[The impact of carbohydrate metabolism disorders on the early and long-term clinical outcomes of patients with COVID-19 according to the AKTIV and AKTIV 2 registries].

BACKGROUND: Numerous studies indicate a high incidence of various disorders of carbohydrate metabolism against the new coronavirus infection. These disorders aggravate the course of infection and increase mortality. Thereby, analysis of risk factors for unfavorable outcomes and assessment of the long-term consequences of COVID-19 in patients with impaired carbohydrate metabolism is of great importance. AIM: To investigate the association between carbohydrate metabolism disorders in COVID-19 patients and mortality, course of infection, long-term consequences, as well as to identify risk factors for an unfavorable disease course. MATERIALS AND METHODS: A retrospective analysis of data from the combined multicenter non-interventional real-world AKTIV and AKTIV 2 registries was performed. The sample included 9290 patients who had COVID-19 with varying severity from June 29, 2020, to November 29, 2020 (AKTIV) and from October 01, 2020, to March 30, 2021 (AKTIV 2). The patients were divided into 3 groups: Group 1 - patients with intact carbohydrate metabolism, n=6606; Group 2 - patients with newly diagnosed hyperglycemia (NDH), n=1073; Group 3 - patients with a history of type 2 diabetes mellitus (DM2), n=1611. The groups were assessed for clinical and laboratory parameters, comorbidities, mortality, carbohydrate metabolic status, and well-being during the infection and at 12 months. RESULTS: The prevalence of carbohydrate metabolism disorders (CMD) was 28,9%, with DM2 patients accounting for 17,3% and patients with newly diagnosed hyperglycemia (NDH) for 11,6%. The mortality rate of patients with hyperglycemia of any origin was 10.6%, which was significantly higher compared to patients without hyperglycemia (3,9%). The probability of lethal outcome increased 2,48-fold in the group of patients with DM2 and 2,04-fold in the group of patients with NDH. At the same time, the probability of a lethal outcome decreased 2,94-fold in patients without CMD. At 12 months, patients with CMD showed a significantly higher frequency and longer persistence of complaints. This trend was more pronounced in patients with DM2 than in those with NDH. Only 1,7% of patients from the NDH group had type 2 diabetes and were receiving oral hypoglycemic medications one year after the infection. A prognostic model was developed to determine the risk of lethal outcome. The model included such known predictors as concomitant ischemic heart disease, history of myocardial infarction or stroke, blood glucose level, and age. CONCLUSION: Carbohydrate metabolism disorders aggravate the course of COVID-19 and increase mortality. One year after infection, patients with DM2 and NDH were more likely to have symptoms typical for post-COVID syndrome, and NDH resolved in most cases after the infection.

Abnormal glucose metabolism in virus associated sepsis.

Sepsis is identified as a potentially lethal organ impairment triggered by an inadequate host reaction to infection (Sepsis-3). Viral sepsis is a potentially deadly organ impairment state caused by the host's inappropriate reaction to a viral infection. However, when a viral infection occurs, the metabolism of the infected cell undergoes a variety of changes that cause the host to respond to the infection. But, until now, little has been known about the challenges faced by cellular metabolic alterations that occur during viral infection and how these changes modulate infection. This study concentrates on the alterations in glucose metabolism during viral sepsis and their impact on viral infection, with a view to exploring new potential therapeutic targets for viral sepsis.

Functional Fine-Tuning of Metabolic Pathways by the Endocannabinoid System-Implications for Health and Disease.

The endocannabinoid system (ECS) employs a huge network of molecules (receptors, ligands, and enzymatic machinery molecules) whose interactions with other cellular networks have still not been fully elucidated. Endogenous cannabinoids are molecules with the primary function of control of multiple metabolic pathways. Maintenance of tissue and cellular homeostasis by functional fine-tuning of essential metabolic pathways is one of the key characteristics of the ECS. It is implicated in a variety of physiological and pathological states and an attractive pharmacological target yet to reach its full potential. This review will focus on the involvement of ECS in glucose and lipid metabolism, food intake regulation, immune homeostasis, respiratory health, inflammation, cancer and other physiological and pathological states will be substantiated using freely available data from open-access databases, experimental data and literature review. Future directions should envision capturing its diversity and exploiting pharmacological options beyond the classical ECS suspects (exogenous cannabinoids and cannabinoid receptor monomers) as signaling through cannabinoid receptor heteromers offers new possibilities for different biochemical outcomes in the cell.

Why blood group A individuals are at risk whereas blood group O individuals are protected from SARS-CoV-2 (COVID-19) infection: A hypothesis regarding how the virus invades the human body via ABO(H) blood group-determining carbohydrates.

