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1
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Ban F, Zhou L, Yang Z, Liu Y, Zhang Y. Aspergillusidone G Potentiates the Anti-Inflammatory Effects of Polaprezinc in LPS-Induced BV2 Microglia: A Bioinformatics and Experimental Study. Mar Drugs 2024; 22:324. [PMID: 39057433 PMCID: PMC11278036 DOI: 10.3390/md22070324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 07/16/2024] [Accepted: 07/16/2024] [Indexed: 07/28/2024] Open
Abstract
Neuroinflammation is one of the main mechanisms involved in the progression of neurodegenerative diseases (NDs), and microglial activation is the main feature of neuroinflammation. Polaprezinc (Pol), a chelator of L-carnosine and zinc, is widely used as a clinical drug for gastric ulcers. However, its potential effects on NDs remain unexplored. In LPS-induced BV-2 microglia, we found that Pol reduced the generation of NO and ROS and revealed inhibited expression of iNOS, COX-2, and inflammatory factors such as IL-6, TNF-α, and 1L-1β by Pol using qRT-PCR and Western blotting. These effects were found to be associated with the suppression of the NF-κB signaling pathway. Moreover, we evaluated the potential synergistic effects of aspergillusidone G (Asp G) when combined with Pol. Remarkably, co-treatment with low doses of Asp G enhanced the NO inhibition by Pol from approximately 30% to 80% in LPS-induced BV2 microglia, indicating a synergistic anti-inflammatory effect. A bioinformatics analysis suggested that the synergistic mechanism of Asp G and Pol might be attributed to several targets, including NFκB1, NRF2, ABL1, TLR4, and PPARα. These findings highlight the anti-neuroinflammatory properties of Pol and its enhanced efficacy when combined with Asp G, proposing a novel therapeutic strategy for managing neuroinflammation in NDs.
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Affiliation(s)
- Fangfang Ban
- Guangdong Provincial Key Laboratory of Aquatic Product Processing and Safety, Guangdong Provincial Engineering Laboratory for Marine Biological Products, Guangdong Provincial Center for Modern Agricultural Scientific Innovation, Shenzhen Institute of Guangdong Ocean University, Zhanjiang Municipal Key Laboratory of Marine Drugs and Nutrition for Brain Health, Research Institute for Marine Drugs and Nutrition, College of Food Science and Technology, Guangdong Ocean University, Zhanjiang 524088, China; (F.B.); (Z.Y.); (Y.L.)
| | - Longjian Zhou
- Guangdong Provincial Key Laboratory of Aquatic Product Processing and Safety, Guangdong Provincial Engineering Laboratory for Marine Biological Products, Guangdong Provincial Center for Modern Agricultural Scientific Innovation, Shenzhen Institute of Guangdong Ocean University, Zhanjiang Municipal Key Laboratory of Marine Drugs and Nutrition for Brain Health, Research Institute for Marine Drugs and Nutrition, College of Food Science and Technology, Guangdong Ocean University, Zhanjiang 524088, China; (F.B.); (Z.Y.); (Y.L.)
- Southern Marine Science and Engineering Guangdong Laboratory (Zhanjiang), Zhanjiang 524088, China
- Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian 116034, China
| | - Zhiyou Yang
- Guangdong Provincial Key Laboratory of Aquatic Product Processing and Safety, Guangdong Provincial Engineering Laboratory for Marine Biological Products, Guangdong Provincial Center for Modern Agricultural Scientific Innovation, Shenzhen Institute of Guangdong Ocean University, Zhanjiang Municipal Key Laboratory of Marine Drugs and Nutrition for Brain Health, Research Institute for Marine Drugs and Nutrition, College of Food Science and Technology, Guangdong Ocean University, Zhanjiang 524088, China; (F.B.); (Z.Y.); (Y.L.)
- Southern Marine Science and Engineering Guangdong Laboratory (Zhanjiang), Zhanjiang 524088, China
- Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian 116034, China
| | - Yayue Liu
- Guangdong Provincial Key Laboratory of Aquatic Product Processing and Safety, Guangdong Provincial Engineering Laboratory for Marine Biological Products, Guangdong Provincial Center for Modern Agricultural Scientific Innovation, Shenzhen Institute of Guangdong Ocean University, Zhanjiang Municipal Key Laboratory of Marine Drugs and Nutrition for Brain Health, Research Institute for Marine Drugs and Nutrition, College of Food Science and Technology, Guangdong Ocean University, Zhanjiang 524088, China; (F.B.); (Z.Y.); (Y.L.)
- Southern Marine Science and Engineering Guangdong Laboratory (Zhanjiang), Zhanjiang 524088, China
- Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian 116034, China
| | - Yi Zhang
- Guangdong Provincial Key Laboratory of Aquatic Product Processing and Safety, Guangdong Provincial Engineering Laboratory for Marine Biological Products, Guangdong Provincial Center for Modern Agricultural Scientific Innovation, Shenzhen Institute of Guangdong Ocean University, Zhanjiang Municipal Key Laboratory of Marine Drugs and Nutrition for Brain Health, Research Institute for Marine Drugs and Nutrition, College of Food Science and Technology, Guangdong Ocean University, Zhanjiang 524088, China; (F.B.); (Z.Y.); (Y.L.)
- Southern Marine Science and Engineering Guangdong Laboratory (Zhanjiang), Zhanjiang 524088, China
- Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian 116034, China
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2
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Addeo R, Caraglia F, Fasano M, Spedaliere R, Cocozza E. Zinc Supplementation in Head and Neck Cancer: Prevention of Chemo-Radio-Induced Complications and an Opportunity for Treatment. Oncology 2024; 102:1004-1008. [PMID: 38976972 DOI: 10.1159/000540248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2024] [Accepted: 07/02/2024] [Indexed: 07/10/2024]
Affiliation(s)
- Raffaele Addeo
- Oncology Operative Unit, Hospital of Frattamaggiore, ASLNA2NORD, Frattamaggiore, Italy
| | - Francesco Caraglia
- Medical Oncology, Department of Precision Medicine, Università degil Studi della Campania "Luigi Vanvitelli", Naples, Italy
| | - Morena Fasano
- Medical Oncology, Department of Precision Medicine, Università degil Studi della Campania "Luigi Vanvitelli", Naples, Italy
| | - Roberta Spedaliere
- Oncology Operative Unit, Hospital of Frattamaggiore, ASLNA2NORD, Frattamaggiore, Italy
- Medical Oncology, Department of Precision Medicine, Università degil Studi della Campania "Luigi Vanvitelli", Naples, Italy
| | - Ermelinda Cocozza
- Pharmacist and Nutritional Biologist, Nutrizione a passi, Saviano, Italy
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3
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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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4
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Gastroprotective, hepatoprotective, and nephroprotective effects of thymol against the adverse effects of acetylsalicylic acid in rats: Biochemical and histopathological studies. Saudi J Biol Sci 2022; 29:103289. [PMID: 35521358 PMCID: PMC9065893 DOI: 10.1016/j.sjbs.2022.103289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 04/09/2022] [Accepted: 04/17/2022] [Indexed: 11/21/2022] Open
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Schulz RM, Ahuja NK, Slavin JL. Effectiveness of Nutritional Ingredients on Upper Gastrointestinal Conditions and Symptoms: A Narrative Review. Nutrients 2022; 14:672. [PMID: 35277031 PMCID: PMC8839470 DOI: 10.3390/nu14030672] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 01/27/2022] [Accepted: 02/01/2022] [Indexed: 01/27/2023] Open
Abstract
Nutritional ingredients, including various fibers, herbs, and botanicals, have been historically used for various ailments. Their enduring appeal is predicated on the desire both for more natural approaches to health and to mitigate potential side effects of more mainstream treatments. Their use in individuals experiencing upper gastrointestinal (GI) complaints is of particular interest in the scientific space as well as the consumer market but requires review to better understand their potential effectiveness. The aim of this paper is to review the published scientific literature on nutritional ingredients for the management of upper GI complaints. We selected nutritional ingredients on the basis of mentions within the published literature and familiarity with recurrent components of consumer products currently marketed. A predefined literature search was conducted in Embase, Medline, Derwent drug file, ToXfile, and PubMed databases with specific nutritional ingredients and search terms related to upper GI health along with a manual search for each ingredient. Of our literature search, 16 human clinical studies including nine ingredients met our inclusion criteria and were assessed in this review. Products of interest within these studies subsumed the categories of botanicals, including fiber and combinations, and non-botanical extracts. Although there are a few ingredients with robust scientific evidence, such as ginger and a combination of peppermint and caraway oil, there are others, such as melatonin and marine alginate, with moderate evidence, and still others with limited scientific substantiation, such as galactomannan, fenugreek, and zinc-l-carnosine. Importantly, the paucity of high-quality data for the majority of the ingredients analyzed herein suggests ample opportunity for further study. In particular, trials with appropriate controls examining dose-response using standardized extracts and testing for specific benefits would yield precise and effective data to aid those with upper GI symptoms and conditions.
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Affiliation(s)
- Rebekah M. Schulz
- Department of Food Science and Nutrition, University of Minnesota, St. Paul, MN 55108, USA;
| | - Nitin K. Ahuja
- Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, PA 19104, USA;
| | - Joanne L. Slavin
- Department of Food Science and Nutrition, University of Minnesota, St. Paul, MN 55108, USA;
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6
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Li M, Sun Z, Zhang H, Liu Z. Recent advances on polaprezinc for medical use (Review). Exp Ther Med 2021; 22:1445. [PMID: 34721687 DOI: 10.3892/etm.2021.10880] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 07/06/2021] [Indexed: 12/13/2022] Open
Abstract
The present study described the chemical and biological properties of zinc complex of L-carnosine (L-CAZ; generic name, polaprezinc; chemical name, catena-(S)-[µ-[N(α)-(3-aminopropionyl) histidinato (2-) N1, N2, O: N(τ)]-zinc], molecular formula, C9H14N4O3Zn; molecular weight, 291.6404; CAS registry number, 107667-60-7). Characterized as a white or yellowish white crystalline powder, this drug is insoluble in glacial acetic acid and almost insoluble in water, methanol, ethanol and ether. It is soluble in dilute hydrochloric acid, dilute nitric acid and sodium hydroxide solution, and its melting point is 260-270˚C. Polaprezinc is an anti-ulcer drug that was jointly studied and developed by Hamari Chemicals Co., Ltd. and Zeria Pharmaceutical Co., Ltd., and was first approved in Japan in 1994. This review article summarizes the research advances of polaprezinc, including the patents, preparations, synthetic routes, pharmacokinetics, pharmacological effects and application in clinical research.
