Recent evidence suggests that oxidative stress and endothelial dysfunction play critical roles in the pathophysiology of COVID-19 and Long-COVID. We hypothesized that a supplementation combining L-Arginine (to improve endothelial function) and Vitamin C (to reduce oxidation) could have favorable effects on Long-COVID symptoms.We designed a survey (LINCOLN: L-Arginine and Vitamin C improves Long-COVID), assessing several symptoms that have been associated with Long-COVID to be administered nationwide to COVID-19 survivors; the survey also included effort perception, measured using the Borg scale. Patients receiving the survey were divided in two groups, with a 2:1 ratio: the first group included patients that received L-Arginine + Vitamin C, whereas the second group received a multivitamin combination (alternative treatment).1390 patients successfully completed the survey. Following a 30-day treatment in both groups, the survey revealed that patients in the L-Arginine + Vitamin C treatment arm had significantly lower scores compared to patients who had received the multivitamin combination. There were no other significant differences between the two groups. When examining effort perception, we observed a significantly lower value (p < 0.0001) in patients receiving L-Arginine + Vitamin C compared to the alternative-treatment arm.Our survey indicates that the supplementation with L-Arginine + Vitamin C has beneficial effects in Long-COVID, in terms of attenuating its typical symptoms and improving effort perception. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9295384

Combining L-Arginine with vitamin C improves long-COVID symptoms: The LINCOLN Survey

We hypothesized that exosomal microRNAs could be implied in the pathogenesis of thromboembolic complications in coronavirus disease 2019 (COVID-19). We isolated circulating exosomes from patients with COVID-19, and then we divided our population in two arms based on the D-dimer level on hospital admission. We observed that exosomal miR-145 and miR-885 significantly correlate with D-dimer levels. Moreover, we demonstrate that human endothelial cells express the main cofactors needed for the internalization of the "Severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2), including angiotensin converting enzyme 2, transmembrane protease serine 2, and CD-147. Interestingly, human endothelial cells treated with serum from COVID-19 patients release significantly less miR-145 and miR-885, exhibit increased apoptosis, and display significantly impaired angiogenetic properties compared with cells treated with non-COVID-19 serum. Taken together, our data indicate that exosomal miR-145 and miR-885 are essential in modulating thromboembolic events in COVID-19. SIGNIFICANCE STATEMENT This work demonstrates for the first time that two specific microRNAs (namely miR-145 and miR-885) contained in circulating exosomes are functionally involved in thromboembolic events in COVID-19. These findings are especially relevant to the general audience when considering the emerging prominence of post-acute sequelae of COVID-19 systemic manifestations known as Long COVID.

/pdf/exosomal-mir-145-and-mir-885-regulate-thrombosis-in-covid-19-29azc6he.pdf

Exosomal miR-145 and miR-885 Regulate Thrombosis in COVID-19

Long COVID, a condition characterized by symptom and/or sign persistence following an acute COVID-19 episode, is associated with reduced physical performance and endothelial dysfunction. Supplementation of l-arginine may improve endothelial and muscle function by stimulating nitric oxide synthesis. A single-blind randomized, placebo-controlled trial was conducted in adults aged between 20 and 60 years with persistent fatigue attending a post-acute COVID-19 outpatient clinic. Participants were randomized 1:1 to receive twice-daily orally either a combination of 1.66 g l-arginine plus 500 mg liposomal vitamin C or a placebo for 28 days. The primary outcome was the distance walked on the 6 min walk test. Secondary outcomes were handgrip strength, flow-mediated dilation, and fatigue persistence. Fifty participants were randomized to receive either l-arginine plus vitamin C or a placebo. Forty-six participants (median (interquartile range) age 51 (14), 30 [65%] women), 23 per group, received the intervention to which they were allocated and completed the study. At 28 days, l-arginine plus vitamin C increased the 6 min walk distance (+30 (40.5) m; placebo: +0 (75) m, p = 0.001) and induced a greater improvement in handgrip strength (+3.4 (7.5) kg) compared with the placebo (+1 (6.6) kg, p = 0.03). The flow-mediated dilation was greater in the active group than in the placebo (14.3% (7.3) vs. 9.4% (5.8), p = 0.03). At 28 days, fatigue was reported by two participants in the active group (8.7%) and 21 in the placebo group (80.1%; p < 0.0001). l-arginine plus vitamin C supplementation improved walking performance, muscle strength, endothelial function, and fatigue in adults with long COVID. This supplement may, therefore, be considered to restore physical performance and relieve persistent symptoms in this patient population.

