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Gastrointestinal Tissue: Oxidative Stress and Dietary Antioxidants
Gastrointestinal Tissue: Oxidative Stress and Dietary Antioxidants
Gastrointestinal Tissue: Oxidative Stress and Dietary Antioxidants
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Gastrointestinal Tissue: Oxidative Stress and Dietary Antioxidants

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Gastrointestinal Tissue: Oxidative Stress and Dietary Antioxidants brings together leading experts from world renowned institutions, combining the basic mechanisms of gastrointestinal diseases with information regarding new and alternative treatments.

The processes within the science of oxidative stress are described in concert with other processes, including apoptosis, cell signaling and receptor mediated responses, further recognizing that diseases are often multifactorial with oxidative stress as a component. By combining the critical molecular processes underlying free radical mediated pathologies and the role of dietary antioxidant molecules, a connection is made that helps advance therapies and the prevention of gastrointestinal pathological processes.

This important reference is well designed with two complementary sections. Section One, Oxidative Stress and Gastroenterology, covers the basic processes of oxidative stress from molecular biology to whole organs, the gastrointestinal anatomy and sources of oxidative stress and free radicals and their products in gastrointestinal diseases. Section Two, Antioxidants and Gastroenterology covers antioxidants in foods, including plants and components.

  • Covers the science of oxidative stress in gastrointestinal tissue and associated conditions and scenarios
  • Provides information on optimal levels for human consumption of antioxidants, suggested requirements per day, recommended dietary allowances and curative/preventive effects of dietary antioxidants
  • Presents an easy to reference guide with two complementary sections that discuss the pathophysiology of gastrointestinal diseases in relation to oxidative stress and antioxidant therapies
LanguageEnglish
Release dateMay 10, 2017
ISBN9780128093009
Gastrointestinal Tissue: Oxidative Stress and Dietary Antioxidants
Author

Jordi Gracia-Sancho

Jordi Gracia-Sancho is the Chief of the Liver Vascular Biology Research Group at the IDIBAPS Research Institute – Hospital Clínic de Barcelona, Associate Researcher at the Department of Visceral Surgery and Medicine – University of Bern, & Scientific Director of the Spanish Research Consortium on Liver & Digestive Diseases (CIBEREHD). He graduated in Biochemistry receiving undergraduate research training in basic hemochromatosis at the London Metropolitan University, pursued pre-doctoral studies in basic portal hypertension at the University of Barcelona Medical School, and post-doctoral training at the Center for Excellence in Vascular Biology - Harvard Medical School & Brigham and Women’s Hospital. In 2012 he obtained the “Ramón y Cajal” Spanish tenure-track position and then promoted to his current senior position. Jordi’s research focuses on liver vascular pathobiology with special interest in the role of sinusoidal cells, and their interactions, in acute and chronic liver diseases, and in aging. He (co-)authored more than 125 peer-reviewed original papers and reviews, and currently serves as Associate Editor for the Journal of Hepatology. In addition, he is invited professor in different universities within Spain and Europe and co-leads diverse educational initiatives including the LiverSeminars Program (www.liverseminars.eu), the 2018 EASL-Basic School of Hepatology, the 2020 APASL-Symposium on Regression of Portal Hypertension, the 2020 AASLD-Symposium on Senescence and Liver Diseases, the 2021 EASL-Symposium on Sinusoidal Cells in Liver Diseases and the 2023 AMH-Irwin Arias Symposium. Prof Gracia has been invited speaker in different national and international conferences, including the annual meetings of the European, American and Asia-Pacific associations of Hepatology. He has been member of the Scientific Committee of the Spanish Association for the Study of the Liver (AEEH) and the Steering Committee of the Portal Hypertension Special Interest Group of the American Association for the Study of Liver Diseases (AASLD). He is now member of the Governing Board of AEEH, the Basic Research Committee of AASLD and the Baveno Cooperation Steering Committee. In 2016 he received the Emerging Leader Award from the European Association for the Study of the Liver (EASL). He served as Scientific Secretary of the International Society for Hepatic Sinusoidal Research (ISHSR) from 2017-2022, being now the President-Elect of this Society.

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    Gastrointestinal Tissue - Jordi Gracia-Sancho

    States

    Dedication and Preface

    Dedication

    To our families, colleagues, and mentors.

    Preface

    Oxidative stress is a feature of gastrointestinal diseases and associated conditions, affecting a variety of molecular and cellular processes that ultimately contribute to the disease pathophysiology. Oxidative stress can arise due to nutritional imbalance during a spectrum of time frames, before the onset of disease, or during its development.

    Considering these premises, there is a fundamental need to better understand the processes inherent to oxidative stress in gastrointestinal tissues, and to evaluate whether oxidative stress can be ameliorated with pharmacological or natural agents with antioxidant properties. Importantly, whilst physicians and clinical workers understand the cellular processes involved in gastrointestinal diseases, they are less conversant with the science of nutrition and dietetics. On the other hand, nutritionists and dieticians are not as familiar with the detailed molecular and cellular mechanisms of gastrointestinal disease, but favor nutritional intervention. Thus gastroenterologists, hepatologists, endocrinologists, food scientists, and nutritionists are separated by divergent skills and professional disciplines that need to be bridged in order to advance medical science and enable preventative or treatment strategies.

    This book, Gastrointestinal Tissue: Oxidative Stress and Dietary Antioxidants, aims to cover in a single volume the science of oxidative stress in gastrointestinal diseases, and the potential therapeutic usage of natural antioxidants in the diet or food matrix, ultimately aiming at helping to build the bridge between physiology and nutrition, between physicians and nutritionists.

    Gastrointestinal Tissue: Oxidative Stress and Dietary Antioxidants imparts holistic information within a structured format:

    Section I, Oxidative Stress and Gastroenterology, covers the basic processes of oxidative stress, from molecular biology to whole organs, in relation to a starter pack composed by the gastrointestinal anatomy and sources of oxidative stress, and redox mechanisms in gastrointestinal diseases; which is followed by chapters depicting the role of oxidative stress in the pathophysiology of cancer, Crohn’s disease, mucosal injury, helicobacter pylori, inflammatory bowel disease, gut dysbiosis, liver diseases, ischemia/reperfusion injury, portal hypertension, necrotizing enterocolitis, pancreatitis, and gallbladder disease.

    Section II, Antioxidants and Gastroenterology, covers antioxidants in foods, including plants and components of the diet, as well as dietary supplements. The section starts with a seminal chapter describing the molecular mechanisms underlying the action of antioxidants, followed by descriptions of the beneficial effects of antioxidant vitamins, selenium, berries, herbs, garlic extract, ginger extract, ginseng, kiwi fruit peptide, magnesium, melatonin, flavonoids, soy peptide, and lycopenes.

    Gastrointestinal Tissue: Oxidative Stress and Dietary Antioxidants is designed for nutritionists, dieticians, food scientists, gastroenterologists, hepatologists, endocrinologists, health care workers, and research scientists.