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Affiliation(s)
- Mingru Li
- Jilin Broadwell Pharmaceutical Co., Ltd., Liaoyuan, Jilin 136200, P.R. China
| | - Zhen Sun
- Department of Gastroenterology, Jilin People's Hospital, Jilin City, Jilin 132000, P.R. China
| | - Hong Zhang
- Jilin Broadwell Pharmaceutical Co., Ltd., Liaoyuan, Jilin 136200, P.R. China
| | - Zhaoyang Liu
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
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7
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Sepehrinezhad A, Rezaeitalab F, Shahbazi A, Sahab-Negah S. A Computational-Based Drug Repurposing Method Targeting SARS-CoV-2 and its Neurological Manifestations Genes and Signaling Pathways. Bioinform Biol Insights 2021; 15:11779322211026728. [PMID: 34211268 PMCID: PMC8216348 DOI: 10.1177/11779322211026728] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 06/01/2021] [Indexed: 01/08/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as a global concern involves infections in multiple organs. Much of the research up to now has been descriptive on neurological manifestations followed by SARS-CoV-2 infection. Despite considerable efforts on effective SARS-CoV-2 vaccine, novel therapeutic options for COVID-19 comorbidities are warranted. One of the fast ways to introduce possible effective drugs for clinical trials is bioinformatics methods. We have conducted a comprehensive enrichment analysis of genes involved in SARS-CoV-2 and neurological disorders associated with COVID-19. For this purpose, gene sets were extracted from the GeneWeaver database. To find out some significant enriched findings for common genes between SARS-CoV-2 and its neurological disorders, several practical databases were used. Finally, to repurpose an efficient drug, DrugBank databases were used. Overall, we detected 139 common genes concerning SARS-CoV-2 and their neurological disorders. Interestingly, our study predicted around 6 existing drugs (ie, carvedilol, andrographolide, 2-methoxyestradiol, etanercept, polaprezinc, and arsenic trioxide) that can be used for repurposing. We found that polaprezinc (zinc l-carnosine) drug is not investigated in the context of COVID-19 till now and it could be used for the treatment of COVID-19 and its neurological manifestations. To summarize, enrichment and network data get us a coherent picture to predict drug repurposing to speed up clinical trials.
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Affiliation(s)
- Ali Sepehrinezhad
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran.,Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Fariborz Rezaeitalab
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Neurology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali Shahbazi
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran.,Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Sajad Sahab-Negah
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Neuroscience, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Shefa Neuroscience Research Center, Khatam Alanbia Hospital, Tehran, Iran.,Society for Brain Mapping and Therapeutics (SBMT), Iranian Chapter, Los Angeles, CA, USA
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8
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Oral management with polaprezinc solution reduces adverse events in haematopoietic stem cell transplantation patients. Int J Oral Maxillofac Surg 2020; 50:906-914. [PMID: 33144049 DOI: 10.1016/j.ijom.2020.10.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 08/26/2020] [Accepted: 10/12/2020] [Indexed: 11/22/2022]
Abstract
The aim of this study was to analyse the effects of gargling with and then swallowing PPAA (polaprezinc in polyacrylic acid solution), in addition to regular oral management, on patients with a haematopoietic neoplasm scheduled for haematopoietic stem cell transplantation (HSCT). A total of 120 patients scheduled for HSCT during the years 2006-2016 were recruited. Patient background, oral adverse events, the incidence and severity of systemic adverse events (sepsis/septic shock, acute graft-versus-host disease (GVHD) after transplantation), and outcomes (survival/death) were compared between groups treated with and without PPAA. The severities of oral adverse events (oral mucositis, oral pain, and dysgeusia) were significantly lower in patients treated with PPAA. There was no significant difference in the incidence of febrile neutropenia (P=0.622) or sepsis/septic shock (P=0.665) as systemic adverse events. The severity of allograft-induced acute graft-versus-host disease (GVHD) was significantly lower in the PPAA group (P=0.011). There was no significant difference in outcome between the two groups (P=0.285). Within the limitations of the study design, it may be concluded that oral management with PPAA reduces adverse events in HSCT. Oral management with concomitant use of PPAA decreased oral adverse events and reduced the systemic complication of GVHD.
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9
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Kitagawa J, Kobayashi R, Nagata Y, Kasahara S, Ono T, Sawada M, Ohata K, Kato-Hayashi H, Hayashi H, Shimizu M, Itoh Y, Tsurumi H, Suzuki A. Polaprezinc for prevention of oral mucositis in patients receiving chemotherapy followed by hematopoietic stem cell transplantation: A multi-institutional randomized controlled trial. Int J Cancer 2020; 148:1462-1469. [PMID: 32984946 DOI: 10.1002/ijc.33316] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 09/06/2020] [Accepted: 09/18/2020] [Indexed: 01/22/2023]
Abstract
Oral mucositis is a common and distressing complication in patients receiving high-dose chemotherapy followed by hematopoietic stem cell transplantation (HSCT). We reported previously in a single-center retrospective analysis that zinc-L-carnosine (polaprezinc [PZ]) reduced the incidence of oral mucositis associated with HSCT. To verify the accuracy of the prophylactic effect of PZ against oral mucositis, we carried out a multi-institutional prospective randomized controlled study. Patients were randomly allocated to either the prevention group, in which PZ lozenge treatment was started before chemotherapy, or the control group, in which administration of PZ lozenges was initiated immediately after the onset of Grade 2 oral mucositis. Oral mucositis was evaluated daily from the start of chemotherapy to 35 days after transplantation. A total of 91 patients were enrolled, and 88 patients (47 in the control group and 41 in the prevention group) were eligible for data analysis. The incidence of Grade ≥2 but not Grade ≥3 oral mucositis was significantly reduced in the prevention group compared to the control group (44.7% in control group vs 22.0% in the prevention group, P = .025). There were no significant differences in the incidence rates of other adverse events or the rate of engraftment (95.6% vs 97.2%, P = .693) between the two groups. These findings suggest that PZ lozenge is effective for prophylaxis against Grade ≥2 oral mucositis associated with chemotherapy in patients undergoing HSCT without any influence on the HSCT outcome.
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Affiliation(s)
- Junichi Kitagawa
- First Department of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Ryo Kobayashi
- Department of Pharmacy, Gifu University Hospital, Gifu, Japan
| | - Yasuyuki Nagata
- Division of Hematology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Senji Kasahara
- Department of Hematology, Gifu Municipal Hospital, Gifu, Japan
| | - Takaaki Ono
- Division of Hematology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Michio Sawada
- Department of Hematology, Japanese Red Cross Gifu Hospital, Gifu, Japan
| | - Koichi Ohata
- Department of Pharmacy, Gifu University Hospital, Gifu, Japan
| | | | - Hideki Hayashi
- Laboratory of Pharmaceutical Engineering, Gifu Pharmaceutical University, Gifu, Japan
| | - Masahito Shimizu
- First Department of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Yoshinori Itoh
- Department of Pharmacy, Gifu University Hospital, Gifu, Japan
| | - Hisashi Tsurumi
- First Department of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Akio Suzuki
- Department of Pharmacy, Gifu University Hospital, Gifu, Japan
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10
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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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11
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Hewlings S, Kalman D. A Review of Zinc-L-Carnosine and Its Positive Effects on Oral Mucositis, Taste Disorders, and Gastrointestinal Disorders. Nutrients 2020; 12:nu12030665. [PMID: 32121367 PMCID: PMC7146259 DOI: 10.3390/nu12030665] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 02/17/2020] [Accepted: 02/27/2020] [Indexed: 12/14/2022] Open
Abstract
Zinc-L-carnosine (ZnC), also called polaprezinc known as PepZin GI™, is a chelated compound that contains L-carnosine and zinc. It is a relatively new molecule and has been associated with multiple health benefits. There are several studies that support ZnC’s benefits in restoring the gastric lining, healing other parts of the gastrointestinal (GI) tract, improving taste disorders, improving GI disorders, and enhancing skin and liver. Oral mucositis is a common complication of cytotoxic radiotherapy and/or chemotherapy. It occurs in almost every person with head and neck cancer who receive radiotherapy. It is often overlooked because it is not considered life threatening. However, mucositis often leads to a decreased quality of life and cessation of treatment, ultimately decreasing positive outcomes. Therefore, solutions to address it should be considered. The primary mechanisms of action are thought to be localized and related to ZnC’s anti-inflammatory and antioxidant functions. Therefore, the purpose of this review is to discuss the research related to ZnC and to explore its benefits, especially in the management of conditions related to damaged epithelial cells, such as oral mucositis. Evidence supports the safety and efficacy of ZnC for the maintenance, prevention, and treatment of the mucosal lining and other epithelial tissues. The research supports its use for gastric ulcers (approved in Japan) and conditions of the upper GI and suggests other applications, particularly for oral mucositis.
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Affiliation(s)
- Susan Hewlings
- Central Michigan University, Department of Nutrition and Dietetics Mount Pleasant, MI 48859, USA
- Correspondence:
| | - Douglas Kalman
- College of Healthcare Sciences, Nova Southeastern University, Fort Lauderdale 33314, USA;
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12
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A new derivative of acetylsalicylic acid and carnosine: synthesis, physical and chemical properties, biological activity. ACTA ACUST UNITED AC 2020; 28:119-130. [PMID: 31902097 DOI: 10.1007/s40199-019-00323-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Accepted: 12/17/2019] [Indexed: 12/29/2022]
Abstract
PURPOSE The aim of this study was to create and assess biological activity of a new compound based on carnosine and acetylsalicylic acid (ASA) that will comprise antioxidant effect with antiplatelet activity, while simultaneously preventing side effects on the gastrointestinal tract. METHODS Salicyl-carnosine (SC) was synthesized by condensation of ASA and carnosine. Antioxidant activity was determined by spectrophotometric and chemiluminescence methods. Antiplatelet activity was carried out by the light transmission-aggregometry method using the inductor ADP. Chronic gastric ulcer in rats was modeled using glacial acetic acid. RESULTS Using SOD-like activity, iron-induced chemiluminescence, BaSO4-activated respiratory burst, and evaluation of red blood cell structure stabilization during oxidative damage induced by sodium hypochlorite, it was shown that SC possesses antioxidant activity analogous, or better, than that of carnosine. Antiplatelet activity of SC was evaluated in the blood of healthy individuals, and was also shown to be comparable to, or exceeding that of ASA. Also SC demonstrates high resistance to hydrolysis by tissue and serum carnosinases. Most importantly, it was shown that SC has protected the gastric mucosa against the formation of stomach ulcerative lesions and promoted their epithelization, therefore overcoming the undesirable inherent side effects of ASA. CONCLUSIONS SC preserves pharmacologically significant properties of ASA and carnosine while retaining an anti-ulcer activity and resistance to the carnosinase hydrolysis at the same time. These properties are particularly promising for the potential development of new anti-inflammatory and antithrombotic drugs. Graphical abstract .
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Fukushima T, Yokooji T, Hirano T, Kataoka Y, Taogoshi T, Matsuo H. Aspirin enhances sensitization to the egg-white allergen ovalbumin in rats. PLoS One 2019; 14:e0226165. [PMID: 31805177 PMCID: PMC6894855 DOI: 10.1371/journal.pone.0226165] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Accepted: 11/20/2019] [Indexed: 12/04/2022] Open
Abstract
Enhancement of oral absorption of food allergens by non-steroidal anti-inflammatory drugs (NSAIDs), especially aspirin, is considered an exacerbating factor in the development of food allergies. In this study, we examined the effect of aspirin on oral sensitization to and absorption of the egg-white allergen ovalbumin (OVA) in rats. The absorption of OVA was evaluated by measuring the plasma concentration of OVA after oral administration by gavage. To evaluate oral sensitization to OVA, plasma levels of immunoglobulin (Ig) E and IgG1 antibodies (Abs) specific to OVA were determined by enzyme-linked immunosorbent assay after initiation of sensitization. High-dose aspirin (30 mg/kg) increased oral OVA absorption and plasma levels of OVA-specific IgE and IgG1 Abs compared with those observed in vehicle-treated rats. In contrast, low-dose aspirin (3 mg/kg) exerted no changes in either absorption or sensitization. Spermine, an absorption enhancer, increased the oral absorption of OVA to nearly the same extent as high-dose aspirin, whereas the plasma levels of OVA-specific IgE and IgG1 Abs exhibited no significant differences between spermine- and vehicle-treated rats. Among the NSAIDs, diclofenac and indomethacin increased sensitization to OVA, similar to high-dose aspirin, but meloxicam exerted no effects on Ab levels. In conclusion, we showed that high-dose aspirin enhanced oral sensitization to OVA. Our study suggests that enhanced oral sensitization to OVA cannot be ascribed to increased absorption of OVA from the intestinal tract. Although the mechanisms underlying this enhancement of sensitization are still controversial, our study suggests that modification of cytokine production due to impairment of the intestinal barrier function and inhibition of cyclooxygenase-1 activity by aspirin may be involved.
