Interdisciplinary Research on Medicines (CIRM), Institute of Chemistry, B6a, ULiège, Allée du six Août, 11, B-4000, Liège, Belgium; Department of Medicinal Chemistry, Center for Interdisciplinary Research on Medicines (CIRM), ULiège, Quartier Hôpital, 15, Avenue de l'Hospital, B-4000, Liège, Belgium
| | - Didier Serteyn
- Center for Oxygen, Research & Development (CORD) & Center for Interdisciplinary Research on Medicines (CIRM), Institute of Chemistry, B6a, ULiège, Allée du six Août, 11, B-4000, Liège, Belgium
| | - Pascal de Tullio
- Center for Oxygen, Research & Development (CORD) & Center for Interdisciplinary Research on Medicines (CIRM), Institute of Chemistry, B6a, ULiège, Allée du six Août, 11, B-4000, Liège, Belgium; Department of Medicinal Chemistry, Center for Interdisciplinary Research on Medicines (CIRM), ULiège, Quartier Hôpital, 15, Avenue de l'Hospital, B-4000, Liège, Belgium
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The investigation of the protective effects of nimesulide on experimental testicular ischemia-reperfusion injury in rats. Rev Int Androl 2020; 18:55-62. [DOI: 10.1016/j.androl.2018.08.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Revised: 08/13/2018] [Accepted: 08/31/2018] [Indexed: 12/24/2022]
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Abat D, Bayazıt Y, Açıkalın A, Dağlıoğlu K, Yenilmez ED, Altunkol A, Erdoğan Ş, Tuli A. Beneficial effects of rolipram, a phosphodiesterase 4 specific inhibitor, on testicular torsion-detorsion injury in rats. J Pediatr Surg 2018; 53:2261-2265. [PMID: 29773452 DOI: 10.1016/j.jpedsurg.2018.04.013] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Revised: 04/01/2018] [Accepted: 04/08/2018] [Indexed: 11/24/2022]
Abstract
INTRODUCTION The aim of the study is to investigate the effect of Rolipram, a selective phosphodiesterase 4 inhibitor, on testicular torsion - detorsion injury. METHODS Sixty young male rats were divided into five groups. In each group, the right testes of six rats were removed four hours after detorsion for biochemical analysis, and the right testes of the remaining six rats were removed 24 h after detorsion for pathological analysis. In group 1 (sham-operated) right orchiectomy was performed without torsion, and right testes were sent to the laboratory for biochemical and pathologic analyses. In group 2 (control) torsion was applied to the right testes for 60 min, and detorsion was performed without the administration of Rolipram. In group 3 torsion was applied to the right testes for 60 min. 1 mg/kg Rolipram was administered 30 min before detorsion. In group 4 torsion was applied to the right testes for 60 min, and 1 mg/kg Rolipram was administered during detorsion. In group 5 torsion was applied to the right testes for 60 min. 1 mg/kg Rolipram was administered 30 min after detorsion. The malondialdehyde and nitric oxide levels were determined. The rates of necrosis and apoptosis were evaluated by histopathological examination. RESULTS The level of malondialdehyde was higher in the torsioned groups (Group 2, 3, 4, 5) than that in group 1 (p = 0.004). There was no statistically significant difference between the groups regarding the level of nitric oxide (p = 0.182). Apoptosis was higher in groups 2, 3 and 4 than in group 1; however, apoptosis was similar in group 1 and group 5 (p = 0.122). The level of necrosis in group 1 was similar to that in groups 4 and 5 (p = 0.194 and p = 0.847, respectively). CONCLUSION We suggest that the administration of Rolipram can decrease the rate of necrosis and apoptosis in testicular ischaemia-reperfusion injury.
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Affiliation(s)
- Deniz Abat
- İskenderun State Hospital, Department of Urology, Hatay, Turkey.
| | - Yıldırım Bayazıt
- Ç ukurova University Faculty of Medicine, Department of Urology, Adana, Turkey.
| | - Arbil Açıkalın
- Çukurova University Faculty of Medicine, Department of Pathology, Adana, Turkey.
| | - Kenan Dağlıoğlu
- Experimental Research Center, Çukurova University School of Medicine, Adana, Turkey.
| | - Ebru Dündar Yenilmez
- Çukurova University Faculty of Medicine, Department of Biochemistry, Adana, Turkey.
| | - Adem Altunkol
- University of Healthy Sciences, Adana City Hospital, Department of Urology, Adana, Turkey.
| | - Şeyda Erdoğan
- Çukurova University Faculty of Medicine, Department of Pathology, Adana, Turkey.
| | - Abdullah Tuli
- Çukurova University Faculty of Medicine, Department of Biochemistry, Adana, Turkey.
