N-Acetyl Cysteine and Glutathione in Health and Cancer-Pharmacogenomics, Research, and Clinical Practice: Hypothesis and Review.

Context: Glutathione (GSH) is a major intracellular antioxidant capable of scavenging free radicals and detoxifying electrophiles from endogenous and exogenous sources via the free thiol group. GSH plays an important role in a multiple cellular process, including cell differentiation, proliferation, and apoptosis. Pharmacogenomics has demonstrated its important role as a key element in cellular health. Objective: The study intended to examine the benefits of using GSH pharmacogenomics as a therapy to prevent side effects and interactions with antineoplastic agents in the diagnosis and treatment of malignancies. Design: The research team performed a narrative review using the Google scholar and PubMed electronic databases. Conclusions: In summary, the involvement of GSH in the carcinogenesis and drug resistance of tumor cells is clear and well understood, but further studies, aimed at understanding the GSH-driven molecular pathways, might be crucial to designing new therapeutic strategies to fight cancer progression, overcoming chemoresistance, using in combination with immunotherapies, and preventing or minimizing their negative side effects.

Evaluation of exosome derivatives as bio-informational reprogramming therapy for cancer.

Exosomes are nanoparticle sized (100 ± 50 nm) extracellular vesicles (ECVs) that play important roles in cell-to-cell communication. They do this by utilizing their natural ability to shuttle signaling molecules across the cellular microenvironment and promote paracrine signaling. Currently, exosomes are being explored for their potential as therapeutic agents for various degenerative diseases including cancer. The rationale behind their therapeutic ability is that they can transfer signaling biomolecules, and subsequently induce metabolic and physiological changes in diseased cells and tissues. In addition, exosomes can be used as a drug delivery system and may be very effective at reducing toxicity and increasing bioavailability of therapeutic molecules and drugs. Although exosomes were first believed to be a waste product of the cell, current research has demonstrated that these particles can serve as modulators of the immune system, act as cancer biomarkers, cause re-differentiation of cancer cells, and induce apoptosis in diseased cells. Extensive research has been performed specifically using amniotic fluid-derived extracellular vesicles, named "cytosomes". While the use of cytosomes in clinical application is still in the early stages, researchers have shown great potential for these EVs in regenerative medicine as immune modulators, in controlling microbial infection and by inducing tissue repair through the activation of endogenous, tissue-specific stem cells. This review emphasizes the capabilities of specific subsets of extracellular vesicles that can potentially be used for cancer therapy, principally as a source of bi-informational reprogramming for malignant cells.

High Dose Intravenous Vitamin C Treatment for Zika Fever.

The Zika Fever is a viral disease caused by a single-stranded RNA virus from the Flavivirus genus, Flaviviridae family, from the Spondweni group. Its transmission occurs through mosquito vectors, principally Aedes Aegypti. The most common symptoms of Zika are fever, rash, joint pain, and conjunctivitis (red eyes). Other common symptoms include muscle pain and headache. As of now, no vaccine exists for the virus and no official treatment has been developed aside from standard procedures of the use of acetaminophen (paracetamol) and non-steroidal anti-inflammatory drugs. This is a case report of a 54 year-old Hispanic female who arrived at the clinic with symptomatology congruent with the Zika fever. The patient was treated with high doses of intravenous vitamin C over three days. The symptoms resolved after the infusions without any side effects at day four. Recovery from this viral infection takes normally around two weeks. Based on the positive outcome in this case, we propose that intravenous vitamin C should be studied further as a potential treatment for acute viral infections.

Archaic RDA Methodology for Vitamin C.

Frei et al's 2012 review entitled "Authors' Perspective: What is the Optimum Intake of Vitamin C in Humans" is both flawed and misleading. RCTs are ill suited to determining the RDA, it is debatable that there is sufficient scientific evidence to determine the optimum intake of vitamin C in humans, observations regarding high-doses of ascorbate have been ignored, and there are inaccuracies of fact with respect to the saturation of blood plasma following low dose intake. Until the limitations of current knowledge are recognised it is unwise to set limits on the dose.