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Affiliation(s)
- Takahiro Fukushima
- Department of Pharmaceutical Services, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Tomoharu Yokooji
- Department of Pharmaceutical Services, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Department of Frontier Science for Pharmacotherapy, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- * E-mail:
| | - Taiki Hirano
- Department of Pharmaceutical Services, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yuta Kataoka
- Department of Pharmaceutical Services, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Takanori Taogoshi
- Department of Pharmaceutical Services, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hiroaki Matsuo
- Department of Pharmaceutical Services, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
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Zinc l-carnosine in gastric ulcers: a profile of its use. DRUGS & THERAPY PERSPECTIVES 2019. [DOI: 10.1007/s40267-019-00667-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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15
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Hsieh SL, Hsieh S, Lai PY, Wang JJ, Li CC, Wu CC. Carnosine Suppresses Human Colorectal Cell Migration and Intravasation by Regulating EMT and MMP Expression. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2019; 47:477-494. [PMID: 30909731 DOI: 10.1142/s0192415x19500241] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Carnosine is an endogenous dipeptide found in the vertebrate skeletal muscles that is usually obtained through the diet. To investigate the mechanism by which carnosine regulates the migration and intravasation of human colorectal cancer (CRC) cells, we used cultured HCT-116 cells as an experimental model in this study. We examined HCT-116 cell migratory and intravasive abilities and expression of epithelial-mesenchymal transition (EMT)-associated molecules and matrix metalloproteinases (MMPs) after carnosine treatment. The results showed that both migration and invasion were inhibited in cells treated with carnosine. We found significant decreases in Twist-1 protein levels and increases in E-cadherin protein levels in HCT-116 cells after carnosine exposure. Although plasminogen activator (uPA) and MMP-9 mRNA and protein levels were decreased, TIMP-1 mRNA and protein levels were increased. Furthermore, the cytosolic levels of phosphorylated I κ B (p-I κ B) and NF- κ B DNA-binding activity were reduced after carnosine treatment. These results indicate that carnosine inhibits the migration and intravasation of human CRC cells. The regulatory mechanism may occur by suppressing NF- κ B activity and modulating MMP and EMT-related gene expression in HCT-116 cells.
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Affiliation(s)
- Shu-Ling Hsieh
- * Department of Seafood Science, National Kaohsiung University of Science and Technology, Kaohsiung 81157, Taiwan
| | - ShuChen Hsieh
- † Department of Chemistry, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan
| | - Po-Yu Lai
- * Department of Seafood Science, National Kaohsiung University of Science and Technology, Kaohsiung 81157, Taiwan
| | - Jyh-Jye Wang
- ‡ Department of Nutrition and Health Science, Fooyin University, Kaohsiung 83102, Taiwan
| | - Chien-Chun Li
- § Department of Nutrition, Chung Shan Medical University, Taichung 40201, Taiwan
| | - Chih-Chung Wu
- ¶ Department of Food and Nutrition, Providence University, Taichung 43301, Taiwan
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16
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Yokooji T, Fukushima T, Hamura K, Ninomiya N, Ohashi R, Taogoshi T, Matsuo H. Intestinal absorption of the wheat allergen gliadin in rats. Allergol Int 2019; 68:247-253. [PMID: 30559050 DOI: 10.1016/j.alit.2018.11.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 11/03/2018] [Accepted: 11/08/2018] [Indexed: 10/27/2022] Open
Abstract
BACKGROUND Aspirin enhances food allergy symptoms by increasing absorption of ingested allergens. The objective of this study is to elucidate the role of aspirin in facilitating intestinal absorption of the wheat allergen, gliadin, in rats. METHODS Plasma concentrations of gliadin were determined after oral administration by gavage or administration into a closed intestinal loop in rats. We used an in situ intestinal re-circulating perfusion experiment to examine the effect of pepsin on aspirin-facilitated gliadin absorption. Fluorescein isothiocyanate (FITC)-labeled dextran-40 (FD-40) was used as a marker of non-specific absorption. The molecular size of gliadin and its allergenicity in plasma were examined using immunoblot analysis and intradermal reaction tests with Evans blue dye (EBD) extravasation, respectively. RESULTS Aspirin increased plasma concentrations of gliadin after oral administration but had no effect in the closed intestinal loop study. An in situ intestinal re-circulating perfusion study showed that FITC-labeled gliadin was absorbed similarly to FD-40. Aspirin increased absorption of both intact and pepsin-digested gliadin, with a more significant effect on absorption of pepsin-treated gliadin. Immunoblotting showed that most gliadin was absorbed in intact form. When the gliadin fraction was extracted from rat plasma after gavage and injected intradermally into gliadin-sensitized rats, EBD extravasation was observed at injection sites in a gliadin dose-dependent manner. CONCLUSIONS Aspirin increased the absorption of intact and pepsin-digested gliadin via the paracellular pathway, maintaining their allergenicity. Moreover, the effect of aspirin on gliadin absorption was enhanced by modification and digestion of gliadin in the stomach.
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17
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Mohamed WA, Abd-Elhakim YM, Ismail SAA. Involvement of the anti-inflammatory, anti-apoptotic, and anti-secretory activity of bee venom in its therapeutic effects on acetylsalicylic acid-induced gastric ulceration in rats. Toxicology 2019; 419:11-23. [PMID: 30885738 DOI: 10.1016/j.tox.2019.03.003] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2018] [Revised: 02/21/2019] [Accepted: 03/12/2019] [Indexed: 12/11/2022]
Abstract
Acetylsalicylic acid (ASA) is the most highly consumed pharmaceutical product worldwide. Importantly, gastrointestinal ulceration due to ASA is a major complication. Hence, the present work aimed to examine, for the first time, the healing properties of bee venom (BV) in acute gastric ulceration induced by ASA. Forty adult male Sprague-Dawley rats were divided into four groups that received distilled water only, ASA (500 mg/kg BW) twice daily for 3 days, ASA for 3 days followed by BV (2 mg/kg BW) for 7 days, or ASA for 3 days followed by ranitidine hydrochloride (50 mg/kg BW) for 7 days. Haematological analysis, haemostatic evaluation, and inflammatory marker estimation were performed. Rat stomachs were collected for ulcer scoring, gene expression analysis, oxidative stress assays, histopathological and immunohistochemical examinations, and tissue eosinophil scoring. The results revealed that BV markedly decreased the ulcer index, pro-inflammatory cytokine levels, malondialdehyde levels, BAX distribution, caspase-3 expression, and tissue eosinophil levels. Additionally, significant increases in antioxidant enzymes and heat shock protein 70 localization in gastric tissue were evident following BV treatment after ASA exposure. Also, BV has been found to attenuate the haematological, haemostatic, and histopathological alterations induced by ASA. Our findings collectively indicate that the gastroprotective effect of BV against ASA-induced ulceration in rats is mediated by its antioxidant, anti-inflammatory, anti-apoptotic, and anti-secretory properties.
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Affiliation(s)
- Wafaa A Mohamed
- Department of Clinical Pathology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt
| | - Yasmina M Abd-Elhakim
- Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt.
| | - Shimaa A A Ismail
- Department of Clinical Pathology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt
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18
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Yoshikawa F, Nakajima T, Hanada M, Hirata K, Masuyama T, Aikawa R. Beneficial effect of polaprezinc on cardiac function post-myocardial infarction: A prospective and randomized clinical trial. Medicine (Baltimore) 2019; 98:e14637. [PMID: 30855449 PMCID: PMC6417532 DOI: 10.1097/md.0000000000014637] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Polaprezinc is clinically used for the treatment of gastric ulcers. It induces the mobilization of mesenchymal stem cells and the mRNA expression of insulin-like growth factor-1 in vascular endothelial cells in order to protect injured gastric tissue or skin. METHODS The current study population included 50 patients with primary acute myocardial infarction (AMI). After percutaneous coronary intervention, the subjects were randomly divided into 2 groups, namely, the nonpolaprezinc and polaprezinc groups. Peripheral blood and urinary samples were collected in a specific time to analyze zinc concentration, cardiac enzymes, and the levels of the inflammation marker interleukin-6. To evaluate the cardiac function, echocardiography was performed upon admission to the hospital and at 9 months post-AMI. RESULTS The urine and blood zinc levels of the polaprezinc group were higher compared with those of the non-polaprezinc group at 8 days after percutaneous coronary intervention. The mean interleukin-6/maximal creatine phosphokinase level was significantly reduced in the polaprezinc group (0.024 [0.003-0.066] vs. 0.076 [0.015-0.212], respectively; P = .045). In addition, echocardiography revealed that the ejection fraction of the nonpolaprezinc group was not significantly increased between day 3 and 9 months post-AMI (53 [49-60.8] vs. 59.5 [52-69.3], respectively; P = .015). However, a significant increase was detected in the ejection fraction of the polaprezinc group at the 2 time points (54 [51-57] vs. 62 [55-71], respectively; P < .01). CONCLUSIONS The results of the present study suggest that polaprezinc has an anti-inflammatory effect and improves cardiac function after AMI.
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Affiliation(s)
- Fumitsugu Yoshikawa
- Kuwana City Medical Center, Kuwana
- Cardiovascular Division, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya
| | | | | | | | - Tohru Masuyama
- Cardiovascular Division, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya
| | - Ryuichi Aikawa
- Kuwana City Medical Center, Kuwana
- Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Japan
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Taslidere E, Vardi N, Parlakpinar H, Yıldız A, Taslidere B, Karaaslan MG. Effects of melatonin on acetylsalicylic acid induced gastroduodenal and jejunal mucosal injury. Biotech Histochem 2018; 93:485-495. [PMID: 30388896 DOI: 10.1080/10520295.2018.1442020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
Abstract
We evaluated the effects of melatonin on acetylsalicylic acid (ASA) induced gastroduodenal and jejunal mucosal injury. We used 40 postpubertal rats divided randomly into five groups of eight animals. The control group consisted of untreated animals. The Mel group was injected intraperitoneally (i.p.) with 5 mg/kg melatonin. The ASA group was injected i.p. with 200 mg/kg ASA. The ASA + Mel group was injected i.p. with 5 mg/kg melatonin 45 min after administering 200 mg/kg ASA i.p. The Mel + ASA group was injected i.p. with 5 mg/kg melatonin 45 min before administering 200 mg/kg ASA i.p. We found no statistically significant differences in mean histopathological scores in the ASA + Mel group compared to the ASA group. ASA caused shortened villi and loss of the apical villus in the duodenum. The histopathological score was increased and villus height was decreased in the ASA group compared to untreated controls. Treatment with melatonin attenuated the histological damage. In the ASA group, occasional areas showed erosion of villi in the jejunum; however, differences in mean histopathological score in ASA group compared to the other groups were not statistically significant. Malondialdehyde (MDA), glutathione (GSH) and superoxide dismutase (SOD) activities were measured in stomach, duodenal and jejunum tissue. We found increased MDA activity in both stomach and duodenal tissues in the ASA group compared to the control group (p < 0.05). We found no statistically significant changes in MDA levels in jejunal tissue in the ASA group compared to the control group. We found no change in SOD activity in either stomach or duodenal tissues in the ASA group compared to the control group. We observed decreased SOD activity in jejunal tissue in the ASA group compared to the control group (p < 0.05). We detected no change in GSH activity in stomach, duodenal or jejunal tissues in the ASA group compared to the control group. The stomach damage was less in melatonin treated groups, but the lesions were not completely eliminated. The jejunum in the ASA group retained a nearly normal appearance. We found that melatonin exhibited some healing effects on ASA induced duodenal mucosal injury.
