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Carroll-Portillo A, Barnes O, Coffman CN, Braun CA, Singh SB, Lin HC. Transcytosis of T4 Bacteriophage Through Intestinal Cells Enhances Its Immune Activation. Viruses 2025; 17:134. [PMID: 39861923 PMCID: PMC11769353 DOI: 10.3390/v17010134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Revised: 01/16/2025] [Accepted: 01/17/2025] [Indexed: 01/27/2025] Open
Abstract
Interactions between bacteriophages with mammalian immune cells are of great interest and most phages possess at least one molecular pattern (nucleic acid, sugar residue, or protein structure) that is recognizable to the immune system through pathogen associated molecular pattern (PAMP) receptors (i.e., TLRs). Given that phages reside in the same body niches as bacteria, they share the propensity to stimulate or quench immune responses depending on the nature of their interactions with host immune cells. While most in vitro research focuses on the outcomes of direct application of phages to immune cells of interest, the potential impact of their transcytosis through the intestinal barrier has yet to be considered. As transcytosis through intestinal cells is a necessary step in healthy systems for access by phage to the underlying immune cell populations, it is imperative to understand how this step may play a role in immune activation. We compared the activation of macrophages (as measured by TNFα secretion) following direct phage application to those stimulated by incubation with phage transcytosed through a polarized Caco2 epithelial barrier model. Our results demonstrate that phages capable of activating TNFα secretion upon direct contact maintain the stimulatory capability following transcytosis. Furthermore, activation of macrophages by a transcytosed phage is enhanced as compared to that occurring with an equivalent multiplicity of directly applied phage.
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Affiliation(s)
- Amanda Carroll-Portillo
- Division of Gastroenterology and Hepatology, University of New Mexico, Albuquerque, NM 87131, USA
| | - October Barnes
- Biomedical Research Institute of New Mexico, Albuquerque, NM 87108, USA; (O.B.); (C.N.C.); (C.A.B.); (S.B.S.)
| | - Cristina N. Coffman
- Biomedical Research Institute of New Mexico, Albuquerque, NM 87108, USA; (O.B.); (C.N.C.); (C.A.B.); (S.B.S.)
| | - Cody A. Braun
- Biomedical Research Institute of New Mexico, Albuquerque, NM 87108, USA; (O.B.); (C.N.C.); (C.A.B.); (S.B.S.)
| | - Sudha B. Singh
- Biomedical Research Institute of New Mexico, Albuquerque, NM 87108, USA; (O.B.); (C.N.C.); (C.A.B.); (S.B.S.)
| | - Henry C. Lin
- Division of Gastroenterology and Hepatology, University of New Mexico, Albuquerque, NM 87131, USA
- Medicine Service, New Mexico VA Health Care System, Albuquerque, NM 87108, USA
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Mentino D, Nicchia GP, Frigeri A, Desantis S, Guglielmi MV, Semeraro D, Scillitani G, Mastrodonato M. Altered glycosylation in secreting cells of the gastric glands of aquaporin-4-deficient mice. Microsc Res Tech 2024; 87:1836-1848. [PMID: 38533927 DOI: 10.1002/jemt.24563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Revised: 03/08/2024] [Accepted: 03/17/2024] [Indexed: 03/28/2024]
Abstract
Aquaporins (AQPs) are important for water transport in the gastrointestinal tract. Changes in their expression and/or localization could cause in disorders and be used as therapeutic targets. Aquaporin-4 (AQP4) is expressed predominantly on the basolateral membrane of the parietal cells in the corpus of the murine gastric glands. Although the secretion of gastric juice is not affected in AQP4-deficient knockout, we evaluated by light microscopy whether the lack of AQP4 affects the glycopatterns of secreting gastric cells. Wild type (WT) and AQP4-deficient knockout mice (KO) were fed a standard diet ad libitum before sacrifice. Segments of stomach corpus were collected, fixed in buffered formalin, and embedded in paraffin wax. Sections, 5-μm thick, were analyzed by histochemical methods (Periodic acid-Schiff, Alcian Blue pH 2.5), and binding of lectins specific to GalNAc (SBA, DBA), Gal (PNA) GlcNAc (WGA, GSAII) mannose and/or glucose (ConA), and fucose (UEA-I, AAA, LTA). Immunohistochemical methods such as anti-Muc6 for neck cells and anti- β- H+/K+-ATPase for parietal cells were also performed. Compared to WT mice, in the mucous cells of KO lower amounts of glycans with galactosyl/galactosaminylated, glycosyl/glycosaminylated, and fucosylated residues were observed; lower fucosylation resulted also in the parietal cells. The observed differences of KO in respect to WT could lead to severer pathological conditions. RESEARCH HIGHLIGHTS: Glycopatterns in gastric glands were compared between wild type (WT) and AQP4-deficient knockout (KO) mice by histochemical and lectin-binding methods. In the mucous cells of KO lower amounts of glycans with galactosyl/galactosaminylated, glycosyl/glycosaminylated and fucosylated residues were observed. In the parietal cells lower fucosylation also resulted. AQP4-deficiency affects glycosylation and could result in altered functionality and pathological conditions.
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Affiliation(s)
- Donatella Mentino
- Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, Bari, Italy
| | - Grazia Paola Nicchia
- Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, Bari, Italy
| | - Antonio Frigeri
- School of Medicine, Department of Translational Biomedicine and Neuroscience, University of Bari Aldo Moro, Bari, Italy
| | - Salvatore Desantis
- Department of Precision and Regenerative Medicine and Ionian Area, Section of Veterinary Clinics and Animal Productions, University of Bari Aldo Moro, Bari, Italy
| | - Marco Vito Guglielmi
- Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, Bari, Italy
| | - Daniela Semeraro
- Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, Bari, Italy
| | - Giovanni Scillitani
- Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, Bari, Italy
| | - Maria Mastrodonato
- Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, Bari, Italy
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Einhorn V, Haase H, Maares M. Interaction and competition for intestinal absorption by zinc, iron, copper, and manganese at the intestinal mucus layer. J Trace Elem Med Biol 2024; 84:127459. [PMID: 38640745 DOI: 10.1016/j.jtemb.2024.127459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Revised: 04/09/2024] [Accepted: 04/16/2024] [Indexed: 04/21/2024]
Abstract
Trace elements such as zinc, manganese, copper, or iron are essential for a wide range of physiological functions. It is therefore crucial to ensure an adequate supply of these elements to the body. Many previous investigations have dealt with the role of transport proteins, in particular their selectivity for, and competition between, different ions. Another so far less well investigated major factor influencing the absorption of trace elements seems to be the intestinal mucus layer. This gel-like substance covers the entire gastrointestinal tract and its physiochemical properties can be mainly assigned to the glycoproteins it contains, so-called mucins. Interaction with mucins has already been demonstrated for some metals. However, knowledge about the impact on the respective bioavailability and competition between those metals is still sketchy. This review therefore aims to summarize the findings and knowledge gaps about potential effects regarding the interaction between gastrointestinal mucins and the trace elements iron, zinc, manganese, and copper. Mucins play an indispensable role in the absorption of these trace elements in the neutral to slightly alkaline environment of the intestine, by keeping them in a soluble form that can be absorbed by enterocytes. Furthermore, the studies so far indicate that the competition between these trace elements for uptake already starts at the intestinal mucus layer, yet further research is required to completely understand this interaction.
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Affiliation(s)
- Vincent Einhorn
- Technische Universität Berlin, Department of Food Chemistry and Toxicology, Straße des 17. Juni 135, Berlin 10623, Germany; Trace Age-DFG Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly, Potsdam-Jena-Wuppertal, Berlin, Germany
| | - Hajo Haase
- Technische Universität Berlin, Department of Food Chemistry and Toxicology, Straße des 17. Juni 135, Berlin 10623, Germany; Trace Age-DFG Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly, Potsdam-Jena-Wuppertal, Berlin, Germany
| | - Maria Maares
- Technische Universität Berlin, Department of Food Chemistry and Toxicology, Straße des 17. Juni 135, Berlin 10623, Germany; Trace Age-DFG Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly, Potsdam-Jena-Wuppertal, Berlin, Germany; Department of Food Chemistry, Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114-116, Nuthetal 14558, Germany.
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Amini-Salehi E, Hassanipour S, Keivanlou MH, Shahdkar M, Orang Goorabzarmakhi M, Vakilpour A, Joukar F, Hashemi M, Sattari N, Javid M, Mansour-Ghanaei F. The impact of gut microbiome-targeted therapy on liver enzymes in patients with nonalcoholic fatty liver disease: an umbrella meta-analysis. Nutr Rev 2024; 82:815-830. [PMID: 37550264 DOI: 10.1093/nutrit/nuad086] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/09/2023] Open
Abstract
CONTEXT Nonalcoholic fatty liver disease (NAFLD) is considered the leading cause of chronic liver disease worldwide. To date, no confirmed medication is available for the treatment of NAFLD. Previous studies showed the promising effects of gut microbiome-targeted therapies; however, the results were controversial and the strength of the evidence and their clinical significance remained unclear. OBJECTIVES This umbrella study summarizes the results of meta-analyses investigating the effects of probiotics, prebiotics, and synbiotics on liver enzymes in the NAFLD population. DATA SOURCE A comprehensive search of the PubMed, Scopus, Web of Science, and Cochrane Library databases was done up to December 20, 2022, to find meta-analyses on randomized control trials reporting the effects of gut microbial therapy on patients with NAFLD. DATA EXTRACTION Two independent investigators extracted data on the characteristics of meta-analyses, and any discrepancies were resolved by a third researcher. The AMSTAR2 checklist was used for evaluating the quality of studies. DATA ANALYSIS A final total of 15 studies were included in the analysis. Results showed that microbiome-targeted therapies could significantly reduce levels of alanine aminotransferase (ALT; effect size [ES], -10.21; 95% confidence interval [CI], -13.29, -7.14; P < 0.001), aspartate aminotransferase (AST; ES, -8.86; 95%CI, -11.39, -6.32; P < 0.001), and γ-glutamyltransferase (ES, -5.56; 95%CI, -7.92, -3.31; P < 0.001) in patients with NAFLD. Results of subgroup analysis based on intervention showed probiotics could significantly reduce levels of AST (ES, -8.69; 95%CI, -11.01, -6.37; P < 0.001) and ALT (ES, -9.82; 95%CI, -11.59, -8.05; P < 0.001). Synbiotics could significantly reduce levels of AST (ES, -11.40; 95%CI, -13.91, -8.88; P < 0.001) and ALT (ES, -11.87; 95%CI, -13.80, -9.95; P < 0.001). Prebiotics had no significant effects on AST and ALT levels (ES, -2.96; 95%CI, -8.12, 2.18, P = 0.259; and ES, -4.69; 95%CI, -13.53, 4.15, P = 0.299, respectively). CONCLUSION Gut microbiome-targeted therapies could be a promising therapeutic approach in the improvement of hepatic damage in patients with NAFLD. However, more studies are needed to better determine the best bacterial strains, duration of treatment, and optimum dosage of gut microbiome-targeted therapies in the treatment of the NAFLD population. SYSTEMATIC REVIEW REGISTRATION PROSPERO registration no. CRD42022346998.
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Affiliation(s)
- Ehsan Amini-Salehi
- Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran
| | - Soheil Hassanipour
- Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran
| | | | - Milad Shahdkar
- School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | | | - Azin Vakilpour
- School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Farahnaz Joukar
- Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran
| | - Mohammad Hashemi
- Student Research Committee, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Nazila Sattari
- Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran
| | | | - Fariborz Mansour-Ghanaei
- Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran
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Miyazaki K, Sasaki A, Mizuuchi H. Advances in the Evaluation of Gastrointestinal Absorption Considering the Mucus Layer. Pharmaceutics 2023; 15:2714. [PMID: 38140055 PMCID: PMC10747107 DOI: 10.3390/pharmaceutics15122714] [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: 10/26/2023] [Revised: 11/23/2023] [Accepted: 11/24/2023] [Indexed: 12/24/2023] Open
Abstract
Because of the increasing sophistication of formulation technology and the increasing polymerization of compounds directed toward undruggable drug targets, the influence of the mucus layer on gastrointestinal drug absorption has received renewed attention. Therefore, understanding the complex structure of the mucus layer containing highly glycosylated glycoprotein mucins, lipids bound to the mucins, and water held by glycans interacting with each other is critical. Recent advances in cell culture and engineering techniques have led to the development of evaluation systems that closely mimic the ecological environment and have been applied to the evaluation of gastrointestinal drug absorption while considering the mucus layer. This review provides a better understanding of the mucus layer components and the gastrointestinal tract's biological defense barrier, selects an assessment system for drug absorption in the mucus layer based on evaluation objectives, and discusses the overview and features of each assessment system.
