The toxicity of gastrointestinal (GI) tract associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) is an important medical and socio-economic problem. The coprescription of traditional gastroprotective drugs such as proton pump inhibitors (PPIs) and H2-receptor antagonist, to reduce gastric acid secretion are the common clinical therapeutically approach. However, these strategies are not effectively to reduce gastrointestinal adverse events of NSAIDs and recently have demonstrated their low safety in long-term use. In the search for new therapeutically approach, the use of selective COX-2 inhibitors and the use of prostaglandin analogue in order to maintain the local prostaglandins was considered. Unfortunately, their adverse events in cardiovascular or renal system provoked that their therapeutic use were discarded. Therefore, the search for new therapeutic strategies has been promoted. The current experimental and preclinical approaches includes very promising alternatives such as H2S-NSAIDs, NO-NSAIDs and the possible use of Docosahexaenoic acid (DHA), an Omega-3 Fatty acid. In this regard, DHA is focused in face the prostaglandin independent mechanism of NSAID-induce gastric injury such as increment of proinflammatory molecules expression and neutrophil–endothelial adherence. However, large studies of these therapeutically approaches are still needed.
Keywords: Non-steroidal Anti-inflammatory Drugs, gastric injury, PPIs, omega-3
For decades, damage of the gastric mucosa was regarded being caused by excessive gastric acid secretion [1]. Nowadays, it is known that under normal conditions the gastrointestinal (GI) tract, is continuously exposed to many noxious factors and substances that can alter its integrity [2]. However, GI tract is capable to face the damaging factors in a dynamic process termed “mucosal defense” [1], the appreciation of contribution of inflammatory process as key component of mucosal defense against exogenous and endogenous factors has been important [3]. On the other hand, it is well known that the use of Nonsteroidal Anti-inflammatory Drugs (NSAIDs) is associated with adverse GI events, such as gastric mucosal erosion, ulceration, bleeding, and perforation [4]. In addition to prostaglandins inhibition, inflammatory mechanism has been involved in the NSAID-induce gastric damage [5]. Furthermore, current therapies do not have the ability to protect the GI tract against NSAID-induce gastric damage, this fact has led the search for new agents to reduce side effects associated with NSAIDs and maintain their therapeutic efficacy.
During digestive process the stomach is daily in contact to a wide range of microorganisms, nutrients and different substances which could trigger local and systemic inflammatory reactions to finally induce damage to the mucosa [2], [6]. Consequently, it has been proposed a complex network of components with the ability to prevent such injury as well as the possibility to repair the epithelium in a quickly manner, so it is termed “mucosal defense” [1], that finally set up a balance between the aggressive and protective factors of gastric mucosa, this term known as “gastroprotection” [7], [8].
The components of mucosal defense can be organized as a hierarchy, according to their anatomical disposition [9]. The first level of defense consists of factors secreted into the lumen, such as hydrochloric acid (HCl) which allow the activity of pepsin and also minimizes the bacterial colonization in the stomach [2], [9], [10]. Followed by the mucus gel, that serve as a lubricant to the gastric movements and restrict bacteria movements through the mucosa [2], [9]. This mucus gel contains phospholipids, and its luminal surface is coated with a film of surfactant phospholipids with strong hydrophobic properties [2], [11]. The secretion of bicarbonate (HC03 -) by the action of cotransporters and proton pumps, allows to maintain a neutral pH at the apical cell surfaces [2], [5], [11].
The second level of defense is formed by a continuous layer of surface epithelial cells interconnected by tight junctions, which form a “physical barrier” against harmful exogenous agents [7], [11], [12]. The epithelium is continually renewed from mucosal progenitor cells and maintains structural integrity of the mucosa in case of injury, through the formation of an appropriate microenvironment (mucoid cap) [7], [13]. The dense network of capillaries under the surface epithelium of the stomach, supplies nutrients and oxygen to the epithelium [1], [2]. The primary afferent sensory neurons and nerves directly affects the tone of submucosal arterioles, which regulate mucosal blood flow [1], [13]. The stimulation of gastric sensory nerves leads to the release calcitonin gene-related peptide (CGRP) and the vasodilatation of submucosal vessels mediated by nitric oxide (NO) generation, this response removes, dilutes and neutralizes toxics substances that have diffused into the mucosa from the lumen [14], [15].
In recent publications, it has been considered mast cells and macrophages resident within the lamina propia as the latest level of mucosal defense, since they prevent the entry of bacterial products or other antigenic material into the systemic circulation [1], [2]. These cells are capable of releasing an array of inflammatory mediator such as histamine, tumor necrosis factor-alpha (TNF-α) or interleukin 1 beta (IL-1β), that can alter mucosal blood flow and enhance the neutrophil recruitment mediated by LTB4 (LTB4) [1], [2], [16]. It is important to mention that many others chemical mediators participate in the coordinated and effective mucosal response to injury, one of them, prostaglandins (PGs) these mediators influence in most of the components of mucosal defense [2], [17], [18].
PGs are members of eicosanoids family, which contains 20 carbons and are derived enzymatically from fatty acids [18], [19]. Their synthesis involves arachidonic acid (5,8,11,14-eicosatetraenoic acid) as a substrate that is de-esterified from cell membrane phospholipids by the action of phospholipase A2 (cPLA2) [18], [19]. Subsequently it is metabolized by ciclooxygenase (prostaglandin endoperoxide synthase) isozymes (COX-1 and COX-2) and converted to PGG2 and then to PGH2, which undergoes in subsequent conversion reactions, ultimately produced five bioactive prostanoids, including PGD2, PGE2, PGF2α, PGI2, and thromboxane [20]. In the gastric mucosa, the constitutive action of COX-1 leads the production of prostaglandin (PGE2) and prostacyclin (PGI2); it is PGE2 through its EP3 receptor the one whose inhibits HCl secretion in the parietal cell by the decrease of cyclic adenosine monophosphate (cAMP) [21], [22]. Meanwhile, in the epithelial cells PGE2 stimulate the mucus and bicarbonate secretion through EP1 receptor, reduces the epithelial permeability and suppresses basal acid secretion, succeeding in maintain gastric mucosal integrity [21]-[23]. Regarding to the microcirculation, the action of PGI2 through the IP receptors lead the increase of blood flow and in consequence to the ischemia prevention [24], [25]. Thus, almost all of the mucosal defense mechanisms are stimulated or facilitated by PGs, and the continuous generation of PGs is required for maintain of gastric mucosal integrity [2], [17], [25]. Although COX-2 gastric levels is detected only in the presence of inflammatory stimuli [18]. Studies in recent years have demonstrated that the inhibition of both COX-1 and COX-2 is required for NSAID-induced gastric injury [3], [26] and that COX-2 can contribute to gastric mucosal defense [3], [18], concluding that the effect of a specific eicosanoid depends on the type of receptor and the coupling signal pathway [18].
