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The oral cavity is a unique environment that consists of teeth surrounded by periodontal tissues, oral mucosae with minor salivary glands, and terminal parts of major salivary glands that open into the oral cavity. The cavity is constantly exposed to viral and microbial pathogens. Recent studies indicate that components of the plasminogen (Plg)/plasmin (Pm) system are expressed in tissues of the oral cavity, such as the salivary gland, and contribute to microbial infection and inflammation, such as periodontitis. The Plg/Pm system fulfills two major functions: (a) the destruction of fibrin deposits in the bloodstream or damaged tissues, a process called fibrinolysis, and (b) non-fibrinolytic actions that include the proteolytic modulation of proteins. One can observe both functions during inflammation. The virus that causes the coronavirus disease 2019 (COVID-19) exploits the fibrinolytic and non-fibrinolytic functions of the Plg/Pm system in the oral cavity. During COVID-19, well-established coagulopathy with the development of microthrombi requires constant activation of the fibrinolytic function. Furthermore, viral entry is modulated by receptors such as TMPRSS2, which is necessary in the oral cavity, leading to a derailed immune response that peaks in cytokine storm syndrome. This paper outlines the significance of the Plg/Pm system for infectious and inflammatory diseases that start in the oral cavity. [ABSTRACT FROM AUTHOR]

Pulmonary fibrosis (PF) is a feared outcome of many pulmonary diseases which results in a reduction in lung compliance and capacity. The development of PF is relatively rare, but it can occur secondary to viral pneumonia, especially COVID-19 infection. While COVID-19 infection and its complications are still under investigation, we can look at a similar outbreak in the past to gain better insight as to the expected long-term outcomes of COVID-19 patient lung function. In the current article, we review the literature relative to PF via PubMed. We also performed a literature search for COVID-related pathological changes in the lungs. Finally, the paper was reviewed and summarized based on the studies' integrity, relative, or power calculations. This article provides a narrative review that endeavors to elucidate the current understanding of the pathophysiological mechanisms underlying PF and therapeutic strategies. We also discussed the potential for preventing progression to the fibrotic state within the context of the COVID-19 pandemic. With the massive scale of the COVID-19 pandemic, we expect there should more instances of PF due to COVID-19 infection. Patients who survive severe COVID-19 infection may suffer from a high incidence of PF. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic has precipitously changed the practice of transplanting fresh allografts. The safety measures adopted during the pandemic prompted the near-universal graft cryopreservation. However, the influence of cryopreserving allogeneic grafts on long-term transplant outcomes has emerged only in the most recent literature. In this review, the basic principles of cell cryopreservation are revised and the effects of cryopreservation on the different graft components are carefully reexamined. Finally, a literature revision on studies comparing transplant outcomes in patients receiving cryopreserved and fresh grafts is illustrated. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) persists throughout the world with over 65 million registered cases of survivors with post-COVID-19 sequelae, also known as LongCOVID-19 (LongC). LongC survivors exhibit various symptoms that span multiple organ systems, including the nervous system. To search for neurological markers of LongC, we investigated the soluble biomolecules present in the plasma and the proteins associated with plasma neuronal-enriched extracellular vesicles (nEVs) in 33 LongC patients with neurological impairment (nLongC), 12 COVID-19 survivors without any LongC symptoms (Cov), and 28 pre-COVID-19 healthy controls (HC). COVID-19 positive participants were infected between 2020 and 2022, not hospitalized, and were vaccinated or unvaccinated before infection. IL-1β was significantly increased in both nLongC and Cov and IL-8 was elevated in only nLongC. Both brain-derived neurotrophic factor and cortisol were significantly elevated in nLongC and Cov compared to HC. nEVs from people with nLongC had significantly elevated protein markers of neuronal dysfunction, including amyloid beta 42, pTau181 and TDP-43. This study shows chronic peripheral inflammation with increased stress after COVID-19 infection. Additionally, differentially expressed nEV neurodegenerative proteins were identified in people recovering from COVID-19 regardless of persistent symptoms. [ABSTRACT FROM AUTHOR]

A major problem in SARS-CoV-2-infected patients is the massive tissue inflammation in certain target organs, including the lungs. Mast cells (MC), basophils (BA), and eosinophils (EO) are key effector cells in inflammatory processes. These cells have recently been implicated in the pathogenesis of SARS-CoV-2 infections. We explored coronavirus receptor (CoV-R) expression profiles in primary human MC, BA, and EO, and in related cell lines (HMC-1, ROSA, MCPV-1, KU812, and EOL-1). As determined using flow cytometry, primary MC, BA, and EO, and their corresponding cell lines, displayed the CoV-R CD13 and CD147. Primary skin MC and BA, as well as EOL-1 cells, also displayed CD26, whereas primary EO and the MC and BA cell lines failed to express CD26. As assessed using qPCR, most cell lines expressed transcripts for CD13, CD147, and ABL2, whereas ACE2 mRNA was not detectable, and CD26 mRNA was only identified in EOL-1 cells. We also screened for drug effects on CoV-R expression. However, dexamethasone, vitamin D, and hydroxychloroquine did not exert substantial effects on the expression of CD13, CD26, or CD147 in the cells. Together, MC, BA, and EO express distinct CoV-R profiles. Whether these receptors mediate virus–cell interactions and thereby virus-induced inflammation remains unknown at present. [ABSTRACT FROM AUTHOR]

The world-wide COVID-19 pandemic has promoted a series of alternative vaccination strategies aiming to elicit neutralizing adaptive immunity in the human host. However, restricted efficacies of these vaccines targeting epitopes on the spike (S) protein that is involved in primary viral entry were observed and putatively assigned to viral glycosylation as an effective escape mechanism. Besides the well-recognized N-glycan shield covering SARS-CoV-2 spike (S) proteins, immunization strategies may be hampered by heavy O-glycosylation and variable O-glycosites fluctuating depending on the organ sites of primary infection and those involved in immunization. A further complication associated with viral glycosylation arises from the development of autoimmune antibodies to self-carbohydrates, including O-linked blood group antigens, as structural parts of viral proteins. This outline already emphasizes the importance of viral glycosylation in general and, in particular, highlights the impact of the site-specific O-glycosylation of virions, since this modification is independent of sequons and varies strongly in dependence on cell-specific repertoires of peptidyl-N-acetylgalactosaminyltransferases with their varying site preferences and of glycan core-specific glycosyltransferases. This review summarizes the current knowledge on the viral O-glycosylation of the SARS-CoV-2 spike protein and its impact on virulence and immune modulation in the host. [ABSTRACT FROM AUTHOR]

Cardiovascular complications are major clinical hallmarks of acute and post-acute coronavirus disease 2019 (COVID-19). However, the mechanistic details of SARS-CoV-2 infectivity of endothelial cells remain largely unknown. Here, we demonstrate that the receptor binding domain (RBD) of the SARS-CoV-2 spike (S) protein shares a similarity with the proline-rich binding ena/VASP homology (EVH1) domain and identified the endoplasmic reticulum (ER) resident calreticulin (CALR) as an S-RBD interacting protein. Our biochemical analysis showed that CALR, via its proline-rich (P) domain, interacts with S-RBD and modulates proteostasis of the S protein. Treatment of cells with the proteasomal inhibitor bortezomib increased the expression of the S protein independent of CALR, whereas the lysosomal/autophagy inhibitor bafilomycin 1A, which interferes with the acidification of lysosome, selectively augmented the S protein levels in a CALR-dependent manner. More importantly, the shRNA-mediated knockdown of CALR increased SARS-CoV-2 infection and impaired calcium homeostasis of human endothelial cells. This study provides new insight into the infectivity of SARS-CoV-2, calcium hemostasis, and the role of CALR in the ER-lysosome-dependent proteolysis of the spike protein, which could be associated with cardiovascular complications in COVID-19 patients. [ABSTRACT FROM AUTHOR]