Metabolic correction: a functional biochemical mechanism against disease--Part 2: mechanisms and benefits.

A healthy physiology depends on a plethora of complex interdependent biochemical reactions. In order for these reactions to occur suitably, the enzymes and cofactors that regulate their flow must be present in the proper balance. The term metabolic correction is used to describe a biochemical-physiological process that improves cellular biochemistry as a means to an individual's achieving metabolic or physiological optimization. Part 2 discusses how metabolic correction, through the increase of cofactors, can supply unmet enzyme needs and compensate for nutritional deficiencies induced by improper nutritional intake or by the increased demand for nutrients caused by genetics, health conditions, medications, or physical or environmental stressors. Nutrient insufficiencies are causing an increase in morbidity and mortality, at great cost to our society. In summary, metabolic correction improves enzymatic function and satisfies the increasing demand for nutrients. Metabolic correction can have a significant impact on the reduction of morbidity and mortality and their financial cost to our society and contribute to improving health and well-being.

Metabolic correction: a functional biochemical mechanism against disease--Part 1: concept and historical background.

Human physiology depends on countless biochemical reactions, numerous of which are co-dependent and interrelated. The speed and level of completion of reactions usually depend on the availability of precursors and enzymes. The enzymatic activity depends on the bioavailability of micronutrient cofactors such as vitamins and minerals. In order to achieve a healthy physiological state, the organism requires that biochemical reactions occur at a controlled rate. To achieve this state it is required that metabolic reactions reach what can be considered an optimal metabolic equilibrium. A combination of genetic makeup, dietary patterns, trauma, disease, toxins, medications, and environmental stressors can elevate the demand for the nutrients needed to reach this optimal metabolic equilibrium. In this, part 1, the general concept of metabolic correction is presented with an elaboration explaining how this concept is increasing in importance as we become aware of the presence of genetic variants that affect enzymatic reactions causing metabolic disturbances that themselves favor or promote the disease state. In addition, part 1 reviews how prominent scientists have contributed in fundamental ways to our understanding of the importance of micronutrients in health and disease and in the development of the metabolic correction concept.

Metabolic Correction as a tool to improve diabetes type 2 management.

Diabetes Mellitus type 2 (DM2) is a metabolic disease that develops by a decrease in sensitivity of insulin receptors as an effect of the disruption certain metabolic functions in the processing of glucose. DM2 patients have, uncontrolled glucose levels, and commonly have problems with obesity and cardiovascular disease. Patients are treated with standard diet, insulin, diabetic oral agents and antihypertensive drugs, but this approach does not completely stops tissue deterioration since it does not address the metabolic root of the disease. Metabolic correction is proposed as a suitable adjunct treatment to improve clinical outcomes. Metabolic correction is based on diet modification, proper hydration and scientific supplementation directed to improve cellular biochemistry and metabolic efficiency. In addition, other possible benefits may include reduction in medication use, disease complications and medical costs. To test the results of a metabolic correction program, 25 patients with DM2 participated in an education program about adequate food consumption that promoted control of blood glucose levels. Anthropometric measurements and blood tests were performed during a 13 week program based on a low carbohydrate diet, proper hydration and magnesium supplementation. The metabolic correction program implemented by a proprietary educational system resulted in significant reductions in glucose, triglycerides, cholesterol, weight and waist circumference. Improvements in these values could represent an important reduction of coronary heart disease risk factors as well as other chronic degenerative diseases. In addition there was medication dosage reduction in one or more medications in 21 of the 25 participating patients, which suggest that the program has the potential to improve health outcomes and reduce health care costs.

[Metabolic correction: a biochemical option against diseases]. / Corrección metabólica: Una opción bioquímica contra las enfermedades.