While the angiotensin converting enzyme 2 (ACE2) protein is defined as the primary severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor, the viral serine molecule might be mobilized by the host's transmembrane protease serine subtype 2 (TMPRSS2) enzyme from the viral spike (S) protein and hijack the host's N-acetyl-D-galactosamine (GalNAc) metabolism. The resulting hybrid, serologically A-like/Tn (T nouvelle) structure potentially acts as a host-pathogen functional molecular bridge. In humans, this intermediate structure will hypothetically be replaced by ABO(H) blood group-specific, mucin-type structures, in the case of infection hybrid epitopes, implicating the phenotypically glycosidic accommodation of plasma proteins. The virus may, by mimicking the synthetic pathways of the ABO(H) blood groups, bind to the cell surfaces of the blood group O(H) by formation of a hybrid H-type antigen as the potential precursor of hybrid non-O blood groups, which does not affect the highly anti-glycan aggressive anti-A and anti-B isoagglutinin activities, exerted by the germline-encoded nonimmune immunoglobulin M (IgM). In the non-O blood groups, which have developed from the H-type antigen, these IgM activities are downregulated by phenotypic glycosylation, while adaptive immunoglobulins might arise in response to the hybrid A and B blood group structures, bonds between autologous carbohydrates and foreign peptides, suggesting the exertion of autoreactivity. The non-O blood groups thus become a preferred target for the virus, whereas blood group O(H) individuals, lacking the A/B phenotype-determining enzymes and binding the virus alone by hybrid H-type antigen formation, have the least molecular contact with the virus and maintain the critical anti-A and anti-B isoagglutinin activities, exerted by the ancestral IgM, which is considered the humoral spearhead of innate immunity.

Exploring lectin-glycan interactions to combat COVID-19: Lessons acquired from other enveloped viruses.

The emergence of a new human coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has imposed great pressure on the health system worldwide. The presence of glycoproteins on the viral envelope opens a wide range of possibilities for the application of lectins to address some urgent problems involved in this pandemic. In this work, we discuss the potential contributions of lectins from nonmammalian sources in the development of several fields associated with viral infections, most notably COVID-19. We review the literature on the use of nonmammalian lectins as a therapeutic approach against members of the Coronaviridae family, including recent advances in strategies of protein engineering to improve their efficacy. The applications of lectins as adjuvants for antiviral vaccines are also discussed. Finally, we present some emerging strategies employing lectins for the development of biosensors, microarrays, immunoassays and tools for purification of viruses from whole blood. Altogether, the data compiled in this review highlight the importance of structural studies aiming to improve our knowledge about the basis of glycan recognition by lectins and its repercussions in several fields, providing potential solutions for complex aspects that are emerging from different health challenges.

Flexible Synthetic Carbohydrate Receptors as Inhibitors of Viral Attachment.

Carbohydrate-receptor interactions are often involved in the docking of viruses to host cells, and this docking is a necessary step in the virus life cycle that precedes infection and, ultimately, replication. Despite the conserved structures of the glycans involved in docking, they are still considered "undruggable", meaning these glycans are beyond the scope of conventional pharmacological strategies. Recent advances in the development of synthetic carbohydrate receptors (SCRs), small molecules that bind carbohydrates, could bring carbohydrate-receptor interactions within the purview of druggable targets. Here we discuss the role of carbohydrate-receptor interactions in viral infection, the evolution of SCRs, and recent results demonstrating their ability to prevent viral infections in vitro. Common SCR design strategies based on boronic ester formation, metal chelation, and noncovalent interactions are discussed. The benefits of incorporating the idiosyncrasies of natural glycan-binding proteins-including flexibility, cooperativity, and multivalency-into SCR design to achieve nonglucosidic specificity are shown. These studies into SCR design and binding could lead to new strategies for mitigating the grave threat to human health posed by enveloped viruses, which are heavily glycosylated viroids that are the cause of some of the most pressing and untreatable diseases, including HIV, Dengue, Zika, influenza, and SARS-CoV-2.

Carbohydrate-Binding Agents: Potential of Repurposing for COVID-19 Therapy.

With the emergence of the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the whole world is suffering from atypical pneumonia, which resulted in more than 559,047 deaths worldwide. In this time of crisis and urgency, the only hope comes from new candidate vaccines and potential antivirals. However, formulating new vaccines and synthesizing new antivirals are a laborious task. Therefore, considering the high infection rate and mortality due to COVID-19, utilization of previous information, and repurposing of existing drugs against valid viral targets have emerged as a novel drug discovery approach in this challenging time. The transmembrane spike (S) glycoprotein of coronaviruses (CoVs), which facilitates the virus's entry into the host cells, exists in a homotrimeric form and is covered with N-linked glycans. S glycoprotein is known as the main target of antibodies having neutralizing potency and is also considered as an attractive target for therapeutic or vaccine development. Similarly, targeting of N-linked glycans of S glycoprotein envelope of CoV via carbohydrate-binding agents (CBAs) could serve as an attractive therapeutic approach for developing novel antivirals. CBAs from natural sources like lectins from plants, marine algae and prokaryotes and lectin mimics like Pradimicin-A (PRM-A) have shown antiviral activities against CoV and other enveloped viruses. However, the potential use of CBAs specifically lectins was limited due to unfavorable responses like immunogenicity, mitogenicity, hemagglutination, inflammatory activity, cellular toxicity, etc. Here, we reviewed the current scenario of CBAs as antivirals against CoVs, presented strategies to improve the efficacy of CBAs against CoVs; and studied the molecular interactions between CBAs (lectins and PRM-A) with Man9 by molecular docking for potential repurposing against CoVs in general, and SARSCoV- 2, in particular.