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Zhang R, Fan J, Zhang Z, Wang Y, Dai W, Liu J. Exploring the bioactive components and mechanism of Biling Weitong Granules in chronic gastric ulcer repair through network analysis and experimental verification. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-04193-w. [PMID: 40299017 DOI: 10.1007/s00210-025-04193-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Accepted: 04/15/2025] [Indexed: 04/30/2025]
Abstract
Biling Weitong Granules (BLWTG) is a clinical formula employed for treating epigastric pain, yet its pharmacodynamic components and mechanisms against chronic gastric ulcers (GU) remain inadequately understood. The objective of this study was to investigate the targets and mechanisms of BLWTG and its bioactive components in chronic GU. Chronic GU model was induced in SD rats through acetic acid injection, and administered BLWTG post-induction. The macroscopic ulcer appearance, microscopic histology, mucosal growth, vascular promoting factors, myeloperoxidase, and inflammatory factors in gastric tissue were assessed. Network analysis was used to predict the potential core targets and pathways. Further, bioactive components were screened based on cell model, identified by HPLC-QTOF-MS and validated in vivo. The results showed that BLWTG effectively mitigated pathological damage, achieving a 63.32% ulcer healing rate. Network analysis and experimental verification showed that the effectiveness of BLWTG stemmed from its capacity lower oxidative stress and inflammation, boost antioxidant levels, and promote the synthesis of gastric mucosal protective factors and repair. Further, the primary active fraction of BLWTG was ethyl acetate fraction, which increased the ulcer healing rate to 75.04%. Among the 55 compounds identified in the ethyl acetate fraction of BLWTG, evodiamine, dehydroevodiamine, berberine and tetrahydropalmatine may represent the active components responsible for facilitating the regeneration and repair of GU. In conclusion, BLWTG and its bioactive components significantly promote healing in rat models of chronic GU, providing a scientific basis for further applications of BLWTG in treating chronic GU.
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Affiliation(s)
- Rui Zhang
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, Jiangsu, China
| | - Jifa Fan
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, Jiangsu, China
| | - Zimeng Zhang
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, Jiangsu, China
| | - Yongxiang Wang
- Yangtze River Pharmaceutical (Group) C., Ltd, Taizhou, 225321, Jiangsu, China
| | - Wenling Dai
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, Jiangsu, China.
| | - Jihua Liu
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, Jiangsu, China.
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, Jiangsu, China.
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Ohara R, Dario FL, Emílio-Silva MT, Assunção R, Rodrigues VP, Bueno G, Raimundo PR, Justulin LA, da Rocha LRM, Hiruma-Lima CA. A high-fat diet changes the interaction of the extracellular matrix, cytokines, and growth factors in gastric ulcer repair. Biochem Biophys Res Commun 2025; 755:151565. [PMID: 40043617 DOI: 10.1016/j.bbrc.2025.151565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2024] [Revised: 02/18/2025] [Accepted: 02/28/2025] [Indexed: 03/17/2025]
Abstract
BACKGROUND Obesity is characterized by persistent low-grade inflammation that alters the gastrointestinal system and healing process. The link between obesity and the prevalence of stomach ulcers has not yet been fully established. AIMS We investigated the healing features of gastric lesions in male Swiss mice fed a standard diet (SD) or high-fat diet (HFD) using morphometric, biochemical, and molecular parameters. METHODS After 12 weeks on different diets, the animals underwent acetic acid-induced stomach ulcer surgery. To evaluate healing patterns, the stomachs of the animals were studied at five post-induction times, including the early, middle, and late phases of healing (1, 3, 7, 10, and 14 days). Morphometric features, activity of matrix metalloproteinases 2 and 9 (MMP-2 and 9), and measurement of inflammatory and growth factors were investigated using multiplex immunoassays. RESULTS Compared with the SD group, the HFD group demonstrated slowing of the early healing process. During the initial phase of the healing process, the SD group had significantly higher levels of EGF, VEGF-A, and VEGF-D than the HFD group. In the intermediate phase, only the SD group showed a 70 % increase in the regeneration area compared with the initial phase of the procedure. In this phase, the SD group also had higher levels of MMP-9, VEGF-D, and HGF than the HFD group. CONCLUSIONS HFD can have a negative impact on the healing process of gastric ulcers in animals by delaying repair in gastric tissue when compared with animals consuming SD.
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Affiliation(s)
- Rie Ohara
- Department of Structural and Functional Biology, Physiology Sector, Institute of Biosciences, São Paulo State University (UNESP), Botucatu, São Paulo, Brazil.
| | - Felipe Lima Dario
- Department of Structural and Functional Biology, Physiology Sector, Institute of Biosciences, São Paulo State University (UNESP), Botucatu, São Paulo, Brazil
| | - Maycon Tavares Emílio-Silva
- Department of Structural and Functional Biology, Physiology Sector, Institute of Biosciences, São Paulo State University (UNESP), Botucatu, São Paulo, Brazil
| | - Renata Assunção
- Department of Structural and Functional Biology, Physiology Sector, Institute of Biosciences, São Paulo State University (UNESP), Botucatu, São Paulo, Brazil
| | - Vinícius Peixoto Rodrigues
- Department of Structural and Functional Biology, Physiology Sector, Institute of Biosciences, São Paulo State University (UNESP), Botucatu, São Paulo, Brazil
| | - Gabriela Bueno
- Department of Structural and Functional Biology, Physiology Sector, Institute of Biosciences, São Paulo State University (UNESP), Botucatu, São Paulo, Brazil
| | - Priscila Romano Raimundo
- Department of Structural and Functional Biology, Physiology Sector, Institute of Biosciences, São Paulo State University (UNESP), Botucatu, São Paulo, Brazil
| | - Luis Antonio Justulin
- Department of Structural and Functional Biology, Morphology Sector, Institute of Biosciences, São Paulo State University (UNESP), Botucatu, São Paulo, Brazil
| | - Lúcia Regina Machado da Rocha
- Department of Structural and Functional Biology, Physiology Sector, Institute of Biosciences, São Paulo State University (UNESP), Botucatu, São Paulo, Brazil
| | - Clelia Akiko Hiruma-Lima
- Department of Structural and Functional Biology, Physiology Sector, Institute of Biosciences, São Paulo State University (UNESP), Botucatu, São Paulo, Brazil
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de Paula Freire G, Almeida Filho LCP, Ribeiro PRV, Nunes PIG, de Lima RP, Portela BYM, de Brito ES, Alves APNN, Viana DDA, Carvalho ADFFU, Santos FA. Gastroprotective and Ulcer Healing Effects of Lonchocarpus sericeus Seed Extract in Rodents. REVISTA BRASILEIRA DE FARMACOGNOSIA 2024; 34:1298-1312. [DOI: 10.1007/s43450-024-00577-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Accepted: 07/18/2024] [Indexed: 01/02/2025]
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Arabacı Tamer S, Mermer KS, Erdoğan Ö, Çevik Ö, Ercan F, Bağcı C, Yeğen BÇ. Neuropeptide W facilitates chronic gastric ulcer healing by the regulation of cyclooxygenase and NF-κB signaling pathways. Inflammopharmacology 2024; 32:1519-1529. [PMID: 38227096 PMCID: PMC11006733 DOI: 10.1007/s10787-023-01403-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Accepted: 11/24/2023] [Indexed: 01/17/2024]
Abstract
AIMS Putative beneficial effects of neuropeptide W (NPW) in the early phase of gastric ulcer healing process and the involvement of cyclooxygenase (COX) enzymes were investigated in an acetic acid-induced gastric ulcer model. MAIN METHODS In anesthetized male Sprague-Dawley rats, acetic acid was applied surgically on the serosa and then a COX-inhibitor (COX-2-selective NS-398, COX-1-selective ketorolac, or non-selective indomethacin; 2 mg/kg/day, 3 mg/kg/day or 5 mg/kg/day; respectively) or saline was injected intraperitoneally. One h after ulcer induction, omeprazole (20 mg/kg/day), NPW (0.1 μg/kg/day) or saline was intraperitoneally administered. Injections of NPW, COX-inhibitors, omeprazole or saline were continued for the following 2 days until rats were decapitated at the end of the third day. KEY FINDINGS NPW treatment depressed gastric prostaglandin (PG) I2 level, but not PGE2 level. Similar to omeprazole, NPW treatment significantly reduced gastric and serum tumor necrosis factor-alpha and interleukin-1 beta levels and depressed the upregulation of nuclear factor kappa B (NF-κB) and COX-2 expressions due to ulcer. In parallel with the histopathological findings, treatment with NPW suppressed ulcer-induced increases in myeloperoxidase activity and malondialdehyde level and replenished glutathione level. However, the inhibitory effect of NPW on myeloperoxidase activity and NPW-induced increase in glutathione were not observed in the presence of COX-1 inhibitor ketorolac or the non-selective COX-inhibitor indomethacin. SIGNIFICANCE In conclusion, NPW facilitated the healing of gastric injury in rats via the inhibition of pro-inflammatory cytokine production, oxidative stress and neutrophil infiltration as well as the downregulation of COX-2 protein and NF-κB gene expressions.
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Affiliation(s)
- Sevil Arabacı Tamer
- Department of Physiology, Sakarya University School of Medicine, Sakarya, Turkey
| | - Kadriye Sezen Mermer
- Department of Physiology, Marmara University School of Medicine, Istanbul, Turkey
| | - Ömer Erdoğan
- Faculty of Medicine, Department of Biochemistry, Aydın Adnan Menderes University, Aydın, Turkey
| | - Özge Çevik
- Faculty of Medicine, Department of Biochemistry, Aydın Adnan Menderes University, Aydın, Turkey
| | - Feriha Ercan
- Department of Histology & Embryology, Marmara University School of Medicine, Istanbul, Turkey
| | - Cahit Bağcı
- Department of Physiology, Sakarya University School of Medicine, Sakarya, Turkey
| | - Berrak Ç Yeğen
- Department of Physiology, Marmara University School of Medicine, Istanbul, Turkey.
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Rodrigues MDF, da Silva JW, de Lima JS, Ramos BDA, Paz ST, Lomonaco D, Zampieri D, Ximenes RM. Antiulcer activity of Mauritia flexuosa L.f. (Arecaceae) pulp oil: An edible Amazonian species with functional properties. Fitoterapia 2024; 174:105857. [PMID: 38354821 DOI: 10.1016/j.fitote.2024.105857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 02/06/2024] [Accepted: 02/11/2024] [Indexed: 02/16/2024]
Abstract
Mauritia flexuosa, known as buriti in Brazil, is a widespread palm tree in Amazonia. It has many ethnobotanical uses, including food, oil, and medicine. The oil obtained from buriti's fruit pulp has high levels of monounsaturated fatty acids, carotenoids, and tocopherols, and is used in the food, cosmetic, and pharmaceutical industries for its antioxidant properties. Many biological activities have been reported for buriti oil, such as antioxidant, antimicrobial, chemopreventive, and immunomodulatory. Due to its high content of bioactive compounds, buriti oil is considered a functional ingredient with possible benefits in preventing oxidative stress and chronic diseases, particularly in the gastrointestinal tract. Peptic ulcer disease is a multifactorial disorder, involving lesions in the stomach and duodenum mucosa, which has a complex healing process. In this context, some nutrients and bioactive compounds help the maintenance of gastrointestinal mucosal integrity and function, such as carotenoids, tocopherols, and unsaturated fatty acids, which makes buriti oil an interesting candidate to be used in the prevention and management of gastrointestinal diseases. This study aimed to evaluate the gastroprotective and antiulcer effects of buriti oil and its possible mechanisms of action. Buriti oil reduced the ulcerative area and lipid peroxidation induced by ethanol. The gastroprotective activity of buriti oil partially depends on nitric oxide and sulfhydryl compounds. In acetic acid-induced gastric ulcers, buriti oil accelerated healing and stimulated the formation of new gastric glands. These results demonstrated the potential of buriti oil as a functional ingredient to promote health benefits in the gastrointestinal tract.
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Affiliation(s)
- Maria de Fátima Rodrigues
- Departamento de Antibióticos, Universidade Federal de Pernambuco, Recife 50740-525, Pernambuco, Brazil
| | - José Wellinton da Silva
- Departamento de Antibióticos, Universidade Federal de Pernambuco, Recife 50740-525, Pernambuco, Brazil
| | - Jucielma Silva de Lima
- Departamento de Antibióticos, Universidade Federal de Pernambuco, Recife 50740-525, Pernambuco, Brazil
| | - Bárbara de Azevedo Ramos
- Departamento de Antibióticos, Universidade Federal de Pernambuco, Recife 50740-525, Pernambuco, Brazil
| | - Silvania Tavares Paz
- Departamento de Patologia, Universidade Federal de Pernambuco, Recife 50670-910, Pernambuco, Brazil
| | - Diego Lomonaco
- Departamento de Química Orgânica e Inorgânica, Universidade Federal do Ceará, Fortaleza 60440-900, Ceará, Brazil
| | - Davila Zampieri
- Departamento de Química Orgânica e Inorgânica, Universidade Federal do Ceará, Fortaleza 60440-900, Ceará, Brazil
| | - Rafael Matos Ximenes
- Departamento de Antibióticos, Universidade Federal de Pernambuco, Recife 50740-525, Pernambuco, Brazil.
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Simomura VL, Miorando D, de Oliveira BMM, Mânica A, Bohnen LC, Buzatto MV, Kunst FM, Ansolin LD, Somensi LB, Vidal Gutiérrez M, Venzon L, de Queiroz E Silva TF, Mota da Silva L, Roman Junior WA. Aqueous extract of the bark of Uncaria tomentosa, an amazonian medicinal plant, promotes gastroprotection and accelerates gastric healing in rats. JOURNAL OF ETHNOPHARMACOLOGY 2024; 321:117542. [PMID: 38056537 DOI: 10.1016/j.jep.2023.117542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 11/29/2023] [Accepted: 11/30/2023] [Indexed: 12/08/2023]
Abstract
ETHNOPHARMACOLOGICAL IMPORTANCE Uncaria tomentosa Willd. DC., is used in the Amazonian region of South America, wherein ethnic groups use the plant to treat diseases, including gastric disorders. However, despite its widespread popular use, this species has yet to be assessed for its anti-ulcer effects. AIM OF THE STUDY In this study, we aimed to evaluate the in vivo gastroprotective and gastric healing activities of an aqueous extract of the bark of Uncaria tomentosa (AEUt) and sought to gain an understanding of the pharmacological mechanisms underlying these biological effects. MATERIALS AND METHODS To verify the gastroprotective properties rats were treated with AEUt (30, 60, or 120 mg/kg) prior to inducing gastric ulceration with ethanol or piroxicam. Additionally, the involvement of nitric oxide, non-protein sulfhydryl compounds (NP-SH), α-2 adrenergic receptors, and prostaglandins was investigated. Furthermore, a pylorus ligature model was employed to investigate the antisecretory activity of AEUt. The gastric healing effects of AEUt (60 mg/kg) were examined in rats in which ulceration had been induced with 80% acetic acid, whereas the quality of healing was evaluated in mice with interleukin-induced recurrent ulcers. We also evaluated the in vivo thickness of the gastric wall using ultrasonography. Moreover, the levels of reduced glutathione (GSH) and malondialdehyde (MDA) were evaluated in ulcerated mucosa, and we determined the activities of the enzymes myeloperoxidase (MPO), N-acetyl-β-D-glycosaminidase, superoxide dismutase, catalase, and glutathione S-transferase. In addition, we assessed the effects of AEUt on cell viability and subjected the AEUt to phytochemical analyses. RESULTS Administration of the AEUt (60 or 120 mg/kg) prevented ethanol- and piroxicam-induced ulceration, which was also confirmed histologically. Moreover, we observed that pre-treatment with NEM and indomethacin abolished the gastroprotective effects of AEUt, thereby indicating the involvement of NP-SH and prostaglandins in these protective effects. In addition, we found that the administration of AEUt had no appreciable effects on the volume, acidity, or peptic activity of gastric juice. Furthermore, the AEUt (60 mg/kg) accelerated the gastric healing of acetic acid-induced ulcers by 46.2% and ultrasonographic findings revealed a reduction in the gastric wall thickness in this group. The gastric healing effect of AEUt was also accompanied by a reduction in MPO activity. The AEUt (60 mg/kg) also minimized ulcer recurrence in mice exposed to IL-1β and was associated with the maintenance of GSH levels and a reduction in MDA contents. We deduce that the biological effects of AEUt could be associated with the activities of polyphenols and the alkaloids isomitraphylline and mitraphylline, identified as predominant constituents of the AEUt. Furthermore, we found no evidence to indicate that AEUt would have any cytotoxic effects. CONCLUSION Collectively, our findings provide compelling evidence indicating the therapeutic efficacy of U. tomentosa. Our data indicate that compounds in AEUt confer gastroprotection and that this preventive effect of AEUt was accompanied by gastric healing and a reduction in gastric ulcer recurrence. Moreover, we provide evidence to indicate that the gastroprotective and gastric healing effects involve the antioxidant system and anti-inflammatory responses that contribute to preserving the gastric mucosa.
