An important call: Suggestion of using IL-10 as therapeutic agent for COVID-19 with ARDS and other complications.

The global coronavirus disease 2019 (COVID-19) pandemic has a detrimental impact on public health. COVID-19 usually manifests as pneumonia, which can progress into acute respiratory distress syndrome (ARDS) related to uncontrolled TH17 immune reaction. Currently, there is no effective therapeutic agent to manage COVID-19 with complications. The currently available anti-viral drug remdesivir has an effectiveness of 30% in SARS-CoV-2-induced severe complications. Thus, there is a need to identify effective agents to treat COVID-19 and the associated acute lung injury and other complications. The host immunological pathway against this virus typically involves the THαß immune response. THαß immunity is triggered by type 1 interferon and interleukin-27 (IL-27), and the main effector cells of the THαß immune response are IL10-CD4 T cells, CD8 T cells, NK cells, and IgG1-producing B cells. In particular, IL-10 exerts a potent immunomodulatory or anti-inflammatory effect and is an anti-fibrotic agent for pulmonary fibrosis. Concurrently, IL-10 can ameliorate acute lung injury or ARDS, especially those caused by viruses. Owing to its anti-viral activity and anti-pro-inflammatory effects, in this review, IL-10 is suggested as a possible treatment agent for COVID-19.

The Perspective of Vitamin D on suPAR-Related AKI in COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic has claimed the lives of millions of people around the world. Severe vitamin D deficiency can increase the risk of death in people with COVID-19. There is growing evidence that acute kidney injury (AKI) is common in COVID-19 patients and is associated with poorer clinical outcomes. The kidney effects of SARS-CoV-2 are directly mediated by angiotensin 2-converting enzyme (ACE2) receptors. AKI is also caused by indirect causes such as the hypercoagulable state and microvascular thrombosis. The increased release of soluble urokinase-type plasminogen activator receptor (suPAR) from immature myeloid cells reduces plasminogen activation by the competitive inhibition of urokinase-type plasminogen activator, which results in low plasmin levels and a fibrinolytic state in COVID-19. Frequent hypercoagulability in critically ill patients with COVID-19 may exacerbate the severity of thrombosis. Versican expression in proximal tubular cells leads to the proliferation of interstitial fibroblasts through the C3a and suPAR pathways. Vitamin D attenuates the local expression of podocyte uPAR and decreases elevated circulating suPAR levels caused by systemic inflammation. This decrease preserves the function and structure of the glomerular barrier, thereby maintaining renal function. The attenuated hyperinflammatory state reduces complement activation, resulting in lower serum C3a levels. Vitamin D can also protect against COVID-19 by modulating innate and adaptive immunity, increasing ACE2 expression, and inhibiting the renin-angiotensin-aldosterone system. We hypothesized that by reducing suPAR levels, appropriate vitamin D supplementation could prevent the progression and reduce the severity of AKI in COVID-19 patients, although the data available require further elucidation.

Immunothrombosis biomarkers as potential predictive factors of acute respiratory distress syndrome in moderate-to-critical COVID-19: A single-center, retrospective cohort study.

BACKGROUND: Immunothrombosis, a process of inflammation and coagulation, is involved in sepsis-induced acute respiratory distress syndrome formation (ARDS). However, the clinical correlation between immunothrombosis biomarkers (including tissue factor [TF] and von Willebrand factor [vWF]) and coronavirus disease 2019 (COVID-19)-related ARDS is unknown. This study investigated ARDS development following moderate-to-critical COVID-19 and examined immunothrombosis biomarkers as ARDS predictors. METHODS: This retrospective cohort study included patients with moderate-to-critical COVID-19 (n = 165) admitted to a northern teaching hospital during the 2021 pandemic in Taiwan, who had no COVID-19 vaccinations. Immunothrombosis biomarkers were compared between COVID-19 patients with and without ARDS (no-ARDS) and a control group consisting of 100 healthy individuals. RESULTS: The study included 58 ARDS and 107 no-ARDS patients. In multivariable analysis, TF (aOR=1.031, 95% CI: 1.009-1.053, p = 0.006); and vWF (aOR=1.053, 95% CI: 1.002-1.105, p = 0.041) were significantly associated with ARDS episodes, after adjusting for other confounding factors. vWF and TF predicted ARDS with the area under the curve of 0.870 (95% CI: 0.796-0.945). Further mechanical ventilation analysis found TF to be correlated significantly with pCO2 and ventilatory ratio. CONCLUSIONS: TF and vWF levels potentially predicted ARDS development within 7 days of admission for COVID-19 after adjusting for traditional risk factors. TF correlated with ventilation impairment in COVID-19 ARDS but further prospective studies are needed.

