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.

Pulmonary Covid Fibrosis a New Pharmaceutic Approach.

BACKGROUND: Patient's post-COVID may develop chronic irreversible respiratory failure with "widespread signs of pulmonary fibrosis." Our study analyzed the causes of this fibrosis to propose a therapeutic protocol. METHODS: Identification of the biochemical causes of fibrosis in COVID-19 analysing the literature and chest CT. RESULTS: The CT imaging shows pulmonary fibrosis. The viral infection produces "interleukin-6", which binds to its receptor, in MUC1 of lung epithelial cells. The biochemical response of the cells promotes an over-expression of MUC1 with fibrosis. Interleukin6 also causes a metabolic imbalance in NO that promotes clots and atherosclerosis of the pulmonary vessels. These results show to promote NO endothelia's formation to block both the excessive expression of MUC1 and the atherosclerosis effect of the vessels. CONCLUSIONS: This study proposes to inhibit phosphodiesterase by vasodilatation of the pulmonary vascular bed and the MUC1 over expression by interleukin6, the Sildenafil with the SGLT2 and N-Acetylcysteine.

COVID-19 Solution.

Coronaviruses (CoV) are RNA viruses that cause endemic infections in various species of mammals and avian birds. There are seven known human CoVs, each of which causes respiratory diseases: together account for about one third of common colds. Some CoVs have recently entered humans from infected animals and lastly we have SARS COVID-19, (CoV), which causes severe acute, often fatal respiratory syndromes. The prevalence of CoV, the easy zoonotic transmission and the potential to cause serious respiratory diseases, lead to urgent research to discover the mechanisms of CoV infection. Our study has identified a possible way to eliminate the danger of this virus by analyzing the structures by which it enters the host cell. This study indicates that the neuroaminidase interrupts the infection.

Free Radical Production in the Smoking of E-Cigarettes and their Possible Effects in Human Health.

BACKGROUND: The increase in smoking e-cigarettes with nicotine or only flavoring compounds requires a deep study on consequences on human health. This research aims to study the possible process, to form free radicals or the nuclei's damages with consequent micronuclei's formation. METHODS: The study analyzed three groups: the first one that uses e-cigarettes with nicotine, (e-nicotine), the second flavoured liquid (e-vapor) and third the not-smoking group. We determinated the salivary malondialdehyde (MDA), the total salivary mucins (SM). and in buccal smear cells the micronuclei (MN). We statistically analyzed the results with the Mann-Whitney U Test Calculator. RESULTS: Smoking e-cigarettes e-nicotine or e-vapor produced a great and significative amount of MDA vs control group: p ≤ 0.05. Only those smoking e-nicotine, have a highest and statically significant amount of salivary mucins vs control group: P value 00496. In both smokers groups, the mean of MN scores has a significant difference vs control group P ≤ 0.05. CONCLUSIONS: This study shows the possible damages of the nuclei, but the increase of radicals, oral mucins and MN needs more researches.

Micronucleus Test for Diagnosing Uncertain Cases (BI-RADS 3) in Breast Cancer Screening: A Review and Preliminary Results.

INTRODUCTION: BI-RADS in mammography screening is the guide to give a standardized terminology in mammary images. The BI-RADS 3 (uncertain cases) protocol requires anew mammography after six months. This matter of time usually generates much concern and anxiety in patients and in the Radiologists. The aim of this study is to show that using the test of micronuclei (MN) in exfoliated mucosa buccal cells a very early diagnosis is achieved. MATERIAL AND METHODS: We performed an extensive search on Pub Med for "micronuclei in exfoliated buccal cells in breast cancer "and micronuclei in breast cancer". We looked for the keywords in free text and with the cross-referencing method application. We experimentally got samples of buccal mucosa cells from twenty women BI-RADS 3 and twenty women BI-RADS 2. We fixed the samples with Papanicolaou staining. We registered the percentage of the cells containing MN in a total of 500 cells for each sample. The U Mann Whitney Calculator is the test for the statistical analysis of the results. RESULTS: Many studies showed that breast cancer produced MN both in exfoliated cells and in needle aspiration. Their score's count was higher than compared to benign cases, while in the peripheral blood lymphocytes, the results for the MN test were not reproducible. In our preliminary study, the mean percentages of MN in buccal mucosa cells of BI-RADS 3 vs BI-RADS2 didn't show a significant difference: p = 0.05. Two samples of BI-RADS 3 group had a much higher count of MN with a mean of 2.91 ±0.09, 2.88 ±0.08, respectively. This case required biopsy despite the in most of the cases of BI-RADS 3 investigated, the MN test confirmed their benignity. DISCUSSION: In literature, several studies have shown that the genetic damage in breast cancer cells results in MN increased production. Our research showed that in some cases of BI-RADS 3 there was a great increase in MN level. This fact happens in the patients who have taken oestrogens for many years. This therapy is definitely a strong risk factor for breast cancer development because the excesses of any type of hormones interacts with normal breast cell differentiation process. This BI-RADS 3 situation needs further investigation. CONCLUSION: It's interesting to apply the MN scoring in BI-RADS3 because in some cases this test can expect a cancer diagnosis by at least six months' time because, in the other cases, test result can reassure both patient and Radiologists who will wait for the next following checkup with no anxiety.

