Receptor-Loaded Virion Endangers GPCR Signaling: Mechanistic Exploration of SARS-CoV-2 Infections and Pharmacological Implications

SARS-CoV-2 exploits the respiratory tract epithelium including lungs as the primary entry point and reaches other organs through hematogenous expansion, consequently causing multiorgan injury. Viral E protein interacts with cell junction-associated proteins PALS1 or ZO-1 to gain massive penetration by disrupting the inter-epithelial barrier. Conversely, receptor-mediated viral invasion ensures limited but targeted infections in multiple organs. The ACE2 receptor represents the major virion loading site by virtue of its wide tissue distribution as demonstrated in highly susceptible lung, intestine, and kidney. In brain, NRP1 mediates viral endocytosis in a similar manner to ACE2. Prominently, PDZ interaction involves the entire viral loading process either outside or inside the host cells, whereas E, ACE2, and NRP1 provide the PDZ binding motif required for interacting with PDZ domain-containing proteins PALS1, ZO-1, and NHERF1, respectively. Hijacking NHERF1 and β-arrestin by virion loading may impair specific sensory GPCR signalosome assembling and cause disordered cellular responses such as loss of smell and taste. PDZ interaction enhances SARS-CoV-2 invasion by supporting viral receptor membrane residence, implying that the disruption of these interactions could diminish SARS-CoV-2 infections and be another therapeutic strategy against COVID-19 along with antibody therapy. GPCR-targeted drugs are likely to alleviate pathogenic symptoms-associated with SARS-CoV-2 infection.     

Role of the Renin–Angiotensin–Aldosterone and Kinin–Kallikrein Systems in the Cardiovascular Complications of COVID-19 and Long COVID

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the virus responsible for the COVID-19 pandemic. Patients may present as asymptomatic or demonstrate mild to severe and life-threatening symptoms. Although COVID-19 has a respiratory focus, there are major cardiovascular complications (CVCs) associated with infection. The reported CVCs include myocarditis, heart failure, arrhythmias, thromboembolism and blood pressure abnormalities. These occur, in part, because of dysregulation of the Renin–Angiotensin–Aldosterone System (RAAS) and Kinin–Kallikrein System (KKS). A major route by which SARS-CoV-2 gains cellular entry is via the docking of the viral spike (S) protein to the membrane-bound angiotensin converting enzyme 2 (ACE2). The roles of ACE2 within the cardiovascular and immune systems are vital to ensure homeostasis. The key routes for the development of CVCs and the recently described long COVID have been hypothesised as the direct consequences of the viral S protein/ACE2 axis, downregulation of ACE2 and the resulting damage inflicted by the immune response. Here, we review the impact of COVID-19 on the cardiovascular system, the mechanisms by which dysregulation of the RAAS and KKS can occur following virus infection and the future implications for pharmacological therapies.     

Pathophysiological Association of Endothelial Dysfunction with Fatal Outcome in COVID-19

The outbreak of coronavirus disease 2019 (COVID-19) caused by the betacoronavirus SARS-CoV-2 is now a worldwide challenge for healthcare systems. Although the leading cause of mortality in patients with COVID-19 is hypoxic respiratory failure due to viral pneumonia and acute respiratory distress syndrome, accumulating evidence has shown that the risk of thromboembolism is substantially high in patients with severe COVID-19 and that a thromboembolic event is another major complication contributing to the high morbidity and mortality in patients with COVID-19. Endothelial dysfunction is emerging as one of the main contributors to the pathogenesis of thromboembolic events in COVID-19. Endothelial dysfunction is usually referred to as reduced nitric oxide bioavailability. However, failures of the endothelium to control coagulation, inflammation, or permeability are also instances of endothelial dysfunction. Recent studies have indicated the possibility that SARS-CoV-2 can directly infect endothelial cells via the angiotensin-converting enzyme 2 pathway and that endothelial dysfunction caused by direct virus infection of endothelial cells may contribute to thrombotic complications and severe disease outcomes in patients with COVID-19. In this review, we summarize the current understanding of relationships between SARS-CoV-2 infection, endothelial dysfunction, and pulmonary and extrapulmonary complications in patients with COVID-19.     