The Coronavirus disease 2019 (COVID-19) pandemic continues to spread worldwide with over 260 million people infected and more than 5 million deaths, numbers that are escalating on a daily basis. Frontline health workers and scientists diligently fight to alleviate life-threatening symptoms and control the spread of the disease. There is an urgent need for better triage of patients, especially in third world countries, in order to decrease the pressure induced on healthcare facilities. In the struggle to treat life-threatening COVID-19 pneumonia, scientists have debated the clinical use of ionizing radiation (IR). The historical literature dating back to the 1940s contains many reports of successful treatment of pneumonia with IR. In this work, we critically review the literature for the use of IR for both diagnostic and treatment purposes. We identify details including the computed tomography (CT) scanning considerations, the radiobiological basis of IR anti-inflammatory effects, the supportive evidence for low dose radiation therapy (LDRT), and the risks of radiation-induced cancer and cardiac disease associated with LDRT. In this paper, we address concerns regarding the effective management of COVID-19 patients and potential avenues that could provide empirical evidence for the fight against the disease. [ABSTRACT FROM AUTHOR]

Respiratory diseases represent a significant economic and health burden worldwide, affecting millions of individuals each year in both human and animal populations. MicroRNAs (miRNAs) play crucial roles in gene expression regulation and are involved in various physiological and pathological processes. Exosomal miRNAs and cellular miRNAs have been identified as key regulators of several immune respiratory diseases, such as chronic respiratory diseases (CRD) caused by Mycoplasma gallisepticum (MG), Mycoplasma pneumoniae pneumonia (MMP) caused by the bacterium Mycoplasma pneumoniae, coronavirus disease 2019 (COVID-19), chronic obstructive pulmonary disease (COPD), asthma, and acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Consequently, miRNAs seem to have the potential to serve as diagnostic biomarkers and therapeutic targets in respiratory diseases. In this review, we summarize the current understanding of the functional roles of miRNAs in the above several respiratory diseases and discuss the potential use of miRNAs as stable diagnostic biomarkers and therapeutic targets for several immune respiratory diseases, focusing on the identification of differentially expressed miRNAs and their targeting of various signaling pathways implicated in disease pathogenesis. Despite the progress made, unanswered questions and future research directions are discussed to facilitate personalized and targeted therapies for patients with these debilitating conditions. [ABSTRACT FROM AUTHOR]

Evidence suggests that patients with long COVID can experience neuropsychiatric, neurologic, and cognitive symptoms. However, these clinical data are mostly associational studies complicated by confounding variables, thus the mechanisms responsible for persistent symptoms are unknown. Here we establish an animal model of long-lasting effects on the brain by eliciting mild disease in K18-hACE2 mice. Male and female K18-hACE2 mice were infected with 4 × 103 TCID50 of SARS-CoV-2 and, following recovery from acute infection, were tested in the open field, zero maze, and Y maze, starting 30 days post infection. Following recovery from SARS-CoV-2 infection, K18-hACE2 mice showed the characteristic lung fibrosis associated with SARS-CoV-2 infection, which correlates with increased expression of the pro-inflammatory kinin B1 receptor (B1R). These mice also had elevated expression of B1R and inflammatory markers in the brain and exhibited behavioral alterations such as elevated anxiety and attenuated exploratory behavior. Our data demonstrate that K18-hACE2 mice exhibit persistent effects of SARS-CoV-2 infection on brain tissue, revealing the potential for using this model of high sensitivity to SARS-CoV-2 to investigate mechanisms contributing to long COVID symptoms in at-risk populations. These results further suggest that elevated B1R expression may drive the long-lasting inflammatory response associated with SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic is a global challenge, demanding researchers address different approaches in relation to prevention, diagnostics and therapeutics. Amongst the many tactics of tackling these therapeutic challenges, small extracellular vesicles (sEVs) or exosomes are emerging as a new frontier in the field of ameliorating viral infections. Exosomes are part of extracellular vesicles (EVs)—spherical biological structures with a lipid bilayer of a diameter of up to 5000 nm, which are released into the intercellular space by most types of eukaryotic cells, both in physiological and pathological states. EVs share structural similarities to viruses, such as small size, common mechanisms of biogenesis and mechanisms for cell entry. The role of EVs in promoting the viral spread by evading the immune response of the host, which is exhibited by retroviruses, indicates the potential for further investigation and possible manipulation of these processes when tackling the spread and treatment of COVID-19. The following paper introduces the topic of the use of exosomes in the treatment of viral infections, and presents the future prospects for the use of these EVs. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19), the pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which counts more than 650 million cases and more than 6.6 million of deaths worldwide, affects the respiratory system with typical symptoms such as fever, cough, sore throat, acute respiratory distress syndrome (ARDS), and fatigue. Other nonpulmonary manifestations are related with abnormal inflammatory response, the "cytokine storm", that could lead to a multiorgan disease and to death. Evolution of effective vaccines against SARS-CoV-2 provided multiple options to prevent the infection, but the treatment of the severe forms remains difficult to manage. The cytokine storm is usually counteracted with standard medical care and anti-inflammatory drugs, but researchers moved forward their studies on new strategies based on cell therapy approaches. The perinatal tissues, such as placental membranes, amniotic fluid, and umbilical cord derivatives, are enriched in mesenchymal stromal cells (MSCs) that exert a well-known anti-inflammatory role, immune response modulation, and tissue repair. In this review, we focused on umbilical-cord-derived MSCs (UC-MSCs) used in in vitro and in vivo studies in order to evaluate the weakening of the severe symptoms, and on recent clinical trials from different databases, supporting the favorable potential of UC-MSCs as therapeutic strategy. [ABSTRACT FROM AUTHOR]

Coronavirus disease (COVID-19) causes various vascular and blood-related reactions, including exacerbated responses. The role of endothelial cells in this acute response is remarkable and may remain important beyond the acute phase. As we move into a post-COVID-19 era (where most people have been or will be infected by the SARS-CoV-2 virus), it is crucial to define the vascular consequences of COVID-19, including the long-term effects on the cardiovascular system. Research is needed to determine whether chronic endothelial dysfunction following COVID-19 could lead to an increased risk of cardiovascular and thrombotic events. Endothelial dysfunction could also serve as a diagnostic and therapeutic target for post-COVID-19. This review covers these topics and examines the potential of emerging vessel-on-a-chip technology to address these needs. Vessel-on-a-chip would allow for the study of COVID-19 pathophysiology in endothelial cells, including the analysis of SARS-CoV-2 interactions with endothelial function, leukocyte recruitment, and platelet activation. "Personalization" could be implemented in the models through induced pluripotent stem cells, patient-specific characteristics, or genetic modified cells. Adaptation for massive testing under standardized protocols is now possible, so the chips could be incorporated for the personalized follow-up of the disease or its sequalae (long COVID) and for the research of new drugs against COVID-19. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). About 45% of COVID-19 patients experience several symptoms a few months after the initial infection and develop post-acute sequelae of SARS-CoV-2 (PASC), referred to as "Long-COVID," characterized by persistent physical and mental fatigue. However, the exact pathogenetic mechanisms affecting the brain are still not well-understood. There is increasing evidence of neurovascular inflammation in the brain. However, the precise role of the neuroinflammatory response that contributes to the disease severity of COVID-19 and long COVID pathogenesis is not clearly understood. Here, we review the reports that the SARS-CoV-2 spike protein can cause blood–brain barrier (BBB) dysfunction and damage neurons either directly, or via activation of brain mast cells and microglia and the release of various neuroinflammatory molecules. Moreover, we provide recent evidence that the novel flavanol eriodictyol is particularly suited for development as an effective treatment alone or together with oleuropein and sulforaphane (ViralProtek®), all of which have potent anti-viral and anti-inflammatory actions. [ABSTRACT FROM AUTHOR]