Possible Effects of Capsaicin (Chili Pepper) on the Oral Health.

BACKGROUND: Capsaicin binds the TRPV1 (transient receptor potential vanilloid), desensitizing the pain fibers that become insensitive to nociceptive stimuli. For this fact that the capsaicin has antipain and antiinflammatory properties, few studies verify possible harmful effects, especially with its use in high amounts. The aim of this study is to check salivary nitric oxide (NO) and malondialdehyde (MDA) as indicators of its possible oral health alterations. METHODS: The protocol calls for twelve volunteers to eat 20 g of sausage with a high content of chili pepper and capsaicin. The study analyzes their salivary concentration of NO and MDA and in control group, 2 min, 1 h, and 1.5 h after ingestion. The U-Mann Whitney Calculator Test statistically analyzes these results. RESULTS: Immediately after eating, there is a significant increase of NO and MDA vs control: P value is 0.03752 and 0.03236, respectively. The values of NO and MDA vs control remain higher after 1 h: P value is 0.04036 and 0.0466, respectively, to return to normality after 1.5 h. DISCUSSION: This study shows that capsaicin increases the simultaneous production of MDA and NO. It is possible to hypothesize that MDA derives mainly from the inflammatory process up-regulated by COX-2, generated by capsaicin. We hypothesize instead that the excess of capsaicin inhibits and reduces the number of TRPV1, which produces an excess of NO and generates nitrosative stress. NO reacts with O2 to form hydroxyl radicals (OH) and H2O, or with superoxide anions to form MDA. CONCLUSIONS: The results of this study clearly show that the use not necessarily excessive of chili leads to developing an inflammatory process.

Betel Chewing: A New Analysis, In Vitro and In Vivo, of the Risk Factors in Oral Cancer.

BACKGROUND: Chewing Betel (areca-nut) can cause oral cancer. This happens when its components are in direct contact with the oral epithelium. The aim of this study is to understand this mechanism by analyzing salivary mucins, in vitro, during and after betel chewing. METHODS: The in vivo analysis would necessarily involve subtraction of betel to understand its effects. This study analyzed the interaction between mucins and betel in vitro. We added increasing amounts of areca powder, and for comparison an equal amount of pure vine tannin to saliva samples provided by a first volunteer. This study analyzes salivary mucins in two volunteers, one of whom is a regular betel consumer, after chewing the areca-nut, on six saliva samples taken at half-hour intervals. RESULTS: In vitro, total precipitation of the salivary mucins occurs after we added 1g of Areca nut (50 mg Tannin equivalent), a concentration five times lower than what is actually present during the chewing period; in vivo, in the first volunteer, there is a statistically significant increase in the mucins after chewing two and half hours: p-value = 0.02034, while for the regular betel consumer there is a significant decrease: p-value = 0.00512. DISCUSSION: In vitro, we conclude that the polyphenol content in betel causes total precipitation of mucins and causes poor defense of the oral epithelium. The increase of mucins in the non-routine consumers, show a transient (up to two hours after the end of chewing) inflammatory process. Inflammation can cause keratinization of the oral epithelium because the saliva increases its viscosity for the higher amount of mucins, with its lower adherence and protection of the oral cavity. Subsequent and regular consumption of betel nut, as in the regular betel consumer, can cause chronic fibrosis in the oral epithelium and cut the salivary mucins.