Gastroprotection is a dynamic process, which involves all the components of mucosal defense that maintain the integrity of gastric mucosa against noxious factors [1]. While, gastric mucosal injury (or damage) occurs when the causative agents such as gastric acid and NSAIDs overwhelm the mucosal defense [17]. NSAIDs are the most important noxious factors that can alters the mucosal defense [27], [28], they are widely used by their analgesic, antipyretic and anti-inflammatory actions [27]; and can be classified according to their selectivity for the cyclooxygenase isozymes, a classification that is useful for the study of gastric damage [29]. The mechanism of action of NSAIDs are mainly due to the inhibition of the activity of one or both COX isoforms enzymes (COX-1 and COX-2), according to their selectivity, therefore reduces prostaglandin synthesis and two key elements of inflammation: vasodilation and pain [20], [30]. NSAID are often preferred over opioid analgesics due to their low abuse potential, robust efficacy, and long history of clinical use [31]. Current guidelines for chronic pain recommended the use of oral NSAIDs for first-line pain management [31], [32].
It has been reported that two major components to the ulcerogenic effects of NSAID in gastric tissue are the topical irritant effects on the epithelium (local actions) and the suppression of prostaglandin synthesis (systemic actions) [33]. NSAIDs can disrupt the layer of surface-active phospholipids on the mucosal surface thereby decreasing the effectiveness of the mucosal pH gradient to protect the epithelium [1], [9]. Also can produce a “ion trapping” phenomenon, where the un-ionized forms of these drugs can enter the epithelial cells, but, once in the neutral intracellular environment, they are converted to an ionized stated and cannot diffuse out and in consequence produces cellular osmotic imbalance and the damage to the epithelium [34], [35]. In addition to the “ion trapping”, the mitochondria are the primary target of NSAIDs generating the uncoupling of the oxidative phosphorylation through the release of cytochrome c, Ca2+ signaling, the decreased the intracellular ATP concentration and the subsequent production of Reactive Oxygen Species (ROS) which results in increased permeability and subsequent mucosal damage [34], [36]- [38].
The most important of the systemic effects of NSAIDs, is their ability to suppress prostaglandin synthesis in gastric tissue [34], leading to marked alterations in the microcirculation of the stomach, besides the negative impact upon the secretion of mucus and bicarbonate that increases the susceptibility to aggressive agents, endotoxins and bacterial invasion [17], [34]. Since inhibition of prostaglandin synthesis, alone, may not result in the formation of gastric injury [2]. Several recent studies suggest the existence of non-prostaglandin-mediated pathway of mucosal damage by indomethacin [14], [39]; which includes the inflammatory response triggered from osmotic lysis of the gastric epithelium [1], [39]. The endogenous noxious agents from cells with irreparable injury are sensed by mast cells, with the resulting release of pro-inflammatory cytokines (such as TNF-α and IL-1β) which contributes to the early systemic responses to inflammation [1, 18]. These inflammatory soluble mediators triggers a massive neutrophil recruitment to the site of injury that is essential in the development of macroscopic lesion [16], [40]. In this process the expression of high affinity adhesion molecules such as ICAM-1, VCAM-1 on endothelium and integrin such as CD11/CD18 on neutrophils are necessary for the adhesion of leukocytes to the vascular endothelium [5], [14], [16], [38]. Once in the site of injury, neutrophils generate Leukotriene B4 (LTB4) a very potent chemotactic that promotes leukocyte recruitment from the vasculature by the expression of adhesion molecules [5], [9], [14]. The excessive neutrophil adhesion to the vascular wall produce an obstruction of capillaries, thereby reducing gastric mucosal blood flow and the release of proteases and ROS formation that increases epithelial necrosis [16], [41].
The commercially available NSAIDs are associated with potential cardiovascular and gastrointestinal side effects [4], [32], [42]. The current strategies that attend to improve gastric tolerability of NSAIDs are shown in Table 1, these strategies are focused in at least three strategies: first the use of selective COX-2 inhibitors, second the coprescription of acid suppressive agents and finally reintroduce the ‘missing’ mucosal prostaglandins by using the prostaglandin analogue misoprostol [32], [43].
Regarding to the first aspect, the synthesis of selective COX-2 inhibitors (Coxibs) to reduce NSAIDs gastric adverse effects succeeded in the reduction of NSAID-gastric damage [44]. However, specialized studies concluded that by inhibiting the synthesis of PGI2 ( anti-thrombotic action) by COX-2 but not the inhibition of COX-1 responsible for the TXA2 synthesis (pro-thrombotic action) in platelets, the natural balance between both effects is disturbed by Coxibs, leading to an increase in thrombotic cardiovascular events in Coxib chronic consumption [32], [44], [45]. As a result, it has been recommended the withdrawal of rofecoxib and the discretion in the use of other NSAIDs alone or in combination with antiplatelet [45], [46]. Currently, the celecoxib is the only Coxib that showed not significantly interference with platelet function, nonetheless its use is subject to certain criteria [47]. Consequently, the use of Coxibs was not an optimal strategy for reducing gastric damage generated by NSAIDs [44]. On the other hand, the use of acid suppressive agents for the treatment of NSAID-gastric related complications covers two great groups: the H2-receptor antagonists and the proton pump inhibitors (PPIs) [32]. The H2-receptor antagonist was the first drug effectively to heal reflux esophagitis as well as peptic ulcers, by blocking the action of histamine at the H2-receptors on the parietal cells and decreasing the acid secretion [32], [42], [48], [49]. However, they are not effective and it might also increase the risk of duodenal ulcer bleeding, because of the masking of warning symptoms (headache, stomachache or sickness), so it has begun to decrease their prescription [32], [49]. Acid suppression by the proton pump inhibitors (PPIs) is more effective compared with the H2-receptor antagonist [50]. The mechanism underlying it is to form a covalent bond with the alpha subunit of the H+/K+- ATPase, inhibiting its action in an irreversible manner [10], [43]. Although the suppression of acid secretion with PPIs was effective at preventing gastric damage, it results in a dramatic exacerbation of NSAID-induced small intestinal ulceration and bleeding [43], [51]. The adverse effects of the PPIs (such omeprazole) includes alterations in the normal intestinal microflora (dysbiosis) that increases the risk of ulcers perforations, anemia and malabsorption [10], [52], [53]. The last aspect in the treatment of NSAID-gastric damage is focus in the replacement of local prostaglandins with prostaglandin analogues such as misoprostol [32], [49]. Despite the fact that misoprostol has shown a reduction in NSAID-induced gastric damage, the side effects such as chronic diarrhea, abdominal pain and the possibility of being an abortive has limited their use to specific situations [43], [49]. The failure of selective COX-2 inhibitors to provide a solution to the problem of NSAID-gastric injury, has improve the interest to develop novel NSAID formulations without untoward effects on the gastrointestinal tract [30]. For example, it has been synthesized novel formulations like gaseous mediator-releasing NSAIDs such as H2S-NSAIDs and NO-NSAIDs that have shown to reduce inflammatory process and increase the resistance of the gastric mucosa to injury [54]-[56]. So far clinical studies of these drugs are underway, therefore their side effects have not been fully identified [56], [57].
