Bromelain: A potential therapeutic application in SARS-CoV-2 infected patients

The SARS-CoV-2 infection has led to a global pandemic which has led to almost 4 million deaths worldwide. However, to date, a specifi c antiviral drug does not exist to treat the disease and control the virus. Here, we focus on the potential use of bromelain in line with its anti-oxidant, anti-infl ammatory, and immunomodulatory effects. Additionally, bromelain exerts fi brinolytic, anti-invasive and antithrombotic activities that may become a therapeutic candidate against SARS-CoV-2 infection. In this paper, we focused on bromelain’s therapeutic potential concerning its potential role in reducing the severity of symptoms and the adverse effects of other antiviral drugs currently being used. The therapeutic effects of bromelain suggests that it may reduce mortality and morbidity rates in patients with CoVID-19 infections, through its anti-oxidant, anti-infl ammatory, immunomodulator and anticoagulant effects. These positive effects leads us to propose that bromelain may be clinically valuable in the treatment of COVID-19 and that it therapeutic attributes should be fully investigated. Mini Review Bromelain: A potential therapeutic application in SARSCoV-2 infected patients Serkan Sayıner1,2, Ayliz Velioğlu-Öğünç3 and Ahmet Özer Şehirli4* 1Department of Biochemistry, Faculty of Veterinary Medicine, Near East University, Nicosia, Cyprus 2Diagnostic Laboratory of Animal Hospital, Faculty of Veterinary Medicine, Near East University, Nicosia, Cyprus 3Vocational School of Health-Related Professions, Marmara University, Istanbul, Turkey 4Department of Pharmacology, Faculty of Dentistry, Near East University, Nicosia, Cyprus Received: 26 April, 2021 Accepted: 18 June, 2021 Published: 19 June, 2021 *Corresponding author: Ahmet Özer Şehirli, Department of Pharmacology, Faculty of Dentistry, Near East University, Near East Boulevard Post Code: 99138, Nicosia, Cyprus, Tel: +90 392 680 20 30; E-mail:


Background
Known as SARS-CoV-2, COVID-19 continues its negative impact on the world with its increasing morbidity and mortality rate [1]. Although the attempted control of the pandemic has been focused on the development of novel vaccine studies, the fact that the virus has reached a dangerous level through multiple mutations, there is necessity to develop newradical treatments and profolatic measures. The most critical factor limiting treatments is the negative potential for side effects due to the high doses of drugs delivered in the treatments so far [2]. For this purpose, the importance of immunomodulatory agents with high therapeutic index, which have anti-oxidant and anti-infl ammatory properties, which can reduce the side effects of these drugs and play a role in the modulation of the immune system and prevent the devastating effects of a cytokine storm [3]. As a potential alternative treatment for COVID-19 we propose that bromelain, a phytotherapeutic drug, may provide an alternative solution .

Bromelain
Bromelain is a group of enzymes present in all parts of the pineapple plant (Ananas comosus), who's enzyme's fi rst isolation was accomplished in 1891 [4,5]. Despite being found in all parts of the pineapple, extracts from the seed are commercially preferential. Bromelain extract is a mixture of different enzymes (thiol endopeptidases and phosphatase, glucosidase, peroxidase, cellulase), glycosidaselike components, carbohydrates, glycoproteins and several protease inhibitors.
Extensive data has been collected from numerous studies on the administration of large doses of bromelain, which are based on close or similar models, which have yielded varying results. Bromelain's LD50 is >10 g/ kg in rodents, 12 g/day orally is a safe dose for humans, without signifi cant side effects [6,7]. proteinases contribute to anti-infl ammatory activity in vivo andit is poorly absorbed when given orally, with resulting plasma levels less than 10 ng/ml in humans given 4 g/day [8,9].

Bromelain and immunomodulation
Bromelain is an immunomodulator with a pleiotropic effect [10]. It has been found to strengthen immunogenicity by increasing IFN-gamma and TNF alpha levels, signifi cantly when the immune system is weakened [11]. In other studies, it has been reported that it inhibits mitogenesis, apoptosis and cytokine formation by preventing T cell activation in cases of infl ammation, by blocking the Raf  1/extracellular-regulated kinase (ERK)-2 pathway, through the reduction of CD4+ and CD25 expression [12,13].
The protective properties of bromelain have been demonstrated in both clinical and experimental infl ammation models. It has achieved protective effects with its immunomodulatory, anti-oxidant and anti-infl ammatory properties [21]. Therefore, it is likely that it may have a protective effect against free oxygen radicals and infl ammatory cytokines, especially during COVID-19 infections ( Figure  1). It has been reported that it may exert a protective effect through the inhibition of T cells-mediated IL-6 and TNF-, an particularly during the cytokine storm seen in CoVID-19 patients [22]. The various benefi cial effects of bromelain which minimize tissue damage during viral infections suggest that it could play a supportive therapeutic role in treatment of COVID-19 infection. Slowing the onset of infl ammation will also prevent the disease from escalating.

Bromelain and its anticoagulant effect
It has been reported that cytokines cause thrombosis by increasing platelet aggregation [23]. Bromelain inhibits platelet aggregation due to its suppression of proinfl ammatory cytokines [24]. It has been shown to suppress kinins synthesis during infl ammation [13]. This is particularly important for increased quinine levels during COVID-19. Because kinins are effective in both infl ammation and coagulation, where they have an important role in multiple organ damage during COVID-19 infections. Thus, it is possible that bromelain, with its antiinfl ammatory and anticoagulant effect, can prevent multiple organ damage through its suppression of the increased quinine synthesis during COVID-19 infections.
Bromelain has plasminogen-plasmin mediated fi brinolytic effect [25]. It has been shown to prevent thrombosis by inhibiting platelet aggregation, primarily by increasing the plasmin concentration. Thrombosis and coagulation are important for ventilation and during COVID infections it causes respiratory problems in patients by reducing erythrocyte transport, [23]. Therefore, bromelain treatment is also important in terms of preventing coagulation and reducing respiratory distress.

Bromelain and neuroprotective effect
The analgesic and neuroprotective effects of bromelain are known [26]. The neurological symptoms of COVID-19 include headache, fever and fatigue [27]. Bromelain inhibits both kinins and PGE2 which is likely to improve these symptoms.
Additionally, it has been reported that bromelain enables the anti-oxidant/oxidant balance to be realized in favour of the anti-oxidant by stimulating endogenous anti-oxidants and decreasing oxidants [26]. Hence, bromelain can limit tissue damage during COVID-19. Although there are limited number of studies related to bromelain's antiviral effect, it can create a synergy with the adverse effects of additional antiviral drugs through its anti-oxidant and anti-infl ammatory properties [21].

Conclusion
Bromelain, a phytotherapeutic drug and a crude proteolytic enzyme extracted from the pineapple plant with numerous benefi cial properties [25], these include: preventing oedema formation, reduction of already-existing oedema in patients, anti-infl ammatory and immunomodulatory effects [21,28,29].
Bromelain also contains different but closely-related proteinases that exerts anti-oedematous, fi brinolytic, antiinvasive, and antithrombotic activities [25,30]. Enzyme extracts of bromelain modulate the functions of adhesion molecules on blood and endothelial cells, and also regulate and activate various immune cells and their cytokine production [25]. Şehirli critically revised the article.