    The Editors sincerely acknowledge the authors, leading experts in the field, for their valuable contributions, and our Elsevier Editorial Project Manager Sam Young, for their help and patience during the preparation of this work.

    Jordi Gracia-Sancho and Josepa Salvadó

    Section I

    Oxidative Stress and Gastroenterology

    Outline

    Chapter 1 The Gastrointestinal System: Anatomy and Sources of Oxidative Stress

    Chapter 2 Redox Mechanism of Reactive Oxygen Species in Gastrointestinal Tract Diseases

    Chapter 3 Oxidative Stress and Gastrointestinal System Cancers

    Chapter 4 The Role of Oxidative Stress in the Pathophysiology of Gastrointestinal Disorders

    Chapter 5 Gastric Mucosal Injury and Oxidative Stress

    Chapter 6 Helicobacter pylori and Reactive Oxygen Species

    Chapter 7 Inflammatory Bowel Diseases: The Crosslink Between Risk Factors and Antioxidant Therapy

    Chapter 8 Oxidative Stress and Gut Microbiota*

    Chapter 9 Oxidative Stress in Liver Diseases

    Chapter 10 Ischemia-reperfusion Injury and Oxidative Stress

    Chapter 11 Role of Oxidative Stress in Portal Hypertension in Cirrhosis

    Chapter 12 Role of Oxidative Stress in Necrotizing Enterocolitis: Advances and Possibilities for Future Therapy

    Chapter 13 Pancreatic Cancer, Pancreatitis, and Oxidative Stress

    Chapter 14 Gallbladder Disease: Relevance of Oxidative Stress

    Chapter 1

    The Gastrointestinal System

    Anatomy and Sources of Oxidative Stress

    José Miranda-Bautista, Rafael Bañares and Javier Vaquero,    Gregorio Marañón University Hospital, Madrid, Spain

    Summary

    This chapter reviews the basic anatomy and histology of the gastrointestinal (GI) system as well as the main sources of oxidative stress. The GI tract, represents a major interface between the human body and its environment, harbors a large microbial community, and represents the first line of defense against potentially harmful effects of ingested materials. Although it is recognized as a major source of oxidative stress in the human body, the GI tract, and particularly its mucosa is endorsed with effective antioxidant defense systems that prevent injury. Excessive generation of oxidative stress, decrease of antioxidant defense systems, and microbiota dysregulation, however, may play a major role in various GI diseases.

    Keywords

    Oxidative stress; free radical; gastrointestinal tract; antioxidant; reactive oxygen species; reactive nitrogen species

    Introduction

    Oxidative stress is an unavoidable consequence of life in an oxygen-rich atmosphere. In living organisms, it is defined as the disturbance of the delicate balance between the oxidants and antioxidants in favor of the oxidants, leading to a disruption of redox signaling and control and/or to direct molecular damage (Fig. 1.1) [1]. Whereas an excessive amount of oxidative stress may cause damage of most cell constituents, a small or moderate amount of oxidative stress plays important roles in normal cell physiology by regulating redox-sensitive signaling pathways [2,3]. The OxyR and SoxR transcription factors in bacteria [4,5] and the NF-κB and Nrf2/Keap1 in higher organisms [6,7], are perfect examples of major oxidative stress-regulated signaling pathways. High amounts of oxidants can also be generated and released in a tightly controlled fashion by specialized immune cells as a defense mechanism against foreign pathogens [8].

    Figure 1.1 The oxidant/antioxidant balance.

    Living organisms are constantly exposed to oxidative stress. In normal conditions, a delicate balance between the generation of oxidants and free radicals and their detoxification exists that prevents injury. Small increases of oxidative stress result in compensatory mechanisms driven by redox-sensitive signaling pathways and compounds that allow restoration of the balance. When the imbalance is considerably larger, damage of cellular constituents may occur.

    The terms oxidative damage, oxidants and free radicals are widely used in scientific and non-scientific forums, but it is important to remind that they are not synonymous nor they should be used indiscriminately (see definitions in Table 1.1). For example, free radicals can be neutral, negatively or positively charged, and their redox potential can range from oxidizing (e.g., hydroxyl radical) to reducing (e.g., superoxide radical). It should also be noted that there are oxidants, such as hydrogen peroxide, that are not free radicals and, therefore, oxidative damage does not need to proceed necessarily via a radical mechanism. In this line, it has been recommended to name the specific chemical reactants involved in particular processes whenever possible rather than to refer to more general terms such as oxidative stress, reactive oxygen species, (ROS) or reactive nitrogen species (RNS) [1].

    Table 1.1

    Definitions

    Since the first report of the presence of free radicals in biological materials [9], extensive research has established an important role of oxidative stress and free radicals in normal cell physiology as well as in aging and a number of clinical disorders such as cancer, neurodegenerative diseases, atherosclerosis, or ischemia-reperfusion injury [2]. The gastrointestinal (GI) tract is receiving increasing attention as a major element for the maintenance of redox homeostasis in mammals, as it represents a major interface between the organism and the environment (both nutrients and intestinal microbiota are sources of oxidative stress). Furthermore, accumulating evidence shows that oxidative stress is an important player in the pathogenesis of various GI diseases [10]. In this chapter, we describe the basic anatomical and histological features of the GI tract and its associated organs, and provide a general overview of the main sources of oxidative stress with attention to those more relevant for the GI tract.

    Anatomy and Histology of the Gastrointestinal Tract

    The GI tract consists of a tubular organ that starts from the mouth and ends at the anus. Its main function is to digest and extract useful components from ingested materials and to expel the waste products at the end. This function is achieved by the progression of the alimentary bolus through different specialized sections of the GI tract together with the participation of accessory organs of the digestive system, which include the salivary glands, the liver, the pancreas, and the gall bladder (Fig. 1.2). Hormone-sensitive effector cells together with the neuro-vegetative system facilitate the autonomous progression of the alimentary bolus through the GI tract. Importantly, the GI tract also harbors a diverse and complex microbial community of about 1000 bacterial species, which has an immense impact on host metabolism, physiology, nutrition, and immune function [11].

    Figure 1.2 Anatomy and histology of the gastrointestinal (GI) tract and its accessory organs.

    The Eesophagus is mostly intrathoracic and impulses the alimentary bolus into the stomach. The stomach is an abdominal sac that changes the consistency of the bolus to semifluid and initiates the digestion. Pancreatic and biliary secretions subsequently converge in the duodenum to continue the digestion and to begin the absorption of nutrients and water along the small intestine. Once in the large intestine, water is further absorbed, and feces are compacted and stored until they are finally removed by defecation. The mucosa and glandular cells are essential elements responsible for all these functions. The drawings located beside the anatomic figure show the basic histological features of the mucosa and glandular cells that cover the different segments of the GI tract as well as those of the liver and pancreas.