“Molecular Masks” for ACE2 to Effectively and Safely Block SARS-CoV-2 Virus Entry

Coronavirus Disease 2019 (COVID-19) remains a global health crisis, despite the development and success of vaccines in certain countries. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, uses its spike protein to bind to the human cell surface receptor angiotensin-converting enzyme 2 (ACE2), which allows the virus to enter the human body. Using our unique cell screening technology, we identified two ACE2-binding peptoid compounds and developed dimeric derivatives (ACE2P1D1 and ACE2P2D1) that effectively blocked spike protein-ACE2 interaction, resulting in the inhibition of SARS-CoV-2 pseudovirus entry into human cells. ACE2P1D1 and ACE2P2D1 also blocked infection by a D614G mutant pseudovirus. More importantly, these compounds do not decrease ACE2 expression nor its enzyme activity (which is important in normal blood pressure regulation), suggesting safe applicability in humans     

Mechanics Insights of Alpha-Lipoic Acid against Cardiovascular Diseases during COVID-19 Infection

Coronavirus disease 2019 (COVID-19) was first reported in Wuhan, China, in late December 2019. Since then, COVID-19 has spread rapidly worldwide and was declared a global pandemic on 20 March 2020. Cardiovascular complications are rapidly emerging as a major peril in COVID-19 in addition to respiratory disease. The mechanisms underlying the excessive effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on patients with cardiovascular comorbidities remain only partly understood. SARS-CoV-2 infection is caused by binding of the viral surface spike (S) protein to the human angiotensin-converting enzyme 2 (ACE2), followed by the activation of the S protein by transmembrane protease serine 2 (TMPRSS2). ACE2 is expressed in the lung (mainly in type II alveolar cells), heart, blood vessels, small intestine, etc., and appears to be the predominant portal to the cellular entry of the virus. Based on current information, most people infected with SARS-CoV-2 virus have a good prognosis, while a few patients reach critical condition, especially the elderly and those with chronic underlying diseases. The “cytokine storm” observed in patients with severe COVID-19 contributes to the destruction of the endothelium, leading to “acute respiratory distress syndrome” (ARDS), multiorgan failure, and death. At the origin of the general proinflammatory state may be the SARS-CoV-2-mediated redox status in endothelial cells via the upregulation of ACE/Ang II/AT1 receptors pathway or the increased mitochondrial reactive oxygen species (mtROS) production. Furthermore, this vicious circle between oxidative stress (OS) and inflammation induces endothelial dysfunction, endothelial senescence, high risk of thrombosis and coagulopathy. The microvascular dysfunction and the formation of microthrombi in a way differentiate the SARS-CoV-2 infection from the other respiratory diseases and bring it closer to cardiovascular diseases like myocardial infarction and stroke. Due the role played by OS in the evolution of viral infection and in the development of COVID-19 complications, the use of antioxidants as adjuvant therapy seems appropriate in this new pathology. Alpha-lipoic acid (ALA) could be a promising candidate that, through its wide tissue distribution and versatile antioxidant properties, interferes with several signaling pathways. Thus, ALA improves endothelial function by restoring the endothelial nitric oxide synthase activity and presents an anti-inflammatory effect dependent or independent of its antioxidant properties. By improving mitochondrial function, it can sustain the tissues’ homeostasis in critical situation and by enhancing the reduced glutathione it could indirectly strengthen the immune system. This complex analysis could open a new therapeutic perspective for ALA in COVID-19 infection.     