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Neuroprotective potential of glibenclamide is mediated by antioxidant and anti-apoptotic pathways in intracerebral hemorrhage. Brain Res Bull 2018; 142:18-24. [PMID: 29933037 DOI: 10.1016/j.brainresbull.2018.06.006] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Revised: 06/04/2018] [Accepted: 06/14/2018] [Indexed: 12/17/2022]
Abstract
The sulfonylurea receptor 1 (SUR1)-regulated NCca-ATP channels were progressively upregulated and demonstrated unchecked opening in central nervous system (CNS) injury, which induced cerebral damage. Glibenclamide (GLI) can block NCca-ATP channels and consequently exert protective effects. Recent studies have found that GLI has antioxidative effects. In this study, we primarily explored the antioxidative effects of GLI in a rat model of intracerebral hemorrhage (ICH). We found that GLI could scavenge free radicals, reduce activated-caspase-3 expression, increase the Bcl-2/Bax ratio, inhibit apoptosis, and improve functional neurological outcomes in a rat model of ICH.
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Qu J, Tao XY, Teng P, Zhang Y, Guo CL, Hu L, Qian YN, Jiang CY, Liu WT. Blocking ATP-sensitive potassium channel alleviates morphine tolerance by inhibiting HSP70-TLR4-NLRP3-mediated neuroinflammation. J Neuroinflammation 2017; 14:228. [PMID: 29178967 PMCID: PMC5702153 DOI: 10.1186/s12974-017-0997-0] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Accepted: 11/07/2017] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Long-term use of morphine induces analgesic tolerance, which limits its clinical efficacy. Evidence indicated morphine-evoked neuroinflammation mediated by toll-like receptor 4 (TLR4) - NOD-like receptor protein 3 (NLRP3) inflammasome was important for morphine tolerance. In our study, we investigated whether other existing alternative pathways caused morphine-induced activation of TLR4 in microglia. We focused on heat shock protein 70 (HSP70), a damage-associated molecular pattern (DAMP), which was released from various cells upon stimulations under the control of KATP channel and bound with TLR4-inducing inflammation. Glibenclamide, a classic KATP channel blocker, can improve neuroinflammation by inhibiting the activation of NLRP3 inflammasome. Our present study investigated the effect and possible mechanism of glibenclamide in improving morphine tolerance via its specific inhibition on the release of HSP70 and activation of NLRP3 inflammasome induced by morphine. METHODS CD-1 mice were used for tail-flick test to evaluate morphine tolerance. The microglial cell line BV-2 and neural cell line SH-SY5Y were used to investigate the pharmacological effects and the mechanism of glibenclamide on morphine-induced neuroinflammation. The activation of microglia was accessed by immunofluorescence staining. Neuroinflammation-related cytokines were measured by western blot and real-time PCR. The level of HSP70 and related signaling pathway were evaluated by western blot and immunofluorescence staining. RESULTS Morphine induced the release of HSP70 from neurons. The released HSP70 activated microglia and triggered TLR4-mediated inflammatory response, leading to the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) p65 and the activation of NLRP3 inflammasome. Moreover, anti-HSP70 neutralizing antibody partly attenuated chronic morphine tolerance. The secretion of HSP70 was under the control of MOR/AKT/KATP/ERK signal pathway. Glibenclamide as a classic KATP channel blocker markedly inhibited the release of HSP70 induced by morphine and suppressed HSP70-TLR4-NLRP3 inflammasome-mediated neuroinflammation, which consequently attenuated morphine tolerance. CONCLUSIONS Our study indicated that morphine-induced extracellular HSP70 was an alternative way for the activation of TLR4-NLRP3 in analgesic tolerance. The release of HSP70 was regulated by MOR/AKT/KATP/ERK pathway. Our study suggested a promising target, KATP channel and a new leading compound, glibenclamide, for treating morphine tolerance.
