The Role of SARS-CoV-2 Spike Protein in Long-term Damage of Tissues and Organs, the Underestimated Role of Retrotransposons and Stem Cells, a Working Hypothesis.

Coronavirus disease-2019 (COVID-19) is a respiratory disease in which Spike protein from SARS-CoV-2 plays a key role in transferring virus genomic code into target cells. Spike protein, which is found on the surface of the SARS-CoV-2 virus, latches onto angiotensin-converting enzyme 2 receptors (ACE2r) on target cells. The RNA genome of coronaviruses, with an average length of 29 kb, is the longest among all RNA viruses and comprises six to ten open reading frames (ORFs) responsible for encoding replicase and structural proteins for the virus. Each component of the viral genome is inserted into a helical nucleocapsid surrounded by a lipid bilayer. The Spike protein is responsible for damage to several organs and tissues, even leading to severe impairments and long-term disabilities. Spike protein could also be the cause of the long-term post-infectious conditions known as Long COVID-19, characterized by a group of unresponsive idiopathic severe neuro- and cardiovascular disorders, including strokes, cardiopathies, neuralgias, fibromyalgia, and Guillaume-Barret's like-disease. In this paper, we suggest a pervasive mechanism whereby the Spike proteins either from SARS-CoV-2 mRNA or mRNA vaccines, tend to enter the mature cells, and progenitor, multipotent, and pluripotent stem cells (SCs), altering the genome integrity. This will eventually lead to the production of newly affected clones and mature cells. The hypothesis presented in this paper proposes that the mRNA integration into DNA occurs through several components of the evolutionarily genetic mechanism such as retrotransposons and retrotransposition, LINE-1 or L1 (long interspersed element-1), and ORF-1 and 2 responsible for the generation of retrogenes. Once the integration phase is concluded, somatic cells, progenitor cells, and SCs employ different silencing mechanisms. DNA methylation, followed by histone modification, begins to generate unlimited lines of affected cells and clones that form affected tissues characterized by abnormal patterns that become targets of systemic immune cells, generating uncontrolled inflammatory conditions, as observed in both Long COVID-19 syndrome and the mRNA vaccine.

The Influence of COVID-19 in Endocrine Research: Critical Overview, Methodological Implications and a Guideline for Future Designs.

The COVID-19 pandemic has changed many aspects of people's lives, including not only individual social behavior, healthcare procedures, and altered physiological and pathophysiological responses. As a result, some medical studies may be influenced by one or more hidden factors brought about by the COVID-19 pandemic. Using the literature review method, we are briefly discussing the studies that are confounded by COVID-19 and facemask-induced partiality and how these factors can be further complicated with other confounding variables. Facemask wearing has been reported to produce partiality in studies of ophthalmology (particularly dry eye and related ocular diseases), sleep studies, cognitive studies (such as emotion-recognition accuracy research, etc.), and gender-influenced studies, to mention a few. There is a possibility that some other COVID-19 related influences remain unrecognized in medical research. To account for heterogeneity, current and future studies need to consider the severity of the initial illness (such as diabetes, other endocrine disorders), and COVID-19 infection, the timing of analysis, or the presence of a control group. Face mask-induced influences may confound the results of diabetes studies in many ways.

Inadequate Hydration Status of Test Subjects Can Affect Bioavailability Studies.

This Viewpoint identifies some of the pitfalls in the bioavailability of water-soluble drugs and introduces a novel bias we term the "hypohydration bias". We suggest that future bioavailability studies take some important neglected confounding factors into account, and we propose that, to avoid such a bias, some relevant variables such as serum and urine osmolality, dry weight adjustment, fluid balance, semi-nude body mass, saliva osmolality, saliva total protein concentration, and urine specific gravity should be controlled to increase the precision of the bioavailability measurements. We suggest that a new definition of hydration status is needed, and that systematic protocols of bioavailability studies should be revisited.

Dietary Temperature's Influence on Energy Balance in Humans: Protocol for a Randomized Controlled Trial and Crossover Design.