In recent decades, the use of medicinal plant products as possible therapeutic alternatives for gastroprotection against NSAID- induced gastropathy has raised the number of scientific reports [58]. Some of those natural compounds include pyridine alkaloid (Trigonelline), commonly found in Trigonella foenum-graecum L. seeds [58]; Cyperus rotundus L. [59], momordica saponins found in the Cochinchina momordica seed extract [60]; flavonoids such as rutin, quercetin and quercitrin reported as major compounds in Buddleja scordioides Kunth [61]. Also, curcumin, the principal ingredient of curcuma longa [62]; anthocyanins, glucoside, ellagic acid, isoquercetin, kaempferol, and myricetin includes in the leafs of Syzygium cumini (L.) [63] and finally Morin, a flavonoid found in almond and other family members of Moraceae [64]. Where reports on these compounds indicated that their gastroprotective effect against NSAID- induced gastric damage in animal models, it is attributed to its antioxidant and anti-inflammatory properties. For example, some anti-inflammatory mechanism includes the decrease of neutrophil infiltration, through the modulation of LTB4 levels [58], [65] or the upregulation of NF-kB activity [65]. While some compounds increased the activity of superoxide dismutase, cellular glutathione and glutathione peroxidase [59], which means an antioxidant defense mechanism. However, the different chemical nature of the compounds makes difficult to reach a consensus on what could be the key mechanism in their gastroprotective action.
The natural compounds for the development of new therapeutic strategies in the pharmaceutical industry, has brought focus to the role of omega-3 fatty acids in part due to the epidemiological studies that indicates a decrease on cardiovascular risk in populations with long-term consumption of fish-oil [66], [67]. Omega-3 (ω−3 or n−3) polyunsaturated fatty acids (PUFAs) found in oily fish and fish oil supplements [68], are a family of polyunsaturated fatty acids (18–22 carbon atoms in chain length) with the first of many double bonds beginning with the third carbon atom (when counting from the methyl end of the fatty acid molecule) [66], [68]. Omega-3 are important for cell membrane structure, vitamins absorption, metabolism and regulation of multiple cellular processes [69], [70]. Research studies with animal models, cell cultures and even clinical and epidemiological studies have reported the beneficial effects of a diet rich in omega-3 in conditions such as hypertension [71], hyperlipidemia [72], coronary heart disease [73], [74], chronic obstructive pulmonary disease [75], Crohn’s disease [76], type 2 diabetes [77], [78], renal disease [79], attention deficit, depression [80] and rheumatoid arthritis mainly [81]. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are n-3 fatty acids found in significant quantities in fish [82], and most of fish oil therapeutic properties are attributed to them [70], [83].
DHA cannot be synthetized in humans [66], [84]. It has been reported that traditional Western diet does not provide the right amount of omega-3 or direct sources of DHA [70]. Therefore, intakes of preformed DHA from fish oil supplements (enriched with EPA and DHA), may be important for maintaining optimal tissue function [85], [86]. So far, the recommended daily doses of DHA in an adult, is at least 200 mg alone and 200 to 500 mg in combination with other omega-3 per day (equivalent to 3-5 servings of fish per week) [87]-[89]. The clinical and experimental studies directed towards the DHA, increased by the current interest in therapeutically benefits of omega-3 intake. Until now, it has been extensively reported the essential role of DHA in synaptogenesis and neurogenesis [90], [91], improvement of higher mental functions and neuroprotection [92], [93], cardioprotection [72], [94] and some metabolic conditions such as type 2 diabetes [95] or dyslipidemia [72]. In addition, DHA has demonstrated to induce an antinociceptive effect during several acute experimental models [96]-[98]. Also it has been reported that DHA has an effect on the resolution of the inflammatory response [84], [99] and offers antioxidant activities in some inflammatory models [84], [100]. The properties of DHA are mainly attributes to its ability to alter membrane fluidity, lipid rafts and signaling pathways [68], [70], [101], [102]. However, most of its mechanism remains unknown.
Concerning to its role in gastric protection, previous studies have been reported the gastroprotective effects of fish oil in several models of gastric injury [103]-[107]; and few studies on the protective effects of fish oil in NSADs- gastropathy has been reported [103], [106]-[108]. The mechanism suggested in the gastroprotective effect of fish oil in some of the gastric injury models includes the decrease in gastric pepsin and acid secretion and an increase in antioxidant enzymes [103]. However, there was not been able to determine which of the omega-3 fatty acid was responsible for their gastroprotective effect. Recently, our group of work has demonstrated that docosahexaenoic acid (DHA) exhibits gastroprotective effect against indomethacin induced gastric injury, and even more it was demonstrated that DHA was not able to reverse the indomethacin-induced prostaglandin inhibition [109]. More importantly, this report shows that gastroprotective effect is mediated by a decrease in gastric LTB4 levels [109] a central molecule for the leukocyte recruitment in the NSAID- induced gastric injury. These studies, support others reports where it has been shown that omega-3 are involved in the resolution of the inflammatory process by decreasing pro-inflammatory cytokines and LTB4 in another animal models such as dextran sulfate sodium induced colitis [110], [111]. Regarding to the role of DHA on inflammation, it has been reported that n-3 PUFAs (EPA and DHA) are alternative substrates for the eicosanoid production that is catalyzed by cytochrome P450 (CYP) enzymes, and these mediators such as LTB5 is weaker chemotactic agent compared to LTB4 In consequence, the inflammation response is weaker [103], [112], this could be a possible mechanism for the DHA gastroprotective effect.