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Affiliation(s)
- Viviane Lazari Simomura
- Postgraduate Program in Health Sciences, Community University of Chapecó Region, CEP 89809-900, Chapecó, SC, Brazil.
| | - Daniela Miorando
- Postgraduate Program in Health Sciences, Community University of Chapecó Region, CEP 89809-900, Chapecó, SC, Brazil.
| | | | - Aline Mânica
- Postgraduate Program in Health Sciences, Community University of Chapecó Region, CEP 89809-900, Chapecó, SC, Brazil.
| | - Lilian Caroline Bohnen
- Postgraduate Program in Health Sciences, Community University of Chapecó Region, CEP 89809-900, Chapecó, SC, Brazil.
| | - Maike Valentin Buzatto
- Laboratory of Pharmacognosy, Community University of the Chapecó Region, CEP 89809-900, Chapecó, SC, Brazil.
| | - Francine Mantelli Kunst
- Laboratory of Pharmacognosy, Community University of the Chapecó Region, CEP 89809-900, Chapecó, SC, Brazil.
| | - Lucas Damo Ansolin
- Laboratory of Pharmacognosy, Community University of the Chapecó Region, CEP 89809-900, Chapecó, SC, Brazil.
| | - Lincon Bordignon Somensi
- Postgraduate Program in Development and Society, Alto Vale do Rio do Peixe University, CEP 89500-199, Caçador, SC, Brazil.
| | - Max Vidal Gutiérrez
- Department of Chemistry, Biology and Agricultural Sciences, Universidad de Sonora, Navojoa Sonora, Mexico.
| | - Larissa Venzon
- Postgraduate Program in Pharmaceutical Sciences, University of Vale do Itajaí, CEP 88302-202, Itajaí, SC, Brazil.
| | | | - Luisa Mota da Silva
- Postgraduate Program in Pharmaceutical Sciences, University of Vale do Itajaí, CEP 88302-202, Itajaí, SC, Brazil; TGI Pharmacology and its interactions Laboratory, Department of Pharmacology, UFSC, SC, Brazil.
| | - Walter Antônio Roman Junior
- Postgraduate Program in Health Sciences, Community University of Chapecó Region, CEP 89809-900, Chapecó, SC, Brazil; Laboratory of Pharmacognosy, Community University of the Chapecó Region, CEP 89809-900, Chapecó, SC, Brazil.
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Huang Z, Hu M, Peng X, Wang R, Song X, Yin J. The protective effect of small black soybean (Vigna Mungo L.) polysaccharide on acetic acid-induced gastric ulcer in SD rats and its impact on gut microbiota and metabolites. FOOD BIOSCI 2023; 56:103187. [DOI: 10.1016/j.fbio.2023.103187] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Lin K, Deng T, Qu H, Ou H, Huang Q, Gao B, Li X, Wei N. Gastric protective effect of Alpinia officinarum flavonoids: mediating TLR4/NF-κB and TRPV1 signalling pathways and gastric mucosal healing. PHARMACEUTICAL BIOLOGY 2023; 61:50-60. [PMID: 36541204 PMCID: PMC9788718 DOI: 10.1080/13880209.2022.2152058] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 10/03/2022] [Accepted: 11/19/2022] [Indexed: 06/17/2023]
Abstract
CONTEXT Our previous studies have found that total flavonoid of Alpinia officinarum Hance (Zingiberaceae) (F.AOH) had protective effects on gastric ulcer (GU). OBJECTIVE To investigate the protective mechanism of F.AOH on acetic acid-induced chronic GUs in rats and ethanol-induced GES-1 cells damage. MATERIALS AND METHODS In vivo: Gastric damage was induced in SD rats by administering acetic acid after oral treatment with F-AOH at 54, 27 and 13.5 mg/kg (2 weeks of continuous gavage). After a comprehensive evaluation of rats' serum and gastric tissue-related indicators, gene transcriptome sequencing, qPCR and Western blotting were used to investigate the mechanism further. In vivo: GES-1 cells were incubated with F-AOH (8, 4 and 2 μg/mL) for 16 h and treated with 7% ethanol for 4 h. Transwell and flow cytometry were employed to detect migration and apoptosis of cells. RESULTS F.AOH effectively reduced the area of GUs in rats (from 11.2 ± 1.89 to 2.19 ± 0.95), reversing ethanol-induced cells apoptosis (from 23 ± 1.3 to 8.11 ± 0.93%). It also inhibited the expression of endothelin-1 (ET-1) and iNOS proteins, decreasing the levels of TNF-α IL-6 in serum, improving oxidative stress levels and increasing the expression of Bcl-2/Bax dimer genes. In addition, 4005 differentially expressed genes between the acetic acid model and the drug groups. Through experimental verification, F.AOH can inhibit the activation of TLR4/NF-κB signalling pathway and TRPV1 receptor. CONCLUSIONS F.AOH, as an effective gastric protective plant component, had potential therapeutic value in anti-inflammatory pain and antioxidative stress gastrointestinal diseases.
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Affiliation(s)
- Kaiwen Lin
- School of Pharmacy, Hainan Medical University, Haikou, China
- Hainan Women and Children’s Medical Center, Haikou, China
| | - Tang Deng
- School of Pharmacy, Hainan Medical University, Haikou, China
- First Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Huijuan Qu
- School of Pharmacy, Hainan Medical University, Haikou, China
| | - Hongya Ou
- School of Pharmacy, Hainan Medical University, Haikou, China
| | - Qifeng Huang
- School of Pharmacy, Hainan Medical University, Haikou, China
- First Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Bingmiao Gao
- School of Pharmacy, Hainan Medical University, Haikou, China
| | - Xiaoliang Li
- School of Pharmacy, Hainan Medical University, Haikou, China
| | - Na Wei
- School of Pharmacy, Hainan Medical University, Haikou, China
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Zhen BX, Cai Q, Li F. Chemical components and protective effects of Atractylodes japonica Koidz. ex Kitam against acetic acid-induced gastric ulcer in rats. World J Gastroenterol 2023; 29:5848-5864. [PMID: 38074916 PMCID: PMC10701307 DOI: 10.3748/wjg.v29.i43.5848] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 10/21/2023] [Accepted: 11/08/2023] [Indexed: 11/20/2023] Open
Abstract
BACKGROUND Atractylodes japonica Koidz. ex Kitam. (A. japonica, Chinese name: Guan-Cangzhu, Japanese name: Byaku-jutsu), a perennial herb, which is mainly distributed in northeast area of China, it’s often used to treat digestive system diseases such as gastric ulcer (GU). However, the mechanism of its potential protective effects against GU remains unclear.
AIM To investigate the protective effects of A. japonica on acetic acid-induced GU rats.
METHODS The chemical constituents of A. japonica were determined by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) analysis. The rat model of GU was simulated by acetic acid method. The pathological changes of gastric tissues were evaluated by hematoxylin-eosin stain, the levels of epidermal growth factor (EGF), EGF receptor (EGFR), nuclear factor kappa-B (NF-κB), interleukin-1β (IL-1β), IL-10, Na+-K+-ATPase (NKA) in serum and gastric tissues were determined by enzyme-linked immunosorbent assay, and the mRNA expressions of EGFR, NF-κBp65, IkappaBalpha (IκBα) and Zonula Occludens-1 (ZO-1) in gastric tissues were determined by real-time reverse transcription polymerase chain reaction, and the efficacy was observed. Then, plasma metabolomic analysis was performed by UPLC-MS/MS to screen the specific potential biomarkers, metabolic pathways and to explore the possible mechanisms.
RESULTS 48 chemical constituents were identified. Many of them have strong pharmacological activity, the results also revealed that A. japonica significantly improved the pathological damage of gastric tissues, increased the expression levels of IL-10, IκBα related to anti-inflammatory factors, decreased the expression levels of IL-1β, NF-κB, NF-κBp65, related to proinflammatory factors, restored the levels of factors about EGF, EGFR, ZO-1 associated with ulcer healing and the levels of factors about NKA associated with energy metabolism. Metabolomic analysis identified 10 potential differential metabolites and enriched 7 related metabolic pathways.
CONCLUSION These findings contribute to the understanding of the potential mechanism of A. japonica to improve acetic acid-induced GU, and will be of great importance for the development and clinical application of natural drugs related to A. japonica.
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Affiliation(s)
- Bi-Xian Zhen
- Department of Medicine, Liaoning University of Traditional Chinese Medicine, Dalian 116600, Liaoning Province, China
| | - Qian Cai
- Department of Medicine, Liaoning University of Traditional Chinese Medicine, Dalian 116600, Liaoning Province, China
| | - Feng Li
- Department of Medicine, Liaoning University of Traditional Chinese Medicine, Dalian 116600, Liaoning Province, China
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Ohara R, Dario FL, Emílio-Silva MT, Assunção R, Rodrigues VP, Bueno G, Raimundo PR, da Rocha LRM, Hiruma-Lima CA. Citral Modulates MMP-2 and MMP-9 Activities on Healing of Gastric Ulcers Associated with High-Fat Diet-Induced Obesity. Int J Mol Sci 2023; 24:ijms24054888. [PMID: 36902320 PMCID: PMC10003425 DOI: 10.3390/ijms24054888] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 01/12/2023] [Accepted: 01/17/2023] [Indexed: 03/06/2023] Open
Abstract
Obesity causes low-grade inflammation that results in the development of comorbidities. In people with obesity, exacerbation of gastric lesion severity and delayed healing may aggravate gastric mucosal lesions. Accordingly, we aimed to evaluate the citral effects on gastric lesion healing in eutrophic and obese animals. C57Bl/6 male mice were divided into two groups: animals fed a standard diet (SD) or high-fat diet (HFD) for 12 weeks. Gastric ulcers were induced using acetic acid (80%) in both groups. Citral (25, 100, or 300 mg/kg) was administered orally for 3 or 10 days. A vehicle-treated negative control (1% Tween 80, 10 mL/kg) and lansoprazole-treated (30 mg/kg) were also established. Lesions were macroscopically examined by quantifying regenerated tissue and ulcer areas. Matrix metalloproteinases (MMP-2 and -9) were analyzed by zymography. The ulcer base area between the two examined periods was significantly reduced in HFD 100 and 300 mg/kg citral-treated animals. In the 100 mg/kg citral-treated group, healing progression was accompanied by reduced MMP-9 activity. Accordingly, HFD could alter MMP-9 activity, delaying the initial healing phase. Although macroscopic changes were undetectable, 10-day treatment with 100 mg/kg citral exhibited improved scar tissue progression in obese animals, with reduced MMP-9 activity and modulation of MMP-2 activation.
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Boeing T, Monteiro Magalhães de Oliveira B, Aldana-Mejía JA, Vidal Ccana-Ccapatinta G, Venzon L, Judah Cury B, Santos França TC, de Souza P, Roman Junior WA, Mota da Silva L, Kenupp Bastos J. Brazilian Red Propolis Accelerates Gastric Healing and Reduces Gastric Submucosal Layer Inflammation in Ultrasound-Monitored Rats. Chem Biodivers 2023; 20:e202200992. [PMID: 36445831 DOI: 10.1002/cbdv.202200992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 11/28/2022] [Accepted: 11/29/2022] [Indexed: 11/30/2022]
Abstract
Propolis has been used for the treatment of gastric disturbances in folk medicine, nevertheless, the gastric healing effects of Brazilian red propolis have not been unveiled. This study aimed to assess the gastric healing effect of the hydroalcoholic extract of red propolis (HERP) in the acetic acid-induced ulcer model. Rats under acetic acid-induced-ulcer were treated with HERP (100 mg/kg, p.o.) twice a day for seven days. Histological changes, oxidative stress, and inflammatory parameters were analyzed in the gastric tissue. Moreover, the gastric wall thickness was measured by ultrasound. The in vitro cytotoxicity of HERP and cellular migration of fibroblasts were evaluated. The treatment with HERP promoted gastric healing, reducing gastric wall thickness, macroscopic lesion area, and histopathological damages compared to the vehicle. Moreover, HERP reduced oxidative stress and inflammation in the gastric tissue but did not change mucin or collagen levels. HERP did not show signs of toxicity either in vivo or in vitro. HERP displayed a healing effect in vivo by reducing oxidative stress and inflammation. These data contribute to validating the popular use of this product in the treatment of gastric disorders and advance scientific knowledge in the search for new drugs for the management of gastric ulcers.
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Affiliation(s)
- Thaise Boeing
- Postgraduate Program in Pharmaceutical Sciences (PPGCF), Universidade do Vale do Itajaí (UNIVALI), Itajaí, Santa Catarina, Brazil
| | | | - Jennyfer Andrea Aldana-Mejía
- School of Pharmaceutical Sciences of Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, São Paulo, Brazil
| | - Gari Vidal Ccana-Ccapatinta
- School of Pharmaceutical Sciences of Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, São Paulo, Brazil
| | - Larissa Venzon
- Postgraduate Program in Pharmaceutical Sciences (PPGCF), Universidade do Vale do Itajaí (UNIVALI), Itajaí, Santa Catarina, Brazil
| | - Benhur Judah Cury
- Postgraduate Program in Pharmaceutical Sciences (PPGCF), Universidade do Vale do Itajaí (UNIVALI), Itajaí, Santa Catarina, Brazil
| | - Tauani Caroline Santos França
- Postgraduate Program in Pharmaceutical Sciences (PPGCF), Universidade do Vale do Itajaí (UNIVALI), Itajaí, Santa Catarina, Brazil
| | - Priscila de Souza
- Postgraduate Program in Pharmaceutical Sciences (PPGCF), Universidade do Vale do Itajaí (UNIVALI), Itajaí, Santa Catarina, Brazil
| | - Walter Antônio Roman Junior
- Postgraduate Program in Health Sciences, Universidade Comunitária da região de Chapecó (UNOCHAPECÓ), Chapecó, Santa Catarina, Brazil
| | - Luísa Mota da Silva
- Postgraduate Program in Pharmaceutical Sciences (PPGCF), Universidade do Vale do Itajaí (UNIVALI), Itajaí, Santa Catarina, Brazil
| | - Jairo Kenupp Bastos
- School of Pharmaceutical Sciences of Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, São Paulo, Brazil
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de Oliveira BMM, Serpa PZ, da Costa Zanatta ME, Aires BA, Steffler AM, Somensi LB, Cury BJ, Dos Santos AC, Venzon L, Boeing T, Mota da Silva L, Roman Junior WA. Gastroprotective and gastric healing effects of the aqueous extract of Casearia sylvestris in rodents: Ultrasound, histological and biochemical analyzes. JOURNAL OF ETHNOPHARMACOLOGY 2022; 298:115660. [PMID: 35995277 DOI: 10.1016/j.jep.2022.115660] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 08/03/2022] [Accepted: 08/16/2022] [Indexed: 06/15/2023]
Abstract
ETHNOPHARMACOLOGICAL IMPORTANCE Casearia sylvestris Sw. (Salicaceae) is a native plant from the Americas, where it is also known as "guaçatonga" or "erva-de-bugre." Although its leaves have been commonly used to treat inflammation and gastrointestinal disorders in South America, the antiulcer effects of an aqueous extract from this medicinal plant, similar to popular use, have not to be investigated yet. AIM OF THE STUDY This study evaluated the hypothesis that the aqueous extract a of C. sylvestris (AEC) prevents the gastric ulcers and accelerates the healing of ulcers already installed, by assessing ultrasound imaging, histological and biochemical analyses. MATERIALS AND METHODS Rats (females) were treated with AEC (3, 30 or 300 mg/kg) prior to the ethanol or piroxicam-induced gastric ulcers. The healing effect of AEC (300 mg/kg) was examined in 80% acetic acid-induced ulcer in rats, whereas the quality of healing was evaluated in recurrent 10% acetic acid-induced ulcer in mice with recurrence induced by interleukin 1β. To assess the responses of the lesions, in addition to the classical methods used to analyze gastroprotection (ex vivo), we also measured the gastric wall thickness (in vivo) using ultrasonography. After euthanasia, the extent of ulcer was determined and the levels of reduced glutathione (GSH), lipid hydroperoxides (LOOH), nitrate, and the activities of myeloperoxidase (MPO), N-acetyl-β-D-glycosaminidase (NAG), superoxide dismutase (SOD), and glutathione S-transferase (GST) were measured. The antisecretory activity of AEC was also examined based on pylorus ligated rats. Furthermore, gastric tissue samples were analyzed histologically, and phytochemical analyses of the C. sylvestris extract were parallelly performed. RESULTS The AEC (30 or 300 mg/kg) prevented ulcers in the ethanol- and piroxicam-induced acute. Moreover, the AEC at a dose of 300 mg/kg also accelerated the gastric healing of acetic acid-induced ulcer in rats by 48% and the ultrasonography records shown a decrease in the wall thickness and the extent of edema of ulcerous lesions promoted by the extract. The gastric healing effect of AEC was also accompanied by reduced MPO and NAG activities at acetic acid-induced ulcer in rats; as well as was by the reduction in the nitrate and LOOH levels, the increase in mucin and SOD activity, and by a partial recovery of GSH levels. The AEC (300 mg/kg) minimized the ulcer recurrence in mice exposed to IL-1β, but the extract administration did not change pH or peptic activity of gastric juice in pylorus ligated rats. CONCLUSION The results of this study provide convincing evidence for the therapeutic efficacy of C. sylvestris with respect to gastroprotection and indicate that ultrasound examination would be a potentially promising approach for evaluating gastroprotective effects in vivo. Collectively, our findings indicate that the gastric the gastroprotective and healing effects of aqueous extract C. sylvestris involve a reduction in acid secretion, promotion of the antioxidant system, reductions in the migration of neutrophils and mast cells, with a consequent lower inflammatory response, and the preservation of mucin.
