COVID-19, Cation Dysmetabolism, Sialic Acid, CD147, ACE2, Viroporins, Hepcidin and Ferroptosis: A Possible Unifying Hypothesis.

Background: iron and calcium dysmetabolism, with hyperferritinemia, hypoferremia, hypocalcemia and anemia have been documented in the majority of COVID-19 patients at later/worse stages. Furthermore, complementary to ACE2, both sialic acid (SA) molecules and CD147 proved relevant host receptors for SARS-CoV-2 entry, which explains the viral attack to multiple types of cells, including erythrocytes, endothelium and neural tissue. Several authors advocated that cell ferroptosis may be the core and final cell degenerative mechanism. Methods: a literature research was performed in several scientific search engines, such as PubMed Central, Cochrane Library, Chemical Abstract Service. More than 500 articles were retrieved until mid-December 2021, to highlight the available evidence about the investigated issues. Results: based on COVID-19 literature data, we have highlighted a few pathophysiological mechanisms, associated with virus-based cation dysmetabolism, multi-organ attack, mitochondria degeneration and ferroptosis. Our suggested elucidated pathological sequence is: a) spike protein subunit S1 docking with sialylated membrane glycoproteins/receptors (ACE2, CD147), and S2 subunit fusion with the lipid layer; b) cell membrane morpho-functional changes due to the consequent electro-chemical variations and viroporin action, which induce an altered ion channel function and intracellular cation accumulation; c) additional intracellular iron concentration due to a deregulated hepcidin-ferroportin axis, with higher hepcidin levels. Viral invasion may also affect erythrocytes/erythroid precursors, endothelial cells and macrophages, through SA and CD147 receptors, with relative hemoglobin and iron/calcium dysmetabolism. AB0 blood group, hemochromatosis, or environmental elements may represent possible factors which affect individual susceptibility to COVID-19.     Conclusions: our literature analysis confirms the combined role of SA molecules, ACE2, CD147, viroporins and hepcidin in determining the cation dysmetabolism and final ferroptosis in the cells infected by SARS-CoV-2. The altered ion channels and electrochemical gradients of the cell membrane have a pivotal role in the virus entry and cell dysmetabolism, with subsequent multi-organ immune-inflammatory degeneration and erythrocyte/hemoglobin alterations.

An Overview of Systematic Reviews of the Role of Vitamin D on Inflammation in Patients with Diabetes and the Potentiality of Its Application on Diabetic Patients with COVID-19.

Almost two years have passed since the outbreak reported for the first time in Wuhan of coronavirus disease 2019 (COVID-19), due to severe acute respiratory syndrome (SARS)-CoV-2 coronavirus, rapidly evolved into a pandemic. This infectious disease has stressed global health care systems. The mortality rate is higher, particularly in elderly population and in patients with comorbidities such as hypertension, diabetes mellitus, cardiovascular disease, chronic lung disease, chronic renal disease, and malignancy. Among them, subjects with diabetes have a high risk of developing severe form of COVID-19 and show increased mortality. How diabetes contributes to COVID-19 severity remains unclear. It has been hypothesized that it may be correlated with the effects of hyperglycemia on systemic inflammatory responses and immune system dysfunction. Vitamin D (VD) is a modulator of immune-response. Data from literature showed that vitamin D deficiency in COVID-19 patients increases COVID-19 severity, likely because of its negative impact on immune and inflammatory responses. Therefore, the use of vitamin D might play a role in some aspects of the infection, particularly the inflammatory state and the immune system function of patients. Moreover, a piece of evidence highlighted a link among vitamin D deficiency, obesity and diabetes, all factors associated with COVID-19 severity. Given this background, we performed an overview of the systematic reviews to assess the association between vitamin D supplementation and inflammatory markers in patients with diabetes; furthermore, vitamin D's possible role in COVID-19 patients was assessed as well. Three databases, namely MEDLINE, PubMed Central and the Cochrane Library of Systematic Reviews, were reviewed to retrieve the pertinent data. The aim of this review is to provide insight into the recent advances about the molecular basis of the relationship between vitamin D, immune response, inflammation, diabetes and COVID-19.

Does Evidence Exist to Blunt Inflammatory Response by Nutraceutical Supplementation during COVID-19 Pandemic? An Overview of Systematic Reviews of Vitamin D, Vitamin C, Melatonin, and Zinc.

More than one year has passed since the first cases of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome (SARS)-CoV-2 coronavirus were reported in Wuhan (China), rapidly evolving into a global pandemic. This infectious disease has become a major public health challenge in the world. Unfortunately, to date, no specific antivirals have been proven to be effective against COVID-19, and although a few vaccines are available, the mortality rate is not decreasing but is still increasing. One therapeutic strategy has been focused on infection prevention and control measures. In this regard, the use of nutraceutical supports may play a role against some aspect of the infection, particularly the inflammatory state and the immune system function of patients, thus representing a strategy to control the worst outcomes of this pandemic. For this reason, we performed an overview including meta-analyses and systematic reviews to assess the association among melatonin, vitamin C, vitamin D, zinc supplementation and inflammatory markers using three databases, namely, MEDLINE, PubMed Central and the Cochrane Library of Systematic Reviews. According to the evidence available, an intake of 50,000 IU/month of vitamin D showed efficacy in CRP. An amount of 1 to 2 g per day of vitamin C demonstrated efficacy both in CRP and endothelial function, and a dosage of melatonin ranging from 5 to 25 mg /day showed good evidence of efficacy in CRP, TNF and IL6. A dose of 50 mg/day of elemental zinc supplementation showed positive results in CRP. Based on the data reported in this review, the public health system could consider whether it is possible to supplement the current limited preventive measures through targeted nutraceutical large-scale administration.

