Pathophysiology of COVID-19: SARS-CoV-2 mimics neoplastic cells and The Long COVID-19 Syndrome can be a Warburg Effect and ACE-2 internalization consequence

doi:10.21203/rs.3.rs-1643416/v1

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Pathophysiology of COVID-19: SARS-CoV-2 mimics neoplastic cells and The Long COVID-19 Syndrome can be a Warburg Effect and ACE-2 internalization consequence

https://doi.org/10.21203/rs.3.rs-1643416/v1

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This article develops the theory involving the SARS-CoV-2 pathophysiological mechanisms, based on an extensive literature review, and reinforced by two years of dealing with COVID-19 patients in different footages of the natural history of the disease. SARS-CoV-2 mimics the Warburg effect (W.E.), a well-described mechanism in neoplastic cells to obtain energy and substrates to enable cell growth. The W.E. is responsible for characteristic clinical and laboratory findings such as elevated lactic dehydrogenase (LDH), lactate, uraemia, and acidosis, in addition to explaining why a specific profile of patients evolves into severe forms of the disease. This article also exposes a hypothesis for maintaining the inflammatory status after acute SARS-COV-2 infection, "The Long COVID-19 Syndrome". Assessment of PubMed platform followed by evaluation of articles that supported issues regarding COVID-19/SARS-CoV-2 AND AEROBIC GLYCOLISIS/WARBURG EFFECT. COVID-19 is a biphasic infectious disease (like Yellow Fever, for example) that causes tenacious immune-metabolic changes that impact the inflammatory status. The hyperlactataemia (type B) in COVID-19 is due to the metabolic shift to aerobic glycolysis (W.E.), and it can differentiate chronic or acute COVID-19 inflammatory status from septic shock hyperlactatemia, especially when associated with negative cultures. This article brings to the light the pathophysiology of SARS-CoV-2 and possibilities for treatment and improvement in the clinical management of patients affected by this severe and catastrophic disease. The COVID-19 signature is the Warburg Effect + ACE-2 + innate response + hypoxia + Phenylalanine (Phe), and Tryptophan (Try) metabolism. The disease’s magnitude is directly proportional to the patient's exposure to hypoxia.

COVID-19

Warburg effect

Lactate

SARS-CoV-2 is a beta coronavirus responsible for a systemic infectious disease with an inflammatory characteristic, with the lungs being just another target affected by this disease. It has a bimodal characteristic, with a viraemic phase, defervescence interphase, and a third, toxaemic (immune-mediated) phase. Most patients progress to convalescence after the defervescence phase, and the minor part progresses to the toxaemic phase. Other diseases have the characteristic of being bimodal: Yellow Fever, Leptospirosis, the severe forms of Dengue, for example(1,2).

SARS-COV-2 uses the Warburg Effect to obtain energy and substrate for its replication. Other viruses also use this exact mechanism, usually via viral proteins that shift metabolism to aerobic glycolysis, to the detriment of oxidative phosphorylation (OXPHOS), which remains active, but is of lesser importance for the maintenance of viral replication mechanisms. EW is also used physiologically by some human body cells, such as the myocardium and cells of innate and adaptive immunity.

The variation between aerobic mechanisms of cellular respiration and aerobic glycolysis is orchestrated impacts the differentiation of immune system cells and the possibility of neoplastic cells to develop and cause metastasis(3–6).

The profile of patients who evolve to the most severe forms of COVID-19 (severe and critical) are those who have inflammatory comorbidities with some degree of hypoxia so that their cells already have their metabolic pathways diverted to perform W.E., and hyperlactatemia is due to metabolic deviation, although mixed situations, that is, increased lactate associated with shock conditions (septic shock, for example) can occur due to immunosuppression secondary to COVID-19(7,8).

COVID-19 presents a very variable chronic form, presenting itself in a pleomorphic form, making its diagnosis difficult. Although the chronic inflammatory status (called "The Long COVID-19 Syndrome) has multiple faces, some signs and symptoms such as gastrointestinal, airway, neuropsychiatric are prevalent. Inflammatory Shock (IS) is the most severe outcome in COVID-19, which can occur immediately after the acute phase of the disease or later (Weeks or months after acute disease). Inflammatory shock, often confused with septic shock and rarely diagnosed, causes great underreporting of deaths from COVID-19.

This article brings the possibility of facing COVID-19 from a structured look at possible and plausible pathophysiology. Much necessary information is in the APPENDIX of this article and is necessary for a global understanding of the presented content. This article is supported by an extensive review of the scientific literature by the author's clinical experience, two years ago dealing with COVID-19 patients in multiple settings, in addition to having carried out other reviews on the subject in the last two years. It follows the theory about the pathophysiology of COVID-19, being aware that they are hypotheses, but based on the primary evidence on the subject (Fig. 1).

ACE-2 and Inflammation

For SARS-CoV-2 infecting human cells, binding the viral surface protein (S protein) with the angiotensin-converting enzyme 2 (ACE-2) protein, expressed in numerous human body tissues, is required.

ACE-2 expression is prevalent in microvilli of the intestinal tract, proximal renal tubules, in membranes of gallbladder epithelium, epididymis epithelium, testicular Sertoli cells and Leydig cells.

ACE-2 is also expressed in the cornea and conjunctiva of the eye, interlobular pancreatic ducts, placental villi (in cytotrophoblasts, syncytiotrophoblast, and extra villous trophoblasts), but not in the placenta decidua. Moreover, there is ACE-2 expression at the base of the ciliated fallopian tube epithelium, endothelial cells and pericytes in several tissues, thyroid, parathyroid, adrenal gland, pancreas, and heart(14–17).

The ACE-2 enzyme is associated with the endothelial surface, and ACE2 activity shifts the ACE/Ang II/AT1R axis to ACE-2/Ang (1–7)/MasR by converting the vasoconstrictor Ang II to Ang (1–7). ACE-2 converts Angiotensin I to Ang (1–9), which yields Ang (1–7). Ang (1–7) exerts potent vasodilatory, anti-inflammatory, and anti-proliferative effects when binding to MasR and the angiotensin type 2 receptor (AT2R). MasR is ubiquitously expressed in neurons, microglia and endothelial cells of the cortex, basal ganglia, thalamus, hypothalamus, hippocampus, and striatum.

The ACE2 gene is located on Xp22.2 and underwent X-inactivation, resulting in phenotypic differences between sexes and, in females, ACE-2 can recognize SARS-CoV-2 receptor-binding domain (RBD) on either of the two X. In children, the ACE2 gene is hypermethylated and silenced. The elderly shows increased expression of ACE2(14,15,18,19).

ACE-2 cleavage occurs by ADAM17 (Disintegrin and Metalloproteinase Domain-Containing Protein 17 or TACE) processing. ADAM17 is an ACE-2 sheddase, which requires arginine and lysine residues and competes with TMPRSS2 for ACE-2 processing.

TMPRSS2 is a human transmembrane serine protease II (TMPRSS2), expressed on the cell surface of several target cells that allows activation of S proteins bound to the ACE-2 receptor on the surface of the viral host cell, inducing fusion of the viral envelope plasma membrane and direct entry of SARS-CoV-2 in cells. Upon binding to ACE-2, SARS-CoV-2 virions are taken up into endosomes and are cleaved and activated by the pH-dependent cysteine protease cathepsin L.

There are two possible routes in SARS-CoV-2 infection: the S protein of some coronaviruses is cleaved into S1 and S2 subunits during their biosynthesis in the infected cells. S protein is cleaved by proprotein convertases such as Furin in the virus-producer cells. S1 subunit binds ACE2, and the S2 subunit anchors the S protein to the membrane. The S2 subunit also includes a peptide fusion and other machinery necessary to mediate membrane fusion upon infection of a new cell. ACE2 engagement by the virus exposes the S2′ site. S2′ site cleavage — by transmembrane protease, serine 2 (TMPRSS2) at the cell surface or by cathepsin L in the endosomal compartment following ACE2-mediated endocytosis. When there are scarce TMPRSS2 or the virus do not encounter TMPRSS2, the virus–ACE2 complex is internalized via clarithrin-mediated endocytosis into the endolysosomes, where S2′ cleavage is performed by cathepsins, which require an acidic environment for their activity. When Ace-2 and TMPRSS2 together, the fusion occurs between viral and cellular membranes, forming a fusion pore, and viral RNA is released into the host cell cytoplasm.

Furin is ubiquitously expressed in the Golgi apparatus of all cells. It is known for its role in viral pathogenesis by cleaving polybasic or multi-basic sites in COVID-19's glycoprotein. This cleavage capacity could explain COVID-19's ability to bind to tissue with relatively lower ACE2 expression. Since furin is a widely expressed protease in the respiratory tract, COVID-19 uses it to increase its infectiveness and transmissibility(20–23).

SARS-CoV-2 entry into the cell by endocytosis, resulting in downregulation of ACE-2 in the lungs by activating A disintegrin and metalloproteinase-17 (ADAM17), cleaving the ACE2 N-terminal.

The decreased expression of ACE-2 prevents the degradation of des-Arg9 bradykinin (DABK) by the epithelial cells in the lungs. It increased DABK results in the activation of DABK/bradykinin receptor B1 results in the release of proinflammatory chemokines by the lung epithelium. Specifically, C-X-C motif chemokine ligand 5 (CXCL5), macrophage inflammatory protein 2 (MIP2), C-X-C motif ligand 1 (CXCL1) and tumour necrosis factor-alpha (TNF)-α are released, leading to an exaggerated neutrophilic response, thereby worsening lung injury.

Additionally, overexpression of ACE2 via genetic therapy increased the production of Ang-(1–7), upregulation of the MAS pathway, inhibition of the extracellular signal-regulated kinase (ERK)/nuclear factor kappa B (NF-κB) pathway, and hence prevention of exaggerated inflammatory response seen in acute respiratory distress syndrome (ARDS). Decreased ERK/NF-κB activation via MAS has been shown to reduce transforming growth factor-beta (TGF-β) and interleukin (IL)-6(24,25).

While the effects of Ang II are rapid, the effects of aldosterone are retarded due to slower effects on downstream targeted gene transcription. The overall physiological net effects of RAS activation is an increase in total body sodium, total body water, and increased vascular tone. Furthermore, the binding of Ang II to AT receptors results in vasoconstriction, endothelial injury, endovascular thrombosis and increase blood volume. Increased Ang II is associated with hypertension and accelerated thrombosis in arterioles by activating the coagulation cascade (both thrombin and platelets). Interestingly, the thrombogenic effects of AngII on the platelets was not reversible by the application of aspirin.

At the cellular level, AngII induces various signalling pathways, including serine/threonine kinase, ERK, JNK/MAPK, and PKC. Studies have shown that Ang II effectively induces IL-6 and TNF-α, possibly through serine tyrosine kinases, ERK/JNK MAPK activation, G protein-coupled receptor activation, or interaction with mineralocorticoid receptors). Ang II is a potent activator of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and hence an inducer of reactive oxygen species (ROS) production.

Ang II stimulates the expression of proinflammatory mediators such as interleukin-8/Cytokine-induced Neutrophil Chemoattractant − 3 and interleukin-6 via both receptor subtypes.

MasR expression is in line with the reduction of proinflammatory cytokines and induction of IL-10, an anti-inflammatory cytokine. These anti-inflammatory effects of ARBs W.E.re associated with the downregulation of multiple signalling pathway-related proteins such as PI3K, phospho- Akt, phospho-p38 MAPK, phospho-JNK, phospho-ERK, and phospho-MAPK-2

Cells expressing pattern recognition receptors which can detect pathogen-associated Molecular Patterns (PAMPs) and Damage-Associated Molecular Patterns (DAMPs), triggers the activation of cytoplasmic NOD-Like Receptor family and Pyrin domain-containing 3 protein (NLRP3) inflammasome pathway. The inflammasome activation in macrophages, epithelial cells, and endothelial cells releases proinflammatory cytokines, Interleukin (IL)‐1β and IL‐18, which produce neutrophilia and leukopenia, contributing to the pathogenic inflammation responsible for the severity of symptoms of COVID‐19

Toll-Like Receptor (TLR)3, TLR7, TLR8, and TLR9, sensing viral RNA, activate the Nuclear Factor kappa B (NF-κB) pathway and a high number of proinflammatory cytokines with a significant role in initiating virus-induced inflammation

The increased secretion of the proinflammatory cytokines and chemokines IL-6, Interferon-gamma (IFN-γ), Monocyte Chemoattractant Protein-1 (MCP-1), and IFN-γ-induced Protein 10 (IP-10), attracts immune cells, notably monocytes and T lymphocytes, but not neutrophils(19,24,26–28).