    In humans, the GI tract includes four major sections that can be individualized in terms of anatomy and histology: esophagus, stomach, small intestine, and large intestine. Although the histology varies with the anatomical region, all the sections have four histological layers that are called mucosa, submucosa, muscularis propria, and adventitia or serosa (from the lumen to the outer wall).

    Esophagus

    The esophagus in adults is a muscular tube of approximately 25 cm long that extends from the pharynx at the cricoid cartilage (at the level of the 6th cervical vertebra) to the cardia (at the level of the 10th or 11th thoracic vertebra). It pierces the left crus of the diaphragm and has an intra-abdominal portion of about 1.5 cm in length. The main function of the esophagus is to transport food, liquids, and saliva from the mouth to the stomach, which is achieved by the coordinated contractions of its muscular wall.

    The esophagus is lined by a mucosa consisting of squamous epithelium, except for a small segment at its lower end that is lined by mucin-secreting columnar epithelium with underlying mucous glands. The latter segment continues into the stomach, which is also lined by columnar epithelium. The squamous-columnar junction occurs approximately at the level of the diaphragm. The squamous mucosa is composed of nonkeratinizing stratified squamous epithelium supported by the connective tissue of the lamina propria, which rests on the underlying muscularis mucosae (Fig. 1.2). The epithelium has a basal zone consisting of several layers of cuboidal or oblong basophilic cells that become larger and progressively flattened toward the lumen, but they retain their nuclei even in the most superficial layer. Isolated lymphoid nodules in the lamina propria are common, as well as single intraepithelial lymphocytes dispersed between the squamous cells. Langerhans cells are antigen-presenting cells with ovoid forms and radiating dendritic processes and they are sparsely distributed across all layers of the esophageal epithelium [12]. Both melanocytes and nonmelanocyte argyrophil cells may be observed randomly distributed in the basal layer of the epithelium. The lamina propria folds into papillae of connective tissue that projects into the thickness of the epithelium, usually less than two-thirds of it. The lamina propria consists of loose connective tissue that contains a sprinkling of lymphocytes and plasma cells accompanied by occasional eosinophils and mast cells. In the cardiac mucosa, the majority of gland cells are mucous, and numerous endocrine cells are also found in this region. The muscularis mucosae consists of smooth muscle bundles orientated longitudinally, and it is thicker than in the stomach and intestine. The submucosa contains deep esophageal glands that are small and drain into ducts that cross the mucosae, and a ramifying lymphatic plexus in a loose connective tissue network. The muscularis propria, the main muscle layer, consists of well-developed circular and longitudinal coats. The muscle coats are striated in the upper segment of the esophagus, and there is a gradual change to smooth muscle in the mid-third. A myenteric nerve plexus is present along the full length of the esophagus, and there are two sets of lymphatic channels (one in the submucosa, and one in the muscle coats).

    Stomach

    The stomach is a J-shaped dilation of the foregut that extends from the lower end of the esophagus to end in the duodenum just to the right of the first lumbar vertebra. It can be divided into four segments. The cardia is a small zone situated immediately distal to the gastroesophageal junction that is macroscopically indistinguishable. It merges distally into the fundus, which is the part of the stomach located above a line drawn horizontally through the gastroesophageal junction. The body or corpus of the stomach comprises approximately two-thirds of the remainder, and the pyloric antrum forms the distal third, leading into the pyloric sphincter. The stomach acts as a dilatable sac, storing for food, controlling onward transmission, breaking it up to a semifluid consistency, adding secretions to it, and allowing digestion to start.

    The mucosa of the stomach is formed by surface (foveolar) epithelium, which is the same in all regions of the stomach [13]. It consists of a single layer of tall columnar mucus-secreting epithelial cells that cover the surface papillae and line the gastric pits, which are the orifices of gastric glands (Fig. 1.2). Cardiac glands are composed of branching tubules that contain mucus-producing cells and are grouped in lobules separated by connective tissue and by prolongations of the muscularis mucosae [14]. Other cells present in smaller numbers include acid-secreting and endocrine cells. Lymphoid follicles are also common in the deeper part of the mucosa. The body and the fundal mucosa are identical. Gastric crypts lined by surface epithelium form the 25% superficial part of the mucosa. The remaining 75% are the body glands, which consist of straight tubules arranged perpendicular to the surface (Fig. 1.2). They run from the base of the crypts to the muscularis mucosae, opening into the bottom of each crypt, and can be divided in three parts: a deep body, an intermediate neck, and an upper isthmus. They are formed by parietal or oxyntic cells (which secrete hydrochloric acid and intrinsic factor), mucous neck cells (which secrete mucus and are found between the parietal cells in the neck of the gland), chief or zymogenic cells (which secrete pepsinogens I and II and other proteolytic proenzymes, including lipase), and endocrine cells (D cells produce somatostatin, EC cells contain serotonin, D1 cells are vasoactive intestinal polypeptide positive, P cells contain bombesin, and PP cells contain pancreatic polypeptide). Forty percent of the antral mucosa is formed by surface pits, which may be branched and are not always perpendicular to the surface. The deep zone consists of coiled tubules that are lined by slightly granular mucin-secreting cells. Chief cells are usually absent, but parietal cells may be present, particularly close to the gastroduodenal junction [15]. The lamina propria has the same characteristics as elsewhere in the gut, and constitutes a loose, cell-rich connective tissue. Plasma cells containing Ig A are found scattered in the lamina propria of body and antral region. Small numbers of T lymphocytes can be found in the lamina propria and epithelium, but less frequently than in the small bowel. The muscularis mucosae varies in thickness from 30 to 210 μm.

    The submucosa of the stomach consists of ganglion cells and blood and lymphatic vessels, which are all embedded in a loose connective tissue with some adipose cells.

    The muscularis propria of the stomach is composed of three muscle layers. The middle circular muscle layer surrounds the whole stomach. The outer longitudinal muscle layer runs from the esophagus to the duodenum and is continuous with the longitudinal fibers of each of them. There is an additional inner oblique muscle layer internal to the circular layer that is not present in other sections of the GI tract. The oblique muscle fibers run down from the cardia slightly parallel to the lesser curve and blend with the circular coat. The circular muscle layer thickens at the pylorus and forms proximal and distal loops. There is no apparent continuity with the circular muscle of the duodenum.

    Lymphatic channels form a plexus in the submucosa from which many small vessels penetrate the muscularis mucosae, ramifying afterward in the deep part (but not in the superficial part) of the mucosa. Terminal branches of the right and left vagal nerves are responsible for parasympathetic cholinergic innervation, while sympathetic innervation comes from the lateral horns of segments D6-D10 of the spinal cord.

