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

Scintigraphy-based analysis of possible pulmonary lesions after foam sclerotherapy: a pilot study

The aims of this study were to assess extemporaneous in vivo binding between 99mTcO4- and two sclerosant detergents in foam sclerotherapy, and subsequently to control any possible damage in lungs and other organs related to sclerosant foam passage. A prospective comparative pilot study was performed on two male patients (62 and 56 years old) affected by varicose veins; each of them underwent scintigraphy investigations with free radiotracer and a scintigraphy investigation after each of the four sessions of sclerotherapy of varicose tributaries of the lower limbs with labeled sclerosant foam. One of the two patients underwent two further scintigraphic investigations, with free radiotracer and with labeled sclerosant foam, at a later stage. Four mL of 2% polidocanol (POL) foam, or four mL of 1% sodiumtetradecylsulfate (STS) foam for session were injected. The sclerosant foam was labeled with the radioactive tracer technetium pertechnetate, 99mTcO4- (120 MBq per exam). Two scintigraphy assessments for free tracer (basal) and five scintigraphy investigations of bound-tosclerosant tracer uptake/transit were obtained. No relevant variations in time/activity curves of the lungs and other organs were documented between the basal and post-sclerotherapy findings, also at the later stage. Free radiotracer mean region-of-interest data were: 336 counts (heart), 208 counts (lungs) and 371 counts (thyroid). Mean values extrapolated from each curve at each step for labeled CO2O2-based sclerosant foam were respectively: 351 counts (POL) and 328 counts (STS) for heart, 202 counts (POL) and 188 counts (STS) for lungs, 335 (POL) and 263 (STS) for thyroid. No pulmonary damage by sclerosant foam was caused. Neither immediately after treatments, nor at short-term follow-up

Timing and modality of the sclerosing agents binding to the human proteins: laboratory analysis and clinical evidences

Sclerosing agents (SA) are blood inactivated. Nevertheless, investigations concerning the interaction among SA and blood components have never been deeply investigated. Aim of the study is to precisely identify SA blood ligands, to determine their binding time and to highlight the clinical consequences. Thirty-one blood samples were collected from chronic venous disease patients and tested by capillary and agarose gel (AGE) electrophoresis before and after adding polidocanol (POL) and sodiumtetradecylsulphate (STS). The two different types of electrophoresis allowed an evaluation of the blood proteins binding with the sclerosing agents, with a reaction time lower than 8 seconds for the AGE. Subsequently six patients underwent foam sclerotherapy and then were subdivided in group A (4 patients) and B (2 patients). In group A blood sample was obtained from the ipsilateral brachial vein immediately before (T0) and repeated 1, 3, 5, and 10 minutes after injection of STS 3% injection into the GSV. In group B, the same procedure was performed with the same timing from the ipsilateral femoral vein. Free STS (fSTS) and total proteinbound STS (bSTS) were measured. POL mainly binds to β-globulins (11%), while STS to albumin and α-globulins (62.6% and 30.7%) on the protidogram, respectively. Both in the brachial and in the femoral vein, the average fSTS was always 0. STS binds to albumin (62.6%) and α-globulins (30.7%), while POL is bound mainly by the b-globulins (11%). The present paper demonstrates how the vast majority of the sclerosing agent is bound to the blood proteins, suggesting the need to look for possible sclerotherapy complications factors also in the used gas and/or in the subsequent cathabolites release

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

Lymphedema and nutrition: A review

Nutrition is considered a basic component in the management of any vascular disease. Lymphedema is characterised by an increase of interstitial fluid due to a lymphatic system morphological and/or functional alteration. Therapeutic management of lymphedema includes a multi-faceted approach based on compression and physiotherapy mainly. Weight control and antiinflammatory and anti-edema diet are two additional necessary components of the holistic therapy in presence of primary or secondary limb lymphedema. This narrative review provides the available information derived from the scientific literature on nutrition in lymphedema, which anyway lacks robust evidence. Additional information and speculations are provided on the role of food, diet, nutraceuticals and fasting on the basic processes at the root of the chronic progressive degeneration of tissue lymph stasis, i.e. weight excess, inflammation, edema, fibroadiposis. More targeted and randomized studies are needed in order to assess and standardise the obvious, so far neglected, role of nutrition in lymphedema patients

Maqui and Omega 3: effects on lipid profile, oxidative stress levels and psycho-physical items in human subjects

