key: cord-0939347-p2zd7omk
authors: Lashgari, Naser-Aldin; Momeni Roudsari, Nazanin; Momtaz, Saeideh; Abdolghaffari, Amir Hossein
title: Transmembrane serine protease 2 and angiotensin-converting enzyme 2 anti-inflammatory receptors for COVID-19/inflammatory bowel diseases treatment
date: 2021-12-14
journal: World J Gastroenterol
DOI: 10.3748/wjg.v27.i46.7943
sha: 00ed16714f7077a9ace7bfca71960f7d17088f13
doc_id: 939347
cord_uid: p2zd7omk

Inflammatory bowel diseases (IBD) refer to a subgroup of chronic, progressive, long-term, and relapsing inflammatory disorders. IBD may spontaneously grow in the colon, and in severe cases may result in tumor lesions such as invasive carcinoma in inflamed regions of the intestine. Recent epidemiological reports indicate that old age and underlying diseases such as IBD contribute to severity and mortality in patients with coronavirus disease 2019 (COVID-19). Currently, the ongoing COVID-19 pandemic caused serious morbidity and mortality worldwide. It has also been shown that the transmembrane serine protease 2 is an essential factor for viral activation and viral engulfment. Generally, viral entry causes a 'cytokine storm' that induces excessive generation of proinflammatory cytokines/chemokines including interleukin (IL)-6, IL-2, IL-7, tumor necrosis factor-α, and interferon-γ. Future research could concentrate on developing inflammatory immunological responses that are efficient to encounter COVID-19. Current analysis elucidates the role of inflammation and immune responses during IBD infection with COVID-19 and provides a list of possible targets for IBD-regulated therapies in particular. Data from clinical, in vitro, and in vivo studies were collected in English from PubMed, Google Scholar, Scopus, and the Cochrane library until May 2021.

Coronavirus disease 2019 (COVID-19) is a primarily respiratory ailment that is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), additionally named as 2019 novel COVID. It is profoundly overwhelming with case casualty rates of 2%-3%. Since its appearance in December 2019 in China, COVID-19 has quickly spread and influenced populaces in virtually all areas of the world[1,2]. Old-age patients and those with chronic conditions are more prone to dreariness and mortality in COVID-19. This high mortality is implicated in misrepresented and misled invulnerable reactions that cause cytokine storms. In brief, SARS-CoV-2 infects the angiotensin-converting enzyme 2 (ACE2) expressing epithelial cells in the lung and/or the intestine, leading to a massive production of mediators that induce the immune cell activation. Overactivation of immune cells leads to severe complications including acute respiratory distress syndrome, shock, and multiorgan failure [3, 4] .

Inflammatory bowel diseases (IBD) include two major types: Ulcerative colitis and Crohn's disease. IBD is characterized with persistent resistant interceded sicknesses that regularly require immunomodulatory and immunosuppressive treatments [5, 6] . Therefore, patients with IBD are at high risk to different shrewd viral and bacterial contaminations. There is no solid evidence that patients with IBD are at higher risk for COVID-19 infection, although it has been indicated that patients with IBD who are pregnant are more vulnerable [7] . The current study discusses the impact of COVID-19 on IBD [8, 9] . We provide evidence on mediatory effects of the transmembrane serine protease 2 (TMPRSS2) and ACE2 signaling pathways against inflammation and introduces the synthetic or natural TMPRSS2 and ACE2 inhibitors as probable approaches for IBD treatment in the COVID-19 situation[9,10].

PubMed, Google Scholar, Scopus, and Cochrane Library were searched and relevant clinical, in vivo, and in vitro articles (in English) were collected until May 2021. Search terms included "corona virus" OR "COVID-19" AND "inflammatory bowel disease" OR "IBD" OR "inflammation" AND "TMPRSS2" OR "ACE2" AND "TMPRSS2 inhibitors" Variations in potency of the SARS-CoV-2 cell entry may account for discovering new solutions to deal with the virus. It has been reported that the entrance of SARS-CoV-2 to the human cells victimizes the SARS-CoV receptor ACE2 and TMPRSS2 for the spike (S) supermolecule priming. It is debatable whether the metallopeptidase domain seventeen [a disintegrin and metalloprotease domain 17 (ADAM17), also referred to as the tumor necrosis factor (TNF)-α-converting accelerator] located in the ACE2 ectodomain shedding may or may not counteract the virus entry by increasing the number of soluble ACE2, or it solely contributes to the ACE1/ACE2 unbalancing, inflammation, and occlusion [11] . The ACE2-receptor/S-protein interaction could be a key factor for success of virus infection and willingness. Similarly, single ester polymorphisms located inside the TMPRSS2 factor (21q22.3) can play a more important role in respiratory disorder [12] . ACE1 and ACE2 collaborate with the reninangiotensin system to balance the native vasoconstrictor/proliferative ACE1/ angiotensin II/angiotensin II type 1/angiotensin (Ang) II/Ang type 1 receptor (ACE1/Ang-II type 1/AT1-axis), and vasodilator/antiproliferative (ACE2/Ang1-7/mitochondrial assembly-axis) actions. This ends up in the protection of organs and blood vessels by the decoagulants, medicinal drugs, anti-proliferation, anti-fibrosis, anti-alveolar vegetative cell caspase-mediated cell death, and anti-oxidative stress activities that are able to antagonize the Ang-II effects [11, 13] .