/pdf/effects-of-l-arginine-plus-vitamin-c-supplementation-on-3p3kj0f8.pdf

Effects of l-Arginine Plus Vitamin C Supplementation on Physical Performance, Endothelial Function, and Persistent Fatigue in Adults with Long COVID: A Single-Blind Randomized Controlled Trial

ABSTRACT In real practice, there is a paradox in the management of patients with ‘long-term Covid-19.’ Indeed, Family physicians (FPs) are on the front line in the management process of these patients. For ‘long-term Covid-19’ patients, and according to the World Health Organization guideline, the cardiopulmonary rehabilitation (CPR) should be provided not only at tertiary- or secondary care but mainly at primary care with a real implication of FPs. However, specific guidelines/recommendations were addressed for FPs. Therefore, an alternative including the CPR minimal advice that an FP should provide to ‘long-term Covid-19’ patients, seems to be necessary to respond to the needs of FPs to face their involvement with ‘long-term Covid-19’ patients. Thus, this paper aimed to report the CPR ‘minimal advice’ that should be provided by FPs managing ‘long-term Covid-19’ patients with incapacity ( i.e. ; alteration of the cardiorespiratory and muscular chain). According to the authors, FPs should be more cautious in the prescription of exercise and nutrition program and informed about the minimal advices related to nutritional and physical exercise rehabilitation guidelines when taking care of ‘long-term Covid-19’ patients, and how these guidelines can relieve the mental and physical problems, improve immunity, and accelerate the recovery process of the patients. With the occurrence of new variants of the severe acute respiratory syndrome coronavirus 2, the nutritional and exercise rehabilitation guidelines implemented by FPs become indispensable to promote the recovery of Covid-19 patients and support a return to normal life.

/pdf/what-should-a-family-physician-know-about-nutrition-and-3ulx9qoa.pdf

What should a family physician know about nutrition and physical exercise rehabilitation’ advices to communicate to ‘long-term COVID-19’ patients?

Coronavirus disease 2019 (COVID-19) represents a major public health crisis that has caused the death of nearly six million people worldwide. Emerging data have identified a deficiency of circulating arginine in patients with COVID-19. Arginine is a semi-essential amino acid that serves as key regulator of immune and vascular cell function. Arginine is metabolized by nitric oxide (NO) synthase to NO which plays a pivotal role in host defense and vascular health, whereas the catabolism of arginine by arginase to ornithine contributes to immune suppression and vascular disease. Notably, arginase activity is upregulated in COVID-19 patients in a disease-dependent fashion, favoring the production of ornithine and its metabolites from arginine over the synthesis of NO. This rewiring of arginine metabolism in COVID-19 promotes immune and endothelial cell dysfunction, vascular smooth muscle cell proliferation and migration, inflammation, vasoconstriction, thrombosis, and arterial thickening, fibrosis, and stiffening, which can lead to vascular occlusion, muti-organ failure, and death. Strategies that restore the plasma concentration of arginine, inhibit arginase activity, and/or enhance the bioavailability and potency of NO represent promising therapeutic approaches that may preserve immune function and prevent the development of severe vascular disease in patients with COVID-19.

/pdf/targeting-arginine-in-covid-19-induced-immunopathology-and-14w03npl.pdf

Targeting Arginine in COVID-19-Induced Immunopathology and Vasculopathy

l-Arginine is involved in many different biological processes and recent reports indicate that it could also play a crucial role in the coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Herein, we present an updated systematic overview of the current evidence on the functional contribution of L-Arginine in COVID-19, describing its actions on endothelial cells and the immune system and discussing its potential as a therapeutic tool, emerged from recent clinical experimentations.

Ayobami Adebayo

Papers

l-Arginine and COVID-19: An Update.