    Small Intestine

    The small intestine in humans has an approximate length of 6 m, and is in continuity with the stomach proximally and the large intestine distally. It is comprised of three sections called the duodenum, the jejunum, and the ileum, although there is no visible division between each of them. The duodenum extends from the pylorus, is almost entirely retroperitoneal, and may be divided into 4 segments. The first three segments of the duodenum form a C-shaped organ that embraces the head of the pancreas. The pancreatic and the common bile ducts open into the second segment of the duodenum, usually through a common orifice on the ampulla of Vater but sometimes separately. The fourth segment of the duodenum is short and not fixed, and it becomes invested in the mesentery continuing with the jejunum, and then the ileum. The jejunum represents the proximal 40% and occupies the upper left portion of the abdomen. The ileum accounts for the distal 60% of the remainder small intestine, and is positioned in the right-half of the abdomen and the upper portion of the pelvis. The so-called ileocecal valve is not a true valve but a sphincter, and provides a barrier that avoids the reflux of colonic content into the terminal ileum.

    The small intestine has digestive, absorptive, secretory, and immunological functions. Proteins from diet are fragmented within the lumen to oligopeptides, which are then hydrolyzed to amino acids by peptidases situated on the brush border of mucosal enterocytes. Fat from diet (mostly water-insoluble triglycerides) is emulsified and hydrolyzed in the small intestinal lumen to diglycerides and then to monoglycerides, free fatty acids and glycerol by the combined action of bile salts and lipases [16]. The resulting micelles are transferred into the enterocytes, where they are reconstituted to triglycerides. Carbohydrates are broken down to monosaccharides mostly on the enterocyte brush border by saccharidases, and their absorption takes place against a concentration gradient.

    The mucosa of the small bowel consists of a basal layer from which villi project into the lumen (Fig. 1.2). Between the villi, intestinal crypts (also called intestinal glands or crypts of Lieberkühn) extend down into the basal layer and often reach the muscularis mucosae. The epithelium covering the villi arises in a continuous fashion from that lining the crypts. Villi are longest in the distal duodenum and proximal jejunum, progressively diminishing in height in the mid-small bowel, and becoming again elongated in the distal ileum [17]. Enterocytes or absorptive cells are the main cells that cover the villi, predominating over goblet cells at the tips of the villi at an 8:1 ratio. Enterocytes are high columnar cells with oval, basally situated reticular nuclei, eosinophilic cytoplasm and a periodic acid Schiff-positive microvillous brush border. These cells and those that form the basal layer are generated from the crypt proliferative zone, situated between the crypt base and the villous compartment [18]. The stem cells in the crypt give rise to all types of intestinal epithelial cells. As they migrate upward to cover the villi, they differentiate and mature to form enterocytes, M (membranous) cells, oligomucous cells and goblet cells [19]. They also migrate downward to form the cells of the basal layer. In the lower crypt zone, we can find Paneth cells, endocrine cells and, immediately beneath the generative zone, oligomucous and goblet cells. Paneth cells may contribute to the maintenance of the crypt epithelial integrity by modulating apoptosis of epithelial cells [20]. Endocrine cells, which constitute part of the diffuse endocrine system of the gut, can be classified using monoclonal antibodies to identify the secretory products by radioimmunoassays [21]. Endocrine cells producing serotonin, vasoactive intestinal peptide, enkephalines, bombesin, and somatostatin are diffusely distributed throughout the gut. Cholecystokinin, secretin, gastric inhibitory peptide, and motilin-containing cells are localized mainly in the upper small intestine, and there are also gastrin-containing cells in the proximal duodenum. Neurotensin-secreting cells are most prominent in the distal ileum and proximal colon. Lymphoid tissue in the duodenum and jejunum is localized in scattered follicles in the mucosa and submucosa, but they aggregate to form Peyer’s patches in the lower ileum, where germinal centers are more common. Both B and T lymphocytes are present, and also plasma cells. Brunner’s glands are a morphological continuation of antral-type mucosa into the submucosa of the duodenum. They extend beneath the muscularis mucosae from the pylorus to the inferior duodenal papilla and sometimes into the proximal jejunum [22]. They consist of ramifying tubules that drain through ducts into the lumen either part way-up the crypts or in between the villi [23]. The submucosa of the small intestine is composed of loose connective tissue that contains fibroblasts, mast cells, blood vessels, and the lymphatic and autonomic nerve plexuses (Meissner’s plexus). The muscularis propria of the small intestine is composed of continuous inner circular and outer longitudinal smooth muscle coats that are present throughout the small bowel and are arranged in a helicoidal manner (Fig. 1.2). The so-called Auerbach’s or myenteric plexus is found between both muscle layers, and it provides motor innervation as well as sympathetic and parasympathetic input to the muscular layer.

    Large Intestine or Colon

    The large intestine is divided into the cecum, which is the part below a horizontal line across the bowel at the level of the ileocecal valve, the ascending colon that extends from this line to the hepatic flexure, the transverse colon from the hepatic to the splenic flexure, the descending colon from the splenic flexure to the point where the colon crosses the brim of the pelvis, and the sigmoid colon from the latter point to the rectosigmoid junction. It is approximately 150 cm in length from the lower pole of the cecum to the anus. The vermiform appendix is a 4 cm-long narrow pouch emerging from the lower part of the cecum, ant its high content in lymphoid tissue suggests that it plays some immune role. The transverse diameter of the colon decreases progressively from the cecum reaching its narrowest point (2.5 cm) at the sigmoid colon, where it is followed by a dilation known as the rectal ampulla.

    The mucosa of the large intestine is composed of epithelial tubules embedded in a connective tissue framework (the lamina propria) that rests on the muscularis mucosae. The epithelial component consists of straight, non-branched, perpendicular tubules. There are no villi, and the crypt and surface epithelium is a one-cell layer (Fig. 1.2). The cell types present in the epithelium are: (1) Columnar cells, which secrete a component that participates in the translocation of IgA, glycoproteins, and have a microvillous brush border that participate in the cellular movement of water and electrolytes, (2) Goblet cells, which are in a higher proportion than in the small intestine, (3) Paneth cells, and (4) Endocrine cells, which produce enteroglucagon, neurotensin, somatostatin, VIP-like and 5-hydroxytryptamine [24]. Stem cells located at the crypt base or next to it are the common origin of the four cell types [25]. The lamina propria has a similar composition to that of the small intestine: reticulin fibers containing fibroblasts, lymphocytes, plasma cells, mast cells, eosinophils, and macrophages. Few neutrophils are seen apart from those inside the capillaries. Lymphocytes are predominantly T cells and plasma cells that mostly produce IgA. The muscularis mucosae is composed of a thin layer of muscle fibers pierced by small vessels, and foci of lymphoid tissue may also be found. Like in the small intestine, the muscularis propria of the large intestine has an outer longitudinal muscle coat and an inner circular muscle coat. The circular muscle layer is divided into bands of smooth-muscle cells separated by connective tissue. The longitudinal muscle fibers merge into three bands called teniae, which start from the appendix and continue to the rectum along the entire colon length. The serosa is a thin sheet of connective tissue that contains blood and lymphatic vessels, and is covered by the peritoneum.

