Inflammation is part of the body’s immune response. It happened when something harmful or irritating affects a part of the body and there is a biological response to try to remove it. The signs and symptoms of inflammation, specifically acute inflammation, revealed that the body is trying to heal itself. Inflammation does not mean infection, even when an infection causes inflammation. Infection is caused by a bacterium, virus or fungus, while inflammation is the body’s response to it including the local reactions and the destruction changes; the destruction was affected by brown seaweed extract and the responses that lead to repair and healing [1] . Thus, inflammation is a fundamental pathologic process consisting of a dynamic complex of histological apparent, infiltration, cellular infiltration and mediator release occurred in affected blood vessels and adjacent tissues, also, in abnormal stimulation caused by physical, chemical, or biologic agent [2] .

Ionizing Radiation (IR) induces beneficial, as well as possible harmful effects to human population, representing one of the most important physical causes of inflammatory responses [3] . Ionizing radiation is known to induce oxidative stress through generation of Reactive Oxygen Species (ROS) resulting in imbalance of the pro- oxidant, and antioxidant in the cells, which is suggested to culminate in cell death [4] . It activates both pro- and anti-proliferative signal pathways altering the homeostatic balance between survival and cell death regulated by several genes and factors involved in cell cycle progression, repair, inflammation and cell death induction [5] . Activation and production of TNF-α and other cytokines are contributed to the inflammatory cascades after radiation exposure and ROS generation [6] .

The process of inflammation comprise activated inflammatory cells (neutrophils, eosinophils, monocytes, phagocytes, and macrophages)which secrete increased amount of inflammatory molecules such as nitric oxide (NO), and tumor necrosis factor (TNF-α) as well as Prostaglandin E2 (PGE2); another important inflammatory mediator produced from arachidonic acid metabolites by a reactions promoted by enhanced COX2 enzymatic system [7] .

In particular, uncontrolled inflammatory responses certainly pave to serious inflammatory diseases. So, it is important to hypothesize diverse strategies to cope with cascades of incontinent inflammation. The use of the herbal medicine has become a useful approach due to the anti-inflammatory properties in conjunction with low toxicity risk. A variety of plants and seaweed have traditionally been used in oriental folk medicine to treat inflammatory diseases.

A diet rich in marine products is considered to result in a lower incidence of certain inflammatory diseases like cardiovascular disease, diabetes, cancer, and stroke. These protective effects are attributed to nutraceuticals contained in marine foods [8] .

The present study is interested in Marine algae (seaweed) exacting the brown seaweed. Microalgae brown seaweed is photosynthetic like plants that lack many of the distinct organs found in terrestrial plants, and whole seaweed plants are available as a biomass resource. Brown seaweed contains carotenoid present in the algae chloroplasts and fucoxanthin is the major carotenoid. The antioxidant properties present in BSWE might be attributed to its carotenoid (fucoxanthin) potent free radicals scavenging capacity [9] .

Following to the previous, in the present study we interested in evaluating of BSWE impact on the COX2/PGE2 inflammatory pathway in irradiated albino rats as well as the role of oxidative imbalance.

To achieve the goals of the present study, we have executed the following cohesive biochemical assessments: 1) Inflammatory response signs (NO, TNF-α, COX2, and PGE2), 2) Pro oxidant indicator and ROS generator system (MDA and XOR system) 3) Atioxidants parameters (GSH, SOD, and CAT).

