SARS-CoV-2, the third major coronavirus of the 21st century, causing COVID-19 disease, profoundly impacts public health and workforces worldwide. Identifying individuals at heightened risk of SARS-CoV-2 infection is crucial for targeted interventions and preparedness. This study investigated 35 SNVs within viral infection-associated genes in SARS-CoV-2 patients and uninfected controls from the Basque Country (March 2020-July 2021). Its primary aim was to uncover genetic markers indicative of SARS-CoV-2 susceptibility and explore genetic predispositions to infection. Association analyses revealed previously unreported associations between SNVs and susceptibility. Haplotype analyses uncovered novel links between haplotypes and susceptibility, surpassing individual SNV associations. Descriptive modelling identified key susceptibility factors, with rs11246068-CC (IFITM3), rs5742933-GG (ORMDL1), rs35337543-CG (IFIH1), and GGGCT (rs2070788, rs2298659, rs17854725, rs12329760, rs3787950) variation in TMPRSS2 emerging as main infection-susceptibility indicators for a COVID-19 pandemic situation. These findings underscore the importance of integrated SNV and haplotype analyses in delineating susceptibility to SARS-CoV-2 and informing proactive prevention strategies. The genetic markers profiled in this study offer valuable insights for future pandemic preparedness.

Despite the growing clinical need, the therapeutic efficacy of drugs for acute lung injury (ALI) remains inadequate. Traditional Chinese Medicine (TCM) holds potential in managing ALI due to its unique therapeutic properties. However, the intricate nature of TCM formulations hinders global adoption. Component-based Chinese medicine (CCM) offers a promising pathway for TCM's internationalization. Phillyrin-Emodin-Baicalin-Liquiritin (PEBL), a CCM with significant anti-inflammatory activity, is derived from the well-established TCM formula Liang-Ge-San. Whether PEBL effectively addresses viral ALI, however, remains unclear.

This study aims to investigate the therapeutic effects and underlying mechanisms of PEBL on viral ALI.

The efficacy of PEBL against Poly(I:C)-induced ALI was assessed by analyzing cytokine production, macrophage infiltration, pulmonary damage, and mortality. Bioinformatics and network pharmacology were employed to identify key targets and signaling pathways. The molecular mechanisms were further validated using Poly(I:C)-treated RAW264.7 cells, Tg(coro1α: GFP) zebrafish, BALB/c mice, and models of Influenza A/Puerto Rico/8/1934 (H1N1) virus strain (PR8)-induced ALI in BALB/c mice and SARS-CoV-2 Omicron XBB.1.16 subvariant (XBB)-induced ALI in hACE2-transgenic C57BL/6 mice.

PEBL mitigated Poly(I:C)-induced ALI, as evidenced by reduced cytokine levels, diminished macrophage infiltration, alleviated lung damage, and decreased mortality. Virtual screening identified the farnesyl X receptor (FXR) and angiotensin-converting enzyme 2 (ACE2) as key therapeutic targets for viral pneumonia. Mechanistically, PEBL downregulated FXR expression, inhibiting FXR binding to ACE2 promoters, which subsequently suppressed NF-κB-p65 nuclear translocation and cytokine production. In vivo, PEBL attenuated cytokine production by inhibiting ACE2 transcription through FXR downregulation, leading to alleviation of Poly(I:C)-induced ALI in both zebrafish and mice. Additionally, PEBL significantly improved symptoms of ALI caused by PR8 and XBB infections, by disrupting the FXR/ACE2 signaling axis, resulting in reduced weight loss, lower lung indices, diminished viral load and titer, fewer pulmonary lesions, and suppressed NF-κB-p65 nuclear translocation, along with decreased cytokine storm.

This study provides the first evidence that PEBL offers protective effects against ALI induced by acute respiratory viruses. PEBL prevents FXR from binding to ACE2 by inhibiting FXR transcription, which reduces macrophage infiltration, cytokine storm formation, and inflammatory injury, thereby ameliorating viral ALI. These findings underscore the potential of PEBL as a candidate for further exploration in the treatment of viral ALI.

Coronavirus disease identified in 2019 (COVID-19), caused by severe acute respiratory syndrome-coronavirus-2, had a global impact on human health and the economy. The aim of this study was to quantify cytokines, chemokines, and acute phase proteins in the plasma of patients with COVID-19 to elucidate potential biomarkers to inform prognostic and treatment decisions. Clustering analysis using the K-prototypes method identified underlying biological patterns in patients with COVID-19. The penalized multinomial logistic regression analysis identified two comorbidities (hypertension, congestive heart failure) and thirteen analytes as potential risk factors for COVID-19 progression with 88.2% accuracy. Based on a patient's age, high concentrations of interleukin (IL)-6, monocyte chemoattractant protein-1, and pentraxin 3 were important biomarkers for lethal COVID-19. Decreased concentrations of interferon gamma-induced protein-10, IL-10, and soluble tumor necrosis factor receptor I were found to be associated with mild COVID-19, while increasing concentrations of these analytes could be used to predict COVID-19 severity.

To evaluate retinal vascular changes by optical coherence tomography angiography (OCTA) in multisystem inflammatory syndrome in children (MIS-C).

This cross-sectional study included 21 patients who were diagnosed with MIS-C and had a history of hospitalization, 20 pediatric outpatients with a coronavirus disease 2019 (COVID-19) diagnosis, and 26 healthy children. All patients underwent a detailed ophthalmologic examination and OCTA. In the MIS-C and pediatric COVID-19 groups, these evaluations were made 6 months after diagnosis. The vascular density values of the superficial, deep, and radial peripapillary capillary plexuses (SCP, DCP, and RPCP, respectively), foveal avascular zone (FAZ) parameters (area, perimeter, acircularity index, and foveal density), and outer retinal and choriocapillaris flow area values were recorded using OCTA.

No pathology was detected in the ophthalmologic examinations of the three groups with similar age and gender distributions. Although the vascular density values of SCP, DCP, and RPCP were found to be higher in most quadrants in the MIS-C group, there was no statistically significant difference among the three groups ( P > 0.05 for all). FAZ parameters and flow area measurements were similar in all three groups ( P > 0.05 for all).

This is the first study to evaluate relatively long-term outcomes in patients with MIS-C and pediatric COVID-19 together. This study shows no changes in the SCP and DCP parameters in pediatric age group, which shows that ocular hemodynamic changes may not be reflected on OCTA after 6 months.