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Affiliation(s)
| | - Patrícia Zanotelli Serpa
- Programa de Pós-Graduação em Ciências da Saúde, Universidade Comunitária da Região de Chapecó, CEP 89809-900, Chapecó, SC, Brazil.
| | | | - Bruna Agnoatto Aires
- Laboratório de Farmacognosia, Universidade Comunitária da Região de Chapecó, CEP 89809-900, Chapecó, SC, Brazil.
| | - Amanda Maria Steffler
- Laboratório de Farmacognosia, Universidade Comunitária da Região de Chapecó, CEP 89809-900, Chapecó, SC, Brazil.
| | - Lincon Bordignon Somensi
- Programa de Pós-Graduação em Desenvolvimento e Sociedade, Universidade Alto Vale do Rio do Peixe, CEP 89500-199, Caçador, SC, Brazil.
| | - Benhur Judah Cury
- Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade do Vale do Itajaí, CEP 88302-202, Itajaí, SC, Brazil.
| | - Ana Caroline Dos Santos
- Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade do Vale do Itajaí, CEP 88302-202, Itajaí, SC, Brazil.
| | - Larissa Venzon
- Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade do Vale do Itajaí, CEP 88302-202, Itajaí, SC, Brazil.
| | - Thaise Boeing
- Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade do Vale do Itajaí, CEP 88302-202, Itajaí, SC, Brazil.
| | - Luisa Mota da Silva
- Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade do Vale do Itajaí, CEP 88302-202, Itajaí, SC, Brazil.
| | - Walter Antônio Roman Junior
- Programa de Pós-Graduação em Ciências da Saúde, Universidade Comunitária da Região de Chapecó, CEP 89809-900, Chapecó, SC, Brazil; Laboratório de Farmacognosia, Universidade Comunitária da Região de Chapecó, CEP 89809-900, Chapecó, SC, Brazil.
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13
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Meurer M, de Oliveira BMM, Cury BJ, Jerônimo DT, Venzon L, França TCS, Mariott M, Silva-Nunes R, Santos AC, Roman-Junior WA, Oliveira RG, Arunachalam K, Santin JR, Benvenutti L, Souza P, Aldana-Mejía JA, da Silva L. Extract of Tagetes erecta L., a medicinal plant rich in lutein, promotes gastric healing and reduces ulcer recurrence in rodents. JOURNAL OF ETHNOPHARMACOLOGY 2022; 293:115258. [PMID: 35378194 DOI: 10.1016/j.jep.2022.115258] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 02/09/2022] [Accepted: 03/29/2022] [Indexed: 06/14/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Tagetes erecta L. (Asteraceae), popularly known as Aztec Marigold, is used in South America to treat several ailments. Despite reports that T. erecta flowers are used in folk medicine to treat gastrointestinal diseases, there is no study regarding its gastric healing effects. AIM OF THE STUDY The effect of dry extract of T. erecta L. (DETe) in gastric healing and gastric ulcer recurrence was evaluated, contributing to the validation of the antiulcer potential of this medicinal plant. METHODS Rats were treated orally with vehicle (1 ml/kg), omeprazole (20 mg/kg), or DETe (3, 30 or 300 mg/kg) for 7 days, twice a day. The lesion area was evaluated, and the levels of reduced glutathione (GSH) and lipoperoxides (LOOH) and the activity of the superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST), and myeloperoxidase (MPO) were measured. The ulcer recurrence was evaluated in mice and induced by interleukin (IL)-1β (1 μg/kg, i.p). The recurred area, gastric wall thickness, GSH and cytokines levels, MPO and N-acetylglucosaminidase (NAG) activities were measured. RESULTS DETe accelerated the healing of gastric ulcers only at 300 mg/kg, reducing the ulcerated area by 66%. In parallel, DETe reduced LOOH levels, SOD, CAT and MPO activities, while increasing GST activity and mucin amount. In the recurrence model, DETe reduced the lesion area by 94%, and in parallel decreased the gastric wall thickness and TNF levels, while increasing IL-10 amount. CONCLUSIONS Corroborating the popular use of T. erecta, DETe favors the antioxidant system and reduce gastric inflammation, accelerating the gastric healing process and reducing the ulcer recurrence.
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Affiliation(s)
- Mariane Meurer
- Postgraduate Program in Pharmaceutical Sciences, Chemical Pharmaceutical Research Nucleus (NIQFAR), University of Vale Do Itajaí, Itajaí, SC, 89809-900, Brazil
| | - Beatriz M M de Oliveira
- Postgraduate Program in Health Sciences, Community University of Chapecó Region, Chapecó, SC, 89809-900, Brazil
| | - Benhur J Cury
- Postgraduate Program in Pharmaceutical Sciences, Chemical Pharmaceutical Research Nucleus (NIQFAR), University of Vale Do Itajaí, Itajaí, SC, 89809-900, Brazil
| | - Daniele T Jerônimo
- Postgraduate Program in Pharmaceutical Sciences, Chemical Pharmaceutical Research Nucleus (NIQFAR), University of Vale Do Itajaí, Itajaí, SC, 89809-900, Brazil
| | - Larissa Venzon
- Postgraduate Program in Pharmaceutical Sciences, Chemical Pharmaceutical Research Nucleus (NIQFAR), University of Vale Do Itajaí, Itajaí, SC, 89809-900, Brazil
| | - Tauani C S França
- Postgraduate Program in Pharmaceutical Sciences, Chemical Pharmaceutical Research Nucleus (NIQFAR), University of Vale Do Itajaí, Itajaí, SC, 89809-900, Brazil
| | - Marihá Mariott
- Postgraduate Program in Pharmaceutical Sciences, Chemical Pharmaceutical Research Nucleus (NIQFAR), University of Vale Do Itajaí, Itajaí, SC, 89809-900, Brazil
| | - Ruan Silva-Nunes
- Postgraduate Program in Pharmaceutical Sciences, Chemical Pharmaceutical Research Nucleus (NIQFAR), University of Vale Do Itajaí, Itajaí, SC, 89809-900, Brazil
| | - Ana C Santos
- Postgraduate Program in Pharmaceutical Sciences, Chemical Pharmaceutical Research Nucleus (NIQFAR), University of Vale Do Itajaí, Itajaí, SC, 89809-900, Brazil
| | - Walter A Roman-Junior
- Postgraduate Program in Health Sciences, Community University of Chapecó Region, Chapecó, SC, 89809-900, Brazil
| | - Ruberlei G Oliveira
- Postgraduate Program in Master's Degree in Sciences Applied to Hospital Care Júlio Müller University Hospital, Federal University of Mato Grosso, Cuiabá, Brazil
| | - Karuppusamy Arunachalam
- Key Laboratory of Economic Plants and Biotechnology and the Yunnan Key Laboratory for Wild Plant Resources, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, People's Republic of China
| | - José Roberto Santin
- Postgraduate Program in Pharmaceutical Sciences, Chemical Pharmaceutical Research Nucleus (NIQFAR), University of Vale Do Itajaí, Itajaí, SC, 89809-900, Brazil
| | - Larissa Benvenutti
- Postgraduate Program in Pharmaceutical Sciences, Chemical Pharmaceutical Research Nucleus (NIQFAR), University of Vale Do Itajaí, Itajaí, SC, 89809-900, Brazil
| | - Priscila Souza
- Postgraduate Program in Pharmaceutical Sciences, Chemical Pharmaceutical Research Nucleus (NIQFAR), University of Vale Do Itajaí, Itajaí, SC, 89809-900, Brazil
| | - Jennyfer A Aldana-Mejía
- Postgraduate Program in Pharmaceutical Sciences, University of São Paulo, Campus Ribeirão Preto, Ribeirão Preto, Brazil
| | - Luisa da Silva
- Postgraduate Program in Pharmaceutical Sciences, Chemical Pharmaceutical Research Nucleus (NIQFAR), University of Vale Do Itajaí, Itajaí, SC, 89809-900, Brazil.
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Wang XY, Wang M, Yin JY, Song YH, Wang YX, Nie SP, Xie MY. Gastroprotective activity of polysaccharide from the fruiting body of Hericium erinaceus against acetic acid-induced gastric ulcer in rats and structure of one bioactive fraction. Int J Biol Macromol 2022; 210:455-464. [PMID: 35483513 DOI: 10.1016/j.ijbiomac.2022.04.153] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 04/16/2022] [Accepted: 04/20/2022] [Indexed: 01/08/2023]
Abstract
This study aimed at investigating gastroprotective activity of Hericium erinaceus polysaccharide (HEP) and characterizing one of its bioactive fractions. Acetic acid-induced gastric ulcer (GU) rat model was used to evaluate the gastroprotective activity of HEP, while H2O2-induced injury GES-1 cell model was conducted to screen the bioactive fractions from HEP. Moreover, one of the bioactive fractions was characterized using methylation and 1D/2D NMR analysis. Results indicated HEP treatment could ameliorate acetic acid-induced GU in rats. HEP supplement decreased levels of interleukin-6, tumor necrosis factor-α and malondialdehyde and myeloperoxidase activity, and increased releases of nitric oxide, prostaglandin E2, epidermal growth factor, vascular endothelial growth factor and basic fibroblast growth factor and superoxide dismutase activity in gastric tissues of ulcerated rats. Five purified polysaccharides from HEP were screened to be bioactive fractions with cytoprotection on H2O2-induced injury in GES-1 cells. Among them, RP-S was characterized to be a (1 → 6)-β-D-glucan, whose backbone was composed of →6)-β-D-Glcp-(1 → residue and branched with T-β-D-Glcp-(1 → residue at O-3 position. In conclusion, HEP possessed gastroprotection against acetic acid-induced GU in rats and one of its bioactive fractions was a β-D-glucan. This study supports the utilization of HEP in anti-GU and provides evidences for the structure of gastroprotective HEP.
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Affiliation(s)
- Xiao-Yin Wang
- State Key Laboratory of Food Science and Technology, China-Canada Joint Lab of Food Science and Technology (Nanchang), Nanchang University, Nanchang 330047, China; School of Public Health and Health Management, Gannan Medical University, Ganzhou 341000, China.
| | - Miao Wang
- State Key Laboratory of Food Science and Technology, China-Canada Joint Lab of Food Science and Technology (Nanchang), Nanchang University, Nanchang 330047, China.
| | - Jun-Yi Yin
- State Key Laboratory of Food Science and Technology, China-Canada Joint Lab of Food Science and Technology (Nanchang), Nanchang University, Nanchang 330047, China.
| | - Ye-Hao Song
- State Key Laboratory of Food Science and Technology, China-Canada Joint Lab of Food Science and Technology (Nanchang), Nanchang University, Nanchang 330047, China.
| | - Yu-Xiao Wang
- State Key Laboratory of Food Science and Technology, China-Canada Joint Lab of Food Science and Technology (Nanchang), Nanchang University, Nanchang 330047, China.
| | - Shao-Ping Nie
- State Key Laboratory of Food Science and Technology, China-Canada Joint Lab of Food Science and Technology (Nanchang), Nanchang University, Nanchang 330047, China.
| | - Ming-Yong Xie
- State Key Laboratory of Food Science and Technology, China-Canada Joint Lab of Food Science and Technology (Nanchang), Nanchang University, Nanchang 330047, China.
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15
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Magierowska K, Magierowski M. COin Gastrointestinal Physiology and Protection. CARBON MONOXIDE IN DRUG DISCOVERY 2022:466-481. [DOI: 10.1002/9781119783435.ch27] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Lupeol Stearate Accelerates Healing and Prevents Recurrence of Gastric Ulcer in Rodents. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:6134128. [PMID: 35463093 PMCID: PMC9020945 DOI: 10.1155/2022/6134128] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 03/01/2022] [Accepted: 03/23/2022] [Indexed: 11/19/2022]
Abstract
Objective The focus of this study was to evaluate the gastric healing effect of lupeol stearate (LS) and its ability to minimize ulcer recurrence in rodents. Methods To evaluate the gastric healing properties of LS, rats were subjected to 80% acetic acid-induced ulcer model and treated with vehicle, LS (1 mg/kg, p.o.), or omeprazole (20 mg/kg, p.o.), twice daily by seven days. The gastric ulcers were evaluated macroscopically, histologically, and biochemically. To evaluate the effects of LS in gastric ulcer recurrence, mice were ulcerated with 10% acetic acid and treated with vehicle, LS (1 mg/kg, p.o.), or ranitidine (100 mg/kg, p.o.), twice a day for ten days. Then, ulcer recurrence in these animals was induced by IL-1β at five days after the treatment period. Results The oral treatment with LS accelerated gastric healing by 63% in rats compared to the vehicle group, evidenced by histological improvement and increased gastric mucin levels. Moreover, the gastric healing effects of LS in rats were accompanied by an elevation in glutathione S-transferase activity and a reduction in myeloperoxidase activity. Furthermore, the LS treatment reduced the recurred lesions in mice. Conclusions The oral treatment of LS accelerates gastric healing in rats by favoring mucus production and reducing neutrophil migration, and it also can reduce ulcer recurrence. These data highlighted this compound as promising for developing new pharmacological strategies for the management of gastric ulcer.
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Sikiric P, Skrtic A, Gojkovic S, Krezic I, Zizek H, Lovric E, Sikiric S, Knezevic M, Strbe S, Milavic M, Kokot A, Blagaic AB, Seiwerth S. Cytoprotective gastric pentadecapeptide BPC 157 resolves major vessel occlusion disturbances, ischemia-reperfusion injury following Pringle maneuver, and Budd-Chiari syndrome. World J Gastroenterol 2022; 28:23-46. [PMID: 35125818 PMCID: PMC8793015 DOI: 10.3748/wjg.v28.i1.23] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 05/14/2021] [Accepted: 12/21/2021] [Indexed: 02/06/2023] Open
Abstract
The stable gastric pentadecapeptide BPC 157 counteracts various venous occlusion-induced syndromes. Summarized are all these arguments, in the Robert's cytoprotection concept, to substantiate the resolution of different major vessel occlusion disturbances, in particular ischemia-reperfusion injury following the Pringle maneuver and Budd-Chiari syndrome, which was obtained by BPC 157 therapy. Conceptually, there is a new point, namely, endothelium maintenance to epithelium maintenance (the recruitment of collateral blood vessels to compensate for vessel occlusion and reestablish blood flow or bypass the occluded or ruptured vessel). In this paper, we summarize the evidence of the native cytoprotective gastric pentadecapeptide BPC 157, which is stable in the human gastric juice, is a membrane stabilizer and counteracts gut-leaky syndrome. As a particular target, it is distinctive from the standard peptide growth factors, involving particular molecular pathways and controlling VEGF and NO pathways. In the early 1990s, BPC 157 appeared as a late outbreak of the Robert's and Szabo's cytoprotection-organoprotection concept, like the previous theoretical/practical breakthrough in the 1980s and the brain-gut axis and gut-brain axis. As the time went on, with its reported effects, it is likely most useful theory practical implementation and justification. Meantime, several reviews suggest that BPC 157, which does not have a lethal dose, has profound cytoprotective activity, used to be demonstrated in ulcerative colitis and multiple sclerosis trials. Likely, it may bring the theory to practical application, starting with the initial argument, no degradation in human gastric juice for more than 24 h, and thereby, the therapeutic effectiveness (including via a therapeutic per-oral regimen) and pleiotropic beneficial effects.
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Affiliation(s)
- Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Anita Skrtic
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Slaven Gojkovic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Ivan Krezic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Helena Zizek
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Eva Lovric
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Suncana Sikiric
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Mario Knezevic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Sanja Strbe
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Marija Milavic
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Antonio Kokot
- Department of Anatomy and Neuroscience, Faculty of Medicine Osijek, J.J.Strossmayer University of Osijek, Osijek 31000, Croatia
| | - Alenka Boban Blagaic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
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da Luz BB, Maria-Ferreira D, Dallazen JL, de Oliveira AF, Queiroz Telles JE, Beltrame OC, Cipriani TR, de Paula Werner MF. Effectiveness of the polyphenols-rich Sedum dendroideum infusion on gastric ulcer healing in rats: Roles of protective endogenous factors and antioxidant and anti-inflammatory mechanisms. JOURNAL OF ETHNOPHARMACOLOGY 2021; 278:114260. [PMID: 34062247 DOI: 10.1016/j.jep.2021.114260] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 05/21/2021] [Accepted: 05/25/2021] [Indexed: 06/12/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Peptic ulcer is an inflammatory disease that therapeutic options are mainly focused in antisecretory drugs. Sedum dendroideum Moc & Sessé ex DC (Crassulaceae) is employed in folk medicine for the treatment of gastric ulcers. Recently, our group demonstrated that Sedum dendroideum infusion (SDI) is rich in polyphenols (flavonol glycosides, myricetin, quercetin and kaempferol) and promoted gastroprotection against acute ulcer models, without changes gastric acid secretion. AIM OF THE STUDY Here, we follow the investigation of the healing effects of SDI (ED50 = 191 mg/kg) in the chronic gastric ulcer model induced by 80% acetic acid in rats, elucidating underlying mechanisms. MATERIAL AND METHODS Rats were orally treated with vehicle (water, 1 mL/kg), SDI (191 mg/kg), omeprazole (40 mg/kg) or sucralfate (100 mg/kg) twice daily for 5 days after ulcer induction. Following treatments, toxicological effects, macroscopic ulcer appearance, microscopic histological (HE, mucin PAS-staining) and immunohistochemical (PCNA and HSP70) analysis, inflammatory (MPO and NAG activity, cytokine levels measurements) and antioxidant (SOD and CAT) parameters were investigated in gastric ulcer tissues. RESULTS Oral treatment with SDI accelerated gastric ulcer healing, maintained mucin content and promoted epithelial cell proliferation. SDI also reduced neutrophil and mononuclear leukocyte infiltration, TNF-α and IL-1β levels and the oxidative stress, restoring SOD and CAT activities in the ulcer tissue. CONCLUSIONS The gastric healing effect of SDI was mediated through endogenous protective events as well as due to the anti-inflammatory and antioxidant actions. Our observations support and reinforce the traditional utilize of Sedum dendroideum as a natural nontoxic therapeutic alternative for the treatment of gastric ulcers.