Background and Methods: Severe COVID-19 is known to induce neurological damage (NeuroCOVID), mostly in aged individuals, by affecting brain-derived neurotrophic factor (BDNF), matrix metalloproteinases (MMP) 2 and 9 and the neurofilament light chain (NFL) pathways. Thus, the aim of this pilot study was to investigate BDNF, MMP-2, MMP-9, and NFL in the serum of aged men affected by COVID-19 at the beginning of the hospitalization period and characterized by different outcomes, i.e., attending a hospital ward or an intensive care unit (ICU) or with a fatal outcome. As a control group, we used a novelty of the study, unexposed age-matched men. We also correlated these findings with the routine blood parameters of the recruited individuals. Results: We found in COVID-19 individuals with severe or lethal outcomes disrupted serum BDNF, NFL, and MMP-2 presence and gross changes in ALT, GGT, LDH, IL-6, ferritin, and CRP. We also confirmed and extended previous data, using ROC analyses, showing that the ratio MMPs (2 and 9) versus BDNF and NFL might be a useful tool to predict a fatal COVID-19 outcome. Conclusions: Serum BDNF and NFL and/or their ratios with MMP-2 and MMP-9 could represent early predictors of NeuroCOVID in aged men. [ABSTRACT FROM AUTHOR]

The omicron variant is thought to cause less olfactory dysfunction than previous variants of SARS-CoV-2, but the reported prevalence differs greatly between populations and studies. Our systematic review and meta-analysis provide information regarding regional differences in prevalence as well as an estimate of the global prevalence of olfactory dysfunction based on 62 studies reporting information on 626,035 patients infected with the omicron variant. Our estimate of the omicron-induced prevalence of olfactory dysfunction in populations of European ancestry is 11.7%, while it is significantly lower in all other populations, ranging between 1.9% and 4.9%. When ethnic differences and population sizes are considered, the global prevalence of omicron-induced olfactory dysfunction in adults is estimated to be 3.7%. Omicron's effect on olfaction is twofold to tenfold lower than that of the alpha or delta variants according to previous meta-analyses and our analysis of studies that directly compared the prevalence of olfactory dysfunction between omicron and previous variants. The profile of the prevalence differences between ethnicities mirrors the results of a recent genome-wide association study that connected a gene locus encoding an odorant-metabolizing enzyme, UDP glycosyltransferase, to the extent of COVID-19-related loss of smell. Our analysis is consistent with the hypothesis that this enzyme contributes to the observed population differences. [ABSTRACT FROM AUTHOR]

Objective: Glioma is the most common primary malignancy of the adult central nervous system (CNS), with a poor prognosis and no effective prognostic signature. Since late 2019, the world has been affected by the rapid spread of SARS-CoV-2 infection. Research on SARS-CoV-2 is flourishing; however, its potential mechanistic association with glioma has rarely been reported. The aim of this study was to investigate the potential correlation of SARS-CoV-2-related genes with the occurrence, progression, prognosis, and immunotherapy of gliomas. Methods: SARS-CoV-2-related genes were obtained from the human protein atlas (HPA), while transcriptional data and clinicopathological data were obtained from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases. Glioma samples were collected from surgeries with the knowledge of patients. Differentially expressed genes were then identified and screened, and seven SARS-CoV-2 related genes were generated by LASSO regression analysis and uni/multi-variate COX analysis. A prognostic SARS-CoV-2-related gene signature (SCRGS) was then constructed based on these seven genes and validated in the TCGA validation cohort and CGGA cohort. Next, a nomogram was established by combining critical clinicopathological data. The correlation between SCRGS and glioma related biological processes was clarified by Gene set enrichment analysis (GSEA). In addition, immune infiltration and immune score, as well as immune checkpoint expression and immune escape, were further analyzed to assess the role of SCRGS in glioma-associated immune landscape and the responsiveness of immunotherapy. Finally, the reliability of SCRGS was verified by quantitative real-time polymerase chain reaction (qRT-PCR) on glioma samples. Results: The prognostic SCRGS contained seven genes, REEP6, CEP112, LARP4B, CWC27, GOLGA2, ATP6AP1, and ERO1B. Patients were divided into high- and low-risk groups according to the median SARS-CoV-2 Index. Overall survival was significantly worse in the high-risk group than in the low-risk group. COX analysis and receiver operating characteristic (ROC) curves demonstrated excellent predictive power for SCRGS for glioma prognosis. In addition, GSEA, immune infiltration, and immune scores indicated that SCRGS could potentially predict the tumor microenvironment, immune infiltration, and immune response in glioma patients. Conclusions: The SCRGS established here can effectively predict the prognosis of glioma patients and provide a potential direction for immunotherapy. [ABSTRACT FROM AUTHOR]

Several reports have shown that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has the potential to also be neurotropic. However, the mechanisms by which SARS-CoV-2 induces neurologic injury, including neurological and/or psychological symptoms, remain unclear. In this review, the available knowledge on the neurobiological mechanisms underlying COVID-19 was organized using the AOP framework. Four AOPs leading to neurological adverse outcomes (AO), anosmia, encephalitis, stroke, and seizure, were developed. Biological key events (KEs) identified to induce these AOs included binding to ACE2, blood–brain barrier (BBB) disruption, hypoxia, neuroinflammation, and oxidative stress. The modularity of AOPs allows the construction of AOP networks to visualize core pathways and recognize neuroinflammation and BBB disruption as shared mechanisms. Furthermore, the impact on the neurological AOPs of COVID-19 by modulating and multiscale factors such as age, psychological stress, nutrition, poverty, and food insecurity was discussed. Organizing the existing knowledge along an AOP framework can represent a valuable tool to understand disease mechanisms and identify data gaps and potentially contribute to treatment, and prevention. This AOP-aligned approach also facilitates synergy between experts from different backgrounds, while the fast-evolving and disruptive nature of COVID-19 emphasizes the need for interdisciplinarity and cross-community research. [ABSTRACT FROM AUTHOR]

There is no vaccine or specific antiviral treatment for COVID-19, which is causing a global pandemic. One current focus is drug repurposing research, but those drugs have limited therapeutic efficacies and known adverse effects. The pathology of COVID-19 is essentially unknown. Without this understanding, it is challenging to discover a successful treatment to be approved for clinical use. This paper addresses several key biological processes of reactive oxygen, halogen and nitrogen species (ROS, RHS and RNS) that play crucial physiological roles in organisms from plants to humans. These include why superoxide dismutases, the enzymes to catalyze the formation of H2O2, are required for protecting ROS-induced injury in cell metabolism, why the amount of ROS/RNS produced by ionizing radiation at clinically relevant doses is ~1000 fold lower than the endogenous ROS/RNS level routinely produced in the cell and why a low level of endogenous RHS plays a crucial role in phagocytosis for immune defense. Herein we propose a plausible amplification mechanism in immune defense: ozone-depleting-like halogen cyclic reactions enhancing RHS effects are responsible for all the mentioned physiological functions, which are activated by H2O2 and deactivated by NO signaling molecule. Our results show that the reaction cycles can be repeated thousands of times and amplify the RHS pathogen-killing (defense) effects by 100,000 fold in phagocytosis, resembling the cyclic ozone-depleting reactions in the stratosphere. It is unraveled that H2O2 is a required protective signaling molecule (angel) in the defense system for human health and its dysfunction can cause many diseases or conditions such as autoimmune disorders, aging and cancer. We also identify a class of potent drugs for effective treatment of invading pathogens such as HIV and SARS-CoV-2 (COVID-19), cancer and other diseases, and provide a molecular mechanism of action of the drugs or candidates. [ABSTRACT FROM AUTHOR]

