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Antioxidant Therapy in Inflammatory Bowel Diseases

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Antioxidant Therapy in Inflammatory Bowel Diseases antioxidants Review Antioxidant Therapy in Inflammatory Bowel Diseases Katarzyna Dzi ˛abowska-Grabias 1, Małgorzata Sztanke 2,* , Przemysław Zaj ˛ac 1, Michał Celejewski 1, Katarzyna Kurek 3, Stanisław Szkutnicki 3, Patryk Korga 4, Włodzimierz Bulikowski 5 and Krzysztof Sztanke 6 1 Department of Gastroenterology, 1st Military Research Hospital, and Polyclinic of Lublin, 20-049 Lublin, Poland; [email protected] (K.D.-G.); [email protected] (P.Z.); [email protected] (M.C.) 2 Department of Medical Chemistry, Medical University of Lublin, 20-093 Lublin, Poland 3 Department of Pneumonology, Oncology, and Allergology, Medical University of Lublin, 20-090 Lublin, Poland; [email protected] (K.K.); [email protected] (S.S.) 4 Department of Gastroenterology, 10ft Military Research Hospital, and Polyclinic of Bydgoszcz, 85-681 Bydgoszcz, Poland; [email protected] 5 Occupational Medicine Centre, 62-200 Gniezno, Poland; [email protected] 6 Laboratory of Bioorganic Synthesis and Analysis, Chair and Department of Medical Chemistry, Medical University of Lublin, 20-093 Lublin, Poland; [email protected] * Correspondence: [email protected]; Tel.: +48-814-486-195 Abstract: Inflammatory bowel diseases (IBD) are a group of chronic, incurable diseases of the diges- tive tract, the etiology of which remains unclear to this day. IBD result in significant repercussions on the quality of patients’ life. There is a continuous increase in the incidence and prevalence of IBD worldwide, and it is becoming a significant public health burden. Pharmaceuticals commonly used in IBD management, for example, mesalamine, sulfasalazine, corticosteroids, and others, expose patients to diverse, potentially detrimental side effects and frequently do not provide sufficient disease control. The chronic inflammation underlies the etiology of IBD and closely associates with Citation: Dzi ˛abowska-Grabias,K.; oxidative/nitrosative stress and a vast generation of reactive oxygen/nitrogen species. Relative Sztanke, M.; Zaj ˛ac,P.; Celejewski, M.; to this, several substances with antioxidant and anti-inflammatory properties are now intensively Kurek, K.; Szkutnicki, S.; Korga, P.; researched as possible adjunctive or independent treatment options in IBD. Representatives of several Bulikowski, W.; Sztanke, K. Antioxidant Therapy in Inflammatory different groups, including natural and chemical compounds will be characterized in this dissertation. Bowel Diseases. Antioxidants 2021, 10, 412. https://doi.org/10.3390/antiox Keywords: inflammatory bowel diseases; oxidative/nitrosative stress; antioxidant therapy; 10030412 antioxidants; inflammation; reactive oxygen/nitrogen species Academic Editor: Fiorella Biasi Received: 2 February 2021 1. Introduction Accepted: 1 March 2021 Inflammatory bowel diseases (IBD) are chronic, incurable diseases of the gastrointesti- Published: 9 March 2021 nal tract, whose etiology is largely unknown. Factors that contribute to the development of IBD include genetic susceptibility, disturbed gut microflora, environmental influences, Publisher’s Note: MDPI stays neutral and an abnormal immune response. There are two principal types of IBD–the first is ulcer- with regard to jurisdictional claims in ative colitis (UC), the second is Crohn’s disease (CD). The spectrum of IBD symptoms is published maps and institutional affil- broad and can extend beyond the digestive tract, but the most frequent symptoms include iations. diarrhea with blood and stomach ache. It is disturbing that the incidence of UC and CD occurrence is subject to constant rise worldwide, also in the regions with previously low incidence and morbidity rates, such as Asia [1–3]. The primary aim of the IBD therapy is to achieve and sustain remission, as well as to Copyright: © 2021 by the authors. influence the life quality through the alleviation of symptoms, but due to the chronic course Licensee MDPI, Basel, Switzerland. of the above-mentioned diseases, the majority of medications applied in the therapy must This article is an open access article be taken regularly over a long period of time. Long-term treatment significantly increases distributed under the terms and the risk of appearance of dangerous side-effect actions, which may pose a potential threat conditions of the Creative Commons to the patient’s life. According to these facts, there is an intense search for new alternative Attribution (CC BY) license (https:// therapeutic options without side effects or minimizing their risk [4–6]. creativecommons.org/licenses/by/ 4.0/). Antioxidants 2021, 10, 412. https://doi.org/10.3390/antiox10030412 https://www.mdpi.com/journal/antioxidants Antioxidants 2021, 10, x FOR PEER REVIEW 2 of 19 