    The Liver and the Biliary Tract

    The liver of adult humans weights from 1300 to 1700 g depending on sex and body size. It is a continuous sponge-like parenchymal mass penetrated by tunnel structures that contain networks of afferent and efferent vessels [26]. This microcirculatory system with its corresponding coating of connective tissue represents the main structural support of the liver. The most distal ramifications of the portal vein and hepatic artery are grouped together in a connective tissue matrix—the portal tracts—that is continuous with the mesenchymal components of the liver’s capsule (Glisson’s capsule). Portal tracts also contain bile ducts, lymphatic vessels, nerves, and other types of cells, such as resident macrophages (Kupffer cells), immune cells, stellate cells, and hematopoietic stem cells [27]. In the portal tracts, the branches of the hepatic artery form a capillary network that is arborized around bile ducts. Small efferent branches from the peri-biliary plexus empty into adjacent portal veins and sinusoids, forming an intrahepatic vascular system. The portal vein supplies blood to the parenchymal mass only through its terminal branches. Although it was traditionally believed that the liver was devoid of lymph vessels, scanning electron microscopy studies suggest that pre-lymphatic vessels are present in the portal tracts [28]. Human liver parenchyma is distributed in two major lobes (right and left) that are irrigated and drained by separate first- and second-order branches of the portal and hepatic veins. Both hepatic lobes are topographically separated by the falciform ligament, which is a remnant of the embryonic umbilical vein that attaches the liver to the diaphragm. The subdivision of liver parenchyma in functional segments using portal and hepatic vein segmentation described by Couinaud is the currently preferred anatomical classification, as it is more accurate than arteriobiliary segmentation [29]. The Couinaud classification divides the liver in eight segments, each of which has its own vascular inflow, biliary, and lymphatic drainage.

    The liver lobules are the structural and functional units of the liver. Each lobule is surrounded by six portal tracts, and has a centrilobular vein in its center that represents the smallest branch of the hepatic veins. Tunnel structures called sinusoids, which are lined by endothelial cells and flanked by hepatocytes, receive the blood at the periphery of the lobule from branches of the portal vein and hepatic artery, delivering it into the central veins (Fig. 1.2).

    Hepatocytes are responsible for most of the synthetic and metabolic functions of the liver, and are the most numerous cells in liver parenchyma. They are large polygonal cells shaped as complex rhomboids, with a central nucleus, and they are polarized. About 35% of the total hepatocyte surface faces sinusoids, 50% faces adjacent hepatocytes, and the rest is invaginated to form the canaliculi. There is a virtual space between the sinusoidal endothelial lining cells and the hepatocyte surface called the space of Disse. Adhesion complexes in the intercellular surface membranes of adjacent hepatocytes pin them together, constituting a permeability barrier between the peri-sinusoidal space of Disse and the bile canaliculi. Cellular membranes also have gap-junctions that allow the communication between adjacent hepatocytes by the transfer of small molecules. Noteworthy, the composition of the canalicular membrane is modified for enabling bile excretion. Lastly, the bidirectional exchange of molecules between blood-stream and hepatocytes takes place in the sinusoidal surface.

    Cholangiocytes comprise less than 1% of the cells in the liver, and they compose the wall of the bile ducts in the portal tracts. Only the smallest bile ducts penetrate the parenchymal mass accompanying terminal portal veins, and connecting with bile canaliculi in hepatic plates. Large bile ducts contain cholangiocytes that rest on the basal membrane and have microvilli in the luminal surface.

    Liver sinusoidal endothelial cells comprise about 3% of the parenchymal volume/mass. They are flattened cells with thin cytoplasm penetrated by fenestrations. The sinusoids lack a basal membrane, but they are surrounded by a complex mixture of molecules, including collagens I, III, IV, V, and VI, laminin, proteoglycans, fibronectin, and chondroitin sulfate [30]. This peculiar structure of endothelial cells, only present in the liver, enables the free exchange of fluid components between hepatocytes and the blood.

    Liver tissue resident macrophages (Kupffer cells) are located in the lumen of sinusoids and comprise about 2% of the parenchymal volume/mass. They are more numerous in the portal regions of the sinusoids and are loosely attached to the sinusoidal endothelium. Liver macrophages are avidly phagocytic through C3 and Fc receptors, clearing sinusoidal blood of relatively large materials including bacteria and effete cells (worn-out erythrocytes, dead or damaged hepatocytes, etc.) [31]. When activated, they can produce a large number of chemokines and cytokines that have a fundamental role in the implementation of the liver’s acute phase reaction, coordinating the response to injury of all parenchymal cells [32].

    Immune cells of the liver—T, NK, and NKT lymphocytes, and dendritic cells—are located along sinusoids and in portal tracts, and are components of a liver-centered immune system that also includes Kupffer cells and sinusoidal endothelial cells. The immune cells within the liver represent a major fraction of the body’s innate immune capacity, and a small component of its acquired immune capacity [32]. They regulate liver reparation after cell injury and loss, and permit the removal of numerous foreign antigens. Virus elimination, clearance of activated T lymphocytes, and development of antigen tolerance are further remarkable functions of the hepatic adaptive immunity [32].

    Stellate cells, located in the space of Disse outside of and partly encircling sinusoids (pericytes), comprise 1.5% of the parenchymal volume/mass. They participate in the metabolism of vitamin A and store this fat-soluble vitamin in lipid inclusions [33]. They are also responsible for the synthesis, secretion, and degradation of components of the peri-sinusoidal extracellular matrix, playing a fundamental role in hepatic fibrogenesis [34].

    Pancreas

    The pancreas is a soft, elongated, flattened gland of 12–20 cm in length. In adults, the gland weighs between 70 and 110 g. The head of the pancreas has a lobular structure and lies on the right side, behind the peritoneum of the posterior abdominal wall and within the curvature of the duodenum. The neck, body, and tail of the pancreas are localized in the posterior abdomen with an oblique direction to the left and up, and extend until the gastric surface of the spleen. Finally, the uncinate process is a prolongation of the head that hooks toward the back of the abdomen. The main pancreatic duct or duct of Wirsung begins near the tail of the pancreas. It is formed from anastomosing ductules that drain the lobules of the gland, and it progressively enlarges from left to right by additional ducts. At the level of the major papilla, the duct turns horizontally, usually joints the common bile duct, and ends into the ampulla of Vater, located in the second segment of the duodenum. An accessory pancreatic duct, the so-called duct of Santorini, is frequently present and usually communicates with the main duct. The accessory duct lies anterior to the bile duct and usually drains into the minor papilla, which is located proximal to the ampulla of Vater in the second segment of the duodenum.

    The pancreas is a finely nodular gland that is grossly similar to the salivary glands, although less compact. It is surrounded by fine connective tissue but it does not have a fibrous tissue capsule. The lobules are visible on gross examination and are separated by connective tissue septa that contain the blood vessels, nerves, lymphatics, and excretory ducts (constituting about 18% of this organ). The pancreas is a mixed endocrine (about 2%) and exocrine (about 80%) organ.