The Variations of Some Salivary Parameters as Probable Indices of the Hereditary Diabetes.

Background: Diabetes has a genetic predisposition and is generally not diagnosed for many years because hyperglycemia develops gradually, without presenting the classic symptoms of diabetes. The aim of this study is to verify whether, in a potentially genetically predisposed population, men and women under the age of 50 years, at the time of the study, not suffering from diabetes can be detected using parameters derived from initial metabolic alteration indices of the possible evolution of pathology. Methods: In the hereditary and healthy group, salivary concentration of malondialdehyde, total mucins, and pH were determined. All participants in the two groups had fasting glucose level below 110 mg/dL. The results were statistically analyzed using Pearson correlation test, Mann-Whitney test, and -Student's t-test. Results: Salivary concentration of malondialdehyde statistically increased in the hereditary group vs the healthy group (P = 0.0368) as the mucins (P ≤ 0.005). The salivary pH decreased but, the values were not statistically significant (P = 0.085). Some alteration processes occur without increase in glucose levels, produced by changes in metabolic redox processes along with an increase in the salivary malondialdehyde index of oxidative stress in the body. The modification of the salivary buffer system lowers the pH, whereas increase in salivary mucins alters the value of spinnbarkeit, which measures the capacity of the mucous layer to adhere to the epithelium, causing alterations of the oral mucosa. Conclusions: This study shows that it is possible to predict in hereditary predisposition conditions the development of diabetes, and the related dangerous consequences by monitoring two salivary parameters - mucins and malondialdehyde.

The Question on the Potential Cancerous Effects of Hair Dyes: The Monitoring of the Oxidative Stress Induced by the Hair Dyes with the Dosage of the Salivary Free Radicals.

BACKGROUND: Many studies indicate the difficulty on assessing the possible carcinogenic effects of hair dyes, for their high time of the latence. OBJECTIVES: Our objective is to determine their prognostic index, by monitoring the oxidative stress, produced exposed to hair dyes, in hairdressers, and in consumers, by measuring the concentration of salivary malondialdehyde. MATERIALS AND METHODS: Saliva samples are provided by the hairdressers, working in private (NP) or shopping center (CC), by users of hair dyes, for at least 10 years, and by a control group. The values of malondialdehyde are determined using the thiobarbituric acid method. The results are statistically analyzed by Kruskal-Wallis and Mann-Whitney test. RESULTS: Comparing the three groups with tests for K-independent Kruskal-Wallis samples (dyed vs. control vs. dyed at least 10 years), there is a significant difference for the amount of MDA (P < 0.001). Proceeding for the median MDA in the subgroups by testing for two independent U-samples of Mann-Whitney: control versus dyed, P < 0.001; control versus CC, P = 0.013; control versus NP, P < 0.001; control versus 10 years, P = 0.111; CC versus NP, P = 0.001; CC versus 10 years, P = 0.462; and NP versus 10 years, P < 0.001. DISCUSSION: In hairdressers, the increase of the salivary MDA versus control group is statistically significant (P ≤ 0.05), with an accentuation in small workplace, for age, probably for a more direct exposure to dyes' gas. Another statistically significant increase of salivary MDA is for the consumers versus control group, also function of the increasing age. CONCLUSIONS: The results of this study show a significant increase of oxidative stress in the hairdressers. This factor involves a potential carcinogenic risk, especially for the bladder, difficult to assess in the short term.

The Exposure to Pollutants of the Auto Repair Workers: Monitoring their Oxidative Stress.

BACKGROUND AND AIM: Auto repair workers are exposed to multiple pollutants, each of them potentially risks, dangerous for several target organs. The aim of this study is to identify their possible overall effect, by monitoring the concentration of salivary malondialdehyde, index of oxidative stress. MATERIALS AND METHODS: Malondialdehyde of 25 male workers, smokers and non-smokers, further divided into two subgroups relatively to the amplitude of their working place, was monitored, in the saliva, with the Thiobarbituric acid method. The control group consists of 12 and 13 male smokers, and 13 non-smokers. Univariate (UVA) and Multivariate (MVA) analysis methods were used to analyze the results. RESULTS: No variable is significant (P ≥ 0.05) for the control group using UVA, while age and smoking significantly increase the levels of MDA (P ≤ 0.05) using MVA. For workers group, the age and the place of work increase the MDA (P ≤ 0.05) using UVA analysis, while only the place of work remains significant (≤0.05) using MVA analysis. MVA analysis reveals that, besides the type of work, also the age and smoking significantly increase the level of MDA, as a result of a higher exposure to pollutants. CONCLUSIONS: You can check the cumulative effect of pollutants on auto repair workers, by monitoring the salivary malondialdehyde.