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Affiliation(s)
- E Taslidere
- a Department of Histology and Embryology, Medical Faculty , Bezmialem Vakif University , Istanbul
| | - N Vardi
- b Department of Histology and Embryology, Medical Faculty , Inonu University , Malatya , Turkey
| | - H Parlakpinar
- c Department of Pharmacology, Medical Faculty , Inonu University , Malatya , Turkey
| | - A Yıldız
- b Department of Histology and Embryology, Medical Faculty , Inonu University , Malatya , Turkey
| | - B Taslidere
- d Department of Emergency Medicine , Malatya State Hospital , Malatya , Turkey
| | - M G Karaaslan
- e Department of Biochemistry, Medical Faculty , Inonu University , Malatya , Turkey
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20
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Doi H, Kuribayashi K, Kijima T. Utility of polaprezinc in reducing toxicities during radiotherapy: a literature review. Future Oncol 2018; 14:1977-1988. [PMID: 30074413 DOI: 10.2217/fon-2018-0021] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Accepted: 03/21/2018] [Indexed: 01/22/2023] Open
Abstract
Chemoradiotherapy is important for treating malignancies. However, radiation-induced toxicities develop as chemoradiotherapy-related complications. Various agents reduce or prevent toxicities, but there are no standard treatments. Polaprezinc (PZ), a chelating compound used for gastric ulcers, has antioxidant and free radical scavenging effects. Although few studies have evaluated PZ and radiation-induced normal tissue damage, several clinical studies have shown the efficacy of PZ for oral mucositis, esophagitis, proctitis and taste alterations during and after radiotherapy. Moreover, preclinical data support the clinical data, indicating good potential of testing PZ in future trials. However, as there are only few well-documented review articles on PZ use in cancer treatment, we conducted this literature review. PZ reduced several radiation-induced toxicities and improved the quality of life.
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Affiliation(s)
- Hiroshi Doi
- Department of Radiation Oncology, Meiwa Cancer Clinic, Nishinomiya, Hyogo, Japan
- Department of Radiology, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
- Department of Radiation Oncology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
| | - Kozo Kuribayashi
- Division of Respiratory Medicine, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Takashi Kijima
- Division of Respiratory Medicine, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
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21
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Adefisayo MA, Akomolafe RO, Akinsomisoye OS, Alabi QK, Ogundipe L, Omole JG, Olamilosoye KP. Protective Effects of Methanol Extract of Vernonia amygdalina ( del.) Leaf on Aspirin-Induced Gastric Ulceration and Oxidative Mucosal Damage in a Rat Model of Gastric Injury. Dose Response 2018; 16:1559325818785087. [PMID: 30013459 PMCID: PMC6043926 DOI: 10.1177/1559325818785087] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Revised: 05/23/2018] [Accepted: 05/29/2018] [Indexed: 11/17/2022] Open
Abstract
This study investigated the quantitative polyphenolic constituents and gastroprotective effects of methanol extract of Vernonia amygdalina leaf (MEVA) against aspirin-induced gastric ulcer in rats. Ulceration was induced by 3 days’ oral administration of aspirin (150 mg/kg body weight). Wistar rats were pretreated with cimetidine (reference drug) at a dose of 100 mg/kg body weight and MEVA at 200, 300, and 400 mg/kg body weight once daily for 28 days prior to ulcer induction. At the end of the experiment, gastric secretions, antioxidant status, and histopathological alteration were evaluated. We observed that the significantly increased ulcer index, gastric volume, free and total acidity, malondialdehyde level, and pepsin activity were effectively reduced following treatment with 200 and 300 mg/kg MEVA. The extract also markedly attenuated the reduced activity of superoxide dismutase and reduced glutathione level as well as pH and mucin content in the ulcerated rats. Administration of the extract also significantly attenuates necrosis of the stomach tissue of the ulcerated rats. The results suggested that the MEVA leaf, preferably at 200 and 300 mg/kg body weight, ameliorated aspirin-induced gastric ulceration via antioxidative and H2 receptor antagonist.
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Affiliation(s)
- Modinat A Adefisayo
- Department of Physiology, Faculty of Basic Medical Sciences, University of Medical Sciences, Ondo State, Nigeria.,Department of Physiological Sciences, Faculty of Basic Medical Sciences, Obafemi Awolowo University, Ile-Ife, Nigeria
| | - Rufus O Akomolafe
- Department of Physiological Sciences, Faculty of Basic Medical Sciences, Obafemi Awolowo University, Ile-Ife, Nigeria
| | - Olumide S Akinsomisoye
- Department of Physiological Sciences, Faculty of Basic Medical Sciences, Obafemi Awolowo University, Ile-Ife, Nigeria
| | - Quadri K Alabi
- Department of Physiological Sciences, Faculty of Basic Medical Sciences, Obafemi Awolowo University, Ile-Ife, Nigeria.,Department of Haematology and Blood Transfusion, Faculty of Basic Medical Sciences, College of Medicine, Afe Babalola University, Ado Ekiti, Nigeria
| | - Laofe Ogundipe
- Department of Public Health and Community Medicine, Afe Babalola University, Ado Ekiti, Nigeria
| | - Joseph G Omole
- Department of Physiological Sciences, Faculty of Basic Medical Sciences, Obafemi Awolowo University, Ile-Ife, Nigeria
| | - Kehinde P Olamilosoye
- Department of Physiological Sciences, Faculty of Basic Medical Sciences, Obafemi Awolowo University, Ile-Ife, Nigeria
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22
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Liu ZY, Xie WB, Ru Li M, Teng N, Liang X, Zhang ZQ. Effects of polaprezinc on gastric mucosal damage and neurotransmitters in a rat model of chemotherapy-induced vomiting. J Int Med Res 2018; 46:2436-2444. [PMID: 29756515 PMCID: PMC6023045 DOI: 10.1177/0300060518771492] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
Objective To investigate the effects of polaprezinc (PZ) on cyclophosphamide (CTX)- or cisplatin (DDP)-induced gastric mucosal injury and on a rat model of neurotransmitter-mediated vomiting. Methods Sprague–Dawley rats were divided at random into Control, CTX, DDP, PZ+CTX, and PZ+DDP groups. After 20 days, brain tissues and sera were analyzed for the levels of dopamine (DA), 5-hydroxytryptamine (5-HT), and nuclear factor kappa B (NF-κB). Hematoxylin and eosin-stained sections of stomach, intestine, and brain tissues were examined using light microscopy. Results The levels of DA, 5-HT, and NF-κB in brain and serum samples of rats treated with CTX or DDP were significantly increased compared with those of rats in the Control group. There was a significant decrease in these values in the PZ group. Moreover, PZ reduced damage to brain tissue caused by CTX or DDP. Conclusions PZ decreased the levels of DA, 5-HT, and NF-κB in blood and brain tissues caused by CTX or DDP and reduced the chemotherapy-induced damage to the small intestine, stomach, and brain. These findings can be translated to the clinic to enhance the efficacy and safety of chemotherapy.
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Affiliation(s)
- Zhao Yang Liu
- 1 National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wen Bo Xie
- 2 Jilin Province Broadwell Pharmaceutical Co., Ltd., Changchun, China
| | - Ming Ru Li
- 2 Jilin Province Broadwell Pharmaceutical Co., Ltd., Changchun, China
| | - Nan Teng
- 2 Jilin Province Broadwell Pharmaceutical Co., Ltd., Changchun, China
| | - Xiao Liang
- 1 National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zi Qiang Zhang
- 1 National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Adefisayo MA, Akomolafe RO, Akinsomisoye SO, Alabi QK, Ogundipe OL, Omole JG, Olamilosoye KP. Gastro-protective effect of methanol extract of Vernonia amygdalina (del.) leaf on aspirin-induced gastric ulcer in Wistar rats. Toxicol Rep 2017; 4:625-633. [PMID: 29657922 PMCID: PMC5897319 DOI: 10.1016/j.toxrep.2017.11.004] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Revised: 11/10/2017] [Accepted: 11/13/2017] [Indexed: 02/07/2023] Open
Abstract
This study investigated the protective effects of methanol extract of Vernonia amygdalina leaf (MEVA) on aspirin induced gastric ulcer in rats. Thirty Wistar rats, 150-200 g were divided into six groups as follows: Group 1 (control) rats received 2 mL/kg of propylene glycol for 28 consecutive days. Group 2 (Ulcer Control) received 150 mg/kg/day of aspirin suspended in 3 mL of 1% carboxymethylcellulose in water orally for 3 consecutive days during which the rats were fasted for the induction of ulcer. Group 3 received cimetidine at 100 mg/kg/day orally for 28 consecutive days and thereafter treated as group 2. Groups 4, 5 and 6 received MEVA orally at 200, 300 and 400 mg/kg/day respectively for 28 consecutive days and thereafter were treated with aspirin as group 2. All the animals were sacrifice at the end of the study to determine the gastric pH, gastric acidity, gastric ulcer score, haematological indices, superoxide dismutase (SOD) activity, reduced glutathione (GSH) and Lipid peroxidation (LPO) levels. The result showed that aspirin significantly (p < 0.05) increased gastric ulcer score and index, decreased gastric pH, gastric acidity, SOD activity, GSH level as well as increased LPO level. It induced significant necrosis of the stomach tissue. Administration of MEVA significantly (p < 0.05) increased gastric pH, but decreased gastric acid secretion and reversed alteration of haematological parameters. It also significantly (p < 0.05) increased SOD activity, GSH level and decreased LPO level. The results suggest that Vernonia amygdalina possesses gastro-protective properties against aspirin-induced gastric ulcer.