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Affiliation(s)
- Kaori Miyazaki
- DMPK Research Laboratories, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida, Aoba-ku, Yokohama 227-0033, Japan; (A.S.); (H.M.)
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Xu Y, Liu Y, Kan X, Li X, Sun H, Zhang J. Application Research of Image Processing and Visualization Thchnology in Gastric Mucosal Protective Factors Using Artificial Intelligence. 2023 INTERNATIONAL CONFERENCE ON TELECOMMUNICATIONS, ELECTRONICS AND INFORMATICS (ICTEI) 2023:792-796. [DOI: 10.1109/ictei60496.2023.00021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
Affiliation(s)
- Yuannan Xu
- Pu'er University,College of Biology and Chemistry,Pu'er,China
| | - Yuan Liu
- Kunming Third People's Hospital,Department of Pharmacy,Kunming,China
| | - Xurundong Kan
- Pu'er University,College of Biology and Chemistry,Pu'er,China
| | - Xueling Li
- Yunnan University of Chinese Medicine,Kunming,China
| | - Hui Sun
- Kunming Third People's Hospital,Department of Pharmacy,Kunming,China
| | - Jianqiang Zhang
- Pu'er University,College of Biology and Chemistry,Pu'er,China
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Özkan B, Altuntaş E, Ünlü Ü, Doğan HH, Özsoy Y, Çakır Koç R. Development of an Antiviral Ion-Activated In Situ Gel Containing 18β-Glycyrrhetinic Acid: A Promising Alternative against Respiratory Syncytial Virus. Pharmaceutics 2023; 15:2055. [PMID: 37631269 PMCID: PMC10458153 DOI: 10.3390/pharmaceutics15082055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 06/16/2023] [Accepted: 06/18/2023] [Indexed: 08/27/2023] Open
Abstract
The human respiratory syncytial virus (hRSV) is a major cause of serious lower respiratory infections and poses a considerable risk to public health globally. Only a few treatments are currently used to treat RSV infections, and there is no RSV vaccination. Therefore, the need for clinically applicable, affordable, and safe RSV prevention and treatment solutions is urgent. In this study, an ion-activated in situ gelling formulation containing the broad-spectrum antiviral 18β-glycyrrhetinic acid (GA) was developed for its antiviral effect on RSV. In this context, pH, mechanical characteristics, ex vivo mucoadhesive strength, in vitro drug release pattern, sprayability, drug content, and stability were all examined. Rheological characteristics were also tested using in vitro gelation capacity and rheological synergism tests. Finally, the cytotoxic and antiviral activities of the optimized in situ gelling formulation on RSV cultured in the human laryngeal epidermoid carcinoma (HEp-2) cell line were evaluated. In conclusion, the optimized formulation prepared with a combination of 0.5% w/w gellan gum and 0.5% w/w sodium carboxymethylcellulose demonstrated good gelation capacity and sprayability (weight deviation between the first day of the experiment (T0) and the last day of the experiment (T14) was 0.34%), desired rheological synergism (mucoadhesive force (Fb): 9.53 Pa), mechanical characteristics (adhesiveness: 0.300 ± 0.05 mJ), ex vivo bioadhesion force (19.67 ± 1.90 g), drug content uniformity (RSD%: 0.494), and sustained drug release over a period of 6 h (24.56% ± 0.49). The optimized formulation demonstrated strong anti-hRSV activity (simultaneous half maximal effective concentration (EC50) = 0.05 µg/mL; selectivity index (SI) = 306; pre-infection EC50 = 0.154 µg/mL; SI = 100), which was significantly higher than that of ribavirin (EC50 = 4.189 µg/mL; SI = 28) used as a positive control against hRSV, according to the results of the antiviral activity test. In conclusion, this study showed that nasal in situ gelling spray can prevent viral infection and replication by directly inhibiting viral entry or modulating viral replication.
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Affiliation(s)
- Burcu Özkan
- Graduate School of Natural and Applied Science, Yildiz Technical University, Istanbul 34220, Turkey;
| | - Ebru Altuntaş
- Faculty of Pharmacy, Department of Pharmaceutical Technology, Istanbul University, Istanbul 34116, Turkey;
| | - Ümmühan Ünlü
- Elderly Care Program, Ataturk Health Services Vocational School, Afyonkarahisar Health Sciences University, Afyonkarahisar 03030, Turkey;
| | - Hasan Hüseyin Doğan
- Department of Biology, Science Faculty, Alaeddin Keykubat Campus, Selcuk University, Konya 42130, Turkey;
| | - Yıldız Özsoy
- Faculty of Pharmacy, Department of Pharmaceutical Technology, Istanbul University, Istanbul 34116, Turkey;
| | - Rabia Çakır Koç
- Faculty of Chemical and Metallurgical Engineering, Department of Bioengineering, Yildiz Technical University, Istanbul 34220, Turkey;
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Cury BJ, Boeing T, Somensi LB, Campos A, Cechinel-Filho V, de Souza P, da Silva LM. Dimethyl Cardamonin from Fruits of Campomanesia reitziana D. Legrand Promotes Gastroprotection and Gastric Healing Effects in Rodents. Chem Biodivers 2022; 19:e202200727. [PMID: 36251014 DOI: 10.1002/cbdv.202200727] [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: 08/02/2022] [Accepted: 10/17/2022] [Indexed: 12/27/2022]
Abstract
Campomanesia reitziana D. Legrand (Myrtaceae) displays antiulcer properties when given to rodents. The major active chemical components of C. reitziana are chalcones, including 4',6'-dihydroxy-2'-methoxy-3',5'-dimethylchalcone or dimethyl cardamonin (DMC); therefore, we hypothesized that this compound could have antiulcer effects and the present study aimed to evaluate its gastroprotective and gastric healing properties. DMC was isolated from the fruits of C. reitziana, and its gastroprotective effect was evaluated by ethanol and indomethacin-induced gastric ulcer models in mice (0.1 mg/kg, i.p. and 1 and 3 mg/kg, p.o.). Oxidative stress and inflammatory parameters were analyzed in the gastric tissue. Moreover, its gastric healing effect was evaluated in rats. In addition, the compound's mode of action was evaluated in vivo and in vitro by measuring H+ -K+ -ATPase activity. Finally, the cytotoxic potential of DMC was tested in fibroblasts and human gastric adenocarcinoma cells. The DMC reduced the ethanol-induced gastric ulcer in mice by 77 %, increased the adhered mucus, and reduced lipoperoxides levels. The block of nonprotein sulfhydryls (NP-SH) compounds by pretreatment with N-ethylmaleimide (NEM), the inhibition of nitric oxide synthase with Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME), or the antagonism of α2 receptor using yohimbine reversed the gastroprotective effects of DMC. Furthermore, DMC reduced the acidity of gastric content in pylorus-ligated rats but did not change H+ , K+ -ATPase (isolated from rabbit) activity in vitro. DMC reduced the lesion area in acetic acid-induced ulcers and decreased myeloperoxidase activity. DMC did not change the viability of fibroblast cells (L929) but reduced the viability of human gastric adenocarcinoma cells (AGS). The results confirmed that DMC could significantly enhance the gastric healing process and prevent ulcers due to improving protective factors on the gastric mucosa and reducing gastric acid secretion.
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Affiliation(s)
- Benhur Judah Cury
- Programa de Pós-graduação em Ciências Farmacêuticas, Núcleo de Investigações Químico-Farmacêuticas, Universidade do Vale do Itajaí, Rua Uruguai, 458, Centro, 88302-901, Itajaí, Santa Catarina, Brazil
| | - Thaise Boeing
- Programa de Pós-graduação em Ciências Farmacêuticas, Núcleo de Investigações Químico-Farmacêuticas, Universidade do Vale do Itajaí, Rua Uruguai, 458, Centro, 88302-901, Itajaí, Santa Catarina, Brazil
| | - Lincon Bordignon Somensi
- Programa de Pós-graduação em Ciências Farmacêuticas, Núcleo de Investigações Químico-Farmacêuticas, Universidade do Vale do Itajaí, Rua Uruguai, 458, Centro, 88302-901, Itajaí, Santa Catarina, Brazil
| | - Adriana Campos
- Programa de Pós-graduação em Ciências Farmacêuticas, Núcleo de Investigações Químico-Farmacêuticas, Universidade do Vale do Itajaí, Rua Uruguai, 458, Centro, 88302-901, Itajaí, Santa Catarina, Brazil
| | - Valdir Cechinel-Filho
- Programa de Pós-graduação em Ciências Farmacêuticas, Núcleo de Investigações Químico-Farmacêuticas, Universidade do Vale do Itajaí, Rua Uruguai, 458, Centro, 88302-901, Itajaí, Santa Catarina, Brazil
| | - Priscila de Souza
- Programa de Pós-graduação em Ciências Farmacêuticas, Núcleo de Investigações Químico-Farmacêuticas, Universidade do Vale do Itajaí, Rua Uruguai, 458, Centro, 88302-901, Itajaí, Santa Catarina, Brazil
| | - Luisa Mota da Silva
- Programa de Pós-graduação em Ciências Farmacêuticas, Núcleo de Investigações Químico-Farmacêuticas, Universidade do Vale do Itajaí, Rua Uruguai, 458, Centro, 88302-901, Itajaí, Santa Catarina, Brazil
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Lee JH, Park DH, Lee S, Seo HJ, Park SJ, Jung K, Kim SY, Kang KS. Potential and beneficial effects of Cinnamomum cassia on gastritis and safety: Literature review and analysis of standard extract. APPLIED BIOLOGICAL CHEMISTRY 2021; 64:95. [DOI: 10.1186/s13765-021-00661-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 12/07/2021] [Indexed: 01/02/2025]
Abstract
AbstractThe prevalence of gastritis in South Korea is rapidly increasing owing to the prevalence of Helicobacter pylori infection and fast eating habit. The usual treatment for acute gastritis following a long intake of non-steroidal anti-inflammatory drugs (NSAIDs) or alcohol is to stop the causal factors. Metronidazole and lansoprazole are recommended for the treatment of H. pylori infection gastritis. Omeprazole a proton pump inhibitor, is used to decrease gastric acid production. However, owing to the side effects and refractoriness of the drug, a safe and efficient treatment is required. Plant-derived phytochemicals have emerged as novel agents against chronic disorders. In this study, firstly, to explore the potential of pharmacological activities, including efficacy and mechanisms of Cinnamomum cassia against gastritis, a literature review was performed based on 20 studies out of a total of 749 records obtained using a search strategy. From the literature review, the therapeutic targets of C. cassia extract and cinnamaldehyde, a compound of C. cassia, were found to be related with NFκB activity, and their signaling pathway were verified by experiments. C. cassia extract plays a role in protection of gastric ulcers induced in four ways (immersion stress-induced, ethanol-induced, hydrochloric acid-induced, or NSAIDs-induced ulcer). None of the clinical studies on C. cassia extracts or compounds met our criteria. When the standardized extract of C. cassia (ECC) was orally administered repeatedly to Beagle Dog for 4 weeks, no toxicologically harmful changes were observed. Therefore, under the test condition, the no observed adverse effect level (NOAEL) of ECC was judged to be 1000 mg/kg/day for both sexes, and no toxic target organ was observed. Administration of ECC in the Sprague–Dawley rat model of acute gastric injury caused by indomethacin administration significantly increased gastric mucus volume. Administration of ECC in the acute gastric injury model caused by indomethacin administration is considered effective in improving gastric injury. However, research and efforts to develop a reliable ‘standardization of natural drugs’ by establishing the best quality evaluation system are limited. Despite the pharmacological potential of ECC, further well-designed experimental studies such as in vitro, in vivo, and clinical trials are required to validate these findings and the underlying mechanisms of ECC.
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Marczynski M, Kimna C, Lieleg O. Purified mucins in drug delivery research. Adv Drug Deliv Rev 2021; 178:113845. [PMID: 34166760 DOI: 10.1016/j.addr.2021.113845] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 06/02/2021] [Accepted: 06/16/2021] [Indexed: 12/20/2022]
Abstract
One of the main challenges in the field of drug delivery remains the development of strategies to efficiently transport pharmaceuticals across mucus barriers, which regulate the passage and retention of molecules and particles in all luminal spaces of the body. A thorough understanding of the molecular mechanisms, which govern such selective permeability, is key for achieving efficient translocation of drugs and drug carriers. For this purpose, model systems based on purified mucins can contribute valuable information. In this review, we summarize advances that were made in the field of drug delivery research with such mucin-based model systems: First, we give an overview of mucin purification procedures and discuss the suitability of model systems reconstituted from purified mucins to mimic native mucus. Then, we summarize techniques to study mucin binding. Finally, we highlight approaches that made use of mucins as building blocks for drug delivery platforms or employ mucins as active compounds.
