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Naproxen sodium nanoparticles are less toxic and gastroprotective agents than the conventional NSAID drug naproxen sodium in Balb/c mice. Toxicol Appl Pharmacol 2022; 452:116192. [PMID: 35952772 DOI: 10.1016/j.taap.2022.116192] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 07/26/2022] [Accepted: 08/02/2022] [Indexed: 11/21/2022]
Abstract
Use of non-steroidal anti-inflammatory drugs (NSAIDs) is one of the leading causes of gastric ulcers. Excellent therapeutic properties have made the use of NSAIDs widespread. Nano-drug delivery to reduce systemic toxicity through modulating drug pharmacokinetics may be a better choice. Presently, we investigated if naproxen nanoformulation (PVA capped NPRS-MgO NPs) is less toxic to be used as an alternative drug. Groups of mice were assigned to control, NPRS-treated, CNF-treated, UNF-treated, and MgO NPs-treated groups. Analyses included gross examination of gastric mucosa, calculation of ulcer and inhibition indices, determination of tissue levels of reactive oxygen species (ROS), malondialdehyde (MDA), catalase (CAT), peroxidase (POD), superoxide dismutase (SOD), and reduced glutathione (GSH), histological and immunohistochemical assessment of i-NOS, COX-2, and caspase-3 of stomach mucosa, q-PCR for the detection of mRNA expression of IL-1β, IL-6, and TNF-α. Results were compared statistically at P < 0.05. Compared to NPRS-treated mice which developed multiple ulcers, had elevated MDA and ROS levels, and deceased CAT, POD, SOD, and GSH levels, significantly increased expression of IL-1β, IL-6, and TNF-α mRNA, damaged surface epithelium with disrupted glandular architecture and leucocyte infiltration of lamina propria with a marked increase in mucosal COX-2, i-NOS, and caspase-3 expression, oral administration of coated and uncoated naproxen nanoformulations prevented the gross mucosal damage by a restoration of all biochemical, histological, and immunohistochemical alterations to near control levels. The present study demonstrates that naproxen sodium nanoformulation has a gastroprotective action and in the clinical setting can be a better alternative to conventional naproxen.
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Tang W, Liu H, Ooi TC, Rajab NF, Cao H, Sharif R. Zinc carnosine: Frontiers advances of supplement for cancer therapy. Biomed Pharmacother 2022; 151:113157. [PMID: 35605299 DOI: 10.1016/j.biopha.2022.113157] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 05/08/2022] [Accepted: 05/16/2022] [Indexed: 11/02/2022] Open
Abstract
Zinc (Zn) has an existence within large quantities in the human brain, while accumulating within synaptic vesicle. There is growing evidence that Zn metabolic equilibrium breaking participates into different diseases (e.g., vascular dementia, carcinoma, Alzheimer's disease). Carnosine refers to an endogenic dipeptide abundant in skeletal muscle and brains and exerts a variety of positive influences (e.g., carcinoma resistance, crosslinking resistance, metal chelation and oxidation limitation). A complex of Zn and carnosine, called Zinc-L-carnosine (ZnC), has been extensively employed within Zn supplement therapeutic method and the treating approach for ulcers. ZnC has been shown to play a variety of roles in the body, including inhibiting intracellular reactive oxygen species(ROS) and free radical levels, inhibiting inflammation, supplementing zinc enzymes and promoting wound healing and mucosal cell repair. The present study conducting a reviewing process for the advances of ZnC in tumor adjuvant therapy.
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Affiliation(s)
- Weiwei Tang
- Center for Healthy Ageing & Wellness, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia; Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Transplantation, Chinese Academy of Medical Sciences, Nanjing, Jiangsu, China
| | - Hanyuan Liu
- General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Theng Choon Ooi
- Center for Healthy Ageing & Wellness, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia
| | - Nor Fadilah Rajab
- Center for Healthy Ageing & Wellness, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia
| | - Hongyong Cao
- General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Razinah Sharif
- Center for Healthy Ageing & Wellness, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia; Biocompatibility Laboratory, Centre for Research and Instrumentation, Universiti Kebangsaan Malaysia, 43600 UKM Bangi, Selangor Darul Ehsan, Malaysia.
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Alshora DH, Ibrahim MA, Zayed G, Al Rwashed MA, Abou-Taleb HA, Ali MF. The role of sodium lauryl sulfate on formulation of directly compressed tablets containing simvastatin and aspirin: Effect on drugs dissolution and gastric mucosa. Saudi Pharm J 2022; 30:635-645. [PMID: 35693440 PMCID: PMC9177453 DOI: 10.1016/j.jsps.2022.02.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Accepted: 02/10/2022] [Indexed: 11/22/2022] Open
Abstract
According to the American College of Cardiology/American Heart Association (ACC/AHA), both aspirin and statin are used in the primary prevention of cardiovascular diseases. Aspirin (ASA) is contraindicated if there is gastrointestinal bleeding because it will exaggerate the condition. In this study, the effect of surfactant; sodium lauryl sulfate (SLS), in enhancing the in vitro dissolution of simvastatin (SIM) and ASA, as well as gastric irritation and upset, was studied. Oral tablets containing both ASA and SIM with and without the SLS were manufactured using the direct compression technique. The prepared tablets were characterized with respect to hardness, friability, uniformity of dosage units, in vitro disintegration, and dissolution. The effect of the addition of SLS in reducing the in vivo irritation and protection of gastric mucosa were also investigated. The results showed that the compressed tablets possessed sufficient hardness, acceptable friability, and are uniform with respect to disintegration, drugs contents, and tablet weight. The results showed that SIM alone exhibited a gastroprotective effect on the induced irritation. In addition, the incorporation of the SLS in the tablets containing SIM and ASA significantly enhanced the dissolution rates of both drugs and significantly decreased the gastric irritation and the ulcer index. The ulcer index of aspirin was decreased from 2.3 for tablets manufactured without SLS to 0.8 for tablets containing SLS. In a conclusion, the addition of pH modifier surfactant; SLS could enhance the dissolution rate of poorly soluble acidic drugs, reduce gastric upset and irritation without any effect on the main characters of the tablets. Moreover, the addition of SLS is very useful in improving the therapeutic activities and reducing the side effects of ASA and SIM for patients who require long-term administration of these drugs.
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Affiliation(s)
- Doaa H. Alshora
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Saudi Arabia
| | - Mohamed A. Ibrahim
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Saudi Arabia
- Department of Pharmaceutics and Industrial Pharmacy, Al-Azhar University, Assiut, Egypt
| | - Gamal Zayed
- Department of Pharmaceutics and Industrial Pharmacy, Al-Azhar University, Assiut, Egypt
- Al-Azhar Centre of Nanosciences and Applications (ACNA), Al-Azhar University, Assiut, Egypt
| | | | - Heba A. Abou-Taleb
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Merit University (MUE), Sohag, Egypt
| | - Marwa F. Ali
- Department of Pathology and Clinical Pathology, Faculty of Veterinary Medicine, Assuit University, Egypt
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Ahmed I, Elkablawy MA, El-Agamy DS, Bazarbay AA, Ahmed N. Carvedilol safeguards against aspirin-induced gastric damage in rats. Hum Exp Toxicol 2020; 39:1257-1267. [PMID: 32295429 DOI: 10.1177/0960327120918306] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
This study investigated the effect of carvedilol on aspirin-induced gastric damage. Male Wistar rats were divided into three groups. Control rats received the vehicle, while the aspirin group received aspirin (200 mg/kg) orally for 4 days. Rats of aspirin + carvedilol group were administered aspirin along with carvedilol (5 mg/kg; intraperitoneal) for 4 days. Animals were euthanized at the end of the treatment period, and gastric tissues were collected to perform histopathological and mechanistic studies. The results revealed that aspirin administration induced gastric ulcer as there were remarkable histopathological lesions in the form of marked necrosis, inflammation, hemorrhage, edema, and dysplastic changes. Lipid peroxidative markers such as malondialdehyde, 4-hydroxynonenal, and protein carbonyl were significantly elevated in the aspirin group. This was concurrent with a significant amelioration of antioxidants such as reduced glutathione, superoxide dismutase, and catalase. Furthermore, aspirin increased the immunoexpression of cyclooxygenase (COX) 2 and nuclear factor kappa-B (NF-κB). Aspirin induced elevation in the inflammatory cytokines such as tumor necrosis factor-α, interleukin-6, and interleukin-1β. Aspirin enhanced the immunoexpression of inducible nitric oxide synthetase (iNOS) and increased the level of nitrite/nitrate in gastric tissue. On the other hand, carvedilol treatment reversed all these pathological changes. Carvedilol succeeded to enhance antioxidants in gastric tissue, attenuated lipid peroxidative parameters, and suppressed the release of inflammatory mediators. It attenuated the immunoexpression of COX-2, NF-κB, and iNOS. Collectively, carvedilol has a gastro-protective effect that could be attributed to its antioxidative and anti-inflammatory properties, which modulate NF-κB/COX-2/iNOS pathways.
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Affiliation(s)
- I Ahmed
- Department of Pharmacology and Toxicology, Nizam Institute of Pharmacy, Jawaharlal Nehru Technological University, Hyderabad, Telangana, India
| | - M A Elkablawy
- Department of Pathology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
| | - D S El-Agamy
- Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia.,Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - A A Bazarbay
- Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia
| | - N Ahmed
- Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia
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A Novel Role of Irbesartan in Gastroprotection against Indomethacin-Induced Gastric Injury in Rats: Targeting DDAH/ADMA and EGFR/ERK Signaling. Sci Rep 2018. [PMID: 29523851 PMCID: PMC5844881 DOI: 10.1038/s41598-018-22727-6] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The advent of angiotensin II type 1 receptor blockers (ARBs) as intriguing gastroprotective candidates and the superior pharmacokinetics and pharmacodynamics displayed by irbesartan compared to many other ARBs raised the interest to investigate its gastroprotective potential in a rat model of gastric injury. Irbesartan (50 mg/Kg) was orally administered to male Wistar rats once daily for 14 days; thereafter gastric injury was induced by indomethacin (60 mg/Kg, p.o). Irbesartan reduced gastric ulcer index, gastric acidity, and ameliorated indomethacin-induced gastric mucosal apoptotic and inflammatory aberrations, as demonstrated by hampering caspase-3, prostaglandin E2 and tumor necrosis factor-alpha levels and cyclooxygenase-2 mRNA expression. This ARB increased mucosal dimethylarginine dimethylaminohydrolase-1 (DDAH-1) gene expression and decreased elevated levels of matrix metalloproteinase-9, asymmetric dimethylarginine (ADMA), epidermal growth factor receptor (EGFR) mRNA and phosphorylated extracellular signal-regulated kinase 1 and 2 (pERK1/2). Histopathological evaluation corroborated biochemical findings. Overall efficacy of irbesartan was comparable to ranitidine, the widely used H2 receptor blocker. In conclusion, irbesartan exerts significant gastroprotection against indomethacin-induced mucosal damage via acid-inhibitory, anti-inflammatory, anti-apoptotic and extracellular matrix remodeling mechanisms that are probably mediated, at least partly, by down-regulating DDAH/ADMA and EGFR/ERK1/2 signaling.