Human development and its physiology depends on a number of complex biochemical body processes, many of which are interactive and codependent. The speed and the degree in which many physiological reactions are completed depend on enzyme activity, which in turn depends on the bioavailability of co-factors and micronutrients such as vitamins and minerals. To achieve a healthy physiological state, organism need that biochemical reactions occur in a controlled and specific way at a particular speed and level or grade fully completed. To achieve this, is required an optimal metabolic balance. Factors such as, a particular genetic composition, inadequate dietary consumption patterns, traumas, diseases, toxins and environmental stress all of these factors rising demands for nutrients in order to obtain optimal metabolic balance. Metabolic correction is a biochemical and physiological concept that explains how improvements in cellular biochemistry of an organism can help the body achieve metabolic and physiological optimization. We summarize the contribution of several pioneers in understanding the role of micronutrients in health management. The concept of metabolic correction is becoming a significant term due to the presence of genetic variants that affect the speed of reactions of enzymes, causing metabolic alterations that enhance or promote the state/development of multiple diseases. Decline in the nutritional value of the food we eat, the increase in demand for certain nutrients caused by normal development, diseases and medications induce, usually, nutrients consumption. These nutritional deficiencies and insufficiencies are causing massive economic costs due to increased morbidity and mortality in our society. In summary, metabolic correction improves the enzymatic function, which favors the physiological normal functions, thus, contributing to improving health and the welfare of the human being. The purpose of this paper is to describe and introduce the concept of optimal metabolic correction as a functional cost-effective mechanism against disease, in addition, to contribute to diseases prevention and regeneration of the body and health.

High Dose Intraveneous Vitamin C and Chikungunya Fever: A Case Report.

The Chikungunya (CHIKV) fever is a viral disease produced by a single-stranded RNA Alphavirus from the Togaviridae genus. Its transmission occurs only through mosquito vectors, principally Aedes aegypti. It requires a human-mosquito-human transmission cycle. It is associated with severe arthritis/arthralgias, myalgias, high fever, headache, and maculopapular rash. Joint ache appears to be symmetrical. The virus has an incubation period of 2 to 7 days, where the high fever is typically presented. It is followed by arthralgias and myalgias, and rashes, which last for 3 to 5 days. However, the arthralgias can persist for months after the infection, which can contribute to severe arthritis. As of now, no vaccine exists for the virus and no official treatment has been developed aside from standard procedures of the use of acetaminophen (paracetamol), and non-steroidal anti-inflammatory drugs. This is a case report of a 54-year old Hispanic individual that reported left shoulder pain, left knee pain and fever. The symptoms started on a Saturday in September 2014 in middle of the night. The patient was treated with high doses of intravenous vitamin C over two days. The symptoms resolved after the infusions without any side effects. Based on the positive outcome in this case, we propose that intravenous vitamin C should be studied further as a potential treatment for acute viral infections.

Dietary patterns and their association with sociodemographic characteristics and perceived academic stress of college students in Puerto Rico.

OBJECTIVE: University students face academic responsibilities that may produce stress, which may lead to changes in dietary patterns (DPs). These changed patterns can become dysfunctional, often resulting in a negative impact on the health of the stressed student. Little is known about DPs in college students in Puerto Rico (PR). The purpose of this study was to describe the DPs of college students in PR and the association of these patterns with socio-demographic characteristics and perceived academic stress. METHODS: This retrospective epidemiological study investigated self-reported DPs in a representative sample of 275 college students, in relation to socio-demographic characteristics, body composition (BC), and perceived academic stress; a Diet Quality Index was developed using the USDA Food Patterns for 2010 to determine whether their DPs were adequate or inadequate. RESULTS: Most of the participating students were female (67.6%), ranged from 21 to 30 years old (88%), lived in low household incomes (42.7%), and had healthy weights (56.4%). Most of the students perceived the stress levels as being moderate (60.7%). Most had diets that were below the dietary recommendations for grains, fruits, vegetables, dairy products, and protein, whereas fat consumption was adequate. Overall, most had inadequate DPs (62%). DP was significantly associated with age (p < 0.05); older students had better DPs than did younger students. In terms of the different schools (p < 0.05), those students from the School of Medicine and those from the School of Public Health had better DPs than did the students from the other schools. DP was not associated with income, gender, BMI, stress level, or course load. CONCLUSION: The majority of the students had inadequate DPs, which inadequacy was associated with both the age of the student and the school that he or she attended.