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Simon E, Călinoiu LF, Mitrea L, Vodnar DC. Probiotics, Prebiotics, and Synbiotics: Implications and Beneficial Effects against Irritable Bowel Syndrome. Nutrients 2021; 13:nu13062112. [PMID: 34203002 PMCID: PMC8233736 DOI: 10.3390/nu13062112] [Citation(s) in RCA: 106] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 06/05/2021] [Accepted: 06/16/2021] [Indexed: 12/12/2022] Open
Abstract
Irritable bowel syndrome (IBS) is still a common functional gastrointestinal disease that presents chronic abdominal symptoms but with a pathophysiology that is not yet fully elucidated. Moreover, the use of the synergistic combination of prebiotics and probiotics, known as synbiotics, for IBS therapy is still in the early stages. Advancements in technology led to determining the important role played by probiotics in IBS, whereas the present paper focuses on the detailed review of the various pathophysiologic mechanisms of action of probiotics, prebiotics, and synbiotics via multidisciplinary domains involving the gastroenterology (microbiota modulation, alteration of gut barrier function, visceral hypersensitivity, and gastrointestinal dysmotility) immunology (intestinal immunological modulation), and neurology (microbiota–gut–brain axis communication and co-morbidities) in mitigating the symptoms of IBS. In addition, this review synthesizes literature about the mechanisms involved in the beneficial effects of prebiotics and synbiotics for patients with IBS, discussing clinical studies testing the efficiency and outcomes of synbiotics used as therapy for IBS.
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Affiliation(s)
- Elemer Simon
- Faculty of Food Science and Technology, University of Agricultural Sciences and Veterinary Medicine, Calea Mănăştur 3–5, 400372 Cluj-Napoca, Romania; (E.S.); (L.F.C.)
| | - Lavinia Florina Călinoiu
- Faculty of Food Science and Technology, University of Agricultural Sciences and Veterinary Medicine, Calea Mănăştur 3–5, 400372 Cluj-Napoca, Romania; (E.S.); (L.F.C.)
- Institute of Life Sciences, University of Agricultural Sciences and Veterinary Medicine, Calea Mănăştur 3–5, 400372 Cluj-Napoca, Romania;
| | - Laura Mitrea
- Institute of Life Sciences, University of Agricultural Sciences and Veterinary Medicine, Calea Mănăştur 3–5, 400372 Cluj-Napoca, Romania;
| | - Dan Cristian Vodnar
- Faculty of Food Science and Technology, University of Agricultural Sciences and Veterinary Medicine, Calea Mănăştur 3–5, 400372 Cluj-Napoca, Romania; (E.S.); (L.F.C.)
- Institute of Life Sciences, University of Agricultural Sciences and Veterinary Medicine, Calea Mănăştur 3–5, 400372 Cluj-Napoca, Romania;
- Correspondence: ; Tel.: +40-747-341-881
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12
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Tavares LM, de Jesus LCL, da Silva TF, Barroso FAL, Batista VL, Coelho-Rocha ND, Azevedo V, Drumond MM, Mancha-Agresti P. Novel Strategies for Efficient Production and Delivery of Live Biotherapeutics and Biotechnological Uses of Lactococcus lactis: The Lactic Acid Bacterium Model. Front Bioeng Biotechnol 2020; 8:517166. [PMID: 33251190 PMCID: PMC7672206 DOI: 10.3389/fbioe.2020.517166] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Accepted: 10/09/2020] [Indexed: 12/15/2022] Open
Abstract
Lactic acid bacteria (LAB) are traditionally used in fermentation and food preservation processes and are recognized as safe for consumption. Recently, they have attracted attention due to their health-promoting properties; many species are already widely used as probiotics for treatment or prevention of various medical conditions, including inflammatory bowel diseases, infections, and autoimmune disorders. Some LAB, especially Lactococcus lactis, have been engineered as live vehicles for delivery of DNA vaccines and for production of therapeutic biomolecules. Here, we summarize work on engineering of LAB, with emphasis on the model LAB, L. lactis. We review the various expression systems for the production of heterologous proteins in Lactococcus spp. and its use as a live delivery system of DNA vaccines and for expression of biotherapeutics using the eukaryotic cell machinery. We have included examples of molecules produced by these expression platforms and their application in clinical disorders. We also present the CRISPR-Cas approach as a novel methodology for the development and optimization of food-grade expression of useful substances, and detail methods to improve DNA delivery by LAB to the gastrointestinal tract. Finally, we discuss perspectives for the development of medical applications of recombinant LABs involving animal model studies and human clinical trials, and we touch on the main safety issues that need to be taken into account so that bioengineered versions of these generally recognized as safe organisms will be considered acceptable for medical use.
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Affiliation(s)
- Laísa M Tavares
- Laboratory of Cellular and Molecular Genetics, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Luís C L de Jesus
- Laboratory of Cellular and Molecular Genetics, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Tales F da Silva
- Laboratory of Cellular and Molecular Genetics, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Fernanda A L Barroso
- Laboratory of Cellular and Molecular Genetics, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Viviane L Batista
- Laboratory of Cellular and Molecular Genetics, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Nina D Coelho-Rocha
- Laboratory of Cellular and Molecular Genetics, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Vasco Azevedo
- Laboratory of Cellular and Molecular Genetics, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Mariana M Drumond
- Laboratory of Cellular and Molecular Genetics, Federal University of Minas Gerais, Belo Horizonte, Brazil.,Departamento de Ciências Biológicas, Centro Federal de Educação Tecnológica de Minas Gerais, Belo Horizonte, Brazil
| | - Pamela Mancha-Agresti
- Laboratory of Cellular and Molecular Genetics, Federal University of Minas Gerais, Belo Horizonte, Brazil.,FAMINAS - BH, Belo Horizonte, Brazil
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13
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Ye X, Zhou L, Jia J, Wei L, Wen Y, Yan X, Huang J, Gan B, Liu K, Lv Y, Hu G. ITRAQ Proteomic Analysis of Yellow and Black Skin in Jinbian Carp ( Cyprinus carpio). Life (Basel) 2020; 10:E226. [PMID: 33007994 PMCID: PMC7601221 DOI: 10.3390/life10100226] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 09/12/2020] [Accepted: 09/24/2020] [Indexed: 01/01/2023] Open
Abstract
Colors are important phenotypic traits for fitness under natural conditions in vertebrates. Previous studies have reported several functional genes and genetic variations of pigmentation, but the formation mechanisms of various skin coloration remained ambiguous in fish. Jinbian carp, a common carp variant, displays two colors (yellow and black) in the skin, thus, it is a good model for investigating the genetic basis of pigmentation. In the present study, using the Jinbian carp as model, isobaric tags for relative and absolute quantification (ITRAQ) proteomics analysis was performed for yellow and black skin, respectively. The results showed that 467 differentially expressed proteins (DEPs) were identified between the yellow skin and the black skin. Similar to mammals, the up-regulated DEPs in black skin included UV excision repair protein RAD23 homolog A (Rad23a), melanoregulin (mreg), 5,6-dihydroxyindole-2-carboxylic acid oxidase5 (tyrp1) and melanocyte protein PMEL (PMEL), which were mainly grouped into melanogenesis pathway. However, several up-regulated DEPs in yellow skin were mainly enriched in nucleotide metabolism, such as GTPase IMAP family member 5 (GIMAP5), AMP deaminase 1 (AMPD1), adenosylhomocysteinase b (ahcy-b), and pyruvate kinase (PKM). In summary, several candidate proteins and their enrichment pathways for color variation in Jinbian carp were identified, which may be responsible for the formation of different colorations.
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Affiliation(s)
- Xiangchen Ye
- Aquatic Species Introduction and Breeding Center of Guangxi, Nanning 530031, China; (X.Y.); (L.W.); (X.Y.); (B.G.); (K.L.)
| | - Lingling Zhou
- College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China; (L.Z.); (J.J.)
| | - Jingyi Jia
- College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China; (L.Z.); (J.J.)
| | - Lingjing Wei
- Aquatic Species Introduction and Breeding Center of Guangxi, Nanning 530031, China; (X.Y.); (L.W.); (X.Y.); (B.G.); (K.L.)
| | - Yanhong Wen
- Extension Station of Fisheries Technology of Liuzhou, Liuzhou 545006, China; (Y.W.); (J.H.)
| | - Xueyu Yan
- Aquatic Species Introduction and Breeding Center of Guangxi, Nanning 530031, China; (X.Y.); (L.W.); (X.Y.); (B.G.); (K.L.)
| | - Jie Huang
- Extension Station of Fisheries Technology of Liuzhou, Liuzhou 545006, China; (Y.W.); (J.H.)
| | - Baojiang Gan
- Aquatic Species Introduction and Breeding Center of Guangxi, Nanning 530031, China; (X.Y.); (L.W.); (X.Y.); (B.G.); (K.L.)
| | - Kang Liu
- Aquatic Species Introduction and Breeding Center of Guangxi, Nanning 530031, China; (X.Y.); (L.W.); (X.Y.); (B.G.); (K.L.)
| | - Yejian Lv
- Aquatic Species Introduction and Breeding Center of Guangxi, Nanning 530031, China; (X.Y.); (L.W.); (X.Y.); (B.G.); (K.L.)
| | - Guangfu Hu
- College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China; (L.Z.); (J.J.)
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14
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Hoffmann W. Trefoil Factor Family (TFF) Peptides and Their Diverse Molecular Functions in Mucus Barrier Protection and More: Changing the Paradigm. Int J Mol Sci 2020; 21:ijms21124535. [PMID: 32630599 PMCID: PMC7350206 DOI: 10.3390/ijms21124535] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 06/17/2020] [Accepted: 06/19/2020] [Indexed: 02/07/2023] Open
Abstract
Trefoil factor family peptides (TFF1, TFF2, TFF3) are typically co-secreted together with mucins. Tff1 represents a gastric tumor suppressor gene in mice. TFFs are also synthesized in minute amounts in the immune and central nervous systems. In mucous epithelia, they support rapid repair by enhancing cell migration ("restitution") via their weak chemotactic and anti-apoptotic effects. For a long time, as a paradigm, this was considered as their major biological function. Within recent years, the formation of disulfide-linked heterodimers was documented for TFF1 and TFF3, e.g., with gastrokine-2 and IgG Fc binding protein (FCGBP). Furthermore, lectin activities were recognized as enabling binding to a lipopolysaccharide of Helicobacter pylori (TFF1, TFF3) or to a carbohydrate moiety of the mucin MUC6 (TFF2). Only recently, gastric TFF1 was demonstrated to occur predominantly in monomeric forms with an unusual free thiol group. Thus, a new picture emerged, pointing to diverse molecular functions for TFFs. Monomeric TFF1 might protect the gastric mucosa as a scavenger for extracellular reactive oxygen/nitrogen species. Whereas, the TFF2/MUC6 complex stabilizes the inner layer of the gastric mucus. In contrast, the TFF3-FCGBP heterodimer (and also TFF1-FCGBP) are likely part of the innate immune defense of mucous epithelia, preventing the infiltration of microorganisms.
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Affiliation(s)
- Werner Hoffmann
- Institute of Molecular Biology and Medicinal Chemistry, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany
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15
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Tristetraprolin targets Nos2 expression in the colonic epithelium. Sci Rep 2019; 9:14413. [PMID: 31595002 PMCID: PMC6783411 DOI: 10.1038/s41598-019-50957-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Accepted: 09/18/2019] [Indexed: 12/15/2022] Open
Abstract
Tristetraprolin (TTP), encoded by the Zfp36 gene, is a zinc-finger protein that regulates RNA stability primarily through association with 3′ untranslated regions (3′ UTRs) of target mRNAs. While TTP is expressed abundantly in the intestines, its function in intestinal epithelial cells (IECs) is unknown. Here we used a cre-lox system to remove Zfp36 in the mouse epithelium to uncover a role for TTP in IECs and to identify target genes in these cells. While TTP was largely dispensable for establishment and maintenance of the colonic epithelium, we found an expansion of the proliferative zone and an increase in goblet cell numbers in the colon crypts of Zfp36ΔIEC mice. Furthermore, through RNA-sequencing of transcripts isolated from the colons of Zfp36fl/fl and Zfp36ΔIEC mice, we found that expression of inducible nitric oxide synthase (iNos or Nos2) was elevated in TTP-knockout IECs. We demonstrate that TTP interacts with AU-rich elements in the Nos2 3′ UTR and suppresses Nos2 expression. In comparison to control Zfp36fl/fl mice, Zfp36ΔIEC mice were less susceptible to dextran sodium sulfate (DSS)-induced acute colitis. Together, these results demonstrate that TTP in IECs targets Nos2 expression and aggravates acute colitis.