In a complex pathophysiological condition like COVID-19, the ACE2 cytoplasmic tail cleavage intervened by TMPRSS2 is a significant event to be considered ( Figure 1 ). Cleavage of the ACE2 tail by TMPRSS2 increases viral load in objective cells, and TMPRSS2 could facilitate the SARS-CoV-2 passage via the SARS-S cleavage, which induces the S protein for film combination. The ACE2 cleavage may enhance viral uptake through the cathepsin L-subordinate pathway, resulting in viral integration with the endosomal layer and eventually cell contamination [11, 14] . In spite of similar explicitness of TMPRSS2 and ADAM17 for ACE2, they act opposite for cleavage of ACE2. To start with, the divisions produced by the cleavage of these proteases have distinctive subatomic sizes, mainly due to various cleavage locales. Second, cleavage of ACE2 by ADAM17 forms the ACE2 ectodomain, which is shed into the extracellular medium, as the soluble ACE biologically dynamic structure [15, 16] . In vitro studies have shown that the ACE2 ectodomain does not separate from the TMPRRS2-induced ACE2 cleavage. This was evidenced by a C-terminal intracellular cleavage. In this manner, the distinctions in the cleavage destinations and its organic outcomes might be basic. For sure, just the soluble ACE2 structure would have a defensive impact on prevention of viral particle aggregations [17] . Therefore, overexpression of ADAM17 and TMPRSS2 could be a primary factor in inflammation storm that is characterized by negative features such as renin-angiotensin system lopsidedness, intense irritation, and intravascular coagulation in older populations with COVID-19 comorbidities. Initiation of inflammation cycles is a key element for SARS-CoV-2 contamination [18, 19] .

ACE2 is the main receptor for SARS-CoV-2, providing additional insurance against the destructive impacts of viral diseases. Moreover, as referenced above, solid confirmations indicate that the outflow of ACE2 is dependent on the companion of hormonal, hereditary, and age-related systems [20, 21] . Overaction of ADAM17 in both COVID-19 and the plasma level of ACE2 has been confirmed by several reports. Overexpression of the ADAM17 gene and its protein level have been implicated in several inflammatory conditions including IBD [22, 23] . High levels of inflammatory cytokines and chemokines in COVID-19 patients are accounted for by more elevated levels of interleukin (IL)-2, IL-7, IL-10, granulocyte colony-stimulating factor, interferon December 14, 2021

Volume 27 Issue 46 

The SARS-CoV-2 receptor ACE2 and TMPRSS2 receptor are central factors in COVID-19-induced IBD pathogenesis (Table 1 and Figure 1 ). These receptors are often found within the lower respiratory lot of pneumocytes and the gastrointestinal tract [7] . The ACE2 receptors are frequently located within the terminal ileum and colon. It was shown that the convergence of these receptors was higher in IBD patients, in both the energetic and calm stages of the disease[33]. The ACE2 receptors are a part of the renin angiotensin-aldosterone system that is assumed to play critical roles in controlling the provocative handle. Terminal ileum and the colon are the most affected areas in IBD [34] . IBD is also correlated with upregulation of inflammatory cytokines and the ACE2 receptors. As we discuss in this article, patients with IBD do not seem powerless against COVID-19[35]. In this context, a few theories have been proposed. For instance, the renin angiotensin-aldosterone system has two specific pathways involved in irritation course. Multiple studies confirmed that ACE2 is upregulated in IBD, and in the SARS-CoV-2 condition ACE2 exacerbates the disease symptoms. Accordingly, prevention of the ACE2 protein expression has been suggested for controlling both COVID-19 and IBD [36, 37] . While the ACE-angiotensin receptor 1 pathway is favorable for inflammation, the ACE2 pathway helps in tissue security. Given the enteric inflammation in IBD, it has been suggested that the ACE2 receptors and the host cell surface proteases like TMPRSS2 may suppress SARS-CoV-2[38,39]. The ACE2 level was shown to be downregulated in colonic aggravation in animal models; thereby, some IBD drugs such as steroids and biologics were found useful for cutting down the ACE2 in infected cells. Another report declared no change in ACE2 receptors or TMPRSS2 in IBD patients when diverged from controls[40,41].