The Warburg Effect/SARS-CoV-2 relationship and the presented phenomena in the clinical and laboratory evaluation

The interference of SARS-CoV-2 in the human immunometabolic pathways seems to be the cause of the severity of the disease, especially in those who have inflammatory comorbidities and divert cellular metabolism to the glycolytic pathway and the immune system to create a tolerant environment in the presence of an inflammatory state. These changes are even more intensified and directly proportional to the lung injury caused by the coronavirus.

The immune axis influences the metabolic axis and vice versa. These relationships are described in a simplistic way below and, in more detail, in the Appendix.

Regarding the immunometabolic axis in COVID-19

SARS-CoV-2 infects cells through the ACE-2 protein, internalizing it and promoting its downregulation. It infects II pneumocytes (highly expressing ACE-2), dendritic cells, macrophages, and other cells and tissues that express this protein. With the internalization of ACE-2, there will be less availability of its soluble fraction, mediated by ADAM17, generating an ACE/ACE-2 imbalance, creating a positive trend of inflammatory stimulus. In addition, ACE-2 is part of the intestinal protein complex responsible for the absorption of the neutral amino acids Tryptophan (Try) and Phenylalanine (Phe), simulating, by hypothesis, Hartnup's disease(16,24,29).

Inside the infected cells, the virus launches mechanisms mediated by viral proteins and glycosylation that delay the immune system's identification of the viral RNA, allowing its replication more peacefully, mainly in the first two days of infection.

By initiating the immune response mainly via the production of Interferon-gamma (IFN-𝛾), the axis of Try metabolism is diverted to the production of Kynurenine, negatively interfering with the serotonin and NAD/NADH + pathways, which are usually in the state of homeostasis. Try is processed by the enzyme Tryptophan hydroxylase (TDO) when in homeostasis; however, in the inflammation status, the liver stops producing TDO and the processing of Try starts to be mediated by the indoleamine 2,3-dioxygenase (IDO) enzyme produced mainly by dendritic cells (DCs), Macrophages (MO) and Monocytes. It remains controversial how IDO-1 influences the tendency towards the Kynurenine pathway. KYNA produces some toxic metabolites that bind to GABA receptors. These metabolites are found in diseases such as Alzheimer's and Parkinson's. These metabolites appear to exert significant neuropsychiatric symptoms in COVID-19 patients, whose symptoms are prevalent. In addition, they hinder the action of anaesthetics in sedation and intubation processes and activate pain mechanisms, especially peripheral ones(30–32).

The deviation of the Try axis promotes lower production of NAD/NADH due to low production of the B complex (mainly B3), causing Pellagra signs in patients and an enzymatic deficit in intracellular aerobic respiration. 5-HT is also compromised, producing less Melatonin, and causing acute depressive symptoms, even in patients with no previously reported psychiatric illness history(33–35).

Kynurenine influences AhR receptors present in T lymphocytes mainly, whose activation by this receptor activates mTOR shifting the immune system to Treg and tolerance, also promoting the activation of the innate system enhanced by the hypoxemic environment due to lung injury. The magnitude of the tolerant environment and the activation of the innate over the adaptive immune system appears to be also proportional to the time of exposure to hypoxia, thus timed intubation appears to be part of the treatment for patients with severity predictors for COVID-19(36–39).

Phe is mainly interfered with by neopterin produced mainly by Monocytes and DCs by IFN-𝛾 stimulation. In monocyte-derived macrophages and dendritic cells, IFN-𝛾 triggers GTP-cyclohydrolase-I, the key enzyme for pteridine derivatives biosynthesis like neopterin 5,6,7,8-tetrahydrobiopterin (BH4).

Neopterin has been linked to the mortality outcome in cardiovascular and other inflammatory diseases, in addition, it influences the increase in the Phe/Tyr and Kin/Tryp ratio PAH may be due to an increased output of reactive oxygen species (ROS), which is produced by macrophages upon stimulation by IFN-𝛾 in parallel to neopterin production(40–42).

The decrease in Tyr due to the increase in Phe/Tyr influences the decreased production of Melatonin, affecting the sleep-wake dynamics, with insomnia being a prevalent symptom in COVID-19 patients.

The decrease in Tyr due to the increase in Phe/Tyr influences the decreased production of Melatonin, affecting the sleep-wake dynamics, with insomnia being a prevalent symptom in acute COVID-19 and the "Long COVID-19 Syndrome". Melatonin is synthesized from serotonin in a two-step process by the sequential action of the key enzymes aralkylamine N-acetyltransferase (AANAT) and acetylserotonin O-methyltransferase (ASMT)(36,43–46).

Melatonin acts in the human body as a sleep-inducing hormone and still preserves the evolutionary characteristic of interacting with various ROS to produce cyclic 3-hydroxymelatonin and other melatonin metabolites, e.g., N1-acetyl-N2-formyl-5-methoxykynuramine and N-acetyl-5-methoxykynuramine. These metabolites function as radical scavengers, sometimes even more aggressively than Melatonin, regarding their capacity to neutralize ROS. Melatonin stimulates the antioxidant enzyme superoxide dismutase (SOD2), an action that involves an elevated level of sirtuin 3 (SIRT3). Melatonin enters mitochondria through the oligopeptide transporters, PEPT1/2 and influences mitochondrial membrane potential by uncoupling protein (UCP); finally, Melatonin from the matrix may leak out of the mitochondria to interact with the melatonin receptors, MT1 and MT2, to control the release of cytochrome c(47–49).

Most of 5-HT originates outside the central nervous system, with only about 3 to 5% of the total produced represented by this system. Most are produced peripherally, most produced by enterochromaffin cells in the intestine. 5-HT, increasingly recognized as a hormone and neurotransmitter, plays an essential role in glycaemic control. Patients with insulin resistance have elevated serum 5-HT concentrations. Adipocyte-derived 5-HT inhibits adaptive thermogenesis in brown and subcutaneous adipose tissues. In contrast, gut-derived 5-HT regulates hepatic lipid accumulation through the gut–liver axis but activates lipolysis specifically in visceral adipocytes under obese conditions via HTR2B signalling, at 5 -HT receptor that couples to G proteins(33,50–53).

In adipose tissue, 5-HT, when in deficit, promotes lipolysis in yellow fat, promoting an important event called thermogenesis. Initially, an adaptive mechanism to cold exposure that becomes harmful in pathological conditions, as in obese patients and with insulin resistance in COVID-19, promotes hyperthermia and tissue damage. This state can be alleviated by using an insulin pump that reverses the lipolysis mechanism. Still, during oxidative stress, the stimulus to greater adrenaline production promotes intensification of thermogenesis, constituting a severe cycle if maintained in critically ill COVID-19 patients. Central 5-HT exerts an opposite effect of peripheral 5-HT on adipocytes, and the central serotonergic neurons may be master regulators of whole-body energy homeostasis. This fact may be associated with an acute situation of exposure to cold in patients with normoglycemia and a situation in which there is chronic hyperuricemia. Peripheral 5-HT is increased in hyperglycaemic status, and adipocyte-derived serotonin may increase energy storage and adipogenesis in WAT through HTR2A and inhibit adaptive thermogenesis in BAT through HTR3. Paracrine and central serotonin act on the pancreas to stimulate insulin production, while peripheral serotonin induces hypoglycaemia and stimulates obesity. This antagonistic action is essential in the homeostatic control of glucose, which is altered in critically ill COVID-19 patients and in patients with insulin resistance and 2TDM(54–57).

Chronic inflammatory status causes deficiency in peripheral and central amounts of serotonin. In COVID-19, the production mechanism is reduced by Try deficiency and consumption due to inflammatory control for Treg induction. Patients with high serum 5-HT start a consumption process due to the a priori issues reported in the inflammatory environment resulting from SARS-CoV-2 infection. Due to the lack of 5-HT, the prevalent phenomena of hyperglycaemia and hyperthermia secondary to thermogenesis or even hypothermia events occur in normoglycemic patients without previous insulin resistance.

The insulin resistance status favours the polarization of M2 macrophages, whose characteristic is an anti-inflammatory action. 5-HT promotes inhibition of IL-12 and TNF-α release, but it increases IL-10, NO, and PGE2 production via 5HT2 receptors. 5HT stimulates macrophage polarization to M2-like phenotype, and this effect is mediated by 5HT2B and 5HT7, which are preferentially expressed by anti-inflammatory M2 macrophages(58–62).

The hypothalamic pituitary adrenal (HPA) axis is responsible for mediating various changes in the body in homeostasis and at the time of stress, as it exerts glycaemic control, sleep-wake control (through the action of the melatonin pathway), in the metabolic axis with peripheral impact and neuropsychiatric, and in the immune system trigger multiple changes, usually anti-inflammatory. Dissociated dynamics between ACTH and glucocorticoids are observed when inflammatory stress is present. Hypothalamic release of corticotropin-releasing factor (CRF) binds to CRF receptors on the anterior pituitary gland, and adrenocorticotropic hormone (ACTH) is released. Because of ACTH, the adrenal cortex produces and releases cortisol. Cortisol exerts negative feedback to the hypothalamus. This hypothalamic cortisol sensitivity decreases with ageing. The hypothalamus responds positively to the catecholaminergic input, representing a major excitatory drive on the HPA axis and inducing CRF expression and protein. Vasopressin also has a positive effect on the activation of the HPA axis.(63–65)

The Warburg Effect is the metabolic signature in COVID-19, as SARS-CoV-2 expresses proteins that favour metabolic modification for anaerobic glycolysis at the expense of oxidative phosphorylation, just as other viruses do. However, the hypoxia caused by lung lesions by the action of the coronavirus intensifies the expression of proteins that facilitate the metabolic mechanism of the Warburg effect even more (Appendix).

The Warburg effect, also called aerobic glycolysis, is a mechanism in which the cell obtains energy (ATP) through the glycolytic pathway at the expense of oxidative phosphorylation and is initially described for neoplastic cells hypoxemic environments with and without hyperglycaemia(3,4,66–69).

The hyperglycaemic environment favours the development of the Warburg effect, as hypoxia and inflammation intensify this effect. That is why inflammatory and neoplastic diseases, obesity, 2MDD and advanced heart failure (diseases now considered inflammatory because they promote tissue hypoxia and, consequently, inflammation) are predictors of severity in COVID-19.

The Warburg effect is essential in favouring the Pentoses pathway to provide nitrogenous bases as a source for viral replication. Furthermore, it causes the displacement of Pyruvate to form lactate, mediated by lactic dehydrogenase (LDH). Thus, oxidative phosphorylation can occur at a lower intensity than what occurs in physiological normality. Lactate travels to the liver to form glucose via the Cori cycle(7,70).

COVID-19 patients have elevated LDH and lactate, a hallmark of the disease, in addition to significant lymphopenia. DHL is stimulated due to the high accumulation of Pyruvate. The citric acid cycle is under-functioning. Thus, the investigation of LDH and Lactate can help diagnose the disease, both in the acute and chronic phases (The long COVID-19 syndrome), being good tests to differentiate, for example, inflammatory syndrome or inflammatory shock from sepsis or septic shock. Although the events may overlap, there is a need to use antimicrobials since systemic inflammation allows bacterial translocation through the skin and intestine in a tolerant and tumorigenic environment as in COVID-19(7,71).

The activated pentose pathway (PPP) supports purine formation, and NADPH generated by the pentose phosphate pathway (PPP) is necessary for glutathione recycling for antioxidant protection and lipid synthesis. Glutamate also plays an essential role in W.E., as this amino acid is required to provide substrate. Glutamate is formed from the breakdown of skeletal tissue, contributing significantly to the wasting syndrome in COVID-19. Glutamine produces oxaloacetate during anaplerotic reactions in various cell types in many c-Myc transformed cells. It is a prevalent condition in the elderly and can be confused due to some neoplasm.

What differentiates neoplastic wasting syndrome from "The long COVID-19 syndrome" is the fact that the latter has acute weight loss, in addition to acute delirium with acute loss of functionality, elevated LDH and lactate and no previous history of neoplasia. Although COVID-19 may open the door to the rapid development of neoplastic cells due to cellular changes brought about by oxidative stress and W.E. (6,69,72,73)

W.E. favours dyslipidaemia, as it favours the formation of fatty acids to be used for ATP production via beta-oxidation. This status is also favoured by oxidative stress with the intensification of hyperglycaemia. This explains recent studies that find alterations in the metabolism of lipids, Branched-chain amino acids (BCAA), Try, Phe and citric acid cycle metabolites(74–77).