A Review of the Potential Effects of Melatonin in Compromised Mitochondrial Redox Activities in Elderly Patients With COVID-19.

Melatonin, an endogenous indoleamine, is an antioxidant and anti-inflammatory molecule widely distributed in the body. It efficiently regulates pro-inflammatory and anti-inflammatory cytokines under various pathophysiological conditions. The melatonin rhythm, which is strongly associated with oxidative lesions and mitochondrial dysfunction, is also observed during the biological process of aging. Melatonin levels decline considerably with age and are related to numerous age-related illnesses. The signs of aging, including immune aging, increased basal inflammation, mitochondrial dysfunction, significant telomeric abrasion, and disrupted autophagy, contribute to the increased severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. These characteristics can worsen the pathophysiological response of the elderly to SARS-CoV-2 and pose an additional risk of accelerating biological aging even after recovery. This review explains that the death rate of coronavirus disease (COVID-19) increases with chronic diseases and age, and the decline in melatonin levels, which is closely related to the mitochondrial dysfunction in the patient, affects the virus-related death rate. Further, melatonin can enhance mitochondrial function and limit virus-related diseases. Hence, melatonin supplementation in older people may be beneficial for the treatment of COVID-19.

The Role of Vitamin D in SARS-CoV-2 Infection and Acute Kidney Injury.

Vitamin D has been described as an essential nutrient and hormone, which can cause nuclear, non-genomic, and mitochondrial effects. Vitamin D not only controls the transcription of thousands of genes, directly or indirectly through the modulation of calcium fluxes, but it also influences the cell metabolism and maintenance specific nuclear programs. Given its broad spectrum of activity and multiple molecular targets, a deficiency of vitamin D can be involved in many pathologies. Vitamin D deficiency also influences mortality and multiple outcomes in chronic kidney disease (CKD). Active and native vitamin D serum levels are also decreased in critically ill patients and are associated with acute kidney injury (AKI) and in-hospital mortality. In addition to regulating calcium and phosphate homeostasis, vitamin D-related mechanisms regulate adaptive and innate immunity. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections have a role in excessive proinflammatory cell recruitment and cytokine release, which contribute to alveolar and full-body endothelial damage. AKI is one of the most common extrapulmonary manifestations of severe coronavirus disease 2019 (COVID-19). There are also some correlations between the vitamin D level and COVID-19 severity via several pathways. Proper vitamin D supplementation may be an attractive therapeutic strategy for AKI and has the benefits of low cost and low risk of toxicity and side effects.

Resveratrol as an Adjunctive Therapy for Excessive Oxidative Stress in Aging COVID-19 Patients.

The coronavirus disease 2019 (COVID-19) pandemic continues to burden healthcare systems worldwide. COVID-19 symptoms are highly heterogeneous, and the patient may be asymptomatic or may present with mild to severe or fatal symptoms. Factors, such as age, sex, and comorbidities, are key determinants of illness severity and progression. Aging is accompanied by multiple deficiencies in interferon production by dendritic cells or macrophages in response to viral infections, resulting in dysregulation of inflammatory immune responses and excess oxidative stress. Age-related dysregulation of immune function may cause a more obvious pathophysiological response to SARS-CoV-2 infection in elderly patients and may accelerate the risk of biological aging, even after recovery. For more favorable treatment outcomes, inhibiting viral replication and dampening inflammatory and oxidative responses before induction of an overt cytokine storm is crucial. Resveratrol is a potent antioxidant with antiviral activity. Herein, we describe the reasons for impaired interferon production, owing to aging, and the impact of aging on innate and adaptive immune responses to infection, which leads to inflammation distress and immunosuppression, thereby causing fulminant disease. Additionally, the molecular mechanism by which resveratrol could reverse a state of excessive basal inflammatory and oxidative stress and low antiviral immunity is discussed.