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Mucins are Involved in the Intestinal Permeation of Lipophilic Drugs in the Proximal Region of Rat Small Intestine. Pharm Res 2019; 36:162. [DOI: 10.1007/s11095-019-2701-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2019] [Accepted: 09/06/2019] [Indexed: 01/08/2023]
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17
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da Cunha Jácome Marques F, da Silva Pantoja P, Matos VEA, Silva RO, Damasceno SRB, Franco ÁX, Alves RC, Justino PFC, de Souza MHLP, Feitosa JPA, Castro RR, Soares PMG. Galactomannan from the seeds of Caesalpinia pulcherrima prevents indomethacin-induced gastrointestinal damage via neutrophil migration. Int J Biol Macromol 2019; 141:68-75. [PMID: 31446106 DOI: 10.1016/j.ijbiomac.2019.08.193] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 08/06/2019] [Accepted: 08/22/2019] [Indexed: 12/18/2022]
Abstract
Galactomannans are neutral polysaccharides isolated from the endosperm of some Leguminosae seeds. They consist of a (1 → 4) linked β-mannopyranosyl backbone partially substituted at O-6 with α-d-galactopyranosyl side groups. C. pulcherrima have anti-inflammatory and muco-adhesive proprieties. Acute gastritis is an inflammatory disease triggered by use of non-steroidal anti-inflammatory drugs. We investigated the gastroprotective effect of galactomannan obtained from the seeds of Caesalpinia pulcherrima L. (GM-CP) in acute gastritis model induced by indomethacin. Gastritis was induced with indomethacin (30 mg/kg, P.·O.) in female Swiss mice. Animal groups (n = 7) were pretreated with saline-dissolved GM-CP (3 mg/kg, 10 mg/kg, 30 mg/kg, P.O.) or vehicle 1 h before gastritis induction. Mice were euthanized seven hours after the induction. The stomach and blood samples were collected for analysis. At 10 mg/kg, GP-CP reduced the extension of macroscopic lesion and the loss of superficial cells by alleviating inflammatory symptoms (neutrophil infiltration, migration and adhesion of mesenteric leukocytes, production of TNF-α and thiobarbituric acid reactive species (TBARS) and helping to maintain mucin labeling of the tissue. Thus, the findings of the study suggest that GM-CP exhibits gastroprotective effects.
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Affiliation(s)
- Fabrícia da Cunha Jácome Marques
- LEFFAG - Laboratório de Estudos da Fisio-Farmacologia Gastrintestinal, Centro de Biomedicina, Rua Coronel Nunes de Melo, 1315, 60430-270, Fortaleza, CE, Brazil; Instituto Superior de Ciências Biomédicas, Universidade Estadual do Ceará, Av. Dr. Silas Munguba 1700, 60740-000 Fortaleza, CE, Brazil
| | - Patrícia da Silva Pantoja
- LEFFAG - Laboratório de Estudos da Fisio-Farmacologia Gastrintestinal, Centro de Biomedicina, Rua Coronel Nunes de Melo, 1315, 60430-270, Fortaleza, CE, Brazil; Instituto Superior de Ciências Biomédicas, Universidade Estadual do Ceará, Av. Dr. Silas Munguba 1700, 60740-000 Fortaleza, CE, Brazil
| | - Victor Emanuel Araujo Matos
- LEFFAG - Laboratório de Estudos da Fisio-Farmacologia Gastrintestinal, Centro de Biomedicina, Rua Coronel Nunes de Melo, 1315, 60430-270, Fortaleza, CE, Brazil
| | - Renan Oliveira Silva
- LEFFAG - Laboratório de Estudos da Fisio-Farmacologia Gastrintestinal, Centro de Biomedicina, Rua Coronel Nunes de Melo, 1315, 60430-270, Fortaleza, CE, Brazil
| | - Samara Rodrigues Bonfim Damasceno
- LEFFAG - Laboratório de Estudos da Fisio-Farmacologia Gastrintestinal, Centro de Biomedicina, Rua Coronel Nunes de Melo, 1315, 60430-270, Fortaleza, CE, Brazil
| | - Álvaro Xavier Franco
- LEFFAG - Laboratório de Estudos da Fisio-Farmacologia Gastrintestinal, Centro de Biomedicina, Rua Coronel Nunes de Melo, 1315, 60430-270, Fortaleza, CE, Brazil
| | - Rômulo Couto Alves
- Instituto Federal de Educação, Ciência e Tecnologia Catarinense, Campus Luzerna Rua Vigário Frei João, n° 550, Centro, Luzerna, SC 89609-000, Brazil
| | - Priscilla Fernanda Campos Justino
- LEFFAG - Laboratório de Estudos da Fisio-Farmacologia Gastrintestinal, Centro de Biomedicina, Rua Coronel Nunes de Melo, 1315, 60430-270, Fortaleza, CE, Brazil
| | | | - Judith Pessoa Andrade Feitosa
- Departamento de Química Orgânica e Inorgânica, Universidade Federal do Ceará, Av. Mister Hull s/n, 60451-970 Fortaleza, CE, Brazil
| | - Rondinelle Ribeiro Castro
- Instituto Superior de Ciências Biomédicas, Universidade Estadual do Ceará, Av. Dr. Silas Munguba 1700, 60740-000 Fortaleza, CE, Brazil; Faculdade de Filosofia Dom Aureliano Matos, Universidade Estadual do Ceará, Av. Dom Aureliano Matos, 2058, 63900-000 Limoeiro do Norte, CE, Brazil
| | - Pedro Marcos Gomes Soares
- LEFFAG - Laboratório de Estudos da Fisio-Farmacologia Gastrintestinal, Centro de Biomedicina, Rua Coronel Nunes de Melo, 1315, 60430-270, Fortaleza, CE, Brazil; Instituto Superior de Ciências Biomédicas, Universidade Estadual do Ceará, Av. Dr. Silas Munguba 1700, 60740-000 Fortaleza, CE, Brazil; Departamento de Morfologia, Universidade Federal do Ceará, Rua Delmiro de Farias s/n, 60430-170 Fortaleza, CE, Brazil.
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Stenger Moura F, Perioli L, Pagano C, Vivani R, Ambrogi V, Bresolin T, Ricci M, Schoubben A. Chitosan composite microparticles: A promising gastroadhesive system for taxifolin. Carbohydr Polym 2019; 218:343-354. [DOI: 10.1016/j.carbpol.2019.04.075] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Revised: 04/23/2019] [Accepted: 04/24/2019] [Indexed: 02/06/2023]
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Wang Y, Zhu Z, Li H, Sun Y, Xie G, Cheng B, Ji F, Fang X. Effects of preoperative oral carbohydrates on patients undergoing ESD surgery under general anesthesia: A randomized control study. Medicine (Baltimore) 2019; 98:e15669. [PMID: 31096498 PMCID: PMC6531268 DOI: 10.1097/md.0000000000015669] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Preoperative oral carbohydrate (POC) has been recommended as an important element of the enhanced recovery after surgery (ERAS) protocol, but its effect on patients undergoing endoscopic submucosal dissection (ESD) remains unclear. Our study aims to investigate the effects of POC for ESD surgery, with particular focus on perioperative well-being and gastric peristalsis. METHODS A prospective, randomized, and controlled study of patients undergoing ESD was conducted. Seventy-three patients were assigned to 2 groups: experiment (36 patients) and control (37 patients). The experiment group received oral carbohydrate solution 710 mL the night before and 355 mL 2 hours prior to operation. The control group fasted for 10 hours prior to operation. Gastric empty assessment, peristaltic score, and operation score were measured. In addition, visual analogue scale (VAS) scores for 6 parameters (thirst, hunger, mouth dryness, nausea, vomit, and weakness) of wellbeing were compared perioperatively. Preoperative basic conditions of patients, postoperative complications, and their clinical outcomes were also recorded. RESULTS Before anesthesia induction, gastric sonography score was higher in experiment group, while sucked fluid by gastroscopy was similar between 2 groups. And no patient had regurgitation. Moreover, gastric peristaltic score and operation score before operation were both lower in experiment group. Importantly, VAS scores for 3 parameters (thirst, hunger, and mouth dryness) were significantly lower in experiment patients. In addition, clinical outcomes including first time exhaust, first time for drinking water, the usage of hemostasis, postoperative complication, lengths of hospital stay, and in-hospital expense were not significantly different between 2 groups. CONCLUSIONS Oral administration of carbohydrates preoperatively instead of fasting improves the feelings of thirst, hunger, and mouth dryness in patients following ESD surgery without enhancing risk of regurgitation. And, avoiding preoperative fasting with POC can decrease the degree of gastric peristalsis that may facilitate the successful completion of ESD surgery.
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Affiliation(s)
| | | | - Hui Li
- Department of Anesthesiology
| | | | | | | | - Feng Ji
- Department of Digestive Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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20
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Stürmer R, Harder S, Schlüter H, Hoffmann W. Commercial Porcine Gastric Mucin Preparations, also Used as Artificial Saliva, are a Rich Source for the Lectin TFF2: In Vitro Binding Studies. Chembiochem 2018; 19:2598-2608. [PMID: 30371971 DOI: 10.1002/cbic.201800622] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Indexed: 12/22/2022]
Abstract
Mucous gels (mucus) cover internal body surfaces. The secretory mucins MUC5AC and MUC6 and the protective peptide TFF2 are characteristic constituents of gastric mucus; TFF2 is co-secreted with MUC6. Herein, we investigated two commercial mucin preparations by FPLC and proteomics, because they are model systems for studying the rheology of gastric mucins. One preparation is also used as a saliva substitute, for example, after radiation therapy. We show that both preparations contain TFF2 (≈0.6 to 1.1 %, w/w). The majority of TFF2 is strongly bound noncovalently to mucin in a manner that is resistant to boiling in SDS. First overlay assays with 125 I-labeled porcine TFF2 revealed that mucin binding is modulated by Ca2+ and can be blocked by the lectin GSA-II and the antibody HIK1083, both recognizing the peripheral GlcNAcα1→4Galβ1→R moiety of MUC6. TFF2 binding was also inhibited in the presence of Me-β-Gal but less so by the α anomer. TFF2 may play a role in the oligomerization and secretion of MUC6, the rheology of gastric mucus, and the adherence of gastric microbiota. TFF2 in artificial saliva may be of benefit. TFF2 might also interact with the sugar moiety of various receptors.