    The endocrine portion is represented by the islets of Langerhans, which consist of anastomosing cords of polygonal light-staining endocrine cells scattered throughout the exocrine tissue of the pancreas (Fig. 1.2). The human pancreas contains around 1 million islets Langerhans. Each islet is about 0.2 mm in diameter, much larger than an acinus, and they are separated from the surrounding exocrine tissue by fine connective tissue fibers, which are continuous with those of the exocrine gland. Endocrine cells can be classified depending on the molecular content of their secretion. B cells (beta cells), which secrete insulin, are the most numerous (50%–80%). A cells or alpha cells (5%–20%) secrete glucagon. PP (pancreatic polypeptide) cells (10%–35%) secrete pancreatic polypeptide. D cells (5%) secrete somatostatin.

    The exocrine pancreas consists of tubulo-acinar glands that contain numerous dark-staining acini composed of tubular and spherical masses of cells, which are the subunits of the lobule (Fig. 1.2). The acinus is formed by a single layer of pyramidal cells (the acinar cells), which have secretory vesicles in their cytoplasm containing the precursors of the digestive enzymes. They are the functional units for synthesis, storage and regulated secretion of pancreatic enzymes. The acinar cells surround a small intercalated duct, the epithelium of which produces the fluid and bicarbonate ions of pancreatic juice. They drain into larger ducts, and finally into interlobular ducts lined by a single layer of columnar epithelium. The interlobular ducts then anastomose to become the main pancreatic duct.

    The secretory granules of the exocrine pancreas may be of two main types: electron-lucent condensing vacuoles or electron-dense zymogen granules. Studies of the chemical composition of the zymogen granules have shown that they contain about 12–15 different digestive enzymes, which make up about 90% of the granule protein. In contrast to endocrine cells that usually secrete a single hormone, acinar cells secrete several digestive enzymes: (1) trypsin, chymotrypsin and carboxypeptidase that hydrolyze proteins into smaller peptides or amino acids, (2) ribonuclease and deoxy-ribonuclease, which split nucleic acids, (3) pancreatic amylase that hydrolyzes starch and glycogen, (4) pancreatic lipase, which breaks down triglycerides, and (5) cholesterol esterase, which hydrolyzes cholesterol esters.

    Sources of Oxidative Stress

    The GI system is a major site of production of ROS and RNS, and the dysfunction of the GI system may also affect the equilibrium between oxidants and antioxidants in other organs, such as the brain [35]. ROS and RNS are known to be implicated in a range of GI diseases, including carcinogenesis [36,37], ulcers, and inflammatory bowel disease (IBD) [38]. Thus, understanding the pathophysiological aspects of oxidative stress imbalance in the GI system may help to develop novel diagnostic and therapeutic options for GI and non-GI disorders.

    The main oxidants produced in living organisms, frequently during normal cellular metabolism, may be grouped under the names of ROS and RNS. ROS are constantly produced as by-products of cellular respiration and they may also be generated by enzymatic reactions. Reduction of molecular oxygen (O2) to H2O via mitochondrial respiration complexes provides ATP, but paradoxically contributes to cell death partly due to ROS generation ), and non-radical compounds such as peroxynitrite (ONOO−), dinitrogen trioxide (N2O3), nitrous oxide (HNO2), nitryl chloride (NO2Cl), or alkyl peroxynitrites (ONOOR).

    Consequences of the Generation of ROS and RNS

    Today, it is well accepted that the generation of ROS and RNS is a process that plays a fundamental role in normal cellular and organ physiology. Some ROS and RNS are specific signaling molecules, and the presence of redox-sensitive signaling pathways reveals the existence of a complex redox regulation of cellular signaling (reviewed in [2,3,40]). In this sense, the induction of smooth muscle relaxation by nitric oxide, and the role of superoxide and other ROS in the control of ventilation or in the activation or inactivation of receptor- and non-receptor mediated signaling pathways such the epidermal growth factor receptor (EGFR) or the mitogen-activated protein kinase (MAPK) cascades, are clear examples of this notion.

    Alteration of the normal balance between ROS/RNS production and the capacity to rapidly detoxify reactive intermediates causes oxidative stress. Whereas a controlled low to moderate generation of ROS may have specific functions in several physiological processes such as apoptosis [41,42] or immune defense [8,43], the disproportionate generation of ROS disturbs normal homeostasis and causes oxidative tissue damage [2,10]. This latter situation leads to deleterious effects in the cell, frequently causing an irreversible disruption or inactivation of target molecules. The most vulnerable among these target molecules are proteins, the DNA, and the membrane lipids:

    • Protein oxidation caused by ROS adds modifications such as hydroxyl and carbonyl groups that may change the function of the proteins and/or alter their degradation [44]. The range of downstream functional consequences is wide, such as the inhibition of enzymatic and binding activities, an increased or a decreased uptake by cells, the inactivation of DNA repair enzymes, or the loss of fidelity of damaged DNA polymerases when replicating DNA [45]. Whereas moderately oxidized soluble cell proteins may be selectively and rapidly degraded by the proteasome, their degradation is compromised when they are severely oxidized [46]. Importantly, the accumulation of such severely oxidized proteins inside the cells has been associated with various pathologies and aging [45].

    • Nuclear and mitochondrial DNA damage from ROS may result in tumorigenic mutations, and in apoptotic or non-apoptotic cell death [47].

    • Lipid oxidation. ROS have the ability to oxidize polyunsaturated fatty acids (PUFAs), which constitute an integral component of cell membranes. This reaction initiates lipid peroxidation, which represents a chain reaction that produces other free radicals and reactive substances such as conjugated dienes, hydroperoxides, lipoperoxides, and toxic aldehydes like malondialdehyde (MDA) [48]. Importantly, lipid peroxidation changes the fluidity of cell membranes. The subsequent increase of membrane permeability reduces the capacity to maintain transmembrane concentration gradients in equilibrium and results in inflammation [49].

    Mechanisms of ROS and RNS Generation

    The presence of a plethora of microbes, the continuous exposure to food ingredients, and the interactions with immune cells are responsible for a considerable production of prooxidants in the GI tract. In addition, epithelial inflammation in response to ingested materials and pathogens may induce the secretion of inflammatory cytokines and other mediators by macrophages and polymorphonuclear cells that further contribute to the generation of oxidative stress [10]. Many of the basic mechanisms by which ROS and RNS are generated in the GI system are, however, similar to those observed in other organs and tissues (Fig. 1.3).

    • Endogenous sources. Intracellular compartments including mitochondria, the endoplasmic reticulum, peroxisomes, the cytosol, plasma membranes, and even the extracellular space are sites of ROS generation [50,51]. Several enzymes may catalyze ROS-generating chemical reactions, such as peroxidases, NAD(P)H oxidases, xanthine oxidase (XO), lipoxygenases, glucose oxidase, myeloperoxidase, nitric oxide synthase, and cyclooxygenases [39].