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has led to a significant burden on global healthcare systems. COVID-19-induced acute kidney injury (AKI) is among one of the complications, that has emerged as a critical and frequent condition in COVID-19 patients. This AKI among COVID-19 patients is associated with poor outcomes, and high mortality rates, especially in those with severe AKI or requiring renal replacement therapy. COVID-19-induced AKI represents a significant complication with complex pathophysiology and multifactorial risk factors. Indeed, several pathophysiological mechanisms, including direct viral invasion of renal cells, systemic inflammation, endothelial and thrombotic abnormalities as well as nephrotoxic drugs and rhabdomyolysis are believed to underlie this condition. Moreover, histopathological and immunohistopathological findings commonly observed in postmortem studies include acute tubular necrosis, glomerular injury, and the presence of viral particles within renal tissue and urine. Identified risk factors for developing AKI vary among studies, depending on regions, underlying conditions, and the severity of the disease. Moreover, histopathological and immunohistopathological findings commonly observed in postmortem studies include show acute tubular necrosis, glomerular injury, and viral particles within renal tissue and urine. While, identified risk factors for developing AKI vary among studies, according to regions, underlying conditions, and the gravity of the disease. This narrative review aims to synthesize current knowledge on the incidence, pathophysiology, risk factors, histopathology, and outcomes of AKI induced by COVID-19.

Ad5-nCoV (Convidecia) is listed for emergency use against COVID-19 by the World Health Organization (WHO) and has been globally administered to millions of people. It utilizes human adenovirus 5 (Ad5) replication-incompetent vector to deliver the spike (S) protein gene from various SARS-CoV-2 strains. Despite promising clinical data, the molecular mechanism underlying its high immunogenicity and adverse reactions remain incompletely understood. Here, we primarily applied cryo-electron tomography (cryo-ET), fluorescence microscopy and mass spectrometry to analyze the Ad5-nCoV_Wu and Ad5-nCoV_O vaccine-induced S antigens. These antigens encode the unmodified SARS-CoV-2 Wuhan-Hu-1 S gene and the stabilized Omicron S gene, respectively. Our findings highlight the structural integrity, antigenicity, and dense distribution on cell membrane of the vaccine-induced S proteins. Ad5-nCoV_O induced S proteins exhibit improved stability and reduced syncytia formation among inoculated cells. Our work demonstrates that Ad5-nCoV is a prominent platform for antigen induction and cryo-ET can be a useful technique for vaccine characterization and development.

Acute appendicitis may be uncomplicated or may present with life threatening complications. Since the outbreak of the COVID-19 pandemic, there has been an increase in the number of cases of complicated appendicitis, suggesting a possible association between them. Therefore, we aimed to determine the association between SARS-CoV-2 infection and complicated appendicitis in surgical patients in Lima, Peru, from March 2020 to December 2021.

A matched case-control study was conducted. Clinical records of patients ≥ 18 years old who underwent surgery for appendicitis and had at least one positive SARS-CoV-2 diagnostic test were selected. Patients undergoing surgery for complicated appendicitis were considered cases, and patients undergoing surgery for uncomplicated appendicitis were controls. A 1:1 matching by sex, age, and month of surgery was performed. Conditional logistic regression modeling was performed to calculate crude and adjusted conditional odds ratios (cOR).

The positivity rate for COVID-19 tests was 73.6% for cases and 26.4% for controls. The crude cOR was 4.88 (95% IC 2.89-8.23, p < 0.001), and the adjusted cOR was 3.52 (95%IC 1.82-6.81, p = 0.001), after controlling for onset time of symptoms and awaiting time before surgery.

Surgery for complicated appendicitis was associated with SARS-CoV-2 infection. Patients with this infection may be at higher risk of complicated appendicitis and thus may need additional clinical monitoring.

A 59-year-old man without risk factors for atherosclerosis was diagnosed with coronavirus disease 2019 (COVID-19). Four days later, he developed dysarthria and gait disturbance. Neurological examination revealed slurred speech, ataxia, and mild cognitive decline. Brain magnetic resonance imaging revealed multiple infarcts in the bilateral middle cerebellar peduncles and leukoencephalopathy, indicating the diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Genetic testing confirmed a pathogenic NOTCH3 variant (c.505C>T, p.Arg169Cys) (NM_000435.3). A skin biopsy supported the diagnosis. He was treated with cilostazol and after three months of rehabilitation, he regained an independent walking ability. COVID-19 increases the risk of ischemic stroke in CADASIL patients, with bilateral middle cerebellar peduncle infarctions being notable in the present case.

Basal cell carcinoma (BCC) is the most prevalent human neoplasm, with constantly increasing annual incidence. Despite its slow growth, BCC is locally invasive and, if left untreated, can cause severe complications, including metastasis and death. The renin-angiotensin system (RAS) plays a key role in electrolyte balance, atrial pressure, tissue development, homeostasis, and inflammation, but also in cancer development. After binding to its type 1 receptor (AT1R), angiotensin II (ANGII), the system's principal hormonal effector, regulates cancer pathways spanning from the formation of the initial cancer cell to the construction and nutrition of the tumor microenvironment, angiogenesis, proliferation, and metastasis. Although the role of RAS in the development of skin pathologies has not been widely researched, RAS-targeting antihypertensive medications have been shown to have a chemoprotective effect against BCC. Based on those findings, our group conducted a series of genetic association studies to investigate the association between common functional variations in key genes related to ANGII production (AGT, ACE, ACE2, AT1R, AT2R, and CMA1) and the risk of BCC occurrence. This review provides a summary of the current understanding of the ANGII involvement in BCC development. The reliable and easily assessed pool of genetic biomarkers may be used for predictive testing and prevention purposes in high-risk individuals.

Black cumin (Nigella sativa L.) (family Ranunculaceae) is a largely utilized therapeutic herb worldwide. This comprehensive review discusses the pharmacological benefits of black cumin seed oil, focusing on its bioactive component thymoquinone (TQ). The review is structured as follows: First, we examine the antimicrobial properties of black cumin oil, followed by an analysis of its antioxidant capabilities. Finally, we explore its therapeutic potential, particularly in neurodegenerative diseases and COVID-19. Phytochemicals from N. sativa have exhibited potential for developing novel preventive and therapeutic strategies against jaundice, gastrointestinal disorders, skin diseases, anorexia, conjunctivitis, dyspepsia, intrinsic hemorrhage, amenorrhea, paralysis, anorexia, rheumatism, diabetes, hypertension, fever, influenza, eczema, asthma, cough, bronchitis, and headache. The broader spectrum of application for N. sativa and its essential bioactives have certainly enhanced the commercial value of this seed oil. TQ, a major constituent of black cumin seed oil, has numerous beneficial properties. Researchers have extensively studied black cumin seed oil and its major component, TQ. These studies have revealed a wide range of pharmacological properties, including anticancer, immunomodulatory, analgesic, antimicrobial, antidiabetic, and anti-inflammatory effects. Additionally, TQ has shown neuroprotective, spasmolytic, bronchodilatory, hepatoprotective, renoprotective, gastroprotective, and antioxidant activities.