Physical activity and its associations with sociodemographic characteristics, dietary patterns, and perceived academic stress in students attending college in Puerto Rico.

OBJECTIVE: The academic environment usually generates stress in students. Increasing physical activity (PA) is one of the stress-coping strategies for students; however, students usually reduce their PA while enrolled in college. OBJECTIVE: To determine the association between PA, self-perceived academic load and stress, and dietary patterns in students attending college in Puerto Rico. METHODS: A proportional stratified sample of 275 students from UPR-MSC completed a self-administered questionnaire on socioeconomic status, academic load and stress, body composition, dietary patterns, and PA. Chi2 was used to assess the association between variables. RESULTS: Most of the participants were female (68%), were aged 21 to 30 years (88%), and had low annual household incomes ($0-$24,999) (43%). Women reported higher levels of stress (p < 0.001) than did men. Overweight and obesity was found in 35.4%, while most students reported a light PA level (46.5%), which was higher among women (p < 0.001). During periods of greater stress, most students increased sedentary activities (68%), and -30% reported a decrease in moderate and vigorous activities; however, 60% reported that PA was an effective coping strategy and 66% would use it again. There was a negative association between PA and stress: those with higher levels of stress had lower PA levels (p = 0.06). No significant associations were found between PA and the others variables studied (p > 0.05). CONCLUSION: Most students reported sedentary lifestyles during periods of greater stress. High level of stress were positively associated with a light PA level.

Alcohol consumption and smoking and their associations with socio-demographic characteristics, dietary patterns, and perceived academic stress in Puerto Rican college students.

OBJECTIVE: College students often use different strategies, such as consuming alcohol and smoking, to cope with stress. We examined the associations between self-perceived academic stress, alcohol consumption, smoking, and dietary patterns in graduate students. METHODS: A representative stratified sample of 275 students from each school of the Medical Science Campus of the University of Puerto Rico (UPR-MSC) completed a 48-item questionnaire that solicited the following: socio-demographic data, estimates of self-perceived stress, estimates of the frequency of alcohol consumption and the type(s) of alcohol consumed, details regarding smoking habits, and information associated with diet (i.e., dietary patterns). Fisher's exact test and the Chi2 test were used to assess the associations between the different study variables. RESULTS: Only 3% were considered smokers (defined as > 1 cigarettes per day), with the greatest number of smokers among those aged 21-30 y (p<0.05). Smoking habits was not associated with academic load/stress or with dietary pattern. Most smokers reported that their main reason for using cigarettes was to cope with stress. About 70% of the students were considered drinkers (defined as > 0 drink/day), with a higher proportion found among women (63.5%), among those aged 21-30 years (90.6%), and among those with a low or moderate household income (p<0.05). Alcohol intake was significantly associated with academic stress, with a greater proportion of drinkers reporting experiencing moderate levels of academic stress (p<0.05), but it was not associated with dietary patterns or academic load (p>0.05). Most subjects classified as drinkers reported that alcohol consumption was not (in their experience) an effective strategy for the management of stress (81%). CONCLUSION: Alcohol consumption was only associated with academic stress. No associations were found between smoking habits and academic stress/load and dietary patterns.

Non-medical use of prescription drugs and its association with socio-demographic characteristics, dietary pattern, and perceived academic load and stress in college students in Puerto Rico.