This systematic review focused on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients that had detected SARS-CoV-2 virus in cerebrospinal fluid (CSF). A systematic literature search was carried out in PubMed, Embase, Scopus, Web of Science, Medrxiv, and Biorxiv databases from inception to 19 December 2021. Case reports or case series involving patients with proved SARS-CoV-2 presence in CSF by polymerize chain reaction were included. Our search strategy produced 23 articles documenting a total of 23 patients with positive SARS-CoV-2 in the CSF. Fever (55%) was the most common symptom, followed by headaches (41%), cough (32%), and vomiting/nausea (32%). The majority of the cases included was encephalitis (57%), 8 of which were confirmed by magnetic resonance imaging. The second most prevalent presentation was meningitis. The cerebral spinal fluid analysis found disparities in protein levels and normal glucose levels in most cases. This study demonstrates that SARS-CoV-2 can enter the nervous system via various routes and cause CNS infection symptoms. SARS-CoV-2 has been shown to infect the CNS even when no respiratory symptoms are present and nasopharyngeal swabs are negative. As a result, SARS-CoV-2 should be considered as a possible cause of CNS infection and tested for in the CSF. [ABSTRACT FROM AUTHOR]

Loss of the sense of smell (anosmia) has been included as a COVID-19 symptom by the World Health Organization. The majority of patients recover the sense of smell within a few weeks postinfection (short-term anosmia), while others report persistent anosmia. Several studies have investigated the mechanisms leading to anosmia in COVID-19; however, the evidence is scattered, and the mechanisms remain poorly understood. Based on a comprehensive review of the literature, we aim here to evaluate the current knowledge and uncertainties regarding the mechanisms leading to short-term anosmia following SARS-CoV-2 infection. We applied an adverse outcome pathway (AOP) framework, well established in toxicology, to propose a sequence of measurable key events (KEs) leading to short-term anosmia in COVID-19. Those KEs are (1) SARS-CoV-2 Spike proteins binding to ACE-2 expressed by the sustentacular (SUS) cells in the olfactory epithelium (OE); (2) viral entry into SUS cells; (3) viral replication in the SUS cells; (4) SUS cell death; (5) damage to the olfactory sensory neurons and the olfactory epithelium (OE). This AOP-aligned approach allows for the identification of gaps where more research should be conducted and where therapeutic intervention could act. Finally, this AOP gives a frame to explain several disease features and can be linked to specific factors that lead to interindividual differences in response to SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

Although dementia is a heterogenous group of diseases, inflammation has been shown to play a central role in all of them and provides a common link in their pathology. This review aims to highlight the importance of immune response in the most common types of dementia. We describe molecular aspects of pro-inflammatory signaling and sources of inflammatory activation in the human organism, including a novel infectious agent, SARS-CoV-2. The role of glial cells in neuroinflammation, as well as potential therapeutic approaches, are then discussed. Peripheral immune response and increased cytokine production, including an early surge in TNF and IL-1β concentrations activate glia, leading to aggravation of neuroinflammation and dysfunction of neurons during COVID-19. Lifestyle factors, such as diet, have a large impact on future cognitive outcomes and should be included as a crucial intervention in dementia prevention. While the use of NSAIDs is not recommended due to inconclusive results on their efficacy and risk of side effects, the studies focused on the use of TNF antagonists as the more specific target in neuroinflammation are still very limited. It is still unknown, to what degree neuroinflammation resulting from COVID-19 may affect neurodegenerative process and cognitive functioning in the long term with ongoing reports of chronic post-COVID complications. [ABSTRACT FROM AUTHOR]

Airway epithelial cells represent the main target of SARS-CoV-2 replication but several pieces of evidence suggest that endothelial cells (ECs), lining pulmonary blood vessels, are key players in lung injury in COVID-19 patients. Although in vivo evidence of SARS-CoV-2 affecting the vascular endothelium exists, in vitro data are limited. In the present study, we set up an organotypic model to dissect the crosstalk between airway epithelium and pulmonary endothelial cells during SARS-CoV-2 infection. We showed that SARS-CoV-2 infected airway epithelium triggers the induction of endothelial adhesion molecules in ECs, suggesting a bystander effect of dangerous soluble signals from the infected epithelium. The endothelial activation was correlated with inflammatory cytokines (IL-1β, IL-6, IL-8) and with the viral replication in the airway epithelium. Interestingly, SARS-CoV-2 infection determined a modulation of endothelial p21, which could be partially reversed by inhibiting IFN-β production from ECs when co-cultured with HAE. Altogether, we demonstrated that SARS-CoV-2 infected epithelium triggers activation/senescence processes in ECs involving type I IFN-β production, suggesting possible antiviral/damage mechanisms occurring in the endothelium. [ABSTRACT FROM AUTHOR]

Virus-specific cellular and humoral responses are major determinants for protection from critical illness after SARS-CoV-2 infection. However, the magnitude of the contribution of each of the components to viral clearance remains unclear. Here, we studied the timing of viral clearance in relation to 122 immune parameters in 102 hospitalised patients with moderate and severe COVID-19 in a longitudinal design. Delayed viral clearance was associated with more severe disease and was associated with higher levels of SARS-CoV-2-specific (neutralising) antibodies over time, increased numbers of neutrophils, monocytes, basophils, and a range of pro-inflammatory cyto-/chemokines illustrating ongoing, partially Th2 dominating, immune activation. In contrast, early viral clearance and less critical illness correlated with the peak of neutralising antibodies, higher levels of CD4 T cells, and in particular naïve CD4+ T cells, suggesting their role in early control of SARS-CoV-2 possibly by proving appropriate B cell help. Higher counts of naïve CD4+ T cells also correlated with lower levels of MIF, IL-9, and TNF-beta, suggesting an indirect role in averting prolonged virus-induced tissue damage. Collectively, our data show that naïve CD4+ T cell play a critical role in rapid viral T cell control, obviating aberrant antibody and cytokine profiles and disease deterioration. These data may help in guiding risk stratification for severe COVID-19. [ABSTRACT FROM AUTHOR]

Despite the major target of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, being the respiratory system, clinical evidence suggests that the male reproductive system may represent another viral target organ. Revealing the effect of SARS-CoV-2 infection on testis and sperm is a priority for reproductive biology, as well as for reproductive medicine. Here, we confirmed that the SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) is highly expressed on human testis and ejaculated sperm; moreover, we provide evidence for the expression of the co-receptors transmembrane protease/serine (TMPRSS2), Basigin (BSG), and Catepsin L (CTSL). Human sperm were readily infected, both in vivo and in vitro, by SARS-CoV-2, as demonstrated by confocal and electron microscopy. The demonstration that the seminiferous epithelium and sperm support SARS-CoV-2 viral replication suggests the possibility that the spermatogenetic process may be detrimentally affected by the virus, and at the same time, supports the need to implement safety measures and guidelines to ensure specific care in reproductive medicine. [ABSTRACT FROM AUTHOR]

The severity of the coronavirus disease in 2019 (COVID-19) is strongly linked to a dysregulated immune response. This fuels the fear of severe disease in patients with autoimmune disorders continuously using immunosuppressive/immunomodulating medications. One complication of COVID-19 is thromboembolism caused by intravascular aggregates of neutrophil extracellular traps (NETs) occluding the affected vessels. Like COVID-19, systemic lupus erythematosus (SLE) is characterized by, amongst others, an increased risk of thromboembolism. An imbalance between NET formation and clearance is suggested to play a prominent role in exacerbating autoimmunity and disease severity. Serologic evidence of exposure to SARS-CoV-2 has a minor impact on the SLE course in a Swedish cohort reportedly. Herein, we assessed NET formation in patients from this cohort by neutrophil elastase (NE) activity and the presence of cell-free DNA, MPO-DNA, and NE-DNA complexes and correlated the findings to the clinical parameters. The presence of NE-DNA complexes and NE activity differed significantly in pre-pandemic versus pandemic serum samples. The latter correlated significantly with the hemoglobin concentration, blood cell counts, and complement protein 3 and 4 levels in the pre-pandemic but only with the leukocyte count and neutrophil levels in the pandemic serum samples. Taken together, our data suggest a change, especially in the NE activity independent of exposure to SARS-CoV-2. [ABSTRACT FROM AUTHOR]

Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) predominantly infects the respiratory system, several investigations have shown the involvement of the central nervous system (CNS) along the course of the illness, with encephalitis being one of the symptoms. The objective of this systematic review was to evaluate the characteristics (clinical, neuro-radiological aspects, and laboratory features) and outcomes of encephalitis in COVID-19 patients. PubMed, Scopus, and Google Scholar databases were searched from 1 December 2019 until 21 July 2022 to identify case reports and case series published on COVID-19 associated with encephalitis. The quality of the included studies was assessed by the Joanna Briggs Institute critical appraisal checklists. This systematic review included 79 studies, including 91 COVID-19 patients (52.7% male) experiencing encephalitis, where 85.6% were adults (49.3 ± 20.2 years), and 14.4% were children (11.2 ± 7.6 years). RT-PCR was used to confirm 92.2% of the COVID-19 patients. Encephalitis-related symptoms were present in 78.0% of COVID-19 patients at the time of diagnosis. In these encephalitis patients, seizure (29.5%), confusion (23.2%), headache (20.5%), disorientation (15.2%), and altered mental status (11.6%) were the most frequently reported neurologic manifestations. Looking at the MRI, EEG, and CSF findings, 77.6%, 75.5%, and 64.1% of the patients represented abnormal results. SARS-CoV-2-associated or -mediated encephalitis were the most common type observed (59.3%), followed by autoimmune encephalitis (18.7%). Among the included patients, 66.7% were discharged (37.8% improved and 28.9% fully recovered), whereas 20.0% of the reported COVID-19-positive encephalitis patients died. Based on the quality assessment, 87.4% of the studies were of high quality. Although in COVID-19, encephalitis is not a typical phenomenon, SARS-CoV-2 seems like a neuropathogen affecting the brain even when there are no signs of respiratory illness, causing a high rate of disability and fatality. [ABSTRACT FROM AUTHOR]

In this study, we investigated whether treatment with palmitoylethanolamide and luteolin (PEA-LUT) leads to improvement in the quantitative or qualitative measures of olfactory dysfunction or relief from mental clouding in patients affected by long COVID. Patients with long COVID olfactory dysfunction were allocated to different groups based on the presence ("previously treated") or absence ("naïve") of prior exposure to olfactory training. Patients were then randomized to receive PEA-LUT alone or in combination with olfactory training. Olfactory function and memory were assessed at monthly intervals using self-report measures and quantitative thresholds. A total of 69 patients (43 women, 26 men) with an age average of 40.6 + 10.5 were recruited. PEA-LUT therapy was associated with a significant improvement in validated odor identification scores at the baseline versus each subsequent month; assessment at 3 months showed an average improvement of 10.7 + 2.6, CI 95%: 6–14 (p < 0.0001). The overall prevalence of parosmia was 79.7% (55 patients), with a significant improvement from the baseline to 3 months (p < 0.0001), namely in 31 patients from the Naïve 1 group (72%), 15 from the Naïve 2 group (93.7%), and 9 from the remaining group (90%). Overall, mental clouding was detected in 37.7% (26 subjects) of the cases, with a reduction in severity from the baseline to three months (p = 0.02), namely in 15 patients from the Naïve 1 group (34.8%), 7 from the Naïve 2 group (43.7%), and 4 from the remaining group (40%). Conclusions. In patients with long COVID and chronic olfactory loss, a regimen including oral PEA-LUT and olfactory training ameliorated olfactory dysfunction and memory. Further investigations are necessary to discern biomarkers, mechanisms, and long-term outcomes. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) have become a trending topic in recent years; they constitute a new intercellular communication paradigm. Extracellular vesicles are 30–4000 nanometers in diameter particles that are limited by a phospholipid bilayer and contain functional biomolecules, such as proteins, lipids, and nucleic acids. They are released by virtually all types of eukaryotic cells; through their cargoes, EVs are capable of triggering signaling in recipient cells. In addition to their functions in the homeostatic state, EVs have gained attention because of their roles in pathological contexts, eventually contributing to disease progression. In the Coronavirus disease 2019 (COVID-19) pandemic, aside from the scientific race for the development of preventive and therapeutic interventions, it is critical to understand the pathological mechanisms involved in SARS-CoV-2 infection. In this sense, EVs are key players in the main processes of COVID-19. Thus, in this review, we highlight the role of EVs in the establishment of the viral infection and in the procoagulant state, cytokine storm, and immunoregulation of innate and adaptive immune responses. [ABSTRACT FROM AUTHOR]

Since it was first reported, the novel coronavirus disease 2019 (COVID-19) remains an unresolved puzzle for biomedical researchers in different fields. Various treatments, drugs, and interventions were explored as treatments for COVID. Nevertheless, there are no standard and effective therapeutic measures. Meanwhile, mesenchymal stem cell (MSC) therapy offers a new approach with minimal side effects. MSCs and MSC-based products possess several biological properties that potentially alleviate COVID-19 symptoms. Generally, there are three classifications of stem cell therapy: cell-based therapy, tissue engineering, and cell-free therapy. This review discusses the MSC-based and cell-free therapies for patients with COVID-19, their potential mechanisms of action, and clinical trials related to these therapies. Cell-based therapies involve the direct use and injection of MSCs into the target tissue or organ. On the other hand, cell-free therapy uses secreted products from cells as the primary material. Cell-free therapy materials can comprise cell secretomes and extracellular vesicles. Each therapeutic approach possesses different benefits and various risks. A better understanding of MSC-based and cell-free therapies is essential for supporting the development of safe and effective COVID-19 therapy. [ABSTRACT FROM AUTHOR]

Coronavirus disease (COVID-19) is an infectious disease that is caused by a highly contagious and severe acute respiratory syndrome—coronavirus 2 (SARS-CoV-2). This infection started to spread across the world in 2019 and rapidly turned into a global pandemic, causing an urgent necessity for treatment strategies development. The mRNA vaccines against SARS-CoV-2 can trigger an immune response, providing genetic information that allows the production of spike glycoproteins. MiRNAs play a crucial role in diverse key cellular processes, including antiviral defense. Several miRNAs are described as key factors in SARS-CoV-2 human infection through the regulation of ACE2 levels and by the inhibition of SARS-CoV-2 replication and spike expression. Consequently, these molecules have been considered as highly promising biomarkers. In numerous human malignancies, it has been recognized that miRNAs expression is dysregulated. Since miRNAs can target SARS-CoV-2-associated mRNAs, in cancer patients, the deregulation of these molecules can impair the immune response to the vaccines. Therefore, in this review, we propose a miRNA profile of seven SARS-CoV-2-related miRNAs, namely miR-214, miR-98-5p, miR-7-5p, miR-24-3p, miR-145-5p, miR-223-3p and miR-15b-5p, that are deregulated in a high number of cancers and have the potential to be used as prognostic biomarkers to stratify cancer patients. [ABSTRACT FROM AUTHOR]

Autophagy is a highly conserved lysosomal degradation pathway active at basal levels in all cells. However, under stress conditions, such as a lack of nutrients or trophic factors, it works as a survival mechanism that allows the generation of metabolic precursors for the proper functioning of the cells until the nutrients are available. Neurons, as post-mitotic cells, depend largely on autophagy to maintain cell homeostasis to get rid of damaged and/or old organelles and misfolded or aggregated proteins. Therefore, the dysfunction of this process contributes to the pathologies of many human diseases. Furthermore, autophagy is highly active during differentiation and development. In this review, we describe the current knowledge of the different pathways, molecular mechanisms, factors that induce it, and the regulation of mammalian autophagy. We also discuss its relevant role in development and disease. Finally, here we summarize several investigations demonstrating that autophagic abnormalities have been considered the underlying reasons for many human diseases, including liver disease, cardiovascular, cerebrovascular diseases, neurodegenerative diseases, neoplastic diseases, cancers, and, more recently, infectious diseases, such as SARS-CoV-2 caused COVID-19 disease. [ABSTRACT FROM AUTHOR]

