Structural and non-structural proteins in SARS-CoV-2: potential aspects to COVID-19 treatment or prevention of progression of related diseases.

Coronavirus disease 2019 (COVID-19) is caused by a new member of the Coronaviridae family known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). There are structural and non-structural proteins (NSPs) in the genome of this virus. S, M, H, and E proteins are structural proteins, and NSPs include accessory and replicase proteins. The structural and NSP components of SARS-CoV-2 play an important role in its infectivity, and some of them may be important in the pathogenesis of chronic diseases, including cancer, coagulation disorders, neurodegenerative disorders, and cardiovascular diseases. The SARS-CoV-2 proteins interact with targets such as angiotensin-converting enzyme 2 (ACE2) receptor. In addition, SARS-CoV-2 can stimulate pathological intracellular signaling pathways by triggering transcription factor hypoxia-inducible factor-1 (HIF-1), neuropilin-1 (NRP-1), CD147, and Eph receptors, which play important roles in the progression of neurodegenerative diseases like Alzheimer's disease, epilepsy, and multiple sclerosis, and multiple cancers such as glioblastoma, lung malignancies, and leukemias. Several compounds such as polyphenols, doxazosin, baricitinib, and ruxolitinib could inhibit these interactions. It has been demonstrated that the SARS-CoV-2 spike protein has a stronger affinity for human ACE2 than the spike protein of SARS-CoV, leading the current study to hypothesize that the newly produced variant Omicron receptor-binding domain (RBD) binds to human ACE2 more strongly than the primary strain. SARS and Middle East respiratory syndrome (MERS) viruses against structural and NSPs have become resistant to previous vaccines. Therefore, the review of recent studies and the performance of current vaccines and their effects on COVID-19 and related diseases has become a vital need to deal with the current conditions. This review examines the potential role of these SARS-CoV-2 proteins in the initiation of chronic diseases, and it is anticipated that these proteins could serve as components of an effective vaccine or treatment for COVID-19 and related diseases. Video Abstract.

Diabetes as one of the long-term COVID-19 complications: from the potential reason of more diabetic patients' susceptibility to COVID-19 to the possible caution of future global diabetes tsunami.

According to recent researches, people with diabetes mellitus (type 1 and 2) have a higher incidence of coronavirus disease 2019 (COVID-19), which is caused by a SARS-CoV-2 infection. In this regard, COVID-19 may make diabetic patients more sensitive to hyperglycemia by modifying the immunological and inflammatory responses and increasing reactive oxygen species (ROS) predisposing the patients to severe COVID-19 and potentially lethal results. Actually, in addition to COVID-19, diabetic patients have been demonstrated to have abnormally high levels of inflammatory cytokines, increased virus entrance, and decreased immune response. On the other hand, during the severe stage of COVID-19, the SARS-CoV-2-infected patients have lymphopenia and inflammatory cytokine storms that cause damage to several body organs such as ß cells of the pancreas which may make them as future diabetic candidates. In this line, the nuclear factor kappa B (NF-κB) pathway, which is activated by a number of mediators, plays a substantial part in cytokine storms through various pathways. In this pathway, some polymorphisms also make the individuals more competent to diabetes via infection with SARS-CoV-2. On the other hand, during hospitalization of SARS-CoV-2-infected patients, the use of some drugs may unintentionally lead to diabetes in the future via increasing inflammation and stress oxidative. Thus, in this review, we will first explain why diabetic patients are more susceptible to COVID-19. Second, we will warn about a future global diabetes tsunami via the SARS-CoV-2 as one of its long-term complications.

Association of MicroRNA-146a with Type 1 and 2 Diabetes and their Related Complications.

Most medical investigations have found a reduced blood level of miR-146a in type 2 diabetes (T2D) patients, suggesting an important role for miR-146a (microRNA-146a) in the etiology of diabetes mellitus (DM) and its consequences. Furthermore, injection of miR-146a mimic has been confirmed to alleviate diabetes mellitus in diabetic animal models. In this line, deregulation of miR-146a expression has been linked to the progression of nephropathy, neuropathy, wound healing, olfactory dysfunction, cardiovascular disorders, and retinopathy in diabetic patients. In this review, besides a comprehensive review of the function of miR-146a in DM, we discussed new findings on type 1 (T1MD) and type 2 (T2DM) diabetes mellitus, highlighting the discrepancies between clinical and preclinical investigations and elucidating the biological pathways regulated through miR-146a in DM-affected tissues.

CD147 and cyclophilin A: a promising potential targeted therapy for COVID-19 and associated cancer progression and chemo-resistance.

Coronavirus disease-2019 (COVID-19), as a worldwide serious issue has been shown to lead to progression and poor outcomes in cancer patients. The underlying mechanisms for SARS-CoV-2 infection's adverse effects on cancer patients have not been fully understood. We hypothesized that CD147 and Cyclophilin A (CyPA) not only can play a significant role in infection severity but also can contribute to cancer progression and chemotherapy resistance in cancer patients with COVID-19. In addition, we hypothesized that the expression of both CD147 and CyPA could be increased by Hypoxia-inducible Factor-1 alpha (HIF-1α) activation during hypoxic conditions that occurred during COVID-19. Therefore, this evidence can open a new window in the management of cancer patients during the pandemic and therapeutic approaches targeting CD147 and CyPA could be a potentially promising therapeutic approach for such patients.

A cellular and molecular biology-based update for ivermectin against COVID-19: is it effective or non-effective?