Host lipid metabolism is via peroxisome proliferator receptor gamma (PPAR-γ)-signalling, one of the central regulators of lipid homeostasis that controls fatty acid uptake, storage and lipogenesis. Many viral and parasitic intracellular pathogens utilize host lipid droplets during their life cycle, as in the dengue virus.

The W.E. de novo increased lipid synthesis, elevated anabolic processes, decreased/altered TCA cycle metabolism, and high glucose usage as an energy and carbon source for cell growth and division. Oncogenes such as myc and ras, and suppressor genes such as p53 are transcriptional factors or signalling molecules that are typically present in cells with W.Epento(77,78).

PPP operates in the oxidative or the non-oxidative mode depending on the relative contribution of G6PDH and transketolase/transaldolase action, substrate inputs (G6P, F6P, Triose-P (3C), NADH/NAD ratio and the removal of F6P by the formation of F1,6 diP, and triose-P by pyruvate kinase The PPP intermediates are parts of the sugar-phosphate system consisting of ketoses, aldoses and sugar alcohols, which oxidation of these promotes amino acid precursors.

Energy metabolism in cells comprises a spectrum of anabolic and catabolic activities driven by a hybrid system, one generating predominantly NADH (anabolic) and the other ATP (catabolic). Reducing equivalents are best used for anabolic processes such as fatty acid synthesis and nucleic acid pentose synthesis, while ATP's are used for macromolecular synthesis, substrate transports, and electrical and mechanical energy generation(78–81).

Many of the enzymes in this glycolysis/pentose cycle compartment are inducible by the hypoxia-induced factor 1 (HIF-1), in addition, viral proteins that favour the shift of metabolism to anaerobic glycolysis, NAD/NADH+ (which is in lacking, for example, by the altered Try pathway), Growth factor stimulation results in signalling through RTKs to activate PI3K/Akt and Ras. Akt promotes glucose transporter activity and stimulates glycolysis by activating several glycolytic enzymes, including hexokinase and phosphofructokinase (PFK). Akt phosphorylation of apoptotic proteins such as Bax makes cancer cells resistant to apoptosis and helps stabilize the outer mitochondrial membrane (OMM) by promoting attachment of mitochondrial hexokinase (mtHK) to the VDAC channel complex. RTK signalling to c-Myc results in transcriptional activation of numerous genes involved in glycolysis and lactate production. The p53 oncogene transactivates TP-53-induced Glycolysis and Apoptosis Regulator (TIGAR) and increases NADPH production by PPS. Signals impacting levels of hypoxia-inducible factor (HIF) can increase expression of enzymes such as LDHA to promote lactate production, and pyruvate dehydrogenase kinase to inhibit the action of pyruvate dehydrogenase and limit the entry of Pyruvate into the Krebs Cycle.

Another important consequence of the breakdown of muscle tissue in search of amino acids and glutamine is the elevation of uraemia, often not associated with renal dysfunction.

W.E. also acts on the immune system, favouring a more tolerant environment than the inflammatory one, being responsible, for example, in the occurrence of metastases, considering its effect on neoplastic cells. The detailed mechanisms of EW are covered in the "APPENDIX" of this article(3,81–86).

W.E. acts on the immune system in several ways, tending the immune system towards tolerance. Negative signalling induced by ligand binding causes a downregulation of the immune response to avoid overactivation of immune activities, and some of the immune checkpoints have been identified, such as PD-1, CTLA4, TIM3, and so on. W.E. stimulates macrophage polarization to M2 induces apoptosis of NK and T-cells of the inflammatory spectrum while favouring innate immunity and the Treg pole.

Myeloid and lymphoid cells of both the innate and adaptive immune systems, ranging from lymphocytes and NK cells to DCs and macrophages, undergo Warburg-like metabolic reprogramming in response to inflammatory stimuli. The balance between EW and OXPHOS is responsible for the differentiation of immune system cells. Upregulation of glycolysis in T cells is a coordinated response to immune activation, with CD28 co-stimulation producing increased glucose transporter expression, glucose uptake, and glycolysis via phosphatidylinositol 3-kinase (PI3K). Glycolysis is necessary for survival/proliferation, differentiation, and effector functions of CD4. It is suggested that glycolytic reprogramming in lymphocytes presents regulators such as Myc and hypoxia-inducible factor 1α, increased expression of the glucose transporter GLUT1, and activation pyruvate dehydrogenase kinase isoform 1(87–90).

For example, Tcm cells use energy mainly via the oxidation of fatty acids, and, with W.E. inhibition, these lymphocytes are inhibited via OXPHOS activation. This existing balance may perhaps suggest the range of phenotypes presented by COVID-19 patients about antibody production, NK cell action and the tendency to Treg in addition to apoptosis of immune system cells in general; may also corroborate the explanation of the immunoparalysis presented in the period after acute infection by SARS-CoV-2.

The acidification of intra and extracellular environments promoted by W.E. contributes to tolerance. Cytosolic lactate is transported out of cells via monocarboxylate transporters (MCT), while protons (H+) are secreted through membrane-bound transporters, leading to extracellular acidification. Vacuole ATPases (V-ATPase) allow H + into the extracellular space, contributing to its acidification by consuming ATP. This acidification mechanism is beneficial for cancer cells in their proliferation, survival, metastasis, and signal transduction(91–93).

Acidification of intra and extracellular media can benefit SARS-CoV-2 by providing an optimal environment for the performance of Cathepsins, especially Cathepsin L, used by the coronavirus in the processing of viral proteins, enabling their replication. This fact corroborates the difficulty in raising the pH in many critically ill patients, using the permissive hypercapnia approach. When thinking about the viral mechanisms of action on the human host, it would be a mistake to allow high CO2 pressures, as it contributes to the maintenance of the low pH stimulated by W.E. activation of cathepsins, syncytium formation and a tendency to immunosuppression (Figs. 2 and Fig. 3).(93,94)

The increased demand for glucose can trigger a hypoglycaemic event, even in a patient with hyperglycaemia due to inflammation stimulating oxidative stress with hyper cortisol production. Elevated uraemia is promoted by increased purine synthesis; dyslipidaemia is motivated by increased lipid synthesis. Hyperlactatemia enters the Cori cycle when the body is deprived of glucose; however, in hyperglycaemia, the cycle is not activated, contributing to the maintenance of high lactate. Created with BioRender.com.

COVID-19 is a multisystem infectious disease since the ACE-2 receptor, for a viral infection to occur, is disseminated to almost all human body tissues.

The most recent proteomics studies show alterations in the metabolism of lipids, Branched-chain amino acids (BCAAs), Tryptophan, Phenylalanine, and components of the citric acid cycle, probably related to the shift from oxidative metabolism, mediated by OXPHOS to aerobic glycolysis metabolism, called the Warburg effect(72,78).

Many viruses use W.E. to carry out replication more effectively within cells, as aerobic glycolysis provides substrate (nitrogenous bases and ATP) for producing genetic material and molecules that make up the viral organization. W.E. is used by neoplastic cells for growth and metastasis and usually occurs in a hyperglycaemic and hypoxemic environment. Although OXPHOS continues to occur, it is less used as the metabolic changes that occur trigger a truncated citric acid cycle.

W.E. cause significant acidosis since there is a large lactate production from pyruvate, which is prevented from going to TCA. The increase in pyruvate is a stimulus for LDH expression. In this way, W.E. explains the laboratory alterations prevalent in COVID-19 patients, especially in severe and critical ones. The lactate produced acidifies the intra and extracellular environments and is the basis for glucose production by the liver (Fig. 2 and Fig. 3).

Uraemia, often present with preserved renal function, is justified by the large consumption of skeletal tissue to obtain amino acids, especially glutamate, which serves as an energy substrate, together with the activation of the pentose pathway (PPP).

Acidaemia allows an optimal environment for activating lysosomal enzymes, for example, cathepsin L, widely used by SARS-CoV-2 for its replicative process to occur in the host cell. In addition, cathepsin L is 6 times higher in the syncytiotrophoblast, and the intense cathepsin activation may explain the formation of the syncytial structure in critically ill patients. That is, permissive hypercapnia without pH correction, which must be performed with 8.4% sodium bicarbonate, provides an optimal environment for the activation of cathepsins, positively contributing to viral replication, in addition to causing a shift in the immune axis to the tolerant pole. and tumorigenic(116).

COVID-19 patients, to a greater or lesser extent, undergo a process of immunosuppression resulting from W.E., although they remain, at the same time, with a tendency to activate the TH17 immune response. This inflammatory environment concomitant with the shift from the pole to Treg is conducive to the emergence of autoantibodies. In addition, lymphocytic apoptosis contributes to the development of neoplasms since there is the death of N.K. and TCD8 + in an environment where cells are under the significant influence of oxidative stress, altering all cellular control mechanisms. Many prevalence studies are still needed, but the development of neoplastic diseases (mainly breast and gastrointestinal system) linked to previous SARS-CoV-2 infection is already being noticed.

The hypoxia resulting from the lung injury caused by the coronavirus is an excellent ally for intensifying the metabolic and immunological mechanisms that lead the patient to the severe and critical forms of the disease. HIF is responsible for stimulating inflammation; at the same time, HIF can be expressed in inflammatory processes. Hypoxia intensifies oxidative stress, causing an increase in cortisol and insulin resistance, contributing to an optimal environment for aerobic glycolysis to occur. This chronic process can cause adrenal insufficiency and be another cause of shock in COVID-19(82,84).

The magnitude of COVID-19 is influenced by multiple factors such as the parasite-host relationship, the host's genetic issues, and the amount of inoculum to which the patient was exposed. However, factors of great importance for the patient to progress to severity are mainly the time of exposure to hypoxia and inflammatory comorbidities that produce some degree of hypoxia in the patient. All these conditions can corroborate to clinical and laboratory symptoms in COVID-19 patient (Fig. 4).

SARS-CoV-2 infection is a catastrophe that continues to claim many victims, especially the elderly, but remains underreported or even unreported. This fact occurs because the patient is admitted to hospitals after the viraemic phase or in "The Long COVID-19 Syndrome", periods in which RT-PCR is negative for the virus (with rare exceptions in acute disease, the viraemic may be more prolonged).

This review and theory show that some tests such as lactate and LDH can contribute to the diagnosis of COVID-19, when associated with the clinical history of the disease, blood gas analysis, hypoglycaemia events and neuropsychiatric changes.

The content of this article also seeks to contribute to improving the clinical management of critically ill patients by identifying important relationships in the host-parasite relationship that impact the metabolic changes found in patients.

COVID-19 is a challenge for doctors, and more studies are necessary to elucidate mechanisms still unexplained in the disease so that more deaths are avoided.

FINAL CONSIDERATIONS

We should not consider serology (IgM or IgG), not even RT-PCR for SARS-CoV-2 to close the diagnosis of COVID-19, as they can be negative on many occasions (RT-PCR is negative, most of the time, because the patient is late admitted to the hospital or is on chronic COVID-19).

One should consider the laboratory tests suggested in this article, natural history of the disease, epidemiological period.

As a suggestion: blood counts containing significant lymphopenia associated with tomographic imaging are very useful for making the diagnosis.

For this review, articles in English were allowed. PubMed and Google academic databases were used, the second being for theoretical complementation when necessary. Thus, it was a database used throughout the production of the manuscript. There was no characterization of the minimum date for the articles. From the descriptors: "COVID-19" AND "WARBURG EFFECT"; "COVID-19" AND "AEROBIC GLYCOLYSIS", "SARS-CoV-2" AND "WARBURG EFFECT" AND "SARS-CoV-2" AND "AEROBIC GLYCOLYSIS". Only five articles referring to "metabolic alterations", "Warburg effect" and aerobic glycolysis" in the abstract were found and considered for this review. There were no articles discarded using the search descriptors. The criteria used were adapted from the PRISMA protocol, at https: //www.canada.ca/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2015-41 /ccdr-volume-41-04-april − 2- 2015/ccdr-volume-41-04-april-2-2015-3.html Accessed on 02/09/2021 Another 119 articles were added during the writing to support the research. The articles are shown in the Table 1.

Table 1

Articles regarding SAR-CoV-2 and Warburg Effect published between 2020 - May 2022
AUTHOR	WARBURG EFFECT, AEROBIC GLYCOLYSIS OR MATABOLIC CHANGES (ABSTRACT)	DOI
Icard P. et al.(9)	Yes	10.1016/j.biochi.2020.11.010
Icard P. et al.(10)	Yes	10.1016/j.biochi.2021.09.009
Ferraro E. et al.(11)	Yes	10.1155/2021/8841911
Tan D.(12)	Yes	10.3390/molecules25194410
Zhihua R. et.al(13)	Yes	10.3389/fmicb.2021.807737

ACKNOWLEDGMENTS

I dedicate this work to all COVID-19 patients who have died or who remain with sequelae.