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Sun Z, Lv J, Zhu Y, Song D, Zhu B, Miao C. Desflurane preconditioning protects human umbilical vein endothelial cells against anoxia/reoxygenation by upregulating NLRP12 and inhibiting non-canonical nuclear factor-κB signaling. Int J Mol Med 2015; 36:1327-34. [PMID: 26329693 DOI: 10.3892/ijmm.2015.2335] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2015] [Accepted: 07/29/2015] [Indexed: 11/06/2022] Open
Abstract
Volatile anesthetics modulate endothelial cell apoptosis and inhibit nuclear factor-κB (NF-κB) signaling. In this study, we aimed to assess whether desflurane preconditioning protects human umbilical vein endothelial cells (HUVECs) agaist anoxia/reoxygenation (A/R) injury. HUVECs were pre-conditioned with desflurane (1.0 MAC) for 30 min, followed by a 15-min washout, then exposed to 60 min anoxia and 60 min reoxygenation (A/R), and incubated with 10 ng/ml tumor necrosis factor (TNF)-α for 60 min. HUVEC viability and apoptosis were measured by MTT assay and annexin V staining, and immunoblot analysis was used to measure the levels of Smac and cellular inhibitor of apoptosis 1 (cIAP1). NF-κB activation was assessed using the NF-κB signaling pathway real‑time PCR array, and the levels of NF-κB inducing kinase (NIK), p52, IκB kinase (IKK)α, p100, RelB and NLR family, pyrin domain containing 12 (NLRP12) were assessed by immunoblot analysis. Desflurane preconditioning attenuated the effects of A/R and/or A/R plus TNF-α on cell viability, decreasing the levels of Smac and enhancing the levels of of cIAP1 (P<0.05). Preconditioning with desflurane also enhanced the mRNA levels of interleukin (IL)-10 and NLRP12 in the cells exposed to A/R by 2.40- and 2.16‑fold, respectively. The HUVECs exposed to A/R had greater levels of NIK and p100 and reduced levels of p52 and IKKα. Desflurance preconditioning further increased p100 levels, decreased the level of NIK, further decreased p52 levels and further reduced IKKα levels. A/R in combination with TNF-α increased the NIK, IKKα, p100 and RelB levels, and this increase was significantly attenuated by desflurance preconditioning (all P<0.05). Desflurane preconditioning enhanced HUVEC survival and protected the cells against A/R injury, and our results suggested that this process involved the upregulation of NLRP12 and the inhibition of non-canonical NF-κB signaling.
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Affiliation(s)
- Zhirong Sun
- Department of Anesthesiology, Fudan University Shanghai Cancer Center, Shanghai, P.R. China
| | - Jianing Lv
- Department of Neurology, Fudan University Shanghai Zhongshan Hospital, Shanghai, P.R. China
| | - Yun Zhu
- Department of Anesthesiology, Fudan University Shanghai Cancer Center, Shanghai, P.R. China
| | - Dongli Song
- Biomedical Research Center, Fudan University Zhongshan Hospital, Shanghai, P.R. China
| | - Biao Zhu
- Department of Anesthesiology and Critical Care Unit, Fudan University Shanghai Cancer Center, Shanghai, P.R. China
| | - Changhong Miao
- Department of Anesthesiology and Critical Care Unit, Fudan University Shanghai Cancer Center, Shanghai, P.R. China
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Strategies to optimize kidney recovery and preservation in transplantation: specific aspects in pediatric transplantation. Pediatr Nephrol 2015; 30:1243-54. [PMID: 25185880 DOI: 10.1007/s00467-014-2924-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2014] [Revised: 07/09/2014] [Accepted: 07/21/2014] [Indexed: 01/08/2023]
Abstract
In renal transplantation, live donor kidney grafts are associated with optimum success rates due to the shorter period of ischemia during the surgical procedure. The current shortage of donor organs for adult patients has caused a shift towards deceased donors, often with co-morbidity factors, whose organs are more sensitive to ischemia-reperfusion injury, which is unavoidable during transplantation. Donor management is pivotal to kidney graft survival through the control of the ischemia-reperfusion sequence, which is known to stimulate numerous deleterious or regenerative pathways. Although the key role of endothelial cells has been established, the complexity of the injury, associated with stimulation of different cell signaling pathways, such as unfolded protein response and cell death, prevents the definition of a unique therapeutic target. Preclinical transplant models in large animals are necessary to establish relationships and kinetics and have already contributed to the improvement of organ preservation. Therapeutic strategies using mesenchymal stem cells to induce allograft tolerance are promising advances in the treatment of the pediatric recipient in terms of reducing/withdrawing immunosuppressive therapy. In this review we focus on the different donor management strategies in kidney graft conditioning and on graft preservation consequences by highlighting the role of endothelial cells. We also propose strategies for preventing ischemia-reperfusion, such as cell therapy.
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2-Arachidonoylglycerol modulates human endothelial cell/leukocyte interactions by controlling selectin expression through CB1 and CB2 receptors. Int J Biochem Cell Biol 2014; 51:79-88. [DOI: 10.1016/j.biocel.2014.03.028] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2013] [Revised: 03/10/2014] [Accepted: 03/28/2014] [Indexed: 12/17/2022]
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Abstract
PURPOSE OF REVIEW Recent advances in T cell biology have shed light on the role of T cell subsets in the pathogenesis of acute kidney injury (AKI). The purpose of this review is to harness our understanding of recent advances in T cell biology in tissue injury and repair and provide a mechanistic insight into the role of T cells in the inflammation of AKI. RECENT FINDINGS New specific reagents and genetic animal models have led to advances in our understanding of the role of T cell subsets involved in renal injury. Whereas some T cells promote innate renal inflammation and injury, other T cells promote protection and repair. Recent studies illuminated the pathogenic mechanisms of invariant natural killer T (NKT) cells and T helper1-type responses, and the beneficial functions of regulatory T cells and NKT cells are just beginning to be explored. Pharmacologic and cell-based therapies that influence T cell responses to experimental AKI suggest that this is a promising approach to preserve renal function. SUMMARY The recent insights gained into how T cells modulate renal injury suggest that strategies targeting specific types of T cells, to either inhibit or enhance their activity, may ameliorate renal injury in patients.
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Affiliation(s)
- Gilbert R Kinsey
- Division of Nephrology and Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia Health System, Charlottesville, Virginia, USA
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Kumar M, Gautam MK, Singh A, Goel RK. Healing effects of Musa sapientum var. paradisiaca in diabetic rats with co-occurring gastric ulcer: cytokines and growth factor by PCR amplification. Altern Ther Health Med 2013; 13:305. [PMID: 24192345 PMCID: PMC3826524 DOI: 10.1186/1472-6882-13-305] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2013] [Accepted: 10/24/2013] [Indexed: 01/30/2023]
Abstract
Background The present study evaluates the effects of extract of Musa sapientum fruit (MSE) on ulcer index, blood glucose level and gastric mucosal cytokines, TNF-α and IL-1β and growth factor, TGF-α (affected in diabetes and chronic ulcer) in acetic acid (AA)-induced gastric ulcer (GU) in diabetic (DR) rat. Methods MSE (100 mg/kg, oral), omeprazole (OMZ, 2.0 mg/kg, oral), insulin (INS, 4 U/kg, sc) or pentoxyphylline (PTX, 10 mg/kg, oral) were given once daily for 10 days in 14 days post-streptozotocin (60 mg/kg, intraperitoneal)-induced diabetic rats while, the normal/diabetic rats received CMC for the same period after induction of GU with AA. Ulcer index was calculated based upon the product of length and width (mm2/rat) of ulcers while, TNF-α, IL-1β and TGF-α were estimated in the gastric mucosal homogenate from the intact/ulcer region. Phytochemical screening and HPTLC analysis of MSE was done following standard procedures. Results An increase in ulcer index, TNF-α and IL-1β were observed in normal (NR)-AA rat compared to NR-normal saline rat, which were further increased in DR-AA rat while, treatments of DR-AA rat with MSE, OMZ, INS and PTX reversed them, more so with MSE and PTX. Significant increase in TGF-α was found in NR-AA rat which did not increase further in DR-AA rat. MSE and PTX tended to increase while, OMZ and INS showed little or no effect on TGF-α in AA-DR rat. Phytochemical screening of MSE showed the presence of saponins, flavonoids, glycosides, steroids and alkaloids and HPTLC analysis indicated the presence of eight active compounds. Conclusion MSE showed antidiabetic and better ulcer healing effects compared with OMZ (antiulcer) or INS (antidiabetic) in diabetic rat and could be more effective in diabetes with concurrent gastric ulcer.
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Koyama S, Ohtani K, Fukuzawa J, Yao N, Fukuda M, Jang SJ, Hasebe N, Kikuchi K, Itabe H, Yoshida I, Suzuki Y, Wakamiya N. The induction of human CL-P1 expression in hypoxia/reoxygenation culture condition and rat CL-P1 after ischemic/reperfusion treatment. Biochim Biophys Acta Gen Subj 2011; 1810:836-42. [PMID: 21723916 DOI: 10.1016/j.bbagen.2011.06.013] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2011] [Revised: 06/12/2011] [Accepted: 06/14/2011] [Indexed: 01/26/2023]
Abstract
BACKGROUND Oxidative stress-induced endothelial dysfunction and oxidized low-density lipoprotein (LDL) might play a key role in the pathogenesis of atherosclerosis. We recently identified a vascular endothelial scavenger receptor, collectin placenta 1 (CL-P1), which acts as a receptor for oxidized LDL as well as for microbes. METHODS We demonstrate how hypoxic and oxidative stress induced CL-P1 expression and compared their effects with the expression of lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1), an endothelial scavenger receptor expressed by oxidative stress. RESULTS Hypoxia/reoxygenation induced CL-P1 mRNA and protein expression in human umbilical vein endothelial cells (HUVECs). The expression of LOX-1 mRNA in these cells peaked slightly at 24 h, while the expression of CL-P1 had an onset at 72 h and was sustained for 120 h after reoxygenation. Furthermore, the exposure of rat carotid artery endothelium to ischemia/reperfusion increased the maximal CL-P1 mRNA expression at 72 h and expression of its protein peaked at 7 days after this treatment. We demonstrate that CL-P1 up-regulation is induced in vitro and in vivo by oxidative stress. GENERAL SIGNIFICANCE The inducible expression of CL-P1 by oxidative stress might play a crucial role in endothelial dysfunction or chronic activation leading to the pathogenesis of atherosclerosis.