Furthermore, another possible mechanism for the DHA gastroprotective effect could be the presence of omega 3 fatty acid- derivated compounds that recently has been reported by lipidomics analysis of inflammatory exudates, thermed SPMs (specialized proresolving mediators) [82], [113]. These novel family of mediator includes lipoxins, resolvins, protectins and maresins [113] and are generated often via transcellular biosynthesis routes during leukocyte interactions with mucosal cells or vascular endothelium [114]. It has been reported that resolvins derived from DHA (RvD) such as RvD1 stimulates key cellular events in the resolution of inflammation, including cessation of polymorphonuclear (PMN) infiltration [115], [116], enhance of macrophage uptake of apoptotic cells [117] and counter-regulate TNF-α and other cytokines in experimental animal models [118], [119]. Additionally, this bioactions have been reported in human PMN and macrophages in vitro after the administration of RvD1 at nano doses [120], [121]. Thus, one possibility is that DHA could modulate prostaglandin-independent mechanism of NSAID-induce gastric damage. However, more studies need to be performed in order to determine whether the SPMs or their implanted pathways mediate the DHA gastroprotective effects.
In summary, gastric mucosal defense and NSAID gastrointestinal injury are crucial for the development of potential future therapies to reduce NSAID gastrointestinal injury. The future approaches of gastroprotective therapies against NSAIDs should be applicable to the esophagus, intestine, and extra intestinal tissues in order to avoid potential secondary effects; due to the fact that the current therapies such as PPIs, H2-receptor antagonist and even Coxibs are focused only in the prostaglandin inhibition, but not in the prostaglandin independent mechanism of NSAID-induced gastric injury. Though, there are some promising developments in this regard for example NO-NSAIDs, H2S-NSAIDs, and the omega-3 fatty acid (DHA) supplementation. The link between omega-3 fatty acids and their roles as potential regulators on physiologic pathways in resolution and unresolved inflammation could provide a new approach for the prevention of NSAID gastropathy. Further studies need to be performed in order to evaluate the mechanism involved in the DHA gastroprotective effect against NSAID-induce gastric injury.
The authors acknowledge the support provided by the National Council for Science and Technology (Project CONACyT 178027) and SIP-IPN 20160493 Elizabeth Arlen Pineda-Peña is a CONACyT fellow (Grant number 252829).
Table 1. Current strategies against NSAID-gastropathys
Strategies |
Mechanism of action |
Side effects |
References |
Selective COX-2 inhibitors/Coxibs |
Selective COX-2 inhibition. |
Significant increase in the rate of vascular events (myocardial infarction or heart stroke). Only Celecoxib is currently approve for certain conditions. |
|
Proton-pump inhibitors |
Inhibition of acid gastric secretion by the irreversible covalent bond with the alpha subunit of the H+/K+- ATPase. |
Alterations in the normal intestinal microflora (dysbiosis) that increases the risk of ulcers perforations, anemia and malabsorption. |
|
H2-receptor antagonists |
Inhibition of acid gastric secretion by blocking the action of histamine at the histamine H2-receptors on the parietal cells. |
Increasing the risk of duodenal ulcer bleeding, by masking of warning symptoms (headache, stomachache or sickness). |
|
Prostaglandin analogue (misoprostol) |
Replacing local prostaglandins, which formation is inhibited by systemic NSAIDs. |
Side effects such as chronic diarrhea, abdominal pain and the possibility of being an abortive has limited their use to specific situations. |
[1] Wallace JL, Granger DN. The cellular and molecular basis of gastric mucosal defense. FASEB. J. 1996; 10:731-740
[2]Laine L, Takeuchi K, Tarnawski A. Gastric mucosal defense and cytoprotection: bench to bedside. Gastroenterology. 2008; 135:41-60
[3]Wallace JL. COX-2: a pivotal enzyme in mucosal protection and resolution of inflammation. Sci. W. J. 2006; 6:577-588
[4]Wallace JL, McKnight W, Reuter BK, Vergnolle N. NSAID-induced gastric damage in rats: requirement for inhibition of both cyclooxygenase 1 and 2 Gastroenterology. 2000; 119:706-714
[5]Wallace JL. Prostaglandins, NSAIDs, and gastric mucosal protection: why doesn't the stomach digest itself?. Physiol. Rev. 2008; 88:1547-1565
[6]Hunt RH, Camilleri M, Crowe SE, El-Omar EM, Fox JG, Kuipers EJ, et al. The stomach in health and disease. Gut. 2015; 64:1650-1668
[7]Viggiano D, Ianiro G, Vanella G, Bibbo S, Bruno G, Simeone G, et al. Gut barrier in health and disease: focus on childhood. Eur. Rev. Med. Pharmacol. Sci. 2015; 19:1077-1085
[8]Kopic S, Murek M, Geibel JP. Revisiting the parietal cell. Am. J. Physiol. Cell. Physiol. 2010; 298:C1-C10
[9]Wallace JL, Granger DN. Pathogenesis of NSAID gastropathy: are neutrophils the culprits?. Trends. Pharmacol. Sci. 1992; 13:129-131
[10]Thomson AB, Sauve MD, Kassam N, Kamitakahara H. Safety of the long-term use of proton pump inhibitors. World. J. Gastroenterol. 2010; 16:2323-2330
[11]Allen A, Flemstrom G. Gastroduodenal mucus bicarbonate barrier: protection against acid and pepsin. Am. J. Physiol. Cell. Physiol. 2005; 288:C1-19
[12]Iwata F, Joh T, Ueda F, Yokoyama Y, Itoh M. Role of gap junctions in inhibiting ischemia-reperfusion injury of rat gastric mucosa. Am. J. Physiol. 1998; 275:G883-888
[13]Van Den Abeele J, Rubbens J, Brouwers J, Augustijns P. The dynamic gastric environment and its impact on drug and formulation behaviour. Eur. J. Pharm. Sci. 2016; 96:207-231
[14]Lanas A. Role of nitric oxide in the gastrointestinal tract. Arthritis. Res. Ther. 2008; 10 Suppl 2:S4
[15]Chen K, Pittman RN, Popel AS. Nitric oxide in the vasculature: where does it come from and where does it go? A quantitative perspective. Antioxid. Redox. Signal. 2008; 10:1185-1198
[16]Cruvinel Wde M, Mesquita DJr, Araujo JA, Catelan TT, de Souza AW, da Silva NP, et al. Immune system - part I. Fundamentals of innate immunity with emphasis on molecular and cellular mechanisms of inflammatory response. Rev. Bras. Reumatol. 2010; 50:434-461
[17]Park KA, Chang KS. The effects of indomethacin of the rat gastric mucosa. Yonsei. Med. J. 1981; 22:101-107
[18]Atay S, Tarnawski AS, Dubois A. Eicosanoids and the stomach. Prostaglandins. Other. Lipid. Mediat. 2000; 61:105-124
[19] Johansson C, Bergstrom S. Prostaglandin and protection of the gastroduodenal mucosa. Scand. J. Gastroenterol. Suppl. 1982; 77:21-46
[20] RaoP, Knaus EE. Evolution of nonsteroidal anti-inflammatory drugs (NSAIDs): cyclooxygenase (COX) inhibition and beyond. J. Pharm. Pharm. Sci. 2008; 11:81s-110s.