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Affiliation(s)
- Modinat A. Adefisayo
- Department of Physiology, Faculty of Basic Medical Sciences, University of Medical Sciences, Ondo State, Nigeria
- Department of Physiological Sciences, Faculty of Basic Medical Sciences, Obafemi Awolowo University, Ile-Ife, Osun State, Nigeria
| | - Rufus O. Akomolafe
- Department of Physiological Sciences, Faculty of Basic Medical Sciences, Obafemi Awolowo University, Ile-Ife, Osun State, Nigeria
| | - Stephen O. Akinsomisoye
- Department of Physiological Sciences, Faculty of Basic Medical Sciences, Obafemi Awolowo University, Ile-Ife, Osun State, Nigeria
| | - Quadri K. Alabi
- Department of Physiological Sciences, Faculty of Basic Medical Sciences, Obafemi Awolowo University, Ile-Ife, Osun State, Nigeria
- Department of Hematology and Blood Transfusion, Faculty of Basic Medical Sciences, College of Medicine, Afe Babalola University, Ado Ekiti, Ekiti State, Nigeria
| | - Olaofe L. Ogundipe
- Department of Public Health and Community Medicine, Afe Babalola University, Ado Ekiti, Ekiti State, Nigeria
| | - Joseph G. Omole
- Department of Physiological Sciences, Faculty of Basic Medical Sciences, Obafemi Awolowo University, Ile-Ife, Osun State, Nigeria
| | - Kehinde P. Olamilosoye
- Department of Physiological Sciences, Faculty of Basic Medical Sciences, Obafemi Awolowo University, Ile-Ife, Osun State, Nigeria
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Ozbayoglu A, Sonmez K, Karabulut R, Turkyilmaz Z, Poyraz A, Gulbahar O, Basaklar AC. Effect of polaprezinc on experimental corrosive esophageal burns in rats. Dis Esophagus 2017; 30:1-6. [PMID: 28881910 DOI: 10.1093/dote/dox104] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2016] [Indexed: 02/06/2023]
Abstract
Unconsciously caustic ingestion is one of the most common causes of serious esophageal strictures in children. The aim of this study is to determine the efficiency of polaprezinc in preventing stricture formation after corrosive esophageal burns (CEB); this was the first time it has been used to treat experimental CEB in rats. Twenty-four rats were divided into four groups, three of which received CEB by the instillation of 1 mL of 10% NaOH solution into their isolated esophageal segments for three minutes. Group C (control) was uninjured and untreated. Group B (esophageal burn) received CEB but were left untreated. Groups PT1 and PT2 had CEB and received 100 mg/kg/day and 200 mg/kg/day, respectively, of intraperitoneal polaprezinc treatment (PT) for the first two weeks, then oral PT for another two weeks. We assessed the treatment's efficiency of the treatment after the fourth week by evaluating the stenosis index (SI) and the histopathological damage score, determining tissue hydroxyproline content (HP), and measuring the weight of the rats before and after the experiment. Mean SI was statistically lower in the groups PT1 and PT2 when compared with Group B (p = 0.006, 0.004, respectively). HP levels were highest in Group B, but it was insignificant (P> 0.05). In terms of histopathological damage score, treatment groups demonstrated less collagen deposition, mucosal, and submucosal damage than both Group B (p = 0.01) and Group C (p = 0.02). Group PT1 and Group PT2 (P> 0.05) showed similar results, indicating the treatment's effectiveness was independent of dosage. Outside of Group C, weight gain was detected only in Group PT2, though it was statistically insignificant. In Group PT1, weight loss was lower than in Group B. Polaprezinc, with its antifibrotic, antioxidant, anti-inflammatory, wound-healing and antiapoptotic effects, was efficient in reducing stricture formation by decreasing HP levels and histopathologic damage, preventing stenosis, and weight gain in higher dosages in the treatment group.
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Affiliation(s)
| | - K Sonmez
- Departments of 1Pediatric Surgery
| | | | | | | | - O Gulbahar
- Biochemistry, Faculty of Medicine, Gazi University, Ankara, Turkey
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Evaluation of anti-inflammatory and ulcerogenic potential of zinc-ibuprofen and zinc-naproxen complexes in rats. Inflammopharmacology 2017; 25:653-663. [PMID: 28536986 PMCID: PMC5671550 DOI: 10.1007/s10787-017-0361-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Accepted: 05/06/2017] [Indexed: 02/07/2023]
Abstract
Because of numerous indications and high availability, non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed and used medicines in the world. However, long-term therapy with and improper use of NSAIDs may lead to gastrointestinal damage. Therefore, improving the therapeutic index of the existing drugs has become a priority over the past decades. Considerable attention in the field has been concentrated on metal complexes of non-steroidal anti-inflammatory drugs. The aim of this study is to evaluate the effect of complexation with zinc on the anti-inflammatory and ulcerogenic effects of ibuprofen and naproxen after single and triple intragastric administration to rats. The anti-inflammatory effect was assessed in carrageenan-induced inflammatory edema in the hind paw of male albino Wistar rats. The mucosal lesions were inspected and evaluated for gross pathology. Single administration of both the investigated complexes, namely zinc-ibuprofen and zinc-naproxen (20 mg/kg equivalent to ibuprofen and naproxen, respectively) and their parent drugs and physical mixtures with zinc hydroaspartate (ZHA doses: 16.05 and 14.37 mg/kg), caused a significant reduction of the edema after the same time from the carrageenan injection in comparison to the control groups. However, no statistically significant differences between the investigated drugs were observed after their single administration. The mean ulceration score for the mixture of ibuprofen and ZHA was statistically lower than the mean score achieved in rats after treatment with ibuprofen alone. On the other hand, triple intragastric administration of the ZHA-ibuprofen and ZHA-naproxen combination showed substantial enhancement of the anti-inflammatory activity against control groups, as well as against the parent NSAIDs. The most potent anti-inflammatory activity was demonstrated after 2 h from the carrageenan injection in animals receiving ZHA together with naproxen. The edema growth was reduced in these animals by 80.9% as compared to the control group. This result was significantly higher than the results achieved in animals receiving zinc-naproxen (50.2%) or naproxen alone (47.9%). Both NSAID complexes with zinc and mixtures with ZHA alleviated ulcerations caused by parent NSAIDs; however, the mixtures of both ibuprofen and naproxen with ZHA after triple administration were the least damaging. In view of the above results, zinc supplementation during NSAID therapy may have a beneficial effect on ulcer prevention and healing by reducing the effective dose of the parent drug and increasing its potency.
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Ooi TC, Chan KM, Sharif R. Antioxidant, Anti-inflammatory, and Genomic Stability Enhancement Effects of Zinc l-carnosine: A Potential Cancer Chemopreventive Agent? Nutr Cancer 2017; 69:201-210. [PMID: 28094570 DOI: 10.1080/01635581.2017.1265132] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Cancer is one of the major causes of death worldwide, and the incidence and mortality rates of cancer are expected to rise tremendously in the near future. Despite a better understanding of cancer biology and advancement in cancer management, current strategies in cancer treatment remain costly and ineffective. Hence, instead of putting more efforts to search for new cancer cures, attention has now been shifted to the development of cancer chemopreventive agents as a preventive measure for cancer formation. It is well known that neoplastic transformation of cells is multifactorial, and the occurrence of oxidative stress, chronic inflammation, and genomic instability events has been implicated in the carcinogenesis of cells. Zinc l-carnosine (ZnC), which is clinically used as gastric ulcer treatment in Japan, has been suggested to have the potential in preventing cancer development. Multiple studies have revealed that ZnC possesses potent antioxidant, anti-inflammatory, and genomic stability enhancement effects. Thus, this review provides some mechanistic insight into the antioxidant, anti-inflammatory, and genomic stability enhancement effects of ZnC in relevance to its chemopreventive potential.
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Affiliation(s)
- Theng Choon Ooi
- a Biomedical Science Programme , School of Diagnostic and Applied Health Sciences, Faculty of Health Sciences, Universiti Kebangsaan Malaysia , Kuala Lumpur , Malaysia
| | - Kok Meng Chan
- b Environmental Health and Industrial Safety Programme , School of Diagnostic and Applied Health Sciences, Faculty of Health Sciences, Universiti Kebangsaan Malaysia , Kuala Lumpur , Malaysia
| | - Razinah Sharif
- c Programme of Nutritional Sciences , School of Healthcare Sciences, Faculty of Health Sciences, Universiti Kebangsaan Malaysia , Kuala Lumpur , Malaysia
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Biological properties of citral and its potential protective effects against cytotoxicity caused by aspirin in the IEC-6 cells. Biomed Pharmacother 2017; 87:653-660. [PMID: 28088731 DOI: 10.1016/j.biopha.2016.12.104] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2016] [Revised: 12/10/2016] [Accepted: 12/22/2016] [Indexed: 02/06/2023] Open
Abstract
Citral, 3,7-dimethyl-2,6-octadienal, is a key component of several essential oils extracted from lemon-scented herbal plants. The present study was designed to investigate the antioxidant activities of citral and assess its possible protective effects against aspirin-induced toxicity in vitro. We used IEC-6 cells (rat small intestine epithelial cells). The antioxidant activities were determined by 1,1-diphenyl-2-picrylhydrazyl (DPPH), β-carotene/linoleic acid and Ferric reducing antioxidant power (FRAP). Cytotoxicity was evaluated by cell viability, anti-oxidant enzyme activities, malondialdehyde (MDA) production and by the expression of MAPKs (Mitogen-Activated Protein Kinases) pathways. According to results, citral showed an important antioxidant activity. It inhibited the oxidation of linoleic acid, a moderate DPPH was found and it showed a Ferric reducing antioxidant potential with an EC50 value of 125±28.86μg/mL. Then, the co-treatment of aspirin with citral significantly decreased the aspirin-induced cell death, and the MDA level. It modulated the superoxide dismutase (SOD) and glutathione (GSH) activities. Also, the activation of MAPKs was attenuated by citral. These findings suggest that citral can protect IEC-6 cells against aspirin-induced oxidative stress that may help to discover new chemicals out of natural antioxidant substances.
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Ooi TC, Chan KM, Sharif R. Zinc Carnosine Inhibits Lipopolysaccharide-Induced Inflammatory Mediators by Suppressing NF-κb Activation in Raw 264.7 Macrophages, Independent of the MAPKs Signaling Pathway. Biol Trace Elem Res 2016; 172:458-464. [PMID: 26749414 DOI: 10.1007/s12011-015-0615-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2015] [Accepted: 12/28/2015] [Indexed: 02/05/2023]
Abstract
This study aimed to investigate the role of the mitogen-activated protein kinases (MAPKs) signaling pathway in the anti-inflammatory effects of zinc carnosine (ZnC) in lipopolysaccharide (LPS)-induced RAW 264.7 cells. Cells were pretreated with ZnC (0-100 μM) for 2 h prior to the addition of LPS (1 μg/ml). Following 24 h of treatment, ZnC was found not to be cytotoxic to RAW 264.7 cells up to the concentration of 100 μM. Our current findings showed that ZnC did not protect RAW 264.7 cells from LPS-induced "respiratory burst". Significant increment in intracellular glutathione (GSH) level and reduction in thiobarbituric acid reactive substances (TBARS) concentration can only be observed in cell pretreated with high doses of ZnC only (50 and 100 μM for GSH and 100 μM only for TBARS). On the other hand, pretreatment of cells with ZnC was able to inhibit LPS-induced inducible nitric oxide synthase and cyclooxygenase-2 expression significantly. Furthermore, results from immunoblotting showed that ZnC was able to suppress nuclear factor-kappaB (NF-κB) activation, and highest suppression can be observed at 100 μM of ZnC pretreatment. However, pretreatment of ZnC did not inhibit the early activation of MAPKs. In conclusion, pretreatment with ZnC was able to inhibit the expression of inflammatory mediators in LPS-induced RAW 264.7 cells, mainly via suppression of NF-κB activation, and is independent of the MAPKs signaling pathway.
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Affiliation(s)
- Theng Choon Ooi
- Biomedical Science Programme, School of Diagnostic and Applied Health Sciences, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300, Kuala Lumpur, Malaysia
| | - Kok Meng Chan
- Environmental Health and Industrial Safety Programme, School of Diagnostic and Applied Health Sciences, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300, Kuala Lumpur, Malaysia
| | - Razinah Sharif
- Programme of Nutritional Sciences, School of Healthcare Sciences, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300, Kuala Lumpur, Malaysia.