Dietary and Protective Factors to Halt or Mitigate Progression of Autoimmunity,COVID-19 and Its Associated Metabolic Diseases

COVID-19 is without any doubt the worst pandemic we have faced since the H1N1 virus outbreak. Even if vaccination against SARS-CoV-2 infection is becoming increasingly available, a more feasible approach for COVID-19 prevention and therapy is still needed. Evidence of a pathological link between metabolic diseases and severe forms of COVID-19 has stimulated critical reflection and new considerations. In particular, an abnormal immune response observed in certain patients with SARS-CoV-2 infection suggested possible common predisposing risk factors with autoimmune diseases such as Type 1 Diabetes (T1D). Correct supplementation with dietary factors may be key to preventing and counteracting both the underlying metabolic impairment and the complications of COVID-19. A set of agents may inhibit the cytokine storm and hypercoagulability that characterize severe COVID-19 infection: vitamin D3, omega-3 polyunsaturated fatty acids, polyphenols like pterostilbene, polydatin and honokiol, which can activate anti-inflammatory and antioxidant sirtuins pathways, quercetin, vitamin C, zinc, melatonin, lactoferrin and glutathione. These agents could be highly beneficial for subjects who have altered immune responses. In this review, we discuss the antiviral and metabolic effects of these dietary factors and propose their combination for potential applications in the prevention and treatment of COVID-19. Rigorous studies will be fundamental for validating preventive and therapeutic protocols that could be of assistance to mitigate disease progression following SARS-CoV-2 infection.     

Structural and Functional Analysis of Female Sex Hormones against SARS-CoV-2 Cell Entry

Emerging evidence suggests that males are more susceptible to severe infection by the SARS-CoV-2 virus than females. A variety of mechanisms may underlie the observed gender-related disparities including differences in sex hormones. However, the precise mechanisms by which female sex hormones may provide protection against SARS-CoV-2 infectivity remains unknown. Here we report new insights into the molecular basis of the interactions between the SARS-CoV-2 spike (S) protein and the human ACE2 receptor. We further report that glycosylation of the ACE2 receptor enhances SARS-CoV-2 infectivity. Importantly, estrogens can disrupt glycan–glycan interactions and glycan–protein interactions between the human ACE2 and the SARS-CoV-2 thereby blocking its entry into cells. In a mouse model of COVID-19, estrogens reduced ACE2 glycosylation and thereby alveolar uptake of the SARS-CoV-2 spike protein. These results shed light on a putative mechanism whereby female sex hormones may provide protection from developing severe infection and could inform the development of future therapies against COVID-19.     

Involvement of the ACE2/Ang-(1–7)/MasR Axis in Pulmonary Fibrosis: Implications for COVID-19

Pulmonary fibrosis is a chronic, fibrotic lung disease affecting 3 million people worldwide. The ACE2/Ang-(1–7)/MasR axis is of interest in pulmonary fibrosis due to evidence of its anti-fibrotic action. Current scientific evidence supports that inhibition of ACE2 causes enhanced fibrosis. ACE2 is also the primary receptor that facilitates the entry of SARS-CoV-2, the virus responsible for the current COVID-19 pandemic. COVID-19 is associated with a myriad of symptoms ranging from asymptomatic to severe pneumonia and acute respiratory distress syndrome (ARDS) leading to respiratory failure, mechanical ventilation, and often death. One of the potential complications in people who recover from COVID-19 is pulmonary fibrosis. Cigarette smoking is a risk factor for fibrotic lung diseases, including the idiopathic form of this disease (idiopathic pulmonary fibrosis), which has a prevalence of 41% to 83%. Cigarette smoke increases the expression of pulmonary ACE2 and is thought to alter susceptibility to COVID-19. Cannabis is another popular combustible product that shares some similarities with cigarette smoke, however, cannabis contains cannabinoids that may reduce inflammation and/or ACE2 levels. The role of cannabis smoke in the pathogenesis of pulmonary fibrosis remains unknown. This review aimed to characterize the ACE2-Ang-(1–7)-MasR Axis in the context of pulmonary fibrosis with an emphasis on risk factors, including the SARS-CoV-2 virus and exposure to environmental toxicants. In the context of the pandemic, there is a dire need for an understanding of pulmonary fibrotic events. More research is needed to understand the interplay between ACE2, pulmonary fibrosis, and susceptibility to coronavirus infection.     