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Affiliation(s)
| | - Daniele Maria-Ferreira
- Department of Pharmacology, Federal University of Parana, Curitiba, PR, Brazil; Pelé Pequeno Príncipe Research Institute, Faculdades Pequeno Príncipe, Curitiba, PR, Brazil
| | - Jorge Luiz Dallazen
- Department of Pharmacology, Federal University of Parana, Curitiba, PR, Brazil
| | - Ana Flávia de Oliveira
- Department of Biochemistry and Molecular Biology, Federal University of Parana, Curitiba, PR, Brazil
| | | | - Olair Carlos Beltrame
- Department of Veterinary Medicine, Federal University of Parana, Curitiba, PR, Brazil
| | - Thales Ricardo Cipriani
- Department of Biochemistry and Molecular Biology, Federal University of Parana, Curitiba, PR, Brazil
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Malvidin Protects against and Repairs Peptic Ulcers in Mice by Alleviating Oxidative Stress and Inflammation. Nutrients 2021; 13:nu13103312. [PMID: 34684313 PMCID: PMC8537945 DOI: 10.3390/nu13103312] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 09/06/2021] [Accepted: 09/08/2021] [Indexed: 12/29/2022] Open
Abstract
Peptic ulcer episodes cause damage to the stomach and intestine, with inflammatory cell infiltration and oxidative stress as the main players. In this study, we investigated the potential of anthocyanidin malvidin for preventive and curative peptic ulcer treatment. The anthocyanidin effects were examined in gastric ulcer mouse models induced by ethanol, non-steroidal anti-inflammatory drugs (NSAIDs), ischemia-reperfusion (IR), acetic acid and duodenal ulcer induced by polypharmacy. Expression levels of oxidative and inflammatory genes were measured to investigate the mechanism of anthocyanin activity. At a dose of 5 mg·kg−1, Malvidin prevented gastric ulcer induction by ethanol, NSAID and repaired the tissue after 6 days of IR. Moreover, the anthocyanidin accelerated the healing of acetic acid-induced ulcer, increased the gene expression of EGF and COX-1, and downregulated MMP-9. Anthocyanin treatment mitigated the effect of polypharmacy on inflammation and oxidative stress observed in the intestine. Additionally, the compound downregulated cytokine expression and TLR4 and upregulated HMOX-1 and IL-10, exhibiting protective activity in the mouse gut. Malvidin thus prevented gastric and duodenal ulcers due to prominent anti-inflammatory and antioxidative effects on the gastrointestinal tract that were related to gene expression modulation and an increase in endogenous defense mechanisms.
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Hashimoto T, Shibata K, Honda K, Nobe K. Acetic acid treatment causes renal inflammation and chronic kidney disease in mice. J Pharmacol Sci 2021; 146:160-168. [PMID: 34030798 DOI: 10.1016/j.jphs.2021.04.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 03/02/2021] [Accepted: 04/12/2021] [Indexed: 02/03/2023] Open
Abstract
We established a novel mouse model of chronic kidney disease (CKD) using acetic acid and compared it with the 5/6-nephrectomized mouse model. In our novel model, significant increases were observed in blood biochemical values and urinary parameters. Moreover, a decrease in creatinine clearance (Ccr) was observed. This model also demonstrated a higher survival rate than the 5/6-nephrectomized model. Observed histological changes in our model included cell infiltration in the renal interstitium, tubular dilation, regenerated tubules, and glomerulosclerosis. Inflammation of the renal interstitium was particularly remarkable. TNF-α, IL-1β, and ICAM-1 mRNA expression were up-regulated prior to elevation of mean blood pressure and prior to changes in blood biochemical values and urinary parameters. Up-regulation of TGF-β mRNA and down-regulation of nephrin mRNA were also observed at 12 weeks after acetic acid treatment. However, no correlation between the progression of CKD and the decrease in renal blood flow was observed. Finally, repeated losartan administration attenuated the effects of acetic acid-induced renal injury. Our findings suggest that chronic kidney conditions associated with this model may be triggered by interstitial inflammation. Moreover, we suggest that this model is useful for understanding the pathophysiological mechanisms of CKD, and for evaluating the effects of therapeutic agents.
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Affiliation(s)
- Terumasa Hashimoto
- School of Pharmacy, Pharmacology Research Center, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142 Japan.
| | - Keita Shibata
- School of Pharmacy, Pharmacology Research Center, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142 Japan
| | - Kazuo Honda
- School of Pharmacy, Pharmacology Research Center, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142 Japan
| | - Koji Nobe
- School of Pharmacy, Pharmacology Research Center, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142 Japan
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Mahattanadul S, Kongpuckdee S, Wiwattanapatapee R, Tansakul P, Nitiruangjaras A, Hansakul P. Comparative Inhibitory Efficacy on the iNOS/NO System of Curcuminand Tetrahydrocurcumin-Self-Microemulsifying Liquid Formulation in Chronic Gastric Ulcer Model. Curr Pharm Biotechnol 2021; 22:1005-1012. [PMID: 32767918 DOI: 10.2174/1389201021666200807105849] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 06/24/2020] [Accepted: 06/27/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Curcumin was found to accelerate gastric ulcer healing by the main mechanism, i.e., the suppression of iNOS mediated inflammation. Although Tetrahydrocurcumin (THC) is claimed to be an active antioxidant element of curcumin, its antiulcer activity has not been systematically examined. The utility of Self-Microemulsifying Drug Delivery Systems (SMEDDSs) for curcumin and THC formulations in the liquid form was also found to increase the rate and extent of release of curcumin- and THC-SMEDDS. Nevertheless, the beneficial antiulcer effect of these nanoproducts has not yet been evaluated. OBJECTIVE This study aimed to evaluate and compare the antiulcer efficacy of curcumin- and THCSMEDDS through the inhibition of the iNOS/NO system in the rat model. METHODS Antiulcer efficacy was compared in terms of the ability to accelerate healing of gastric ulcer including the efficient inhibitory action on inflammatory NO production in activated macrophages and iNOS mRNA expression at the ulcerated area. RESULTS THC was found to have less ulcer healing capacity than curcumin with a lack of significant inhibitory effect on the iNOS/NO system. The SMEDDS used in the study significantly increased the inhibitory efficacy of THC on iNOS/NO production and iNOS mRNA expression compared to the inhibitory potency of curcumin. An oral administration of curcumin- or THC-SMEDDS once a day was appropriate for exerting a comparable curative efficacy to a twice-daily oral administration of curcumin or THC. CONCLUSION The SMEDDS used in the study was observed to enhance the inhibitory efficacy of the antiulcer drug on the iNOS/NO system, leading to a reduction of daily dosing and dosing frequency.
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Affiliation(s)
- Sirima Mahattanadul
- Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat Yai, Songkhla 90110, Thailand
| | - Sonsawan Kongpuckdee
- Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat Yai, Songkhla 90110, Thailand
| | - Ruedeekorn Wiwattanapatapee
- Department of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat-Yai, Songkhla, Thailand
| | - Pimpimon Tansakul
- Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat-Yai, Songkhla, Thailand
| | - Anupong Nitiruangjaras
- Department of Pathology, Faculty of Medicine, Prince of Songkla University, Hat-Yai, Songkhla, Thailand
| | - Pintusorn Hansakul
- Department of Preclinical Sciences, Faculty of Medicine, Thammasat University, Ransit Campus, Klongluang, Pathumthani, Thailand
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Bueno G, Chavez Rico SL, Périco LL, Ohara R, Rodrigues VP, Emílio-Silva MT, Assunção R, Machado da Rocha LR, Nunes DS, Besten MA, Heiden G, Lima Camargo AC, Justulin LA, Hiruma-Lima CA. The essential oil from Baccharis trimera (Less.) DC improves gastric ulcer healing in rats through modulation of VEGF and MMP-2 activity. JOURNAL OF ETHNOPHARMACOLOGY 2021; 271:113832. [PMID: 33460758 DOI: 10.1016/j.jep.2021.113832] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 12/12/2020] [Accepted: 01/11/2021] [Indexed: 06/12/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Baccharis trimera (Less.) DC known as "carqueja" in Brazil has been acknowledged as a medicinal plant in folk medicine for the treatment of stomach aches and gastrointestinal disorders. AIM OF THE STUDY The present study aimed to evaluate the gastroprotective and healing effects of essential oil from B. trimera (EOBT) against gastric ulcer lesions caused by absolute ethanol and acetic acid, respectively, and to identify the mechanism of action of this essential oil in male Wistar rats. MATERIALS AND METHODS The plant material used to obtain EOBT was collected in the southern region of Brazil and was analyzed by chromatography-mass spectrometry (GCMS) demonstrate its characteristic chemical composition, with carquejyl acetate as its main component. Different doses of EOBT (50, 100, and 200 mg/kg) were administered orally in male Wistar rats as an acute treatment against absolute ethanol-induced gastric lesions. The gastric healing effect of EOBT (100 mg/kg) was evaluated once a day after 7, 10, and 14 days of treatment. After treatment, the stomachs of rats from all groups were collected to measure the lesion area (mm2), the activity of myeloperoxidase (MPO), and the relative expression of caspases -3, -8, -9, cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF). The zymography method was used to elucidate the activity of matrix metalloproteinase-2 (MMP-2) and -9 (MMP-9) in the healing action of EOBT. We also analyzed toxicological parameters (body weight evolution and biochemical parameters) that could result after treatment with this essential oil for 14 days. RESULTS Pretreatment with EOBT (100 and 200 mg/kg) significantly decreased the severity of gastric damage induced by absolute ethanol and decreased MPO activity in gastric tissue. After 10 and 14 days of treatment with EOBT (100 mg/kg) once a day, the lesion area was significantly reduced by 61% and 65.5%, respectively, compared to the negative control group. The gastric healing effect of EOBT was followed by a decrease in the expression of COX-1 compared to that in the negative control group. Notably, treatment with EOBT for 14 days increased the expression of VEGF compared to that using an anti-ulcer drug (lansoprazole). Additionally, analyses of MMP-2 and MMP-9 activities in the gastric mucosa confirmed the accelerated gastric healing effect of EOBT, with a significant decrease in the activity of pro-MMP-2. No sign of toxicity was observed after treatment with EOBT for 14 consecutive days. CONCLUSION These findings indicated that EOBT was effective in preventing and accelerating ulcer healing by decreasing MPO activity, increasing VEGF expression, and decreasing MMP-2 activity. These actions collectively contribute to the rapid recovery of gastric mucosa following treatment with EOBT, without any observed toxicity.
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Affiliation(s)
- Gabriela Bueno
- Department of Structural and Functional Biology (Physiology), Biosciences Institute, UNESP-São Paulo State University, CEP, 18618-689, Botucatu, São Paulo, Brazil
| | - Stefanni Liliane Chavez Rico
- Department of Structural and Functional Biology (Physiology), Biosciences Institute, UNESP-São Paulo State University, CEP, 18618-689, Botucatu, São Paulo, Brazil
| | - Larissa Lucena Périco
- Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Alberta, Canada
| | - Rie Ohara
- Department of Structural and Functional Biology (Physiology), Biosciences Institute, UNESP-São Paulo State University, CEP, 18618-689, Botucatu, São Paulo, Brazil
| | - Vinicius Peixoto Rodrigues
- Department of Structural and Functional Biology (Physiology), Biosciences Institute, UNESP-São Paulo State University, CEP, 18618-689, Botucatu, São Paulo, Brazil
| | - Maycon Tavares Emílio-Silva
- Department of Structural and Functional Biology (Physiology), Biosciences Institute, UNESP-São Paulo State University, CEP, 18618-689, Botucatu, São Paulo, Brazil
| | - Renata Assunção
- Department of Structural and Functional Biology (Physiology), Biosciences Institute, UNESP-São Paulo State University, CEP, 18618-689, Botucatu, São Paulo, Brazil
| | - Lucia Regina Machado da Rocha
- Department of Structural and Functional Biology (Physiology), Biosciences Institute, UNESP-São Paulo State University, CEP, 18618-689, Botucatu, São Paulo, Brazil
| | - Domingos Sávio Nunes
- Department of Chemistry, UEPG-Ponta Grossa State University, CEP, 84030-900, Ponta Grossa, Paraná, Brazil
| | | | - Gustavo Heiden
- Herbário ECT - Embrapa Clima Temperado, Rodovia BR 392, Km 78, CEP, 96010-971, Pelotas, RS, Brazil
| | - Ana Carolina Lima Camargo
- Department of Structural and Functional Biology (Morphology), Biosciences Institute, UNESP-São Paulo State University, CEP, 18618-689, Botucatu, São Paulo, Brazil
| | - Luis Antonio Justulin
- Department of Structural and Functional Biology (Morphology), Biosciences Institute, UNESP-São Paulo State University, CEP, 18618-689, Botucatu, São Paulo, Brazil
| | - Clélia Akiko Hiruma-Lima
- Department of Structural and Functional Biology (Physiology), Biosciences Institute, UNESP-São Paulo State University, CEP, 18618-689, Botucatu, São Paulo, Brazil.
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Taxifolin and gastro-adhesive microparticles containing taxifolin promotes gastric healing in vivo, inhibits Helicobacter pylori in vitro and proton pump reversibly in silico. Chem Biol Interact 2021; 339:109445. [PMID: 33741339 DOI: 10.1016/j.cbi.2021.109445] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 02/22/2021] [Accepted: 03/10/2021] [Indexed: 01/02/2023]
Abstract
Taxifolin (3,5,7,3,4-pentahydroxy flavanone or dihydroquercetin, Tax) was identified as a gastroprotective compound and a gastroadhesive formulation was recently developed to prolong its residence time and release in the stomach. So, the gastric healing effectiveness of Tax and gastro-mucoadhesive microparticles containing Tax (MPTax) against the acetic acid induced-gastric ulcer in rats was investigated in this study. Moreover, the interactions between Tax and H+/K+-ATPase were investigated in silico, and its anti- H. pylori activity was determined in vitro. The oral treatment with MPTax (81.37 mg/kg, containing 12.29% of Tax) twice a day for seven days reduced the ulcer area by 63%, compared to vehicle-treated group (Veh: 91.9 ± 10.3 mm2). Tax (10 mg/kg, p.o) reduced the ulcer by 40% but with a p = 0.07 versus Veh group. Histological analysis confirmed these effects. Tax and MPTax increased the gastric mucin amount, reduced the myeloperoxidase activity, and increased the glutathione reduced content at ulcer site. However, only MPTax decreased the lipoperoxide accumulation at ulcer site. Besides, Tax and MPTax normalize the catalase and glutathione S-transferase activity. Tax showed reversible interaction with H+/K+-ATPase in silico and its anti-H. pylori effects was confirmed (MIC = 625 μg/mL). These results suggest that the antiulcer property of Tax involves the strengthening of the gastric protective factors in parallel to its inhibitory interaction with H+/K+-ATPase and H. pylori. Considering that ulcer healing action displayed by Tax was favored by gastroadhesive microparticles, this approach seems to be promising for its oral delivery to treat acid-peptic diseases.
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Wu H, Wei M, Li N, Lu Q, Shrestha SM, Tan J, Zhang Z, Wu G, Shi R. Clopidogrel-Induced Gastric Injury in Rats is Attenuated by Stable Gastric Pentadecapeptide BPC 157. Drug Des Devel Ther 2020; 14:5599-5610. [PMID: 33376304 PMCID: PMC7763470 DOI: 10.2147/dddt.s284163] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Accepted: 11/18/2020] [Indexed: 12/12/2022] Open
Abstract
AIM Although Clopidogrel is safe in healthy volunteers, it can induce recurrence of gastric ulcers in high-risk patients. Here, we investigated the protective effect of the natural product, stable gastric pentadecapeptide 157 (BPC 157) on Clopidogrel-induced gastric injury. METHODS We used acetic acid to induce gastric ulcer in Sprague Dawley rats. Clopidogrel alone or in combination with BPC 157 or L-NAME (nitric oxide system blockade) were administered after healing of acetic acid-induced ulcer. One percent methylcellulose solution was used as control. Ulcer recurrence rate and the ulcer index were compared between these groups. Gastric mucosal apoptosis rate, microscopic inflammation activity and angiogenesis markers vascular endothelial growth factor A (VEGF-A) and CD34 were examined by TUNEL, histological evaluations (HE) and immunohistochemistry (IHC). Pathways involved, expressions of endoplasmic reticulum (ER) stress apoptosis marker CHOP, angiogenic markers VEGF-A and its receptor VEGFR1, and endothelial NO synthase (eNOS) were all analyzed by Western blot. RESULTS This study indicated that Clopidogrel significantly induced the gastric ulcers recurrence, severe inflammation and ER stress related apoptosis of the gastric mucosa, suppressed the synthesis of angiogenic markers and eNOS. Furthermore, Clopidrogel intervention resulted in the activation of protein kinase B (AKT) and p38 mitogen-activated protein kinase (p38/MAPK). BPC 157 attenuated the gastric mucosal damage caused by Clopidogrel and reversed these molecular effects. However, NO blockade L-NAME weakened the protective effect and thus the molecular effects of BPC 157 on gastric mucosa. CONCLUSION In conclusion, these results suggest that BPC 157 inhibited Clopidogrel-induced gastric mucosa injury partially by inhibition of gastric mucosa cell ER stress-mediated apoptosis and inflammation, and promoting gastric mucosa angiogenesis via VEGF-A/VEGFR1 mediated-AKT/p38/MAPK signaling pathways.