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Affiliation(s)
- Satoshi Koyama
- Department of Microbiology and Immunochemistry, Asahikawa Medical University, Asahikawa 078-8510, Japan
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Nutritional Composition, Antioxidant Activities, and Antiulcer Potential of Lentinus squarrosulus (Mont.) Mycelia Extract. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2011; 2011:539356. [PMID: 21423634 PMCID: PMC3057541 DOI: 10.1155/2011/539356] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/20/2010] [Revised: 12/24/2010] [Accepted: 01/12/2011] [Indexed: 11/30/2022]
Abstract
Water extract of Lentinus squarrosulus mycelia was analysed for nutritional content, antioxidant capacity, and antiulcer ability. The extract contains high protein (57.6 g/100 g) and low total fat (0.5 g/100 g) and is rich in magnesium (0.4 g/100 g), potassium (3.8 g/100 g), vitamins B1 (1.42 mg/100 g), and B3 (194.29 mg/100 g) with total phenolic content of 39.16 mg/100 g. The cupric reducing antioxidant capacity and 1,1-diphenyl-2-picrylhydrazyl radical scavenging activity of the extract were A450 of 0.20 ± 0.03 at 0.5 mg/ml and IC50 of 14.29 mg/ml, respectively. Oral feeding of L. squarrosulus extract (250 mg/kg) offered significant gastric mucosal protection of Sprague-Dawley rats compared to cimetidine (50 mg/kg). The ulcer healing rate of ulcerated rats after 24, 48, and 72 hours of treatment was 82%, 90%, and 100%, respectively. The IL-1β level in the serum and the NF-κB level in the tissues indicate that the healing potential was associated with attenuation of proinflammatory cytokines.
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Liu YX, Jin LM, Zhou L, Xie HY, Jiang GP, Chen H, Zheng SS. Sirolimus attenuates reduced-size liver ischemia-reperfusion injury but impairs liver regeneration in rats. Dig Dis Sci 2010; 55:2255-62. [PMID: 19856103 DOI: 10.1007/s10620-009-1002-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2008] [Accepted: 09/21/2009] [Indexed: 01/02/2023]
Abstract
BACKGROUND Evidence has suggested that immunosuppressive drugs impact ischemia-reperfusion injury. AIMS The purpose of the present study was to evaluate the effect of sirolimus on hepatic injury and regeneration in a rat reduced-size liver ischemia-reperfusion model. METHODS Using a newly developed rat reduced-size liver ischemia-reperfusion injury model, the effects of sirolimus were evaluated by assessing liver cell apoptosis and aspartate aminotransferase, myeloperoxidase, and malondialdehyde levels. In addition, liver regeneration after sirolimus treatment was evaluated by measuring liver weight resumption and by the histological examination of bromodeoxyuridine and proliferating cell nuclear antigen expression. RESULTS Sirolimus significantly decreased liver cell apoptosis as well as tissue myeloperoxidase and malondialdehyde levels, but impaired postischemic liver regeneration. Ischemia-reperfusion-induced elevation of aspartate aminotransferase serum levels was significantly decreased by sirolimus. CONCLUSIONS Despite an impairment of postischemic liver proliferation, sirolimus demonstrated beneficial amelioration of ischemia-reperfusion-induced liver injury in a reduced-size liver model in rats.
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Affiliation(s)
- Yuan-Xing Liu
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, Zhejiang Province, People's Republic of China
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The Potential Effect of Proteasome Inhibitor PS-341 on Severe Acute Pancreatitis Detected by Positron Emission Tomography in ICR Mice. J Surg Res 2010; 162:193-202. [DOI: 10.1016/j.jss.2009.06.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2008] [Revised: 05/26/2009] [Accepted: 06/09/2009] [Indexed: 01/20/2023]
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Osman M, Russell J, Granger DN. Lymphocyte-derived interferon-gamma mediates ischemia-reperfusion-induced leukocyte and platelet adhesion in intestinal microcirculation. Am J Physiol Gastrointest Liver Physiol 2009; 296:G659-63. [PMID: 19118114 PMCID: PMC2660175 DOI: 10.1152/ajpgi.90495.2008] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Although previous studies have implicated lymphocytes in the gut microvascular and inflammatory responses to ischemia-reperfusion (I/R), the lymphocyte population and lymphocyte-derived products that mediate these responses have not been defined. Platelet and leukocyte adhesion was measured in intestinal postcapillary venules of wild-type (WT) mice and mice genetically deficient in either CD4+ T cells (CD4-/-), CD8+ T cells (CD8-/-), B cells (B cell-/-), or interferon-gamma (IFN-gamma-/-) subjected to 45 min of ischemia and 4 h of reperfusion. The I/R-induced platelet and leukocyte recruitment responses were also evaluated following adoptive transfer of WT splenocytes into CD4-/-, CD8-/-, B cell-/-, and IFN-gamma-/- mice. WT mice exposed to gut I/R exhibited significant increases in the adhesion of both platelets and leukocytes, compared with sham-WT mice. These blood cell adhesion responses to I/R were greatly attenuated in CD4-/-, CD8-/-, B cell-/-, and IFN-gamma-/- mice. Adoptive transfer of WT splenocytes restored the WT responses to I/R in all mutants except the B cell-/- mice. These findings implicate both T and B cells and lymphocyte-derived IFN-gamma as mediators of the proinflammatory and prothrombogenic phenotype assumed by intestinal microvessels after I/R.
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Affiliation(s)
- Mohammad Osman
- Department of Molecular and Cellular Physiology, Louisiana State University Health Science Center, Shreveport, Louisiana
| | - Janice Russell
- Department of Molecular and Cellular Physiology, Louisiana State University Health Science Center, Shreveport, Louisiana
| | - D. Neil Granger
- Department of Molecular and Cellular Physiology, Louisiana State University Health Science Center, Shreveport, Louisiana
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Koizumi S, Odashima M, Otaka M, Jin M, Linden J, Watanabe S, Ohnishi H. Attenuation of gastric mucosal inflammation induced by indomethacin through activation of the A2A adenosine receptor in rats. J Gastroenterol 2009; 44:419-25. [PMID: 19333545 PMCID: PMC3328190 DOI: 10.1007/s00535-009-0028-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2008] [Accepted: 12/15/2008] [Indexed: 02/04/2023]
Abstract
BACKGROUND Nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin induce gastric mucosal lesions in part by the activation of inflammatory cells and the production of proinflammatory cytokines. The activation of adenosine A(2A) receptors inhibits inflammation by increasing cyclic AMP in leukocytes and reducing both the production of various proinflammatory cytokines and neutrophil chemotaxis. The aim of present study was to determine whether administration of an orally active adenosine A(2A) receptor agonist (4-[3-[6-amino-9-(5-cyclopropylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl]-piperidine-1-carboxylic acid methyl ester; ATL-313) ameliorated indomethacin-induced gastric mucosal lesions in rats. METHODS Gastric lesions were produced by oral gavage of indomethacin (30 mg/kg). ATL-313 (1-10 microg/kg) was given orally just before the indomethacin administration. RESULTS The ulcer index induced by indomethacin was significantly (>50%) reduced by pretreatment with ATL-313 and this effect was blocked completely by the addition of equimolar ZM241385, a selective A(2A) receptor antagonist. The gastric content of myeloperoxidase (MPO) and proinflammatory cytokines was significantly reduced by 10 microg/kg ATL-313, but gastric mucosal prostaglandin 2 (PGE2) was not affected. CONCLUSION We conclude that ATL-313 does not inhibit the mucosal damaging effect of indomethacin, but it does block secondary injury due to stomach inflammation. A(2A) agonists may represent a class of new therapeutic drugs for NSAID-induced gastric ulcers.
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Affiliation(s)
- Shigeto Koizumi
- Department of Gastroenterology, Akita University School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan
| | - Masaru Odashima
- Department of Gastroenterology, Akita University School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan
| | - Michiro Otaka
- Department of Gastroenterology, Juntendo University, Tokyo, Japan
| | - Mario Jin
- Department of Gastroenterology, Akita University School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan
| | - Joel Linden
- Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA
| | - Sumio Watanabe
- Department of Gastroenterology, Juntendo University, Tokyo, Japan
| | - Hirohide Ohnishi
- Department of Gastroenterology, Akita University School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan
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The A20 gene protects kidneys from ischaemia/reperfusion injury by suppressing pro-inflammatory activation. J Mol Med (Berl) 2008; 86:1329-39. [PMID: 18813897 DOI: 10.1007/s00109-008-0405-4] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2008] [Revised: 08/20/2008] [Accepted: 08/29/2008] [Indexed: 12/12/2022]
Abstract
Ischaemia followed by reperfusion (I/R) can induce inflammation and injury and is a risk factor for delayed graft function and rejection of transplanted kidneys. Inflammation is regulated by NF-kappaB transcription factors which induce pro-inflammatory molecules in endothelial cells (EC). We examined whether A20, a negative regulator of NF-kappaB, can protect kidneys from I/R injury. To mimic the fluctuations in endothelial oxygenation that occur during I/R we exposed cultured human umbilical vein EC (HUVEC) to hypoxia (1% O(2) for 4 h) followed by re-oxygenation (21% O(2) for 1 h-24 h). We observed transient expression of pro-inflammatory molecules (E-selectin, VCAM-1 and IL-8) and sustained expression of A20 in HUVEC exposed to hypoxia/re-oxygenation. The effect of A20 on endothelial responses to hypoxia/re-oxygenation was assessed. We observed that pre-treatment of HUVEC with an adenovirus containing A20 (Ad-A20) suppressed activation of NF-kappaB and induction of pro-inflammatory molecules by hypoxia/re-oxygenation, whereas a control adenovirus had little or no effect. Thus the induction of A20 may form a negative feedback loop in pro-inflammatory signalling in cells exposed to hypoxia/re-oxygenation. To validate our cell culture experiments we examined the role of A20 in renal responses to I/R. We observed that A20 was induced in rat kidneys exposed to I/R. Moreover, pre-treatment of animals with Ad-A20 significantly reduced acute tubular necrosis, renal expression of VCAM-1 and NF-kappaB activation in response to I/R, whereas pre-treatment with control adenovirus did not. Our observations suggest that A20 maintains physiological homeostasis in kidneys exposed to I/R by protecting them from inflammation and injury.
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Reciprocal Activation Between CD4+ T Cells and Kupffer Cells During Hepatic Ischemia-Reperfusion. Transplantation 2008; 86:710-8. [DOI: 10.1097/tp.0b013e3181821aa7] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Zhang X, Tajima K, Kageyama K, Kyoi T. Irsogladine maleate suppresses indomethacin-induced elevation of proinflammatory cytokines and gastric injury in rats. World J Gastroenterol 2008; 14:4784-90. [PMID: 18720540 PMCID: PMC2739341 DOI: 10.3748/wjg.14.4784] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the mucosal protective effect and the mechanisms of action of the anti-ulcer drug irsogladine maleate in gastric injury induced by indomethacin in rats.
METHODS: Gastric mucosal injury was induced in male Hos:Donryu rats by oral administration of indomethacin at a dose of 48 mg/kg. One hour before indomethacin treatment, animals were orally pretreated with irsogladine maleate at doses of 1 mg/kg, 3 mg/kg or 10 mg/kg. Four hours after indomethacin administration, the animals were sacrificed and their stomachs were rapidly removed and processed for the evaluation of gastric mucosal damage and the determination of the concentrations of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-8 and myeloperoxidase (MPO) in mucosal tissues.