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Affiliation(s)
- René Stürmer
- Institute of Molecular Biology and Medicinal Chemistry, Otto-von-Guericke University Magdeburg, Leipziger Strasse 44, 39120, Magdeburg, Germany
| | - Sönke Harder
- Institute for Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
| | - Hartmut Schlüter
- Institute for Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
| | - Werner Hoffmann
- Institute of Molecular Biology and Medicinal Chemistry, Otto-von-Guericke University Magdeburg, Leipziger Strasse 44, 39120, Magdeburg, Germany
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Carrillo W, Monteiro KM, Martínez-Maqueda D, Ramos M, Recio I, Carvalho JED. Antiulcerative Activity of Milk Proteins Hydrolysates. J Med Food 2018; 21:408-415. [PMID: 29216438 DOI: 10.1089/jmf.2017.0087] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Affiliation(s)
- Wilman Carrillo
- Research Institute of Food Science (CIAL), (CSIC-UAM), Cantoblanco Campus, Autonomous University of Madrid, Madrid, Spain
- Laboratory of Functional Foods, Faculty of Foods Science and Engineering, Technical University of Ambato, Ambato, Ecuador
- Research Department Faculty of Health and Human Sciences, Bolivar State University, Guaranda, Ecuador
| | | | - Daniel Martínez-Maqueda
- Research Institute of Food Science (CIAL), (CSIC-UAM), Cantoblanco Campus, Autonomous University of Madrid, Madrid, Spain
| | - Mercedes Ramos
- Research Institute of Food Science (CIAL), (CSIC-UAM), Cantoblanco Campus, Autonomous University of Madrid, Madrid, Spain
| | - Isidra Recio
- Research Institute of Food Science (CIAL), (CSIC-UAM), Cantoblanco Campus, Autonomous University of Madrid, Madrid, Spain
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22
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Jouini M, Abdelhamid A, Chaouch MA, le Cerf D, Bouraoui A, Majdoub H, Ben Jannet H. Physico-chemical characterization and pharmacological activities of polysaccharides from Opuntia microdasys var. rufida cladodes. Int J Biol Macromol 2018; 107:1330-1338. [DOI: 10.1016/j.ijbiomac.2017.10.003] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2017] [Revised: 09/21/2017] [Accepted: 10/01/2017] [Indexed: 11/25/2022]
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23
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Adeniyi OS, Makinde OV, Friday ET, Olaleye SB. Effects of quinine on gastric ulcer healing in Wistar rats. JOURNAL OF COMPLEMENTARY & INTEGRATIVE MEDICINE 2017; 14:/j/jcim.ahead-of-print/jcim-2016-0132/jcim-2016-0132.xml. [PMID: 28665790 DOI: 10.1515/jcim-2016-0132] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/28/2016] [Accepted: 03/22/2017] [Indexed: 11/15/2022]
Abstract
Background Quinine (QT) is an important anti-malarial drug; however, there is little information about its effects on the gut. Therefore, this study aimed to investigate the effects of a therapeutic dose of QT on the healing of gastric ulcer in rats. Methods Male Wistar rats weighing 150-200 g were divided into three groups: control rats without ulcer (group 1), ulcerated rats treated with 1 mL/kg (p.o.) normal saline (NS) (group 2), and ulcerated rats treated with 10 mg/kg (p.o.) QT (group 3). Ulcers were induced by serosal application of 80 % acetic acid to the stomach of rats anaesthetized with 50 mg/kg thiopentone sodium and treatment was given three times daily. Healing was assessed on days 3, 7 and 10 after ulcer induction by macroscopic measurement of: ulcer area, histology, lipid peroxidation, superoxide dismutase activity and gastric mucus secretion. Results At day 3, there was no significant difference (p>0.05) in ulcer areas between NS- and QT-treated rats. By day 10, however, the percentage area healed in NS treated (59.6±2.35 %) was significantly higher (p<0.05) than in QT rats (49.0±2.20 %) and clearing of inflammatory cells and re-epithelization was greater in NS-treated group. By days 7 and 10, lipid peroxidation was significantly higher in QT animals, when compared with NS-treated rats and controls (p<0.05). Superoxide dismutase activity and mucus secretion were significantly (p<0.05) higher in NS-treated than QT-treated rats. Conclusions QT delayed ulcer healing by prolonging the inflammatory phase of healing, increasing oxidative stress, reducing antioxidant activity and gastric mucus secretion.
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Nascimento AM, Maria-Ferreira D, de Souza EFJ, de Souza LM, Sassaki GL, Iacomini M, de P. Werner MF, Cipriani TR. Gastroprotective effect and chemical characterization of a polysaccharide fraction from leaves of Croton cajucara. Int J Biol Macromol 2017; 95:153-159. [PMID: 27864055 DOI: 10.1016/j.ijbiomac.2016.11.044] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Revised: 10/28/2016] [Accepted: 11/14/2016] [Indexed: 12/18/2022]
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Shore R, Björne H, Omoto Y, Siemiatkowska A, Gustafsson JÅ, Lindblad M, Holm L. Sex differences and effects of oestrogen in rat gastric mucosal defence. World J Gastroenterol 2017; 23:426-436. [PMID: 28210078 PMCID: PMC5291847 DOI: 10.3748/wjg.v23.i3.426] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Revised: 10/05/2016] [Accepted: 10/19/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate sex differences and the effects of oestrogen administration in rat gastric mucosal defence.
METHODS Sex differences in gastric mucus thickness and accumulation rate, absolute gastric mucosal blood flow using microspheres, the integrity of the gastric mucosal epithelium in response to a chemical irritant and the effects of oestrogen administration on relative gastric mucosal blood flow in an acute setting was assessed in an in vivo rat experimental model. Subsequently, sex differences in the distribution of oestrogen receptors and calcitonin gene related peptide in the gastric mucosa of animals exposed to oestrogen in the above experiments was evaluated using immunohistochemistry.
RESULTS The absolute blood flow in the GI-tract was generally higher in males, but only significantly different in the corpus part of the stomach (1.12 ± 0.12 mL/min•g in males and 0.51 ± 0.03 mL/min•g in females) (P = 0.002). After removal of the loosely adherent mucus layer the thickness of the firmly adherent mucus layer in males and females was 79 ± 1 µm and 80 ± 3 µm respectively. After 60 min the mucus thickness increased to 113 ± 3 µm in males and 121 ± 3 µm in females with no statistically significant difference seen between the sexes. Following oestrogen administration (0.1 followed by 1 µg/kg•min), mean blood flow in the gastric mucosa decreased by 31% [68 ± 13 perfusion units (PFU)] in males which was significantly different compared to baseline (P = 0.02). In females however, mean blood flow remained largely unchanged with a 4% (5 ± 33 PFU) reduction. The permeability of the gastric mucosa increased to a higher level in females than in males (P = 0.01) after taurocholate challenge. However, the calculated mean clearance increase did not significantly differ between the sexes [0.1 ± 0.04 to 1.1 ± 0.1 mL/min•100 g in males and 0.4 ± 0.3 to 2.1 ± 0.3 mL/min•100 g in females (P = 0.065)]. There were no significant differences between 17β-Estradiol treated males (mean ratio of positive staining ± SEM) (0.06 ± 0.07) and females (0.11 ± 0.11) in the staining of ERα (P = 0.24). Also, there were no significant differences between 17β-Estradiol treated males (0.18 ± 0.21) and females (0.06 ± 0.12) in the staining of ERβ (P = 0.11). Finally, there were no significant differences between 17β-Estradiol treated males (0.04 ± 0.05) and females (0.11 ± 0.10) in the staining of CGRP (P = 0.14).
CONCLUSION Gastric mucosal blood flow is higher in male than in female rats and is reduced in male rats by oestrogen administration.
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Akıncı A, Eşrefoğlu M, Taşlıdere E, Ateş B. Petroselinum Crispum is Effective in Reducing Stress-Induced Gastric Oxidative Damage. Balkan Med J 2017; 34:53-59. [PMID: 28251024 PMCID: PMC5322505 DOI: 10.4274/balkanmedj.2015.1411] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2015] [Accepted: 08/07/2016] [Indexed: 01/02/2023] Open
Abstract
Background: Oxidative stress has been shown to play a principal role in the pathogenesis of stress-induced gastric injury. Parsley (Petroselinum crispum) contains many antioxidants such as flavanoids, carotenoids and ascorbic acid. Aims: In this study, the histopathological and biochemical results of nutrition with a parsley-rich diet in terms of eliminating stress-induced oxidative gastric injury were evaluated. Study Design: Animal experimentation Methods: Forty male Wistar albino rats were divided into five groups: control, stress, stress + standard diet, stress + parsley-added diet and stress + lansoprazole (LPZ) groups. Subjects were exposed to 72 hours of fasting and later immobilized and exposed to the cold at +4 degrees for 8 hours to create a severe stress condition. Samples from the animals’ stomachs were arranged for microscopic and biochemical examinations. Results: Gastric mucosal injury was obvious in rats exposed to stress. The histopathologic damage score of the stress group (7.00±0.57) was higher than that of the control group (1.50±0.22) (p<0.05). Significant differences in histopathologic damage score were found between the stress and stress + parsley-added diet groups (p<0.05), the stress and stress + standard diet groups (p<0.05), and the stress and stress + LPZ groups (p<0.05). The mean tissue malondialdehyde levels of the stress + parsley-added group and the stress + LPZ group were lower than that of the stress group (p<0.05). Parsley supported the cellular antioxidant system by increasing the mean tissue glutathione level (53.31±9.50) and superoxide dismutase (15.18±1.05) and catalase (16.68±2.29) activities. Conclusion: Oral administration of parsley is effective in reducing stress-induced gastric injury by supporting the cellular antioxidant defence system.
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Affiliation(s)
| | - Mukaddes Eşrefoğlu
- Department of Histology and Embryology, Bezmialem Vakıf University Faculty of Medicine, İstanbul, Turkey
| | - Elif Taşlıdere
- Department of Histology and Embryology, Bezmialem Vakıf University Faculty of Medicine, İstanbul, Turkey
| | - Burhan Ateş
- Department of Chemistry, İnönü University Faculty of Science and Art, Malatya, Turkey
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KHODER GHALIA, AL-MENHALI ASMAA, AL-YASSIR FARAH, KARAM SHERIFM. Potential role of probiotics in the management of gastric ulcer. Exp Ther Med 2016; 12:3-17. [PMID: 27347010 PMCID: PMC4906699 DOI: 10.3892/etm.2016.3293] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2015] [Accepted: 03/03/2016] [Indexed: 02/07/2023] Open
Abstract
Gastric ulcer is one of the most common chronic gastrointestinal diseases characterized by a significant defect in the mucosal barrier. Helicobacter pylori (H. pylori) infection and the frequent long-term use of non-steroidal anti-inflammatory drugs are major factors involved in gastric ulcer development. Acid inhibitors and antibiotics are commonly used to treat gastric ulcer. However, in the last few decades, the accumulating evidence for resistance to antibiotics and the side effects of antibiotics and acid inhibitors have drawn attention to the possible use of probiotics in the prevention and treatment of gastric ulcer. Probiotics are live microorganisms that when administered in adequate amounts confer health benefits on the host. Currently, the available experimental and clinical studies indicate that probiotics are promising for future applications in the management of gastric ulcers. This review aims to provide an overview of the general health benefits of probiotics on various systemic and gastrointestinal disorders with a special focus on gastric ulcer and the involved cellular and molecular mechanisms: i) Protection of gastric mucosal barrier; ii) upregulation of prostaglandins, mucus, growth factors and anti-inflammatory cytokines; iii) increased cell proliferation to apoptosis ratio; and iv) induction of angiogenesis. Finally, some of the available data on the possible use of probiotics in H. pylori eradication are discussed.
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Affiliation(s)
- GHALIA KHODER
- Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - ASMA A. AL-MENHALI
- Department of Biology, College of Science, United Arab Emirates University, Al-Ain 17666, United Arab Emirates
| | - FARAH AL-YASSIR
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain 17666, United Arab Emirates
| | - SHERIF M. KARAM
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain 17666, United Arab Emirates
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Niu H, Wang Z, Hou H, Zhang Z, Li B. Protective Effect of Cod (Gadus macrocephalus) Skin Collagen Peptides on Acetic Acid-Induced Gastric Ulcer in Rats. J Food Sci 2016; 81:H1807-15. [PMID: 27219644 DOI: 10.1111/1750-3841.13332] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2015] [Revised: 03/30/2016] [Accepted: 04/06/2016] [Indexed: 12/14/2022]
Abstract
This research was performed to explore the protective effect of cod skin collagen peptides (CCP) on gastric ulcer induced by acetic acid. The CCP were fractionated into low molecular CCP (LMCCP, Mw < 3 kDa) and high molecular CCP (HMCCP, Mw > 3 kDa). In HMCCP and LMCCP, glycine of accounted for about one-third of the total amino acids without cysteine and tryptophan, and hydrophobic amino acids accounted for about 50%. After 21 d CCP treatment (60 or 300 mg/kg, p.o./daily), the healing effects on acetic acid-induced gastric ulcers were evaluated by macroscopic measure, microscopic measure, and immune histochemistry. Moreover, the expression levels of the growth factors, such as vascular endothelial growth factor, epidermal growth factor, transforming growth factor β1 (TGFβ1), and the heat shock protein 70 (HSP70) was detected. The results showed that both LMCCP and HMCCP could significantly decrease the ulcer areas and promote the healing of the lesions. They also could improve the levels of hexosamine, glutathione, superoxide dismutase, and glutathione peroxidase, and reduce the content of malondialdehyde and inducible nitric oxide synthase. In addition, the expression level of TGFβ1 gene and HSP70 mRNA was significantly improved by the treatment. It suggested that CCP could be able to improve symptoms of gastric ulcer and probably be used in the treatment of gastric ulcer.