In order to evade the development of serious inflammatory complications, we have to shed light on the mechanisms of inflammation targeting the suggestion of adequate solutions which includes the using of different anti-inflammatory agents preferring the natural nonsteroidal anti-inflammatories. Alterations to COX2 expression and the abundance of its enzymatic products PGE2 (COX2/

PGE2 pathway) have key roles in developments of many serious inflammatory diseases [18] . In the present study, significant increases in COX2 activities and PGE2 concentrations were observed in rats exposed to fractionated gamma radiation 8 Gy; 2 Gy × 4 every other 3 days) (Figure 1(a) & Figure 1(b)). The COX2 enzymatic activity upregulation could be attributed to the activation of several TNF-α dependent intracellular signaling pathway which plays a key role in the control of COX-2 induction. Nam et al. [19] stated that different protein kinases and transcriptional factors that are greatly regulated by TNF-α are contributed to COX2 upregulation. The expression of COX2 mRNA and protein is often enhanced in various human cell types by inflammatory cytokines such as interleukin-1beta (IL-1beta) and TNF-α [20] . Further, TNF-α induced PGE2 release that caused pain and support inflammatory process is mediated by activation of COX2 transcription. Arachidonic acid is transformed into PGE2, important lipid mediators of numerous physiological and pathophysiological processes via cyclooxygenase (COX) enzymes and terminal prostaglandin E synthases (PGES) [21] . Likewise, PG syntheses can be stimulated in response to distinct pathophysiological situations, including inflammation, pain, and cancer. Undoubtedly, prostaglandin E2 (PGE2) is a principal mediator of inflammation in diseases. The nonsteroidal anti-inflammatory medications (NSAIDs) and selective cyclooxygenase-2 (COX-2) inhibitors reduce PGE2 production to diminish the inflammation seen in these diseases [22] . Subsequently, inhibition of COX-2 expression and blocking of pro-inflammatory cytokines (TNF-alpha, production are likely included in the anti-inflammatory process. In addition, as the interaction of various enzymes in the PGE2 synthetic pathway is complex and tightly regulated, the potential of targeting PGES is a more precise strategy for inhibiting PGE2 production [19] .

In the same issue, Ionizing radiation (IR) activates both pro-and antiproliferative signal pathways producing an imbalance in cell Fate decision. Our data reveals a kind of these imbalances manifested by significant increases in TNF-α protein expression as well as in the concentration of proinflammatory mediator NO in rats after gamma radiation exposure (Figure 1(c) & Figure 1(d)). Tissue fixed macrophages, such as liver Kupffer cells, are believed to be major sources of TNF-α. However, other cell types, including endothelial cells, epithelial cells, monocytes, T-cells, smooth muscle cells, adipocytes, and fibroblasts, secrete significant amounts of TNF-α when exposed to the appropriate stimuli [23] . Schaue et al. [24] reported that exposure to ionizing radiation has a significant effect on the immune system modulation through the activation of cytokine cascades. The reported variation in TNF-α concentration along the 2 experimental times could be interpreted in the light of cytokine production is time- dependent, peaking usually at 4 - 24 hrs after irradiation with a subsequent decrease to baseline levels within 24 hrs to a few days [25] . Furthermore, enhancement of TNF-α release in response to exposure to gamma radiation as recorded in the present study could participate in the induction of NO release. Nitric oxide (NO) is a signaling molecule undergoes over production in abnormal situations and plays a key role in the pathogenesis of inflammation [26] . The increased NO generation could be attributed to radiation stimulation of inducible nitric oxide synthase (i-NOS) [27] . Multiple reports demonstrate that TNF-α regulated NOS (Nitric oxide synthases) expression and/or increased activity directly affect NO production [28] . TNF-α markedly augmented the expression of iNOS which is, an enzyme not normally produced in most cells. It is provoked and presented under certain conditions [29] . The inducible (calcium-indepen- dent) isoform (iNOS) produces much larger amounts of NO and is only expressed during inflammation [30] . It was demonstrated that iNOS, activated by pro-inflammatory cytokines, can radiosensitize tumor cells through endogenous production of NO [31] . The generation of NO and reactive nitrogen species (NO/RNS) by iNOS is a critical feature of the inflammatory environment [32] . Worth mention, in the study of Gorbunov et al. [33] the induction of iNOS expression and iNOS-dependent release of nitric oxide in bone marrow stromal cells was observed within 24 h after irradiation and were similar in magnitude to that observed in cultures incubated with IL-1β and TNF-α.