I dedicate this work to my mother, who was strong and overcoming severe COVD-19.

I dedicate this work to my professor Esper G. Kallás, to my colleagues from the Laboratory of Immunopathology and Allergy, and to colleagues from the Research Centre II of the University of São Paulo - Medicine School.

I dedicate this work to my colleagues at the Emergency Room of the University Hospital of the University of São Paulo.

LIMITATIONS OF THE ARTICLE

This article requires studies to be carried out in order to control the altered metabolic pathways in COVID-19. There are also studies that prove the production of the drugs operations in this work.

AUTHOR'S CONTRIBUTION

Luiz Zanella wrote this article and created all the figures presented using Biorender.com.

CONFLICTS OF INTEREST

The author has no conflicts of interest.

FUNDING

The author did not receive any type of funding to prepare this article.

1. Pathogens Hijack Host Cell Metabolism: Intracellular Infection as a Driver of the Warburg Effect in Cancer and Other Chronic Inflammatory Conditions. Immunometabolism. 2021;

2. Gonzaga L, de Assis Barros D’ F, Zanella E. The COVID-19 “Bad Tryp” Syndrome: NAD/NADH+, Tryptophan Phenylalanine Metabolism and Thermogenesis like Hecatomb - The Hypothesis of Pathophysiology Based on a Compared COVID-19 and Yellow Fever Inflammatory Skeleton. Journal of Infectious Diseases and Epidemiology. 2022 Jan 13;8(1):243.

3. Bartrons R, Caro J. Hypoxia, glucose metabolism and the Warburg’s effect. J Bioenerg Biomembr [Internet]. 2007 Jun [cited 2022 Jan 20];39(3):223–9. Available from: https://pubmed.ncbi.nlm.nih.gov/17661163/

4. Venkatesh K v., Darunte L, Bhat PJ. Warburg Effect. Encyclopedia of Systems Biology [Internet]. 2013 [cited 2022 Jan 20];2349–50. Available from: https://link.springer.com/referenceworkentry/10.1007/978-1-4419-9863-7_703

5. Schwartz L, Supuran C, Alfarouk K. The Warburg Effect and the Hallmarks of Cancer. Anti-Cancer Agents in Medicinal Chemistry. 2017 Jan 24;17(2):164–70.

6. Vaupel P, Multhoff G, Bennet L, Chan J, Vaupel P, Multhoff G, et al. Revisiting the Warburg effect: historical dogma versus current understanding. The Journal of Physiology [Internet]. 2021 Mar 1 [cited 2022 Jan 20];599(6):1745–57. Available from: https://onlinelibrary.wiley.com/doi/full/10.1113/JP278810

7. Suistomaa M, Ruokonen E, Kari A, Takala J. Time-pattern of lactate and lactate to pyruvate ratio in the first 24 hours of intensive care emergency admissions. Shock [Internet]. 2000 [cited 2022 May 4];14(1):8–12. Available from: https://pubmed.ncbi.nlm.nih.gov/10909886/

8. Velavan TP, Linh LTK, Kreidenweiss A, Gabor J, Krishna S, Kremsner PG. Longitudinal Monitoring of Lactate in Hospitalized and Ambulatory COVID-19 Patients. The American Journal of Tropical Medicine and Hygiene [Internet]. 2021 Mar 3 [cited 2021 Dec 9];104(3):1041–4. Available from: https://www.ajtmh.org/view/journals/tpmd/104/3/article-p1041.xml

9. Icard P, Lincet H, Wu Z, Coquerel A, Forgez P, Alifano M, et al. The key role of Warburg effect in SARS-CoV-2 replication and associated inflammatory response. Biochimie. 2021 Jan 1;180:169–77.

10. Icard P, Simula L, Rei J, Fournel L, de Pauw V, Alifano M. On the footsteps of Hippocrates, Sanctorius and Harvey to better understand the influence of cold on the occurrence of COVID-19 in European countries in 2020. Biochimie [Internet]. 2021 Dec 1 [cited 2022 May 6];191:164–71. Available from: https://pubmed.ncbi.nlm.nih.gov/34555456/

11. Ferraro E, Germanò M, Mollace R, Mollace V, Malara N. HIF-1, the Warburg Effect, and Macrophage/Microglia Polarization Potential Role in COVID-19 Pathogenesis. Oxidative Medicine and Cellular Longevity. 2021;2021.

12. Yang HC, Ma TH, Tjong WY, Stern A, Chiu DTY. G6PD deficiency, redox homeostasis, and viral infections: implications for SARS-CoV-2 (COVID-19). https://doi.org/101080/1071576220201866757 [Internet]. 2021 [cited 2022 May 5];55(4):364–74. Available from: https://www.tandfonline.com/doi/abs/10.1080/10715762.2020.1866757

13. Ren Z, Yu Y, Chen C, Yang D, Ding T, Zhu L, et al. The Triangle Relationship Between Long Noncoding RNA, RIG-I-like Receptor Signaling Pathway, and Glycolysis. Frontiers in Microbiology. 2021 Nov 30;12:3693.

14. Barzegar M, Stokes KY, Chernyshev O, Kelley RE, Alexander JS. The Role of the ACE2/MasR Axis in Ischemic Stroke: New Insights for Therapy. Biomedicines 2021, Vol 9, Page 1667 [Internet]. 2021 Nov 11 [cited 2022 Feb 23];9(11):1667. Available from: https://www.mdpi.com/2227-9059/9/11/1667/htm

15. Medina-Enríquez MM, Lopez-León S, Carlos-Escalante JA, Aponte-Torres Z, Cuapio A, Wegman-Ostrosky T. ACE2: the molecular doorway to SARS-CoV-2 [Internet]. Vol. 10, Cell and Bioscience. BioMed Central Ltd; 2020 [cited 2021 May 30]. p. 1–17. Available from: https://doi.org/10.1186/s13578-020-00519-8

16. Dhaundiyal A, Kumari P, Jawalekar SS, Chauhan G, Kalra S, Navik U. Is highly expressed ACE 2 in pregnant women “a curse” in times of COVID-19 pandemic? Life Sciences [Internet]. 2021 Jan 1 [cited 2021 Sep 4];264:118676. Available from: /pmc/articles/PMC7598563/

17. Chaudhry F, Lavandero S, Xie X, Sabharwal B, Zheng YY, Correa A, et al. Manipulation of ACE2 expression in COVID-19. Open Heart [Internet]. 2020 Dec 1 [cited 2022 Feb 24];7(2):e001424. Available from: https://openheart.bmj.com/content/7/2/e001424

18. Gengler C, Dubruc E, Favre G, Greub G, Leval L de, Baud D. SARS-CoV-2 ACE-receptor detection in the placenta throughout pregnancy. Clinical Microbiology and Infection [Internet]. 2021 Mar 1 [cited 2021 Sep 4];27(3):489–90. Available from: http://www.clinicalmicrobiologyandinfection.com/article/S1198743X20306030/fulltext

19. Samavati L, Uhal BD. ACE2, Much More Than Just a Receptor for SARS-COV-2. Frontiers in Cellular and Infection Microbiology. 2020 Jun 5;10:317.

20. Chen F, Zhang Y, Li X, Li W, Liu X, Xue X. The Impact of ACE2 Polymorphisms on COVID-19 Disease: Susceptibility, Severity, and Therapy. Frontiers in Cellular and Infection Microbiology. 2021 Oct 22;11:1002.

21. Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science (1979) [Internet]. 2020 Mar 27 [cited 2021 May 30];367(6485):1444–8. Available from: http://science.sciencemag.org/

22. Zhang H, Li HB, Lyu JR, Lei XM, Li W, Wu G, et al. Specific ACE2 expression in small intestinal enterocytes may cause gastrointestinal symptoms and injury after 2019-nCoV infection. International Journal of Infectious Diseases [Internet]. 2020;96:19–24. Available from: https://doi.org/10.1016/j.ijid.2020.04.027

23. Shook LL, Bordt EA, Meinsohn MC, Pepin D, Guzman RM de, Brigida S, et al. Placental expression of ACE2 and TMPRSS2 in maternal SARS-CoV-2 infection: are placental defenses mediated by fetal sex? bioRxiv [Internet]. 2021 Apr 1 [cited 2021 Sep 1];2021.04.01.438089. Available from: https://www.biorxiv.org/content/10.1101/2021.04.01.438089v1

24. Heurich A, Hofmann-Winkler H, Gierer S, Liepold T, Jahn O, Pohlmann S. TMPRSS2 and ADAM17 Cleave ACE2 Differentially and Only Proteolysis by TMPRSS2 Augments Entry Driven by the Severe Acute Respiratory Syndrome Coronavirus Spike Protein. Journal of Virology [Internet]. 2014 Jan 15 [cited 2022 Feb 23];88(2):1293–307. Available from: https://journals.asm.org/journal/jvi

25. Li M, Chen L, Zhang J, Xiong C, Li X. The SARS-CoV-2 receptor ACE2 expression of maternal-fetal interface and fetal organs by single-cell transcriptome study. PLOS ONE [Internet]. 2020 Apr 1 [cited 2021 Sep 1];15(4):e0230295. Available from: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0230295

26. Camargo SMR, Vuille-Dit-Bille RN, Meier CF, Verrey F. ACE2 and gut amino acid transport [Internet]. Vol. 134, Clinical Science. Portland Press Ltd; 2020 [cited 2021 Feb 15]. p. 2823–33. Available from: https://pubmed.ncbi.nlm.nih.gov/33140827/

27. Gemmati D, Bramanti B, Serino ML, Secchiero P, Zauli G, Tisato V. COVID-19 and Individual Genetic Susceptibility/Receptivity: Role of ACE1/ACE2 Genes, Immunity, Inflammation and Coagulation. Might the Double X-Chromosome in Females Be Protective against SARS-CoV-2 Compared to the Single X-Chromosome in Males? International Journal of Molecular Sciences 2020, Vol 21, Page 3474 [Internet]. 2020 May 14 [cited 2022 Feb 23];21(10):3474. Available from: https://www.mdpi.com/1422-0067/21/10/3474/htm

28. Xiang Z, Liu J, Shi D, Chen W, Li J, Yan R, et al. Glucocorticoids improve severe or critical COVID-19 by activating ACE2 and reducing IL-6 levels. International Journal of Biological Sciences [Internet]. 2020 [cited 2022 Feb 24];16(13):2382. Available from: /pmc/articles/PMC7378642/

29. Ouyang Y, Bagalkot T, Fitzgerald W, Sadovsky E, Chu T, Martínez-Marchal A, et al. Term Human Placental Trophoblasts Express SARS-CoV-2 Entry Factors ACE2, TMPRSS2, and Furin. mSphere. 2021 Apr 28;6(2).

30. Merlo LMF, DuHadaway JB, Montgomery JD, Peng WD, Murray PJ, Prendergast GC, et al. Differential Roles of IDO1 and IDO2 in T and B Cell Inflammatory Immune Responses. Frontiers in Immunology [Internet]. 2020 Aug 18 [cited 2021 Feb 10];11:1861. Available from: https://www.frontiersin.org/article/10.3389/fimmu.2020.01861/full

31. de Araújo EF, Feriotti C, de Lima Galdino NA, Preite NW, Calich VLG, Loures FV. The IDO-AhR axis controls Th17/Treg immunity in a pulmonary model of fungal infection. Frontiers in Immunology [Internet]. 2017 Jul;8(JUL):880. Available from: www.frontiersin.org

32. Torosyan R, Huang S, Bommi P v., Tiwari R, An SY, Schonfeld M, et al. Hypoxic preconditioning protects against ischemic kidney injury through the IDO1/kynurenine pathway. Cell Reports [Internet]. 2021 Aug 17 [cited 2021 Oct 9];36(7). Available from: http://www.cell.com/article/S2211124721009815/fulltext

33. Wyler SC, Lord CC, Lee S, Elmquist JK, Liu C. Serotonergic Control of Metabolic Homeostasis. Frontiers in Cellular Neuroscience. 2017 Sep 20;0:277.

34. O’Mahony SM, Clarke G, Borre YE, Dinan TG, Cryan JF. Serotonin, tryptophan metabolism and the brain-gut-microbiome axis. Vol. 277, Behavioural Brain Research. Elsevier; 2015. p. 32–48.

35. Shong KE, Oh CM, Namkung J, Park S, Kim H. Serotonin regulates de novo lipogenesis in adipose tissues through serotonin receptor 2a. Endocrinology and Metabolism. 2020;35(2):470–9.