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Affiliation(s)
- Jie Qu
- Neuroprotective Drug Discovery Key Laboratory of Nanjing Medical University, Department of Pharmacology, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu, 211166, China
| | - Xue-You Tao
- Neuroprotective Drug Discovery Key Laboratory of Nanjing Medical University, Department of Pharmacology, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu, 211166, China.,Department of Anesthesiology, Yangzhou Maternal and Child Health Hospital Affiliated with Yangzhou Medical University, Yangzhou, China.,Department of Anesthesiology, 1st Affiliated Hospital, Nanjing Medical University, Nanjing, China
| | - Peng Teng
- Neuroprotective Drug Discovery Key Laboratory of Nanjing Medical University, Department of Pharmacology, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu, 211166, China
| | - Yan Zhang
- Neuroprotective Drug Discovery Key Laboratory of Nanjing Medical University, Department of Pharmacology, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu, 211166, China.,Research Division of Pharmacology, China Pharmaceutical University, Nanjing, China
| | - Ci-Liang Guo
- Neuroprotective Drug Discovery Key Laboratory of Nanjing Medical University, Department of Pharmacology, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu, 211166, China
| | - Liang Hu
- Neuroprotective Drug Discovery Key Laboratory of Nanjing Medical University, Department of Pharmacology, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu, 211166, China
| | - Yan-Ning Qian
- Department of Anesthesiology, 1st Affiliated Hospital, Nanjing Medical University, Nanjing, China
| | - Chun-Yi Jiang
- Neuroprotective Drug Discovery Key Laboratory of Nanjing Medical University, Department of Pharmacology, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu, 211166, China.
| | - Wen-Tao Liu
- Neuroprotective Drug Discovery Key Laboratory of Nanjing Medical University, Department of Pharmacology, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu, 211166, China. .,Department of Pharmacy, Sir Run Run Shaw Hospital Affiliated to Nanjing Medical University, Nanjing, China.
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A Protective Role of Glibenclamide in Inflammation-Associated Injury. Mediators Inflamm 2017; 2017:3578702. [PMID: 28740332 PMCID: PMC5504948 DOI: 10.1155/2017/3578702] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2016] [Revised: 03/26/2017] [Accepted: 04/06/2017] [Indexed: 12/13/2022] Open
Abstract
Glibenclamide is the most widely used sulfonylurea drug for the treatment of type 2 diabetes mellitus (DM). Recent studies have suggested that glibenclamide reduced adverse neuroinflammation and improved behavioral outcomes following central nervous system (CNS) injury. We reviewed glibenclamide's anti-inflammatory effects: abundant evidences have shown that glibenclamide exerted an anti-inflammatory effect in respiratory, digestive, urological, cardiological, and CNS diseases, as well as in ischemia-reperfusion injury. Glibenclamide might block KATP channel, Sur1-Trpm4 channel, and NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome activation, decrease the production of proinflammatory mediators (TNF-α, IL-1β, and reactive oxygen species), and suppress the accumulation of inflammatory cells. Glibenclamide's anti-inflammation warrants further investigation.
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Effect of paricalcitol on pancreatic oxidative stress, inflammatory markers, and glycemic status in diabetic rats. Ir J Med Sci 2017; 187:75-84. [PMID: 28551720 DOI: 10.1007/s11845-017-1635-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2016] [Accepted: 05/18/2017] [Indexed: 01/09/2023]
Abstract
OBJECTIVES This study is designed to explore the effect of paricalcitol (vitamin D receptor agonist) on pancreatic oxidative stress, inflammatory markers, and adiponectin and glycemic status in diabetic rats. MATERIALS AND METHODS Forty Sprague-Dawley male rats aged 10-12 weeks (150-250 g) were used in this study. Type 2 diabetes was developed by providing 4 weeks of high-fat-diet feeding before one shot of streptozotocin injection (40 mg/kg i.p.). Four study groups were designed as normal control rats, diabetic control vehicle-treated, diabetic paricalcitol-treated (0.8 μg/kg), and diabetic glibenclamide-treated (0.6 mg/kg) groups with 10 animals in each. After treatment of diabetic rats for 3 months, pancreatic inflammatory and oxidative stress markers, plasma adiponectin, glycemic status parameters, and histopathological pancreatic islet changes were evaluated. RESULTS Paricalcitol and glibenclamide treatment significantly (P < 0.05) decreased plasma glucose, insulin resistance, and pancreatic malondialdehyde and tumor necrosis factor-α levels. Moreover, they significantly (P < 0.05) increased plasma fasting insulin, C-peptide, adiponectin, pancreatic IL-2, catalase, superoxide dismutase, glutathione peroxidase, and reduced glutathione when contrasted with diabetic control rats. Furthermore, they prevented extensive histopathological damage in the pancreas of diabetic rats. CONCLUSIONS Paricalcitol reduced pancreatic oxidative stress and inflammatory markers, and improved glycemic status in diabetic rats.