The entry and infection of the Severe Acute Respiratory Syndrome Coronavirus 2 virus (SARS-CoV-2) involve recognition and binding of the receptor-binding domain (RBD) of the virus surface spike protein to the peptidase domain (PD) of the host cellular Angiotensin-Converting Enzyme-2 (ACE2) receptor. ACE2 is also involved in normal blood pressure control. An association between hypertension and COVID-19 severity and fatality is evident, but how hypertension predisposes patients diagnosed with COVID-19 to unfavorable outcomes remains unclear. High temperature early during SARS-CoV-2 infection impairs binding to human cells and retards viral progression. Low body temperature can prelude poor prognosis. In this study, all-atom molecular dynamics simulations were performed to examine the effects of high pressure and temperature on RBD/PD binding. A high blood pressure of 940 mmHg enhanced RBD/PD binding. A high temperature above 315 K significantly weakened RBD/PD binding, while a low temperature of 305 K enhanced binding. The curvature of the PD α1-helix and proximity of the PD β3β4-hairpin tip to the RBM motif affected the compactness of the binding interface and, hence, binding affinity. These findings provide novel insights into the underlying mechanisms by which hypertension predisposes patients to unfavorable outcomes in COVID-19 and how an initial high temperature retards viral progression.

Angiotensin-converting enzyme 2 (ACE2) is a transmembrane protein known for its physiological role in the renin-angiotensin system that also serves as a receptor for entry of SARS-CoV-1, SARS-CoV-2, and the seasonal human coronavirus NL63 (hCoV-NL63). ACE2 contains seven N-linked glycosylation sites. Molecular simulation and binding analyses suggest that some of them are involved in the interaction with the Spike (S) proteins of hCoVs, but their relevance in S-mediated fusion and viral entry is poorly investigated. To address this, we determined the impact of all seven N-linked glycosylation sites in ACE2 on S-mediated SARS-CoV-2 and hCoV-NL63 infection as well as cell-to-cell fusion. We found that all mutant ACE2 proteins are expressed and localized at the cell surface, albeit ACE2 lacks all glycans at decreased levels. On average, changes in T92I, N322A, and N690A, as well as combined mutation of all N-linked glycosylation sites increased endocytic VSVpp infection mediated by early HU-1 as well as Omicron BA.2, BA.5, and XBB.1.5 SARS-CoV-2 S proteins. In comparison, only the lack of glycan at N322 in ACE2 enhanced syncytia formation and only in the case of HU-1 and XBB.1.5 S proteins. Changes in N90A, T92I, and N322A increased infection by the early SARS-CoV-2 HU-1 strain about twofold to threefold but had lesser effects on infection by genuine Omicron variants. Despite reduced cell surface expression of ACE2, elimination of all N-linked glycosylation sites usually enhanced SARS-CoV-2 infection via the endocytic pathway while having little effect on entry at the cell surface in the presence of TMPRSS2. Our results provide insights into the role of N-linked glycans in the ability of human ACE2 (hACE2) to serve as receptors for coronavirus infection.

Several human coronaviruses use angiotensin-converting enzyme 2 (ACE2) as a primary receptor for infection of human cells. ACE2 is glycosylated at seven distinct positions, and the role of glycans for the entry of SARS-CoV-2 and hCoV-NL63 into their target cells is incompletely understood. Here, we examined the impact of individual and combined mutations in hACE2 glycosylation sites on Spike-mediated VSV-pseudoparticle and genuine SARS-CoV-2 and hCoV-NL63 infection and cell-to-cell fusion. Our results provide new information on the role of glycans in hACE2 for infection by highly pathogenic and seasonal coronaviruses.

The coronavirus disease 2019 (COVID-19) pandemic has resulted in high mortality among hospitalized patients; thus, identifying mortality markers in treating these patients is essential. To evaluate the association between viral load and serum biomarkers with mortality among hospitalized patients with COVID-19.

A retrospective cohort study was conducted among 198 inpatient records from a tertiary hospital in Mexico City between January and April 2021. The association between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load and serum biomarkers with death due to COVID-19 was assessed using Cox regression models.

The median age was 54.9 years, and 61.6% were males. The mortality rate was 43.4%. After adjusting for potential confounders, patients with higher viral load [adjusted hazard ratio (aHR) = 1.56; 95% confidence interval (95% CI) = 1.01, 2.42; P value = 0.041]; and higher concentrations of BUN (aHR = 4.87;95% CI = 2.70, 8.79; P value = 0.001), creatinine (aHR = 1.60;95% CI = 1.01, 2.54; P value = 0.043), osmolality (aHR = 4.37;95% CI = 2.34, 8.14; P value = 0.001), and glucose (aHR = 2.41;95% CI = 1.40, 4.18; P value = 0.001) were more likely to have a fatal prognosis. Conversely, mortality risk was lower among patients with high concentrations of lymphocytes (aHR = 0.47;95% CI = 0.30, 0.72; P value = 0.001).

SARS-CoV-2 viral load and serum biomarkers such as BUN, creatinine, glucose, osmolarity, and lymphocytes could help physicians identify individuals who require closer monitoring.

The SARS-CoV-2 pandemic had widespread and severe impacts on both the global economy and human health. Facing the continuously mutating virus, this crisis has heightened concerns among consumers and businesses regarding viral transmission through seafood, particularly in the face of emerging, unknown viruses, underscoring our preparedness gaps. This review provides a succinct overview of the survival mechanisms of prevalent viruses in seafood, examines potential transmission pathways to humans during seafood processing, and discusses strategies for mitigating their spread throughout the seafood supply chain. Furthermore, the discussion highlights emerging trends in innovative antiviral technologies aimed at enhancing food safety. Person-to-person transmission remains the most likely source of infection within the supply chain. Therefore, it is still imperative to adhere to the implementation of standard processes, namely good manufacturing practices (GMP) and good hygiene practices (GHP), in the seafood business. In light of the significant losses caused by this crisis and the persistent presence of various viruses within the seafood supply chain, efforts are needed to implement predictive and preventive measures against potential emerging viruses. Future research should focus on monitoring and limiting viral transmission by integrating Industry 4.0 applications, smart technologies, and antiviral packaging, maximizing the potential of these emerging solutions.