36. Oxenkrug G. Insulin resistance and dysregulation of tryptophan-kynurenine and kynurenine-nicotinamide adenine dinucleotide metabolic pathways. In: Molecular Neurobiology [Internet]. Humana Press Inc.; 2013. p. 294–301. Available from: /pmc/articles/PMC3779535/?report=abstract

37. Geisler S, Mayersbach P, Becker K, Schennach H, Fuchs D, Gostner JM. Serum tryptophan, kynurenine, phenylalanine, tyrosine and neopterin concentrations in 100 healthy blood donors. Pteridines [Internet]. 2015 Mar 1 [cited 2022 Feb 28];26(1):31–6. Available from: https://www.degruyter.com/document/doi/10.1515/pterid-2014-0015/html

38. Nguyen NT, Nakahama T, Le DH, Son L van, Chu HH, Kishimoto T. Aryl Hydrocarbon Receptor and Kynurenine: Recent Advances in Autoimmune Disease Research. Frontiers in Immunology [Internet]. 2014 [cited 2021 Aug 26];5(OCT). Available from: /pmc/articles/PMC4212680/

39. Du L, Xing Z, Tao B, Li T, Yang D, Li W, et al. Both IDO1 and TDO contribute to the malignancy of gliomas via the Kyn–AhR–AQP4 signaling pathway. Signal Transduction and Targeted Therapy [Internet]. 2020 Dec 1 [cited 2021 Feb 22];5(1):1–13. Available from: https://doi.org/10.1038/s41392-019-0103-4

40. Gürcü S, Girgin G, Yorulmaz G, Kılıçarslan B, Efe B, Baydar T. Neopterin and biopterin levels and tryptophan degradation in patients with diabetes. Scientific Reports 2020 10:1 [Internet]. 2020 Oct 12 [cited 2021 Nov 4];10(1):1–8. Available from: https://www.nature.com/articles/s41598-020-74183-w

41. How Do Patients With Myeloproliferative Neoplasms Fare After COVID-19 Infection? - ASH Clinical News [Internet]. [cited 2021 Sep 8]. Available from: https://www.ashclinicalnews.org/news/literature-scan/patients-myeloproliferative-neoplasms-fare-covid-19-infection/

42. Deac OM, Mills JL, Gardiner CM, Shane B, Quinn L, Midttun Ø, et al. Serum Immune System Biomarkers Neopterin and Interleukin-10 Are Strongly Related to Tryptophan Metabolism in Healthy Young Adults. The Journal of Nutrition [Internet]. 2016 Sep 1 [cited 2021 Nov 4];146(9):1801–6. Available from: https://academic.oup.com/jn/article/146/9/1801/4584888

43. Mohapatra SR, Sadik A, Tykocinski LO, Dietze J, Poschet G, Heiland I, et al. Hypoxia Inducible Factor 1α Inhibits the Expression of Immunosuppressive Tryptophan-2,3-Dioxygenase in Glioblastoma. Frontiers in Immunology. 2019 Dec 4;0:2762.

44. Broekhuizen M, Klein T, Hitzerd E, Rijke YB de, Schoenmakers S, Sedlmayr P, et al. l-Tryptophan–Induced Vasodilation Is Enhanced in Preeclampsia. Hypertension [Internet]. 2020 Jul 1 [cited 2021 Aug 20];76(1):184–94. Available from: https://www.ahajournals.org/doi/abs/10.1161/HYPERTENSIONAHA.120.14970

45. Oxenkrug GF, Turski WA, Zgrajka W, Weinstock J v, Summergrad P. Tryptophan-Kynurenine Metabolism and Insulin Resistance in Hepatitis C Patients. Hepatitis Research and Treatment [Internet]. 2013;2013:1–4. Available from: /pmc/articles/PMC3777117/?report=abstract

46. Vyavahare S, Kumar S, Cantu N, Kolhe R, Bollag WB, McGee-Lawrence ME, et al. Tryptophan-Kynurenine Pathway in COVID-19-Dependent Musculoskeletal Pathology: A Minireview. deng zhenhan, editor. Mediators of Inflammation [Internet]. 2021 Oct 5 [cited 2021 Oct 10];2021:1–6. Available from: https://www.hindawi.com/journals/mi/2021/2911578/

47. Boutin JA, Audinot V, Ferry G, Delagrange P. Molecular tools to study melatonin pathways and actions. Trends in Pharmacological Sciences. 2005 Aug;26(8):412–9.

48. Reiter RJ, Ma Q, Sharma R. Melatonin in Mitochondria: Mitigating Clear and Present Dangers. 2020 [cited 2022 Feb 18]; Available from: www.physiologyonline.org

49. Sanchez-Sanchez AM, Antolin I, Puente-Moncada N, Suarez S, Gomez-Lobo M, Rodriguez C, et al. Melatonin Cytotoxicity Is Associated to Warburg Effect Inhibition in Ewing Sarcoma Cells. PLOS ONE [Internet]. 2015 Aug 7 [cited 2022 Feb 18];10(8):e0135420. Available from: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0135420

50. Paulmann N, Grohmann M, Voigt JP, Bert B, Vowinckel J, Bader M, et al. Intracellular serotonin modulates insulin secretion from pancreatic β-cells by protein serotonylation. PLoS Biology. 2009 Oct;7(10).

51. Serotonylation: A novel histone H3 marker | Signal Transduction and Targeted Therapy [Internet]. [cited 2021 Feb 15]. Available from: https://www.nature.com/articles/s41392-019-0048-7

52. Kim M, Lee SM, Jung J, Kim YJ, Moon KC, Seo1 JH, et al. Pinealectomy increases thermogenesis and decreases lipogenesis. Molecular Medicine Reports [Internet]. 2020 Nov 1 [cited 2021 May 22];22(5):4289–97. Available from: https://pubmed.ncbi.nlm.nih.gov/33000192/

53. Lettieri-Barbato D, Aquilano K. Aging and Immunometabolic Adaptations to Thermogenesis [Internet]. Vol. 63, Ageing Research Reviews. Elsevier Ireland Ltd; 2020 [cited 2021 May 22]. Available from: https://pubmed.ncbi.nlm.nih.gov/32810648/

54. Townsend KL, Tseng YH. Brown fat fuel utilization and thermogenesis [Internet]. Vol. 25, Trends in Endocrinology and Metabolism. Elsevier Inc.; 2014 [cited 2021 May 22]. p. 168–77. Available from: https://pubmed.ncbi.nlm.nih.gov/24389130/

55. Müller MJ, Bosy-Westphal A. Adaptive thermogenesis with weight loss in humans [Internet]. Vol. 21, Obesity. Obesity (Silver Spring); 2013 [cited 2021 May 22]. p. 218–28. Available from: https://pubmed.ncbi.nlm.nih.gov/23404923/

56. Periasamy M, Herrera JL, Reis FCG. Skeletal Muscle Thermogenesis and Its Role in Whole Body Energy Metabolism. Diabetes & Metabolism Journal [Internet]. 2017 Oct 24 [cited 2021 Oct 29];41(5):327–36. Available from: http://www.e-dmj.org/journal/view.php?number=494

57. Crane JD, Palanivel R, Mottillo EP, Bujak AL, Wang H, Ford RJ, et al. Inhibiting peripheral serotonin synthesis reduces obesity and metabolic dysfunction by promoting brown adipose tissue thermogenesis. Nature Medicine 2014 21:2 [Internet]. 2014 Dec 8 [cited 2021 Oct 21];21(2):166–72. Available from: https://www.nature.com/articles/nm.3766

58. Mauler M, Bode C, Duerschmied D. Platelet serotonin modulates immune functions [Internet]. Vol. 36, Hamostaseologie. Schattauer GmbH; 2016 [cited 2021 May 22]. p. 11–6. Available from: https://pubmed.ncbi.nlm.nih.gov/25693763/

59. Attademo L, Bernardini F. Are dopamine and serotonin involved in COVID-19 pathophysiology? Vol. 35, European Journal of Psychiatry. Elsevier Espana S.L.U; 2021. p. 62–3.

60. Scotton WJ, Hill LJ, Williams AC, Barnes NM. Serotonin Syndrome: Pathophysiology, Clinical Features, Management, and Potential Future Directions. Int J Tryptophan Res [Internet]. 2019 Jan;12:1178646919873925. Available from: http://www.ncbi.nlm.nih.gov/pubmed/31523132

61. Amireault P, Bayard E, Launay JM, Sibon D, Kim CL van, Colin Y, et al. Serotonin Is a Key Factor for Mouse Red Blood Cell Survival. PLoS ONE [Internet]. 2013 Dec 17 [cited 2021 Oct 9];8(12):83010. Available from: /pmc/articles/PMC3866204/

62. Navin K, Kuppili PP, Menon V. Repurposing Selective Serotonin Reuptake Inhibitors for COVID-19: Rationale and Concerns. Indian Journal of Psychological Medicine [Internet]. 2020 Nov 2 [cited 2021 May 30];42(6):578–80. Available from: https://www.mha.gov.in/sites/default/

63. Kaur H, Bose C, Mande SS. Tryptophan Metabolism by Gut Microbiome and Gut-Brain-Axis: An in silico Analysis. Frontiers in Neuroscience [Internet]. 2019 Jul;13:1365. Available from: www.frontiersin.org

64. Demiselle J, Fage N, Radermacher P, Asfar P. Vasopressin and its analogues in shock states: a review. Annals of Intensive Care [Internet]. 2020 Dec 1 [cited 2021 Aug 31];10(1). Available from: /pmc/articles/PMC6975768/

65. Erickson EN, Carter CS, Emeis CL. Oxytocin, Vasopressin and Prolactin in New Breastfeeding Mothers: Relationship to Clinical Characteristics and Infant Weight Loss: https://doi.org/101177/0890334419838225 [Internet]. 2019 Apr 29 [cited 2021 Aug 31];36(1):136–45. Available from: https://journals.sagepub.com/doi/full/10.1177/0890334419838225

66. Akie TE, Liu L, Nam M, Lei S, Cooper MP. OXPHOS-mediated induction of NAD+ promotes complete oxidation of fatty acids and interdicts non-alcoholic fatty liver disease. PLoS ONE. 2015 May 1;10(5).

67. Liu Y. Fatty acid oxidation is a dominant bioenergetic pathway in prostate cancer [Internet]. Vol. 9, Prostate Cancer and Prostatic Diseases. Nature Publishing Group; 2006 [cited 2021 Feb 21]. p. 230–4. Available from: www.nature.com/pcan

68. Sena CM, Leandro A, Azul L, Seiça R, Perry G. Vascular oxidative stress: Impact and therapeutic approaches [Internet]. Vol. 9, Frontiers in Physiology. Frontiers Media S.A.; 2018 [cited 2021 Feb 15]. p. 1668. Available from: www.frontiersin.org

69. Mor A, Tankiewicz-Kwedlo A, Krupa A, Pawlak D. Role of Kynurenine Pathway in Oxidative Stress during Neurodegenerative Disorders. Cells 2021, Vol 10, Page 1603 [Internet]. 2021 Jun 26 [cited 2021 Oct 9];10(7):1603. Available from: https://www.mdpi.com/2073-4409/10/7/1603/htm

70. Chou JY, Mansfield BC, Weinstein DA. Renal Disease in Type I Glycogen Storage Disease. Genetic Diseases of the Kidney. 2009;693–708.