[21] Kato S, Aihara E, Yoshii K, Takeuchi K. Dual action of prostaglandin E2 on gastric acid secretion through different EP-receptor subtypes in the rat. Am. J. Physiol. Gastrointest. Liver. Physiol. 2005; 289:G64-69
[22] Takeuchi K, Aihara E, Sasaki Y, Nomura Y, Ise F. Involvement of cyclooxygenase-1, prostaglandin E2 and EP1 receptors in acid-induced HC03 - secretion in stomach. J. Physiol. Pharmacol. 2006; 57:661-676
[23] Takeuchi K, Kato S, Amagase K. Prostaglandin EP receptors involved in modulating gastrointestinal mucosal integrity. J. Pharmacol. Sci. 2010; 114:248-261
[24] Brzozowski T, Konturek PC, Pajdo R, Ptak-Belowska A, Kwiecien S, Pawlik M, et al. Physiological mediators in nonsteroidal anti-inflammatory drugs (NSAIDs)-induced impairment of gastric mucosal defense and adaptation. Focus on nitric oxide and lipoxins. J. Physiol. Pharmacol. 2008; 59 Suppl 2:89-102
[25] Brzozowski T, Konturek PC, Konturek SJ, Brzozowska I, Pawlik T. Role of prostaglandins in gastroprotection and gastric adaptation. J. Physiol. Pharmacol. 2005; 56 Suppl 5:33-55
[26] Wallace JL, Vong L, Dharmani P, Srivastava V, Chadee K. Muc-2-deficient mice display a sex-specific, COX-2-related impairment of gastric mucosal repair. Am. J. Pathol. 2011; 178:1126-1133
[27] Wallace JL. Mechanisms, prevention and clinical implications of nonsteroidal anti-inflammatory drug-enteropathy. World. J. Gastroenterol. 2013; 19:1861-1876
[28] Cryer B. NSAID-associated deaths: the rise and fall of NSAID-associated GI mortality. Am. J. Gastroenterol. 2005; 100:1694-1695
[29] Brunton B CB, Knollman B. Autacoides derivados de los lípidos: eicosanoides y factor activador de plaquetas. In Goodman & Gilman Las bases farmacológicas de la terapéutica. 12ª edition. Edited by B. B. México: McGraw-Hill; 2012; 937-957
[30] Rich M, Scheiman JM. Nonsteroidal anti-inflammatory drug gastropathy at the new millennium: mechanisms and prevention. Semin. Arthritis. Rheum. 2000; 30:167-179
[31] Brune K, Patrignani P. New insights into the use of currently available non-steroidal anti-inflammatory drugs. J. Pain. Res. 2015; 8:105-118
[32] Becker JC, Domschke W, Pohle T. Current approaches to prevent NSAID-induced gastropathy--COX selectivity and beyond. Br. J. Clin. Pharmacol. 2004; 58:587-600
[33] Wallace JL, Keenan CM, Cucala M, Mugridge KG, Parente L. Mechanisms underlying the protective effects of interleukin 1 in experimental nonsteroidal anti-inflammatory drug gastropathy. Gastroenterology. 1992; 102:1176-1185
[34] Bastaki SM, Wallace JL. Pathogenesis of nonsteroidal anti-inflammatory drug gastropathy: clues to preventative therapy. Can. J. Gastroenterol. 1999; 13:123-127
[35] Boegh M, Nielsen HM. Mucus as a barrier to drug delivery - understanding and mimicking the barrier properties. Basic. Clin. Pharmacol. Toxicol. 2015; 116:179-186
[36] Leite AZ, Sipahi AM, Damiao AO, Coelho AM, Garcez AT, Machado MC, et al. Protective effect of metronidazole on uncoupling mitochondrial oxidative phosphorylation induced by NSAID: a new mechanism. Gut. 2001; 48:163-167
[37] Maity P, Bindu S, Dey S, Goyal M, Alam A, Pal C, et al. Indomethacin, a non-steroidal anti-inflammatory drug, develops gastropathy by inducing reactive oxygen species-mediated mitochondrial pathology and associated apoptosis in gastric mucosa: a novel role of mitochondrial aconitase oxidation. J. Biol. Chem. 2009; 284:3058-3068
[38] Matsui H, Shimokawa O, Kaneko T, Nagano Y, Rai K, Hyodo I. The pathophysiology of non-steroidal anti-inflammatory drug (NSAID)-induced mucosal injuries in stomach and small intestine. J. Clin. Biochem. Nutr. 2011; 48:107-111
[39] Bindu S, Mazumder S, Dey S, Pal C, Goyal M, Alam A, et al. Nonsteroidal anti-inflammatory drug induces proinflammatory damage in gastric mucosa through NF-kappaB activation and neutrophil infiltration: anti-inflammatory role of heme oxygenase-1 against nonsteroidal anti-inflammatory drug. Free. Radic. Biol. Med. 2013; 65:456-467
[40] Qureshi MH, Cook-Mills J, Doherty DE, Garvy BA. TNF-alpha-dependent ICAM-1- and VCAM-1-mediated inflammatory responses are delayed in neonatal mice infected with Pneumocystis carinii. J. Immunol. 2003; 171:4700-4707
[41] Uchida M, Matsueda K, Shoda R, Muraoka A, Yamato S. Nitric oxide donating compounds inhibit HCl-induced gastric mucosal lesions mainly via prostaglandin. Jpn. J. Pharmacol. 2001; 85:133-138
[42] Syer SD, Blackler RW, Martin R, de Palma G, Rossi L, Verdu E, et al. NSAID enteropathy and bacteria: a complicated relationship. J. Gastroenterol. 2015; 50:387-393
[43] Cavallini ME, Andreollo NA, Metze K, Araujo MR. Omeprazole and misoprostol for preventing gastric mucosa effects caused by indomethacin and celecoxib in rats. Acta. Cir. Bras. 2006; 21:168-176
[44] Suleyman H, Demircan B, Karagoz Y. Anti-inflammatory and side effects of cyclooxygenase inhibitors. Pharmacol. Rep. 2007; 59:247-258