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Affiliation(s)
- Hailu Wu
- Medical School of Southeast University, Nanjing210009, People’s Republic of China
- Department of Gastroenterology, Zhongda Hospital Affiliated to Southeast University, Nanjing210009, People’s Republic of China
| | - Ming Wei
- Department of Gastroenterology, Zhongda Hospital Affiliated to Southeast University, Nanjing210009, People’s Republic of China
| | - Nan Li
- Department of Gastroenterology, Zhongda Hospital Affiliated to Southeast University, Nanjing210009, People’s Republic of China
| | - Qin Lu
- Department of Gastroenterology, Zhongda Hospital Affiliated to Southeast University, Nanjing210009, People’s Republic of China
| | | | - Jiacheng Tan
- Department of Gastroenterology, Zhongda Hospital Affiliated to Southeast University, Nanjing210009, People’s Republic of China
| | - Zhenyu Zhang
- Division of Gastroenterology, Department of Medicine, Nanjing Medical University Nanjing First Hospital, Nanjing210009, People’s Republic of China
| | - Guoqiu Wu
- Center of Clinical Laboratory Medicine, Zhongda Hospital, Southeast University, Nanjing210009, People’s Republic of China
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Nanjing210009, People’s Republic of China
| | - Ruihua Shi
- Department of Gastroenterology, Zhongda Hospital Affiliated to Southeast University, Nanjing210009, People’s Republic of China
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Longo B, Sommerfeld EP, Dos Santos AC, da Silva RDCMVDAF, Somensi LB, Mariano LNB, Boeing T, Faloni de Andrade S, de Souza P, da Silva LM. Dual role of eugenol on chronic gastric ulcer in rats: Low-dose healing efficacy and the worsening gastric lesion in high doses. Chem Biol Interact 2020; 333:109335. [PMID: 33245926 DOI: 10.1016/j.cbi.2020.109335] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 11/08/2020] [Accepted: 11/20/2020] [Indexed: 12/11/2022]
Abstract
This study evaluated the gastric healing activity of eugenol, the main bioactive compound from clove (Syzygium aromaticun) essential oil. Five groups of female Wistar rats were submitted to acetic acid-induced ulcer model and treated with Vehicle (1 mL/kg, p.o.), eugenol (1, 10 or 100 mg/kg, p.o) or omeprazole (20 mg/kg, p.o), twice a day, by seven or fourteen days. Macroscopic, microscopic and biochemical analyses were performed in the ulcerated site. Eugenol (1 mg/kg, p.o) administered by 7 or 14 days accelerated the gastric healing process by 33% and 52%, respectively. The healing actions of eugenol were accompanied by the rescue on the histological architecture and the normalization of the superoxide dismutase and catalase activity. Moreover, eugenol (1 mg/kg, p.o) reduced the gastric mucosal myeloperoxidase activity and increased the mucin secretion. In contrast, eugenol at a dose of 100 mg/kg administered by 7 days enhanced 49% the ulcerated area, but at 10 mg/kg did not change the ulcer area after 7 or 14 days of treatment. Thus, despite the undesirable results due to the worsening of the gastric lesion with the use of eugenol in high doses, the antiulcer potential of this compound is evident and manageable in an adequate dose.
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Affiliation(s)
- Bruna Longo
- Curso de Nutrição, Escola de Ciências da Saúde (ECS), Universidade do Vale do Itajaí (UNIVALI), Rua Uruguai, 458, 88302-901, Santa Catarina, SC, Brazil
| | - Ellen Perfoll Sommerfeld
- Curso de Nutrição, Escola de Ciências da Saúde (ECS), Universidade do Vale do Itajaí (UNIVALI), Rua Uruguai, 458, 88302-901, Santa Catarina, SC, Brazil
| | - Ana Caroline Dos Santos
- Programa de Pós-Graduação em Ciências Farmacêuticas, Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí (UNIVALI), Rua Uruguai, 458, 88302-901, Santa Catarina, SC, Brazil
| | | | - Lincon Bordignon Somensi
- Programa de Pós-Graduação em Ciências Farmacêuticas, Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí (UNIVALI), Rua Uruguai, 458, 88302-901, Santa Catarina, SC, Brazil
| | - Luísa Nathalia Bolda Mariano
- Programa de Pós-Graduação em Ciências Farmacêuticas, Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí (UNIVALI), Rua Uruguai, 458, 88302-901, Santa Catarina, SC, Brazil
| | - Thaise Boeing
- Programa de Pós-Graduação em Ciências Farmacêuticas, Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí (UNIVALI), Rua Uruguai, 458, 88302-901, Santa Catarina, SC, Brazil
| | - Sérgio Faloni de Andrade
- Programa de Pós-Graduação em Ciências Farmacêuticas, Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí (UNIVALI), Rua Uruguai, 458, 88302-901, Santa Catarina, SC, Brazil
| | - Priscila de Souza
- Programa de Pós-Graduação em Ciências Farmacêuticas, Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí (UNIVALI), Rua Uruguai, 458, 88302-901, Santa Catarina, SC, Brazil
| | - Luísa Mota da Silva
- Programa de Pós-Graduação em Ciências Farmacêuticas, Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí (UNIVALI), Rua Uruguai, 458, 88302-901, Santa Catarina, SC, Brazil.
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Mishra AP, Bajpai A, Chandra S. A Comprehensive Review on the Screening Models for the Pharmacological Assessment of Antiulcer Drugs. ACTA ACUST UNITED AC 2020; 14:175-196. [PMID: 30864527 DOI: 10.2174/1574884714666190312143846] [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: 12/30/2018] [Revised: 02/15/2019] [Accepted: 02/27/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND Due to inappropriate diet, smoking, alcohol consumption, regular use of drugs like NSAIDs and sedentary lifestyle, one may feel upper abdominal pain which may be the predictor of the gastrointestinal disorder called Peptic Ulcer. When an imbalance occurs between the defensive factor and aggressive factor of the stomach, ulcer formation in the esophageal lining, stomach, or duodenum takes place. This leads to the formation of small sores that cause pain. Another condition that synergizes the abdominal pain is vomiting materials which look like coffee grounds, blood in the stool, black or tarry stools. This pain may increase after lunch or dinner. This problem persists, that often leads to the gastroenterologist's consultation. OBJECTIVE There are many antiulcer screening models present for the determination of antiulcer activity of the drug molecule. The main objective of this study is to find which model is best for the determination of antiulcer activity. METHODS A literature search was conducted on the databases namely Science direct and PubMed with the help of different keywords such as "Anti-ulcer", "In-vitro models" and "In-vivo models". The search was customized by applying the appropriate filters so as to get the most relevant articles to meet the objective of this review article. RESULT There are different research and review papers based on the antiulcer screening models for the determination of antiulcer activity of new drug molecules. CONCLUSION On the basis of our study, we found some useful models for the antiulcer activity of drugs and suggested that, if we use in-vitro and in-vivo methods together, then we may obtain the most relevant result in our research area.
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Affiliation(s)
- Abhinav P Mishra
- Department of Pharmacy, Pranveer Singh Institute of Technology, Kanpur - Agra - Delhi National Highway -2, Bhauti, Kanpur, Uttar Pradesh 209305, India
| | - Ankit Bajpai
- Department of Pharmacy, Pranveer Singh Institute of Technology, Kanpur - Agra - Delhi National Highway -2, Bhauti, Kanpur, Uttar Pradesh 209305, India
| | - Suresh Chandra
- Department of Pharmacy, Pranveer Singh Institute of Technology, Kanpur - Agra - Delhi National Highway -2, Bhauti, Kanpur, Uttar Pradesh 209305, India
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Gastric healing effect of p-coumaric acid isolated from Baccharis dracunculifolia DC on animal model. Naunyn Schmiedebergs Arch Pharmacol 2020; 394:49-57. [PMID: 32780226 DOI: 10.1007/s00210-020-01928-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Accepted: 06/18/2020] [Indexed: 02/07/2023]
Abstract
The p-coumaric acid is a phenolic compound present in large quantities in the extract of Baccharis dracunculifolia DC, a Brazilian medicinal plant used to treat gastric ulcer. Given the necessity for finding new chemical components capable of accelerating gastric healing, in this study, the effects of the p-coumaric acid were evaluated in the acetic acid-induced ulcer model in rats, where histological, inflammatory, and oxidative parameters were analyzed. The healing property was also evaluated in the scratch assay on fibroblast cells (L929) and the cytotoxicity of p-coumaric acid was assessed in both L929 and human gastric adenocarcinoma (AGS) cells by MTT assay. The treatment with p-coumaric acid (10 mg/kg, p.o.) for 7 days, twice a day, decreased by 44.6% the acetic acid-induced gastric ulcer compared with the vehicle-treated group. The vehicle control-treated group showed a larger extension of the ulcer base and an extensive damage into the mucosa and submucosa layers, which were mitigated by the treatment with p-coumaric acid. This beneficial effect was also associated with increased levels of mucin and reduced glutathione, decreased amount of lipid hydroperoxides, and increased superoxide dismutase and catalase activities without interfering with the activity of myeloperoxidase in the gastric tissue. The compound promoted the restructuring of the cell monolayer in the scratch test and did not show toxicity in the L929 cell line, while reduced the viability of the AGS, a lineage of human gastric adenocarcinoma. Thus, p-coumaric acid may be considered a natural source for the treatment of gastric ulcers, by reinforcing protective factors of gastric mucosa and by accelerating gastric healing.
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Seraine Custódio Viana AF, Fernandes HB, Chaves MH, Viana DA, Santos VG, Silva ACA, Lopes MTP, Oliveira RDCM. Cenostigma macrophyllum Tul. var. acuminata Teles Freire Fraction Leaves Stimulate Gastric Healing in Rats and Human Cell Cultures. J Med Food 2020; 24:248-257. [PMID: 32598207 DOI: 10.1089/jmf.2020.0013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Cenostigma macrophyllum Tul. var. acuminata Teles Freire (Leguminosae-Caesalpinioideae) is a medicinal plant traditionally used for treatment of gastric ulcer. This study evaluated the ulcer-healing activity of the hydroalcoholic fraction of C. macrophyllum Tul. var. acuminata Teles Freire leaves (Cm-FHA) and the tea of the leaves of C. macrophyllum (Cm-tea), as well as the possible action of Cm-FHA, through in vitro models. Leaves of C. macrophyllum were dried and powdered to obtain the Cm-FHA. Subsequently, the Cm-FHA was characterized phytochemically and biologically. Besides, Cm-tea was prepared. The gastric healing effects of Cm-tea and Cm-FHA were analyzed using the model of acetic acid-induced gastric ulcer in rats. The human gastric adenocarcinoma (AGS) cell line was employed as an in vitro model. Cm-tea promoted a protective effect against gastric ulcers induced by absolute ethanol. Cm-FHA or Cm-tea (100 mg/kg/7 days) exhibited a significant healing effect on ulcers induced by acetic acid. In the histological analysis, gastric mucosa treated with Cm-FHA or Cm-tea advanced restoration of the mucosal epithelium. In vitro, lower concentrations of Cm-FHA stimulated cell proliferation in the BrdU assay and cell migration. Cm-tea and Cm-FHA present a significant gastric healing effect in in vivo and in vitro models.
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Affiliation(s)
| | - Hélio B Fernandes
- Medicinal Plants Research Center, Federal University of Piauí, Teresina, Brazil
| | - Mariana H Chaves
- Department of Chemistry, Federal University of Piauí, Teresina, Brazil
| | - Daniel A Viana
- Pathology Laboratory and Forensic Medicine-Favet, State University of Ceará, Fortaleza, Brazil
| | - Verlane G Santos
- Department of Pharmacology, Laboratory of Antitumor Substances-LSAT, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Ariadne C A Silva
- Department of Pharmacology, Laboratory of Antitumor Substances-LSAT, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Miriam T P Lopes
- Department of Pharmacology, Laboratory of Antitumor Substances-LSAT, Federal University of Minas Gerais, Belo Horizonte, Brazil
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Arabacı Tamer S, Üçem S, Büke B, Güner M, Karaküçük AG, Yiğit N, Şirvancı S, Çevik Ö, Ercan F, Yeğen BÇ. Regular moderate exercise alleviates gastric oxidative damage in rats via the contribution of oxytocin receptors. J Physiol 2020; 598:2355-2370. [PMID: 32266969 DOI: 10.1113/jp279577] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Accepted: 03/31/2020] [Indexed: 01/12/2023] Open
Abstract
KEY POINTS A moderate level of exercise has beneficial effects for the prevention of gastric ulcers. Although regular aerobic exercise was shown to elevate serum oxytocin levels and exogenously administered oxytocin exerts an anti-ulcer activity, the role of endogenous oxytocin in the gastroprotective effects of exercise has not yet been elucidated. We showed that increased anxiety and oxidative gastric damage induced by gastric ulcers were reversed in pre-exercised rats, while reduced hypothalamic oxytocin expression and decreased myenteric oxytocin receptor expression due to gastric ulcers were abolished by exercise. We also reported that the blockade of oxytocin receptors exaggerated gastric damage in exercised rats with ulcers. Our data establish that endogenous oxytocin is the key mediator in the beneficial effects of regular physical activity in alleviating gastric injury. ABSTRACT Exercise increases serum oxytocin levels and exogenous oxytocin exerts an anti-ulcer activity; but the role of oxytocin in the protective effects of exercise against gastric ulcers has not yet been evaluated. This study was designed to investigate the impact of regular swimming exercise on oxidative gastric injury, and the role of oxytocin receptor activity in the anxiolytic and anti-inflammatory actions of exercise. Adult Wistar albino rats of both sexes performed swimming exercise (30 min/day, 5 days) or stayed sedentary. At the end of the 6-week exercise/sedentary protocol, rats were injected intraperitoneally with atosiban (0.1 mg/kg/day) or saline for 4 days. On the 5th day, under anaesthesia, acetic acid (ulcer) or saline (sham) was applied onto the gastric serosa and the treatments were continued. On the 9th day, anxiety levels were determined; gastric blood flow was measured, and blood, gastric and brain tissues were obtained. Induction of ulcers in sedentary rats increased anxiety and serum corticosterone levels; but reduced gastric blood flow and resulted in apoptosis and oxidative gastric damage with increased cytokine expressions. However, when ulcers were induced in pre-exercised rats, behavioural and biochemical alterations due to gastric damage were reversed. The inhibition of oxytocin receptors by atosiban exaggerated pro-inflammatory cytokine expressions and gastric lipid peroxidation in the stomachs of exercised rats with ulcers. When rats had regularly exercised prior to ulcer induction, reductions in the immunolabelling of hypothalamic oxytocin and myenteric oxytocin receptors were abolished, suggesting that exercise-induced alleviation of gastric injury may involve the reversal of down-regulated oxytocinergic activity.
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Affiliation(s)
- Sevil Arabacı Tamer
- Departments of Physiology and Histology and Embryology, School of Medicine, Marmara University, İstanbul, Turkey
| | - Selen Üçem
- Departments of Physiology and Histology and Embryology, School of Medicine, Marmara University, İstanbul, Turkey
| | - Berk Büke
- Departments of Physiology and Histology and Embryology, School of Medicine, Marmara University, İstanbul, Turkey
| | - Muhammed Güner
- Departments of Physiology and Histology and Embryology, School of Medicine, Marmara University, İstanbul, Turkey
| | - Alp Giray Karaküçük
- Departments of Physiology and Histology and Embryology, School of Medicine, Marmara University, İstanbul, Turkey
| | - Niyazi Yiğit
- Departments of Physiology and Histology and Embryology, School of Medicine, Marmara University, İstanbul, Turkey
| | - Serap Şirvancı
- Histology and Embryology, School of Medicine, Marmara University, İstanbul, Turkey
| | - Özge Çevik
- Department of Biochemistry, School of Medicine, Adnan Menderes University, Aydın, Turkey
| | - Feriha Ercan
- Histology and Embryology, School of Medicine, Marmara University, İstanbul, Turkey
| | - Berrak Ç Yeğen
- Departments of Physiology and Histology and Embryology, School of Medicine, Marmara University, İstanbul, Turkey
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Chrysin Modulates Genes Related to Inflammation, Tissue Remodeling, and Cell Proliferation in the Gastric Ulcer Healing. Int J Mol Sci 2020; 21:ijms21030760. [PMID: 31979417 PMCID: PMC7038074 DOI: 10.3390/ijms21030760] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Revised: 12/15/2019] [Accepted: 12/16/2019] [Indexed: 12/24/2022] Open
Abstract
Chrysin exhibits anti-inflammatory and antioxidant activities. Here, the gastroprotective effect of chrysin was investigated in mouse models of gastric ulcer induced by absolute ethanol, acetic acid, and ischemia-reperfusion injury. The gastric-healing effect was evaluated at 7 and 14 days after treatment; the mechanism of action was verified using the expression of metalloproteinase 2 (MMP-2) and 9 (MMP-9), caspase-3, cyclooxygenase 1 (COX-1) and 2 (COX-2), epidermal growth factor (EGF), and interleukin-10. Chrysin (10 mg/kg) inhibited macroscopic lesions and increased catalase activity in the mouse model established using absolute ethanol. It ameliorated the gastric ulcer caused by acetic acid by improving the expression of inflammatory genes such as COX-2, inhibiting negative remodeling promoted by MMP-9, increasing cell proliferation effect via EGF, and reducing cellular apoptosis by modulating caspase-3. A faster healing effect was evident in the first 7 days of treatment compared to 14 days of treatment, indicating the pharmacological potential of chrysin. Overall, these results demonstrate the potent effect of chrysin in the gastrointestinal tract and elucidate the genes involved in the healing of gastric ulcers. Moreover, an increase in the levels of gastric mucosa defensive factors is involved in the activity of chrysin in the gastric mucosa.