Pandemics pose significant threats to social, economic, and public health. The novel coronavirus (COVID-19), which emerged in late 2019, quickly became a global public health crisis due to its high contagion and pathogenicity. Using data from the World Health Organization (WHO), this study applied the Logistic model to analyze the spread patterns of COVID-19 in 16 countries with over 10 million infections from 2020 to 2023. The findings reveal that as of December 31, 2023, global infections exceeded 772 million with over seven million deaths. The USA and China had the highest infection numbers, while Brazil had the highest mortality rate. The study identified three main outbreak patterns: initial, late, and gradual development, reflecting different stages of the pandemic. Countries with earlier outbreaks, such as India, Brazil, the USA, and Argentina, generally had higher mortality rates, while those with later outbreaks, such as China, Pakistan, Japan, and Australia, had lower mortality rates. Significant differences were observed in the duration and speed of the spread, with China showing the shortest average duration and Russia the longest. The Logistic model's parameter k values revealed policy adjustments, with Australia, Vietnam, and China showing significant changes over time, while the USA, France, and Russia showed less impact on epidemic control. These results provide an important perspective for understanding global pandemic transmission patterns and assessing the effectiveness of quarantine strategies across countries. They also provide a scientific basis for future public health policy and pandemic response development, helping countries to develop more targeted prevention and control strategies according to the characteristics of virus transmission, rationally allocate medical resources, and reduce social harm.

Data are limited for assessing the effect of COVID infection on endothelial function, pre- and post-pandemic. The objective of this study was to assess changes in pre-pandemic cardiovascular parameters after COVID-19 infection. This prospective cohort study used EndoPAT2000 Itamar Medical Ltd., Caesarea, Israel, to measure the augmentation index (AI; arterial elasticity) and reactive hyperemic index (RHI; endothelial function). Markers of endothelial function, inflammation, and gut integrity were collected at pre- and post-pandemic visits. COVID-negative and COVID-positive participants were matched on pre-pandemic covariates, and AI ≥ 5.0 was defined as having worse AI. Among the 156 participants, 50% had documented COVID-19 infection. Groups were balanced (p > 0.05) on pre-pandemic characteristics. Increases in oxLDL (p = 0.03) were observed in the COVID-positive group, and COVID infection had a negative effect on inflammatory markers (sVCAM-1, sTNF-RI, sTNF-RII, sCD14) and gut integrity (I-FABP, BDG) compared to COVID-negative participants (p < 0.05). There was a 16.7% (p = 0.02) increase in the proportion of COVID-positive participants with AI ≥ 5.0, without a significant change (p = 0.09) among the COVID-negative group. COVID-positive status, female sex, and higher IL-6 and sCD163 were associated (p < 0.05) with an increase in having worse AI. COVID infection is independently associated with arterial stiffness. For COVID survivors, female sex and higher markers of inflammation were associated with arterial stiffness.

Background: Heart rate turbulence (HRT) is a non-invasive technique that can be used to evaluate autonomic nervous system (ANS) function and cardiac arrhythmia. The objective of this study is to investigate whether COVID-19 can lead to long-term blunted HRT following recovery. Methods: This retrospective cohort study included 253 individuals with a confirmed history of COVID-19, referred to as the recovered COVID-19 group, along with 315 healthy participants who had no history of the virus. The recovered COVID-19 group was categorized into three subgroups based on their chest CT severity scores. The HRT analyses were obtained from a 24-h electrocardiography-Holter recording. Results: This study revealed that the HRT onset value was elevated in the recovered COVID-19 group, while the HRT slope value showed a significant decrease when compared to the control group. Correlation analyses indicated a positive relationship between the chest CT severity score and HRT onset, whereas a negative correlation was observed between the chest CT severity score and HRT slope. Regression analyses identified recovery from severe COVID-19, chest CT severity score, hypertension (HT), and smoking as independent predictors of both abnormal HRT onset and the existence of an abnormal HRT slope. Conclusions: Individuals who have recovered from severe COVID-19 are expected to encounter a permanent blunting of HRT, which is regarded as a significant indicator of an increased risk of ventricular arrhythmias and impaired autonomic nervous system (ANS) function. Recovered severe COVID-19 individuals should be carefully evaluated for HRT with 24-h ECG-Holter.

This umbrella review synthesizes and discusses systematic reviews (SRs) and meta-analyses (MAs) on auditory outcomes associated with COVID-19 infection and vaccination side effects. It is innovative in offering a comprehensive synthesis of evidence across adults and infants while summarizing vaccine-related auditory side effects.

This literature search followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines, with no restrictions on population age or symptom severity. Four electronic databases were searched from their inception to October 2024. The Assessment of Multiple Systematic Reviews 2 checklist and Risk of Bias in Systematic Reviews tool were used to assess the quality of evidence and the risk of bias.

The systematic search identified 534 articles, narrowed down to 14 SRs following a full-text review: Nine focused on auditory outcomes of COVID-19; two, on outcomes in infants born to mothers infected during pregnancy; and three, on the auditory side effects of vaccination. A random-effects model revealed significantly high pooled estimates of hearing loss (5.0%, 95% CI [1.0, 9.0], p < .012, three MAs, N = 21,932) and tinnitus (13.5%, 95% CI [5.9, 21.1], p ≤ .001, four MAs, N = 36,236) in adults. However, current evidence in nonhospitalized patients indicates that auditory symptoms often improve after recovery. Studies also show a low rate of hearing loss in infants whose mothers contracted COVID-19 during pregnancy. Similarly, whereas COVID-19 vaccination has been linked to hearing loss and tinnitus, these effects are rare, and most patients experience improvement within weeks to months.

Evidence suggests a significantly high rate of hearing loss and tinnitus associated with COVID-19 in adults, although auditory symptoms remain rare in newborns and following vaccination. However, caution is warranted due to limitations and variability across the studies.

COVID-19, caused by the SARS-CoV-2 virus, is not only characterized by respiratory symptoms but is also associated with a wide range of systemic complications, including significant hematologic abnormalities. This is a comprehensive review of the current literature, using PubMed and Google Scholar, on the pathophysiology and incidence of thromboembolic events in COVID-19 patients and thromboprophylaxis. COVID-19 infection induces a prothrombotic state in patients through the dysregulation of the renin-angiotensin-aldosterone system (RAAS), endothelial dysfunction, elevated von Willebrand factor (vWF), and a dysregulated immune response involving the complement system and neutrophil extracellular traps (NETs). As a result, thromboembolic complications have emerged in COVID-19 cases, occurring more frequently in severe cases and hospitalized patients. These thrombotic events affect both venous and arterial circulation, with increased incidences of deep venous thrombosis (DVT), pulmonary embolism (PE), systemic arterial thrombosis, and myocardial infarction (MI). While DVT and PE are more common, the literature highlights the potential lethal consequences of arterial thromboembolism (ATE). This review also briefly examines the ongoing discussions regarding the use of anticoagulants for the prevention of thrombotic events in COVID-19 patients. While theoretically promising, current studies have yielded varied outcomes: Some suggest potential benefits, whereas others report an increased risk of bleeding events among hospitalized patients. Therefore, further large-scale studies are needed to assess the efficacy and safety of anticoagulants for thromboprophylaxis in COVID-19 patients.