Despite community vaccination against coronavirus disease 2019 (COVID-19) and reduced mortality, there are still challenges in treatment options for the disease. Due to the continuous mutation of SARS-CoV-2 virus and the emergence of new strains, diversity in the use of existing antiviral drugs to combat the epidemic has become a crucial therapeutic chance. As a broad-spectrum antiparasitic and antiviral drug, ivermectin has traditionally been used to treat many types of disease, including DNA and RNA viral infections. Even so, based on currently available data, it is still controversial that ivermectin can be used as one of the effective antiviral agents to treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or not. The aim of this study was to provide comprehensive information on ivermectin, including its safety and efficacy, as well as its adverse effects in the treatment of COVID-19.

Hypoxia-inducible factor 1 alpha (HIF-1α) stimulated and P2X7 receptor activated by COVID-19, as a potential therapeutic target and risk factor for epilepsy.

Based on available evidence, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a neuroinvasive virus. According to the centers for disease control and prevention (CDC), coronavirus disease 2019 (COVID-19) may cause epilepsy. In this line, COVID-19 can stimulate hypoxia-inducible factor-1 alpha (HIF-1α) and activate P2X7 receptor. Both HIF-1α and P2X7 receptors are linked to epileptogenesis and seizures. Therefore, in the current study, we suggested that COVID-19 may have a role in epileptogenesis and seizure through HIF-1α stimulation and P2X7 receptor activation. Consequently, pharmacological targeting of these factors could be a promising therapeutic approach for such patients.

Hesperetin as an anti-SARS-CoV-2 agent can inhibit COVID-19-associated cancer progression by suppressing intracellular signaling pathways.

Hesperetin, an aglycone metabolite of hesperidin with high bioavailability, recently gained attention due to its anti-COVID-19 and anti-cancer properties. Multiple studies revealed that cancer patients are prone to experience a severe form of COVID-19 and higher mortality risk. In addition, studies suggested that COVID-19 can potentially lead to cancer progression through multiple mechanisms. This study proposes that hesperetin not only can be used as an anti-COVID-19 agent but also can reduce the risk of multiple cancer progression by suppressing several intracellular signaling pathways in cancer patients with COVID-19. Therefore, in this review, we attempted to provide evidence demonstrating anti-COVID-19/cancer properties of hesperetin with several mechanisms.

Possible role of autophagy induced by COVID-19 in cancer progression, chemo-resistance, and tumor recurrence.

COVID-19 infection is a serious threat to patients with primary diseases, especially multiple cancers. Studies suggest that cancer patients are one of the most susceptible populations to experience severe COVID-19 and death. In addition, a number of studies suggest various mechanisms for SARS-CoV-2 in cancer progression. In this study, we discussed the role of SARS-CoV-2 in the induction of autophagy and we hypothesized that autophagy induced by COVID-19 not only can contribute to viral replication but also potentially can lead to cancer progression, chemo-resistance, and tumor recurrence in multiple cancer patients. Therefore, targeting autophagy-related signaling pathways and cellular and molecular processes could be a potentially promising therapeutic approach for cancer patients with COVID-19. Hence, this study can shed light on a new window on the management of such patients. However, more investigations in the future are required to understand other pathological effects of COVID-19 infection on cancer patients to provide new therapeutic strategies to combat these complications in these patients.

Lectins and lectibodies: potential promising antiviral agents.

In nature, lectins are widely dispersed proteins that selectively recognize and bind to carbohydrates and glycoconjugates via reversible bonds at specific binding sites. Many viral diseases have been treated with lectins due to their wide range of structures, specificity for carbohydrates, and ability to bind carbohydrates. Through hemagglutination assays, these proteins can be detected interacting with various carbohydrates on the surface of cells and viral envelopes. This review discusses the most robust lectins and their rationally engineered versions, such as lectibodies, as antiviral proteins. Fusion of lectin and antibody's crystallizable fragment (Fc) of immunoglobulin G (IgG) produces a molecule called a "lectibody" that can act as a carbohydrate-targeting antibody. Lectibodies can not only bind to the surface glycoproteins via their lectins and neutralize and clear viruses or infected cells by viruses but also perform Fc-mediated antibody effector functions. These functions include complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), and antibody-dependent cell-mediated phagocytosis (ADCP). In addition to entering host cells, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein S1 binds to angiotensin-converting enzyme 2 (ACE2) and downregulates it and type I interferons in a way that may lead to lung disease. The SARS-CoV-2 spike protein S1 and human immunodeficiency virus (HIV) envelope are heavily glycosylated, which could make them a major target for developing vaccines, diagnostic tests, and therapeutic drugs. Lectibodies can lead to neutralization and clearance of viruses and cells infected by viruses by binding to glycans located on the envelope surface (e.g., the heavily glycosylated SARS-CoV-2 spike protein).

The roles of Eph receptors, neuropilin-1, P2X7, and CD147 in COVID-19-associated neurodegenerative diseases: inflammasome and JaK inhibitors as potential promising therapies.

The novel coronavirus disease 2019 (COVID-19) pandemic has spread worldwide, and finding a safe therapeutic strategy and effective vaccine is critical to overcoming severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Therefore, elucidation of pathogenesis mechanisms, especially entry routes of SARS-CoV-2 may help propose antiviral drugs and novel vaccines. Several receptors have been demonstrated for the interaction of spike (S) protein of SARS-CoV-2 with host cells, including angiotensin-converting enzyme (ACE2), ephrin ligands and Eph receptors, neuropilin 1 (NRP-1), P2X7, and CD147. The expression of these entry receptors in the central nervous system (CNS) may make the CNS prone to SARS-CoV-2 invasion, leading to neurodegenerative diseases. The present review provides potential pathological mechanisms of SARS-CoV-2 infection in the CNS, including entry receptors and cytokines involved in neuroinflammatory conditions. Moreover, it explains several neurodegenerative disorders associated with COVID-19. Finally, we suggest inflammasome and JaK inhibitors as potential therapeutic strategies for neurodegenerative diseases.