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Affiliation(s)
- Huina Niu
- College of Food Science and Engineering, Ocean Univ. of China, No. 5, Yu Shan Road, Qingdao, Shandong Province, 266003, P.R. China
| | - Zhicong Wang
- College of Food Science and Engineering, Ocean Univ. of China, No. 5, Yu Shan Road, Qingdao, Shandong Province, 266003, P.R. China
| | - Hu Hou
- College of Food Science and Engineering, Ocean Univ. of China, No. 5, Yu Shan Road, Qingdao, Shandong Province, 266003, P.R. China
| | - Zhaohui Zhang
- College of Food Science and Engineering, Ocean Univ. of China, No. 5, Yu Shan Road, Qingdao, Shandong Province, 266003, P.R. China
| | - Bafang Li
- College of Food Science and Engineering, Ocean Univ. of China, No. 5, Yu Shan Road, Qingdao, Shandong Province, 266003, P.R. China
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Lee CA, Kim BS, Cho CW. Quantitative evaluation of mucoadhesive polymers to compare the mucoadhesion. JOURNAL OF PHARMACEUTICAL INVESTIGATION 2016. [DOI: 10.1007/s40005-016-0233-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Borato DG, Scoparo CT, Maria-Ferreira D, da Silva LM, de Souza LM, Iacomini M, Werner MFDP, Baggio CH. Healing mechanisms of the hydroalcoholic extract and ethyl acetate fraction of green tea (Camellia sinensis (L.) Kuntze) on chronic gastric ulcers. Naunyn Schmiedebergs Arch Pharmacol 2015; 389:259-68. [PMID: 26715119 DOI: 10.1007/s00210-015-1200-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2015] [Accepted: 12/14/2015] [Indexed: 02/07/2023]
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Petersson J, Jädert C, Phillipson M, Borniquel S, Lundberg JO, Holm L. Physiological recycling of endogenous nitrate by oral bacteria regulates gastric mucus thickness. Free Radic Biol Med 2015; 89:241-7. [PMID: 26163002 DOI: 10.1016/j.freeradbiomed.2015.07.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2015] [Revised: 06/30/2015] [Accepted: 07/01/2015] [Indexed: 02/08/2023]
Abstract
BACKGROUND Inorganic nitrate from exogenous and endogenous sources is accumulated in saliva, reduced to nitrite by oral bacteria and further converted to nitric oxide (NO) and other bioactive nitrogen oxides in the acidic gastric lumen. To further explore the role of oral microbiota in this process we examined the gastric mucus layer in germ free (GF) and conventional mice given different doses of nitrate and nitrite. METHODS Mice were given either nitrate (100mg/kg/d) or nitrite (0.55-11 mg/kg/d) in the drinking water for 7 days, with the lowest nitrite dose resembling the levels provided by swallowing of fasting saliva. The gastric mucus layer was measured in vivo. RESULTS GF animals were almost devoid of the firmly adherent mucus layer compared to conventional mice. Dietary nitrate increased the mucus thickness in conventional animals but had no effect in GF mice. In contrast, nitrite at all doses, restored the mucus thickness in GF mice to the same levels as in conventional animals. The nitrite-mediated increase in gastric mucus thickness was not inhibited by the soluble guanylyl cyclase inhibitor ODQ. Mice treated with antibiotics had significantly thinner mucus than controls. Additional studies on mucin gene expression demonstrated down regulation of Muc5ac and Muc6 in germ free mice after nitrite treatment. CONCLUSION Oral bacteria remotely modulate gastric mucus generation via bioactivation of salivary nitrate. In the absence of a dietary nitrate intake, salivary nitrate originates mainly from NO synthase. Thus, oxidized NO from the endothelium and elsewhere is recycled to regulate gastric mucus homeostasis.
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Affiliation(s)
- Joel Petersson
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Cecilia Jädert
- Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden
| | - Mia Phillipson
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Sara Borniquel
- Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden
| | - Jon O Lundberg
- Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
| | - Lena Holm
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
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Hoffmann W. TFF2, a MUC6-binding lectin stabilizing the gastric mucus barrier and more (Review). Int J Oncol 2015. [PMID: 26201258 DOI: 10.3892/ijo.2015.3090] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The peptide TFF2 (formerly 'spasmolytic polypeptide'), a member of the trefoil factor family (TFF) containing two TFF domains, is mainly expressed together with the mucin MUC6 in the gastric epithelium and duodenal Brunner's glands. Pathologically, TFF2 expression is observed ectopically during stone diseases, chronic inflammatory conditions and in several metaplastic and neoplastic epithelia; most prominent being the 'spasmolytic polypeptide-expressing metaplasia' (SPEM), which is an established gastric precancerous lesion. TFF2 plays a critical role in maintaining gastric mucosal integrity and appears to restrain tumorigenesis in the stomach. Recently, porcine TFF2 has been shown to interact with the gastric mucin MUC6 and thus stabilize the gastric mucus barrier. On the one hand, TFF2 binds to MUC6 via non-covalent lectin interactions with the glycotope GlcNAcα1→4Galβ1→R. On the other hand, TFF2 is probably also covalently bound to MUC6 via disulfide bridges. Thus, implications for the complex multimeric assembly, cross-linking, and packaging of MUC6 as well as the rheology of gastric mucus are discussed in detail in this review. Furthermore, TFF2 is also expressed in minor amounts in the immune and nervous systems. Thus, similar to galectins, its lectin activity would perfectly enable TFF2 to form multivalent complexes and cross-linked lattices with a plethora of transmembrane glycoproteins and thus modulate different signal transduction processes. This could explain the multiple and diverse biological effects of TFF2 [e.g., motogenic, (anti)apoptotic, and angiogenic effects]. Finally, a function during fertilization is also possible for TFF domains because they occur as shuffled modules in certain zona pellucida proteins.
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Affiliation(s)
- Werner Hoffmann
- Institute of Molecular Biology and Medicinal Chemistry, Otto-von-Guericke-University Magdeburg, D-39120 Magdeburg, Germany
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Boback SM, McCann KJ, Wood KA, McNeal PM, Blankenship EL, Zwemer CF. Snake constriction rapidly induces circulatory arrest in rats. J Exp Biol 2015. [DOI: 10.1242/jeb.121384] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
ABSTRACT
As legless predators, snakes are unique in their ability to immobilize and kill their prey through the process of constriction, and yet how this pressure incapacitates and ultimately kills the prey remains unknown. In this study, we examined the cardiovascular function of anesthetized rats before, during and after being constricted by boas (Boa constrictor) to examine the effect of constriction on the prey's circulatory function. The results demonstrate that within 6 s of being constricted, peripheral arterial blood pressure (PBP) at the femoral artery dropped to 1/2 of baseline values while central venous pressure (CVP) increased 6-fold from baseline during the same time. Electrocardiographic recordings from the anesthetized rat's heart revealed profound bradycardia as heart rate (fH) dropped to nearly half of baseline within 60 s of being constricted, and QRS duration nearly doubled over the same time period. By the end of constriction (mean 6.5±1 min), rat PBP dropped 2.9-fold, fH dropped 3.9-fold, systemic perfusion pressure (SPP=PBP−CVP) dropped 5.7-fold, and 91% of rats (10 of 11) had evidence of cardiac electrical dysfunction. Blood drawn immediately after constriction revealed that, relative to baseline, rats were hyperkalemic (serum potassium levels nearly doubled) and acidotic (blood pH dropped from 7.4 to 7.0). These results are the first to document the physiological response of prey to constriction and support the hypothesis that snake constriction induces rapid prey death due to circulatory arrest.
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Affiliation(s)
- Scott M. Boback
- Dickinson College, Department of Biology, Carlisle, PA 17013, USA
| | | | - Kevin A. Wood
- Dickinson College, Department of Biology, Carlisle, PA 17013, USA
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Cortés A, Muñoz-Antoli C, Sotillo J, Fried B, Esteban JG, Toledo R. Echinostoma caproni (Trematoda): differential in vivo mucin expression and glycosylation in high- and low-compatible hosts. Parasite Immunol 2015; 37:32-42. [PMID: 25382212 DOI: 10.1111/pim.12159] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2014] [Accepted: 11/04/2014] [Indexed: 12/25/2022]
Abstract
Enhanced mucus production and release appears to be a common mechanism for the clearance of intestinal helminths, and this expulsion is normally mediated by Th2-type immune responses. To investigate the factors determining the expulsion of intestinal helminths, we have analysed in vivo expression of mucin genes at the site of infection in two host species displaying different compatibility with Echinostoma caproni (Trematoda). Surprisingly, a general down-regulation on mucin mRNA expression was detected in low-compatible hosts (rats) coinciding with the development of Th2/Th17 responses and the early rejection of the worms from the intestinal lumen. This suggests the existence of a mechanism by which the parasites can modulate the mucus barrier to favour their survival. In highly compatible hosts (mice), some mucin genes were found to be up-regulated throughout the infection, probably, to protect the intestinal epithelium against the infection-induced inflammation developed in this host species. Moreover, infection-induced changes on mucin glycans were also studied by lectin histochemistry. Similar alterations were detected in the ileum of infected mice and rats, except with SNA lectin, indicating that sylated mucins might play an important role in determining the evolution of the infection in each host species.
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Affiliation(s)
- A Cortés
- Departamento de Parasitología, Facultad de Farmacia, Universidad de Valencia, Burjassot, Valencia, Spain
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Pereira C, Barbosa RM, Laranjinha J. Dietary nitrite induces nitrosation of the gastric mucosa: the protective action of the mucus and the modulatory effect of red wine. J Nutr Biochem 2015; 26:476-83. [PMID: 25701398 DOI: 10.1016/j.jnutbio.2014.12.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2014] [Revised: 12/01/2014] [Accepted: 12/02/2014] [Indexed: 12/13/2022]
Abstract
The stomach chemical environment promotes the production of new molecules that can induce post-translational modifications of endogenous proteins with physiological impact. The nitrate-nitrite-nitric oxide pathway is relevant in this process via production of nitric oxide ((•)NO) and nitric oxide-derived nitrogen oxides (NOx) at high concentrations. Using a highly sensitive and selective chemiluminescence approach, we found that exposure the stomach of rats to nitrite yielded S- and N-nitroso derivatives in gastric mucus cysteine-rich glycoproteins (mucins). To lesser extent, the underlying epithelial cell layers also suffered nitrite-driven S- and N-nitroso modifications which increased upon mucus removal, indicating that, under normal nitrite load, (•)NO and NOx can reach inner layers of the stomach wall and locally modify proteins. S-nitrosation was by large the predominant modification. In vitro and ex vivo experiments indicated that the gastric nitrosation pattern is triggered by dietary nitrite in a concentration dependent manner, encompassing the intermediary formation of (•)NO and is susceptible to modulation by dietary reductants, notably red wine polyphenols. Collectively, these results suggest a protective action of the mucus and potential (•)NO-dependent biochemical effects at deeper cells layers of the mucosa.
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Affiliation(s)
- Cassilda Pereira
- Center for Neuroscience and Cell Biology and Faculty of Pharmacy, University of Coimbra, 3000 Coimbra, Portugal
| | - Rui M Barbosa
- Center for Neuroscience and Cell Biology and Faculty of Pharmacy, University of Coimbra, 3000 Coimbra, Portugal
| | - João Laranjinha
- Center for Neuroscience and Cell Biology and Faculty of Pharmacy, University of Coimbra, 3000 Coimbra, Portugal.
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Niv Y, Boltin D, Halpern M, Cohen M, Levi Z, Vilkin A, Morgenstern S, Manugian V, Lawrence ES, Gagneux P, Kaur S, Sharma P, Batra SK, Ho SB. Membrane-bound mucins and mucin terminal glycans expression in idiopathic or Helicobacter pylori, NSAID associated peptic ulcers. World J Gastroenterol 2014; 20:14913-14920. [PMID: 25356051 PMCID: PMC4209554 DOI: 10.3748/wjg.v20.i40.14913] [Citation(s) in RCA: 6] [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: 08/12/2013] [Revised: 09/28/2013] [Accepted: 11/29/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine the expression of membrane-bound mucins and glycan side chain sialic acids in Helicobacter pylori (H. pylori)-associated, non-steroidal inflammatory drug (NSAID)-associated and idiopathic-gastric ulcers.
METHODS: We studied a cohort of randomly selected patients with H. pylori (group 1, n = 30), NSAID (group 2, n = 18), combined H. pylori and NSAID associated gastric ulcers (group 3, n = 24), and patients with idiopathic gastric ulcers (group 4, n = 20). Immunohistochemistry for MUC1, MUC4, MUC17, and staining for Erythrina cristagalli agglutinin and Sambucus nigra agglutinin (SNA) lectins was performed on sections from the ulcer margins.
RESULTS: Staining intensity of MUC17 was higher in H. pylori ulcers (group 1) than in idiopathic ulcers (group 4), 11.05 ± 3.67 vs 6.93 ± 4.00 for foveola cells, and 10.29 ± 4.67 vs 8.00 ± 3.48 for gland cells, respectively (P < 0.0001). In contrast, MUC1 expression was higher in group 4 compared group 1, 9.89 ± 4.17 vs 2.93 ± 5.13 in foveola cells and 7.63 ± 4.60 vs 2.57± 4.50 for glands, respectively (P < 0.0001). SNA lectin staining was increased in group 4, in parallel to elevated MUC1 expression, indicating more abundant α2-6 sialylation in that group.