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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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Carlotto J, Maria-Ferreira D, de Souza LM, da Luz BB, Dallazen JL, de Paula Werner MF, Cipriani TR. A polysaccharide fraction from “ipê-roxo” (Handroanthus heptaphyllus) leaves with gastroprotective activity. Carbohydr Polym 2019; 226:115239. [DOI: 10.1016/j.carbpol.2019.115239] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 08/14/2019] [Accepted: 08/22/2019] [Indexed: 02/07/2023]
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Costa P, Somensi LB, da Silva RDCMVDAF, Mariano LNB, Boeing T, Longo B, Perfoll E, de Souza P, Gushiken LFS, Pellizzon CH, Rodrigues DM, Bastos JK, de Andrade SF, da Silva LM. Role of the antioxidant properties in the gastroprotective and gastric healing activity promoted by Brazilian green propolis and the healing efficacy of Artepillin C. Inflammopharmacology 2019; 28:1009-1025. [PMID: 31745698 DOI: 10.1007/s10787-019-00649-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Accepted: 09/16/2019] [Indexed: 12/11/2022]
Abstract
Green propolis is a resinous substance used in folk medicine given its anti-inflammatory, antibacterial, and anti-ulcer effects. Our research group has already confirmed the gastroprotective activity of hydroalcoholic extract from green propolis (HEGP), as well as of its main isolated compounds. In continuity, this study evaluated the antioxidant mode of action involved in the preventive effect induced by HEGP, and its therapeutic gastric healing potential on installed ulcers. In addition, the healing effect of its main compound Artepillin C was also investigated. Acute and chronic ulcers were induced in rats by given ethanol or acetic acid, respectively. In acute model, the rats were orally pre-treated with vehicle (water plus 1% Tween, 1 mL/kg), HEGP (30-300 mg/kg), or carbenoxolone (200 mg/kg) 1 h prior the ulcer induction. In the chronic ulcer protocol, the rats received vehicle (water plus 1% Tween, 1 mL/kg), HEGP (300 mg/kg), or omeprazole (20 mg/kg) twice a day by 7 days, whereas groups of mice received vehicle (water plus 1% Tween, 1 mL/kg), Artepillin C (18 mg/kg), or ranitidine (20 mg/kg) twice a day by 4 days. Ulcerated tissue was collected for histological, histochemical, immunostaining, oxidative, and inflammatory analyses. The in vitro scavenger activity of HEGP was also verified using the DPPH assay. The oral pre-treatment with HEGP (100 and 300 mg/kg) prevented the gastric epithelial damage promoted by ethanol. Besides, HEGP (100 and 300 mg/kg) reduced SOD activity about 11% and 26%, respectively, and increased the activity of GST around 20% and CAT in 80%. HEGP (300 mg/kg) also reduced the production of reactive oxygen species, as well as lipoperoxidation levels in the ethanol-ulcerated tissue. In the acetic acid-induced chronic ulcer, the daily treatment with HEGP (300 mg/kg) accelerates the healing process by 71%. In this model, HEGP normalized SOD and CAT activity and increased GST activity by 109% when compared to non-ulcerated rats. In both models, the extract administration increased the mucin PAS staining and reduced the myeloperoxidase activity at the ulcer site. Moreover, the treatment with HEGP enhanced the PCNA immunostaining, but did not alter the concentration of collagen in the acetic acid-ulcerated tissue. The extract had a direct DPPH radical-scavenging ability (LogIC50: 0.56). Besides, as expected, HPLC analysis showed Artepillin C as a major compound and its administration at 18 mg/kg also accelerated the gastric healing ulcer process in mice. Our findings confirm that HEGP displays both gastroprotective and gastric healing properties, contributing to the validation of its popular use as preventive and therapeutic approaches. These actions occur through the increase in mucin production and the reestablishment of the oxidative balance due to a reduction in gastric inflammation.
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Affiliation(s)
- Philipe Costa
- Programa de Pós-Graduação em Ciências Farmacêuticas, Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí (UNIVALI), Rua Uruguai, 458, Santa Catarina, SC, 88302-901, Brazil.,Departamento de Morfologia, Universidade do Estado de São Paulo (Unesp), Instituto de Biociências, Botucatu, Rua Professor Antônio Celso Wagner Zanin s/n, São Paulo, SP, 18618-689, Brazil.,Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo (USP), Avenida do Café, s/n, Ribeirão Preto, SP, 14040-903, Brazil
| | - Lincon Bordignon Somensi
- Programa de Pós-Graduação em Ciências Farmacêuticas, Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí (UNIVALI), Rua Uruguai, 458, Santa Catarina, SC, 88302-901, Brazil
| | | | - Luísa Nathalia Bolda Mariano
- Programa de Pós-Graduação em Ciências Farmacêuticas, Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí (UNIVALI), Rua Uruguai, 458, Santa Catarina, SC, 88302-901, Brazil
| | - Thaise Boeing
- Programa de Pós-Graduação em Ciências Farmacêuticas, Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí (UNIVALI), Rua Uruguai, 458, Santa Catarina, SC, 88302-901, Brazil
| | - Bruna Longo
- Programa de Pós-Graduação em Ciências Farmacêuticas, Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí (UNIVALI), Rua Uruguai, 458, Santa Catarina, SC, 88302-901, Brazil.,Departamento de Morfologia, Universidade do Estado de São Paulo (Unesp), Instituto de Biociências, Botucatu, Rua Professor Antônio Celso Wagner Zanin s/n, São Paulo, SP, 18618-689, Brazil.,Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo (USP), Avenida do Café, s/n, Ribeirão Preto, SP, 14040-903, Brazil
| | - Ellen Perfoll
- Programa de Pós-Graduação em Ciências Farmacêuticas, Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí (UNIVALI), Rua Uruguai, 458, Santa Catarina, SC, 88302-901, Brazil
| | - Priscila de Souza
- Programa de Pós-Graduação em Ciências Farmacêuticas, Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí (UNIVALI), Rua Uruguai, 458, Santa Catarina, SC, 88302-901, Brazil
| | - Lucas Fernando Sérgio Gushiken
- Departamento de Morfologia, Universidade do Estado de São Paulo (Unesp), Instituto de Biociências, Botucatu, Rua Professor Antônio Celso Wagner Zanin s/n, São Paulo, SP, 18618-689, Brazil
| | - Cláudia Helena Pellizzon
- Departamento de Morfologia, Universidade do Estado de São Paulo (Unesp), Instituto de Biociências, Botucatu, Rua Professor Antônio Celso Wagner Zanin s/n, São Paulo, SP, 18618-689, Brazil
| | - Débora Munhoz Rodrigues
- Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo (USP), Avenida do Café, s/n, Ribeirão Preto, SP, 14040-903, Brazil
| | - Jairo Kenupp Bastos
- Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo (USP), Avenida do Café, s/n, Ribeirão Preto, SP, 14040-903, Brazil
| | - Sérgio Faloni de Andrade
- Programa de Pós-Graduação em Ciências Farmacêuticas, Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí (UNIVALI), Rua Uruguai, 458, Santa Catarina, SC, 88302-901, Brazil
| | - Luísa Mota da Silva
- Programa de Pós-Graduação em Ciências Farmacêuticas, Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí (UNIVALI), Rua Uruguai, 458, Santa Catarina, SC, 88302-901, Brazil.
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da Silva LM, Pezzini BC, Somensi LB, Bolda Mariano LN, Mariott M, Boeing T, dos Santos AC, Longo B, Cechinel-Filho V, de Souza P, de Andrade SF. Hesperidin, a citrus flavanone glycoside, accelerates the gastric healing process of acetic acid-induced ulcer in rats. Chem Biol Interact 2019; 308:45-50. [PMID: 31095933 DOI: 10.1016/j.cbi.2019.05.011] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 04/25/2019] [Accepted: 05/08/2019] [Indexed: 02/07/2023]
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Costa P, Boeing T, Somensi LB, Cury BJ, Espíndola VL, França TCS, de Almeida MO, Arruda C, Bastos JK, da Silva LM, de Andrade SF. Hydroalcoholic extract from Baccharis dracunculifolia recovers the gastric ulcerated tissue, and p-coumaric acid is a pivotal bioactive compound to this action. Biofactors 2019; 45:479-489. [PMID: 30974027 DOI: 10.1002/biof.1503] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Accepted: 02/26/2019] [Indexed: 12/28/2022]
Abstract
Baccharis dracunculifolia is a medicinal plant native to southeastern Brazil and is the main botanical source used by bees (Apis mellifera) in the manufacture of green propolis and display similar gastroprotective action and chemical profile. This article reports the healing gastric ulcer activity of the hydroethanolic extract of B. dracunculifolia (HEBD) in an acetic acid-induced ulcer model. In addition to the extract, the isolated compounds ferulic acid, p-coumaric acid, caffeic acid, baccharin, and aromadendrin-4'-O-methyl ether were also assayed. HEBD at a dose of 300 mg/kg reduced the ulcerated area by 49.4% after treatment for 7 days, twice a day. Histological analyses revealed that the margins and base of the ulcer obtained significant regeneration, and periodic acid Schiff base staining showed a 78.2% increase in the mucin levels. The action on the enzymatic antioxidant system demonstrated an increased activity of superoxide dismutase and glutathione-S-transferase, in addition to raising glutathione reduced levels and myeloperoxidase activity. HEBD did not show cytotoxicity in the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenylterazole bromine test. In vitro, HEBD inhibited the H+ /K+ -ATPase enzyme and showed antioxidant activity in the 2,2 diphenyl-1-picryllydrazyl test. Regarding the isolated compounds, oral administration of p-coumaric acid (15 mg/kg) reduced the ulcerated area by 66.2%. The results suggest that HEBD recovers the gastric ulcerated tissue, raising mucus and antioxidant enzyme levels, and reducing the H+ /K+ -ATPase activity. In addition, the findings confirm that p-coumaric acid is a pivotal bioactive compound on the gastric healing effects elicited by HEBD. © 2019 BioFactors, 45(3):479-489, 2019.
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Affiliation(s)
- Philipe Costa
- Programa de Pós-Graduação em Ciências Farmacêuticas, Núcleo de Investigações Químico-Farmacêuticas, Universidade do Vale do Itajaí, Itajaí, South Carolina, Brazil
| | - Thaise Boeing
- Programa de Pós-Graduação em Ciências Farmacêuticas, Núcleo de Investigações Químico-Farmacêuticas, Universidade do Vale do Itajaí, Itajaí, South Carolina, Brazil
| | - Lincon Bordignon Somensi
- Programa de Pós-Graduação em Ciências Farmacêuticas, Núcleo de Investigações Químico-Farmacêuticas, Universidade do Vale do Itajaí, Itajaí, South Carolina, Brazil
| | - Benhur Judah Cury
- Programa de Pós-Graduação em Ciências Farmacêuticas, Núcleo de Investigações Químico-Farmacêuticas, Universidade do Vale do Itajaí, Itajaí, South Carolina, Brazil
| | - Vanessa Lopes Espíndola
- Programa de Pós-Graduação em Ciências Farmacêuticas, Núcleo de Investigações Químico-Farmacêuticas, Universidade do Vale do Itajaí, Itajaí, South Carolina, Brazil
| | - Tauani Caroline Santos França
- Programa de Pós-Graduação em Ciências Farmacêuticas, Núcleo de Investigações Químico-Farmacêuticas, Universidade do Vale do Itajaí, Itajaí, South Carolina, Brazil
| | - Marília Oliveira de Almeida
- School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Caroline Arruda
- School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Jairo Kenupp Bastos
- School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Luisa Mota da Silva
- Programa de Pós-Graduação em Ciências Farmacêuticas, Núcleo de Investigações Químico-Farmacêuticas, Universidade do Vale do Itajaí, Itajaí, South Carolina, Brazil
| | - Sérgio Faloni de Andrade
- Programa de Pós-Graduação em Ciências Farmacêuticas, Núcleo de Investigações Químico-Farmacêuticas, Universidade do Vale do Itajaí, Itajaí, South Carolina, Brazil
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Magierowska K, Bakalarz D, Wójcik D, Chmura A, Hubalewska-Mazgaj M, Licholai S, Korbut E, Kwiecien S, Sliwowski Z, Ginter G, Brzozowski T, Magierowski M. Time-dependent course of gastric ulcer healing and molecular markers profile modulated by increased gastric mucosal content of carbon monoxide released from its pharmacological donor. Biochem Pharmacol 2019; 163:71-83. [PMID: 30753813 DOI: 10.1016/j.bcp.2019.02.011] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Accepted: 02/08/2019] [Indexed: 01/16/2023]
Abstract
BACKGROUND AND PURPOSE Besides hydrogen sulfide (H2S) and nitric oxide (NO), carbon monoxide (CO) contributes to the maintenance of gastric mucosal integrity. We investigated increased CO bioavailability effects on time-dependent dynamics of gastric ulcer healing mediated by particular growth factors, anti-inflammatory and molecular pathways. EXPERIMENTAL APPROACH Wistar rats with gastric ulcers induced by serosal acetic acid application (day 0) were treated i.g. throughout 3, 6 or 14 days with vehicle or CO-releasing tricarbonyldichlororuthenium (II) dimer (CORM-2, 2.5 mg/kg). Gross and microscopic alterations in gastric ulcer size and gastric blood flow (GBF) at ulcer margin were determined by planimetry, histology and laser flowmetry, respectively. Gastric mRNA/protein expressions of platelet derived growth factors (PDGFA-D), insulin-like growth factor (IGF-1), epidermal growth factor (EGF), hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGFA) and their receptors, heme oxygenases (HMOX), nuclear factor (erythroid-derived 2)-like 2 (Nrf-2), cyclooxygenase (COX-2), hypoxia inducible factor (HIF)-1α, anti-inflammatory annexin-1 and transforming growth factor (TGF-β1) were assessed by real-time PCR or Western blot. TGF-β1-3 and IL-10 plasma concentration were measured using Luminex platform. Prostaglandin E2 content at ulcer margin was assessed by ELISA. KEY RESULTS CORM-2 decreased ulcer area and increased GBF after 6 and 14 days of treatment comparing to vehicle. CO donor upregulated HGF, HGFr, VEGFR1, VEGFR2, TGF-β1, annexin-1 and maintained increased IGF-1, PDGFC and EGF expression at various time-intervals of ulcer healing. TGF-β3 and IL-10 plasma concentration were significantly increased after COMR-2 vs. vehicle. CONCLUSIONS CO time-dependently accelerates gastric ulcer healing and raises GBF at ulcer margin by mechanism involving subsequent upregulation of anti-inflammatory, growth promoting and angiogenic factors response, not observed physiologically.
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Affiliation(s)
- Katarzyna Magierowska
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, Poland
| | - Dominik Bakalarz
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, Poland; Department of Forensic Toxicology, Institute of Forensic Research, 9 Westerplatte Street, 31-033 Cracow, Poland
| | - Dagmara Wójcik
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, Poland
| | - Anna Chmura
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, Poland
| | - Magdalena Hubalewska-Mazgaj
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, Poland
| | - Sabina Licholai
- Department of Molecular Biology and Clinical Genetics, Jagiellonian University Medical College, 8 Skawinska Street, 31-066 Cracow, Poland
| | - Edyta Korbut
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, Poland
| | - Slawomir Kwiecien
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, Poland
| | - Zbigniew Sliwowski
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, Poland
| | - Grzegorz Ginter
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, Poland
| | - Tomasz Brzozowski
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, Poland
| | - Marcin Magierowski
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, Poland.