    • The mitochondrial respiratory chain, which occurs in 2%–3% of the total amount of oxygen consumption [52]. Complex IV is the last enzyme component of the mitochondrial respiratory chain and it reduces O2 to two molecules of H2O via a four-electron reduction, but this reaction is not considered a relevant source or ROS.

    • Respiratory burst and NADPH oxidase) into the extracellular space or phagosomes. NADPH oxidase catalyzes the following reaction:

    NADPH oxidase is a multicomponent enzyme present in the plasma membrane and phagosomes of phagocytes such as monocytes, macrophages, neutrophils, and eosinophils ) has a high potential to depolymerize GI mucin, and to promote oxidation of proteins and carbohydrates, as well as excision of DNA [54].

    • Xanthine oxidase. Xanthine oxidase (XO) is mainly expressed in the liver and in the mucosa of the small intestine [55]. It catalyzes the oxidation of hypoxanthine to xanthine, and then of xanthine to uric acid, during urine catabolism [56] in the following reactions:

    ) is generated during both reactions. Remarkably, the intestinal mucosa has a tremendous capacity to oxidize hypoxanthine by XO.

    • Lipoxygenases. Lipoxygenases (LOX) are a family of nonheme iron-containing enzymes that catalyze the deoxygenation of PUFAs yielding hydroperoxyl derivatives including hydroperoxy-eicosatetraenoic acids (HPETEs) ) and other ROS during its oxidation [58,59].

    • Myeloperoxidase. Myeloperoxidase (MPO) is a peroxidase heme-containing enzyme that is abundantly expressed in neutrophils and is also present in macrophages and monocytes. The enzyme is stored in lysosomes and granules that may be released to the extracellular space. MPO catalyzes the following reactions:

    Therefore, this enzyme chlorinates hydrogen peroxide (H2O2) to produce the highly reactive molecule HOCl. In addition, it can also catalyze the oxidation of thiocyanate to generate hypothiocyanite, which is another reactive compound [60]. HOCl can further react with hydrogen peroxide (H2O2) producing the chloride ion (Cl−) and singlet oxygen (¹O2), which is not a free radical but is also highly reactive. Lactoperoxidase present in the airway and digestive tract epithelia is also capable of generating hypothiocyanite [61].

    • Nitric oxide synthase) from the oxidation of L-arginine. Two of the NOS isozymes, the neuronal NOS (nNOS or NOS-1) and the endothelial NOS (eNOS or NOS-3), are constitutively expressed, and the third isozyme called inducible NOS (iNOS or NOS-2) is highly induced by endotoxin and diverse cytokines ) in the following reaction [63]:

    N-hydroxy-L-arginine, an intermediate of the prior reaction, is a moderate inhibitor of arginase, an enzyme that catalyzes the last step of the urea cycle . All these RNS may react with most cellular components, including proteins, lipid membranes, and nucleic acids, disrupting their function by causing the nitration and nitrosation of specific residues.

    All isoforms of NOS are expressed in the GI tract. Nitric oxide production from NOS in the GI tract is involved in normal physiology and mucosal defense, participating, e.g., in the maintenance of mucosal integrity by regulating gastric mucosal blood flow, epithelial secretion, and barrier function [68]. On the other hand, increased iNOS expression and deleterious effects of nitric oxide production are thought to play a pathogenic role in diverse injury processes, such as in ulcerative colitis and peptic ulcers [68]. Importantly, the activity of NOS and the production of nitric oxide are known to be influenced by a large number of dietary factors [69].

    • Cyclooxygenase. Cyclooxygenase is an enzyme that uses arachidonic acid as substrate to produce prostanoids through two steps involving cyclooxygenase and peroxidase activities of the enzyme as follows:

    Cyclooxygenase has two isoforms called COX-1 and COX-2, although a variant (COX-3) encoded by the same gen of COX-1 has also been described ) in the presence of NADH or NADPH [73]. Once prostaglandin H2 has been produced, it may be subsequently metabolized by various enzymes to stable prostanoids such as prostaglandin E2, prostacyclins, or thromboxane A2. Both COX-1 and COX-2 enzymes have been shown in normal gastric mucosa. Their expression has been noted to increase in Helicobacter pylori gastritis as well as in macrophages, endothelial cells, and myofibroblasts localized in the rim of ulcers [74].

    • Transition metals. Iron (Fe²+) and copper (Cu+) may act as catalysts for the formation of highly reactive hydroxyl radicals (HO•) from hydrogen peroxide (H2O2), which is known as the Fenton reaction. These metals are oxidized to Fe³+ and Cu²+, and the production of hydroxyl radicals through this pathway may accelerate lipid peroxidation [75]. The presence of heme-iron in certain proteins has also been related to the production of superoxide and oxidative stress during exercise [76].

    • Exogenous or environmental sources. There are many exogenous or environmental factors that can produce oxidative and nitrosative stress in the GI system. Exposure to ionizing radiations, e.g., can generate hydroxyl radicals directly by oxidation of water (H2O) or indirectly by the formation of ROS intermediates [77]. Antioxidants such as N-acetyl-cysteine have been shown to prevent or attenuate radiation-induced GI injury in mice [78]. Many chemotherapeutic agents also induce the generation of high levels of ROS [79], which play a role in their mechanism of action by inducing cancer cell death but also in the development of GI toxicity. Paradoxically, ROS may also decrease the efficacy of chemotherapy by slowing cancer cell growth and interfering with apoptosis, which was prevented or attenuated by the addition of antioxidants to antineoplastic regimens [80]. Radiation and chemotherapy have shown in several studies to cause oxidative stress by reducing the levels of antioxidants, such as vitamin E or beta-carotene [81,82]. Air pollutants and cigarette smoke are other important sources of oxidative and nitrosative stress [83]. Cigarette smoke is known to contain and to generate numerous oxygen-, nitrogen-, and carbon-centered free radicals [84]. Remarkably, smoking habit has been shown to influence the natural history of various GI diseases, including peptic ulcers, Crohn’s disease, GI cancers, and others [83,84]. Intake of certain foods or alcohol is another common source of oxidative stress and ROS generation relevant for the GI tract, including the development of liver and pancreatic disease as well as GI cancer [10]. Finally, many medications ) in vascular endothelial cells [85], and nonsteroidal antiinflammatory drugs (NSAIDs) may also generate ROS by blocking the formation of prostaglandin E2 by cyclooxygenase [86].

    Figure 1.3 Main sources of oxidative stress and major antioxidant defense systems in cells.

    ), lipid peroxides (LOOH) and their end-products malondialdehyde (MDA) or 4-hydroxynonenal (4-HNE). The antioxidant defenses against oxidative stress include antioxidant molecules that directly react with ROS such as reduced glutathione (GSH) or reduced thioredoxin (TXRred) as well as antioxidant enzyme systems including SODs, catalases (CAT), or GPX.