Acute Kidney Injury in COVID-19

COVID-19 is mainly considered a respiratory illness, but since SARS-CoV-2 uses the angiotensin converting enzyme 2 receptor (ACE2) to enter human cells, the kidney is also a target of the viral infection. Acute kidney injury (AKI) is the most alarming condition in COVID-19 patients. Recent studies have confirmed the direct entry of SARS-CoV-2 into the renal cells, namely podocytes and proximal tubular cells, but this is not the only pathomechanism of kidney damage. Hypovolemia, cytokine storm and collapsing glomerulopathy also play an important role. An increasing number of papers suggest a strong association between AKI development and higher mortality in COVID-19 patients, hence our interest in the matter. Although knowledge about the role of kidneys in SARS-CoV-2 infection is changing dynamically and is yet to be fully investigated, we present an insight into the possible pathomechanisms of AKI in COVID-19, its clinical features, risk factors, impact on hospitalization and possible ways for its management via renal replacement therapy.     

COVID-19: Direct and Indirect Mechanisms of Statins

The virus responsible for the current COVID-19 pandemic is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): a new virus with high infectivity and moderate mortality. The major clinical manifestation of COVID-19 is interstitial pneumonia, which may progress to acute respiratory distress syndrome (ARDS). However, the disease causes a potent systemic hyperin-flammatory response, i.e., a cytokine storm or macrophage activation syndrome (MAS), which is associated with thrombotic complications. The complexity of the disease requires appropriate intensive treatment. One of promising treatment is statin administration, these being 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors that exert pleiotropic anti-inflammatory effects. Recent studies indicate that statin therapy is associated with decreased mortality in COVID-19, which may be caused by direct and indirect mechanisms. According to literature data, statins can limit SARS-CoV-2 cell entry and replication by inhibiting the main protease (Mpro) and RNA-dependent RNA polymerase (RdRp). The cytokine storm can be ameliorated by lowering serum IL-6 levels; this can be achieved by inhibiting Toll-like receptor 4 (TLR4) and modulating macrophage activity. Statins can also reduce the complications of COVID-19, such as thrombosis and pulmonary fibrosis, by reducing serum PAI-1 levels, attenuating TGF-β and VEGF in lung tissue, and improving endothelial function. Despite these benefits, statin therapy may have side effects that should be considered, such as elevated creatinine kinase (CK), liver enzyme and serum glucose levels, which are already elevated in severe COVID-19 infection. The present study analyzes the latest findings regarding the benefits and limitations of statin therapy in patients with COVID-19.     

Cigarette Smoke Stimulates SARS-CoV-2 Internalization by Activating AhR and Increasing ACE2 Expression in Human Gingival Epithelial Cells

A large body of evidence shows the harmful effects of cigarette smoke to oral and systemic health. More recently, a link between smoking and susceptibility to coronavirus disease 2019 (COVID-19) was proposed. COVID-19 is due to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which uses the receptor ACE2 and the protease TMPRSS2 for entry into host cells, thereby infecting cells of the respiratory tract and the oral cavity. Here, we examined the effects of cigarette smoke on the expression of SARS-CoV-2 receptors and infection in human gingival epithelial cells (GECs). We found that cigarette smoke condensates (CSC) upregulated ACE2 and TMPRSS2 expression in GECs, and that CSC activated aryl hydrocarbon receptor (AhR) signaling in the oral cells. ACE2 was known to mediate SARS-CoV-2 internalization, and we demonstrate that CSC treatment potentiated the internalization of SARS-CoV-2 pseudovirus in GECs in an AhR-dependent manner. AhR depletion using small interference RNA decreased SARS-CoV-2 pseudovirus internalization in CSC-treated GECs compared with control GECs. Our study reveals that cigarette smoke upregulates SARS-CoV-2 receptor expression and infection in oral cells. Understanding the mechanisms involved in SARS-CoV-2 infection in cells of the oral cavity may suggest therapeutic interventions for preventing viral infection and transmission.     