One of the most important factors affecting the systemic inflammation in response to radiation exposure is cellular redox status. Our previous researchers pointed to alteration in redox status post radiation exposure perceptible by an accumulation of lipid peroxidation products MDA (measured as TBARS) and antioxidant decline [34] [35] . The plenty of ROS production and/or decreased antioxidant activity results in this deleterious status is comprehensible. Side-ef- fects of radiation are linked to the imbalance between ROS and the antioxidant defense system. Also, Rao et al. [36] stated that ROS have been implicated in the induction and complications of many diseases.

In this study, exposure of rats to fractionated whole body gamma radiation produce significant increases of TBARS (Figure 2(a)), alteration in XOR system and significant decrease in antioxidants system (GSH, CAT, and SOD) (Figures 3(a)-(c)). Thiobarbituric reactive substances (TBARS), one of the important indices of oxidative stress appeared due to overproduction of ROS that elicit vigorous lipid peroxidation process ended with an accumulation of thiobarbituric reactive substances; malondialdehyde (MDA) [37] . Important sources of ROS as both signaling molecules and mediators of inflammation in the living cell are include mitochondria, NAD (P)H oxidase, cyclooxygenase (COX), lipo-oxidase (LOX), xanthine oxidase (XO), cytochrome P450 (CYP450) as well as a number of other physiologically relevant systems [38] . Our results reveal significant changes in XOR system (constitute of 2 inter convertible enzymes) represented by significant increases of XO associated with significant decrease of XDH in irradiated rats (Figures 2(a)-(c)). This could interpret the oxidative stress elicited in the cells after radiation exposure where the XO, an enzyme react with molecular oxygen and produce ROS, is plentiful over XDH an enzyme form dominant in normal conditions [33] . In addition, ROS such as superoxide radicals can rapidly combine with NO present in abundant as that reported in our data (Figure 1(d)) to form reactive nitrogen species (RNS). RNS, in turn, induces nitrosative stress, which adds to the pro-inflammatory burden of ROS. The decline occurred in antioxidant enzymatic activities (SOD and CAT) and also a nonenzyme antioxidant (GSH) participated in oxidative stress emerged after radiation exposure. The antioxidant system frustration might be due to lose a lot of GSH molecules in ROS neutralization process and/or denaturing of enzymatic antioxidant protein molecules attacked by free radicals. Wu et al. [39] reported that bursts of ROS and RNS may affect directly or indirectly proteins/genes that participate in oxidative metabolism. Largely, our data drive us to propose that oxidative stress is responsible for the induction of inflammatory cytokines where the alteration in cellular redox tune is accompanied with an increase in TNF-α after irradiation (Figure 1(c)). Shah and Channon [38] stated that oxidative stress can activate a variety of transcription factors leading to the expression of over 500 different genes, including those for growth factors, inflammatory cytokines, chemokines, cell cycle regulatory molecules, and anti-inflammatory molecules. Among the commonly used inflammatory mediators to stimulate inflammation are cytokines (e.g., TNF-α) which induce only a subset of changes that are associated with full-blown inflammation [40] .

In this study, we aimed to regulate the systemic inflammatory responses induced after radiation exposure by injection of adequate, adjustable doses of BSWE to irradiated animals. Targeted a successful anti-inflammatory process we have to include the inhibition of COX2 expression and blocking of pro-inflam- matory cytokines in our practical protocol.