CONCLUSION: Cytoplasmic MUC17 staining was significantly decreased in the cases with idiopathic ulcer. The opposite was observed for both MUC1 and SNA lectin. This observation may reflect important pathogenic mechanisms, since different mucins with altered sialylation patterns may differ in their protection efficiency against acid and pepsin.
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Brownlee I. The impact of dietary fibre intake on the physiology and health of the stomach and upper gastrointestinal tract. ACTA ACUST UNITED AC 2014. [DOI: 10.1016/j.bcdf.2014.09.005] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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Hanisch FG, Bonar D, Schloerer N, Schroten H. Human trefoil factor 2 is a lectin that binds α-GlcNAc-capped mucin glycans with antibiotic activity against Helicobacter pylori. J Biol Chem 2014; 289:27363-75. [PMID: 25124036 DOI: 10.1074/jbc.m114.597757] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Helicobacter pylori infection is the major cause of gastric cancer and remains an important health care challenge. The trefoil factor peptides are a family of small highly conserved proteins that are claimed to play essential roles in cytoprotection and epithelial repair within the gastrointestinal tract. H. pylori colocalizes with MUC5AC at the gastric surface epithelium, but not with MUC6 secreted in concert with TFF2 by deep gastric glands. Both components of the gastric gland secretome associate non-covalently and show increased expression upon H. pylori infection. Although blood group active O-glycans of the Lewis-type form the basis of H. pylori adhesion to the surface mucin layer and to epithelial cells, α1,4-GlcNAc-capped O-glycans on gastric mucins were proposed to inhibit H. pylori growth as a natural antibiotic. We show here that the gastric glycoform of TFF2 is a calcium-independent lectin, which binds with high specificity to O-linked α1,4-GlcNAc-capped hexasaccharides on human and porcine stomach mucin. The structural assignments of two hexasaccharide isomers and the binding active glycotope were based on mass spectrometry, linkage analysis, (1)H nuclear magnetic resonance spectroscopy, glycan inhibition, and lectin competition of TFF2-mucin binding. Neoglycolipids derived from the C3/C6-linked branches of the two isomers revealed highly specific TFF2 binding to the 6-linked trisaccharide in GlcNAcα1-4Galβ1-4GlcNAcβ1-6(Fucα1-2Galβ1-3)GalNAc-ol(Structure 1). Supposedly, lectin TFF2 is involved in protection of gastric epithelia via a functional relationship to defense against H. pylori launched by antibiotic α1,4-GlcNAc-capped mucin glycans. Lectin-carbohydrate interaction may have also an impact on more general functional aspects of TFF members by mediating their binding to cell signaling receptors.
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Affiliation(s)
- Franz-Georg Hanisch
- From the Institute of Biochemistry II, Medical Faculty, University of Cologne, Joseph-Stelzmann-Str. 52, 50931 Köln, the Center for Molecular Medicine Cologne, University of Cologne, Robert-Koch-Str. 21, 50931 Köln,
| | - David Bonar
- From the Institute of Biochemistry II, Medical Faculty, University of Cologne, Joseph-Stelzmann-Str. 52, 50931 Köln
| | - Nils Schloerer
- the Institute of Organic Chemistry, University of Cologne, Greinstr. 4, 50939 Köln, and
| | - Horst Schroten
- the University Children's Hospital, Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany
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Scoparo CT, Borato DG, Souza LM, Dartora N, Silva LM, Maria-Ferreira D, Sassaki GL, Gorin PAJ, Baggio CH, Iacomini M. Gastroprotective bio-guiding fractionation of hydro-alcoholic extracts from green- and black-teas (Camellia sinensis). Food Res Int 2014; 64:577-586. [PMID: 30011691 DOI: 10.1016/j.foodres.2014.07.043] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2014] [Revised: 07/16/2014] [Accepted: 07/24/2014] [Indexed: 11/16/2022]
Abstract
Hydro-alcoholic extracts from leaves of Camellia sinensis (green- and black-tea leaves) were submitted to a fractionation, promoting the compound separation according to their polarity, and analyzed by ultra-high performance liquid chromatography-mass spectrometry. A wide range of compounds could be identified, such as catechins and their gallate (esters) or oxidation derivatives (theaflavins), glycosylated flavonoids and other phenolics, as well as lipids, saponins and alkaloids. Also have been developed, via bio-guided examination, the gastroprotective property of the compounds identified. The samples were assayed using the model of acute gastric lesions induced in rats by ethanol. Hydro-alcoholic extracts of green-tea and black-tea protected the gastric mucosa with ED50=3.6 and 10.2mg/kg, respectively, with participation of gastric mucus and reduced glutathione (GSH). The ethyl acetate fraction from green-tea and aqueous fraction from black-tea were, respectively, 6 and 10 times more effectiveness than the initial extracts. Moreover, the epigallocatechin gallate (EGCG, 0.204mg/kg), a main component of ethyl acetate fraction from green tea, reduced the gastric lesion by 56% and restored the mucus levels, however the rutin (0.0133mg/kg), a flavonoid found in the most active fraction of black-tea, was less significant at the natural concentrations. These results have confirmed that the different compounds present in green- and black-tea hydro-alcoholic extracts and partitioned fractions produce relevant gastroprotection mainly via maintenance of the protective factors, mucus and GSH.
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Affiliation(s)
- Camila T Scoparo
- Department of Biochemistry and Molecular Biology, Sector of Biological Sciences, Federal University of Paraná, Curitiba, PR, Brazil
| | - Débora G Borato
- Department of Pharmacology, Sector of Biological Sciences, Federal University of Paraná, Curitiba, PR, Brazil
| | - Lauro M Souza
- Department of Biochemistry and Molecular Biology, Sector of Biological Sciences, Federal University of Paraná, Curitiba, PR, Brazil
| | - Nessana Dartora
- Department of Biochemistry and Molecular Biology, Sector of Biological Sciences, Federal University of Paraná, Curitiba, PR, Brazil
| | - Luísa M Silva
- Department of Pharmacology, Sector of Biological Sciences, Federal University of Paraná, Curitiba, PR, Brazil
| | - Daniele Maria-Ferreira
- Department of Pharmacology, Sector of Biological Sciences, Federal University of Paraná, Curitiba, PR, Brazil
| | - Guilherme L Sassaki
- Department of Biochemistry and Molecular Biology, Sector of Biological Sciences, Federal University of Paraná, Curitiba, PR, Brazil
| | - Philip A J Gorin
- Department of Biochemistry and Molecular Biology, Sector of Biological Sciences, Federal University of Paraná, Curitiba, PR, Brazil
| | - Cristiane H Baggio
- Department of Pharmacology, Sector of Biological Sciences, Federal University of Paraná, Curitiba, PR, Brazil.
| | - Marcello Iacomini
- Department of Biochemistry and Molecular Biology, Sector of Biological Sciences, Federal University of Paraná, Curitiba, PR, Brazil.
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Abstract
Crohn's disease (CD) is characterized by a breakdown of the intestinal epithelial barrier function leading to an uncontrolled immune response to bacterial antigens. Available data demonstrate that appropriate response and early host defense against invading bacteria are crucial to maintain tolerance towards commensal bacteria. When the mechanisms of early removal of invading bacteria are disturbed, a loss of tolerance and a full-blown adaptive immune reaction, which is mounted against the usually harmless commensal flora, are induced. Dysfunction of autophagy caused by genetic variations within CD susceptibility genes, such as ATG16L1 and IRGM, results in defective handling of intracellular and invading bacteria and causes prolonged survival and defective clearance of those microbes. Dysfunction of ATG16L1 and IRGM has also been shown to cause aberrant Paneth cell function and uncontrolled secretion of proinflammatory cytokines finally resulting in increased susceptibility to bacterial infection and the onset of colitis. Interestingly, autophagy can also be regulated by other CD susceptibility genes, such as NOD2 (nucleotide oligomerization domain 2) or PTPN2 (protein tyrosine phosphatase nonreceptor type 2) and the presence of the CD-associated variations within these genes results in similar effects. Taken together, more and more evidence suggests a close functional correlation between loss of tolerance and defective autophagy in CD patients. Therefore, most likely, the onset of CD is triggered by both a loss of tolerance as well as a dysfunction of autophagy, which finally results in the onset of chronic intestinal inflammation.
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Affiliation(s)
- Marianne R Spalinger
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
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41
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Abstract
Gastric epithelium is the first significant barrier between the inner body and the potentially toxic material in the lumen. Nutrients affect gastric barrier continuously--alcohol, coffee, spices, salted food, etc. Also, very potent noxious agents are widely prescribed drugs--nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin and selective serotonin reuptake inhibitors. Helicobacter pylori is a well-known and well-investigated pathogen associated with serious gastric damage and gastric carcinoma. For its defense and maintenance of homeostasis and integrity, except acid secretion and maintenance of low luminal pH, gastric mucosa also has a specific structure, and its function is influenced by different control mechanisms. These include control of mucosal blood flow, control of mucus and bicarbonate secretion, constant cell renewal, and neuronal and hormonal control of defense mechanisms. These mechanisms are mediated by prostaglandins, nitric oxide, growth factors, heat-shock proteins and a neuropeptide called calcitonin gene-related protein. Adrenal glucocorticoids and the central nervous system also play an important role in regulating gastro-protection, especially hypothalamus and the dorsal vagal complex. Gastric mucosa is also an important component of the body's immune system and gut-associated lymphoid tissue which serves as the initiation site for antigen-specific humoral and cell-mediated immune response. Treatment options for gastric barrier dysfunction and damage due to aforementioned noxious agents are guided by the nature of damage and our understanding of the pathophysiological mechanisms involved. Currently, management is guideline driven and depends upon eradication treatment in patients infected with H. pylori and treatment or prevention of aspirin or NSAID ulceration.
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Affiliation(s)
- Yaron Niv
- Department of Gastroenterology, Rabin Medical Center, Tel Aviv University, Tel Aviv, Israel
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Aviles-Jimenez F, Vazquez-Jimenez F, Medrano-Guzman R, Mantilla A, Torres J. Stomach microbiota composition varies between patients with non-atrophic gastritis and patients with intestinal type of gastric cancer. Sci Rep 2014; 4:4202. [PMID: 24569566 PMCID: PMC3935187 DOI: 10.1038/srep04202] [Citation(s) in RCA: 263] [Impact Index Per Article: 23.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2013] [Accepted: 02/10/2014] [Indexed: 02/07/2023] Open
Abstract
We aimed to characterize microbiota of the gastric mucosa as it progress to intestinal type of cancer. Study included five patients each of non-atrophic gastritis (NAG), intestinal metaplasia (IM) and intestinal-type gastric cancer (GC). Gastric tissue was obtained and DNA extracted for microbiota analyses using the microarray G3 PhyloChip. Bacterial diversity ranged from 8 to 57, and steadily decreased from NAG to IM to GC (p = 0.004). A significant microbiota difference was observed between NAG and GC based on Unifrac-presence/absence and weighted-Unifrac-abundance metrics of 283 taxa (p < 0.05). HC-AN analyses based on presence/absence of 238 taxa revealed that GC and NAG grouped apart, whereas IM overlapped with both. An ordinated analyses based on weighted-Unifrac distance given abundance of 44 taxa showing significance across categories revealed significant microbiota separation between NAG and GC. This study is the first to show a gradual shift in gastric microbiota profile from NAG to IM to GC.