OBJECTIVE: Stress can have deleterious effects on health and academic performance. Common stress-relieving activities among college students include the non-medical use of prescription drugs (NMUPD). The aim of this study was to determine the associations between self-perceived academic load and stress, NMUPD (stimulants, depressants, and sleeping medication), and dietary pattern in college students in PR. METHODS: A questionnaire to evaluate academic load and stress, NMUPD, and dietary pattern was used on a representative sample of 275 first- and second-year students from one campus. RESULTS: In total, 27.6% reported NMUPD in the past 6 months, with higher use among students aged 21-30 years (93.4%) than in those aged 31-53 years (6.6%; p=0.062). Those with high levels of stress had higher NMUPD (42.1%) than did those with low (26.3%) or moderate (31.6%) stress levels, after controlling for age and sex (p=0.03). Among those who reported NMUPD over the previous 6 months, 74% reported that such use was effective as a coping strategy, and 35% reported that it helped them to improve academic performance. Although no significant association was found between NMUPD and dietary pattern, 57% of the participants reported that their appetites decreased when they engaged in NMUPD. CONCLUSION: To our knowledge, this is the first study that has associated self-perceived academic load and stress, NMUPD, and dietary pattern among college students in Puerto Rico. NMUPD's prevalence was 27.6%, which prevalence appeared to be higher in students aged 21-30 years than in those of any other age. High levels of stress were significantly related to high NMUPD in this sample.

Caffeinated-beverage consumption and its association with socio-demographic characteristics and self-perceived academic stress in first and second year students at the University of Puerto Rico Medical Sciences Campus (UPR-MSC).

OBJECTIVE: To determine the association between caffeinated-beverage consumption, self-perceived academic load, and self-perceived stress levels in first and second year students at UPR-MSC. METHODS: A descriptive epidemiological study was performed using a self-administered anonymous questionnaire given to a representative stratified sample of 275 students. Questions included information regarding socio-demographic characteristics, academic load and stress indicators, and caffeinated-beverage consumption. Chi2 was used to assess the associations between these variables. RESULTS: Most participants were women (68%), aged 21-30 years (88%), with low annual household incomes (43%). Most perceived their academic loads as being heavy (68%), and most perceived their academic stress levels as being moderate (37%). Academic load was significantly correlated with stress level (p<0.001). About 88% of the participants reported consuming caffeinated beverages; of those, 87% drank soft drinks, 83% drank coffee, 56% drank hot chocolate, 40% drank tea, and 29% drank energy drinks, all of which were--according to the participants (54%)--used mainly to stay awake. Soft drinks and coffee intake increased in periods of high stress, and many (49%) reported that these beverages were useful for coping with stress. Energy drinks, in particular, were consumed more often by men compared to women (p<0.05). None of these beverages were significantly associated with academic stress or load. CONCLUSION: Consuming caffeinated beverages is a popular practice among participants in this sample, with soft drinks and coffee being the ones that are the most frequently consumed. No associations were found between the consumption of caffeinated beverages and academic stress or load.

Schedule Dependence in Cancer Therapy: Intravenous Vitamin C and the Systemic Saturation Hypothesis.

Despite the significant number of in vitro and in vivo studies to assess vitamin C effects on cancer following the application of large doses and its extensive use by alternative medicine practitioners in the USA; the precise schedule for successful cancer therapy is still unknown. Based on interpretation of the available data, we postulate that the relationship between Vitamin C doses and plasma concentration x time, the capability of tissue stores upon distribution, and the saturable mechanism of urinary excretion are all important determinants to understand the physiology of high intravenous vitamin C dose administration and its effect on cancer. Practitioners should pay more attention to the cumulative vitamin C effect instead of the vitamin C concentrations to account for observed discrepancy in antitumor response. We suggest that multiple, intermittent, short-term intravenous infusions of vitamin C over a longer time period will correlate with greater antitumor effects than do single continuous IV doses of the same total exposure. This approach would be expected to minimize saturation of renal reabsorption, providing a continuous "dynamic flow" of vitamin C in the body for optimal systemic exposure and clinical outcomes. This prevents the "systemic saturation" phenomena, which may recycle vitamin C and render it less effective as an anticancer agent. Nonetheless, more pharmacokinetic and pharmacodynamic studies are needed to fully understand this schedule-dependence phenomenon.

Intravenous ascorbic acid to prevent and treat cancer-associated sepsis?