PCSK9 inhibition, LDL and lipopolysaccharides: a complex and "dangerous" relationship.

Literature concerning the causative factors of atherosclerotic cardiovascular disease shows complex and sometimes contrasting evidence. Most guidelines suggest a strategy aimed at lowering circulating low density lipoproteins (LDL) and ApoB lipoprotein levels. The use of statins and of cholesteryl ester transfer protein inhibitors has led to a number of controversial outcomes, generating a certain degree of concern about the real efficacy and especially safety of these drugs. Literature data show that the use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors results in a dramatic reduction of various markers of lipid metabolism (namely LDL); however, several critical scientific papers have questioned the value, the need and especially the safety of these innovative drugs. LDL are a protective factor against lipopolysaccharides and other microbial derivatives. Similarly, these gram-negative bacteria-derived compounds have been identified as probable culprits of cardiovascular atherogenesis; moreover, lipopolysaccharides increase hepatic synthesis of PCSK9, as defense mechanism. This enzyme modulates LDL receptors level in the liver, as well as in other organs, such as adrenal gland and reproductive organs. Hence, PCSK9 inhibition may influence glucocorticoid secretion and fertility. Lastly, the consequent reduction of circulating LDL may relevantly hindrance immune system and favor lipopolysaccharides diffusion.

Gut Microbiome in Retina Health: The Crucial Role of the Gut-Retina Axis.

The term microbiome means not only a complex ecosystem of microbial species that colonize our body but also their genome and the surrounding environment in which they live. Recent studies support the existence of a gut-retina axis involved in the pathogenesis of several chronic progressive ocular diseases, including age-related macular disorders. This review aims to underline the importance of the gut microbiome in relation to ocular health. After briefly introducing the characteristics of the gut microbiome in terms of composition and functions, the role of gut microbiome dysbiosis, in the development or progression of retinal diseases, is highlighted, focusing on the relationship between gut microbiome composition and retinal health based on the recently investigated gut-retina axis.

COVID-19: hemoglobin, iron, and hypoxia beyond inflammation. A narrative review.

Coronavirus disease-19 (COVID-19) has been regarded as an infective-inflammatory disease, which affects mainly lungs. More recently, a multi-organ involvement has been highlighted, with different pathways of injury. A hemoglobinopathy, hypoxia and cell iron overload might have a possible additional role. Scientific literature has pointed out two potential pathophysiological mechanisms: i) severe acute respiratory syndrome-coronavirus-2 (SARS-CoV- 2) interaction with hemoglobin molecule, through CD147, CD26 and other receptors located on erythrocyte and/or blood cell precursors; ii) hepcidin-mimetic action of a viral spike protein, inducing ferroportin blockage. In this translational medicinebased narrative review, the following pathologic metabolic pathways, deriving from hemoglobin denaturation and iron metabolism dysregulation, are highlighted: i) decrease of functioning hemoglobin quote; ii) iron overload in cell/tissue (hyperferritinemia); iii) release of free toxic circulating heme; iv) hypoxemia and systemic hypoxia; v) reduction of nitric oxide; vi) coagulation activation; vii) ferroptosis with oxidative stress and lipoperoxidation; viii) mitochondrial degeneration and apoptosis. A few clinical syndromes may follow, such as pulmonary edema based on arterial vasoconstriction and altered alveolo-capillary barrier, sideroblastic-like anemia, endotheliitis, vasospastic acrosyndrome, and arterio- venous thromboembolism. We speculated that in COVID-19, beyond the classical pulmonary immune-inflammation view, the occurrence of an oxygen-deprived blood disease, with iron metabolism dysregulation, should be taken in consideration. A more comprehensive diagnostic/therapeutic approach to COVID-19 is proposed, including potential adjuvant interventions aimed at improving hemoglobin dysfunction, iron over-deposit and generalized hypoxic state.

Gut microbiome response to a modern Paleolithic diet in a Western lifestyle context.

The modern Paleolithic diet (MPD), featured by the consumption of vegetables, fruit, nuts, seeds, eggs, fish and lean meat, while excluding grains, dairy products, salt and refined sugar, has gained substantial public attention in recent years because of its potential multiple health benefits. However, to date little is known about the actual impact of this dietary pattern on the gut microbiome (GM) and its implications for human health. In the current scenario where Western diets, low in fiber while rich in industrialized and processed foods, are considered one of the leading causes of maladaptive GM changes along human evolution, likely contributing to the increasing incidence of chronic non-communicable diseases, we hypothesize that the MPD could modulate the Western GM towards a more "ancestral" configuration. In an attempt to shed light on this, here we profiled the GM structure of urban Italian subjects adhering to the MPD, and compared data with other urban Italians following a Mediterranean Diet (MD), as well as worldwide traditional hunter-gatherer populations from previous publications. Notwithstanding a strong geography effect on the GM structure, our results show an unexpectedly high degree of biodiversity in MPD subjects, which well approximates that of traditional populations. The GM of MPD individuals also shows some peculiarities, including a high relative abundance of bile-tolerant and fat-loving microorganisms. The consumption of plant-based foods-albeit with the exclusion of grains and pulses-along with the minimization of the intake of processed foods, both hallmarks of the MPD, could therefore contribute to partially rewild the GM but caution should be taken in adhering to this dietary pattern in the long term.