RESULTS: Linear hemorrhagic mucosal lesions were observed primarily in the glandular stomach 4 h after oral administration of indomethacin. Pretreatment with irsogladine maleate markedly reduced the number and severity of these lesions in a dose-dependent manner. The mucosal concentrations of proinflammatory cytokines (TNF-α, IL-1β, and IL-8) and MPO, which indicates the degree of mucosal infiltration by neutrophils, increased concomitantly with the occurrence of gastric injury in the indomethacin-treated rats. Pretreatment with irsogladine maleate significantly decreased the levels of these inflammatory factors in gastric tissue elicited by indomethacin.
CONCLUSION: The mucosal protective effects afforded by irsogladine maleate on gastric injury induced by indomethacin are mediated by inhibition of mucosal proinflammatory cytokine production and neutrophil infiltration, leading to suppression of mucosal inflammation and subsequent tissue destruction.
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20
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Mehra R, Redline S. Sleep apnea: a proinflammatory disorder that coaggregates with obesity. J Allergy Clin Immunol 2008; 121:1096-102. [PMID: 18466782 DOI: 10.1016/j.jaci.2008.04.002] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2008] [Revised: 04/01/2008] [Accepted: 04/03/2008] [Indexed: 11/26/2022]
Abstract
Both obesity and sleep apnea are prevalent health conditions that frequently coaggregate. Obesity-associated inflammation may influence asthma control; the relation of sleep apnea to asthma or allergic rhinitis may be bidirectional. Both obesity and sleep apnea are associated with augmented levels of inflammation and oxidative stress, and it is biologically plausible that the proinflammatory effects of one disorder influence the expression of the other disorder. This article elucidates mechanistic associations among obesity, sleep apnea, and systemic inflammation; highlights interrelationships between these factors with cardiopulmonary disease; and identifies specific areas for future research directions.
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Affiliation(s)
- Reena Mehra
- Department of Medicine, Case Comprehensive Cancer Center, Case School of Medicine, Cleveland, OH 44106-6003, USA.
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Yu SJ, Oh DJ, Yu SH. The investigation of macrophage infiltration in the early phase of ischemic acute renal failure in mice. Korean J Intern Med 2008; 23:64-71. [PMID: 18646508 PMCID: PMC2686976 DOI: 10.3904/kjim.2008.23.2.64] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND/AIMS Inflammation plays a key role in ischemic acute renal failure (ARF). The present study investigated the infiltration of macrophages in the early phase of ischemic ARF in mice. METHODS Ischemic ARF was induced by renal clamping for 22 min, while the control mice underwent sham surgery (no clamping). The serum creatinine and blood urea nitrogen (BUN) levels were measured in the control and post-ischemia mice. Immunofluorescence staining was used to measure the number of CD 11b-positive cells in the kidney tissue sections to determine the amount of post-ischemic macrophage infiltration. Lipo-Cl2MBP (clodronate) for macrophages depletion was injected via a tail vein 5 d before ischemia induction and again 2 d before ischemia induction. RESULTS The study found that the post-ischemia mice had higher levels of serum creatinine and BUN at 16 and 24 h compared to the controls. Immunofluorescence staining showed there were more macrophages in the post-ischemic tissue at 2, 8, 16 and 24 h compared to the control tissue, and that most of these macrophages were located in the outer medulla. The mice treated with clodronate prior to ischemia induction were found to have lower levels of serum creatinine compared to those mice that weren't treated with clodronate. CONCLUSIONS There was significant infiltration of macrophages from the early phase of ischemic ARF, and this peaked at 16-24 h. Macrophage depletion using clodronate was protective against ischemic ARF.
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Affiliation(s)
- Soo-Jeong Yu
- Department of Internal Medicine, Incheon Christian Hospital, Korea
| | - Dong-Jin Oh
- Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, Korea
| | - Suk-Hee Yu
- Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, Korea
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Walshe TE, D'Amore PA. The role of hypoxia in vascular injury and repair. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2008; 3:615-43. [PMID: 18039132 DOI: 10.1146/annurev.pathmechdis.3.121806.151501] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Although the terms ischemia and hypoxia are often used interchangeably, they represent distinct processes that result in different modulatory effects at the cellular level. Hypoxia is a reduction in oxygen delivery below tissue demand, whereas ischemia is a lack of perfusion, characterized not only by hypoxia but also by insufficient nutrient supply. Hypoxia can be either acute or chronic, and both are centrally regulated by hypoxia-inducible factor, a transcription factor that governs the expression of key response genes such as vascular endothelial growth factor and erythropoietin. Whereas severe chronic hypoxia can cause cell death, less-severe hypoxia can protect against subsequent damage, a phenomenon known as hypoxic conditioning. Several important processes are characterized by hypoxia, including ischemia-reperfusion, tumor growth and progression, inflammation, myocardial ischemia, and a number of ocular pathologies.
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Affiliation(s)
- Tony E Walshe
- Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA.
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Odashima M, Otaka M, Ohba R, Jin M, Wada I, Horikawa Y, Matsuhashi T, Hatakeyama N, Oyake J, Watanabe S. Attenuation of gastric mucosal inflammation induced by aspirin through inhibition of selective type III phospshodiesterase in rats. Dig Dis Sci 2007; 52:1355-9. [PMID: 17372821 DOI: 10.1007/s10620-006-9553-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2006] [Accepted: 07/31/2006] [Indexed: 12/09/2022]
Abstract
Cilostazol, a selective type III phosphodiesterase inhibitor, is widely used for treatment of ischemic symptoms of peripheral vascular disease. Recent studies have reported that the mechanism of cilostazol is related to suppression of pro-inflammatory cytokine production and improvement of local microcirculation disturbances. The activation of inflammatory cells and pro-inflammatory cytokine production play critical roles in the pathogenesis of aspirin-induced gastric irritation. The aim of the present study was to determine whether cilostazol can ameliorate aspirin-induced gastric mucosal lesions in rats, reduce neutrophil accumulation, and reduce the production of pro-inflammatory cytokines. Gastric lesions were produced by oral gavage of aspirin (200 mg/kg) and HCl (0.15 N, 8.0 ml/kg). Cilostazol (1-10 mg/kg, IP) was injected 30 min before aspirin administration. Also, we measured the gastric mucosal concentrations of myeloperoxidase and interleukin-1 beta, tumor necrosis factor-alpha, and cytokine-induced neutrophil chemoattractants-1, as an index of neutrophil accumulation, and the pro-inflammatory cytokines. Cilostazol ameliorated the gastric mucosal lesions induced by aspirin administration (P<0.01). The gastric contents of myeloperoxidase and pro-inflammatory cytokines were all increased after aspirin administration and significantly reduced by cilostazol treatment. In this study, we demonstrated that a selective type III phosphodiesterase inhibitor, cilostazol, reduced aspirin-induced gastric inflammation and damage via suppression of the production of proinflammatory cytokines. Cilostazol may be useful for preventing gastric mucosal lesions induced by aspirin.
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Affiliation(s)
- Masaru Odashima
- Department of Gastroenterology, Akita University of Medicine, 1-1-1, Hondo, Akita City, 010-8543, Akita, Japan.
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Taniguchi M, Uchinami M, Doi K, Yoshida M, Sasaki H, Tamagawa K, Horiuchi T, Tanaka K. Edaravone reduces ischemia-reperfusion injury mediators in rat liver. J Surg Res 2006; 137:69-74. [PMID: 17064733 DOI: 10.1016/j.jss.2006.06.033] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2005] [Revised: 06/12/2006] [Accepted: 06/27/2006] [Indexed: 11/24/2022]
Abstract
BACKGROUND In hepatic ischemia-reperfusion (I/R) injury, oxidative stress both directly injures the liver and promotes an inflammatory reaction by up-regulating various inflammatory mediators. We investigated whether edaravone, a new hydroxy radical scavenger, could reduce hepatic I/R injury including expression of inflammatory mediators such as cytokines and adhesion molecules. MATERIALS AND METHODS Male Sprague-Dawley rats were subjected to 30 min of partial hepatic pedicle clamping (70%) followed by reperfusion. Just after initiation of reperfusion and again 1 h later, edaravone was administered intraportally. After reperfusion hepatic lipid peroxidation was measured by thiobarbituric acid assay, and hepatic injury was quantified by measuring hepatic enzymes in plasma. We serially quantified hepatic expression of mRNAs for tumor necrosis factor (TNF)-alpha and E-selectin, and histologically examined E-selectin expression and neutrophil accumulation. RESULTS In the edaravone group, hepatic lipid peroxidation and hepatic enzyme leakage were significantly less than in the saline group. Hepatic expression of TNF-alpha and E-selectin mRNAs was significantly lower in the edaravone than the saline group, at 2 h after initiation of reperfusion. Histologically, E-selectin immunoreactivity and neutrophil accumulation were less evident in hepatic sections from the edaravone group. CONCLUSIONS Edaravone reduced hepatic I/R injury by minimizing oxidative stress, and inhibited subsequent injurious inflammation by reducing expression of inflammatory cytokines and adhesion molecules.
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Affiliation(s)
- Masanobu Taniguchi
- Second Department of Surgery, Faculty of Medical Sciences, University of Fukui, Shimoaizuki, Fukui, Japan.
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Takekawa S, Matsui T, Arakawa Y. The protective effect of the soybean polyphenol genistein against stress-induced gastric mucosal lesions in rats, and its hormonal mechanisms. J Nutr Sci Vitaminol (Tokyo) 2006; 52:274-80. [PMID: 17087054 DOI: 10.3177/jnsv.52.274] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
The present study investigated the effect of the soybean polyphenol genistein on the stomach using a water immersion restraint (WIR) stress model. Male Wistar rats were administered 50 or 100 mg/kg/d of genistein for 2 wk or were not given any drug. Rats were subjected to WIR stress for 4 h. At the end of the WIR period, rats were sacrificed. Subsequently, rats underwent measurement of the ratio of the mucosal hemorrhagic erosion area to the whole stomach body area, myeloperoxidase (MPO) activity, superoxide dismutase (SOD) activity, thiobarbituric acid reactive substances (TBARS) level, and proinflammatory cytokines (tumor necrosis factor (TNF)-a and cytokine-induced neutrophil chemoattractant (CINC)-1) levels in the gastric tissue. Furthermore, an isolated rat stomach infusion model was employed for the endocrinological investigation of the effect of genistein. The extracted stomach canal and the vascular system, which comprised the experimental model, were subjected to perfusion. After 20 min of perfusion, the perfusate from the portal vein was collected, and the concentrations of histamine, gastrin, and somatostatin in the perfusate were measured. Experiments demonstrated that genistein administration resulted in significant suppression of WIR stress-induced gastric mucosal injury and MPO activity, Further, genistein significantly elevated SOD activity and significantly suppressed the TBARS level, production of TNF-alpha and CINC-1, and secretion of gastrin, histamine, and somatostatin. These data suggest that genistein protected against gastric mucosal injury, likely via its ability to inhibit oxidation, inflammation, and secretion of gastrin and histamine.