Perspective of the Relationship between the Susceptibility to Initial SARS-CoV-2 Infectivity and Optimal Nasal Conditioning of Inhaled Air

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as with the influenza virus, has been shown to spread more rapidly during winter. Severe coronavirus disease 2019 (COVID-19), which can follow SARS-CoV-2 infection, disproportionately affects older persons and males as well as people living in temperate zone countries with a tropical ancestry. Recent evidence on the importance of adequately warming and humidifying (conditioning) inhaled air in the nasal cavity for reducing SARS-CoV-2 infectivity in the upper respiratory tract (URT) is discussed, with particular reference to: (i) the relevance of air-borne SARS-CoV-2 transmission, (ii) the nasal epithelium as the initial site of SARS-CoV-2 infection, (iii) the roles of type 1 and 3 interferons for preventing viral infection of URT epithelial cells, (iv) weaker innate immune responses to respiratory viral infections in URT epithelial cells at suboptimal temperature and humidity, and (v) early innate immune responses in the URT for limiting and eliminating SARS-CoV-2 infections. The available data are consistent with optimal nasal air conditioning reducing SARS-CoV-2 infectivity of the URT and, as a consequence, severe COVID-19. Further studies on SARS-CoV-2 infection rates and viral loads in the nasal cavity and nasopharynx in relation to inhaled air temperature, humidity, age, gender, and genetic background are needed in this context. Face masks used for reducing air-borne virus transmission can also promote better nasal air conditioning in cold weather. Masks can, thereby, minimise SARS-CoV-2 infectivity and are particularly relevant for protecting more vulnerable persons from severe COVID-19.     

Viral Infection and Cardiovascular Disease: Implications for the Molecular Basis of COVID-19 Pathogenesis

The current pandemic of coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While this respiratory virus only causes mild symptoms in younger healthy individuals, elderly people and those with cardiovascular diseases such as systemic hypertension are susceptible to developing severe conditions that can be fatal. SARS-CoV-2 infection is also associated with an increased incidence of cardiovascular diseases such as myocardial injury, acute coronary syndrome, and thromboembolism. Understanding the mechanisms of the effects of this virus on the cardiovascular system should thus help develop therapeutic strategies to reduce the mortality and morbidity associated with SARS-CoV-2 infection. Since this virus causes severe and fatal conditions in older individuals with cardiovascular comorbidities, effective therapies targeting specific populations will likely contribute to ending this pandemic. In this review article, the effects of various viruses—including other coronaviruses, influenza, dengue, and human immunodeficiency virus—on the cardiovascular system are described to help provide molecular mechanisms of pathologies associated with SARS-CoV-2 infection and COVID-19. The goal is to provide mechanistic information from the biology of other viral infections in relation to cardiovascular pathologies for the purpose of developing improved vaccines and therapeutic agents effective in preventing and/or treating the acute and long-term consequences of SARS-CoV-2 and COVID-19.     

A Review on the Role of Stem Cells against SARS-CoV-2 in Children and Pregnant Women

Since the COVID-19 outbreak was acknowledged by the WHO on 30 January 2020, much research has been conducted to unveil various features of the responsible SARS-CoV-2 virus. Different rates of contagion in adults, children, and pregnant women may guide us to understand the underlying infection conditions of COVID-19. In this study, we first provide a review of recent reports of COVID-19 clinical outcomes in children and pregnant women. We then suggest a mechanism that explains the curious case of COVID-19 in children/pregnant women. The unique stem cell molecular signature, as well as the very low expression of angiotensin-converting enzyme 2 and the lower ACE/ACE2 ratio in stem cells of children/pregnant women compared to adults might be the cause of milder symptoms of COVID-19 in them. This study provides the main molecular keys on how stem cells can function properly and exert their immunomodulatory and regenerative effects in COVID-19-infected children/pregnant women, while failing to replicate their role in adults. This can lay the groundwork for both predicting the pattern of spread and severity of the symptoms in a population and designing novel stem cell-based treatment and prevention strategies for COVID-19.     