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Hayashi H, Kobayashi R, Suzuki A, Yamada Y, Ishida M, Shakui T, Kitagawa J, Hayashi H, Sugiyama T, Takeuchi H, Tsurumi H, Itoh Y. Preparation and clinical evaluation of a novel lozenge containing polaprezinc, a zinc-L-carnosine, for prevention of oral mucositis in patients with hematological cancer who received high-dose chemotherapy. Med Oncol 2016; 33:91. [PMID: 27418192 PMCID: PMC4945687 DOI: 10.1007/s12032-016-0795-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2016] [Accepted: 06/14/2016] [Indexed: 11/28/2022]
Abstract
We previously reported that oral ingestion of polaprezinc, a zinc-L-carnosine, suspended in sodium alginate solution prevents oral mucositis in patients receiving radiotherapy or high-dose chemotherapy. In the present study, we developed a novel preparation of polaprezinc and evaluated clinical effect of the lozenge preparation in patients receiving high-dose chemotherapy for hematopoietic stem cell transplantation. The preparation contained 18.75 mg polaprezinc in a tablet and showed an excellent uniformity and stability up to 24 weeks after storage under room temperature. The incidence rate of grade ≥ 2 oral mucositis was 74 % in patients without premedication, whereas the rate was remarkably reduced in patients receiving the suspension (23 %) or lozenge (13 %) of polaprezinc (P < 0.01). The use of non-opioid analgesic drugs such as anti-inflammatory agents and local anesthetics for oral pain was also greatly reduced by polaprezinc suspension or its lozenge (16 % for suspension and 13 % for lozenge compared with 89 % with no premedication, P < 0.01). These findings suggest that polaprezinc lozenge is simple to apply and highly effective for prevention of oral mucositis associated with high-dose chemotherapy for hematopoietic stem cell transplantation.
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Affiliation(s)
- Hiroko Hayashi
- Department of Pharmacy, Gifu University Hospital, 1-1 Yanagido, Gifu, 501-1194, Japan
| | - Ryo Kobayashi
- Department of Pharmacy, Gifu University Hospital, 1-1 Yanagido, Gifu, 501-1194, Japan
| | - Akio Suzuki
- Department of Pharmacy, Gifu University Hospital, 1-1 Yanagido, Gifu, 501-1194, Japan.
| | - Yuto Yamada
- Department of Pharmacy, Gifu University Hospital, 1-1 Yanagido, Gifu, 501-1194, Japan
| | - Masayuki Ishida
- Department of Pharmacy, Gifu University Hospital, 1-1 Yanagido, Gifu, 501-1194, Japan
| | - Toshinobu Shakui
- Laboratory of Pharmacy Practice and Social Science, Gifu Pharmaceutical University, Gifu, Japan
| | - Junichi Kitagawa
- First Department of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Hideki Hayashi
- Laboratory of Pharmacy Practice and Social Science, Gifu Pharmaceutical University, Gifu, Japan
| | - Tadashi Sugiyama
- Laboratory of Pharmacy Practice and Social Science, Gifu Pharmaceutical University, Gifu, Japan
| | - Hirofumi Takeuchi
- Laboratory of Pharmaceutical Engineering, Gifu Pharmaceutical University, Gifu, Japan
| | - Hisashi Tsurumi
- First Department of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Yoshinori Itoh
- Department of Pharmacy, Gifu University Hospital, 1-1 Yanagido, Gifu, 501-1194, Japan
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Murakami-Nakayama M, Tsubota M, Hiruma S, Sekiguchi F, Matsuyama K, Kimura T, Moriyama M, Kawabata A. Polaprezinc attenuates cyclophosphamide-induced cystitis and related bladder pain in mice. J Pharmacol Sci 2015; 127:223-8. [DOI: 10.1016/j.jphs.2015.01.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2014] [Revised: 01/09/2015] [Accepted: 01/14/2015] [Indexed: 01/05/2023] Open
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Zhang JY, Wu QF, Wan Y, Song SD, Xu J, Xu XS, Chang HL, Tai MH, Dong YF, Liu C. Protective role of hydrogen-rich water on aspirin-induced gastric mucosal damage in rats. World J Gastroenterol 2014; 20:1614-1622. [PMID: 24587639 PMCID: PMC3925872 DOI: 10.3748/wjg.v20.i6.1614] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2013] [Revised: 10/24/2013] [Accepted: 12/06/2013] [Indexed: 02/07/2023] Open
Abstract
AIM: To investigate the role of the hydrogen-rich water (HRW) in the prevention of aspirin-induced gastric mucosal injury in rats.
METHODS: Forty male rats were allocated into four groups: normal control group, HRW group, aspirin group, and HRW plus aspirin group. The protective efficacy was tested by determining the gastric mucosal damage score. Malondialdehyde (MDA), superoxide dismutase (SOD), myeloperoxidase (MPO), interleukin (IL)-06 and tumor necrosis factor (TNF)-α in gastric tissues were evaluated. The serum levels of IL-1β and TNF-α were also detected. Histopathology of gastric tissues and localization of Cyclooxygenase 2 (COX-2) were detected using hematoxylin and eosin staining and immunohistochemistry, respectively.
RESULTS: Pretreatment with HRW obviously reduced aspirin-induced gastric damage scores (4.04 ± 0.492 vs 2.10 ± 0.437, P < 0.05). The oxidative stress levels of MDA and MPO in the gastric tissues increased significantly in the aspirin-treated group compared with the HRW group (2.43 ± 0.145 vs 1.79 ± 0.116 nmol/mg prot, P < 0.05 and 2.53 ± 0.238 vs 1.40 ± 0.208 U/g tissue, P < 0.05, respectively). HRW could obviously elevated the SOD levels in the gastric tissues (37.94 ± 8.44 vs 59.55 ± 9.02 nmol/mg prot, P < 0.05). Pretreatment with HRW significantly reduced IL-06 and TNF-α in the gastric tissues (46.65 ± 5.50 vs 32.15 ± 4.83 pg/mg, P < 0.05 and 1305.08 ± 101.23 vs 855.96 ± 93.22 pg/mg, P < 0.05), and IL-1β and TNF-α in the serum (505.38 ± 32.97 vs 343.37 ± 25.09 pg/mL, P < 0.05 and 264.53 ± 28.63 vs 114.96 ± 21.79 pg/mL, P < 0.05) compared to treatment with aspirin alone. HRW could significantly decrease the COX-2 expression in the gastric tissues (staining score: 8.4 ± 2.1 vs 2.9 ± 1.5, P < 0.05).
CONCLUSION: HRW pretreatment alleviated the aspirin-induced gastric lesions by inhibiting the oxidative stress, inflammatory reaction and reducing the COX-2 in the gastric tissues.
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Yokooji T, Hamura K, Matsuo H. Intestinal absorption of lysozyme, an egg-white allergen, in rats: Kinetics and effect of NSAIDs. Biochem Biophys Res Commun 2013; 438:61-5. [DOI: 10.1016/j.bbrc.2013.07.024] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2013] [Accepted: 07/09/2013] [Indexed: 12/01/2022]
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Choi HS, Lim JY, Chun HJ, Lee M, Kim ES, Keum B, Seo YS, Jeen YT, Um SH, Lee HS, Kim CD, Ryu HS, Sul D. The effect of polaprezinc on gastric mucosal protection in rats with ethanol-induced gastric mucosal damage: comparison study with rebamipide. Life Sci 2013; 93:69-77. [PMID: 23743168 DOI: 10.1016/j.lfs.2013.05.019] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2013] [Revised: 05/06/2013] [Accepted: 05/22/2013] [Indexed: 02/07/2023]
Abstract
AIMS Polaprezinc (PZ), which consists of l-carnosine and zinc, is widely used to treat gastric ulcers. We compared the effects of PZ with those of rebamipide (RM) on the expression of inflammatory cytokines, antioxidants, growth factors, and heat shock proteins (HSP) in a rat model. MAIN METHODS Seventy Sprague-Dawley rats were randomly assigned to test groups according to the dose of PZ at 5, 10, or 30 mg/kg or RM at 10, 30, or 100 mg/kg. Next, we obtained ulcer indices from rats with ethanol-induced gastric mucosal damage. Western blot analysis was used to evaluate the expression of various target proteins. KEY FINDINGS Pathological ulcer indices in the PZ and RM groups were significantly lower than those in the control group. The levels of inflammatory cytokines (interleukin 1β [IL-1β], IL-6, IL-8, and tumor necrosis factor α) decreased, whereas the levels of platelet-derived growth factor-B, vascular endothelial growth factor, and nerve growth factor significantly increased after PZ administration. Furthermore, the expression of antioxidants (superoxide dismutase 1 [SOD-1], SOD-2, heme oxygenase-1, glutathione S-transferase, peroxidredoxin-1, and peroxidredoxin-5) was significantly higher in the PZ group, and the levels of HSP 90, 70, 60, 47, 27, and 10 significantly increased with an increase in PZ dose. SIGNIFICANCE In a rat model of ethanol-induced gastric mucosal damage, PZ administration ameliorated ethanol-induced mucosal injury and showed protective effects on the mucosa by reducing the levels of inflammatory cytokines and increasing the expression of antioxidant enzymes and growth factors. Furthermore, PZ showed cytoprotective effects by increasing the HSP levels.
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Affiliation(s)
- Hyuk Soon Choi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Institute of Digestive Disease and Nutrition, Korea University College of Medicine, Seoul, Republic of Korea
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Hasgul R, Uysal S, Haltas H, Akyol S, Yuksel Y, Gurel A, Armutcu F. Protective effects of Ankaferd blood stopper on aspirin-induced oxidative mucosal damage in a rat model of gastric injury. Toxicol Ind Health 2012; 30:888-95. [PMID: 23114375 DOI: 10.1177/0748233712466134] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The exposure of gastric mucosa to damaging factors, such as ethanol and some therapeutic drugs, produces pathological changes: inflammatory process, hemorrhagic erosions and even acute ulcers. Ankaferd blood stopper (ABS) comprises a standardized mixture of five different plant extracts. The purpose of our present investigations is to explain the participation of reactive oxygen species in acute gastric mucosal damage by acetylsalicylic acid (ASA) and the effects of new hemostatic agent ABS. Experiments were carried out on 23 male Wistar rats. To assess gastric mucosal damage, biochemical and histopathological data were used. The colorimetric assays were used to determine the malondialdehyde (MDA) and superoxide dismutase (SOD) activity. The level of myeloperoxidase (MPO) activity, the level of nitric oxide (NO) and the proinflammatory cytokine tumor necrosis factor-α (TNF-α) were measured by enzyme-linked immunosorbent assay technique. We demonstrated that the biological effects of ROS were estimated by measuring the tissue and plasma levels of MDA, the products of lipid peroxidation, as well as the activity of SOD and the scavenger of ROS produced by ASA in the experiment group. Moreover, it was found that MPO activity as well as NO and TNF-α levels also demonstrated significant improvement by ABS treatment. The pathogenesis of experimental ASA-induced mucosal damage in rat stomach includes the generation of ROS that seems to play an important role, due to the generation of lipid peroxides, accompanied by the impairment of antioxidative enzyme activity of cells. ABS appeared to attenuate the oxidative and inflammatory changes caused by ASA-induced gastric mucosal damage in rats.
