A Brief Overview to TNF-a Inhibitors Therapy on Covid-19: Functions Inside Cell Cascades

angiotension converting enzyme (ACE2) [10]. This mini review targets to emphasize the importance of relationship between TNF (Tumor Necrosis Factors) inhibitors cell and and macrophages important for of clinical researchers are to search on novel TNF inhibitor molecules Some TNF inhibitor molecules shown Table and a few of them are used thesedays for the treatment of Covid-19. Abstract Viral Covid-19 has spreaded all over the World only in a few months and caused much deaths. Covid-19 is belong to coronavirus family (called also SARS-CoV-2). Virus entry into cell occurs by unification with membrane receptors by releasing viral capsids or by endocytosis. TNF inhibitors aim to block receptors that bind to intracellular pathways as soluble form or by membrane bounding. Some TNF-α inhibitors have been used on severe Covid-19 patients nowadays.


Introduction
SARS-CoV-2, also named Covid-19, was emerged firstly in Wuhan, China at the end of November, 2019 and began to spread as a pandemic viral-infected illness all over the World.
Originally, it is a type of coronoviruses. Coronaviruses are belong to Coronaviridae family and positive single stranded RNA viruses encircled with an envelope [1]. Generally they are divided into 4 groups as alpha (α), beta (β), gamma and delta (ᵟ) coronaviruses [2]. SARS-CoV (severe acute respiratory syndrome coronavirus) is a type of the Alphacoronavirus genus [3] and emerged firsty in late 2002 in China as a characteristic pneumonia [4]. As reported previously, SARS viruses are mostly fatal therefore, highligthting of the pathological disorders of SARS is very important [4]. Apoptotic and MAPKs (Mitogen Activated Protein Kinases) activations play significiant role in SARS-CoV viral infections [4,[5][6][7]. Several in vitro and in vivo studies showed that MAPK signal cascade may inhibit viral infections (SARS-CoV-infections) by involving in apoptosis or regulating extracellular cytokine activation [4]. Virus penetration inside cell takes place by fusion with membrane by releasing viral mirids or by endocytosis [8,9]. Recent studies showed that during transmission of human SARS-CoV viruses, Covid-19 (SARS-CoV-2) also uses the same receptor for angiotension converting enzyme (ACE2) [10]. This mini review targets to emphasize the importance of relationship between TNF (Tumor Necrosis Factors) inhibitors and intracellular signal transduction mechanism on Covid-19.

Tnf Inhibitors
Tumor Necrosis Factors (TNF) are generally known as proteins that are responsible from killing malign cells; among them especially TNF-α and TNF-β are cytokines and have same receptors. They play important role on autoimmune diseases.
Biological effects of TNF against disease depend on speed of stimuli in response [11]. Responses contain fever, shock, tissue and organ (especially lung in coronaviruses) injury, tumor necrosis, anorexia, induction of other cytokines and immunoregulatory molecules, cell proliferation, differentiation, and apoptosis [11,12]. Also, TNFs

are so important in initiation and enhancing imflammation on
Covid-19 patients [6]. According to the latest studies, pathological disorders of lung of Covid-19 patients showed capillary fluids are ouflowed and immune-inflammatory lymphocytes, neutrophils, and macrophages are enlisted [13]. FDA approved some important

TNF-inhibitors for treatment of inflammatory diseases about 20
years ago [14]. Therefore, clinical researchers are tend to search on novel TNF inhibitor molecules [14,15]. Some TNF inhibitor molecules was shown in Table 1 and a few of them are used thesedays for the treatment of Covid-19.  with tocilizumab and showed successful performance [17]. Fever and respiratory disorders began to improve in patients after a few days [12,15,18,19]. According to updated output number Covid-19 patients (on 22 th May 2020) in Turkey, mortality rate has diminished vigorously (to 27) and also ICU and entubated patients are decreasing day by day. These data showed that treatment strategy was discovered successful in Turkey.
TNF-α can be in soluble or membrane bound form. Cell signaling of TNF-α in Covid-19 is complex and react with several tumor necrosis factor receptors [17]. Multiple signal cascades activate JAK (Janus kinase) and STAT (Signal transducer and activation of transcription). On account of this pathway activation PI3K activation initiates and destroyed cells begin to proliferate, survive, differentiate and pro-inflammatory transcription takes place. Ruxolitinib is a type of IL-6 receptor blocking molecule and ihibits JAK/STAT signaling pathway by binding to IFNγ [17]. It can be also potential molecule like other IL-6 inhibitor molecules for treatment of critical Covid-19 patients and also may be used as combinetherapy with other antiviral compounds [20][21][22][23][24].

Conclusion
Covid-19 has become a serious pandemi for months, there is no direct therapy for patients so clinical researchers need urgent treatment plan. Latest studies showed that TNF-α inhibitors could be potential candidate for spesific therapy, because mortality rate showed that cancer, diabetes and immunological disorders patients are tend to have more respiratory problems than the other. Some pathological problems cause sepsis into cell pathway. Therefore novel TNF-α inihibitors especially targetting apoptotic pathways (for elimination of destroyed cells) and IL-6 receptors (for blocking interleukins) could be potential candidate for the treatment of Covid-19. Highlighting the pathway mechanism behind virus penetration into cell is crucial in order to select correct drug for therapy.

Conflicts
There is no conflicts.