Infection of Brain Pericytes Underlying Neuropathology of COVID-19 Patients

A wide range of neurological manifestations have been associated with the development of COVID-19 following SARS-CoV-2 infection. However, the etiology of the neurological symptomatology is still largely unexplored. Here, we used state-of-the-art multiplexed immunostaining of human brains (n = 6 COVID-19, median age = 69.5 years; n = 7 control, median age = 68 years) and demonstrated that expression of the SARS-CoV-2 receptor ACE2 is restricted to a subset of neurovascular pericytes. Strikingly, neurological symptoms were exclusive to, and ubiquitous in, patients that exhibited moderate to high ACE2 expression in perivascular cells. Viral dsRNA was identified in the vascular wall and paralleled by perivascular inflammation, as signified by T cell and macrophage infiltration. Furthermore, fibrinogen leakage indicated compromised integrity of the blood–brain barrier. Notably, cerebrospinal fluid from additional 16 individuals (n = 8 COVID-19, median age = 67 years; n = 8 control, median age = 69.5 years) exhibited significantly lower levels of the pericyte marker PDGFRβ in SARS-CoV-2-infected cases, indicative of disrupted pericyte homeostasis. We conclude that pericyte infection by SARS-CoV-2 underlies virus entry into the privileged central nervous system space, as well as neurological symptomatology due to perivascular inflammation and a locally compromised blood–brain barrier.     

Cardiovascular Outcomes in the Acute Phase of COVID-19

The cumulative number of cases in the current global coronavirus disease 19 (COVID-19) pandemic, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has exceeded 100 million, with the number of deaths caused by the infection having exceeded 2.5 million. Recent reports from most frontline researchers have revealed that SARS-CoV-2 can also cause fatal non-respiratory conditions, such as fatal cardiovascular events. One of the important mechanisms underlying the multiple organ damage that is now known to occur during the acute phase of SARS-CoV-2 infection is impairment of vascular function associated with inhibition of angiotensin-converting enzyme 2. To manage the risk of vascular dysfunction-related complications in patients with COVID-19, it would be pivotal to clearly elucidate the precise mechanisms by which SARS-CoV-2 infects endothelial cells to cause vascular dysfunction. In this review, we summarize the current state of knowledge about the mechanisms involved in the development of vascular dysfunction in the acute phase of COVID-19.     

ERAP1 and ERAP2 Enzymes: A Protective Shield for RAS against COVID-19?

Patients with coronavirus disease 2019 (COVID-19) have a wide variety of clinical outcomes ranging from asymptomatic to severe respiratory syndrome that can progress to life-threatening lung lesions. The identification of prognostic factors can help to improve the risk stratification of patients by promptly defining for each the most effective therapy to resolve the disease. The etiological agent causing COVID-19 is a new coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that enters cells via the ACE2 receptor. SARS-CoV-2 infection causes a reduction in ACE2 levels, leading to an imbalance in the renin-angiotensin system (RAS), and consequently, in blood pressure and systemic vascular resistance. ERAP1 and ERAP2 are two RAS regulators and key components of MHC class I antigen processing. Their polymorphisms have been associated with autoimmune and inflammatory conditions, hypertension, and cancer. Based on their involvement in the RAS, we believe that the dysfunctional status of ERAP1 and ERAP2 enzymes may exacerbate the effect of SARS-CoV-2 infection, aggravating the symptomatology and clinical outcome of the disease. In this review, we discuss this hypothesis.     

The Rationale for Angiotensin Receptor Neprilysin Inhibitors in a Multi-Targeted Therapeutic Approach to COVID-19

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) determines the angiotensin converting enzyme 2 (ACE2) down-regulation and related decrease in angiotensin II degradation. Both these events trigger “cytokine storm” leading to acute lung and cardiovascular injury. A selective therapy for COVID-19 has not yet been identified. Clinical trials with remdesivir gave discordant results. Thus, healthcare systems have focused on “multi-targeted” therapeutic strategies aiming at relieving systemic inflammation and thrombotic complications. No randomized clinical trial has demonstrated the efficacy of renin angiotensin system antagonists in reducing inflammation related to COVID-19. Dexamethasone and tocilizumab showed encouraging data, but their use needs to be further validated. The still-controversial efficacy of these treatments highlighted the importance of organ injury prevention in COVID-19. Neprilysin (NEP) might be an interesting target for this purpose. NEP expression is increased by cytokines on lung fibroblasts surface. NEP activity is elevated in acute respiratory distress syndrome and it is conceivable that it is also high in COVID-19. NEP is implicated in the degradation of natriuretic peptides, bradykinin, substance P, adrenomedullin, and apelin that account for prevention of organ injury. Thus, NEP/angiotensin receptor type 1 (AT1R) inhibitor sacubitril/valsartan (SAC/VAL) may increase levels of these molecules and block AT1Rs required for ACE2 endocytosis in SARS-CoV-2 infection. Moreover, SAC/VAL has a positive impact on acute heart failure that is very frequently observed in deceased COVID-19 patients. The current review aims to summarize actual therapeutic strategies for COVID-19 and to examine the data supporting the potential benefits of SAC/VAL in COVID-19 treatment.     