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Tsarenko SV, Dzyadz'ko AM, Rybalko SS. [Glibenclamide as a promising agent for prevention and treatment of cerebral edema]. ZHURNAL VOPROSY NEIROKHIRURGII IMENI N. N. BURDENKO 2017; 81:88-93. [PMID: 28665392 DOI: 10.17116/neiro201781388-93] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
The article presents a review of the literature on the use of a fundamentally new technique for prevention and treatment of cerebral edema. A drug glibenclamide, which is used to treat type 2 diabetes mellitus, is able to reduce cerebral edema and neuronal damage as evidenced by the results of preclinical trials in rodents and the first results of drug application in patients. The article describes the mechanism of glibenclamide action and discusses the potential for its application.
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Affiliation(s)
- S V Tsarenko
- Treatment and Rehabilitation Center, Moscow, Russia
| | - A M Dzyadz'ko
- Republican Scientific and Practical Center of Organ and Tissue Transplantation, Minsk, Republic of Belarus
| | - S S Rybalko
- Republican Scientific and Practical Center of Neurology and Neurosurgery, Minsk, Republic of Belarus
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15
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Shimizu S, Tsounapi P, Dimitriadis F, Higashi Y, Shimizu T, Saito M. Testicular torsion-detorsion and potential therapeutic treatments: A possible role for ischemic postconditioning. Int J Urol 2016; 23:454-63. [DOI: 10.1111/iju.13110] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Accepted: 03/29/2016] [Indexed: 01/30/2023]
Affiliation(s)
- Shogo Shimizu
- Department of Pharmacology; Kochi Medical School; Kochi University; Nankoku Kochi Japan
| | - Panagiota Tsounapi
- Division of Urology; Tottori University School of Medicine; Yonago Tottori Japan
| | - Fotios Dimitriadis
- Department of Urology; School of Medicine; Ioannina University; Ioannina Greece
| | - Youichirou Higashi
- Department of Pharmacology; Kochi Medical School; Kochi University; Nankoku Kochi Japan
| | - Takahiro Shimizu
- Department of Pharmacology; Kochi Medical School; Kochi University; Nankoku Kochi Japan
| | - Motoaki Saito
- Department of Pharmacology; Kochi Medical School; Kochi University; Nankoku Kochi Japan
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Mertoğlu C, Senel U, Cayli S, Tas U, Küskü Kiraz Z, Özyurt H. Protective role of methylprednisolone and heparin in ischaemic-reperfusion injury of the rat testicle. Andrologia 2015; 48:737-44. [PMID: 26626546 DOI: 10.1111/and.12503] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/24/2015] [Indexed: 12/15/2022] Open
Abstract
This study evaluated the therapeutic efficacy of heparin and methylprednisolone in the treatment of ischaemic reperfusion (IR) injury of the testis. Twenty-four male Sprague-Dawley rats were allocated equally into three groups of eight animals each. The left testes were rotated 720° for 2 h in the rats in the torsion-detorsion group. Rats in the treatment groups underwent the same surgical procedure as the torsion-detorsion group but were also given methylprednisolone (group II) or heparin (group III) by an intraperitoneal route 30 min prior to detorsion. Left orchiectomy was performed in all rats from each experimental animal at 2 h after detorsion, and the tissue was harvested for the measurement of malondialdehyde (MDA), protein carbonyl (PC) and nitric oxide (NO) and the endogenous antioxidant enzymes, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase. Additional tissue was evaluated using histopathological and immunohistochemical changes. PC and MDA levels were significantly reduced in the treated groups compared to the control group. There was no statistically significant difference in NO level or SOD, GSH-Px and catalase activity among the treatment groups. Histopathological and immunohistochemical findings supported biochemical changes. It is concluded that pre-treatment with methylprednisolone or heparin protects the testis in ischaemic reperfusion injury caused by testicular torsion-detorsion.