71. Redant S, Hussein H, Mugisha A, Attou R, Bels D de, Honore PM, et al. Differentiating Hyperlactatemia Type A From Type B: How Does the Lactate/pyruvate Ratio Help? J Transl Int Med [Internet]. 2019 Jul 11 [cited 2022 May 4];7(2):43–5. Available from: https://pubmed.ncbi.nlm.nih.gov/31380235/

72. Kim SH, Baek KH. Regulation of Cancer Metabolism by Deubiquitinating Enzymes: The Warburg Effect. International Journal of Molecular Sciences 2021, Vol 22, Page 6173 [Internet]. 2021 Jun 8 [cited 2022 May 2];22(12):6173. Available from: https://www.mdpi.com/1422-0067/22/12/6173/htm

73. Zanella LGF de ABD. NEUROCOV/PSYCCOV: Neuropsychiatric Phenomena in COVID-19 - Exposing Their Hidden Essence and Warning against Iatrogenesis. Journal of Infectious Diseases and Epidemiology [Internet]. 2021 Aug 6 [cited 2021 Aug 27];7(8):222. Available from: https://www.clinmedjournals.org/articles/jide/journal-of-infectious-diseases-and-epidemiology-jide-7-222.php?jid=jide

74. Wu LE, Sinclair DA. SIRT2 controls the pentose phosphate switch. The EMBO Journal [Internet]. 2014 Jun 17 [cited 2022 Feb 25];33(12):1287–8. Available from: https://onlinelibrary.wiley.com/doi/full/10.15252/embj.201488713

75. Patra KC, Hay N. The pentose phosphate pathway and cancer. Trends in Biochemical Sciences [Internet]. 2014 Aug 1 [cited 2022 Feb 25];39(8):347–54. Available from: http://www.cell.com/article/S0968000414001066/fulltext

76. Wu LE, Sinclair DA. SIRT2 controls the pentose phosphate switch. The EMBO Journal [Internet]. 2014 Jun 17 [cited 2022 Feb 24];33(12):1287–8. Available from: https://onlinelibrary.wiley.com/doi/full/10.15252/embj.201488713

77. Jiang P, Du W, Wu M. Regulation of the pentose phosphate pathway in cancer. Protein & Cell [Internet]. 2014 [cited 2022 Jan 7];5(8):592. Available from: /pmc/articles/PMC4112277/

78. Ge T, Yang J, Zhou S, Wang Y, Li Y, Tong X. The Role of the Pentose Phosphate Pathway in Diabetes and Cancer. Frontiers in Endocrinology. 2020 Jun 9;11:365.

79. XiaoWusheng, WangRui-Sheng, E. H, LoscalzoJoseph. NAD(H) and NADP(H) Redox Couples and Cellular Energy Metabolism. https://home.liebertpub.com/ars [Internet]. 2018 Jan 20 [cited 2021 Aug 16];28(3):251–72. Available from: https://www.liebertpub.com/doi/abs/10.1089/ars.2017.7216

80. Ying W. NAD+/NADH and NADP+/NADPH in Cellular Functions and Cell Death: Regulation and Biological Consequences. https://home.liebertpub.com/ars [Internet]. 2007 Dec 25 [cited 2021 Sep 4];10(2):179–206. Available from: https://www.liebertpub.com/doi/abs/10.1089/ars.2007.1672

81. Nguyen HP, Yi D, Lin F, Viscarra JA, Tabuchi C, Ngo K, et al. Aifm2, a NADH Oxidase, Supports Robust Glycolysis and Is Required for Cold- and Diet-Induced Thermogenesis. Molecular Cell [Internet]. 2020 Feb 6 [cited 2021 May 22];77(3):600-617.e4. Available from: https://pubmed.ncbi.nlm.nih.gov/31952989/

82. Kim J, Shao Y, Sang YK, Kim S, Hyun KS, Jun HJ, et al. Hypoxia-induced IL-18 Increases Hypoxia-inducible Factor-1α Expression through a Rac1-dependent NF-κB Pathway. Molecular Biology of the Cell [Internet]. 2008 Feb [cited 2022 Mar 5];19(2):433. Available from: /pmc/articles/PMC2230593/

83. Colgan SP, Eltzschig HK. Adenosine and Hypoxia-Inducible Factor Signaling in Intestinal Injury and Recovery. Annu Rev Physiol [Internet]. 2012 [cited 2021 Aug 16];74:153–75. Available from: /pmc/articles/PMC3882030/

84. Xu C, Li X, Guo P, Wang J. Hypoxia-Induced Activation of JAK/STAT3 Signaling Pathway Promotes Trophoblast Cell Viability and Angiogenesis in Preeclampsia. Medical Science Monitor : International Medical Journal of Experimental and Clinical Research [Internet]. 2017 Oct 14 [cited 2021 Aug 16];23:4909. Available from: /pmc/articles/PMC5652249/

85. Kierans SJ, Taylor CT. Regulation of glycolysis by the hypoxia-inducible factor (HIF): implications for cellular physiology. The Journal of Physiology [Internet]. 2021 Jan 1 [cited 2022 Jan 20];599(1):23–37. Available from: https://onlinelibrary.wiley.com/doi/full/10.1113/JP280572

86. Wise LM, Xi Y, Purdy JG. Hypoxia-inducible factor 1α (Hif1α) suppresses virus replication in human cytomegalovirus infection by limiting kynurenine synthesis. mBio [Internet]. 2021 Apr 27 [cited 2021 May 25];12(2). Available from: https://doi.org/10.1128/mBio.02956-20.

87. Zhang Z, Li P, Wang Y, Yan H. Hypoxia‑induced expression of CXCR4 favors trophoblast cell migration and invasion via the activation of HIF‑1α. International Journal of Molecular Medicine [Internet]. 2018 Sep 1 [cited 2021 Aug 15];42(3):1508–16. Available from: http://www.spandidos-publications.com/10.3892/ijmm.2018.3701/abstract

88. Lu J, Tan M, Cai Q. The Warburg effect in tumor progression: Mitochondrial oxidative metabolism as an anti-metastasis mechanism. Cancer Letters. 2015 Jan 28;356(2):156–64.

89. Niemann B, Rohrbach S, Miller MR, Newby DE, Fuster V, Kovacic JC. Oxidative Stress and Cardiovascular Risk: Obesity, Diabetes, Smoking, and Pollution: Part 3 of a 3-Part Series. Vol. 70, Journal of the American College of Cardiology. Elsevier USA; 2017. p. 230–51.

90. Doroftei B, Ilie OD, Cojocariu RO, Ciobica A, Maftei R, Grab D, et al. Minireview exploring the biological cycle of Vitamin B3 and its influence on oxidative stress: Further molecular and clinical aspects. Molecules [Internet]. 2020;25(15):3323. Available from: www.mdpi.com/journal/molecules

91. Abboud-Jarrous G, Atzmon R, Peretz T, Palermo C, Gadea BB, Joyce JA, et al. Cathepsin L Is Responsible for Processing and Activation of Proheparanase through Multiple Cleavages of a Linker Segment *. Journal of Biological Chemistry. 2008;283:18167–76.

92. Kitamura H, Kamon H, Sawa SI, Park SJ, Katunuma N, Ishihara K, et al. IL-6-STAT3 Controls Intracellular MHC Class II ab Dimer Level through Cathepsin S Activity in Dendritic Cells. Immunity. 2005;23:491–502.

93. Hadjadj J, Yatim N, Barnabei L, Corneau A, Boussier J, Smith N, et al. Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients. Science (1979) [Internet]. 2020 Aug 7 [cited 2021 Feb 21];369(6504):718–24. Available from: http://science.sciencemag.org/

94. Patel S, Homaei A, El-Seedi HR, Akhtar N. Cathepsins: Proteases that are vital for survival but can also be fatal. Biomedicine & Pharmacotherapy [Internet]. 2018 Sep 1 [cited 2021 Sep 3];105:526. Available from: /pmc/articles/PMC7172164/

95. Schurink B, Roos E, Vos W, Breur M, van der Valk P, Bugiani M. ACE2 Protein Expression During Childhood, Adolescence, and Early Adulthood: https://doi.org/101177/10935266221075312 [Internet]. 2022 Feb 28 [cited 2022 Apr 15];2022(0):1–5. Available from: https://journals.sagepub.com/doi/full/10.1177/10935266221075312

96. Feldstein LR, Rose EB, Horwitz SM, Collins JP, Newhams MM, Son MBF, et al. Multisystem Inflammatory Syndrome in U.S. Children and Adolescents. New England Journal of Medicine [Internet]. 2020 Jul 23 [cited 2022 Apr 15];383(4):334–46. Available from: https://www.nejm.org/doi/full/10.1056/NEJMoa2021680

97. AA D, P P, JS B. Presumptive Neonatal Multisystem Inflammatory Syndrome in Children Associated with Coronavirus Disease 2019. Am J Perinatol [Internet]. 2021 May 1 [cited 2021 Aug 19];38(6):632–6. Available from: https://pubmed.ncbi.nlm.nih.gov/33757142/

98. Dioguardi M, Cazzolla AP, Arena C, Sovereto D, Caloro GA, Dioguardi A, et al. Innate Immunity in Children and the Role of ACE2 Expression in SARS-CoV-2 Infection. Pediatric Reports [Internet]. 2021 [cited 2022 Apr 15];13(3):363. Available from: /pmc/articles/PMC8293341/

99. Pousa PA, Mendonça TSC, Oliveira EA, Simões-e-Silva AC, Pousa PA, Mendonça TSC, et al. Extrapulmonary manifestations of COVID-19 in children: a comprehensive review and pathophysiological considerations. Jornal de Pediatria [Internet]. 2021 Mar 1 [cited 2022 Apr 15];97(2):116–39. Available from: http://old.scielo.br/scielo.php?script=sci_arttext&pid=S0021-75572021000200116&lng=en&nrm=iso&tlng=en

100. Massalska MA, Gober HJ. How Children Are Protected From COVID-19? A Historical, Clinical, and Pathophysiological Approach to Address COVID-19 Susceptibility. Frontiers in Immunology. 2021 Jun 11;12:2191.

101. R KB, P BB, SP P, PA H. COVID-19-Related Potential Multisystem Inflammatory Syndrome in Childhood in a Neonate Presenting as Persistent Pulmonary Hypertension of the Newborn. Pediatr Infect Dis J [Internet]. 2021 [cited 2021 Aug 19];40(4):E162–4. Available from: https://pubmed.ncbi.nlm.nih.gov/33464010/

102. Chow EJ. The Multisystem Inflammatory Syndrome in Adults With SARS-CoV-2 Infection-Another Piece of an Expanding Puzzle. 2021; Available from: https://jamanetwork.com/

103. Chow EJ. The Multisystem Inflammatory Syndrome in Adults With SARS-CoV-2 Infection-Another Piece of an Expanding Puzzle. 2021; Available from: https://jamanetwork.com/

104. Guidance: Paediatric multisystem inflammatory syndrome temporally associated with COVID-19.

105. Multisystem Inflammatory Syndrome in Adults (MIS-A) Case Definition Information for Healthcare Providers [Internet]. [cited 2022 Jan 7]. Available from: https://www.cdc.gov/mis/mis-a/hcp.html

106. Roger C. COVID-19: should we consider it as a septic shock? (The treatment of COVID-19 patients in the ICU). Curr Opin Anaesthesiol [Internet]. 2021 Apr 1 [cited 2021 Dec 4];34(2):119–24. Available from: https://pubmed.ncbi.nlm.nih.gov/33470663/

107. Page-Wilson G, Arakawa R, Nemeth S, Bell F, Girvin Z, Tuohy MC, et al. Obesity is independently associated with septic shock, renal complications, and mortality in a multiracial patient cohort hospitalized with COVID-19. PLOS ONE [Internet]. 2021 Aug 1 [cited 2021 Dec 5];16(8):e0255811. Available from: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0255811

108. Hollenberg SM, Safi L, Parrillo JE, Fata M, Klinkhammer B, Gayed N, et al. Hemodynamic Profiles of Shock in Patients With COVID-19. The American Journal of Cardiology. 2021 Aug 15;153:135–9.

109. Poston JT, Patel BK, Davis AM. Management of Critically Ill Adults With COVID-19. JAMA [Internet]. 2020 May 12 [cited 2021 Dec 5];323(18):1839–41. Available from: https://jamanetwork.com/journals/jama/fullarticle/2763879

110. Arina P, Moro V, Baso B, Baxter-Derrington C, Singer M. Sepsis in severe COVID-19 is rarely septic shock: a retrospective single-centre cohort study. British Journal of Anaesthesia [Internet]. 2021 Nov 1 [cited 2021 Dec 5];127(5):e182–5. Available from: http://www.bjanaesthesia.org.uk/article/S0007091221005146/fulltext

111. Ibrahim ME, AL-Aklobi OS, Abomughaid MM, Al-Ghamdi MA. Epidemiological, clinical, and laboratory findings for patients of different age groups with confirmed coronavirus disease 2019 (COVID-19) in a hospital in Saudi Arabia. PLOS ONE [Internet]. 2021 Apr 1 [cited 2021 Dec 5];16(4):e0250955. Available from: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0250955

112. Barbui T, Iurlo A, Masciulli A, Carobbio A, Ghirardi A, Rossi G, et al. Long-term follow-up of recovered MPN patients with COVID-19. Blood Cancer Journal 2021 11:6 [Internet]. 2021 Jun 16 [cited 2021 Sep 8];11(6):1–4. Available from: https://www.nature.com/articles/s41408-021-00509-0

113. Yan R, Zhang Y, Li Y, Xia L, Zhou Q. Structure of dimeric full-length human ACE2 in complex with B0AT1. bioRxiv [Internet]. 2020 Feb 18 [cited 2022 May 6];2020.02.17.951848. Available from: https://www.biorxiv.org/content/10.1101/2020.02.17.951848v1

114. Nisoli E, Cinti S, Valerio A. COVID-19 and Hartnup disease: an affair of intestinal amino acid malabsorption. Eating and Weight Disorders [Internet]. 2021 Jun 1 [cited 2022 May 6];26(5):1647–51. Available from: https://link.springer.com/article/10.1007/s40519-020-00963-y

115. Bates CJ. Niacin. Encyclopedia of Human Nutrition. 1998;253–9.

116. Turk V, Stoka V, Vasiljeva O, Renko M, Sun T, Turk B, et al. Cysteine cathepsins: From structure, function and regulation to new frontiers. Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 2012 Jan 1;1824(1):68–88.