[45] Watson DJ, Harper SE, Zhao PL, Quan H, Bolognese JA, Simon TJ. Gastrointestinal tolerability of the selective cyclooxygenase-2 (COX-2) inhibitor rofecoxib compared with nonselective COX-1 and COX-2 inhibitors in osteoarthritis. Arch. Intern. Med. 2000; 160:2998-3003
[46] Fosbol EL, Folke F, Jacobsen S, Rasmussen JN, Sorensen R, Schramm TK, et al. Cause-specific cardiovascular risk associated with nonsteroidal antiinflammatory drugs among healthy individuals. Circ. Cardiovasc. Qual. Outcomes. 2010; 3:395-405
[47] Whelton A, Lefkowith JL, West CR, Verburg KM. Cardiorenal effects of celecoxib as compared with the nonsteroidal anti-inflammatory drugs diclofenac and ibuprofen. Kidney. Int. 2006; 70:1495-1502
[48] Abramson SB, Weaver AL. Current state of therapy for pain and inflammation. Arthritis. Res. Ther. 2005; 7 Suppl 4:S1-6
[49] Brooks J, Warburton R, Beales IL. Prevention of upper gastrointestinal haemorrhage: current controversies and clinical guidance. Ther. Adv. Chronic. Dis. 2013; 4:206-222
[50] Latimer N, Lord J, Grant RL, O'Mahony R, Dickson J, Conaghan PG. Cost effectiveness of COX 2 selective inhibitors and traditional NSAIDs alone or in combination with a proton pump inhibitor for people with osteoarthritis. BMJ. 2009; 339:b2538
[51] Biswas K, Bandyopadhyay U, Chattopadhyay I, Varadaraj A, Ali E, Banerjee RK. A novel antioxidant and antiapoptotic role of omeprazole to block gastric ulcer through scavenging of hydroxyl radical. J. Biol. Chem. 2003; 278:10993-11001
[52] Imaoka H, Ishihara S, Kazumori H, Kadowaki Y, Aziz MM, Rahman FB, et al. Exacerbation of indomethacin-induced small intestinal injuries in Reg I-knockout mice. Am. J. Physiol. Gastrointest. Liver. Physiol. 2010; 299:G311-319
[53] Wallace JL, Syer S, Denou E, de Palma G, Vong L, McKnight W, et al. Proton pump inhibitors exacerbate NSAID-induced small intestinal injury by inducing dysbiosis. Gastroenterology. 2011; 141:1314-1322.
54] Ghosh S, DeCoffe D, Brown K, Rajendiran E, Estaki M, Dai C, et al. Fish oil attenuates omega-6 polyunsaturated fatty acid-induced dysbiosis and infectious colitis but impairs LPS dephosphorylation activity causing sepsis. PLoS. One. 2013; 8:e55468
[55] Gemici B, Elsheikh W, Feitosa KB, Costa SK, Muscara MN, Wallace JL. H2S-releasing drugs: anti-inflammatory, cytoprotective and chemopreventative potential. Nitric. Oxide. 2015; 46:25-31
[56] Wallace JL, Dicay M, McKnight W, Martin GR. Hydrogen sulfide enhances ulcer healing in rats. FASEB. J. 2007; 21:4070-4076
[57] Fiorucci S, Santucci L, Distrutti E. NSAIDs, coxibs, CINOD and H2S-releasing NSAIDs: what lies beyond the horizon. Dig. Liver. Dis. 2007; 39:1043-1051
[58] Antonisamy P, Arasu MV, Dhanasekaran M, Choi KC, Aravinthan A, Kim NS, et al. Protective effects of trigonelline against indomethacin-induced gastric ulcer in rats and potential underlying mechanisms. Food. Funct. 2016; 7:398-408
[59] Thomas D, Govindhan S, Baiju EC, Padmavathi G, Kunnumakkara AB, Padikkala J. Cyperus rotundus L. prevents non-steroidal anti-inflammatory drug-induced gastric mucosal damage by inhibiting oxidative stress. J. Basic. Clin. Physiol. Pharmacol. 2015; 26:485-490
[60] Lim JH, Kim JH, Kim N, Lee BH, Seo PJ, Kang JM, et al: Gastroprotective effect of Cochinchina momordica seed extract in nonsteroidal anti-inflammatory drug-induced acute gastric damage in a rat model. Gut. Liver. 2014; 8:49-57
[61] Diaz-Rivas JO, Herrera-Carrera E, Gallegos-Infante JA, Rocha-Guzman NE, Gonzalez-Laredo RF, Moreno-Jimenez MR, et al. Gastroprotective potential of Buddleja scordioides Kunth Scrophulariaceae infusions; effects into the modulation of antioxidant enzymes and inflammation markers in an in vivo model. J. Ethnopharmacol. 2015; 169:280-286
[62] Thong-Ngam D, Choochuai S, Patumraj S, Chayanupatkul M, Klaikeaw N. Curcumin prevents indomethacin-induced gastropathy in rats. World. J. Gastroenterol. 2012; 18:1479-1484
[63] Chanudom L, Tangpong J. Anti-Inflammation Property of Syzygium cumini (L.) Skeels on Indomethacin-Induced Acute Gastric Ulceration. Gastroenterol. Res. Pract. 2015; 2015:343642
[64] Sinha K, Sadhukhan P, Saha S, Pal PB, Sil PC. Morin protects gastric mucosa from nonsteroidal anti-inflammatory drug, indomethacin induced inflammatory damage and apoptosis by modulating NF-kappaB pathway. Biochim. Biophys. Acta. 2015; 1850:769-783
[65] Carrasco-Pozo C, Castillo RL, Beltran C, Miranda A, Fuentes J, Gotteland M. Molecular mechanisms of gastrointestinal protection by quercetin against indomethacin-induced damage: role of NF-kappaB and Nrf2 J. Nutr. Biochem. 2016; 27:289-298
[66] Holub BJ. Clinical nutrition: 4 Omega-3 fatty acids in cardiovascular care. CMAJ. 2002; 166:608-615
[67] Hokari R, Matsunaga H, Miura S. Effect of dietary fat on intestinal inflammatory diseases. J. Gastroenterol. Hepatol. 2013; 28 Suppl 4:33-36
[68] Calder PC. Omega-3 polyunsaturated fatty acids and inflammatory processes: nutrition or pharmacology?. Br. J. Clin. Pharmacol. 2013; 75:645-662
[69] Connor WE. Importance of n-3 fatty acids in health and disease. Am. J. Clin. Nutr. 2000; 71:171S-175S.