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Affiliation(s)
- Sachio Takekawa
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Kamimachi, Ooyaguchi, Itabashi-ku, Tokyo 173-8610, Japan
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Jainu M, Devi CSS. Gastroprotective action of Cissus quadrangularis extract against NSAID induced gastric ulcer: Role of proinflammatory cytokines and oxidative damage. Chem Biol Interact 2006; 161:262-70. [PMID: 16797507 DOI: 10.1016/j.cbi.2006.04.011] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2005] [Revised: 03/31/2006] [Accepted: 04/07/2006] [Indexed: 11/26/2022]
Abstract
The objective of this research was to analyse the gastroprotective effect of Cissus quadrangularis extract (CQE) along with its mechanism underlying the therapeutic action against the gastric mucosal damage induced by aspirin. In this study, we investigated the effect of CQE on the course of experimentally induced gastric ulcer by analyzing the levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), microvascular permeability, activity of nitric oxide synthase-2 (NOS-2), mitochondrial antioxidants, lipid peroxidation and DNA damage. A significant increase in vascular permeability, NOS-2 activity, TNF-alpha, IL-1beta levels and oxidative damage were noted in aspirin administered rats. Pretreatment with CQE (500 mg/kg bw/day) by oral gavage for 7 days significantly attenuated these biochemical changes caused by aspirin in rats. Tissue damage was showed by decreased levels of glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) and an associated rise in lipid peroxidation (LPO) in mitochondria, which were reversed by CQE. In addition, CQE prevents oxidative damage of DNA by reducing DNA fragmentation indicating its block on cell death. Ulcer protection in CQE treated rats was confirmed by histoarchitecture, which was comprised of reduced size of ulcer crater and restoration of mucosal epithelium. Thus, reduced neutrophil infiltration, antiapoptotic and antioxidant action have a pivotal role in the gastroprotective effect of CQE.
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Affiliation(s)
- Mallika Jainu
- Department of Biochemistry, University of Madras, A.C. Tech, Guindy Campus, Chennai 600025, Tamil Nadu, India.
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Day YJ, Huang L, Ye H, Li L, Linden J, Okusa MD. Renal ischemia-reperfusion injury and adenosine 2A receptor-mediated tissue protection: the role of CD4+ T cells and IFN-gamma. THE JOURNAL OF IMMUNOLOGY 2006; 176:3108-14. [PMID: 16493070 DOI: 10.4049/jimmunol.176.5.3108] [Citation(s) in RCA: 178] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
A(2A) adenosine receptor (A(2A)R)-expressing bone marrow (BM)-derived cells contribute to the renal protective effect of A(2A) agonists in renal ischemia-reperfusion injury (IRI). We performed IRI in mice lacking T and B cells to determine whether A(2A)R expressed in CD4+ cells mediate protection from IRI. Rag-1 knockout (KO) mice were protected in comparison to wild-type (WT) mice when subjected to IRI. ATL146e, a selective A(2A) agonist, did not confer additional protection. IFN-gamma is an important early signal in IRI and is thought to contribute to reperfusion injury. Because IFN-gamma is produced by kidney cells and T cells we performed IRI in BM chimeras in which the BM of WT mice was reconstituted with BM from IFN-gamma KO mice (IFN-gamma KO-->WT chimera). We observed marked reduction in IRI in comparison to WT-->WT chimeras providing additional indirect support for the role of T cells. To confirm the role of CD4+ A(2A)R in mediating protection from IRI, Rag-1 KO mice were subjected to ischemia-reperfusion. The protection observed in Rag-1 KO mice was reversed in Rag-1 KO mice that were adoptively transferred WT CD4+ cells (WT CD4+-->Rag-1 KO) or A(2A) KO CD4+ cells (A(2A) KO CD4+-->Rag-1 KO). ATL146e reduced injury in WT CD4+-->Rag-1 KO mice but not in A(2A) KO CD4+-->Rag-1 KO mice. Rag-1 KO mice reconstituted with CD4+ cells derived from IFN-gamma KO mice (IFN-gamma CD4+-->Rag-1 KO) were protected from IRI; ATL146e conferred no additional protection. These studies demonstrate that CD4+ IFN-gamma contributes to IRI and that A(2A) agonists mediate protection from IRI through action on CD4+ cells.
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Affiliation(s)
- Yuan-Ji Day
- Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA
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Odashima M, Otaka M, Jin M, Komatsu K, Wada I, Horikawa Y, Matsuhashi T, Hatakeyama N, Oyake J, Ohba R, Watanabe S, Linden J. Attenuation of gastric mucosal inflammation induced by aspirin through activation of A 2A adenosine receptor in rats. World J Gastroenterol 2006; 12:568-73. [PMID: 16489670 PMCID: PMC4066089 DOI: 10.3748/wjg.v12.i4.568] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine whether a specific adenosine A2A receptor agonist (ATL-146e) can ameliorate aspirin-induced gastric mucosal lesions in rats, and reduce neutrophil accumulation and production of pro-inflammatory cytokines.
METHODS: Gastric lesions were produced by oral gavage of aspirin (200 mg/kg) and HCl (0.15 mol/L, 8.0 mL/kg). 4-{3-[6-Amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}-cyclohexanecarboxylic acid methyl ester (ATL-146e, 2.5-5 μg/kg, IP) was injected 30 min before the administration of aspirin. Tissue myeloperoxidase (MPO) concentration in gastric mucosa was measured as an index of neutrophil infiltration. Gastric mucosal concentrations of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were determined by ELISA. Also, we examined the effect of ATL-146e on tissue prostaglandin E2 (PGE2) production and gastric secretion.
RESULTS: Intragastric administration of aspirin induced multiple hemorrhagic erosions in rat gastric mucosa. The total length of gastric erosions (ulcer index) in control rats was 29.8±7.75 mm and was reduced to 3.8±1.42 mm after pretreatment with 5.0 g/kg ATL-146e (P< 0.01). The gastric contents of MPO and pro-inflammatory cytokines were all increased after the administration of aspirin and reduced to nearly normal levels by ATL-146e. Gastric mucosal PGE2 concentration was not affected by intraperitoneal injection of ATL-146e.
CONCLUSION: The specific adenosine A2A receptor agonist, ATL-146e, has potent anti-ulcer effects presumably mediated by its anti-inflammatory properties.
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Affiliation(s)
- Masaru Odashima
- Department of Gastroenterology, Akita University School of Medicine, 1-1-1 Hondo, Akita City 010-8543, Japan.
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Ohba R, Otaka M, Odashima M, Jin M, Komatsu K, Konishi N, Wada I, Horikawa Y, Matsuhashi T, Oyake J, Hatakeyama N, Watanabe S. Effect of cilostazol, a selective type-III phosphodiesterase inhibitor, on water-immersion stress-induced gastric mucosal injury in rats. J Gastroenterol 2006; 41:34-40. [PMID: 16501855 DOI: 10.1007/s00535-005-1686-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2005] [Accepted: 06/23/2005] [Indexed: 02/04/2023]
Abstract
BACKGROUND Cilostazol, a specific type-III phosphodiesterase inhibitor, is widely used for the treatment of ischemic symptoms of peripheral vascular disease. Recent studies have reported that the mechanism of cilostazol is related to the suppression of pro-inflammatory cytokine production and improvement of local microcirculation disturbances. The pathogenesis of stress-induced gastric mucosal lesions is characterized by the activation of inflammatory cells and the production of inflammatory cytokines. The effects of cilostazol on the development of gastric mucosal lesions have not been reported. In the present study, we examined the effect of a cilostazol on water-immersion stress-induced gastric mucosal lesions. METHODS Rats were subjected to water-immersion stress with or without pretreatment with a single intraperitoneal injection of the selective type-III phosphodiesterase inhibitor, cilostazol. We measured the gastric mucosal lesion and the concentrations of myeloperoxidase (MPO), interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and cytokine-induced neutrophil chemoattractant-1 (GRO/CINC-1), as an index of neutrophil accumulation and pro-inflammatory cytokine production. RESULTS Cilostazol ameliorated the gastric mucosal injury induced by water-immersion stress (P<0.001). The gastric contents of MPO, TNF-alpha, IL-1beta, and CRO/CINC-1 were all increased after water-immersion stress and were reduced to almost normal levels by cilostazol. CONCLUSIONS In this study, we demonstrated that a selective type-III phosphodiesterase inhibitor, cilostazol, inhibited stress-induced gastric inflammation and damage via suppressing the production of pro-inflammatory cytokines. Cilostazol may be useful for preventing gastric mucosal lesions.
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Affiliation(s)
- Reina Ohba
- Department of Internal Medicine, Akita University School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan
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Shimamura K, Kawamura H, Nagura T, Kato T, Naito T, Kameyama H, Hatakeyama K, Abo T. Association of NKT cells and granulocytes with liver injury after reperfusion of the portal vein. Cell Immunol 2005; 234:31-8. [PMID: 15963482 DOI: 10.1016/j.cellimm.2005.04.022] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2005] [Revised: 04/21/2005] [Accepted: 04/22/2005] [Indexed: 12/23/2022]
Abstract
Reperfusion of the liver was conducted by clamping the portal vein for 30 min in mice, followed by unclamping. Unique variation in the number of lymphocytes was induced and liver injury occurred thereafter. The major expander cells in the liver were estimated to be natural killer T cells (i.e., NKT cells), whereas conventional T cells and NK cells increased only slightly or somewhat decreased in number and proportion at that time. Reflecting the expansion of NKT cells in the liver, a Th0-type of cytokine profile was detected in sera, and cytotoxic activity was enhanced in liver lymphocytes. In NKT cell-deficient mice including CD1d (-/-) mice and athymic nude mice, the magnitude of liver injury decreased up to 50% of that of control mice. It was also suspected that accumulating granulocytes which produce superoxides might be associated with liver injury after reperfusion. This might be due to stress-associated production of catecholamines. It is known that granulocytes bear surface adrenergic receptors and that they are activated by sympathetic nerve stimulation after stress. The present results therefore suggest that liver injury after reperfusion may be mainly caused by the activation of NKT cells and granulocytes, possibly by their cytotoxicity and superoxide production, respectively.
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Affiliation(s)
- Kazuhiko Shimamura
- Department of Immunology, Niigata University School of Medicine, Niigata 951-8510, Japan
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Higashihara H, Kokura S, Imamoto E, Ueda M, Naito Y, Yoshida N, Yoshikawa T. Hypoxia-reoxygenation enhances interleukin-8 production from U937 human monocytic cells. Redox Rep 2005; 9:365-9. [PMID: 15720834 DOI: 10.1179/135100004225006894] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
Abstract
Hypoxia--reoxygenation (H/R) occurs in both inflammatory spots and tumor tissues, sites in which damage is amplified either acutely or chronically through the infiltration of inflammatory cells. Interleukin-8 (IL-8) is a cytokine with chemotactic and angiogenic properties. This study was designed to investigate the effects of H/R on IL-8 production in the U937 human monocytic cell line. Two hours of hypoxia followed by 4 h of reoxygenation induced a significant increase in IL-8 protein production and IL-8 mRNA expression in U937 cells. Pretreatment with proteasome inhibitor (PSI), a peptide aldehyde known to inhibit the chymotrypsin-like activity of the 26S proteasome specifically, suppressed IL-8 protein production and IL-8 mRNA expression induced by H/R. The production of IL-8 protein induced by H/R was decreased by pioglitazone and 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)), which have been identified as peroxisome proliferator-activated receptorgamma (PPAR-gamma) ligands. Moreover, transfection of U937 cells with a dominant negative IkappaBalphaexpression vector (IkappaBalphaM) decreased IL-8 protein production induced by H/R. These results suggest that NF-kappaB and PPAR-gamma regulate H/R-stimulated IL-8 production in U937 cells.