Mitochondrial Modulations,Autophagy Pathways Shifts in Viral Infections: Consequences of COVID-19

Mitochondria are vital intracellular organelles that play an important role in regulating various intracellular events such as metabolism, bioenergetics, cell death (apoptosis), and innate immune signaling. Mitochondrial fission, fusion, and membrane potential play a central role in maintaining mitochondrial dynamics and the overall shape of mitochondria. Viruses change the dynamics of the mitochondria by altering the mitochondrial processes/functions, such as autophagy, mitophagy, and enzymes involved in metabolism. In addition, viruses decrease the supply of energy to the mitochondria in the form of ATP, causing viruses to create cellular stress by generating ROS in mitochondria to instigate viral proliferation, a process which causes both intra- and extra-mitochondrial damage. SARS-COV2 propagates through altering or changing various pathways, such as autophagy, UPR stress, MPTP and NLRP3 inflammasome. Thus, these pathways act as potential targets for viruses to facilitate their proliferation. Autophagy plays an essential role in SARS-COV2-mediated COVID-19 and modulates autophagy by using various drugs that act on potential targets of the virus to inhibit and treat viral infection. Modulated autophagy inhibits coronavirus replication; thus, it becomes a promising target for anti-coronaviral therapy. This review gives immense knowledge about the infections, mitochondrial modulations, and therapeutic targets of viruses.     

Disorders of the Cholinergic System in COVID-19 Era—A Review of the Latest Research

The appearance of the SARS-CoV-2 virus initiated many studies on the effects of the virus on the human body. So far, its negative influence on the functioning of many morphological and physiological units, including the nervous system, has been demonstrated. Consequently, research has been conducted on the changes that SARS-CoV-2 may cause in the cholinergic system. The aim of this study is to review the latest research from the years 2020/2021 regarding disorders in the cholinergic system caused by the SARS-CoV-2 virus. As a result of the research, it was found that the presence of the COVID-19 virus disrupts the activity of the cholinergic system, for example, causing the development of myasthenia gravis or a change in acetylcholine activity. The SARS-CoV-2 spike protein has a sequence similar to neurotoxins, capable of binding nicotinic acetylcholine receptors (nAChR). This may be proof that SARS-CoV-2 can bind nAChR. Nicotine and caffeine have similar structures to antiviral drugs, capable of binding angiotensin-converting enzyme 2 (ACE 2) epitopes that are recognized by SARS-CoV-2, with the potential to inhibit the formation of the ACE 2/SARS-CoV-2 complex. The blocking is enhanced when nicotine and caffeine are used together with antiviral drugs. This is proof that nAChR agonists can be used along with antiviral drugs in COVID-19 therapy. As a result, it is possible to develop COVID-19 therapies that use these compounds to reduce cytokine production. Another promising therapy is non-invasive stimulation of the vagus nerve, which soothes the body’s cytokine storm. Research on the influence of COVID-19 on the cholinergic system is an area that should continue to be developed as there is a need for further research. It can be firmly stated that COVID-19 causes a dysregulation of the cholinergic system, which leads to a need for further research, because there are many promising therapies that will prevent the SARS-CoV-2 virus from binding to the nicotinic receptor. There is a need for further research, both in vitro and in vivo. It should be noted that in the functioning of the cholinergic system and its connection with the activity of the COVID-19 virus, there might be many promising dependencies and solutions.