117. Pinto-Lopes P, Silva AS, Pimenta J. “Non-resolving pneumonia”: A case of cryptogenic organizing pneumonia. Porto Biomedical Journal [Internet]. 2016 Nov 1 [cited 2021 Dec 5];1(5):191–2. Available from: https://www.elsevier.es/en-revista-porto-biomedical-journal-445-articulo-non-resolving-pneumonia-a-case-cryptogenic-S2444866416301027

118. Saxena P, Kumar K, Mittal S, Goyal N, Trikha S, Vashisth A. Acute fibrinous and organizing pneumonia: A rare form of nonbacterial pneumonia. Indian Journal of Critical Care Medicine [Internet]. 2016;20(4):245–7. Available from: /pmc/articles/PMC4906338/?report=abstract

119. Saxena P, Kumar K, Mittal S, Goyal N, Trikha S, Vashisth A. Acute fibrinous and organizing pneumonia: A rare form of nonbacterial pneumonia. Indian Journal of Critical Care Medicine [Internet]. 2016;20(4):245–7. Available from: /pmc/articles/PMC4906338/?report=abstract

120. de Oliveira Filho CM, Vieceli T, de Fraga Bassotto C, da Rosa Barbato JP, Garcia TS, Scheffel RS. Organizing pneumonia: A late phase complication of COVID-19 responding dramatically to corticosteroids. The Brazilian Journal of Infectious Diseases [Internet]. 2021 Jan 1 [cited 2021 Dec 5];25(1). Available from: http://bjid.elsevier.es/en-organizing-pneumonia-a-late-phase-articulo-S1413867021000040

121. Beasley MB, Franks TJ, Galvin JR, Gochuico B, Travis WD. Acute fibrinous and organizing pneumonia: A histologic pattern of lung injury and possible variant of diffuse alveolar damage. Archives of Pathology and Laboratory Medicine. 2002;126(9):1064–70.

122. Penha D, Pinto EG, Matos F, Hochhegger B, Monaghan C, Taborda-Barata L, et al. CO-RADS: Coronavirus Classification Review. Journal of Clinical Imaging Science [Internet]. 2021 [cited 2022 Apr 14];11(1). Available from: /pmc/articles/PMC7981938/

123. The Radiology Assistant : COVID-19 CO-RADS classification [Internet]. [cited 2022 Apr 11]. Available from: https://radiologyassistant.nl/chest/covid-19/corads-classification

124. Prokop M, van Everdingen W, van Rees Vellinga T, van Ufford HQ, Stöger L, Beenen L, et al. CO-RADS: A Categorical CT Assessment Scheme for Patients Suspected of Having COVID-19-Definition and Evaluation. Radiology [Internet]. 2020 Aug 1 [cited 2022 Apr 11];296(2):E97–104. Available from: https://pubs.rsna.org/doi/full/10.1148/radiol.2020201473

125. Aljondi R, Alghamdi S. Diagnostic Value of Imaging Modalities for COVID-19: Scoping Review. J Med Internet Res [Internet]. 2020 Aug 1 [cited 2021 Dec 1];22(8). Available from: https://pubmed.ncbi.nlm.nih.gov/32716893/

126. de Oliveira Filho CM, Vieceli T, de Fraga Bassotto C, da Rosa Barbato JP, Garcia TS, Scheffel RS. Organizing pneumonia: A late phase complication of COVID-19 responding dramatically to corticosteroids. The Brazilian Journal of Infectious Diseases. 2021 Jan 1;25(1):101541.

127. George PM, Barratt SL, Condliffe R, Desai SR, Devaraj A, Forrest I, et al. Respiratory follow-up of patients with COVID-19 pneumonia. Thorax [Internet]. 2020 Nov 1 [cited 2022 May 6];75(11):1009–16. Available from: https://thorax.bmj.com/content/75/11/1009

128. Duzgun SA, Durhan G, Demirkazik FB, Akpinar MG, Ariyurek OM. COVID-19 pneumonia: the great radiological mimicker. Insights into Imaging [Internet]. 2020 Dec 1 [cited 2022 May 6];11(1):1–15. Available from: https://insightsimaging.springeropen.com/articles/10.1186/s13244-020-00933-z

129. Bowser JL, Lee JW, Yuan X, Eltzschig HK. The hypoxia-adenosine link during inflammation. https://doi.org/101152/japplphysiol001012017 [Internet]. 2017 Nov 1 [cited 2021 Aug 16];123(5):1303–20. Available from: https://journals.physiology.org/doi/abs/10.1152/japplphysiol.00101.2017

130. Meng F, Guo Z, Hu Y, Mai W, Zhang Z, Zhang B, et al. CD73-derived adenosine controls inflammation and neurodegeneration by modulating dopamine signalling. Brain [Internet]. 2019 Mar 1 [cited 2021 Feb 10];142(3):700–18. Available from: https://pubmed.ncbi.nlm.nih.gov/30689733/

131. Lennon PF, Taylor CT, Stahl GL, Colgan SP. Neutrophil-derived 5’-adenosine monophosphate promotes endothelial barrier function via CD73-mediated conversion to adenosine and endothelial A(2B) receptor activation. Journal of Experimental Medicine [Internet]. 1998 Oct 19 [cited 2021 Feb 10];188(8):1433–43. Available from: http://www.jem.org

132. Bin A, Caputi V, Bistoletti M, Montopoli M, Colucci R, Antonioli L, et al. The ecto-enzymes CD73 and adenosine deaminase modulate 5′-AMP-derived adenosine in myofibroblasts of the rat small intestine. Purinergic Signalling [Internet]. 2018 Dec 1 [cited 2021 Feb 10];14(4):409–21. Available from: https://doi.org/10.1007/s11302-018-9623-6

133. Adenosine Receptors - an overview | ScienceDirect Topics [Internet]. [cited 2021 Aug 15]. Available from: https://www.sciencedirect.com/topics/neuroscience/adenosine-receptors

134. Borea PA, Gessi S, Merighi S, Vincenzi F, Varani K. Pharmacology of Adenosine Receptors: The State of the Art. https://doi.org/101152/physrev000492017 [Internet]. 2018 May 31 [cited 2021 Aug 25];98(3):1591–625. Available from: https://journals.physiology.org/doi/abs/10.1152/physrev.00049.2017

135. Dézsi L, Tuka B, Martos D, Vécsei L. Alzheimer’s disease, astrocytes and kynurenines. Vol. 12, CURRENT ALZHEIMER RESEARCH. 2015.

136. Guillemin GJ, Williams KR, Smith DG, Smythe GA, Croitoru-Lamoury J, Brew BJ. Quinolinic acid in the pathogenesis of alzheimer’s disease. In: Advances in Experimental Medicine and Biology. Kluwer Academic/Plenum Publishers; 2003. p. 167–76.

137. Gonçalves FQ, Lopes JP, Silva HB, Lemos C, Silva AC, Gonçalves N, et al. Synaptic and memory dysfunction in a β-amyloid model of early Alzheimer’s disease depends on increased formation of ATP-derived extracellular adenosine. Neurobiology of Disease. 2019 Dec 1;132.

138. Vécsei L, Szalárdy L, Fülöp F, Toldi J. Kynurenines in the CNS: Recent advances and new questions [Internet]. Vol. 12, Nature Reviews Drug Discovery. Nature Publishing Group; 2013. p. 64–82. Available from: www.nature.com/reviews/drugdisc

139. Lawler NG, Gray N, Kimhofer T, Boughton B, Gay M, Yang R, et al. Systemic Perturbations in Amine and Kynurenine Metabolism Associated with Acute SARS-CoV-2 Infection and Inflammatory Cytokine Responses. Journal of Proteome Research [Internet]. 2021 May 7 [cited 2021 Oct 10];20(5):2796–811. Available from: https://pubs.acs.org/doi/full/10.1021/acs.jproteome.1c00052

140. Pelletier AN, Tomazella M, Carvalho K de, Nicolau A, Marmoratto M, Silveira C, et al. Yellow fever disease severity is driven by an acute cytokine storm modulated by an interplay between the human gut microbiome and the metabolome. medRxiv [Internet]. 2021 Sep 27 [cited 2021 Oct 3];2021.09.25.21264125. Available from: https://www.medrxiv.org/content/10.1101/2021.09.25.21264125v1

141. Páez-Franco JC, Torres-Ruiz J, Sosa-Hernández VA, Cervantes-Díaz R, Romero-Ramírez S, Pérez-Fragoso A, et al. Metabolomics analysis reveals a modified amino acid metabolism that correlates with altered oxygen homeostasis in COVID-19 patients. Scientific Reports 2021 11:1 [Internet]. 2021 Mar 18 [cited 2021 Oct 9];11(1):1–12. Available from: https://www.nature.com/articles/s41598-021-85788-0

142. Masoodi M, Peschka M, Schmiedel S, Haddad M, Frye M, Maas C, et al. Disturbed lipid and amino acid metabolisms in COVID-19 patients. Journal of Molecular Medicine [Internet]. 2022 Jan 22 [cited 2022 Mar 5];1:1–14. Available from: https://link.springer.com/article/10.1007/s00109-022-02177-4

143. Strasser B, Sperner-Unterweger B, Fuchs D, Gostner JM, Strasser B, Gostner JM, et al. Mechanisms of Inflammation-Associated Depression: Immune Influences on Tryptophan and Phenylalanine Metabolisms. 2016;

144. Ramanathan M, Pinhal-Enfield G, Hao I, Leibovich SJ. Synergistic Up-Regulation of Vascular Endothelial Growth Factor (VEGF) Expression in Macrophages by Adenosine A2A Receptor Agonists and Endotoxin Involves Transcriptional Regulation via the Hypoxia Response Element in the VEGF Promoter. https://doi.org/101091/mbc.e06-07-0596 [Internet]. 2006 Oct 25 [cited 2021 Aug 25];18(1):14–23. Available from: https://www.molbiolcell.org/doi/abs/10.1091/mbc.e06-07-0596

145. Goralska M, Fleisher LN, McGahan MC. Hypoxia induced changes in expression of proteins involved in iron uptake and storage in cultured lens epithelial cells. Experimental Eye Research [Internet]. 2014 [cited 2021 May 25];125:135–41. Available from: /pmc/articles/PMC4154372/

146. Balogun OO, Fawole A, Osemwinyen E, Balogun B. The Placental Buffer Effect and the Pathophysiology of COVID-19: Possibilities for a Guide Aimed at Pregnant and Postpartum Women Considering Praxis: Theory, Clinical and Laboratory Observation. Journal of Infectious Diseases and Epidemiology [Internet]. 2021 Nov 5 [cited 2021 Dec 9];7(11):234. Available from: https://www.clinmedjournals.org/articles/jide/journal-of-infectious-diseases-and-epidemiology-jide-7-234.php?jid=jide

147. Ali RA, Gandhi AA, Meng H, Yalavarthi S, Vreede AP, Estes SK, et al. Adenosine receptor agonism protects against NETosis and thrombosis in antiphospholipid syndrome. Nature Communications 2019 10:1 [Internet]. 2019 Apr 23 [cited 2021 Oct 8];10(1):1–12. Available from: https://www.nature.com/articles/s41467-019-09801-x

148. Sailem HZ, al Haj Zen A. Morphological landscape of endothelial cell networks reveals a functional role of glutamate receptors in angiogenesis. Scientific Reports [Internet]. 2020 Dec 1 [cited 2021 Feb 28];10(1):1–14. Available from: https://doi.org/10.1038/s41598-020-70440-0

149. Kimura A, Naka T, Nohara K, Fujii-Kuriyama Y, Kishimoto T. Aryl hydrocarbon receptor regulates Stat1 activation and participates in the development of Th17 cells. Proceedings of the National Academy of Sciences [Internet]. 2008 Jul 15 [cited 2021 Oct 15];105(28):9721–6. Available from: https://www.pnas.org/content/105/28/9721

150. Ghiboub M, Verburgt CM, Sovran B, Benninga MA, de Jonge WJ, van Limbergen JE. Nutritional therapy to modulate tryptophan metabolism and aryl hydrocarbon-receptor signaling activation in human diseases. Vol. 12, Nutrients. MDPI AG; 2020. p. 1–21.