[70] Hashimoto M, Hossain S, Al Mamun A, Matsuzaki K, Arai H. Docosahexaenoic acid: one molecule diverse functions. Crit. Rev. Biotechnol. 2016; 17:1-19
[71] Morin C, Rousseau E, Blier PU, Fortin S. Effect of docosahexaenoic acid monoacylglyceride on systemic hypertension and cardiovascular dysfunction. Am. J. Physiol. Heart. Circ. Physiol. 2015; 309:H93-H102
[72] Leslie MA, Cohen DJ, Liddle DM, Robinson LE, Ma DW. A review of the effect of omega-3 polyunsaturated fatty acids on blood triacylglycerol levels in normolipidemic and borderline hyperlipidemic individuals. Lipids. Health. Dis. 2015;14:53
[73] Ahn J, Park SK, Park TS, Kim JH, Yun E, Kim SP, et al. Effect of n-3 Polyunsaturated Fatty Acids on Regression of Coronary Atherosclerosis in Statin Treated Patients Undergoing Percutaneous Coronary Intervention. Korean. Circ. J. 2016; 46:481-489
[74] de Lorgeril M, Salen P, Martin JL, Monjaud I, Delaye J, Mamelle N. Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study. Circulation. 1999; 99:779-785
[75] Fulton AS, Hill AM, Williams MT, Howe PR, Coates AM. Paucity of evidence for a relationship between long-chain omega-3 fatty acid intake and chronic obstructive pulmonary disease: a systematic review. Nutr. Rev. 2015; 73:612-623
[76] Yates CM, Calder PC, Ed Rainger G. Pharmacology and therapeutics of omega-3 polyunsaturated fatty acids in chronic inflammatory disease. Pharmacol. Ther. 2014; 141:272-282
[77] Connor WE, Prince MJ, Ullmann D, Riddle M, Hatcher L, Smith FE, et al. The hypotriglyceridemic effect of fish oil in adult-onset diabetes without adverse glucose control. Ann. N. Y. Acad. Sci. 1993; 683:337-340
[78] Han E, Yun Y, Kim G, Lee YH, Wang HJ, Lee BW, et al. Effects of Omega-3 Fatty Acid Supplementation on Diabetic Nephropathy Progression in Patients with Diabetes and Hypertriglyceridemia. PLoS. One. 2016; 11:e0154683
[79] De Caterina R, Caprioli R, Giannessi D, Sicari R, Galli C, Lazzerini G, et al. n-3 fatty acids reduce proteinuria in patients with chronic glomerular disease. Kidney. Int. 1993; 44:843-850
[80] Husted KS, Bouzinova EV. The importance of n-6/n-3 fatty acids ratio in the major depressive disorder. Medicina. 2016; 52:139-147
[81] Simopoulos AP. Omega-3 fatty acids in inflammation and autoimmune diseases. J. Am. Coll. Nutr. 2002; 21:495-505
[82] Serhan CN. Novel chemical mediators in the resolution of inflammation: resolvins and protectins. Anesthesiol. Clin. 2006; 24:341-364
[83] Calder PC. Polyunsaturated fatty acids and inflammatory processes: New twists in an old tale. Biochimie. 2009; 91:791-795
[84] Tvrzicka E, Kremmyda LS, Stankova B, Zak A. Fatty acids as biocompounds: their role in human metabolism, health and disease--a review. Part 1: classification, dietary sources and biological functions. Biomed. Pap. Med. Fac. Univ. Palacky. Olomouc. Czech. Repub. 2011; 155:117-130
[85] Burdge GC, Calder PC. Conversion of alpha-linolenic acid to longer-chain polyunsaturated fatty acids in human adults. Reprod. Nutr. Dev. 2005; 45:581-597
[86] Burdge GC, Jones AE, Wootton SA. Eicosapentaenoic and docosapentaenoic acids are the principal products of alpha-linolenic acid metabolism in young men. Br. J. Nutr. 2002; 88:355-363
[87] Bradbury J. Docosahexaenoic acid (DHA): an ancient nutrient for the modern human brain. Nutrients. 2011; 3:529-554
[88] Kris-Etherton PM, Grieger JA, Etherton TD. Dietary reference intakes for DHA and EPA. Prostaglandins. Leukot. Essent. Fatty. Acids. 2009; 81:99-104
[89] Global Recommendations for EPA and DHA Intake http://www.goedomega3.com/index.php/files/download/304
[90] Cao D, Kevala K, Kim J, Moon HS, Jun SB, Lovinger D, et al. Docosahexaenoic acid promotes hippocampal neuronal development and synaptic function. J. Neurochem. 2009; 111:510-521
[91] Kim HY, Moon HS, Cao D, Lee J, Kevala K, Jun SB, Lovinger DM, Akbar M, Huang BX. N-Docosahexaenoylethanolamide promotes development of hippocampal neurons. Biochem. J. 2011; 435:327-336
[92] Bascoul-Colombo C, Guschina IA, Maskrey BH, Good M, O'Donnell VB, Harwood JL. Dietary DHA supplementation causes selective changes in phospholipids from different brain regions in both wild type mice and the Tg2576 mouse model of Alzheimer's disease. Biochim. Biophys. Acta. 2016; 1861:524-537
[93] Song C, Shieh CH, Wu YS, Kalueff A, Gaikwad S, Su KP. The role of omega-3 polyunsaturated fatty acids eicosapentaenoic and docosahexaenoic acids in the treatment of major depression and Alzheimer's disease: Acting separately or synergistically?. Prog. Lipid. Res. 2016; 62:41-54
[94] Liu L, Hu Q, Wu H, Xue Y, Cai L, Fang M, et al. Protective role of n6/n3 PUFA supplementation with varying DHA/EPA ratios against atherosclerosis in mice. J. Nutr. Biochem. 2016; 32:171-180
[95] Toupchian O, Sotoudeh G, Mansoori A, Nasli-Esfahani E, Djalali M, Keshavarz SA, et al. Effects of DHA-enriched fish oil on monocyte/macrophage activation marker sCD163, asymmetric dimethyl arginine, and insulin resistance in type 2 diabetic patients. J. Clin. Lipidol. 2016; 10:798-807
[96] Nakamoto K, Nishinaka T, Mankura M, Fujita-Hamabe W, Tokuyama S. Antinociceptive effects of docosahexaenoic acid against various pain stimuli in mice. Biol. Pharm. Bull. 2010; 33:1070-1072
[97] Morisseau C, Inceoglu B, Schmelzer K, Tsai HJ, Jinks SL, Hegedus CM, Hammock BD. Naturally occurring monoepoxides of eicosapentaenoic acid and docosahexaenoic acid are bioactive antihyperalgesic lipids. J. Lipid. Res. 2010; 51:3481-3490