Industrial Pollutants and Nasopharyngeal Cancer: An Open Question.

INTRODUCTION AND OBJECTIVES: Nasopharyngeal Carcinoma represents 0.7% of the total cancer cases in the world with an ASR index of 1.7 and is widely associated with Epstein-Barr virus. It is not common in Italy (ASR index of 0.5) while in China (ASR 1.9), one third of the clinical cases are observed in Guangdong (ASR index 11.3). It is also quite common in Malaysia and Indonesia. The activation of the cancerogenesis process happens after the exposure to some environmental parameters that epidemiological studies have indicated with various dietary habits, mainly for salted fish consumption. The purpose of this work is to highlight such as exposure to compounds, such as formaldehyde, which is present in the different working conditions of these countries and may lead to the real cause to establish the carcinogenic process. MATERIALS AND METHODS: The most recent publications regarding the impact of various external factors on Pub Med, Google, TOXLINE, Chem Abstract, were analyzed with the radiological data that were found in Milan hospitals database. RESULTS: The relationship between food consumption and nasopharyngeal cancer are not clear and statistically insignificant in Indonesia. In Malaysia, the preparation of natural rubber for the use of formaldehyde is a dangerous environmental factor. The same exposure is a risk factor in Guangdong, where many workers are employed in the wood panel industry. Incidence of cancer in these Chinese ethnic groups decreases when they migrate to other countries. In the last 5 years, few cases were recorded in Italy, without any apparent change in ethnic environmental factors or HBV infection Discussion: In the production of natural rubber, a lot of people are exposed to formaldehyde during the various steps of preparation and production such as stripping, drying and coagulation without observing proper environmental hygiene precautions. The same working conditions are present in industrial production of wood panels in Guangdong, China. The relationship between exposure to formaldehyde and nasopharyngeal cancer is demonstrated by the fact that epidemiological studies on the population of this Chinese district whose immigrant populations were not exposed to these pollutants, the appearance of these tumors decreases. Also an examination of our radiological data in Italy shows that in about one hundred sixty cases of nasopharyngeal cancer none of the patients were Indonesian or Chinese Conclusion: The preliminary results of our study suggest that EPST-BARR virus could be a risk factor if associated with exposure to compounds such as formaldehyde which is present in industrial productions of countries like Indonesia, Malaysia, and China.

The Possible Role of Diabetes in the Etiology of Laryngeal Cancer.

BACKGROUND: Laryngeal cancer and oral cancer are not always correlated with genetic mutations, HPV infection, smoking, and alcohol abuse. In the absence of these risk factors, there is an increase on these cancers with a parallel increase of diabetes. The aim of this study is to verify if diabetes could be a risk factor for the laryngeal cancer. METHODS: A questionnaire was given to a group of ninety laryngectomees to verify if these patients have presented diabetes and xerostomia before surgery. In two groups, diabetics and healthy persons, the values of the salivary mucins and the pH were evaluated. The results were statistically analysed using Fisher Exact Test and Chisquare Test Results: Diabetes is a risk factor: p= 0.0445 for laryngectomees male vs control group. Xerostomia inlaryngectomees male is a risk factor: p= 0.050. The values of mucins and pH in diabetic group show significant difference: p=0.05 vs control group Discussion: In all autoimmune diseases, a decrease in the value of pH and salivary flow consequently decreases the value of spinnbarkeit which measures the capacity of the mucous layer to adhere to the epithelium and alter the protective oral mucin layer. We find that diabetes is epidemiologically correlated with laryngeal cancer. In fact, only diabetes increases the concentration of salivary mucins with a formation of mucin layer even more reduced, and so completely ineffective in protecting the mucosa. CONCLUSIONS: The increase of mucin secretion in diabetes alters much the protective layer allowing the risk factors to promote cancer growth.