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Viana AFSC, Lopes MTP, Oliveira FTB, Nunes PIG, Santos VG, Braga AD, Silva ACA, Sousa DP, Viana DA, Rao VS, Oliveira RDCM, Santos FA. (-)-Myrtenol accelerates healing of acetic acid-induced gastric ulcers in rats and in human gastric adenocarcinoma cells. Eur J Pharmacol 2019; 854:139-148. [PMID: 30991046 DOI: 10.1016/j.ejphar.2019.04.025] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Revised: 03/02/2019] [Accepted: 04/11/2019] [Indexed: 02/07/2023]
Abstract
The gastroprotective property of (-)-myrtenol, a monoterpenoid, has been demonstrated previously against acute gastric ulceration induced by ethanol. However, the healing property of (-)-myrtenol in a chronic gastric ulcer model remains to be verified. This study evaluated its healing efficacy and the mechanism involved using the rat model of chronic gastric ulcer induced by serosal injection of 80% acetic acid in vivo, and human gastric adenocarcinoma cells (AGS) in vitro. The results showed that compared to vehicle-treated ulcer controls, oral administration of (-)-myrtenol (50 and 100 mg/kg/day) for 7 days promoted ulcer healing, as indicated by significant decreases in ulcer area and volume. The macroscopic and microscopic findings confirmed the healing potential of (-)-myrtenol. The ulcer healing activity was also associated with significant increases in gastric mucin content, collagen deposition, number of cells with positive marking for proliferating cell nuclear antigen (PCNA), and by changes in the expression of the inflammatory parameters tumor necrosis factor (TNF)-α, interleukin (IL)-1β and cyclooxygenase (COX)-2, as well as a decrease of metalloproteinases (MMP-9 and MMP-2) activity. Furthermore, in vitro assays using the AGS cultures revealed that (-)-myrtenol favors wound healing activity via stimulation of cell proliferation and migration without altering the cell viability. Taken together, these findings indicate that (-)-myrtenol has gastro-cytoprotective and ulcer healing properties that can be further explored to develop a new therapeutic agent from a natural source for the treatment of gastric ulcer.
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Affiliation(s)
- Ana Flavia S C Viana
- Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil; Medicinal Plants Research Center, Health Sciences Center, Federal University of Piauí, Teresina, Piauí, Brazil.
| | - Miriam Teresa P Lopes
- Department of Pharmacology, Laboratory of Antitumor Substances, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Francisca Tuelly B Oliveira
- Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil
| | - Paulo Iury G Nunes
- Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil
| | - Verlane G Santos
- Department of Pharmacology, Laboratory of Antitumor Substances, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Ariadne D Braga
- Department of Pharmacology, Laboratory of Antitumor Substances, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Ana Cândida A Silva
- Department of Pharmacology, Laboratory of Antitumor Substances, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Damião P Sousa
- Department of Pharmaceutical Sciences, Federal University of Paraiba, João Pessoa, Paraiba, Brazil
| | - Daniel A Viana
- Laboratory of Pathology and Legal Medicine, Faculty of Veterinary Science, State University of Ceará, Fortaleza, Ceará, Brazil
| | - Vietla S Rao
- Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil
| | - Rita de Cássia M Oliveira
- Medicinal Plants Research Center, Health Sciences Center, Federal University of Piauí, Teresina, Piauí, Brazil
| | - Flavia A Santos
- Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil
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Treatment Effects of Jinlingzi Powder and Its Extractive Components on Gastric Ulcer Induced by Acetic Acid in Rats. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2019; 2019:7365841. [PMID: 30719066 PMCID: PMC6335817 DOI: 10.1155/2019/7365841] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Revised: 11/24/2018] [Accepted: 12/19/2018] [Indexed: 12/26/2022]
Abstract
Jinlingzi powder comprises Melia toosendan Sieb. et Zucc. and Corydalis yanhusuo (Y.H. Chou & Chun C.Hsu) W.T. Wang ex Z.Y. Su & C.Y. Wu and is usually applied in clinic as traditional Chinese medicine for pain. The present study aims to investigate the therapeutic actions of Jinlingzi powder and its extracted components and theirs treatment mechanism on the acetic acid induced-gastric ulcer in rats. The gastric ulcer model was induced by the administration of acetic acid in rats (84 male). Jinlingzi powder water decoction, its polysaccharide, and nonalkaloid and alkaloid components were used to investigate the therapeutic actions on the acetic acid induced-gastric ulcer by measuring the related pharmacy and pharmacodynamic factors, including ulcer index, ulcer area, ulcer healing rate, interleukin-8 (IL-8), tumor necrosis factor-α (TNF-α), neurotensin (NT), platelet activating factor (PAF), thromboxane B2 (TXB2), and vascular endothelial growth factor (VEGF) in rat serum, acetylcholinesterase (AChE) in brain tissue, prostaglandin E2 (PGE2), and basic fibroblast growth factor (bFGF) in gastric tissue. Among the various groups, Jinlingzi powder and the nonalkaloid components caused significant changes in IL-8, TNF-α, NT, PAF TXB2, and VEGF values in the serum. The AChE content in the rats' brain tissue was also reduced after using Jinlingzi powder and the nonalkaloid components. Additionally, Jinlingzi powder and the nonalkaloid components considerably affect the amount of PGE2 and bFGF in a rat's stomach tissue. Therefore, Jinlingzi powder and the nonalkaloid components can effectively inhibit neutral neutrophil activation, prevent capillaries thrombosis, and protect gastric mucosa. Thus, the nonalkaloid components of the Jinlingzi powder play a key role in the treatment of gastric ulcer.
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Antichronic Gastric Ulcer Effect of Zinc-Baicalin Complex on the Acetic Acid-Induced Chronic Gastric Ulcer Rat Model. Gastroenterol Res Pract 2018; 2018:1275486. [PMID: 30510570 PMCID: PMC6230421 DOI: 10.1155/2018/1275486] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Revised: 08/11/2018] [Accepted: 09/02/2018] [Indexed: 12/26/2022] Open
Abstract
Background Baicalin (BA) has been shown to have anti-inflammatory and antioxidant activity. Zinc is a nutrient element. Objective This study is aimed at investigating the antichronic gastric ulcer activity of Zn-Baicalin complex (BA-Zn) and its related mechanisms in an acetic acid-induced gastric ulcer rat model. Results The severely ulcerated gastric mucosa of model rats had lower GSH-Px (52.21 ± 7.13) and SOD (7.03 ± 0.10) activity, and higher MDA (2.39 ± 0.03) content compared to sham rats. BA-Zn reduced the gastric ulcer index in a dose-dependent manner, significantly increased SOD activity and GSH-Px level, and reduced the MDA content and IL-8 and TNF-α levels in the gastric mucosa. BA-Zn (6.5 and 13 mg/kg) exerted a greater antiulcerogenic effect than both BA and zinc-gluconate, leading to a reduced ulcer index (18.43 ± 1.11, 15.00 ± 1.44), decreased MDA content (1.33 ± 0.07, 0.63 ± 0.01), and increased SOD activity (17.62 ± 0.11, 20.12 ± 0.32) and GSH-Px levels (102.12 ± 9.11, 120.25 ± 9.07). In addition, our results from Western blot suggested that BA-Zn (6.5 and 13 mg/kg) has a greater antiulcerogenic effect than both BA and zinc-gluconate. Conclusion The BA-Zn complex possesses greater antichronic gastric ulcer properties compared to BA and zinc-gluconate due to its ability of oxidation resistance and anti-inflammatory effects.
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Périco LL, Rodrigues VP, Ohara R, Bueno G, Nunes VVA, dos Santos RC, Camargo ACL, Júnior LAJ, de Andrade SF, Steimbach VMB, da Silva LM, da Rocha LRM, Vilegas W, dos Santos C, Hiruma-Lima CA. Sex-specific effects of Eugenia punicifolia extract on gastric ulcer healing in rats. World J Gastroenterol 2018; 24:4369-4383. [PMID: 30344421 PMCID: PMC6189849 DOI: 10.3748/wjg.v24.i38.4369] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Revised: 07/11/2018] [Accepted: 08/01/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the sex-specific effects of a hydroalcoholic extract from Eugenia punicifolia (HEEP) leaves on gastric ulcer healing.
METHODS In this rat study involving males, intact (cycling) females, and ovariectomized females, gastric ulcers were induced using acetic acid. A vehicle, lansoprazole, or HEEP was administered for 14 d after ulcer induction. Body weight was monitored throughout the treatment period. At the end of treatment, the rats were euthanized and the following in vivo and in vitro investigations were performed: macroscopic examination of the lesion area and organ weights, biochemical analysis, zymography, and evaluation of protein expression levels. Additionally, the concentration-dependent effect of HEEP was evaluated in terms of subacute toxicity and cytotoxicity.
RESULTS Compared to the vehicle, HEEP demonstrated a great healing capacity by substantially reducing the ulcerative lesion area in males (52.44%), intact females (85.22%), and ovariectomized females (65.47%), confirming that HEEP accelerates the healing of acetic acid-induced gastric lesions and suggesting that this effect is modulated by female sex hormones. The antiulcer effect of HEEP was mediated by prostaglandin E2 only in male rats. Overall, the beneficial effect of HEEP was the highest in intact females. Notably, HEEP promoted the expression of vascular endothelial growth factor (intact vs ovariectomized females) and decreased the expression of Caspase-8 and Bcl-2 (intact female vs male or ovariectomized female). Additionally, HEEP enhanced fibroblast proliferation and migration into a wounded area in vitro, confirming its healing effect. Finally, no sign of subacute toxicity or cytotoxicity of HEEP was observed.
CONCLUSION In gastric ulcers, HEEP-induced healing (modulated by female sex hormones; in males, mediated by prostaglandin) involves extracellular matrix remodeling, with gastric mucosa cell proliferation and migration.
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Affiliation(s)
- Larissa Lucena Périco
- Department of Physiology, Institute of Biosciences, São Paulo State University (UNESP), Botucatu 18618-970, São Paulo, Brazil
| | - Vinícius Peixoto Rodrigues
- Department of Physiology, Institute of Biosciences, São Paulo State University (UNESP), Botucatu 18618-970, São Paulo, Brazil
| | - Rie Ohara
- Department of Physiology, Institute of Biosciences, São Paulo State University (UNESP), Botucatu 18618-970, São Paulo, Brazil
| | - Gabriela Bueno
- Department of Physiology, Institute of Biosciences, São Paulo State University (UNESP), Botucatu 18618-970, São Paulo, Brazil
| | - Vânia Vasti Alfieri Nunes
- Department of Physiology, Institute of Biosciences, São Paulo State University (UNESP), Botucatu 18618-970, São Paulo, Brazil
| | - Raquel Cássia dos Santos
- Laboratory of Bioactive Compounds, São Francisco University, Bragança Paulista 12916-900, São Paulo, Brazil
| | - Ana Carolina Lima Camargo
- Department of Morphology, Institute of Biosciences, São Paulo State University (UNESP), Botucatu 18618-970, São Paulo, Brazil
| | - Luis Antônio Justulin Júnior
- Department of Morphology, Institute of Biosciences, São Paulo State University (UNESP), Botucatu 18618-970, São Paulo, Brazil
| | - Sérgio Faloni de Andrade
- Programa de Pós-graduação em Ciências Farmacêuticas, Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí - UNIVALI, Itajaí 88302-901, Santa Catarina, Brazil
| | - Viviane Miranda Bispo Steimbach
- Programa de Pós-graduação em Ciências Farmacêuticas, Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí - UNIVALI, Itajaí 88302-901, Santa Catarina, Brazil
| | - Luísa Mota da Silva
- Programa de Pós-graduação em Ciências Farmacêuticas, Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí - UNIVALI, Itajaí 88302-901, Santa Catarina, Brazil
| | - Lúcia Regina Machado da Rocha
- Department of Physiology, Institute of Biosciences, São Paulo State University (UNESP), Botucatu 18618-970, São Paulo, Brazil
| | - Wagner Vilegas
- Coastal Campus of São Vicente, São Paulo State University (UNESP), São Vicente 11330-900, São Paulo, Brazil
| | - Catarina dos Santos
- Department of Biological Science, Faculty of Sciences and Languages, São Paulo State University (UNESP), Assis 19806-900, São Paulo, Brazil
| | - Clélia Akiko Hiruma-Lima
- Department of Physiology, Institute of Biosciences, São Paulo State University (UNESP), Botucatu 18618-970, São Paulo, Brazil
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Magierowska K, Brzozowski T, Magierowski M. Emerging role of carbon monoxide in regulation of cellular pathways and in the maintenance of gastric mucosal integrity. Pharmacol Res 2018; 129:56-64. [PMID: 29360501 DOI: 10.1016/j.phrs.2018.01.008] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2017] [Revised: 01/12/2018] [Accepted: 01/18/2018] [Indexed: 12/14/2022]
Abstract
Heme oxygenase (HO) catalyzes the degradation of toxic free heme to the equimolar amounts of biliverdin, Fe2+ and concurrently releases of carbon monoxide (CO). CO is nowadays increasingly recognized as an important signaling molecule throughout the body that is involved in many physiological processes and shows multidirectional biological activity. Recent evidence indicates that CO exhibits the anti-inflammatory, anti-proliferative, anti-apoptotic, anti-aggregatory and vasodilatory properties. The cellular mechanisms underlying the activity of CO involve stimulation of cGMP-dependent signaling pathway and large conductance calcium activated K+ channels, the activation of mitogen-activated protein kinases and the nuclear factor k-light chain-enhancer of activated B cells transcription factor pathway. Stimulation of endogenous CO production by HO inducers or the inhalation of CO or the delivery of this gaseous molecule by novel pharmaceutical agents have been found in experimental animal models to be promising in the future therapy of various diseases. CO appears to act as a significant component of the complex mechanism of gastrointestinal (GI) mucosal defense. This gaseous molecule plays an important role in diabetic gastroparesis, prevention of the upper GI mucosal damage, post-operative ileus and the healing of ulcerative colitis. This review focuses on the better understanding mechanisms through which CO contributes to the mechanism of protection, resistance to injury and ulcer healing. It is becoming apparent that the pleiotropic effect of this molecule may increase clinical applicability of CO donors and their implementation in many pharmacological research areas, pharmaceutical industry and health-care system.
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Affiliation(s)
- Katarzyna Magierowska
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, Poland
| | - Tomasz Brzozowski
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, Poland
| | - Marcin Magierowski
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, Poland.
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Magierowski M, Magierowska K, Hubalewska-Mazgaj M, Surmiak M, Sliwowski Z, Wierdak M, Kwiecien S, Chmura A, Brzozowski T. Cross-talk between hydrogen sulfide and carbon monoxide in the mechanism of experimental gastric ulcers healing, regulation of gastric blood flow and accompanying inflammation. Biochem Pharmacol 2018; 149:131-142. [PMID: 29203367 DOI: 10.1016/j.bcp.2017.11.020] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2017] [Accepted: 11/29/2017] [Indexed: 12/26/2022]
Abstract
Hydrogen sulfide (H2S) and carbon monoxide (CO) exert gastroprotection against acute gastric lesions. We determined the cross-talk between H2S and CO in gastric ulcer healing process and regulation of gastric blood flow (GBF) at ulcer margin. Male Wistar rats with acetic acid-induced gastric ulcers were treated i.g. throughout 9 days with vehicle (control), NaHS (0.1-10 mg/kg) +/- zinc protoporphyrin (ZnPP, 10 mg/kg), d,l-propargylglycine (PAG, 30 mg/kg), CO-releasing CORM-2 (2.5 mg/kg) +/- PAG. GBF was assessed by laser flowmetry, ulcer area was determined by planimetry/histology. Gastric mucosal H2S production was analysed spectrophotometrically. Protein and/or mRNA expression at ulcer margin for vascular endothelial growth factor (VEGF)A, epidermal growth factor receptor (EGFr), cystathionine-γ-lyase (CSE), cystathionine-β-synthase (CBS), 3-mercaptopyruvate sulfurtransferase (3-MST), heme oxygenases (HOs), nuclear factor (erythroid-derived 2)-like 2 (Nrf-2), cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS), IL-1β, TNF-α and hypoxia inducible factor (HIF)-1α were determined by real-time PCR or western blot. IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IFN-γ, TNF-α, GM-CSF plasma concentration was assessed using Luminex platform. NaHS dose-dependently decreased ulcer area and increased GBF but ZnPP attenuated these effects. PAG decreased H2S production but failed to affect CORM-2-mediated ulcer healing and vasodilation. NaHS increased Nrf-2, EGFr, VEGFA and decreased pro-inflammatory markers expression and IL-1β, IL-2, IL-13, TNF-α, GM-CSF plasma concentration. CORM-2 decreased IL-1β and GM-CSF plasma levels. We conclude that NaHS accelerates gastric ulcer healing increasing microcirculation and Nrf-2, EGFr, VEGFA expression. H2S-mediated ulcer healing involves endogenous CO activity while CO does not require H2S. NaHS decreases systemic inflammation more effectively than CORM-2.