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Affiliation(s)
| | - Flor Vazquez-Jimenez
- Unidad de Investigación en Enfermedades Infecciosas, Tubo Digestivo Alto, UMAE Oncologia
| | | | - Alejandra Mantilla
- Servicio de Patologia, UMAE Oncologia, Centro Medico Nacional SXXI, Mexico City
| | - Javier Torres
- Unidad de Investigación en Enfermedades Infecciosas, Tubo Digestivo Alto, UMAE Oncologia
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Maria-Ferreira D, da Silva LM, Mendes DAGB, Cabrini DDA, Nascimento AM, Iacomini M, Cipriani TR, Santos ARS, de Paula Werner MF, Baggio CH. Rhamnogalacturonan from Acmella oleracea (L.) R.K. Jansen: gastroprotective and ulcer healing properties in rats. PLoS One 2014; 9:e84762. [PMID: 24416280 PMCID: PMC3885607 DOI: 10.1371/journal.pone.0084762] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2013] [Accepted: 11/19/2013] [Indexed: 01/14/2023] Open
Abstract
A rhamnogalacturonan (RGal) isolated from Acmella oleracea (L.) R.K. Jansen administered by oral route showed gastroprotective activity against acute lesions induced by ethanol. In this study, we investigated the gastric ulcer healing effect of RGal and its mechanisms of action. Intraperitoneal treatment of animals with RGal protected the gastric mucosa against acute lesions induced by ethanol, with participation of gastric mucus. Furthermore, in the chronic ulcer model, oral administration of RGal accelerates the gastric ulcer healing, accompanied by increasing of cellular proliferation and gastric mucus content, reducing inflammatory parameters and oxidative stress. In addition, the repeated 7 days-treatment of animals with RGal did not show alterations of clinical and behavioral symptoms, body and organs weights or plasmatic biochemical parameters. Collectively, these results showed that RGal has an interesting antiulcerogenic activity and could constitute an attractive molecule of interest for the development of new antiulcer agents.
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Affiliation(s)
- Daniele Maria-Ferreira
- Department of Pharmacology, Sector of Biological Sciences, Federal University of Paraná, Curitiba, PR, Brazil
| | - Luisa Mota da Silva
- Department of Pharmacology, Sector of Biological Sciences, Federal University of Paraná, Curitiba, PR, Brazil
| | | | - Daniela de Almeida Cabrini
- Department of Pharmacology, Sector of Biological Sciences, Federal University of Paraná, Curitiba, PR, Brazil
| | - Adamara Machado Nascimento
- Department of Biochemistry and Molecular Biology, Sector of Biological Sciences, Federal University of Paraná, Curitiba, PR, Brazil
| | - Marcello Iacomini
- Department of Biochemistry and Molecular Biology, Sector of Biological Sciences, Federal University of Paraná, Curitiba, PR, Brazil
| | - Thales Ricardo Cipriani
- Department of Biochemistry and Molecular Biology, Sector of Biological Sciences, Federal University of Paraná, Curitiba, PR, Brazil
| | - Adair Roberto Soares Santos
- Department of Physiological Sciences, Center of Biological Sciences, Federal University of Santa Catarina, Florianópolis, SC, Brazil
| | | | - Cristiane Hatsuko Baggio
- Department of Pharmacology, Sector of Biological Sciences, Federal University of Paraná, Curitiba, PR, Brazil
- * E-mail:
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44
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Meng-Lund E, Muff-Westergaard C, Sander C, Madelung P, Jacobsen J. A mechanistic based approach for enhancing buccal mucoadhesion of chitosan. Int J Pharm 2014; 461:280-5. [DOI: 10.1016/j.ijpharm.2013.10.047] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2013] [Revised: 10/24/2013] [Accepted: 10/28/2013] [Indexed: 11/25/2022]
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Antoni L, Nuding S, Weller D, Gersemann M, Ott G, Wehkamp J, Stange EF. Human colonic mucus is a reservoir for antimicrobial peptides. J Crohns Colitis 2013; 7:e652-64. [PMID: 23787054 DOI: 10.1016/j.crohns.2013.05.006] [Citation(s) in RCA: 82] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2012] [Revised: 05/14/2013] [Accepted: 05/22/2013] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS To prevent bacterial adherence and translocation, the colonic mucosa is covered by a protecting mucus layer and the epithelium synthesizes antimicrobial peptides. The present qualitative study investigated the contents and interaction of these peptides in and with rectal mucus. METHODS Rectal mucus extracts were analyzed for antimicrobial activity and screened with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, Dot blot and immunohistochemistry for antimicrobial peptides. In addition, binding of AMPs to mucins was investigated by Western blot and enzyme-linked lectin assays. RESULTS In functional tests the mucus layer exhibited a strong antimicrobial activity. We detected 11 antimicrobial peptides in mucus extracts from healthy persons including the defensins HBD-1 and -3, the cathelicidin LL-37, ubiquitin, lysozyme, histones, high mobility group nucleosome-binding domain-containing protein 2, ubiquicidin and other ribosomal proteins. AMPs were bound by mucins but this was demonstrated to be reversible and inhibition of antibacterial activity was limited. CONCLUSION These findings indicate that epithelial antimicrobial peptides are retained in the intestinal mucus layer without losing their efficacy. Thus, the mucus layer and its composition provide an attractive drug target to restore antimicrobial barrier function in intestinal diseases.
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Affiliation(s)
- Lena Antoni
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, University of Tübingen, Stuttgart, Germany
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46
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Abstract
To prevent bacterial overgrowth, colonization of the epithelium and subsequent translocation, the gastrointestinal tract maintains an effective mucosal barrier. Besides mucus the most important components of this protective system are epithelial antimicrobial peptides such as defensins, the cathelicidin LL-37, lysozyme, phospholipase A, and proteins with additional antimicrobial properties such as ubiquicidin, ribosomal proteins or histones. Commensal species may tolerate intestinal antimicrobial peptides, for example Bacteroides ssp. or Parabacteroides ssp. as major species in the human colon were highly resistant to the constitutive defensin HBD-1 and only susceptible to the inducible defensin HBD-3. Reduction of disulfide bonds is an important mechanism activating HBD-1. As several studies show, alterations in the expression of antimicrobial peptides directly influence the composition of the intestinal flora. Correspondingly, an increased production of defensins or inhibition of the processing of mouse defensins to their active form led to a quantitative shift of luminal and mucosal bacterial species. On the other hand, microorganisms also modulate the synthesis of host defensins by induction or inhibition of specific peptides. Lactobacilli, the probiotic strain Escherichia coli Nissle and Salmonella enteritica stimulate HBD-2 expression, whereas Shigella flexneri downregulates the synthesis of HBD-1, HBD-3 and LL-37. Thus, the proper balance between the luminal flora and the mucosa is a permanently dynamic, sensitive and host-specific relationship.
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Affiliation(s)
- S Nuding
- University of Tübingen, Tübingen, Germany
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47
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Yang I, Nell S, Suerbaum S. Survival in hostile territory: the microbiota of the stomach. FEMS Microbiol Rev 2013; 37:736-61. [DOI: 10.1111/1574-6976.12027] [Citation(s) in RCA: 108] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2013] [Revised: 05/28/2013] [Accepted: 06/07/2013] [Indexed: 02/06/2023] Open
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Rodríguez-Piñeiro AM, Bergström JH, Ermund A, Gustafsson JK, Schütte A, Johansson MEV, Hansson GC. Studies of mucus in mouse stomach, small intestine, and colon. II. Gastrointestinal mucus proteome reveals Muc2 and Muc5ac accompanied by a set of core proteins. Am J Physiol Gastrointest Liver Physiol 2013; 305:G348-56. [PMID: 23832517 PMCID: PMC3761249 DOI: 10.1152/ajpgi.00047.2013] [Citation(s) in RCA: 119] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The mucus that protects the surface of the gastrointestinal tract is rich in specialized O-glycoproteins called mucins, but little is known about other mucus proteins or their variability along the gastrointestinal tract. To ensure that only mucus was analyzed, we combined collection from explant tissues mounted in perfusion chambers, liquid sample preparation, single-shot mass spectrometry, and specific bioinformatics tools, to characterize the proteome of the murine mucus from stomach to distal colon. With our approach, we identified ∼1,300 proteins in the mucus. We found no differences in the protein composition or abundance between sexes, but there were clear differences in mucus along the tract. Noticeably, mucus from duodenum showed similarities to the stomach, probably reflecting the normal distal transport. Qualitatively, there were, however, fewer differences than might had been anticipated, suggesting a relatively stable core proteome (∼80% of the total proteins identified). Quantitatively, we found significant differences (∼40% of the proteins) that could reflect mucus specialization throughout the gastrointestinal tract. Hierarchical clustering pinpointed a number of such proteins that correlated with Muc2 (e.g., Clca1, Zg16, Klk1). This study provides a deeper knowledge of the gastrointestinal mucus proteome that will be important in further understanding this poorly studied mucosal protection system.
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Affiliation(s)
| | - Joakim H. Bergström
- Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden
| | - Anna Ermund
- Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden
| | - Jenny K. Gustafsson
- Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden
| | - André Schütte
- Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden
| | | | - Gunnar C. Hansson
- Department of Medical Biochemistry, University of Gothenburg, Gothenburg, Sweden
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Ermund A, Schütte A, Johansson MEV, Gustafsson JK, Hansson GC. Studies of mucus in mouse stomach, small intestine, and colon. I. Gastrointestinal mucus layers have different properties depending on location as well as over the Peyer's patches. Am J Physiol Gastrointest Liver Physiol 2013; 305:G341-7. [PMID: 23832518 PMCID: PMC3761247 DOI: 10.1152/ajpgi.00046.2013] [Citation(s) in RCA: 274] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Colon has been shown to have a two-layered mucus system where the inner layer is devoid of bacteria. However, a complete overview of the mouse gastrointestinal mucus system is lacking. We now characterize mucus release, thickness, growth over time, adhesive properties, and penetrability to fluorescent beads from stomach to distal colon. Colon displayed spontaneous mucus release and all regions released mucus in response to carbachol and PGE2, except the distal colon and domes of Peyer's patches. Stomach and colon had an inner mucus layer that was adherent to the epithelium. In contrast, the small intestine and Peyer's patches had a single mucus layer that was easily aspirated. The inner mucus layer of the distal colon was not penetrable to beads the size of bacteria and the inner layer of the proximal colon was only partly penetrable. In contrast, the inner mucus layer of stomach was fully penetrable, as was the small intestinal mucus. This suggests a functional organization of the intestinal mucus system, where the small intestine has loose and penetrable mucus that may allow easy penetration of nutrients, in contrast to the stomach, where the mucus provides physical protection, and the colon, where the mucus separates bacteria from the epithelium. This knowledge of the mucus system and its organization improves our understanding of the gastrointestinal tract physiology.
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Affiliation(s)
- Anna Ermund
- Dept. Medical Biochemistry, Univ. of Gothenburg, Box 440, 40530 Gothenburg, Sweden.
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Schreiber O, Petersson J, Waldén T, Ahl D, Sandler S, Phillipson M, Holm L. iNOS-dependent increase in colonic mucus thickness in DSS-colitic rats. PLoS One 2013; 8:e71843. [PMID: 23977158 PMCID: PMC3747056 DOI: 10.1371/journal.pone.0071843] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2013] [Accepted: 07/03/2013] [Indexed: 01/01/2023] Open
Abstract
Aim To investigate colonic mucus thickness in vivo in health and during experimental inflammatory bowel disease. Methods Colitis was induced with 5% DSS in drinking water for 8 days prior to experiment, when the descending colonic mucosa of anesthetized rats was studied using intravital microscopy. Mucus thickness was measured with micropipettes attached to a micromanipulator. To assess the contributions of NOS and prostaglandins in the regulation of colonic mucus thickness, the non-selective NOS-inhibitor L-NNA (10 mg/kg bolus followed by 3 mg/kg/h), the selective iNOS-inhibitor L-NIL (10 mg/kg bolus followed by 3 mg/kg/h) and the non-selective COX-inhibitor diclofenac (5 mg/kg) were administered intravenously prior to experiment. To further investigate the role of iNOS in the regulation of colonic mucus thickness, iNOS −/− mice were used. Results Colitic rats had a thicker firmly adherent mucus layer following 8 days of DSS treatment than untreated rats (88±2 µm vs 76±1 µm). During induction of colitis, the thickness of the colonic mucus layer initially decreased but was from day 3 significantly thicker than in untreated rats. Diclofenac reduced the mucus thickness similarly in colitic and untreated rats (−16±5 µm vs −14±2 µm). While L-NNA had no effect on colonic mucus thickness in DSS or untreated controls (+3±2 µm vs +3±1 µm), L-NIL reduced the mucus thickness significantly more in colitic rats than in controls (−33±4 µm vs −10±3 µm). The importance of iNOS in regulating the colonic mucus thickness was confirmed in iNOS−/− mice, which had thinner colonic mucus than wild-type mice (35±3 µm vs 50±2 µm, respectively). Furthermore, immunohistochemistry revealed increased levels of iNOS in the colonic surface epithelium following DSS treatment. Conclusion Both prostaglandins and nitric oxide regulate basal colonic mucus thickness. During onset of colitis, the thickness of the mucus layer is initially reduced followed by an iNOS mediated increase.
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Affiliation(s)
- Olof Schreiber
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Joel Petersson
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Tomas Waldén
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - David Ahl
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Stellan Sandler
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Mia Phillipson
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Lena Holm
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
- * E-mail:
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