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Affiliation(s)
- Hiroshi Higashihara
- Departments of Inflammation and Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
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Odashima M, Otaka M, Jin M, Komatsu K, Konishi N, Wada I, Horikawa Y, Matsuhashi T, Ohba R, Oyake J, Hatakeyama N, Watanabe S. Rolipram, a specific type IV phosphodiesterase inhibitor, ameliorates aspirin-induced gastric mucosal injury in rats. Dig Dis Sci 2005; 50:1097-102. [PMID: 15986861 DOI: 10.1007/s10620-005-2711-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Inhibition of type IV phosphodiesterase (PDE IV) activity reduces the production of various proinflammatory cytokine and suppresses neutrophil activation. Nonsteroidal anti-inflammatory drugs such as aspirin induce gastric mucosal lesions. In the pathogenesis of aspirin-induced gastric mucosal lesion, the contributions, of activated inflammatory cells and proinflammatory cytokine production are critical. The specific PDE IV inhibitor rolipram is known to be a potent inhibitor of inflammation by increasing intracellular cyclic AMP in leukocytes. The aim of the present study was to determine whether rolipram can ameliorate aspirin-induced gastric mucosal lesions in rats and whether the agent can inhibit the inrease in neutrophil accumulation and the production of proinflammatory cytokines. Gastric lesions were produced by administration of aspirin (200 mg/kg) and HCI (0.15 N; 8.0 ml/kg). Rolipram was injected 30 min before aspirin administration. The tissue myeloperoxidase concentration in gastric mucosa was measured as an indicat or of neutrophil infiltration. The gastric mucosal concentrations of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) were determined by ELISA. The intragastric administration of aspirin induced multiple hemorrhagic erosions in rat gastric mucosa. Gastric mucosal lesions induced by aspirin were significantly inhibited by treatment with rolipram. The mucosal myeloperoxidase concentration was also suppressed by rolipram. Increases in the gastric content of TNF-alpha and IL-1beta after aspirin administration were inhibited by pretreatment with rolipram. We demonstrated that the specific type IV PDE inhibitor, rolipram, could have a potent antiulcer effect, presumably mediated by its anti-inflammatory properties.
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Affiliation(s)
- Masaru Odashima
- Department of Gastroenterology, Akita University School of Medicine, 1-1-1 Hondo, Akita City, Akita, Japan 010-8543
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Katada K, Naito Y, Shimozawa M, Mizushima K, Kuroda M, Takagi T, Kokura S, Ichikawa H, Yoshida N, Matsui H, Yoshikawa T. Gene expression analysis following hypoxia-reoxygenation in rat gastric epithelial cells using a high-density oligonucleotide array. Redox Rep 2005; 9:337-42. [PMID: 15720829 DOI: 10.1179/135100004225006849] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
Abstract
Recent investigations have demonstrated that the signaling of hypoxia-re-oxygenation is a major contributing pathway leading to gastric mucosal injury induced by stress, non-steroidal anti-inflammatory drugs, and Helicobacter pylori. The aim of the present study was to perform a gene expression analysis on the gastric mucosal cellular response to hypoxia-reoxygenation using a high-density oligonucleotide array. Cells were subjected to hypoxia with 95% N(2) and 5% CO(2) at 37 degrees C for 2 h. Reoxygenation was initiated by placing the cells in an environment of normoxia for 2 h. Total RNA was extracted, and differences in gene expression profiles between the normoxia and hypoxia-reoxygenation groups were investigated using a GeneChip of Rat Toxicology U34 array (Affymetrix). Hypoxia-reoxygenation up-regulated the stress-related genes (heat shock protein-70 [HSP-70], catalase). The enhanced expression of HSP-70 was confirmed by Western blot analysis. In conclusion, these results suggest that up-regulation of the HSP-70 gene after reoxygenation may play a role in maintaining cell survival and supporting cell function as a molecular chaperone.
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Affiliation(s)
- Kazuhiro Katada
- Department of Inflammation and Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
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Odashima M, Otaka M, Jin M, Komatsu K, Wada I, Matsuhashi T, Horikawa Y, Hatakeyama N, Oyake J, Ohba R, Linden J, Watanabe S. Selective adenosine A receptor agonist, ATL-146e, attenuates stress-induced gastric lesions in rats. J Gastroenterol Hepatol 2005; 20:275-80. [PMID: 15683432 DOI: 10.1111/j.1440-1746.2004.03555.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
BACKGROUND Activation of adenosine A(2A) receptors reduces the production of various pro-inflammatory cytokines and suppresses neutrophil activation. Water-immersion restraint is well known to cause gastric mucosal lesions due to stress. The pathogenesis of stress-induced gastric mucosal lesions is characterized by activation of inflammatory cells and production of inflammatory cytokines. Agonists of adenosine A(2A) receptors are known to be anti-inflammatory, but the effects of these compounds on the development of gastric mucosal lesions has not been reported. In the present study, the effect of a potent and selective adenosine A(2A) receptor agonist, ATL-146e, on water-immersion stress-induced gastric mucosal lesions was studied. METHODS Rats were subjected to water-immersion stress with or without pretreatment with a single intraperitoneal injection of a potent and selective agonist of the adenosine A(2A) receptor. The gastric concentrations of myeloperoxidase (MPO), as an index of neutrophil accumulation, and the pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta), were measured. RESULTS The total length of gastric erosions (ulcer index) in control rats was 21.6 +/- 3.23 mm and was reduced by 86% to 3.1 +/- 0.83 mm by pretreatment with 5.0 microg/kg ATL146e (P < 0.001). The gastric content of MPO, TNF-alpha and IL-1beta were all increased after water-immersion stress and reduced to near normal levels by ATL-146e. CONCLUSION A specific adenosine A(2A) agonist inhibits stress-induced gastric inflammation and damage. A(2A) agonist compounds may be useful for preventing ulcers and appear to act by blocking gastric inflammation.
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Affiliation(s)
- Masaru Odashima
- Department of Internal Medicine, Akita University of Medicine, 1-1-1 Hondo, Akita City, Akita 010-8543, Japan
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Day YJ, Huang L, Ye H, Linden J, Okusa MD. Renal ischemia-reperfusion injury and adenosine 2A receptor-mediated tissue protection: role of macrophages. Am J Physiol Renal Physiol 2004; 288:F722-31. [PMID: 15561971 DOI: 10.1152/ajprenal.00378.2004] [Citation(s) in RCA: 207] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The role of monocytes/macrophages in the pathogenesis of ischemia-reperfusion injury (IRI) is unknown. We sought to determine whether activation of macrophage adenosine 2A (A(2A)) receptors (A(2A)Rs) mediates tissue protection. We subjected C57Bl/6 mice infused with clodronate [dichloromethylene bisphosphonate (Cl(2)MBP)] to IRI (32 min of ischemia followed by 24 h of reperfusion) to deplete them of macrophages. IRI induced an elevation of plasma creatinine that was reduced with Cl(2)MBP (26% of control). Adoptive transfer of murine RAW 264.7 cells reconstituted injury, an effect blocked significantly by A(2A) agonists (27% of plasma creatinine from mice reconstituted with macrophages). Macrophages subjected to A(2A) knockout by small interfering RNA were adoptively transferred to macrophage-depleted mice and reconstituted injury (110% of control mice); however, the increase in plasma creatinine was blocked by A(2A) agonists (20% of vehicle treatment). Finally, the A(2A) agonist effect on IRI was blocked in macrophage-depleted A(2A)-knockout mice reconstituted with wild-type RAW 264.7 cells. RNase protection assays 24 h after IRI demonstrated that macrophages are required for IL-6 and TGF-beta mRNA induction. However, A(2A) agonist-mediated tissue protection is independent of IL-6 and TGF-beta mRNA. We conclude that the full extent of IRI requires macrophages and that A(2A) agonist-mediated tissue protection is independent of activation of macrophage A(2A)Rs.
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Affiliation(s)
- Yuan-Ji Day
- Div. of Nephrology, Box 133, Univ. of Virginia Health System, Charlottesville, VA 22908, USA
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Affiliation(s)
- A M Padilla
- Servicio de Farmacia. Hospital General de Castellón. Castellón. Spain
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de Perrot M, Young K, Imai Y, Liu M, Waddell TK, Fischer S, Zhang L, Keshavjee S. Recipient T cells mediate reperfusion injury after lung transplantation in the rat. THE JOURNAL OF IMMUNOLOGY 2004; 171:4995-5002. [PMID: 14607895 DOI: 10.4049/jimmunol.171.10.4995] [Citation(s) in RCA: 76] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Leukocytes have been implicated in ischemia-reperfusion (IR) injury of the lung, but the individual role of T cells has not been explored. Recent evidence in mice suggests that T cells may play a role in IR injury. Using a syngeneic (Lewis to Lewis) rat lung transplant model, we observed that recipient CD4(+) T cells infiltrated lung grafts within 1 h of reperfusion and up-regulated the expression of CD25 over the ensuing 12 h. Nude rats (rnu/rnu) and heterozygous rats (rnu/+) were used to determine the role of T cells in IR injury. No significant difference in lung function was observed between nude and heterozygous recipient rats after 2 h of reperfusion. However, after 12 h of reperfusion, recipient nude rats had significantly higher oxygenation and lower peak airway pressure than recipient heterozygous rats. This was associated with significantly lower levels of IFN-gamma in transplanted lung tissue of recipient nude rats. Reconstitution of recipient nude rats with T cells from heterozygous rats restored IR injury after 12 h of reperfusion. The effect of T cells was independent of neutrophil recruitment and activation in the transplanted lung. These results demonstrate that recipient T cells are activated and mediate IR injury during lung transplantation in rats.