In the last 30 years the adipose cell has been object of several studies, turning its reputation from an inert cell into the main character involved in the pathophysiology of multiple diseases, including the ongoing COVID-19 pandemic, which has changed the clinical scenario of the last two years. Composed by two types of tissue (white and brown), with opposite roles, the adipose organ is now classified as a real endocrine organ whose dysfunction is involved in different diseases, mainly obesity and type 2 diabetes. In this mini-review we aim to retrace the adipose organ history from physiology to physiopathology, to provide therapeutic perspectives for the prevention and treatment of its two main related diseases (obesity and type 2 diabetes) and to summarize the most recent discoveries linking adipose tissue to COVID-19. [ABSTRACT FROM AUTHOR]

Glucose-6-phosphate dehydrogenase (G6PD) is the second rate-limiting enzyme of the pentose phosphate pathway. This enzyme is present in the cytoplasm of all mammalian cells, and its activity is essential for an adequate functioning of the antioxidant system and for the response of innate immunity. It is responsible for the production of nicotinamide adenine dinucleotide phosphate (NADPH), the first redox equivalent, in the pentose phosphate pathway. Viral infections such as SARS-CoV-2 may induce the Warburg effect with an increase in anaerobic glycolysis and production of lactate. This condition ensures the success of viral replication and production of the virion. Therefore, the activity of G6PD may be increased in COVID-19 patients raising the level of the NADPH, which is needed for the enzymatic and non-enzymatic antioxidant systems that counteract the oxidative stress caused by the cytokine storm. G6PD deficiency affects approximately 350–400 million people worldwide; therefore, it is one of the most prevalent diseases related to enzymatic deficiency worldwide. In G6PD-deficient patients exposed to SARS-CoV-2, the amount of NADPH is reduced, increasing the susceptibility for viral infection. There is loss of the redox homeostasis in them, resulting in severe pneumonia and fatal outcomes. [ABSTRACT FROM AUTHOR]

Both SARS-CoV-2 infection and vaccination have previously been demonstrated to elicit robust, yet somewhat limited immunity against the evolving variants of SARS-CoV-2. Nevertheless, reports performing side-by-side comparison of immune responses following infection vs. vaccination have been relatively scarce. The aim of this study was to compare B-cell response to adenovirus-vectored vaccination in SARS-CoV-2-naive individuals with that observed in the COVID-19 convalescent patients six months after the first encounter with the viral antigens. We set out to use a single analytical platform and performed comprehensive analysis of serum levels of receptor binding domain (RBD)-specific and virus-neutralizing antibodies, frequencies of RBD-binding circulating memory B cells (MBCs), MBC-derived antibody-secreting cells, as well as RBD-specific and virus-neutralizing activity of MBC-derived antibodies after Gam-COVID-Vac (Sputnik V) vaccination and/or natural SARS-CoV-2 infection. Overall, natural immunity was superior to Gam-COVID-Vac vaccination. The levels of neutralizing MBC-derived antibodies in the convalescent patients turned out to be significantly higher than those found following vaccination. Our results suggest that after six months, SARS-CoV-2-specific MBC immunity is more robust in COVID-19 convalescent patients than in Gam-COVID-Vac recipients. Collectively, our data unambiguously indicate that natural immunity outperforms Gam-COVID-Vac-induced immunity six months following recovery/vaccination, which should inform healthcare and vaccination decisions. [ABSTRACT FROM AUTHOR]

COVID-19 infection causes complications, even in people who have had a mild course of the disease. The most dangerous seem to be neurological ailments: anxiety, depression, mixed anxiety–depressive (MAD) syndromes, and irreversible dementia. These conditions can negatively affect the respiratory system, circulatory system, and heart functioning. We believe that phytotherapy can be helpful in all of these conditions. Clinical trials confirm this possibility. The work presents plant materials (Valeriana officinalis, Melissa officinalis, Passiflora incarnata, Piper methysticum, Humulus lupulus, Ballota nigra, Hypericum perforatum, Rhodiola rosea, Lavandula officinalis, Paullinia cupana, Ginkgo biloba, Murraya koenigii, Crataegus monogyna and oxyacantha, Hedera helix, Polygala senega, Pelargonium sidoides, Lichen islandicus, Plantago lanceolata) and their dominant compounds (valeranon, valtrate, apigenin, citronellal, isovitexin, isoorientin, methysticin, humulone, farnesene, acteoside, hypericin, hyperforin, biapigenin, rosavidin, salidroside, linalool acetate, linalool, caffeine, ginkgolide, bilobalide, mihanimbine, epicatechin, hederacoside C,α-hederine, presegenin, umckalin, 6,7,8-trixydroxybenzopyranone disulfate, fumaroprotocetric acid, protolichesteric acid, aucubin, acteoside) responsible for their activity. It also shows the possibility of reducing post-COVID-19 neurological, respiratory, and cardiovascular complications, which can affect the functioning of the nervous system. [ABSTRACT FROM AUTHOR]

Background: Polyphenols are the largest class of bioactive compounds in plants, which are synthesized as secondary metabolites. In the last few years, interesting studies have demonstrated the efficacy of polyphenols against coronavirus infections. Methods: we conducted a phase II multicentric clinical trial (TAEROVID-19) during the first wave of the COVID-19 pandemic in order to assess the safety and feasibility of Taurisolo® aerosol formulation in hospitalized patients suffering from SARS-CoV-2 pneumonia. Results: we observed a rapid decline of symptoms and a low rate of intensive care in patients treated with Taurisolo®, with a faster decline of symptoms. Conclusions: This is the first trial assessing the safety and feasibility of Taurisolo® aerosol formulation. We could argue that this treatment could act as an add-on therapy in the treatment of COVID-19 patients, owing to both its anti-inflammatory and antioxidant effects. Further controlled trials are needed, which may be of interest to evaluate the compound's efficacy. [ABSTRACT FROM AUTHOR]

Human SARS-CoV-2 and avian infectious bronchitis virus (IBV) are highly contagious and deadly coronaviruses, causing devastating respiratory diseases in humans and chickens. The lack of effective therapeutics exacerbates the impact of outbreaks associated with SARS-CoV-2 and IBV infections. Thus, novel drugs or therapeutic agents are highly in demand for controlling viral transmission and disease progression. Mesenchymal stem cells (MSC) secreted factors (secretome) are safe and efficient alternatives to stem cells in MSC-based therapies. This study aimed to investigate the antiviral potentials of human Wharton's jelly MSC secretome (hWJ-MSC-S) against SARS-CoV-2 and IBV infections in vitro and in ovo. The half-maximal inhibitory concentrations (IC50), cytotoxic concentration (CC50), and selective index (SI) values of hWJ-MSC-S were determined using Vero-E6 cells. The virucidal, anti-adsorption, and anti-replication antiviral mechanisms of hWJ-MSC-S were evaluated. The hWJ-MSC-S significantly inhibited infection of SARS-CoV-2 and IBV, without affecting the viability of cells and embryos. Interestingly, hWJ-MSC-S reduced viral infection by >90%, in vitro. The IC50 and SI of hWJ-MSC secretome against SARS-CoV-2 were 166.6 and 235.29 µg/mL, respectively, while for IBV, IC50 and SI were 439.9 and 89.11 µg/mL, respectively. The virucidal and anti-replication antiviral effects of hWJ-MSC-S were very prominent compared to the anti-adsorption effect. In the in ovo model, hWJ-MSC-S reduced IBV titer by >99%. Liquid chromatography-tandem mass spectrometry (LC/MS-MS) analysis of hWJ-MSC-S revealed a significant enrichment of immunomodulatory and antiviral proteins. Collectively, our results not only uncovered the antiviral potency of hWJ-MSC-S against SARS-CoV-2 and IBV, but also described the mechanism by which hWJ-MSC-S inhibits viral infection. These findings indicate that hWJ-MSC-S could be utilized in future pre-clinical and clinical studies to develop effective therapeutic approaches against human COVID-19 and avian IB respiratory diseases. [ABSTRACT FROM AUTHOR]