Analysis of our data could drive us to a perception that BSWE might revise balances between pro-inflammatory and anti inflammatory cytokines. In rats exposed to gamma irradiation and received several doses of BSWE, a significant amelioration of TNF-α and NO concentrations were observed (Figure 1(a) & Figure 1(b)). The modulatory action of BSWE on the concentrations of TNF-α could be exerted via the intervention of pathways participate in the induction of TNF-α, and NO production. Mhadhebi et al. [41] stated that, seaweeds are an excellent source of bioactive compounds polyphenols polysaccharides mero terpenoids and terpenoids which demonstrated a broad range of biological activities such as anti-inflammatory. Fung et al. [42] reported that fucoxanthin, a brown seaweed pigment (xanthophylls) found in most brown seaweeds has a molecule structurally similar to beta-carotene and vitamin A. Fucoxanthin is able to suppress the inflammatory response as assessed by NOS and COX-2 induction as well as cytokine and nitric oxide secretion [43] . Further, recent reports revealed seaweeds to be a rich source of antioxidant compounds [44] . The fucoxanthin inimitable structure carotenoids molecule could be responsible for the antioxidant activity of BSWE identified in our work by amelioration of SOD, CAT activities and GSH concentration as well as decreases in MDA (Figure 2(a)). It could be mention that adjustment of cellular redox tone might lead to ending pathways of TNF-stimulation and NO production related cascades. Moreover, Low molecular weight Fucoidan and fucoxanthin both appeared to reduce the level of pro-inflammatory mediators, including IL-1β and TNF-α via the inhibition of NF-κB activation. It seems that LMF, HS-Fucox, and LMF + HS − Fucox were trying to balance the immune disorder under LPS-induced inflammation [45] . Also, fucoidan downregulates the expression of pro-inflam- matory genes involved in the synthesis of NO, PGE2, TNF-α and IL-1β by suppressing NF-κB activity [46] .

Many carotenoids do not show direct free radical scavenging properties (β- carotene, β-cryptoxanthin, zeaxanthin, and lutein) making fucoxanthin somewhat unique in this regard, and the metabolite known as fucoxanthin appears to be more potent where fucoxanthin appears to scavenge free radicals with potency slightly less than vitamin C [47] .

Overall, our data indicated that BSWE treatment significantly inhibited excessive production of nitric oxide (NO) and prostaglandin E₂ (PGE₂) in gamma- irradiated rats. It also attenuated activation of COX2, and pro-inflammatory cytokines (Figure 1(a)-(c)). It seems that BSWE revising imbalances induced after irradiation between proinflammatory mediators and anti-inflammatory molecules appeared in our results through the down-regulation of TNF-α and NO in association with amelioration of antioxidants SOD, CAT, and GSH) could be contributed to attenuation of the inflammatory path COX2/PGE2. Pawel [48] declared that overproduction of PGE2 in response to pro-inflammatory molecules is associated with up-regulation of COX-2. In most physiologic conditions, the rate of PGE2 synthesis is controlled by local expression and activity of COX2.According to our data, inhibition of COX2 seemed to be a good candidate to regulate systemic inflammation after radiation exposure. It was affirmed that, mRNA of iNOS and COX-2 were affected by brown seaweed extract (fucoxanthin). Expression of TNF-α protein was also suppressed by fucoxanthin along with its mRNA [43] .

Putting together all data obtained we can conclude that brown seaweed extract possesses a good potential against radiation-induced systemic inflammation via revising imbalance between pro-inflammatory mediators and anti-inflammatory factors manifested by inhibition of COX2/PGE2 inflammatory signal. It could recommend using brown seaweed extract as an adjuvant in therapeutics protocols that includes exposure to ionizing radiation.

Authors wish to express great appreciation to Radiation Biology Department, National Center for Radiation Research and Technology, Egyptian Atomic Energy Authority for introducing all equipments and chemicals used in this study.

The authors declare they have no conflict of interest with the present study.

Azab, Kh.Sh., Meky, N.H., El-Deghidy, E.A.M. and Azoz, G. (2017) Response of COX2/PGE2 Inflammatory Pathway to Brown Seaweed Extract in Rats Exposed to Gamma Radiation. World Journal of Nuclear Science and Technology, 7, 189-205. https://doi.org/10.4236/wjnst.2017.73016