As mentioned, there are limited data on the possible impact of SARS-CoV-2 contamination on patients with IBD. Various methodologies can be utilized alone or concurrently to conquer the infection. Blockage of the ACE2 receptors and the viral S protein are the main focus of current investigations on SARS-CoV-2 regulation. So far, we discussed that blockage of the TMPRSS2 receptor and/or the ACE2/TMPRSS2 complex is likewise a plausible approach to modulate this infection. In this context, a number of synthetic or natural TMPRSS2 and ACE2 inhibitors that are able to mediate the TMPRSS2 and ACE2 signaling have been explored. . Several studies reported that SARS-CoV-2 is able to infect the central nervous system through TMRPSS2 and ACE2 receptors. It was also shown that ACE2 participates in neuroprotective responses, hence playing a critical role in treatment of COVID-19. Phytochemicals such as baicalin, scutellarin, and hesperetin can bind to ACE2 and prevent neurological impairments caused by COVID-19.

It was shown that hesperidin, chrysin, and emodin are also effective for COVID-19 treatment by attenuating the harmful effect of viral infection within cells [48] . Kaempferol, quercetin, and fisetin can bind with human angiotensin-converting enzyme-S-protein. In silico studies demonstrated that quercetin, quercetin 3 glucuronide-7-glucoside, quercetin 3-vicianoside, absinthin, glabridin, and gallic acid have strong affinity toward ACE2 to suppress COVID-19. Nuclear docking examination elucidated that dithymoquinone (aquinone) encounters the COVID-19 neurological side effects through blockade of ACE2. An in silico study reported that two chalcones namely azobechalcone and isolophirachalcone and some alkaloids (i.e. fangchinoline and tetrandrine) had high limiting proclivity to the S protein of SARS-CoV-2[49]. Flavonoids reduce the ACE2 expression through inducing the nuclear factor erythroid 2-related factor 2, thus fighting SARS-CoV-2 by means of their antioxidant properties. Kaempferol, quercetin, and fisetin are promising flavonoids against COVID-19-induced adverse neurological effects. Stilbenes, in particular resveratrol, are promising candidates for COVID-19 treatments, mainly by disturbing the formation of the S protein and the ACE2 receptor complex [50] . A variety of phenolic compounds including naringenin, hesperetin, hesperidin, and baicalin (alone or in combination) showed inhibitory effects on ACE2 activity and can be considered as potential treatments for COVID-19 [51] .

Different studies exhibited that some other phenolic compounds such as cinnamaldehyde as well as terpenoids such as carvacrol, geraniol, anethole, L-4-terpineol, cinnamyl acidic, thymol, and pulegone possess antiviral activities through blockade of the viral S protein [52, 53] . It was reported that the binding affinity of ACE2 linkage with scutellarin (a flavonoid glycoside) and glycyrrhizin (a triterpenoid) was stronger than baicalin, hesperetin, and nicotianamine [54] .

Limonoids and triterpenoids also displayed similar inhibitory effects on ACE2. Another in silico study similarly demonstrated that limonin, obacunone, ursolic destructive, glycyrrhizin destructive, 7-deacetyl-7-benzoylgedunin, maslinic acid, and corosolic acid effectively target SARS-CoV-2 proteins [55] . In this line, nimbin (a triterpenoid) and curcumin exhibited high limiting proclivity on ACE2 and the S protein [56]. Epigallocatechin-3-gallate and theaflavin gallate were shown to have inhibitory effects on the S-protein central channel of SARS-CoV-2. Moreover, three alkaloids, including cepharanthine, fangchinoline, and tetrandrine, inhibited the S protein of Human coronavirus Subtype OC43 (Human-CoV-OC43) expression, while tetrandrine exhibited moderating effects on viral sicknesses. An indazole alkaloid isolated from the seeds of Nigella sativa, called nigellidine, was shown to bind the dynamic areas of SARS-CoV-2, thereby paralyzing the virus. In another study, anthraquinone emodin blocked the ACE2 and S protein conjunction[57,58].