The pandemic of SARS-CoV2 is not only limited to the health issues and fatalities encountered in a worldwide overwhelming burden but also the social, economic, and well-being devastation. Many trials were done to find a safe and reliable therapy for COVID-19. Isotretinoin was reported as a possible therapy for COVID-19 through the mining of post-transcriptomic and genomic datasets, which revealed isotretinoin as a potent down-regulator of the ACE2 protein the crucial gateway of SARS-CoV2 to hijack host cells. A total of 106 patients with mild to moderate COVID-19 were recruited. Patients were randomized into two groups and treated with the Standard Care (STD) protocol of the Ministry of Health, Egypt, or the STD in combination with isotretinoin (0.5 mg/kg/day) for 5 days. The study involved 66 (63 %) females and 39 (37 %) males, median age 42 years (interquartile 32-55.5 y). The main findings revealed a significant reduction in the time to improvement in the isotretinoin-treated (6.6 ± 2 d) compared to the STD-treated patients (10.4 ± 3.3). Survival analysis (HR: 4.1, 95 % CI: 2.5-6.6) in comparison to the STD-treated patients. The main adverse event reported during the therapeutic duration was the dryness of the skin, which was of acceptable tolerability through skin care instructions to the patients. The data presented herein highlights the efficacy of isotretinoin in the management of mild to moderate COVID-19 patients with a significant reduction of the time to recovery. The adverse events reported were tolerable and did not outweigh the therapeutic benefits.

COVID-19 commonly leads to respiratory issues, yet numerous patients also exhibit a diverse range of neurological conditions, suggesting a detrimental impact of SARS-CoV-2 or the viral Spike protein on the central nervous system. Nonetheless, the molecular pathway behind neurological pathology and the presumed neurotropism of SARS-CoV-2 remains largely unexplored. We generated human cortical organoids (HCOs) derived from human induced pluripotent stem cells (hiPSC) to assess: (1) the expression of SARS-CoV-2 main entry factors; (2) their vulnerability to SARS-CoV-2 infection; and (3) the impact of SARS-CoV-2 infection and exposure to the Spike protein on their transcriptome. Results proved that (1) HCOs express the main SARS-CoV-2 receptors and co-receptors; (2) HCOs may be productively infected by SARS-CoV-2; (3) the viral particles released by SARS-CoV-2-infected HCOs are able to re-infect another cellular line; and (4) the infection resulted in the activation of apoptotic and stress pathways, along with inflammatory processes. Notably, these effects were recapitulated when HCOs were exposed to the Spike protein alone. The data obtained demonstrate that SARS-CoV-2 likely infects HCOs probably through the binding of ACE2, CD147, and NRP1 entry factors. Furthermore, exposure to the Spike protein alone proved sufficient to disrupt their homeostasis and induce neurotoxic effects, potentially contributing to the onset of long-COVID symptoms.

To examine the subclinical alterations in the retina and choroid between patients with 2019 coronavirus disease (COVID-19)-related lung involvement and the healthy control group.

In this prospective case-control study, 85 cases with lung involvement due to COVID-19 and 50 healthy cases were included. Best-corrected visual acuity, intraocular pressure measurement, and anterior and posterior segment examination were performed on both eyes for each individual. Choroidal and retinal changes were examined and recorded by optical coherence tomography angiography.

All choroidal thickness measurements of the COVID-19 group showed no statistically significant difference when compared to healthy individuals. When vascular density and perfusion density values were compared, there was a decrease in the average of these values in the COVID-19 group, although it was not statistically significant (P=0.088, P=0.065 respectively). When the fovea avascular zone (FAZ) area values were compared, the average was 0.57±0.38 in the COVID-19 group, while it was 0.54±0.24 in the control group.

Although our data are not statistically significant, the decrease in vascularity and perfusion and the accompanying FAZ expansion are detected in the acute period (1st month). These changes may anatomically alter the retina in the long term and affect functional vision. Future ischemia-related alterations in the retina caused by a prior COVID-19 infection may arise in situations without comorbidities and may require concern in the patient's systemic assessment.

Asthma has long been associated with increased susceptibility to viral respiratory infections, leading to significant exacerbations and poorer clinical outcomes. Contrarily and interestingly, emerging data and research surrounding the COVID-19 pandemic have shown that patients with asthma infected with SARS-CoV-2 experienced decreased severity of disease, lower hospitalization rates, as well as decreased morbidity and mortality. Research has shown that eosinophils could enhance immune defense against viral infections, while inhaled corticosteroids can assist in controlling systematic inflammation. Moreover, reduced ACE-2 expression in individuals with asthma may restrict viral entry, and the Th2 immune response may offset the Th1 response typically observed in severe COVID-19 patients. These factors may help explain the favorable outcomes seen in asthmatic patients during the COVID-19 pandemic. This review highlights potential protective mechanisms seen in asthmatic patients, including eosinophilia, the use of inhaled corticosteroids, reduced ACE-2 expression, and a dominate Th2 immune response. Such a study will be helpful to better manage patients with asthma who have contracted COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters host cells via the angiotensin-converting enzyme 2 (ACE2) receptor. Mounting evidence has indicated the presence of hepatic SARS-CoV-2 infection and liver injury in patients with coronavirus disease 2019 (COVID-19). Understanding the mechanisms of hepatic SARS-CoV-2 infection is crucial for addressing COVID-19-related liver pathology and developing targeted therapies. This editorial discusses the significance of ACE2 in hepatic SARS-CoV-2 infection, drawing on the research by Jacobs et al. Their findings indicate that hepatic ACE2 expression, frequency of hepatic SARS-CoV-2 infection, and severity of liver injury are elevated in patients with pre-existing chronic liver diseases. These data suggest that hepatic ACE2 could be a promising therapeutic target for COVID-19.