This review is a comprehensive analysis of the effects of SARS-CoV-2 infection on Unconventional T cells and innate lymphoid cells (ILCs). COVID-19 affected patients show dysregulation of their adaptive immune systems, but many questions remain unsolved on the behavior of Unconventional cells and ILCs during infection, considering their role in maintaining homeostasis in tissue. Therefore, we highlight the differences that exist among the studies in cohorts of patients who in general were categorized considering symptoms and hospitalization. Moreover, we make a critical analysis of the presence of particular clusters of cells that express activation and exhausted markers for each group in order to bring out potential diagnostic factors unconsidered before now. We also focus our attention on studies that take into consideration recovered patients. Indeed, it could be useful to determine Unconventional T cells' and ILCs' frequencies and functions in longitudinal studies because it could represent a way to monitor the immune status of SARS-CoV-2-infected subjects. Possible changes in cell frequencies or activation profiles could be potentially useful as prognostic biomarkers and for future therapy. Currently, there are no efficacious therapies for SARS-CoV-2 infection, but deep studies on involvement of Unconventional T cells and ILCs in the pathogenesis of COVID-19 could be promising for targeted therapies. [ABSTRACT FROM AUTHOR]

The novel coronavirus (2019-nCoVCOVID-19) belongs to the Beta coronavirus family, which contains MERS-CoV (Middle East respiratory syndrome coronavirus) and SARS-CoV (severe acute respiratory syndrome coronavirus). SARS-CoV-2 activates the innate immune system, thereby activating the inflammatory mechanism, causing the release of inflammatory cytokines. Moreover, it has been suggested that COVID-19 may penetrate the central nervous system, and release inflammatory cytokines in the brains, inducing neuroinflammation and neurodegeneration. Several links connect COVID-19 with Alzheimer's disease (AD), such as elevated oxidative stress, uncontrolled release of the inflammatory cytokines, and mitochondrial apoptosis. There are severe concerns that excessive immune cell activation in COVID-19 may aggravate the neurodegeneration and amyloid-beta pathology of AD. Here, we have collected the evidence, showing the links between the two diseases. The focus has been made to collect the information on the activation of the inflammation, its contributors, and shared therapeutic targets. Furthermore, we have given future perspectives, research gaps, and overlapping pathological bases of the two diseases. Lastly, we have given the short touch to the drugs that have equally shown rescuing effects against both diseases. Although there is limited information available regarding the exact links between COVID-19 and neuroinflammation, we have insight into the pathological contributors of the diseases. Based on the shared pathological features and therapeutic targets, we hypothesize that the activation of the immune system may induce neurological disorders by triggering oxidative stress and neuroinflammation. [ABSTRACT FROM AUTHOR]

The risk of complications following surgical procedures is significantly increased in patients with SARS-CoV-2 infection. However, the mechanisms underlying these correlations are not fully known. Spinal cord injury (SCI) patients who underwent reconstructive surgery for pressure ulcers (PUs) before and during the COVID-19 pandemic were included in this study. The patient's postoperative progression was registered, and the subcutaneous white adipose tissue (s-WAT) surrounding the ulcers was analyzed by proteomic and immunohistochemical assays to identify the molecular/cellular signatures of impaired recovery. Patients with SCI and a COVID-19-positive diagnosis showed worse recovery and severe postoperative complications, requiring reintervention. Several proteins were upregulated in the adipose tissue of these patients. Among them, CKMT2 and CKM stood out, and CKM increased for up to 60 days after the COVID-19 diagnosis. Moreover, CKMT2 and CKM were largely found in MGCs within the s-WAT of COVID patients. Some of these proteins presented post-translational modifications and were targeted by autoantibodies in the serum of COVID patients. Overall, our results indicate that CKMT2, CKM, and the presence of MGCs in the adipose tissue surrounding PUs in post-COVID patients could be predictive biomarkers of postsurgical complications. These results suggest that the inflammatory response in adipose tissue may underlie the defective repair seen after surgery. [ABSTRACT FROM AUTHOR]

The infection with SARS-CoV-2 impairs the glucose–insulin axis and this contributes to oxidative (OS) and nitrosative (NSS) stress. Here, we evaluated changes in glucose metabolism that could promote the loss of redox homeostasis in COVID-19 patients. This was comparative cohort and analytical study that compared COVID-19 patients and healthy subjects. The study population consisted of 61 COVID-19 patients with and without comorbidities and 25 healthy subjects (HS). In all subjects the plasma glucose, insulin, 8-isoprostane, Vitamin D, H2S and 3-nitrotyrosine were determined by ELISA. The nitrites (NO2−), lipid-peroxidation (LPO), total-antioxidant-capacity (TAC), thiols, glutathione (GSH) and selenium (Se) were determined by spectrophotometry. The glucose, insulin and HOMA-IR (p < 0.001), 8-isoprostanes, 3-nitrotyrosine (p < 0.001) and LPO were increased (p = 0.02) while Vitamin D (p = 0.01), H2S, thiols, TAC, GSH and Se (p < 0.001) decreased in COVID-19 patients in comparison to HS. The SARS-CoV-2 infection resulted in alterations in the glucose–insulin axis that led to hyperglycemia, hyperinsulinemia and IR in patients with and without comorbidities. These alterations increase OS and NSS reflected in increases or decreases in some oxidative markers in plasma with major impact or fatal consequences in patients that course with metabolic syndrome. Moreover, subjects without comorbidities could have long-term alterations in the redox homeostasis after infection. [ABSTRACT FROM AUTHOR]

In "Cellular Immunology and COVID-19" (a Special Issue of I Cells i ), a panel of leading scientists provides an exhaustive overview of the different aspects of the immune mechanisms underlying COVID-19. Although immunized patients with primary antibody deficiency generated atypical memory B cells, possibly by extra-follicular or incomplete germinal center reactions, SARS-CoV-2 convalescents responded to the infection by generating spike-specific memory B cells that were improved by the subsequent immunization. Moreover, the cytokine hyper activation in COVID-19 appears to be similar to that seen in rheumatoid arthritis, shedding light on the pathological crosstalk between COVID-19 and rheumatoid arthritis, and the aspects of SARS-CoV-2 infection in RA development [[7]]. A dominant spike-derived CD8+ T cell epitope activates a poly functional CD8+ T cell response in recovered COVID-19 patients, possibly being a promising target to prime and boost CD8+ T cells against SARS-CoV-2 infection [[10]]. [Extracted from the article]

Severe acute respiratory syndrome virus 2 (SARS-CoV2) has infected an estimated 400 million people world-wide, causing approximately 6 million deaths from severe coronavirus disease 2019 (COVID-19). The SARS-CoV2 Spike protein plays a critical role in viral attachment and entry into host cells. The recent emergence of highly transmissible variants of SARS-CoV2 has been linked to mutations in Spike. This review provides an overview of the structure and function of Spike and describes the factors that impact Spike's ability to mediate viral infection as well as the potential limits to how good (or bad) Spike protein can become. Proposed here is a framework that considers the processes of Spike-mediated SARS-CoV2 attachment, dissociation, and cell entry where the role of Spike, from the standpoint of the virus, is to maximize cell entry with each viral-cell collision. Key parameters are identified that will be needed to develop models to identify mechanisms that new Spike variants might exploit to enhance viral transmission. In particular, the importance of considering secondary co-receptors for Spike, such as heparan sulfate proteoglycans is discussed. Accurate models of Spike-cell interactions could contribute to the development of new therapies in advance of the emergence of new highly transmissible SARS-CoV2 variants. [ABSTRACT FROM AUTHOR]