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Affiliation(s)
- Marc de Perrot
- Thoracic Surgery Research Laboratory and Department of Laboratory Medicine, Toronto General Hospital Research Institute, University of Toronto, Toronto, Canada
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Naito Y, Takagi T, Uchiyama K, Handa O, Tomatsuri N, Imamoto E, Kokura S, Ichikawa H, Yoshida N, Yoshikawa T. Suppression of intestinal ischemia-reperfusion injury by a specific peroxisome proliferator-activated receptor-gamma ligand, pioglitazone, in rats. Redox Rep 2003; 7:294-9. [PMID: 12688513 DOI: 10.1179/135100002125000983] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Neutrophil activation and tumor necrosis factor-alpha (TNF-alpha) induction play a critical role in ischemia-reperfusion-induced intestinal inflammation. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a member of the nuclear hormone receptor superfamily, has recently been implicated as a regulator of inflammatory responses. The aim of the present study was to determine whether pioglitazone, a specific PPAR-gamma ligand, can ameliorate reperfusion-induced intestinal injury in rats, and whether the agent can inhibit the increase in neutrophil accumulation associated with TNF-alpha expression. Intestinal damage was induced in male Sprague-Dawley rats by clamping the superior mesenteric artery for 30 min followed by reperfusion. Reperfusion after 30 min ischemia resulted in an increase in luminal protein concentrations with levels reaching a maximum after 60 min of reperfusion. In contrast, pretreatment with pioglitazone 2 h before ischemia inhibited the increase in luminal protein concentrations after 60 min reperfusion in a dose-dependent manner (1-30 mg/kg). The increase in tissue-associated myeloperoxidase activity, an index of neutrophil infiltration, after reperfusion was significantly inhibited by pretreatment with pioglitazone. Pioglitazone also inhibited increases in intestinal TNF-alpha protein and mRNA expression determined by ELISA and RT-PCR, respectively. In conclusion, activation of PPAR-gamma may represent a novel approach to the treatment of intestinal inflammation induced by ischemia-reperfusion.
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Affiliation(s)
- Yuji Naito
- First Department of Medicine, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kyoto, Japan.
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Paysant JR, Rupin A, Verbeuren TJ. Effect of NADPH oxidase inhibition on E-selectin expression induced by concomitant anoxia/reoxygenation and TNF-alpha. ENDOTHELIUM : JOURNAL OF ENDOTHELIAL CELL RESEARCH 2003; 9:263-71. [PMID: 12572857 DOI: 10.1080/10623320214737] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
The aim of this study was to quantify the expression of E-selectin, intercellular cell adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in human umbilical vascular endothelial cells (HUVECs) exposed to anoxia/reoxygenation (A/R) in the presence or absence of an inflammatory context (0.1 IU/ml tumor necrosis factor-alpha [TNF-alpha]) and to investigate the effects of two different NADPH inhibitors, apocynin and diphenyleneiodonium (DPI), on the expression of the endothelial cell adhesion molecules. Confluent HUVECs were exposed to anoxia for 3 hours (100% N2), followed by a reoxygenation period of 4 hours. TNF-alpha at 0.1 IU/ml was added to the medium either under normoxic conditions for 7 hours (TNF-alpha) or just before the start of anoxia (A/R + TNF-alpha). Levels of E-selectin, VCAM-1, and ICAM-1 were quantified using specific monoclonal antibodies revealed by an alkaline phosphatase-labeled goat F(ab)'2 fragment against mouse IgG antibody and the fluorescent substrate Attophos. Adhesion experiments were also performed using calcein-labeled U937 leukocytes. HUVECs submitted to A/R overexpressed E-selectin but not VCAM-1 or ICAM-1, whereas TNF-alpha at 0.1 IU/ ml increased the expression of all three adhesion molecules. In endothelial cells subjected to A/R in the presence of TNF-alpha, a synergistic increase of E-selectin expression and a synergistic adhesion of U937 cells was noted. The NADPH oxidase inhibitors apocynin and DPI both decreased significantly the U937 adhesion and the E-selectin overexpression on HUVECs submitted to A/R, TNF-alpha, or A/R + TNF-alpha. These results suggest that E-selectin expression is implicated in the leukocyte adhesion to HUVECs caused by A/R in the presence or absence of an inflammatory context. NADPH oxidase appears to participate in the E-selectin overexpression on HUVECs subjected either to A/R and/or TNF-alpha, suggesting a major role of this enzyme in the ischemia/reperfusion syndrome.
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Affiliation(s)
- Jérôme R Paysant
- Division of Angiology, Servier Research Institute, Suresnes, France
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Dyugovskaya L, Lavie P, Lavie L. Phenotypic and functional characterization of blood gammadelta T cells in sleep apnea. Am J Respir Crit Care Med 2003; 168:242-9. [PMID: 12724124 DOI: 10.1164/rccm.200210-1226oc] [Citation(s) in RCA: 111] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Hypoxia-induced lymphocyte dysfunction may be implicated in endothelial cell damage in obstructive sleep apnea (OSA) syndrome. gammadelta T cells' unique migration, cytotoxic features, and accumulation in atherosclerotic plaques are considered critical in cardiovascular disorders. We characterized the phenotype, cytokine profile, adhesion properties, and cytotoxicity of gammadelta T cells in patients with OSA and control subjects. The following is a summary of our major findings regarding OSA gammadelta T cells: (1) a significant increase in the expression of the inhibitory natural killer B1 receptors was found; (2) the intracellular content of proinflammatory cytokines tumor necrosis factor (TNF)-alpha and interleukin-8 was increased, and the content of the antiinflammatory cytokine interleukin-10 was decreased; (3) gammadelta T cells of patients with OSA adhered significantly more avidly to nonactivated endothelial cells in culture than those of control subjects; (4) L-selectin expression was higher; (5) anti-E/P-selectin antibodies and anti-TNF-alpha antibodies decreased the adhesion index of OSA gammadelta T lymphocytes/endothelial cells but not of control subjects; and (6) cytotoxicity of OSA gammadelta T lymphocytes against endothelial cells in culture was 2.5-fold higher than that of control subjects and could be prevented by pretreatment with anti-TNF-alpha. Collectively these data implicate gammadelta T lymphocyte function in atherogenic sequelae in OSA.
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Affiliation(s)
- Larissa Dyugovskaya
- Unit of Anatomy and Cell Biology, The Bruce Rappaport Faculty of Medicine, Technion, POB 9649, 31096 Haifa, Israel
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Nakamura C, Otaka M, Odashima M, Jin M, Konishi N, Horikawa Y, Matsuhashi T, Watanabe S. Rolipram, a specific type IV phosphodiesterase inhibitor, ameliorates indomethacin-induced gastric mucosal injury in rats. ACTA ACUST UNITED AC 2003; 9:195-200. [PMID: 14567935 DOI: 10.1016/s0928-4680(03)00005-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Inhibition of type IV phosphodiesterase activity is beneficial in various inflammation mediated by its function to suppress the production of inflammatory cytokines in inflammatory cells. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin are well known to develop gastric mucosal lesion. As pathogenesis of indomethacin induced gastric mucosal lesion, activation of neutrophils and inflammatory cytokine production play critical roles. However, the effect of phosphodiesterase inhibitors on development of gastric mucosal lesion has not been reported. In the present study, we examined the effect of specific type IV phosphodiesterase inhibitor (rolipram) on NSAIDs-induced gastric mucosal lesion. Also, we examined the effect of rolipram on tissue prostaglandin E2 (PGE2) production. Indomethacin-induced gastric mucosal injury was produced by the intragastric administration of indomethacin (30 mg/kg). Rolipram was injected to the rats intraperitoneally 30 min before the indomethacin administration. Ulcer index and tissue myeloperoxidase (MPO) activity of the gastric mucosa was evaluated. The gastric concentration of PGE2 was determined by RIA. Gastric mucosal lesion induced by indomethacin was significantly inhibited with treatment of rolipram. Mucosal MPO activity was also suppressed by administration of rolipram. Gastric mucosal PGE2 concentration was not affected by intraperitoneal injection of rolipram. Based on these data, the beneficial effects of rolipram on indomethacin-induced gastric mucosal injury may be attributed to its anti-inflammatory properties.
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Affiliation(s)
- Chieko Nakamura
- First Department of Medicine, Akita University School of Medicine, 1-1-1 Hondo, Akita 010-8543, Akita city, Japan
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Kaminski KA, Bonda TA, Korecki J, Musial WJ. Oxidative stress and neutrophil activation—the two keystones of ischemia/reperfusion injury. Int J Cardiol 2002; 86:41-59. [PMID: 12243849 DOI: 10.1016/s0167-5273(02)00189-4] [Citation(s) in RCA: 229] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
The widespread introduction of fibrinolytics and recently also PTCA in the treatment of myocardial infarction has changed the picture of modern cardiology. But this therapy also raises new problems and challenges. One of them is the occurrence of extensive tissue injury caused by reperfusion. Reinstitution of oxygen to the ischemic tissues initiates various processes leading to generation of reactive oxygen species (ROSs). Acting on the plasma membrane ROS damage its organization and release various proinflammatory agents. Different proteins, including receptors, ionic channels, transporters or components of transduction pathways are substrates of oxidation by ROSs. Their changed structure results in altered functioning and disruption of vital cellular processes. Another key factor of reperfusion injury is activation and infiltration of infarcted area by polymorphonuclear leukocytes (PMNs). Multiple studies identified consecutive stages of PMN activation and substances being involved in it. Main interest lies in cellular adhesion molecules, particularly selectins and beta2 integrins, as their antagonists were repeatedly found to diminish neutrophil activation and infarct size. Nevertheless new publications strike at the foundations of the established order and confront the relation between neutrophil infiltration and infarct size. PMNs are linked by close ties to other cells involved in inflammatory response. Seemingly also in cardiac ischemia-reperfusion injury, the activity of neutrophils is modulated by lymphocytes and macrophages. The article describes mutual interactions between different factors involved in the reperfusion injury that may enable preparing new treatments, hopefully as effective and successful as reperfusion therapy.
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Affiliation(s)
- Karol A Kaminski
- Department of Cardiology, Medical Academy of Bialystok, ul. M. Sklodowskiej-Curie 24a, Bialystok, Poland
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Glosli H, Tronstad KJ, Wergedal H, Müller F, Svardal A, Aukrust P, Berge RK, Prydz H. Human TNF-alpha in transgenic mice induces differential changes in redox status and glutathione-regulating enzymes. FASEB J 2002; 16:1450-2. [PMID: 12205044 DOI: 10.1096/fj.01-0948fje] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Tumor necrosis factor a (TNF-alpha) is a pleiotropic cytokine involved in several diseases. Various effects of TNF-alpha are mediated by the induction of a cellular state consistent with oxidative stress. Glutathione (GSH) is a major redox-buffer of eukaryotic cells and is important in the defense against oxidative stress. We hypothesized that persistent TNF-alpha secretion could induce oxidative stress through modulation of GSH metabolism. This hypothesis was examined in a transgenic mouse model with low, persistent expression of human TNF-alpha in the T cell compartment. Major findings were i) marked tissue-specific changes in GSH redox status and GSH regulating enzymes, with the most pronounced changes in liver; ii) moderate changes in GSH metabolism and up-regulation of GSH-regulating enzymes were observed in lung and kidney from transgenic mice; and iii) liver, lung and kidney from transgenic mice had decreased levels of total glutathione, whereas splenic CD4+ and CD8+ T cells had a marked increase in oxidized glutathione as the major change. Oxidative stress induced by persistent low-grade exposure to TNF-alpha in transgenic mice appears to involve marked organ-specific alterations in glutathione redox status and glutathione-regulating enzymes with the most pronounced changes in the liver. These mice constitute a useful model for immunodeficiency syndromes and chronic inflammatory diseases involving pathogenic interaction between TNF-alpha and oxidative stress.