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Affiliation(s)
- C Mertoğlu
- Medical Biochemistry, Faculty of Medicine, Erzincan University, Erzincan, Turkey
| | - U Senel
- Pediatric Surgery, Faculty of Medicine, Ufuk Şenel: Gaziosmanpasa University, Tokat, Turkey
| | - S Cayli
- Histology and Embryology, Faculty of Medicine, Yildirim Beyazit University, Ankara, Turkey
| | - U Tas
- Anatomy, Faculty of Medicine, Gaziosmanpasa University, Tokat, Turkey
| | | | - H Özyurt
- Medical Biochemistry, Faculty of Medicine, Gaziosmanpasa University, Tokat, Turkey
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He H, Li N, Zhao Z, Han F, Wang X, Zeng Y. Ischemic postconditioning improves the expression of cellular membrane connexin 43 and attenuates the reperfusion injury in rat acute myocardial infarction. Biomed Rep 2015; 3:668-674. [PMID: 26405543 DOI: 10.3892/br.2015.485] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2015] [Accepted: 05/21/2015] [Indexed: 11/05/2022] Open
Abstract
To investigate the effects of cellular membrane connexin 43 (Cx43) and the potential details in ischemic postconditioning (IPOC)-induced cardioprotection, ischemia/reperfusion (IR) models were generated in 8-week-old male Sprague-Dawley rats by ligating the left coronary artery anterior descending branch. The serum levels of myocardial creatases, nitric oxide (NO) and malondialdehyde (MDA) levels, infarct size, arrhythmia events, expression and distribution of Cx43, ultrastructure and apoptosis in the myocardium in different treatments with IR, IR + IPOC, IR + diazoxide or IR + IPOC + 5-hydroxydecanoate acid (5-HD) were investigated. Consequently, IPOC decreased infarct size (10.9 vs. 43.3%, P<0.01) and the levels of myocardial creatases, NO and MDA, and improved the expression (16.8 vs. 25.2% and 6.4 vs. 32.8%, after 1- and 3-h reperfusion, respectively; P<0.01) and distribution of Cx43, ultrastructure and apoptosis (19.2 vs. 42.9%, P<0.01) significantly. Diazoxide partly simulated the effects, and 5-HD attenuated but not completely abolished the effects of IPOC. In addition, the phosphorylated Cx43 (p-Cx43) level in the IR + IPOC group was lower than that in the IR + diazoxide group after 1-h reperfusion (26.1 vs. 29.4%, P>0.05); however, it was reversed after 3-h reperfusion and the p-Cx43 level in the IR + IPOC group was significantly higher than that in the IR + diazoxide group (32.8 vs. 18.7%, P<0.01). In conclusion, cell membrane Cx43 is also involved in the process of IPOC-induced cardioprotection and the improvement of membrane Cx43 is more dependent on mitochondrial KATP in the earlier phase of IPOC compared to the late phase of IPOC.
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Affiliation(s)
- Hua He
- Department of Emergency Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, P.R. China
| | - Nan Li
- Department of Cardiology, China-Japan Friendship Hospital, Beijing 100029, P.R. China
| | - Zhihong Zhao
- Department of Cardiology, Pudong New Area District Zhoupu Hospital, Shanghai 201318, P.R. China
| | - Fusheng Han
- Department of Emergency Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, P.R. China
| | - Xifu Wang
- Department of Emergency Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, P.R. China
| | - Yujie Zeng
- Department of Emergency Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, P.R. China
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Shih HJ, Yen JC, Chiu AW, Chow YC, Pan WH, Wang TY, Huang CJ. FTY720 mitigates torsion/detorsion-induced testicular injury in rats. J Surg Res 2015; 196:325-31. [DOI: 10.1016/j.jss.2015.03.014] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2014] [Revised: 01/12/2015] [Accepted: 03/10/2015] [Indexed: 01/02/2023]
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