Antioxidants 2021, 10, 412 tial threat to the patient’s life. According to these facts, there is an intense search for 2new of 18 alternative therapeutic options without side effects or minimizing their risk [4–6]. Chronic inflammation is the pathophysiological process typical of IBD. In the course of inflammation,Chronic inflammation as well as isother the pathophysiologicalpathological conditions, process such typical as hypoxia of IBD. Inor theinfection, course anof increase inflammation, in the asintensity well as of other oxidative pathological stress markers conditions, is observed. such as hypoxia Oxidative or infection,stress (OS), an asincrease well as in nitrosative the intensity stress of oxidative (NS), are stress phenomena markers based is observed. on the Oxidativeexcessive stressformation (OS), of as reactivewell as nitrosativeoxygen species stress (ROS) (NS),are and phenomena reactive nitrogen based on species. the excessive (RNS), formation which leads of reactive to the advantageoxygen species of oxidants (ROS) andover reactiveantioxidants. nitrogen One species. of the main (RNS), places which ofleads these toreactive the advantage species productionof oxidants is over the antioxidants.digestive system, One ofand the the main formation places of of these them reactive is continuous species and production not al- waysis the harmful. digestive These system, are and highly the formation reactive ofmo themlecules is continuoustaking part, and among not always others, harmful. in the woundThese arehealing highly processes reactive or molecules pathogen taking neutrali part,zation. among Nevertheless, others, in both the woundtheir excessive healing productionprocesses or and pathogen insufficient neutralization. removal lead Nevertheless, to the damage both of theirthe cell’s excessive structural production elements– and proteins,insufficient lipids, removal or DNA. lead The to the core damage of the ofinflammatory the cell’s structural process elements–proteins, during IBD is ROS/RNS lipids, stimulatingor DNA. The the core excessive of the inflammatoryproduction of processpro-inflammatory during IBD cytokines, is ROS/RNS which stimulating secondarily the leadsexcessive to increasing production ROS/RNS of pro-inflammatory production and cytokines, oxidative/nitrosative which secondarily stress leads intensification to increasing [7–9].ROS/RNS production and oxidative/nitrosative stress intensification [7–9]. ScientificScientific studies studies confirm confirm that that oxidative/nitrosative oxidative/nitrosative stress stress plays plays an animportant important role role in thein thepathophysiology pathophysiology of ofinflammatory inflammatory bowe bowell diseases. diseases. The The currently currently used used medications medications appliedapplied in in the IBD treatmenttreatment cancan causecause multiple multiple side side effects effects as as well, well, as as they they do do not not provide pro- videsufficient sufficient control control over the over illness the (Figureillness 1(Figure). Thus, 1). new Thus, antioxidant new antioxidant substances substances are constantly are constantlybeing searched being for. searched These substances for. These are substa supposednces are to expresssupposed a high to safetyexpress profile a high as wellsafety as profileto influence as well the as course to influence of disease the positively. course of The disease present positively. dissertation The aims present to summarize dissertation the aimscurrent to summarize scientific knowledge the current on scientific the topic ofknow antioxidantsledge on the in inflammatory topic of antioxidants bowel diseases in in- flammatorytherapy. bowel diseases therapy. Figure 1. The connection between oxidative stress (OS) and inflammatory bowel diseases (IBD) and the key role of the antioxidants. ROS—reactive oxygen species. Antioxidants 2021, 10, 412 3 of 18 2. Oxidative/Nitrosative Stress in IBD Free radicals (FR) are particles that have at least one unpaired electron on O (reactive oxygen species) or N (reactive nitrogen species) atom. These reactive species are character- ized by high reactivity and ease of chemical interaction with cellular components. They are generated during the natural course of metabolic processes, and the principal place of their formation is the mitochondrial respiratory chain. Both internal and exogenous factors can contribute to the unrestrained generation of reactive oxygen/nitrogen species and the accumulation of the oxidative/nitrosative stress. Enzymes involved directly in the reactions leading to ROS/RNS formation are, for example, myeloperoxidase, nitrogen oxide synthase, and others. Inducible nitrogen oxide synthase (iNOS), through the influ- ence on the increased production of nitrogen oxide (NO) in the foci of the inflammatory process, plays
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