The persistence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) on substrates, and the impact of fomites on Coronavirus Disease 19 (COVID-19) transmission, is until now, widely discussed. Consequently, further investigations are required for a correct risk assessment in high-risk facilities such as hospitals, healthcare facilities (HCFs), and long-term care facilities (LTCFs). Therefore, appropriate surveillance and disinfection programs represent the best approach to guarantee the safety of these communities. This study proposes an environmental SARS-CoV-2 surfaces routine monitoring approach in HCF and communities' settings, to provide rapid and effective evaluation of surface hygienic conditions and the effectiveness of applied sanitization measures. Surfaces samples (n = 118) were collected using the SRK® kit (Copan Italia) from 2020 to 2023. Three molecular techniques were compared: Reverse Transcription Loop mediated isothermal AMPlification (RT-LAMP, Enbiotech), Reverse-Transcription quantitative polymerase chain reaction (RT-qPCR) (RT-qPCR, Seegene) and droplet digital PCR (ddPCR, Bio-Rad). For ddPCR, two RNA extraction methods were compared: TRIzol LS (Invitrogen) versus QIAmp Viral Mini kit (QIAGEN), showing how the latter is more suitable for surfaces. Regarding the quantitative ddPCR results, the ROC analysis allowed to reduce the manufacturer cut-off for droplets number (from 3 to 1) for the positive samples. Moreover, a new cut-off for the viral RNA copies' number/μL for each target (N1 and N2) on environmental monitoring was fixed at 2,82. The results obtained using the QIAmp kit, suggested that the N2 target is more stable in the environment and could be most suitable for the virus environmental detection. The percentage of positive samples was similar among the techniques (26% for RT-LAMP, 36% for ddPCR and 23% for RT-qPCR). Using RT-qPCR as reference method, a sensitivity (SE) of 30% for RT-LAMP and 41% for ddPCR was observed. By contrast, specificity (SP) was higher for RT-LAMP (75%) respect to ddPCR (66%). Comparing the faster RT-LAMP with the sensitive ddPCR the 26% and 74% of SE and SP for RT-LAMP, were reported. The low sensitivity for RT-LAMP and ddPCR could be explained with the use of clinical rather than environmental kits, other than the changing in the virus prevalence during the sampling campaign. Although the RT-LAMP requires improvements in term of SE and SP, this research presents an innovative environmental monitoring and prevention method for SARS-CoV-2, that could be extended to other pathogens that are under environmental surveillance.

ACE2 (angiotensin-converting enzyme 2) is a monocarboxypeptidase that cleaves Ang II (angiotensin II) among other substrates. ACE2 is present in the cell membrane of many organs, most abundantly in epithelial cells of kidney proximal tubules and the small intestine, and also exists in soluble forms in plasma and body fluids. Membrane-bound ACE2 exerts a renoprotective action by metabolizing Ang II and therefore attenuating the undesirable actions of excess Ang II. Therefore, soluble ACE2, by downregulating this peptide, may exert a therapeutic action. Our laboratory has designed ACE2 truncates that pass the glomerular filtration barrier to target the kidney renin-angiotensin system directly and, therefore, compensate for loss of kidney membrane-bound ACE2. Membrane-bound ACE2 is also the essential receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Soluble ACE2 proteins have been studied as a way to intercept SARS-CoV-2 from binding to membrane-bound ACE2 and prevent cell entry of SARS-CoV-2 altogether. We bioengineered a soluble ACE2 protein, termed ACE2 618-DDC-ABD, with increased binding affinity for SARS-CoV-2 and prolonged duration of action, which, when administered intranasally, provides near-complete protection from lethality in k18hACE2 mice infected with different SARS-CoV-2 variants. The main advantage of soluble ACE2 proteins for the neutralization of SARS-CoV-2 is their immediate onset of action and universality for current and future emerging SARS-CoV-2 variants. It is notable that ACE2 is critically involved in 2 dissimilar functions: as a receptor for cell entry of many coronaviruses and as an enzyme in the metabolism of Ang II, and yet in both cases, it is a therapeutic target.

A 61-year-old man with chronic renal failure had an embolic stroke of undetermined source that was treated with warfarin. Five weeks later, the patient contracted coronavirus disease (COVID-19). Six days after the onset of COVID-19, high blood pressure (>200 ‍mmHg) and consciousness disturbance were reported. CT demonstrated symmetrical hypodensity areas in the bilateral cerebellar hemispheres. MRI revealed hyperintensity lesions in the bilateral cerebellar hemispheres and pons on the T2-weighted and fluid-attenuated inversion recovery images. Moreover, cerebellar lesions appeared as hyperintensity areas on apparent diffusion coefficient mapping. Based on these findings, a diagnosis of posterior reversible encephalopathy syndrome (PRES) was made. The patient was treated with antihypertensive drugs, and the consciousness level improved gradually. MRI after one month showed that the lesions had disappeared. PRES should be considered if the brain CT of patients with COVID-19 shows a low-density lesion, especially in patients with risk factors for PRES such as chronic renal failure or hypertension.

The coronavirus disease 2019 (COVID-19) epidemic has brought major challenges to the global health system, and influenza is also a problem that cannot be ignored. We aimed to explore and compare the clinical characteristics of COVID-19 and influenza to deepen the understanding of these two diseases and provide some guidance for clinicians to make differential diagnoses. We searched PubMed, Embase and Web of Science for articles and performed a meta-analysis using Stata 14.0 with a random-effects model. This meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. One hundred articles involving 226,913 COVID-19 patients and 201,617 influenza patients were included, and all the articles included patients with these two diseases as experimental and control groups. Compared to influenza, COVID-19 was more common among men (OR = 1.46, 95% CI: 1.23-1.74) and people with a higher body mass index (MD = 1.43, 95% CI: 1.09-1.77). The proportion of current smokers among COVID-19 patients was lower than that among influenza patients (OR = 0.25, 95% CI: 0.18-0.33). Patients with COVID-19 had longer stays in the hospital (MD = 3.20, 95% CI: 2.58-3.82) and ICU (MD = 3.10, 95% CI: 1.44-4.76), required mechanical ventilation more frequently (OR = 2.30, 95% CI: 1.77-3.00), and had higher mortality (OR = 2.22, 95% CI: 1.93-2.55). We also found significant differences in some blood parameters between the two groups of patients. Upper respiratory symptoms were more obvious in influenza patients, and the proportion of comorbidities was higher than that among COVID-19 patients. There are some differences in the major characteristics, symptoms, laboratory findings and comorbidities between COVID-19 patients and influenza patients. COVID-19 patients often require more medical resources and have worse clinical outcomes.