BACKGROUND: According to the first law of thermodynamics, energy cannot be created or destroyed in an isolated system. Water has a characteristically high heat capacity, indicating that the temperature of ingested fluids and meals could contribute to energy homeostasis. Citing the underlying molecular mechanisms, we present a novel hypothesis that states that the temperature of one's food and drink contributes to energy balance and plays a role in the development of obesity. We provide strong associations with certain molecular mechanisms that are activated by heat and correlate them with obesity and a hypothetical trial that could test this hypothesis. We conclude that if meal or drink temperature proves to contribute to energy homeostasis, then depending on its contribution and scale, future clinical trials should attempt to adjust this effect when analyzing data. In addition, previous research and established relationships of disease states with dietary patterns, energy intake, and food component intakes should be revisited. We understand the common assumption that thermal energy in food is absorbed by the body during digestion and dissipated as heat into the environment, not contributing to the energy balance. We challenge this assumption herein, including a proposed study design that would test our hypothesis. OBJECTIVE: This paper hypothesizes that the temperature of ingested foods or fluids influences energy homeostasis through the expression of heat shock proteins (HSPs), especially HSP-70 and HSP-90, which are expressed to a greater extent in obesity and are known to cause deficits in glucose metabolism. METHODS: We provide preliminary evidence supporting our hypothesis that greater dietary temperatures disproportionally induce activation of both intracellular and extracellular HSPs and that these HSPs influence energy balance and contribute to obesity. RESULTS: This trial protocol has not been initiated and funding has not been sought at the time of this publication. CONCLUSIONS: To date, no clinical trials are available regarding the potential effects of meal and fluid temperature on weight status or its confounding effects in data analysis. A potential mechanism is proposed as a basis by which higher temperatures of foods and beverages might influence energy balance via HSP expression. On the basis of the evidence supporting our hypothesis, we propose a clinical trial that will further elucidate these mechanisms. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/42846.

Anti(angiogenic) food components: can be a major source of bias in the investigation of angiogenesis inhibitors.

Background: Natural and diet-derived angiogenesis inhibitors/promotors are widely found in diets. These compounds can in several ways impact the results of oncological research of angiogenesis inhibitors. Methods: We very briefly overview some of the most important examples to show how these compounds can create a bias in current research of cancer. Implications of this expert opinion cover similar angiogenesis-related diseases. Results: Significant intra-individual differences in terms of dietary intake and differential effect of food processing techniques result in differential bioactivity and bioavailability of these compounds. There are only a handful of validated dietary questionnaire to quantify natural angiogenesis inhibitors/promotors. A corollary consequence is that participants in non-randomized clinical trials will have different baseline levels of serum/plasma/tissue/organ diet-derived angiogenesis inhibitors/promotors. This will lead to creation of clinical uncertainty and a hidden bias and consequently creation of translational efficiency bias, sampling efficiency, and waste of resources. We call for developing and validating a semi-quantitative food frequency questionnaire (FFQ) to gather data on these agents, specifically designed for oncological research because there is a clear gap in the literature of oncology. Conclusions: This might facilitate the discovery of better prognostic, diagnostic, preventive measures, and therapeutic agents for the management of different cancers. Implications of this paper cover similar settings like ophthalmologic research.

Melatonin Supplementation and Anthropometric Indices: A Randomized Double-Blind Controlled Clinical Trial.

Obesity, as the most common metabolic disorder in the world, is characterized by excess body fat. This study is aimed at determining the effects of melatonin supplementation on body weight, nody mass index (BMI), waist circumference (WC), and body fat mass percentage (BFMP) in people with overweight or obesity. Thirty eight overweight or class-I obese adult individuals were recruited in the study (8 men and 30 women). Participants prescribed a weight-loss diet and then randomly were allocated to melatonin or placebo groups. Participants received either a 3-milligram melatonin or placebo tablet per day for 12 weeks. In order to assess differences at the significance level of 0.05, repeated measure ANOVA and paired t-test were used. According to the results, a significant reduction was found in participants' body weight, WC, and BMI in both groups (p = 0.001). However, for the last six weeks, significant reductions of these parameters were observed only in the melatonin group (p = 0.01). The BFMP of participants in the melatonin group showed a significant reduction at the end of the study compared to the initial measurements (p = 0.008). Nevertheless, the results of the present study alone are not sufficient to conclude on the effects of melatonin consumption on anthropometric indices, and it seems that further studies are required in this regard.

Aquaporin5-Targeted Treatment for Dry Eye Through Bioactive Compounds and Gut Microbiota.

Dry eye and dry mouth are the principal sources of morbidity for patients with Sjögren's syndrome (SS). There are few effective treatments, particularly systemic ones. Targeting aquaprin-5 (AQP5)-mediated tear secretion has been tested as a novel ancillary strategy and has proved promising. Patients have a great interest in using complementary medicine, including nutraceuticals and bioactive compounds to alleviate their symptoms. Potential mechanisms by which phytocompounds and bioactive compounds may benefit SS ocular and mouth symptoms through modulation of AQP5 activity are presented within this review. Supplementation with prebiotics (such as polyphenols with high bioavailability) in SS patients with lower Firmicutes/Bacteroides (F/B) community ratio phenotype, through administration of butyrate-producing diets, is proposed as ancillary strategy for dry eye and mouth. The potential use of natural bioactive compounds to treat dry eye could also apply to dry mouth occurring in the context of aging and SS. This novel hypothesis could have implications with respect to planning a successful dietary regimen for achieving and maintaining a normal gut microbiota in SS patients. This regimen would include augmenting butyrate-producing foodstuffs and/or polyphenol-rich syrups, and high amounts of some specific probiotic-rich foodstuffs such as yogurt, soy yogurt, or as probiotic supplements. There are applications for pharmaceutical and nutraceutical products aiming to relieve dry eye and mouth.