Severe COVID-19 patients present a clinical and laboratory overlap with other hyperinflammatory conditions such as hemophagocytic lymphohistiocytosis (HLH). However, the underlying mechanisms of these conditions remain to be explored. Here, we investigated the transcriptome of 1596 individuals, including patients with COVID-19 in comparison to healthy controls, other acute inflammatory states (HLH, multisystem inflammatory syndrome in children [MIS-C], Kawasaki disease [KD]), and different respiratory infections (seasonal coronavirus, influenza, bacterial pneumonia). We observed that COVID-19 and HLH share immunological pathways (cytokine/chemokine signaling and neutrophil-mediated immune responses), including gene signatures that stratify COVID-19 patients admitted to the intensive care unit (ICU) and COVID-19_nonICU patients. Of note, among the common differentially expressed genes (DEG), there is a cluster of neutrophil-associated genes that reflects a generalized hyperinflammatory state since it is also dysregulated in patients with KD and bacterial pneumonia. These genes are dysregulated at the protein level across several COVID-19 studies and form an interconnected network with differentially expressed plasma proteins that point to neutrophil hyperactivation in COVID-19 patients admitted to the intensive care unit. scRNAseq analysis indicated that these genes are specifically upregulated across different leukocyte populations, including lymphocyte subsets and immature neutrophils. Artificial intelligence modeling confirmed the strong association of these genes with COVID-19 severity. Thus, our work indicates putative therapeutic pathways for intervention. [ABSTRACT FROM AUTHOR]

Among the first clinical symptoms of the SARS-CoV-2 infection is olfactory–gustatory deficit; this continues for weeks and, in some cases, can be persistent. We prospectively evaluated 162 patients affected by COVID-19 using a visual analogue scale (VAS) for nasal and olfactory–gustatory symptoms. Patients were checked after 7, 14, 21, 28, 90, and 180 days. A total of 118 patients (72.8%) reported an olfactory VAS < 7 at baseline (group B), and 44 (27.2%) reported anosmia (VAS ≥ 7) (group A) and underwent the Brief Smell Identification Test (B-SIT) and Burghart Taste Strips (BTS) to quantify the deficit objectively and repeated the tests to confirm the sense recovery. Group A patients showed B-SIT anosmia and hyposmia in 44.2% and 55.8% of cases, respectively. A total of 88.6% of group A patients reported ageusia with VAS ≥ 7, and BTS confirmed 81.8% of ageusia and 18.2% of hypogeusia. VAS smell recovery was recorded starting from 14 days, with normalization at 28 days. The 28-day B-SIT score showed normosmia in 90.6% of group A patients. The mean time for full recovery (VAS = 0) was shorter in group B (22.9 days) than in group A (31.9 days). Chemosensory deficit is frequently the first symptom in patients with COVID-19, and, in most cases, recovery occurs after four weeks. [ABSTRACT FROM AUTHOR]

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is the pathogenic agent of Coronavirus-Induced Disease-2019 (COVID-19), a multi-organ syndrome which primarily targets the respiratory system. In this review, considering the large amount of data pointing out the role of the Aryl hydrocarbon Receptor (AhR) in the inflammatory response and in the modulation of innate and adaptive immunity, we describe some mechanisms that strongly suggest its involvement in the management of COVID-19′s inflammatory framework. It regulates both the expression of Angiotensin Converting Enzyme-2 (ACE-2) and its stabilizing partner, the Broad neutral Amino acid Transporter 1 (B0AT1). It induces Indolamine 2,3 dioxygenase (IDO-1), the enzyme which, starting from Tryptophan (Trp), produces Kynurenine (Kyn, Beta-Anthraniloyl-L-Alanine). The accumulation of Kyn and the depletion of Trp arrest T cell growth and induce apoptosis, setting up an immune-tolerant condition, whereas AhR and interferon type I (IFN-I) build a mutual inhibitory loop that also involves NF-kB and limits the innate response. AhR/Kyn binding boosts the production of Interleukin-6 (IL-6), thus reinforcing the inflammatory state and counteracting the IDO-dependent immune tolerance in the later stage of COVID-19. Taken together, these data depict a framework where sufficient clues suggest the possible participation of AhR in the management of COVID-19 inflammation, thus indicating an additional therapeutic target for this disease. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is an extremely contagious disease whereby the virus damages the host's respiratory tract via entering through the ACE2 receptor. Cardiovascular disorder is being recognized in the majority of COVID-19 patients; yet, the relationship between SARS-CoV-2 and heart failure has not been established. In the present study, SARS-CoV-2 infection was induced in the monkey model. Thereafter, heart tissue samples were collected, and pathological changes were analyzed in the left ventricular tissue by hematoxylin and eosin, trichrome, and immunohistochemical staining specific to T lymphocytes and macrophages. The findings revealed that SARS-CoV-2 infection induces several pathological changes in the heart, which cause cardiomyocyte disarray, mononuclear infiltrates of inflammatory cells, and hypertrophy. Furthermore, collagen-specific staining showed the development of cardiac fibrosis in the interstitial and perivascular regions in the hearts of infected primates. Moreover, the myocardial tissue samples displayed multiple foci of inflammatory cells positive for T lymphocytes and macrophages within the myocardium. These findings suggest the progression of the disease, which can lead to the development of severe complications, including heart failure. Additionally, SARS-CoV-2 antigen staining detected the presence of virus particles in the myocardium. Thus, we found that SARS-CoV-2 infection is characterized by an exaggerated inflammatory immune response in the heart, which possibly contributes to myocardial remodeling and subsequent fibrosis. [ABSTRACT FROM AUTHOR]

A recent comparison of clinical and inflammatory parameters, together with biomarkers of oxidative stress, in patients who died from aggressive COVID-19 and survivors suggested that the lipid peroxidation product 4-hydroxynonenal (4-HNE) might be detrimental in lethal SARS-CoV-2 infection. The current study further explores the involvement of inflammatory cells, systemic vascular stress, and 4-HNE in lethal COVID-19 using specific immunohistochemical analyses of the inflammatory cells within the vital organs obtained by autopsy of nine patients who died from aggressive SAR-CoV-2 infection. Besides 4-HNE, myeloperoxidase (MPO) and mitochondrial superoxide dismutase (SOD2) were analyzed alongside standard leukocyte biomarkers (CDs). All the immunohistochemical slides were simultaneously prepared for each analyzed biomarker. The results revealed abundant 4-HNE in the vital organs, but the primary origin of 4-HNE was sepsis-like vascular stress, not an oxidative burst of the inflammatory cells. In particular, inflammatory cells were often negative for 4-HNE, while blood vessels were always very strongly immunopositive, as was edematous tissue even in the absence of inflammatory cells. The most affected organs were the lungs with diffuse alveolar damage and the brain with edema and reactive astrocytes, whereas despite acute tubular necrosis, 4-HNE was not abundant in the kidneys, which had prominent SOD2. Although SOD2 in most cases gave strong immunohistochemical positivity similar to 4-HNE, unlike 4-HNE, it was always limited to the cells, as was MPO. Due to their differential expressions in blood vessels, inflammatory cells, and the kidneys, we think that SOD2 could, together with 4-HNE, be a potential link between a malfunctioning immune system, oxidative stress, and vascular stress in lethal COVID-19. [ABSTRACT FROM AUTHOR]

The novel coronavirus SARS-CoV-2 has caused a pandemic resulting in millions of deaths worldwide. While multiple vaccines have been developed, insufficient vaccination combined with adaptive mutations create uncertainty for the future. Here, we discuss novel strategies to control COVID-19 relying on Defective Interfering Particles (DIPs) and related particles that arise naturally during an infection. Our intention is to encourage and to provide the basis for the implementation of such strategies by multi-disciplinary teams. We therefore provide an overview of SARS-CoV-2 for a multi-disciplinary readership that is specifically tailored to these strategies, we identify potential targets based on the current knowledge of the properties and functions of coronaviruses, and we propose specific strategies to engineer DIPs and other interfering or therapeutic nanoparticles. [ABSTRACT FROM AUTHOR]