Aims: to assess short-term efficacy of supplementation with Maqui (Aristotelia Chilensis (Mol.Stuntz)), a polyphenol with antioxidant power, and EPA/DHA concerning metabolism, oxidative stress and mental/physical state. Patients and Methods: a pilot prospective observational clinical/laboratory study was performed on 17 apparently healthy subjects (8 males and 9 females, mean age 47 years). All subjects received for two months: a) Maqui 600 mg per day and b) 360 mg of EPA and 240 mg of DHA (salmon oil) daily. At day 0 and day 60 all subjects underwent nine laboratory tests related to inflammation, metabolism (lipid profile mainly) and oxidative stress parameters. Pre-post treatment weight and BMI was calculated. A few physical and mental parameters were assessed by means of Short-Form 12 questionnaire. Statistical analysis was applied to the resulting data through Wilcoxon test and t-paired test. Results: laboratory results before and after Maqui + EPA/DHA supplementation were respectively (mean and p-value for the comparison): total cholesterol 228.8/199.8 mg/dl, p=0.23; low density lipoproteins 127.4/122.1 mg/dl, p=0.13; high density lipoproteins 59.1/57.6 mg/dl, p=0.25; Reactive C Protein 0.18/0.09 mg/dl, p=0.32; triglycerides 106.1/91.1 mg/dl p=0.09, glycemia 92.9/92.8 mg/dl p= 0.92; total free radicals 338.0/303.6 U.Carr., p=0.002; serum anti-oxidant capacity 2075/2190 umol/l, p= 0.04; oxidized lipoproteins 641.8/553.1 uEq/l, p=0.10. SF12 physical and mental items (mean values and SD) were 51.2 (+/- 6.2) and 41.2 (+/- 3,3) at day 0 and 54.6 (+/- 11.6) and 47.2 (+/- 9.7) at day 60 respectively. One case of transient constipation was recorded. Conclusions: daily supplementation with Maqui 600 mg + Omega 3 fatty acids (EPA 360 mg + DHA 240 mg) in apparently healthy middle-aged subjects resulted in a statistically significant improvement of oxidative stress parameters. An overall (non statistically significant) improvement of dysmetabolism biomarkers was achieved. Mental and physical parameters have mildly improved

A phlebo-lymphology humanitarian trip to Matagalpa, Nicaragua

Amigos de Salud and Vene e Linfatici Foundation took part in a volunteer medical trip in Nicaragua. A detailed description of the provided healthcare is reported

New Perspectives in Phlebology and Lymphology

The recent research on chronic degenerative diseases (CDD), such as obesity, diabetes, neurodegeneration, atherosclerosis, autoimmune diseases, cancer and aging itself, has shown that Venous and Lymphatic Diseases (VLD) may play an important role in their development, de facto pushing phlebology and especially lymphology under a spotlight in biomedical research [...

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 medicine-based 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

Medicine and Phlebolymphology: Time to Change?

Biomedical science is undergoing a reappraisal of its scientific advancement process and of the related healthcare management. Progress in medicine should combine improvements of knowledge, efficacy, and safety of diagnostic/therapeutic procedures, with adequate cost-effectiveness profiles. This narrative review is aimed at assessing in medicine, more specifically in phlebology and lymphology: (a) scientific literature possible biases, (b) the level of evidence, comprehensiveness, and cost-effectiveness of the main therapeutic options, and (c) the possible contribution of integrative and translational medicine. Current medical research may have cognitive biases, or industry-tied influences, which impacts clinical practice. Some reductionism, with an increasing use of drugs and technology, often neglecting the understanding and care of the root causative pathways of the diseases, is affecting biomedical science as well. Aging brings a relevant burden of chronic degenerative diseases and disabilities, with relevant socio-economic repercussions; thus, a major attention to cost-effectiveness and appropriateness of healthcare is warranted. In this scenario, costly and innovative but relatively validated therapies may tend to be adopted in venous and lymphatic diseases, such as varicose veins, leg venous ulcer, post-thrombotic syndrome, pelvic congestion syndrome, and lymphedema. Conversely, a more comprehensive approach to the basic pathophysiology of chronic venous and lymphatic insufficiency and the inclusion of pharmacoeconomics analyses would benefit overall patients’ management. Erroneous lifestyle and nutrition, together with chronic stress-induced syndromes, significantly influence chronic degenerative phlebo-lymphatic diseases. The main active epigenetic socio-biologic factors are obesity, dysfunctions of musculo-respiratory-vascular pumps, pro-inflammatory nutrition, hyperactivation of stress axis, and sedentarism. An overall critical view of the scientific evidence and innovations in phebolymphology could be of help to improve efficacy, safety, and sustainability of current practice. Translational and integrative medicine may contribute to a patient-centered approach. Conversely, reductionism, eminence/reimbursement-based decisional processes, patients’ lack of education, industry-influenced science, and physician’s improvable awareness, may compromise efficacy, safety, appropriateness, and cost-effectiveness of future diagnostic and therapeutic patterns of phlebology and lymphology