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Affiliation(s)
- Marcin Magierowski
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street 31-531 Cracow, Poland.
| | - Katarzyna Magierowska
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street 31-531 Cracow, Poland
| | - Magdalena Hubalewska-Mazgaj
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street 31-531 Cracow, Poland
| | - Marcin Surmiak
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street 31-531 Cracow, Poland
| | - Zbigniew Sliwowski
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street 31-531 Cracow, Poland
| | - Mateusz Wierdak
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street 31-531 Cracow, Poland
| | - Slawomir Kwiecien
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street 31-531 Cracow, Poland
| | - Anna Chmura
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street 31-531 Cracow, Poland
| | - Tomasz Brzozowski
- Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street 31-531 Cracow, Poland
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Current insight into pathophysiology of gastroduodenal ulcers: Why do only some ulcers perforate? J Trauma Acute Care Surg 2018; 80:1045-8. [PMID: 26998777 DOI: 10.1097/ta.0000000000001035] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Essential oil of Cymbopogon citratus (lemongrass) and geraniol, but not citral, promote gastric healing activity in mice. Biomed Pharmacother 2017; 98:118-124. [PMID: 29248831 DOI: 10.1016/j.biopha.2017.12.020] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Revised: 11/16/2017] [Accepted: 12/04/2017] [Indexed: 02/06/2023] Open
Abstract
Cymbopogon citratus, popularly known as lemongrass, is used for the treatment of gastric, nervous and hypertensive disorders, in addition to its use in the food and pharmaceutical industries. This study evaluated the gastroprotective and gastric healing effect of essential oil of C. citratus (EOCC), citral and geraniol at doses of 1-100 mg/kg (p.o) on acute ethanol-induced ulcer and chronic acetic acid-induced ulcer. Histological and histochemical evaluation was also performed, as well as the in vitro evaluation of the effects of these phytochemicals on H+/K+-ATPase activity. In the ethanol-induced gastric ulcer, the minimum effective oral dose of EOCC, citral and geraniol were 10, 100 and 3 mg/kg, reducing the ulcer area by 51.67%, 96.57% and 55.74%, respectively, compared to vehicle group (25.82 ± 3.59 mm2). Moreover, EOCC (10 mg/kg, p.o) and geraniol (3 mg/kg), but not citral (100 mg/kg), accelerated the gastric healing process by 34.52 and 80.57%, compared to acetic-acid ulcerated group treated with vehicle (36.04 ± 1.03 mm2). These healing effects were confirmed histologically by the contraction of the ulcer base and by the enhancement on mucin staining in slices of ulcer site from mice treated with EOCC or geraniol. Interestingly, EOCC and citral at 100 μg/ml inhibited the H+/ K+-ATPase activity by 28.26% and 44.36%, whereas geraniol did not change this parameter. Together, these findings confirm the gastroprotective and healing gastric ulcer effects of essential oil from aerial parts of C. citratus and added the information that geraniol, but not citral, promotes healing effects on installed ulcers.
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Magierowski M, Magierowska K, Hubalewska‐Mazgaj M, Sliwowski Z, Ginter G, Pajdo R, Chmura A, Kwiecien S, Brzozowski T. Carbon monoxide released from its pharmacological donor, tricarbonyldichlororuthenium (II) dimer, accelerates the healing of pre-existing gastric ulcers. Br J Pharmacol 2017; 174:3654-3668. [PMID: 28768046 PMCID: PMC5610153 DOI: 10.1111/bph.13968] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Revised: 07/10/2017] [Accepted: 07/25/2017] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND AND PURPOSE Carbon monoxide (CO), a gaseous mediator produced by haem oxygenases (HOs), has been shown to prevent stress-, ethanol-, aspirin- and alendronate-induced gastric damage; however, its role in gastric ulcer healing has not been fully elucidated. We investigated whether CO released from tricarbonyldichlororuthenium (II) dimer (CORM-2) can affect gastric ulcer healing and determined the mechanisms involved in this healing action. EXPERIMENTAL APPROACH Gastric ulcers were induced in Wistar rats by serosal application of acetic acid. Animals received 9 days of treatment with RuCl3 [2.5 mg·kg-1 intragastrically (i.g.)], haemin (5 mg·kg-1 i.g.), CORM-2 (0.1-10 mg·kg-1 i.g.) administered alone or with zinc protoporphyrin IX (ZnPP, 10 mg·kg-1 i.g.), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 5 mg·kg-1 i.g.), NG -nitro-l-arginine (l-NNA, 15 mg·kg-1 i.g.), indomethacin (5 mg·kg-1 i.g.) or glibenclamide (10 mg·kg-1 i.g.). Gastric ulcer area and gastric blood flow (GBF) were assessed planimetrically, microscopically and by laser flowmeter respectively. Gastric mRNA/protein expressions of EGF, EGF receptors, VEGFA, HOs, nuclear factor (erythroid-derived 2)-like 2 (Nrf2), COX-2, hypoxia-inducible factor (HIF)-1α and pro-inflammatory iNOS, IL-1β and TNF-α were determined by real-time PCR or Western blots. KEY RESULTS CORM-2 and haemin but not RuCl3 or ZnPP decreased ulcer size while increasing GBF. These effects were reduced by ODQ, indomethacin, l-NNA and glibenclamide. CORM-2 significantly decreased the expression of pro-inflammatory markers, Nrf2/HO1 and HIF-1α, and up-regulated EGF. CONCLUSIONS AND IMPLICATIONS CO released from CORM-2 or endogenously produced by the HO1/Nrf2 pathway accelerates gastric ulcer healing via an increase in GBF, an up-regulation in EGF expression and down-regulation of the inflammatory response.
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Affiliation(s)
- Marcin Magierowski
- Department of Physiology, Faculty of MedicineJagiellonian University Medical CollegeCracowPoland
| | - Katarzyna Magierowska
- Department of Physiology, Faculty of MedicineJagiellonian University Medical CollegeCracowPoland
| | | | - Zbigniew Sliwowski
- Department of Physiology, Faculty of MedicineJagiellonian University Medical CollegeCracowPoland
| | - Grzegorz Ginter
- Department of Physiology, Faculty of MedicineJagiellonian University Medical CollegeCracowPoland
| | - Robert Pajdo
- Department of Physiology, Faculty of MedicineJagiellonian University Medical CollegeCracowPoland
| | - Anna Chmura
- Department of Physiology, Faculty of MedicineJagiellonian University Medical CollegeCracowPoland
| | - Slawomir Kwiecien
- Department of Physiology, Faculty of MedicineJagiellonian University Medical CollegeCracowPoland
| | - Tomasz Brzozowski
- Department of Physiology, Faculty of MedicineJagiellonian University Medical CollegeCracowPoland
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Somensi LB, Boeing T, Cury BJ, Steimbach VMB, Niero R, de Souza LM, da Silva LM, de Andrade SF. Hydroalcoholic extract from bark of Persea major (Meisn.) L.E. Kopp (Lauraceae) exerts antiulcer effects in rodents by the strengthening of the gastric protective factors. JOURNAL OF ETHNOPHARMACOLOGY 2017; 209:294-304. [PMID: 28807848 DOI: 10.1016/j.jep.2017.08.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/22/2017] [Revised: 07/28/2017] [Accepted: 08/02/2017] [Indexed: 06/07/2023]
Abstract
ETHOPHARMACOLOGICAL RELEVANCE The Persea major (Meisn.) L.E. Kopp (Lauraceae) (botanical synonym: Persea pyrifolia (D. Don) Spreng, Persea pyrifolia Nees and Mart., Persea cordata var. major (Meisn.) Mez and Persea willdenovii Kosterm) is a medicinal plant native in the south of Brazil, where is popularly known as Pau de Andrade, Maçaranduba or Abacate-do-Mato. Its barks are commonly used to prepare an infusion which is administered orally or topically to treat ulcers and wounds, respectively. Thus, this study has been undertaken to contribute to the validation of the popular use of P. major to treat of ulcerative disorders from gastrointestinal system, using different experimental models in rodents. MATERIAL AND METHODS Firstly, ultra-performance liquid chromatography coupled to a mass spectrophotometer has been performed. Next, the potential gastroprotective of hydroalcoholic extract of P. major barks (HEPM) (30-300mg/kg) has been evaluated in ulcer models acute as: ethanol, ethanol/HCl and indomethacin-induced ulcer. The extract (300mg/kg) has been also tested in acetic acid-induced chronic ulcer model. Histological, toxicological, histochemical, oxidative stress and gastric secretion parameters were analyzed. RESULTS The main compounds found in HEPM were polyphenols as condensed tannins, flavonoids heterosides derivatives from quercetin and kaempferol. HEPM (300mg/kg, p.o) prevented gastric lesions induced by ethanol or indomethacin in rats by 58.98% and 97.48%, respectively, compared to vehicle group (148.00±14.83mm2 and 12.07±1.61mm2, respectively). In acetic acid-induced chronic ulcer model the HEPM (300mg/kg, p.o) reduced the ulcer are by 40.58%, compared to vehicle group (127.90±12.04mm2). The healing effect was confirmed histologically, by an increase in mucin content and by the reduction in oxidative and inflammatory parameters at the ulcer site. Neither significant effect on gastric acid secretion nor toxicological effects and cytotoxicity were provoked by administration of HEPM. CONCLUSIONS The results allows to conclude that HEPM exerts gastroprotective and gastric cicatrizing effects favoring on protective defenses, but not possess antisecretory effect in contrast to the current antiulcer therapy, besides the extract present good tolerability and absence of cytotoxicity. Moreover, the results presented here contribute to the validation to the popular use of the P. major in the treatment of gastric ulcer.
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Affiliation(s)
- Lincon Bordignon Somensi
- Programa de Pós-Graduação em Ciências Farmacêuticas (PPGCF), Núcleo de Investigacões Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí (UNIVALI), Rua Uruguai, 458, Centro, 88302-202 Itajaí, SC, Brazil
| | - Thaise Boeing
- Programa de Pós-Graduação em Ciências Farmacêuticas (PPGCF), Núcleo de Investigacões Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí (UNIVALI), Rua Uruguai, 458, Centro, 88302-202 Itajaí, SC, Brazil
| | - Benhur Judah Cury
- Programa de Pós-Graduação em Ciências Farmacêuticas (PPGCF), Núcleo de Investigacões Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí (UNIVALI), Rua Uruguai, 458, Centro, 88302-202 Itajaí, SC, Brazil
| | - Viviane Miranda Bispo Steimbach
- Programa de Pós-Graduação em Ciências Farmacêuticas (PPGCF), Núcleo de Investigacões Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí (UNIVALI), Rua Uruguai, 458, Centro, 88302-202 Itajaí, SC, Brazil
| | - Rivaldo Niero
- Programa de Pós-Graduação em Ciências Farmacêuticas (PPGCF), Núcleo de Investigacões Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí (UNIVALI), Rua Uruguai, 458, Centro, 88302-202 Itajaí, SC, Brazil
| | - Lauro Mera de Souza
- Instituto de Pesquisa Pelé Pequeno Príncipe, Faculdades Pequeno Príncipe, 80250-200 Curitiba, Paraná, Brazil
| | - Luisa Mota da Silva
- Programa de Pós-Graduação em Ciências Farmacêuticas (PPGCF), Núcleo de Investigacões Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí (UNIVALI), Rua Uruguai, 458, Centro, 88302-202 Itajaí, SC, Brazil
| | - Sérgio Faloni de Andrade
- Programa de Pós-Graduação em Ciências Farmacêuticas (PPGCF), Núcleo de Investigacões Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí (UNIVALI), Rua Uruguai, 458, Centro, 88302-202 Itajaí, SC, Brazil.
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Wang M, Li YQ, Cao J, Gong M, Zhang Y, Chen X, Tian MX, Xie HQ. Accelerating effects of genipin-crosslinked small intestinal submucosa for defected gastric mucosa repair. J Mater Chem B 2017; 5:7059-7071. [PMID: 32263897 DOI: 10.1039/c7tb00517b] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Slow healing of gastric mucosa defects caused by endoscopic surgery is a common but severe clinical problem for lack of an effective treatment. Small intestinal submucosa (SIS) is a bio-derived extracellular matrix scaffold with remarkable repairing ability for soft tissue, but its rapid degradation and poor mechanical properties in the stomach environment limit its application for gastric mucosa regeneration. Herein, we modified SIS by genipin, a natural crosslinking agent, to improve its resistance against degradation in gastric juice and to promote the healing of gastric mucosa defects. The crosslinking characteristics of genipin-crosslinked SIS (GP-CR SIS) were evaluated by crosslinking degree, swelling ratio and FITR, respectively. GP-CR SIS was highly resistant to gastric juice digestion and had a great improvement in mechanical properties. Additionally, GP-CR SIS maintained excellent biocompatibility according to a cytotoxicity test, hemolysis test, and rat subcutaneous implant assay. In an in vivo study, we treated defected gastric mucosa with GP-CR SIS in a rabbit endoscopic submucosal dissection (ESD)-related ulcer model. After two weeks of surgical treatment, GP-CR SIS significantly expedited wound closure and ameliorated newly constructed tissue by providing a protective microenvironment for rapid granulation tissue formation and accelerating angiogenesis/re-epithelialization. In conclusion, this study demonstrates the huge therapeutic potential of GP-CR SIS scaffolds for accelerating defected gastric mucosa regeneration.
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Affiliation(s)
- Min Wang
- Laboratory of Stem Cell and Tissue Engineering, Regenerative Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, P. R. China.
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Ajeigbe KO, Owonikoko WM, Egbe V, Iquere I, Adeleye G. Gastroprotective and mucosa homeostatic activities of coconut milk and water on experimentally induced gastropathies in male wistar rats. Tissue Cell 2017; 49:528-536. [PMID: 28844402 DOI: 10.1016/j.tice.2017.06.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2017] [Revised: 06/27/2017] [Accepted: 06/29/2017] [Indexed: 11/16/2022]
Abstract
In this biphasic study, 45 male wistar rats were divided into 9 groups. In Phase 1, Group 1 was treated with normal saline and served as the overall control, group 2 was treated with 95% Ethanol and represents the ulcer control, groups 3 and 4 received coconut water (CW; 4ml/100g BWt) and milk (CM; 4ml/100g BWt) for 4weeks while group 5 received Omeprazole (Omep; 20mg/kg BWt) during terminal week. 95% Ethanol-induced ulceration followed the treatments in all except group 1. In the second phase, Group 1 was the overall control, group 2 served as ulcer control by receiving acetic acid only, group 3 received coconut milk, and group 4 received omep. CM and omep were administered post-ulcer induction for 3 and 6days twice daily. Blood collection after 1hour was through cardiac puncture for haemocytometry, and gastric tissues harvested for histopathological investigations. Results showed significantly reduced ulcer score and gastric lesion index in Omep, CW and CM groups compared to ulcer control. WBC, neutrophil, lymphocyte counts in Omep, CW and CM groups were significantly reduced compared to ulcer and overall control groups. C-reactive protein was significantly reduced in CM compared to control. Neutrophil Infiltration score reduced while mucus cell density increased significantly in Omep; CM compared to control. EGFR and CD 31 assessment revealed significantly higher expressions in coconut-milk group compared to the ulcer control. We conclude that the protective effects of coconut (water and milk) is expressed by inflammation suppression, upregulation of mucus cell population and catalyses mucosa homeostasis via angiogenesis and mucosal cell proliferation following mucosa. erosion.
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Affiliation(s)
- K O Ajeigbe
- Igbinedion University, Okada, Edo State, Nigeria
| | | | - V Egbe
- Igbinedion University, Okada, Edo State, Nigeria
| | - I Iquere
- Igbinedion University, Okada, Edo State, Nigeria
| | - G Adeleye
- Ekiti state University, Ado Ekiti, Ekiti State, Nigeria
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Bush J, van den Boom R, Franklin S. Comparison of aloe vera and omeprazole in the treatment of equine gastric ulcer syndrome. Equine Vet J 2017; 50:34-40. [DOI: 10.1111/evj.12706] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Accepted: 05/16/2017] [Indexed: 11/30/2022]
Affiliation(s)
- J. Bush
- School of Animal and Veterinary Science; Adelaide South Australia Australia
| | - R. van den Boom
- School of Animal and Veterinary Science; Adelaide South Australia Australia
| | - S. Franklin
- School of Animal and Veterinary Science; Adelaide South Australia Australia
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50
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Uchida M, Kobayashi O, Shimizu K. Gastric emptying after artificial ulceration in rats: differences due to the site of the ulcer and the effects of prokinetic drugs. J Smooth Muscle Res 2017; 53:48-56. [PMID: 28652516 PMCID: PMC5487827 DOI: 10.1540/jsmr.53.48] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Background This study aimed to evaluate the effects of the position of
an acetic acid-induced gastric ulcer and the effects of prokinetic drugs on gastric
emptying. Materials and Methods Male Sprague-Dawley rats were used in
this study. Acetic acid ulcers were induced either in the region between the fundus and
pylorus on the anterior wall of the stomach or in the glandular region on the greater
curvature of the stomach to determine whether there were regional differences in the
effect of the ulcers. Gastric emptying was evaluated with a breath test using
[1-13C] acetic acid. In addition, the effects of the prokinetic drugs,
metoclopramide and mosapride, on gastric emptying were also evaluated.
Results Acetic acid induced ulcers in the region between the fundus and
pylorus on the anterior wall of the stomach significantly delayed gastric emptying as
compared with control rats, but not the acetic acid induced ulcers in the glandular region
on the greater curvature of the stomach. Metoclopramide and mosapride did not improve the
delayed gastric emptying even at doses that enhanced gastric emptying in normal rats.
Conclusion These findings show that gastric emptying is influenced by
the position of the ulcer and the region between the fundus and pylorus on the anterior
wall plays an important role in gastric emptying. Moreover, it was found that
metoclopramide and mosapride do not improve the delayed gastric emptying caused by acetic
acid ulcers induced on the anterior wall in the region between the fundus and pylorus.
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Affiliation(s)
- Masayuki Uchida
- Food Science Research Laboratories, Division of Research and Development, Meiji Co., Ltd., Japan
| | - Orie Kobayashi
- Food Science Research Laboratories, Division of Research and Development, Meiji Co., Ltd., Japan
| | - Kimiko Shimizu
- Food Science Research Laboratories, Division of Research and Development, Meiji Co., Ltd., Japan
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