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Affiliation(s)
- Heidi Glosli
- Biotechnology Centre of Oslo, University of Oslo, PB 1125 Blindern, 0317 Oslo, Norway
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Naito Y, Handa O, Takagi T, Ishikawa T, Imamoto E, Nakagawa S, Yamaguchi T, Yoshida N, Matsui H, Yoshikawa T. Ubiquitin-proteasome inhibitor enhances tumour necrosis factor-alpha-induced apoptosis in rat gastric epithelial cells. Aliment Pharmacol Ther 2002; 16 Suppl 2:59-66. [PMID: 11966525 DOI: 10.1046/j.1365-2036.16.s2.30.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/08/2022]
Abstract
BACKGROUND Tumour necrosis factor (TNF-alpha) is a candidate factor for involvement in inflammation-mediated gastric mucosal injury. However, the effect of this cytokine on gastric epithelial cells has been poorly investigated. In the present study, we examined whether gastric epithelial cells are resistant to TNF-alpha-induced apoptosis, and whether this resistance is related to ubiquitin-proteasome-associated nuclear factor-kappaB (NF-kappaB) activation. METHODS The rat gastric mucosal cell line RGM-1 was grown in DMEM/F12 medium supplemented with 10% FCS. Confluent monolayers of cells were pretreated or not for 60 min with PSI, a peptide aldehyde known to specifically inhibit the chymotrypsin-like activity of 26S proteasome. Cells were subsequently stimulated with recombinant rat TNF-alpha and their viability was determined by WST-1 assay. Apoptosis was confirmed by fluorescence microscopy after staining with Hoechst 33342 and propidium iodide, and DNA fragmentation was determined by flow cytometry using an APO-BRDU kit. IkappaB-alpha and the p65 binding subunit of NF-kappaB were detected by Western blots. RESULTS Twenty-four-hour incubation with TNF-alpha alone or PSI alone did not affect the cell viability of RGM-1 cells. Pretreatment with PSI significantly enhanced the level of apoptosis induced by TNF-alpha. In RGM-1 cells treated with TNF-alpha, cytoplasmic IkappaB-alpha decreased and p65 in nuclear extracts increased markedly 30 min after cytokine stimulation. Pretreatment with PSI at 12.5 micromol/L blocked these TNF-alpha-induced changes. CONCLUSION PSI enhances TNF-alpha-induced apoptosis through inhibition of NF-kappaB activation in RGM-1 cells.
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Affiliation(s)
- Y Naito
- First Department of Medicine, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Japan.
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Abstract
While reperfusion therapy in myocardial infarction is associated with better short- and long-term outcomes, it paradoxically results in reperfusion injury mediated by interactions between leukocytes, endothelial cells, platelets, and the myocardium. Several surface receptors, adhesion molecules, and ligands have been shown to be important in the pathogenesis of myocardial reperfusion injury, and therapeutic strategies employing the use of monoclonal antibodies have been attempted against many of them. These have included monoclonal antibodies against activated complement 5 (C5a) to inhibit leukotaxis, monoclonal antibodies against P-selectin, P-selectin glycoprotein ligand (PSGL)-1, L-selectin and E-selectin to inhibit leukocyte rolling, and monoclonal antibodies against the Mac-1 (CD11b/CD18) receptor and intercellular adhesion molecule (ICAM)-1 to block firm adhesion of leukocytes to endothelial cells. In addition, although initially developed as an antiplatelet agent, the glycoprotein IIb/IIIa receptor antagonist abciximab shows significant ability to diminish or prevent reperfusion injury, presumably through its ability to block the Mac-1 receptor on leukocytes. Finally, monoclonal antibodies have also been tested against several cytokines and adhesion molecules implicated in so-called subacute endothelial activation, including interleukin-8 and vascular cell adhesion molecule (VCAM)-1. Studies in animals evaluating the use of monoclonal antibodies in reperfusion injury against various potential targets have largely been successful; however, studies in humans have been disappointing, underscoring the pitfalls of using animal models for the study of complex diseases. Based upon current knowledge, it is becoming clear that a successful strategy against reperfusion injury will require targeting several pathways at once, rather than attempting to block one final common pathway. In addition, inhibition of subacute endothelial activation through inhibition of transcription factors, namely nuclear factor (NF)-kappa B, may be a prerequisite to significantly reducing the extent of myocardial damage in this condition. The future of monoclonal antibodies in the overall strategy remains unclear. Newer small molecule inhibitors are also under development, and the eventual role of gene therapy remains to be elucidated.
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Affiliation(s)
- Anil Nigam
- Mayo Alliance for Clinical Trials, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55902, USA
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47
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de Perrot M, Fischer S, Liu M, Jin R, Bai XH, Waddell TK, Keshavjee S. Prostaglandin E1 protects lung transplants from ischemia-reperfusion injury: a shift from pro- to anti-inflammatory cytokines. Transplantation 2001; 72:1505-12. [PMID: 11707737 DOI: 10.1097/00007890-200111150-00006] [Citation(s) in RCA: 68] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
INTRODUCTION Prostaglandin E1 (PGE1) has been demonstrated to reduce ischemia-reperfusion (IR) injury following lung transplantation. However, the cytoprotective mechanisms remain largely unknown. The purpose of this study was to determine whether the mechanism through which PGE1 improves IR injury is related to the level of apoptosis or the release of inflammatory cytokines. METHODS In a rat single-lung-transplant model, animals were randomly allocated into four groups of five animals each. Group 1 received normal saline (NS) in the preservation solution and during the 2-hr reperfusion period. Group 2 received NS in the preservation solution and PGE1 during the reperfusion period. Group 3 received PGE1 in the preservation solution and NS during the reperfusion period. Group 4 received PGE1 in the preservation solution and during the reperfusion period. RESULTS The two groups that received PGE1 during the reperfusion period had a significantly higher partial pressure of oxygen (PaO2), lower wet-dry weight ratio, and lower peak airway pressure at the end of the reperfusion period than did the two groups that received NS. In the two groups that received PGE1 during the reperfusion period, we observed significantly higher levels of interleukin (IL)-10 in the transplanted lung tissue and plasma and significantly lower levels of tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, and IL-12 in lung tissue. The levels of IL-4 and macrophage inflammatory protein-2 (MIP-2) were not significantly different between groups. The number of apoptotic cells and the expression of Bcl-2 were not significantly different between groups. CONCLUSIONS PGE1 does not decrease the amount of apoptosis after reperfusion and does not significantly upregulate Bcl-2. We have demonstrated that PGE1 administered during the reperfusion period reduces IR injury and improves lung function through a mechanism that is likely mediated by a shift between pro- and anti-inflammatory cytokine release.
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Affiliation(s)
- M de Perrot
- Thoracic Surgery Research Laboratory, Toronto General Hospital Research Institute, University Health Network, Canada
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Kaur J, Woodman RC, Ostrovsky L, Kubes P. Selective recruitment of neutrophils and lymphocytes by thrombin: a role for NF-kappaB. Am J Physiol Heart Circ Physiol 2001; 281:H784-95. [PMID: 11454583 DOI: 10.1152/ajpheart.2001.281.2.h784] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
With the use of a whole blood laminar flow chamber system, we examined the types of leukocytes, adhesion molecules and the role of nuclear factor-kappaB (NF-kappaB) in thrombin-induced leukocyte recruitment. Primary human umbilical vein endothelial cells (HUVEC) stimulated with thrombin induced a significant increase in P-selectin-dependent neutrophil recruitment. Unexpectedly, brief thrombin stimulation (3 min) of endothelium also induced a significant lymphocyte recruitment 4 h later in addition to neutrophil recruitment. E-selectin antibody reduced neutrophil recruitment by >90%, whereas vascular adhesion molecule-1 (VCAM-1)/alpha4-integrin were primarily responsible for lymphocyte recruitment. To examine whether NF-kappaB contributed to leukocyte recruitment 4 h post thrombin stimulation, we treated HUVEC with the NF-kappaB inhibitor MG-132 for 1 h before thrombin stimulation. MG-132 significantly reduced the number of rolling (77.1%) and adherent (79.9%) leukocytes compared with thrombin stimulation alone. The inhibitor was more effective at preventing lymphocyte than neutrophil recruitment, consistent with its greater effect on VCAM-1 versus E-selectin expression. Tumor necrosis factor-alpha- and MG-132-treated HUVEC displayed no inhibition of leukocyte recruitment despite a decrease in NF-kappaB activation. In summary, thrombin causes predominant neutrophil recruitment via rapid P-selectin expression but also a delayed E-selectin- and VCAM-1-dependent neutrophil and lymphocyte recruitment via de novo protein synthesis. Although NF-kappaB mobilization was essential for thrombin-mediated VCAM-1-dependent recruitment, it only partially contributed to E-selectin-dependent recruitment.
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Affiliation(s)
- J Kaur
- Immunology Research Group and Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada T2N 4N1
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Naito Y, Takagi T, Matsuyama K, Yoshida N, Yoshikawa T. Pioglitazone, a specific PPAR-gamma ligand, inhibits aspirin-induced gastric mucosal injury in rats. Aliment Pharmacol Ther 2001; 15:865-73. [PMID: 11380325 DOI: 10.1046/j.1365-2036.2001.00983.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
BACKGROUND Neutrophils activation and tumour necrosis factor-alpha (TNF-alpha) induction play a critical role in aspirin-induced gastric mucosal injury. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a member of the nuclear hormone receptor superfamily, has recently been implicated as a regulator of inflammatory responses. The aim of the present study was to determine whether pioglitazone, a specific PPAR-gamma ligand, can ameliorate aspirin-induced gastric mucosal injury in rats, and whether the agent can inhibit the increase in neutrophil accumulation associated with TNF-alpha expression. METHODS Aspirin-induced injury was produced by the intragastric administration of aspirin (200 mg/kg) and HCl (0.15 N, 8.0 mL/kg). Pioglitazone was given to the rats by gastric intubation 1 h before the aspirin administration. Thiobarbituric acid-reactive substances and tissue-associated myeloperoxidase activity were measured in gastric mucosa as indices of lipid peroxidation and neutrophil infiltration. The gastric concentration of TNF-alpha and the expression of TNF-alpha mRNA was determined by ELISA and reverse transcriptase-polymerase chain reaction. RESULTS The intragastric administration of acidified aspirin induced hyperemia and haemorrhagic erosions in rat stomachs. The increase in the total gastric erosive area after aspirin administration was significantly inhibited by treatment with pioglitazone in a dose-dependent manner. The increases in thiobarbituric acid-reactive substances and myeloperoxidase activity after aspirin administration were both significantly inhibited by pre-treatment with pioglitazone (10 mg/kg). The gastric content of TNF-alpha increased and the expression of TNF-alpha mRNA was up-regulated after aspirin treatment. However, the peak TNF-alpha mRNA expression 1 h after aspirin administration was inhibited by pioglitazone. CONCLUSION Based on these data, the beneficial effects of pioglitazone on aspirin-induced gastric mucosal injury may be attributed to its anti-inflammatory properties.
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Affiliation(s)
- Y Naito
- First Department of Medicine, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan.
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