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Affiliation(s)
- Rukiye Hasgul
- Department of Biochemistry, Faculty of Medicine, Fatih University, Ankara, Turkey
| | - Sema Uysal
- Department of Biochemistry, Numune Training and Research Hospital, Ankara, Turkey
| | - Hacer Haltas
- Department of Pathology, Faculty of Medicine, Fatih University, Ankara, Turkey
| | - Sumeyye Akyol
- Department of Biochemistry, Faculty of Medicine, Fatih University, Ankara, Turkey
| | - Yasemin Yuksel
- Department of Histology, Faculty of Medicine, Fatih University, Ankara, Turkey
| | - Ayse Gurel
- Department of Pharmacology, Faculty of Medicine, Fatih University, Ankara, Turkey
| | - Ferah Armutcu
- Department of Biochemistry, Faculty of Medicine, Fatih University, Ankara, Turkey
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Hill TL, Blikslager AT. Effect of a zinc L-carnosine compound on acid-induced injury in canine gastric mucosa ex vivo. Am J Vet Res 2012; 73:659-63. [PMID: 22533397 DOI: 10.2460/ajvr.73.5.659] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
OBJECTIVE To examine whether a zinc L-carnosine compound used for treatment of suspected gastric ulcers in dogs ameliorates acid-induced injury in canine gastric mucosa. SAMPLE Gastric mucosa from 6 healthy dogs. PROCEDURES Mucosa from the gastric antrum was harvested from 6 unadoptable shelter dogs immediately after euthanasia and mounted on Ussing chambers. The tissues were equilibrated for 30 minutes in neutral Ringer's solution prior to incubation with acidic Ringer's solution (HCl plus Ringer's solution [final pH, 1.5 to 2.5]), acidic Ringer's solution plus zinc L-carnosine compound, or zinc L-carnosine compound alone. Tissues were maintained for 180 minutes in Ussing chambers, during which permeability was assessed by measurement of transepithelial electrical resistance. After the 180-minute treatment period, tissues were removed from Ussing chambers and labeled with immunofluorescent anti-active caspase-3 antibody as an indicator of apoptosis. RESULTS Permeability of the gastric mucosa was significantly increased in a time-dependent manner by addition of HCl, whereas control tissues maintained viability for the study period. Change in permeability was detected within the first 15 minutes after acid application and progressed over the subsequent 150 minutes. The zinc L-carnosine compound had no significant effect on this increase in permeability. Apoptosis was evident in acid-treated tissues but not in control tissues. The zinc L-carnosine compound did not protect against development of apoptosis. CONCLUSIONS AND CLINICAL RELEVANCE Addition of HCl caused a dose-dependent increase in gastric permeability over time and apparent induction of apoptosis as determined on the basis of immunofluorescence. However, there was no significant protective effect of a zinc L-carnosine compound. Nonetheless, results suggested the utility of this method for further studies of canine gastric injury.
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Affiliation(s)
- Tracy L Hill
- Department of Clinical Science, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27607, USA
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Ko JK, Leung CC. Ginger extract and polaprezinc exert gastroprotective actions by anti-oxidant and growth factor modulating effects in rats. J Gastroenterol Hepatol 2010; 25:1861-8. [PMID: 21091998 DOI: 10.1111/j.1440-1746.2010.06347.x] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Contemporary medications used in the treatment of gastric ulcers involve the use of novel mucosal protective drugs. The present study aimed to investigate the gastroprotective effect of ginger extract and polaprezinc in a rat model of acetic acid-induced gastric ulcer. METHODS 'Kissing' ulcers were induced in male Sprague-Dawley rats by using 60% acetic acid. Rhizoma Zingiber officinale (ginger) extract (1.5-5 g/kg) or polaprezinc (30 and 60 mg/kg) was orally given to the animals once daily for three consecutive days after ulcer induction. All animals were killed on day 5 by an overdose of ketamine. RESULTS Both ginger extract and polaprezinc significantly reduce the gastric ulcer area in a dose-dependent manner, with concomitant attenuation of the elevated activities of xanthine oxidase and myeloperoxidase, as well as malondialdehyde level in the ulcerated mucosa. Nevertheless, only polaprezinc could restore the mucosal glutathione level. Polaprezinc also causes the overexpression of basic fibroblast growth factor, vascular endothelial growth factor and ornithine decarboxylase, whereas ginger extract only increases the expression of the two growth factors in the gastric mucosa. Furthermore, polaprezinc could consistently downregulate the protein expression of tumor necrosis factor (TNF)-α, interleukin-1β, macrophage inflammatory protein-2 and cytokine-induced neutrophil chemoattractant-2α that have been activated in the ulcerated tissues, whereas ginger extract mainly inhibits the expression of the chemokines and to some extent TNF-α. CONCLUSION Ginger extract and polaprezinc both show anti-oxidation that consequently alleviates gastric mucosal damage and promotes ulcer healing, which together serve as effective mucosal protective agents.
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Affiliation(s)
- Joshua K Ko
- Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.
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Baan M, Sherding RG, Johnson SE. Effects of zinc-L-carnosine and vitamin E on aspirin-induced gastroduodenal injury in dogs. J Vet Intern Med 2010; 25:39-46. [PMID: 21092006 DOI: 10.1111/j.1939-1676.2010.0638.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND Nonsteroidal anti-inflammatory drugs frequently cause gastrointestinal (GI) injury. Zinc-L-carnosine has antioxidant, anti-inflammatory, mucosal protective, and healing properties in rodent models and in some human studies of GI injury. HYPOTHESIS The combination of zinc-L-carnosine and vitamin E attenuates aspirin-induced gastroduodenal mucosal injury. ANIMALS Eighteen healthy random-source Foxhound dogs. METHODS In this randomized, double-blinded, placebo-controlled study dogs were treated with placebo (n = 6; 0X group), 30 mg/30 IU (n = 6; 1X group), or 60 mg/60 IU (n = 6; 2X group) zinc-L-carnosine/vitamin E orally every 12 hours for 35 days. Between Day 7 and 35, GI mucosal lesions were induced with aspirin (25 mg/kg p.o. q8h). Mucosal injury lesions (hemorrhage, erosion, and ulcer) were assessed by gastroduodenoscopy on Days 14, 21, and 35 with a 12-point scoring scale. RESULTS At baseline (Day -1) gastroscopy scores were not significantly different between groups (mean ± SD: 0X, 4.4 ± 0.8; group 1X, 4.4 ± 0.6; group 2X, 4.2 ± 0.3; P= .55). Gastroscopy scores increased significantly in all groups between Day -1 and Days 14, 21, and 35 (P < .0001). On Day 35, gastroscopy scores were 29.2 ± 5.2 (0X), 27.3 ± 3.7 (1X), and 28.6 ± 3.3 (2X). Mean gastroscopy scores were not significantly different among treatment groups on any of the days (P = .61). CONCLUSIONS AND CLINICAL IMPORTANCE Administration of the combination of zinc-L-carnosine and vitamin E at 1X or 2X dosing did not attenuate aspirin-induced gastroduodenal mucosal injury.
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Affiliation(s)
- M Baan
- Department of Medical Sciences, School of Veterinary Medicine, The University of Wisconsin-Madison, Madison, WI 53706, USA.
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Elseweidy MM, Taha MM, Younis NN, Ibrahim KS, Hamouda HA, Eldosouky MA, Soliman H. Gastritis induced by Helicobacter pylori infection in experimental rats. Dig Dis Sci 2010; 55:2770-2777. [PMID: 20094782 DOI: 10.1007/s10620-009-1103-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2009] [Accepted: 12/10/2009] [Indexed: 02/08/2023]
Abstract
BACKGROUND Gastritis, an inflammation of gastric mucosa, may be due to many pathological factors and infection, such as with Helicobacter pylori. The use of experimental models of gastritis is important to evaluate the biochemical changes and study chemotherapeutic intervention. In a previous study we demonstrated an acute gastritis model induced by iodoacetamide. AIMS Our objective in this study was to evaluate a new gastritis model induced by H. pylori infection in experimental rats in terms of certain biomarkers in serum and mucosal tissues in addition to histopathological examination. METHODS Gastritis was induced in 20 albino Wistar rats by H. pylori isolated from antral biopsy taken from a 49-year-old male patient endoscopically diagnosed as having H. pylori infection. Another ten rats were used as controls. Serum gastrin, pepsinogen I activity, interleukin-6 (IL-6) and gastric mucosal myeloperoxidase (MPO) activity and prostaglandin E(2) (PGE(2)) were measured. Immunostaining for inducible nitric oxide synthase (iNOS), nitrotyrosine and DNA fragmentation were used to further evaluate H. pylori-induced gastritis. RESULTS Serum gastrin, IL-6, mucosal MPO activity, and PGE(2) demonstrated significant increases joined with a decreased serum pepsinogen I activity (P < 0.001). Immunohistochemistry demonstrated positive reaction for iNOS, nitrotyrosine and DNA fragmentation. CONCLUSIONS Helicobacter pylori-induced gastritis models demonstrated massive oxidative stress and pronounced injury in mucosal tissue. Since our model in rats reflected the clinical picture of H. pylori infection, it can be considered as a consistent model to study chemotherapeutic intervention for this type of gastritis.
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Affiliation(s)
- Mohamed M Elseweidy
- Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.
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Watanabe T, Ishihara M, Matsuura K, Mizuta K, Itoh Y. Polaprezinc prevents oral mucositis associated with radiochemotherapy in patients with head and neck cancer. Int J Cancer 2010; 127:1984-90. [PMID: 20104529 DOI: 10.1002/ijc.25200] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Oral mucositis is frequent but serious adverse event associated with radiotherapy or radiochemotherapy in head and neck cancer severely impairs health-related quality of life, leading to poor prognosis due to discontinuation of the therapy. Although a number of compounds have been tested for prophylaxis of oral mucositis, few of them are satisfactory. We investigated the effect of polaprezinc (zinc L-carnosine), a gastric mucosal protective drug, on radiochemotherapy-induced oral mucositis, pain, xerostomia and taste disturbance in patients with head and neck cancer. Patients were randomly assigned to receive polaprezinc (n = 16) or azulene oral rinse as the control (n = 15). The incidence rates of mucositis, pain, xerostomia and taste disturbance were all markedly lower in polaprezinc group than in control. Moreover, the use of analgesics was significantly (p = 0.003) less frequent and the amount of food intake was significantly (p = 0.002) higher in polaprezinc group than in control. On the other hand, tumor response rate in patients with neoadjuvant radiochemotherapy was not significantly affected by polaprezinc, in which the response rate (complete plus partial response) was 88% for polaprezinc and 92% for control (p = 1.000). Therefore, it is highly assumable that polaprezinc is potentially useful for prevention of oral mucositis and improvement of quality of life without reducing the tumor response.
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Affiliation(s)
- Tomoko Watanabe
- Department of Pharmacy, Gifu University Hospital, 1-1 Yanagido, Gifu, Japan
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Hipkiss AR. Carnosine and its possible roles in nutrition and health. ADVANCES IN FOOD AND NUTRITION RESEARCH 2009; 57:87-154. [PMID: 19595386 DOI: 10.1016/s1043-4526(09)57003-9] [Citation(s) in RCA: 150] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/28/2023]
Abstract
The dipeptide carnosine has been observed to exert antiaging activity at cellular and whole animal levels. This review discusses the possible mechanisms by which carnosine may exert antiaging action and considers whether the dipeptide could be beneficial to humans. Carnosine's possible biological activities include scavenger of reactive oxygen species (ROS) and reactive nitrogen species (RNS), chelator of zinc and copper ions, and antiglycating and anticross-linking activities. Carnosine's ability to react with deleterious aldehydes such as malondialdehyde, methylglyoxal, hydroxynonenal, and acetaldehyde may also contribute to its protective functions. Physiologically carnosine may help to suppress some secondary complications of diabetes, and the deleterious consequences of ischemic-reperfusion injury, most likely due to antioxidation and carbonyl-scavenging functions. Other, and much more speculative, possible functions of carnosine considered include transglutaminase inhibition, stimulation of proteolysis mediated via effects on proteasome activity or induction of protease and stress-protein gene expression, upregulation of corticosteroid synthesis, stimulation of protein repair, and effects on ADP-ribose metabolism associated with sirtuin and poly-ADP-ribose polymerase (PARP) activities. Evidence for carnosine's possible protective action against secondary diabetic complications, neurodegeneration, cancer, and other age-related pathologies is briefly discussed.