    Antioxidants: The Other Arm of the Balance

    The production of free radicals and reactive molecular species is not the only determinant of the generation of oxidative stress, as the antioxidant capacity of the surrounding environment needs to be taken also into account. In this sense, mammals are provided with diverse antioxidant systems that contribute to the modulation of redox-sensitive signaling as well as prevent the damage of relevant cellular molecules by becoming the target of ROS and RNS themselves [87]. We provide here only a brief review of the main antioxidant enzyme systems, as the Section II of the present book reviews in detail the different antioxidant molecules and systems.

    Humans possess potent endogenous mechanisms to detoxify ROS and RNS that include both enzymatic and non-enzymatic reactions (Fig. 1.3) [10,87]. The most relevant enzymes that participate in antioxidant defense are superoxide dismutases (SODs), catalase, glutathione peroxidase (GPX), glutathione reductase, and hemeoxygenase, whereas endogenous antioxidant molecules include glutathione, thioredoxin, melatonin, peroxiredoxin, and others. Relevant exogenous antioxidants that can be incorporated in the diet include vitamins C and E, vitamin A and other carotenoids, minerals, and polyphenols.

    SODs ), enhancing by 10,000-fold the rate of the spontaneous reaction [88]. Of the three known types of SOD in humans, two of them contain copper and zinc as metal cofactors: Cu-Zn-SOD that is present in the cytosol and in the mitochondrial intermembrane space, and EC-SOD that is extracellular. The third isoform, Mn-SOD, contains manganese and is localized in the mitochondrial matrix [89]. Thus, superoxide generated during mitochondrial respiration is converted by SODs to the more stable and diffusible hydrogen peroxide, which can then be transformed to H2O by GPX in the mitochondria or by peroxidases and catalase in other cellular compartments. SODs are normally expressed in the mucosa of the GI tract. Its activity has been shown to be decreased in the borders of active ulcers and to increase during the healing process in several studies, suggesting a protective function [90,91]. Induction of SOD mRNA expression has also been reported in gastric and colorectal carcinomas [92].

    Catalase is an enzyme found in most tissues, including the liver and the GI tract. It has four porphyrin heme groups that allow its reaction with hydrogen peroxide, transforming this ROS into water and oxygen (2 H2O2 → 2 H2O + O2).

    The enzyme glutathione peroxidase (GPX), present in all cell compartments, also mediates the transformation of hydrogen peroxide to water, which is achieved by oxidizing reduced glutathione (GSH) to oxidized glutathione disulfide (GSSG) in the process (2 GSH + H2O2 → GSSG + 2 H2O). GPX is thought to play a major role when the concentration of hydrogen peroxide is high [87]. Another major function of the enzyme is to reduce lipid hydroperoxides (LOOH) to their corresponding alcohols. Eight isoforms of glutathione peroxidase (GPX 1–8) have been identified in humans so far. While GPX1 is almost ubiquitous, the expression of GPX2 is mainly restricted to the epithelium of the GI tract. GPX2 appears to account for at least fifty percent of GPX activity in the GI epithelium [93]. GPX activity appears to have an essential protective role for the GI tract, as combined disruption of GPX1 and GPX2 leads to intestinal inflammation and cancer in several murine experimental models [94–96]. The generation of GSSG by GPX is coupled to the regeneration of GSH by the enzyme glutathione reductase using NADPH and FAD as cofactors (GSSG + NADPH → 2 GSH + NADP+). The deficit of riboflavin, a precursor of FAD, in the diet has been associated with reduced glutathione reductase activity [97,98].

    Hemeoxygenases (HOs) are ubiquitously expressed and the rate-limiting enzymes in heme catabolism [99]. They catalyze the oxidative degradation of heme (a molecule that may favor the production of free radicals and lipid peroxidation) resulting in the generation of carbon monoxide, free ferrous iron, and biliverdin, which is subsequently converted to bilirubin by biliverdin reductase [100]. Rather than being metabolic waste products, the three products generated by the hemeoxygenase reaction are thought to have important beneficial vasodilatory, antioxidant, and anti-inflammatory properties [101]. Whereas the HO-2 isoform is constitutively expressed, the HO-1 isoform is highly inducible by oxidative stress as well as by other stimuli such as its substrate heme, inflammation, or hypoxia [102]. HO-1 has been reported to be upregulated by intestinal inflammation in both patients and experimental models of colitis [103]. Whereas the induction of HO-1 expression attenuated the severity of experimental colitis [104,105], the inability to induce HO-1 resulted in increased severity [106], suggesting that the induction of HO-1 is an important cytoprotective response to injury.

    The Starring Role of the Mucosa

    The most superficial layer of the GI wall is the mucosa, therefore, representing the interface between an organism and its luminal environment. The mucosa comprises the gut epithelium and the immune, vascular, and structural support that composes its lamina propria. The GI mucosa has crucial functions such as nutrient digestion and absorption, the healthy maintenance of microbiota, and the protection against harmful external agents. Because of its location, the mucosa is the first affected by oxidative damage induced by luminal oxidants.

    The epithelium of the mammalian GI tract is a highly proliferative tissue [107]. The asymmetric division of intestinal stem cells residing at the base of intestinal crypts leads to two daughter cells, one of which will become part of the stem-cell population whereas the other will undergo differentiation. The differentiation and maturation occurs progressively as the epithelial cells get to the tip of the villi, where they will suffer apoptosis and will get detached from the intestinal wall to be eliminated in the intestinal lumen. In this manner, the complete intestinal epithelium is renewed every 4–5 days, representing a dynamic and sequential process in which proliferation, migration, differentiation, and apoptosis are constantly and simultaneously occurring, while maintaining proper barrier function.

    The development of oxidative and nitrosative stress in the intestinal mucosa is thought to play a role in the pathogenesis of several GI diseases. Because the intestinal mucosa is constantly challenged with diet- and bacterial-derived oxidants and carcinogens, redox imbalance may develop and lead to impaired DNA methylation, which could be relevant in carcinogenesis and other GI diseases [108,109]. Also, excessive oxidative and nitrosative stress could contribute to the development of inflammation in the intestinal epithelium by activating redox-sensitive transcription factors such as nuclear transcription factor-κB (NF-κB) that upregulate the expression of proinflammatory molecules [110,111]. In turn, inflammatory cellular infiltrates of leukocytes, monocytes, and neutrophils can also increase intestinal ROS production through both respiratory burst and prostaglandin and leukotriene metabolism [112]. Supporting this scenario, a correlation between colonic NO and severity of the disease has been reported in patients with ulcerative colitis [113], and endogenous antioxidants have been shown to be decreased in the presence of intestinal inflammation [114]. Despite these and other observations, it has not been fully elucidated yet whether the excessive ROS and RNS levels in the inflamed intestinal mucosa of patients with IBD reflect a primary role of oxidative stress in the pathogenesis of the disease or whether they are just a consequence of the inflammatory process [115]. Both possibilities, however, are not mutually

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