Various classes of medications, with different powers and immunosuppressive potentials, are used for IBD treatment (Table 1 and Figure 1 ). At present, limited data are available for the utilization of different medications in IBD under the COVID-19 condition, henceforth the level of proof is not yet certain [59] . Current suggestions, proposed by specialists and different social orders, are overwhelmingly based on the recounted proof from the utilization of these medications during other viral pandemics like SARS and Middle East respiratory syndrome coronavirus or a few distributed case reports [60] . By and large, usage of intense immunosuppressants in IBD patients should be limited, except if totally essential. Notwithstanding, patients December 14, 2021

Volume 27 Issue 46 who are on stable upkeep portions may keep on doing as such with close contact with their physicians [61, 62] .

Salicylates: Salicylates are usually utilized in either oral form or as a bowel purge. They have a neighborhood activity and are improbable to influence the course of COVID-19 when are used in IBD patients, thereby they may be securely proceeded in dosages [63] .

Corticosteroids: Corticosteroids are the most common drugs that are used in IBD, mainly due to their intense calming effects. Therefore, steroids may be valuable in suppression of COVID-19, particularly in conditions like intense lung injury, intense respiratory trouble disorder, and septic shock. During the SARS and Middle East respiratory syndrome pandemic, corticosteroids treatment helped to postpone viremia [64, 65] , while there were no general improvement in terms of septic shock or psychosis, etc. [66] . Given the absence of adequacy, the World Health Organization suggested that routine corticosteroids ought to be avoided except in explicit circumstances. Steroids are possibly kept away from the first line therapies in recently analyzed IBD patients. Notwithstanding, considering their tremendous advantages in IBD, it was suggested that the main steroids might be beneficial at low doses in patients with COVID-19 and IBD, specifically in patients that are already on treatment [67, 68] . Steroids with limited site of action, for example budesonide, seem harmless to be used. Infliximab might be a therapeutic option for COVID-19 positive patients with mild respiratory symptoms [61, 69] .

Cyclosporin: Cyclosporin is used for serious ulcerative colitis as an option in contrast to steroids. Although, some data pointed out that cyclosporine can inhibit the coronavirus replication proteins in vitro, its prescription is controversial in patients with COVID-19 due to its strong immunosuppressive properties [70] [71] [72] .

Azathioprine and methotrexate: Azathioprine is a thiopurine that is often used for IBD treatment, particularly for upkeep treatment. Curiously, past investigations have demonstrated that thiopurine analogs have both immediate and roundabout activities on smothering antiviral movement. They also hinder viral proteases once the host proteins were engaged with viral replication [73, 74] . Depending on the perception of genuine viral contaminations in IBD patients who are using thiopurine, the treatment time can be estimated. Interruption in treatment up to 14 d after recuperation from COVID-19 has been suggested. Methotrexate can perhaps continue without issues [75, 76] .

Biologics: Current data show that infliximab and adalimumab (TNF-α inhibitors) have no unfavorable effects on the clinical course of COVID-19 [62, 77] . One reason speculated is the strong mitigating impact of TNF blockage, which may indeed constrict the cytokine storm in serious types of COVID-19 [78, 79] . Co-administration of medicines (i.e. thiopurine and infliximab) might be an option. Also, monotherapy with natural products may be considered [60, 80, 81] . Vedolizumab (an adversary of α4β7 integrin) is significantly explicit for movement on the gut, hence it is favorable for fundamental or pneumonic responses in COVID-19 [62, 82] . Ustekinumab is an approved clinical therapy for patients with IBD. Ustekinumab is a cytokine antibody and an inhibitor of IL-12 and IL-23. Currently, there are no major concerns about usage of ustekinumab in patients with IBD and COVID-19. Vedolizumab or ustekinumab might be the primary therapeutic options for individuals at higher risk of COVID-19 if biological treatments are thought of[79, 83, 84 ].

Information on the physiologic and pathophysiologic functions of ACE2/TMPRSS2 is still scant. ACE2/TMPRSS2 is very much described in the cardiovascular and renal frameworks. Yet little data exist regarding other organ frameworks, for example the gastrointestinal system. Moreover, specific function of the ACE2/TMPRSS2 axis in pathologic conditions was traditionally restricted to cardiovascular illnesses. Although, considering the ACE2/TMPRSS2 as a multifunctional protein has accomplished significance as of late. The current COVID-19 pandemic has featured the importance of ACE2/TMPRSS2 as a receptor for SARS-CoV-2, yet research is expected to determine whether the ACE2/TMPRSS2 levels enhance the pathogenesis of COVID-19 or could benefit the course of illness by diminishing the malicious impacts of Ang II. Moreover, the

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