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Affiliation(s)
- Alan R Hipkiss
- School of Clinicial and Experimental Medicine, College of Medical and Dental Sciences, The Univeristy of Birmingham, Edgbaston, Birmingham, UK
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Elseweidy MM, Younis NN, Amin RS, Abdallah FR, Fathy AM, Yousif ZA. Effect of some natural products either alone or in combination on gastritis induced in experimental rats. Dig Dis Sci 2008; 53:1774-1784. [PMID: 18368490 DOI: 10.1007/s10620-008-0246-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2004] [Accepted: 07/12/2005] [Indexed: 02/08/2023]
Abstract
Gastritis, an inflammatory state in gastric mucosa, can be induced experimentally in various ways. The present study considered the iodoacetamide model (Iodo). Omega-3 fatty acids (fish oil), black seed oil, and curcuminoids (natural products) in addition to omeprazole (synthetic proton-pump inhibitor) were tested. Supplementation of 0.1% iodoacetamide to drinking water of experimental rats for two consecutive weeks resulted in: (i) increased serum nitric oxide (NO) and gastrin, and decreased pepsinogen, (ii) depletion of gastric mucosal glutathione (GSH), and (iii) increased gastric mucosal lipid peroxidation (MDA), but failed to affect gastric mucosal myeloperoxidase (MPO) activity. Histological examination showed marked neutrophilic infiltration after 1 week of iodoacetamide administration and shedding of apical cell layer with pale edematous vacuolated gastric gland cells and thickening of muscularis mucosa after 2 weeks of iodoacetamide intake. Individual administration of omega-3 fatty acids 12 mg/kg, black seed oil 50 mg/kg, and curcuminoids 50 mg/kg body weight orally daily for 3 weeks decreased MDA, gastrin, and NO, and normalized mucosal GSH but failed to affect serum pepsinogen level. Combined administration of these natural products for 3 weeks normalized MPO activity, and other effects were nearly the same as with individual use. Omeprazole administration 30 mg/kg body weight orally daily for 3 weeks induced a similar response except for an observed increase in serum gastrin and pepsinogen levels.
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Affiliation(s)
- Mohamed M Elseweidy
- Biochemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.
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Suzuki T, Yoshida N, Nakabe N, Isozaki Y, Kajikawa H, Takagi T, Handa O, Kokura S, Ichikawa H, Naito Y, Matsui H, Yoshikawa T. Prophylactic effect of rebamipide on aspirin-induced gastric lesions and disruption of tight junctional protein zonula occludens-1 distribution. J Pharmacol Sci 2008; 106:469-77. [PMID: 18360096 DOI: 10.1254/jphs.fp0071422] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Aspirin and nonsteroidal anti-inflammatory agents are known to induce gastroduodenal complications such as ulcer, bleeding, and dyspepsia. In this study, we examined the prophylactic effect of rebamipide, an anti-ulcer agent with free-radical scavenging and anti-inflammatory effect, on acidified aspirin-induced gastric mucosal injury in rats. In addition, we investigated the mucosal barrier functions disrupted by aspirin. Oral administration of acidified aspirin resulted in linear hemorrhagic erosions with increasing myeloperoxidase activity and thiobarbituric acid-reactive substance concentrations in the gastric mucosa. Rebamipide suppressed these acidified aspirin-induced gastric lesions and inflammatory changes significantly, and its protective effect was more potent in the case of repeated (twice daily for 3 days) treatment than single treatment before aspirin administration. Immunostaining of zonula occludens (ZO)-1, one of the tight junctional proteins, was strengthened in rat gastric mucosa after repeated administration of rebamipide. In addition, aspirin induced the increasing transport of fluorescine isothiocyanate-labeled dextrans with localized disruption and decreased expression of ZO-1 protein on rat gastric mucosal cell line RGM-1. Rebamipide effectively prevented aspirin-induced permeability changes and disruption of ZO-1 distribution. These results suggest that rebamipide protects against aspirin-induced gastric mucosal lesions by preserving gastric epithelial cell-to cell integrity in addition to the anti-inflammatory effects.
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Affiliation(s)
- Takahiro Suzuki
- Inflammation and Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Japan
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Ohkawara T, Nishihira J, Nagashima R, Takeda H, Asaka M. Polaprezinc protects human colon cells from oxidative injury induced by hydrogen peroxide: Relevant to cytoprotective heat shock proteins. World J Gastroenterol 2006; 12:6178-81. [PMID: 17036391 PMCID: PMC4088113 DOI: 10.3748/wjg.v12.i38.6178] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.9] [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 investigate the effect of polaprezinc on cellular damage induced by hydrogen peroxide (H2O2) in human colon CaCo2 cells.
METHODS: CaCo2 cells were treated with polaprezinc (10-100 μmol/L) for 6 h. After polaprezinc treatment, the cells were incubated with H2O2 (20 μmol/L) for 1 h. Cell viability was measured by MTT assay. Western blot analysis for heat shock protein (HSP) 27 and HSP72 in the cells was performed. Moreover, cells were pretreated with quercetin (200 μmol/L), an inhibitor of HSP synthesis, 2 h before polaprezinc treatment, and cell viability and the expression of HSP27 and 72 were assessed in these cells.
RESULTS: Polaprezinc significantly protected CaCo2 cells from cell damage induced by H2O2, and up-regulated the expressions of HSP27 and HSP72 in the cells (10, 30 and 100 μmol/L of polaprezinc; 35.0% ± 7.7%, 58.3% ± 14.6% and 64.2% ± 8.2%, respectively. P < 0.01 versus polaprezinc-nontreated cells; 6.0% ± 4.4%). Quercetin inhibited the up-regulation of HSP27 and HSP72 by polaprezinc and diminished the protective effect of polaprezinc against H2O2-caused injury in the cells.
CONCLUSION: Polaprezinc is a useful therapeutic agent for treatment of colitis and its effects depend on the function of cytoprotective HSP in colon.
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Affiliation(s)
- Tatsuya Ohkawara
- Department of Gastroenterology and Hematology, Hokkaido University Graduate School of Medicine, Kita15, Nishi7, Kita-ku, 060-8678 Sapporo, Japan.
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Ichikawa H, Yoshida N, Takagi T, Handa O, Naito Y, Okanoue T, Yoshikawa T. Administration of FR167653, a New Anti-Inflammatory Compound, Inhibits Aspirin-Induced Gastric Mucosal Injury in Rats. J Clin Biochem Nutr 2006. [DOI: 10.3164/jcbn.39.69] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
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Ohkawara T, Takeda H, Kato K, Miyashita K, Kato M, Iwanaga T, Asaka M. Polaprezinc (N-(3-aminopropionyl)-L-histidinato zinc) ameliorates dextran sulfate sodium-induced colitis in mice. Scand J Gastroenterol 2005; 40:1321-7. [PMID: 16334442 DOI: 10.1080/00365520510023530] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Polaprezinc (N-(3-Aminopropionyl)-L-histidinato zinc), an anti-ulcer drug, has been reported to have an anti-inflammatory action in several inflammatory diseases. The aim of this study was to investigate the effect of polaprezinc on dextran sulfate (DSS)-induced colitis in mice. MATERIAL AND METHODS Mice with colitis induced by DSS were intrarectally treated with polaprezinc (15 mg/kg) or zinc sulfate (7.5 mg/kg) every day after the administration of DSS for 7 days. Disease activity index (DAI) and histological tissue damage were assessed. Levels of myeloperoxidase (MPO) activity, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma in the colon were measured. Expression of heat shock protein (HSP) 25 and HSP70 in the colon was analyzed by Western blot analysis. RESULTS DAI and histological scores were remarkably reduced in polaprezinc-treated mice with DSS-induced colitis. Polaprezinc suppressed the increase of MPO activity and the production of TNF-alpha and IFN-gamma in the colon tissues of mice with DSS-induced colitis. Expression of HSP25 and HSP70 was remarkably up-regulated in the colon tissues of polaprezinc-treated mice during DSS treatment. CONCLUSIONS Polaprezinc suppresses DSS-induced colitis in mice, partly through inhibition of production of pro-inflammatory cytokine, suppression of neutrophils accumulation and cytoprotection by overexpression of HSPs. Polaprezinc could be useful in the treatment of inflammatory bowel diseases.
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Affiliation(s)
- Tatsuya Ohkawara
- Department of Gastroenterology and Hematology, Hokkaido University Graduate School of Medicine, Sapporo, 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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Ishiwata Y, Okamoto M, Yokochi S, Hashimoto H, Nakamura T, Miyachi A, Naito Y, Yoshikawa T. Non-steroidal anti-inflammatory drug, nabumetone, prevents indometacin-induced gastric damage via inhibition of neutrophil functions. J Pharm Pharmacol 2003; 55:229-37. [PMID: 12635655 DOI: 10.1211/002235702478] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Nabumetone is a non-steroidal anti-inflammatory drug (NSAID). It works as a prodrug and is extensively metabolized to an active metabolite, 6-methoxy-2-naphthylacetic acid (6MNA). It is well known that neutrophil infiltration and activation are critical in the pathogenesis of NSAID-induced gastric injury, and nabumetone shows less incidence of gastrointestinal irritancy. We examined the effects of nabumetone on neutrophil activation and on indometacin-induced gastric damage. In the indometacin-induced gastric mucosal injury, rats were treated with indometacin and then nabumetone or 6MNA was orally administered. Nabumetone prevented gastric damage accompanied by the reduction of neutrophil infiltration into gastric mucosa, but such an effect was not observed with 6MNA. Nabumetone reduced the formyl methionyl leucyl phenylalanine (fMLP)-induced respiratory burst of human neutrophils to 30% of the control level in-vitro, but 6MNA did not. In addition, nabumetone prevented the fMLP-induced migration of neutrophils. Nabumetone did not inhibit O2- generation in the xanthine-xanthine oxidase system. These results suggest that nabumetone prevents gastric damage induced by the active metabolite, 6MNA, via the suppression of neutrophil activation in gastric mucosa.
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Affiliation(s)
- Yoshiro Ishiwata
- Central Research Laboratory, Sanwa Kagaku Kenkyusho Co. Ltd, Mie, Japan.
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Abstract
Gastroduodenal mucosal defense is composed of structural features of the mucosa, cellular monitors of pending or actual injury, and a web of effector cells that protect the mucosa from damage and govern its recovery from injury. By virtue of these systems, the gastroduodenal mucosa can cope with the harmful ingredients of ingested food and the potentially deleterious effects of gastric acid and pepsin. It is increasingly appreciated that a network of chemical messengers coordinates the alarm, defensive, and healing mechanisms. This article highlights some of the advances from the past year that have furthered our understanding of the regulatory systems that govern gastroduodenal mucosal homeostasis. Particular emphasis is given to control of the mucous and epithelial phospholipid barriers, the mucosal microcirculation, and the epithelial, neural, immune, and inflammatory mediators of the mucosal repair mechanisms.
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Affiliation(s)
- P Holzer
- Department of Experimental and Clinical Pharmacology, University of Graz, Austria.
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