151. Dancey JT, Deubelbeiss KA, Harker andFinch LACA. Neutrophil kinetics in man. Journal of Clinical Investigation. 1976;58(3):705–15.

152. Bories GFP, Leitinger N. Macrophage metabolism in atherosclerosis. FEBS Letters [Internet]. 2017;591(19):3042–60. Available from: http://doi.wiley.com/10.1002/1873-3468.12786

153. Moon P, Minhas PS. Reexamining IFN-γ Stimulation of De Novo NAD+ in Monocyte-Derived Macrophages [Internet]. Vol. 11, International Journal of Tryptophan Research. SAGE Publications Ltd; 2018 [cited 2021 Feb 21]. p. 12–9. Available from: /pmc/articles/PMC5958421/

154. Zhu J, Luo L, Tian L, Yin S, Ma X, Cheng S, et al. Aryl Hydrocarbon Receptor Promotes IL-10 Expression in Inflammatory Macrophages Through Src-STAT3 Signaling Pathway. Frontiers in Immunology. 2018 Sep 19;0(SEP):2033.

155. Masuda K, Kimura A, Hanieh H, Nguyen NT, Nakahama T, Chinen I, et al. Aryl hydrocarbon receptor negatively regulates LPS-induced IL-6 production through suppression of histamine production in macrophages. International Immunology [Internet]. 2011 Oct 1 [cited 2021 Aug 26];23(10):637–45. Available from: https://academic.oup.com/intimm/article/23/10/637/719147

156. Gonzaga L, de Assis Barros D’ F, Zanella E, De LGF. Out of Sight, Out of Mind, Right? Not in COVID-19 Shock or Anaerobic and Exhaustive Shock versus Septic Shock Dilemma That Means to Live or Die. Emergency Attention and a Necessity of Trials. Open Journal of Emergency Medicine [Internet]. 2022 Feb 11 [cited 2022 Apr 22];10(1):19–47. Available from: http://www.scirp.org/journal/PaperInformation.aspx?PaperID=115450

157. Lee JS, Shin EC. The type I interferon response in COVID-19: implications for treatment [Internet]. Vol. 20, Nature Reviews Immunology. Nature Research; 2020 [cited 2021 Feb 21]. p. 585–6. Available from: https://doi.org/10.1038/

158. Watchorn J, Huang DY, Joslin J, Bramham K, Hutchings SD. Critically Ill COVID-19 Patients With Acute Kidney Injury Have Reduced Renal Blood Flow and Perfusion Despite Preserved Cardiac Function: A Case-Control Study Using Contrast-Enhanced Ultrasound. Shock [Internet]. 2021 Apr 1 [cited 2021 Dec 5];55(4):479–87. Available from: https://journals.lww.com/shockjournal/Fulltext/2021/04000/Critically_Ill_COVID_19_Patients_With_Acute_Kidney.7.aspx

159. Singh R, Bajpai M, Yadav P, Kumar Maheshwari A, Kumar S, Agrawal S, et al. Sustained expression of inflammatory monocytes and activated T cells in COVID-19 patients and recovered convalescent plasma donors Title: Sustained expression of inflammatory monocytes and activated T cells in COPLA donors. [cited 2021 Oct 16]; Available from: https://doi.org/10.1101/2020.11.17.20233668

160. Grant RS. Indoleamine 2,3-Dioxygenase Activity Increases NAD+ Production in IFN-γ-Stimulated Human Primary Mononuclear Cells. Int J Tryptophan Res [Internet]. 2018 Jan 8 [cited 2021 Feb 21];11:1178646917751636. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29343967

161. Jackson CB, Farzan M, Chen B, Choe H. Mechanisms of SARS-CoV-2 entry into cells. Nature Reviews Molecular Cell Biology 2021 23:1 [Internet]. 2021 Oct 5 [cited 2022 Feb 24];23(1):3–20. Available from: https://www.nature.com/articles/s41580-021-00418-x

162. Qvisth V, Hagström-Toft E, Enoksson S, Bolinder J. Catecholamine Regulation of Local Lactate Production in Vivo in Skeletal Muscle and Adipose Tissue: Role of β-Adrenoreceptor Subtypes. The Journal of Clinical Endocrinology & Metabolism [Internet]. 2008 Jan 1 [cited 2022 May 6];93(1):240–6. Available from: https://academic.oup.com/jcem/article/93/1/240/2598605

163. Kreisberg RA. Lactate homeostasis and lactic acidosis. Annals of Internal Medicine. 1980;92(2 I):227–37.

164. Ham M, Lee JW, Choi AH, Jang H, Choi G, Park J, et al. Macrophage Glucose-6-Phosphate Dehydrogenase Stimulates Proinflammatory Responses with Oxidative Stress. Molecular and Cellular Biology [Internet]. 2013 Jun 15 [cited 2022 May 5];33(12):2425. Available from: /pmc/articles/PMC3700093/

165. Kelder T, Pico AR, Hanspers K, van Iersel MP, Evelo C, Conklin BR. Mining Biological Pathways Using WikiPathways Web Services. PLoS ONE [Internet]. 2009 Jul 30 [cited 2022 May 4];4(7):6447. Available from: /pmc/articles/PMC2714472/

166. Iepsen UW, Plovsing RR, Tjelle K, Foss NB, Meyhoff CS, Ryrsø CK, et al. The role of lactate in sepsis and COVID-19: Perspective from contracting skeletal muscle metabolism. Exp Physiol [Internet]. 2021 [cited 2021 Dec 9]; Available from: https://pubmed.ncbi.nlm.nih.gov/34058787/

167. Caniggia I, Mostachfi H, Winter J, Gassmann M, Lye SJ, Kuliszewski M, et al. Hypoxia-inducible factor-1 mediates the biological effects of oxygen on human trophoblast differentiation through TGFβ3. Journal of Clinical Investigation [Internet]. 2000 [cited 2021 Aug 15];105(5):577. Available from: /pmc/articles/PMC289179/

168. Miao D, Li DY, Chen M, Zhao MH. Platelets are activated in ANCA-associated vasculitis via thrombin-PARs pathway and can activate the alternative complement pathway. Arthritis Research and Therapy [Internet]. 2017 Nov;19(1):252. Available from: https://arthritis-research.biomedcentral.com/articles/10.1186/s13075-017-1458-y

169. Kow CS, Hasan SS. The use of antiplatelet agents for arterial thromboprophylaxis in COVID-19. Revista Espanola De Cardiologia (English Ed) [Internet]. 2021 Jan [cited 2021 Oct 5];74(1):114. Available from: /pmc/articles/PMC7455174/

170. Ageno W. Arterial and Venous Thrombosis: Clinical Evidence for Mechanistic Overlap. Blood. 2014;124(21):SCI--3--SCI--3.

171. Bozzani A, Arici V, Tavazzi G, Franciscone MM, Danesino V, Rota M, et al. Acute arterial and deep venous thromboembolism in COVID-19 patients: Risk factors and personalized therapy. Surgery (United States). 2020;168(6):987–92.

172. Mohapatra SR, Sadik A, Sharma S, Poschet G, Gegner HM, Lanz T v., et al. Hypoxia Routes Tryptophan Homeostasis Towards Increased Tryptamine Production. Frontiers in Immunology. 2021 Feb 19;0:8.

173. Monneret G, Lepape A, Voirin N, Bohé J, Venet F, Debard AL, et al. Persisting low monocyte human leukocyte antigen-DR expression predicts mortality in septic shock. Intensive Care Medicine. 2006;32(8):1175–83.

174. Manzoli TF, Delgado AF, Troster EJ, de Carvalho WB, Antunes ACB, Marques DM, et al. Lymphocyte count as a sign of immunoparalysis and its correlation with nutritional status in pediatric intensive care patients with sepsis: A pilot study. Clinics [Internet]. 2016 Nov;71(11):644–9. Available from: http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1807-59322016001100644&lng=en&nrm=iso&tlng=en

175. Fanelli G, Romano M, Nova-Lamperti E, Sunderland MW, Nerviani A, Scottà C, et al. PD-L1 signaling on human memory CD4+ T cells induces a regulatory phenotype. PLOS Biology [Internet]. 2021 Apr 1 [cited 2022 Apr 20];19(4):e3001199. Available from: https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3001199

176. Rha MS, Jeong HW, Ko JH, Choi Y, Peck KR, Shin EC, et al. PD-1-Expressing SARS-CoV-2-Specific CD8 + T Cells Are Not Exhausted, but Functional in Patients with COVID-19 ll PD-1-Expressing SARS-CoV-2-Specific CD8 + T Cells Are Not Exhausted, but Functional in Patients with COVID-19. Immunity [Internet]. 2021 [cited 2021 Feb 14];54:44-52.e3. Available from: https://doi.org/10.1016/j.immuni.2020.12.002

177. Pispa J, Thesleff I. Mechanisms of ectodermal organogenesis. Developmental Biology. 2003 Oct 15;262(2):195–205.

178. Jiménez-Rojo L, Granchi Z, Graf D, Mitsiadis TA. Stem cell fate determination during development and regeneration of ectodermal organs. Frontiers in Physiology. 2012;3 APR:107.

179. Silvagno F, Vernone A, Pescarmona GP. The Role of Glutathione in Protecting against the Severe Inflammatory Response Triggered by COVID-19. Antioxidants [Internet]. 2020 Jul;9(7):624. Available from: https://www.mdpi.com/2076-3921/9/7/624

180. Edalatifard M, Akhtari M, Salehi M, Naderi Z, Jamshidi A, Mostafaei S, et al. Intravenous methylprednisolone pulse as a treatment for hospitalised severe COVID-19 patients: results from a randomised controlled clinical trial. European Respiratory Journal [Internet]. 2020;56(6):2002808. Available from: /pmc/articles/PMC7758541/?report=abstract

181. Zaitsev AA, Golukhova EZ, Mamalyga ML, Chernov SA, Rybka MM, Kryukov E v, et al. Efficacy of methylprednisolone pulse therapy in patients with COVID-19. Clinical Microbiology and Antimicrobial Chemotherapy. 2020;22(2):88–91.

182. Sauñe PM, Bryce-Alberti M, Portmann-Baracco AS, Accinelli RA. Methylprednisolone pulse therapy: An alternative management of severe COVID-19. Respiratory Medicine Case Reports [Internet]. 2020 Jul;31. Available from: https://pubmed.ncbi.nlm.nih.gov/32995261/

183. Salton F, Confalonieri P, Meduri GU, Santus P, Harari S, Scala R, et al. Prolonged Low-Dose Methylprednisolone in Patients With Severe COVID-19 Pneumonia. Open Forum Infectious Diseases [Internet]. 2020;7(10). Available from: https://academic.oup.com/ofid/article/doi/10.1093/ofid/ofaa421/5904996

184. Salton F, Confalonieri P, Meduri GU, Santus P, Harari S, Scala R, et al. Prolonged Low-Dose Methylprednisolone in Patients With Severe COVID-19 Pneumonia. Open Forum Infectious Diseases [Internet]. 2020;7(10). Available from: https://academic.oup.com/ofid/article/doi/10.1093/ofid/ofaa421/5904996

185. Zanella LGF de ABD, Paraskevopoulos DK de S, Galv&atilde L de L, o, Yamaguti A, Zanella LGF de ABD, et al. Methylprednisolone Pulse Therapy in COVID-19 as the First Choice for Public Health: When Right Timing Breaks Controversies—Emergency Guide. Open Journal of Emergency Medicine [Internet]. 2021 Jul 2 [cited 2021 Aug 27];9(3):84–114. Available from: http://www.scirp.org/journal/PaperInformation.aspx?PaperID=111400

No competing interests reported.

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Pathophysiology of COVID-19: SARS-CoV-2 mimics neoplastic cells and The Long COVID-19 Syndrome can be a Warburg Effect and ACE-2 internalization consequence

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Abstract

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Introduction

Results

ACE-2 and Inflammation

The Warburg Effect/SARS-CoV-2 relationship and the presented phenomena in the clinical and laboratory evaluation

Discussion

Conclusions

FINAL CONSIDERATIONS

Methods

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ACKNOWLEDGMENTS

LIMITATIONS OF THE ARTICLE

AUTHOR'S CONTRIBUTION

CONFLICTS OF INTEREST

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References

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Supplementary Files

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