[98] Nowak JZ. Oxidative stress, polyunsaturated fatty acids-derived oxidation products and bisretinoids as potential inducers of CNS diseases: focus on age-related macular degeneration. Pharmacol. Rep. 2013; 65:288-304
[99] Picq M, Chen P, Perez M, Michaud M, Vericel E, Guichardant M, et al. DHA metabolism: targeting the brain and lipoxygenation. Mol. Neurobiol. 2010; 42:48-51
[100] Hsu YM, Yin MC. EPA or DHA enhanced oxidative stress and aging protein expression in brain of d-galactose treated mice. Biomedicine. 2016; 6:17
[101] Brenner RR, Jose P. Action of Linolenic and Docosahexaenoic Acids Upon the Eicosatrienoic Acid Level in Rat Lipids. J. Nutr. 1965; 85:196-204
[102] Calder PC. Marine omega-3 fatty acids and inflammatory processes: Effects, mechanisms and clinical relevance. Biochim. Biophys. Acta. 2015; 1851:469-484
[103] Bhattacharya A, Ghosal S, Bhattacharya SK. Effect of fish oil on offensive and defensive factors in gastric ulceration in rats. Prostaglandins. Leukot. Essent. Fatty. Acids. 2006; 74:109-116
104] al-Harbi MM, Islam MW, al-Shabanah OA, al-Gharably NM. Effect of acute administration of fish oil (omega-3 marine triglyceride) on gastric ulceration and secretion induced by various ulcerogenic and necrotizing agents in rats. Food. Chem. Toxicol. 1995; 33:553-558
[105] Manjari V, Das UN. Effect of polyunsaturated fatty acids on dexamethasone-induced gastric mucosal damage. Prostaglandins. Leukot. Essent. Fatty. Acids. 2000; 62:85-96
[106] Faust T, Redfern JS, Lee E, Feldman M. Effects of fish oil on gastric mucosal 6-keto-PGF1 alpha synthesis and ethanol-induced injury. Am. J. Physiol. 1989; 257:G9-13
[107] Hunter B, McDonald GS, Gibney MJ. The effects of acute and chronic administration of n-6 and n-3 polyunsaturated fatty acids on ethanol-induced gastric haemorrhage in rats. Br. J. Nutr. 1992; 67:501-507
[108] Guzel C, Ulak G, Sermet A, Cicek R, Ulak M. Effect of fish oil on indometacin-induced gastric lesions in rats. Arzneimittelforschung. 1995; 45:1172-1173
[109] Pineda-Pena EA, Jimenez-Andrade JM, Castaneda-Hernandez G, Chavez-Pina AE. Docosahexaenoic acid, an omega-3 polyunsaturated acid protects against indomethacin-induced gastric injury. Eur. J. Pharmacol. 2012; 697:139-143
[110] Faust TW, Redfern JS, Podolsky I, Lee E, Grundy SM, Feldman M. Effects of aspirin on gastric mucosal prostaglandin E2 and F2 alpha content and on gastric mucosal injury in humans receiving fish oil or olive oil. Gastroenterology. 1990; 98:586-591
[111] Hudert CA, Weylandt KH, Lu Y, Wang J, Hong S, Dignass A, et al. Transgenic mice rich in endogenous omega-3 fatty acids are protected from colitis. Proc. Natl. Acad. Sci. USA. 2006; 103:11276-11281
[112] Arnold C, Konkel A, Fischer R, Schunck WH. Cytochrome P450-dependent metabolism of omega-6 and omega-3 long-chain polyunsaturated fatty acids. Pharmacol. Rep. 2010; 62:536-547
[113] Fredman G, Serhan CN. Specialized proresolving mediator targets for RvE1 and RvD1 in peripheral blood and mechanisms of resolution. Biochem. J. 2011; 437:185-197
[114] Serhan CN, Chiang N. Endogenous pro-resolving and anti-inflammatory lipid mediators: a new pharmacologic genus. Br. J. Pharmacol. 2008; 153 Suppl 1:S200-215
[115] Wang B, Gong X, Wan JY, Zhang L, Zhang Z, Li HZ, et al. Resolvin D1 protects mice from LPS-induced acute lung injury. Pulm. Pharmacol. Ther. 2011; 24:434-441
[116] Duffield JS, Hong S, Vaidya VS, Lu Y, Fredman G, Serhan CN, et al. Resolvin D series and protectin D1 mitigate acute kidney injury. J. Immunol. 2006; 177:5902-5911
[117] Luo B, Han F, Xu K, Wang J, Liu Z, Shen Z. Resolvin D1 Programs Inflammation Resolution by Increasing TGF-beta Expression Induced by Dying Cell Clearance in Experimental Autoimmune Neuritis. J. Neurosci. 2016; 36:9590-9603
[118] Liao Z, Dong J, Wu W, Yang T, Wang T, Guo L; Resolvin D1 attenuates inflammation in lipopolysaccharide-induced acute lung injury through a process involving the PPARgamma/NF-kappaB pathway. Respir. Res. 2012; 13:110
[119] Recchiuti A, Serhan CN. Pro-Resolving Lipid Mediators (SPMs) and Their Actions in Regulating miRNA in Novel Resolution Circuits in Inflammation. Front. Immunol. 2012; 3:298
[120] Norling LV, Dalli J, Flower RJ, Serhan CN, Perretti M: Resolvin D1 limits polymorphonuclear leukocyte recruitment to inflammatory loci: receptor-dependent actions. Arterioscler Thromb Vasc Biol 2012; 32:1970-1978
[121] Prieto P, Rosales-Mendoza CE, Terron V, Toledano V, Cuadrado A, Lopez-Collazo E, Bannenberg G, Martin-Sanz P, Fernandez-Velasco M, Bosca L: Activation of autophagy in macrophages by pro-resolving lipid mediators. Autophagy 2015; 11:1729-1744
[a]Laboratory of Pharmacology, Doctoral Program in Biotechnology of the National Polytechnic Institute (IPN), National School of Medicine and Homeopathy (ENMyH), National Polytechnic Institute (IPN), Mexico City, Mexico.
[b]Institutional Program in Molecular Biomedicine, National School of Medicine and Homeopathy (ENMyH), National Polytechnic Institute (IPN), Mexico City, Mexico.
[*]Corresponding author: Aracely Evangelina Chávez Piña, Laboratory of Pharmacology, National School of Medicine and Homeopathy (ENMyH), Guillermo Massieu Helguera, No. 239, Fracc. La Escalera, Ticomán, C.P. 07320, Mexico City, Mexico. Phone: (+52) (55) 5729 6000, ext. 55583; E-mail: achavezp@ipn.mx and arapina@yahoo.com