The COVID-19 pandemic caused by SARS-CoV-2 continues to pose a major challenge to global health. Targeting the main protease of the virus (Mpro), which is essential for viral replication and transcription, offers a promising approach for therapeutic intervention. In this study, advanced computational techniques such as molecular docking and molecular dynamics simulations were used to screen a series of antiviral compounds for their potential inhibitory effect on the SARS-CoV-2 Mpro. A comprehensive analysis of compounds from the ChemDiv and PubChem databases was performed. The physicochemical properties, pharmacokinetics, and ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) profiles were evaluated to determine drug similarity and safety. Compound 4896 - 4038 proved to be the most promising candidate. It exhibited a favorable balance between molecular weight (491.06) and lipophilicity (logP 3.957), high intestinal absorption (92.119%), and broad tissue distribution (VDss of 0.529), indicating good oral bioavailability and therapeutic potential. Molecular docking studies showed that 4896 - 4038 has a strong binding affinity to the active site of Mpro and forms key interactions, such as hydrogen bonds, carbon-hydrogen bonds, pi-sulfur, and multiple van der Waals and pi-pi stacked bonds. The binding energy was comparable to that of the reference drug X77, indicating potential efficacy. Molecular dynamics simulations over 300 ns confirmed the stability of the Mpro/4896 - 4038 complex of protein-ligand. Free energy landscape mapping and MM/PBSA calculations further substantiated the favorable binding and stability of the complex. Importantly, 4896 - 4038 exhibited a comparatively favorable safety profile. In summary, compound 4896 - 4038 shows significant potential as a potent SARS-CoV-2 Mpro inhibitor, combining potent inhibitory activity with favorable pharmacokinetic and safety profiles. These results support the further development of 4896 - 4038 as a promising therapeutic agent in the fight against COVID-19 that warrants experimental validation and clinical investigation.

Coronavirus epidemics have posed a serious threat to both human and animal health. To combat emerging infectious diseases caused by coronaviruses, various animal infection models have been developed and applied in research, including non-human primate models, ferret models, hamster models, mouse models, and others. Moreover, new approaches have been utilized to develop animal models that are more susceptible to infection. These approaches include using viral delivery methods to induce the expression of viral receptors in mouse tissues and employing gene-editing techniques to create genetically modified mice. This has led to the successful establishment of infection models for multiple coronaviruses, significantly advancing related research. In contrast, livestock and pets that can be infected by animal coronaviruses provide valuable insights when used as infection models, enabling the collection of accurate clinical data through the analysis of post-infection pathological features. However, despite the potential insights, there is a paucity of research data pertaining to these infection models. In this review, we provide a detailed overview of recent progress in the development of animal models for coronaviruses that cause diseases in both humans and animals and suggest ways in which animal models can be adapted to further enhance their value in research.

COVID-19 has been a challenge at the healthcare level not only in the early stages of the pandemic, but also in the subsequent appearance of long-term COVID-19. Several investigations have attempted to identify proteomic biomarkers in an attempt to improve clinical care, guide treatment and predict possible patient outcomes. Proteins such as C-reactive protein (CRP) or interleukin 6 (IL-6) are clear markers of severe disease, but many others have been proposed that could help in risk stratification and in the prediction of specific complications. This review aims to bring together the most relevant studies in this regard, providing information to identify the most notable biomarkers in relation to COVID-19 found to date.

Coronavirus disease (COVID-19), caused by severe acquired respiratory syndrome-Coronavirus-2 (SARS-CoV-2), triggered a global pandemic with severe medical and socioeconomic consequences. Although fatality rates are higher among the elderly and those with underlying comorbidities, host factors that promote susceptibility to SARS-CoV-2 infection and severe disease are poorly understood. Although individuals with certain autoimmune/inflammatory disorders show increased susceptibility to viral infections, there is incomplete knowledge of SARS-CoV-2 susceptibility in these diseases. The aim of our study was to investigate whether the autoimmunity risk gene, PTPN2, which also confers elevated risk to develop inflammatory bowel disease, affects susceptibility to SARS-CoV-2 viral uptake.

Using samples from PTPN2 genotyped patients with inflammatory bowel disease, PTPN2-deficient mice, and human intestinal and lung epithelial cell lines, we investigated how PTPN2 affects expression of the SARS-CoV-2 receptor angiotensin converting enzyme 2 (ACE2), and uptake of virus-like particles expressing the SARS-CoV2 spike protein and live SARS-CoV-2 virus.

We report that the autoimmune PTPN2 loss-of-function risk variant rs1893217 promotes expression of the SARS-CoV-2 receptor, ACE2, and increases cellular entry of SARS-CoV-2 spike protein and live virus. Elevated ACE2 expression and viral entry were mediated by increased Janus kinase-signal transducers and activators of transcription signaling and were reversed by the Janus kinase inhibitor, tofacitinib.

Collectively, our findings uncover a novel risk biomarker for increased expression of the SARS-CoV-2 receptor and viral entry, and identify a clinically approved therapeutic agent to mitigate this risk.

The COVID-19 pandemic impacted all areas of daily life, including medical care. Unfortunately, to date, no specific treatments have been found for the cure of this disease, and therefore, it is advisable to implement all possible strategies to prevent infection. In this context, it is important to better define the role of all behaviors, in particular nutrition, in order to establish whether these can both prevent infection and improve the outcome of the disease in patients with COVID-19. There is sufficient evidence to demonstrate that immune response can be weakened by inadequate nutrition. Nutrition management and treatment are very important to enhance the immune response of an infected person against RNA viral infection. A complete nutritional assessment should include anthropometric, dietary, and laboratorial assessment, as well as a multidisciplinary discussion about the patient's clinical condition. In this way, it is possible to establish an individualized nutritional approach to contribute to improving clinical and nutritional prognoses. From this point of view, diet, through intake of vitamins and trace elements and maintaining adequate functioning of the intestinal barrier, can reduce the severity of the COVID-19 infection. In this study, we provide an overview of the effects of diet on COVID-19 infection in non-cancer patients. This notion needs to be further evaluated, and thus, identification, characterization, and targeting of the right nutrition principles related to the management of patients with COVID-19 are likely to improve outcomes and may prevent the infection or lead to a cure.

SARS-CoV-2, which originated in China in late 2019, quickly fueled the global COVID-19 pandemic, profoundly impacting health and the economy worldwide. A series of vaccines, mostly based on the full SARS-CoV-2 Spike protein, were rapidly developed, showing excellent humoral and cellular responses and high efficacy against both symptomatic infection and severe disease. However, viral evolution and the waning humoral neutralizing responses strongly challenged vaccine long term effectiveness, mainly against symptomatic infection, making necessary a strategy of repeated and updated booster shots. In this repeated vaccination context, antibody repertoire diversification was evidenced, although immune imprinting after booster doses or reinfection was also demonstrated and identified as a major determinant of immunological responses to repeated antigen exposures. Considering that a small domain of the SARS-CoV-2 Spike protein, the receptor binding domain (RBD), is the major target of neutralizing antibodies and concentrates most viral mutations, the following text aims to provide insights into the ongoing debate over the best strategies for vaccine boosters. We address the relevance of developing new booster vaccines that target the evolving RBD, thus focusing on the relevant antigenic sites of the SARS-CoV-2 new variants. A combination of this strategy with immunofusing and computerized approaches could minimize immune imprinting, therefore optimizing neutralizing immune responses and booster vaccine efficacy.

Tissue expansion is a widely employed technique in reconstructive surgery aimed at addressing considerable skin defects. Nevertheless, matters like inadequate expansion capability and the potential for skin breakage due to the fragility of the expanded tissue present notable hurdles in enhancing skin regeneration during this process. Angiotensin-converting enzyme 2 (ACE2) is recognized for its essential role in facilitating tissue renewal and regeneration. However, its precise impact on skin renewal during tissue expansion remains underexplored. This study seeks to elucidate ACE2's contribution to skin regeneration, specifically examining its role in collagen synthesis.

This study evaluated the expression and distribution of ACE2 in expanded skin using samples derived from both rats and human patients. Additionally, we investigated ACE2 expression in stretched keratinocytes in vitro. ACE2 knockout keratinocytes were transfected with small interfering RNA (siRNA) and cocultured with fibroblasts to observe fibroblast proliferation and migration. MLN-4760 was utilized to inhibit the ACE2 enzymatic activity. Additionally, we analyzed parameters such as the size of expanded skin, dermal thickness, and the levels of collagen I (COL I), collagen III (COL III), and transforming growth factor β (TGF-β) to elucidate the role of ACE2 in the context of expanded skin.

The thinning of the expanded dermis was linked with elevated ACE2 expression. Enzymatic activity and ACE2 expression were both increased by mechanical stress. Additionally, ACE2 utilized Ang II to activate the migration and proliferation of human dermal fibroblasts. In vivo, the ACE2 inhibitor MLN-4760 promoted skin regeneration and reduced dermal thinning by elevating COL I, COL III, and TGF-β during expansion.

This finding suggest that mechanical stretch increases ACE2 expression, which in turn promotes the regeneration of expanded skin. The basis for using ACE2 in clinical settings to increase tissue expansion efficacy is provided by this work.

Pulmonary hypertension (PH) is a severe condition characterized by elevated pressure in the pulmonary artery, where metabolic and mitochondrial dysfunction may contribute to its progression. Within the PH spectrum, pulmonary arterial hypertension (PAH) stands out with its primary pulmonary vasculopathy. PAH's prevalence varies from 0.4 to 1.4 per 100,000 individuals and is associated with diverse conditions, including viral infections such as HIV. Notably, recent observations highlight an increased occurrence of PAH among COVID-19 patients, even in the absence of pre-existing cardiopulmonary disorders. While current treatments offer partial relief, there's a pressing need for innovative therapeutic strategies, among which mesenchymal stromal cells (MSCs) and their derivatives hold promise. This review critically evaluates recent investigations into viral-induced PAH, encompassing pathogens like human immunodeficiency virus, herpesvirus, Cytomegalovirus, Hepatitis B and C viruses, SARS-CoV-2, and Human endogenous retrovirus K (HERKV), with a specific emphasis on mitochondrial dysfunction. Furthermore, we explore the underlying rationale driving novel therapeutic modalities, including MSCs, extracellular vesicles, and mitochondrial interventions, within the framework of PAH management.

Toll-like receptors (TLRs) of human are considered as the most critical immunological mediators of inflammatory pathogenesis of COVID-19. These immunoregulatory glycoproteins are located on the surface and/or intracellular compartment act as innate immune sensors. Upon binding with distinct SARS-CoV-2 ligand(s), TLRs signal activation of different transcription factors that induce expression of the proinflammatory mediators that collectively induce 'cytokine storm'. Similarly, TLR activation is also pivotal in conferring protection to infection and invasion as well as upregulating the tissue repair pathways. This dual role of the human TLRs in deciding the fate of SARS-CoV-2 has made these receptor proteins as the critical mediators of immunoprotective and immunopathogenic consequences associated with COVID-19. Herein, pathbreaking discoveries exploring the immunobiological importance of the TLRs in COVID-19 and developing TLR-directed therapeutic intervention have been reviewed by accessing the up-to-date literatures available in the public domain/databases. In accordance with our knowledge in association with the importance of TLRs' role against viruses and identification of viral particles, they have been recognized as suitable candidates with high potential as vaccine adjuvants. In this regard, the agonists of TLR4 and TLR9 have effective potential in vaccine technology while the others need further investigations. This comprehensive review suggests that basal level expression of TLRs can act as friends to keep our body safe from strangers but act as a foe via overexpression. Therefore, selective inhibition of the overexpressed TLRs appears to be a solution to counteract the cytokine storm while TLR-agonists as vaccine adjuvants could lessen the risk of infection in the naïve population.

The angiotensin-converting enzyme-2 (ACE-2) alters the pathophysiology of various fatal cardiovascular diseases, including ischemic heart disease, whereas angiotensin 1-7 (Ang 1-7) exerts a wide range of actions. The effects of ischemia-reperfusion (IR) injury include damage to myocardial tissue that initiates protease action, causing cardiac cell death. Angiotensin- II (Ang-II) contributes through the renin-angiotensin system (RAS) to the IR injury, whereas Ang 1-7 paradoxically exerts a protective effect through the same. Thus, the myocardial ischemic reperfusion injury (MIRI) may be altered by the RAS of the heart. This review paper focuses on ACE-2, angiotensin-converting enzyme (ACE), and Ang 1-7 regulation in the RAS of the heart in the pathophysiology of MIRI. The treatment in such conditions using ACE-2 activator, ACE inhibitor, and Ang-II antagonists may promote vascular functions as well as cardio- protection.

SARS-CoV-2 infection is accompanied by elevated liver enzymes, and patients with pre-existing liver conditions experience more severe disease. While it was known that SARS-CoV-2 infects human hepatocytes, our study determines the mechanism of infection, demonstrates viral replication and spread, and highlights direct hepatocyte damage. Viral replication was readily detectable upon infection of primary human hepatocytes and hepatoma cells with the ancestral SARS-CoV-2, Delta, and Omicron variants. Hepatocytes express the SARS-CoV-2 receptor ACE2 and the host cell protease TMPRSS2, and knocking down ACE2 and TMPRSS2 impaired SARS-CoV-2 infection. Progeny viruses released from infected hepatocytes showed the typical coronavirus morphology by electron microscopy and proved infectious when transferred to fresh cells, indicating that hepatocytes can contribute to virus spread. Importantly, SARS-CoV-2 infection rapidly induced hepatocyte death in a replication-dependent fashion, with the Omicron variant showing faster onset but less extensive cell death. C57BL/6 wild-type mice infected with a mouse-adapted SARS-CoV-2 strain showed high levels of viral RNA in liver and lung tissues. ALT peaked when viral RNA was cleared from the liver. Liver histology revealed profound tissue damage and immune cell infiltration, indicating that direct cytopathic effects of SARS-CoV-2 and immune-mediated killing of infected hepatocytes contribute to liver pathology.