The history of ascorbic acid (AA) and cancer has been marked with controversy. Clinical studies evaluating AA in cancer outcome continue to the present day. However, the wealth of data suggesting that AA may be highly beneficial in addressing cancer-associated inflammation, particularly progression to systemic inflammatory response syndrome (SIRS) and multi organ failure (MOF), has been largely overlooked. Patients with advanced cancer are generally deficient in AA. Once these patients develop septic symptoms, a further decrease in ascorbic acid levels occurs. Given the known role of ascorbate in: a) maintaining endothelial and suppression of inflammatory markers; b) protection from sepsis in animal models; and c) direct antineoplastic effects, we propose the use of ascorbate as an adjuvant to existing modalities in the treatment and prevention of cancer-associated sepsis.

Effect of green tea on glycemic control in patients with type 2 diabetes mellitus: A systematic review and meta-analysis.

BACKGROUND AND AIMS: Several studies have investigated the potential beneficial effects of green tea in patients with type 2 diabetes mellitus (T2DM). Therefore, we aimed to perform a systematic review and meta-analysis of the randomized controlled trials (RCTs) that assessed the effect of supplementary intake of green tea on fasting plasma glucose (FPG), fasting insulin, hemoglobin A1c (HbA1c) and HOMA-IR in patients with T2DM. METHODS: A systematic search was performed in Web of Science, PubMed and Scopus without any language and time restriction up to June 2019, to retrieve the related RCTs. Meta-analysis was carried out using both the random and fixed effects model where appropriate. I2 index was used to evaluate the heterogeneity. RESULTS: Initial search yielded 780 publications. Fourteen articles were eligible. Our meta-analysis indicated that the supplementary intake of green tea had no significant effect on FPG, fasting insulin, HbA1c and HOMA-IR in patients with T2DM. CONCLUSION: Results of the present systematic review and meta-analysis indicated that the supplementary intake of green tea had no significant effect on FPG, fasting insulin, HbA1c and HOMA-IR in patients with T2DM.

Effect of Green Tea on Anthropometric Indices and Body Composition in Patients with Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis.

AIM: Previous studies that investigated the effect of green tea/green tea extract on anthropometric indices among type 2 diabetes mellitus (T2DM) patients found inconsistent results. Thus, in order to clarify the efficacy of green tea supplementation on anthropometric indices and body composition, we conducted a systematic review and meta-analysis to sum up the evidence of randomized controlled trials. METHODS: A systematic search was conducted in the Scopus, ISI Web of Science and PubMed to find the related articles, up to June 2019. Meta-analysis was performed using the random effects model, and the I2 index was used to evaluate the heterogeneity. RESULTS: Eleven articles were eligible. Our meta-analysis indicated that green tea consumption significantly decreased body weight, body mass index (BMI), and body fat (BF). The beneficial effect of green tea intake was observed in long-term intervention (>8 weeks), at lower doses of green tea (dosage ≤800 mg/day), and in overweight patients. CONCLUSION: This study revealed the beneficial effects of green tea consumption in reducing body weight, BMI, and BF in T2DM patients. It should be noted that green tea was effective in long-term intervention, at lower doses of green tea, and in overweight patients.

The Effects of Vitamin C on the Multiple Pathophysiological Stages of COVID-19.

Currently available anti-viral drugs may be useful in reducing the viral load but are not providing the necessary physiological effects to reduce the SARS-CoV-2 complications efficiently. Treatments that provide better clinical outcomes are urgently needed. Vitamin C (ascorbic acid, AA) is an essential nutrient with many biological roles that have been proven to play an important part in immune function; it serves as an antioxidant, an anti-viral, and exerts anti-thrombotic effects among many other physiological benefits. Research has proven that AA at pharmacological doses can be beneficial to patients with acute respiratory distress syndrome (ARDS) and other respiratory illnesses, including sepsis. In addition, High-Dose Intravenous Vitamin C (HDIVC) has proven to be effective in patients with different viral diseases, such as influenza, chikungunya, Zika, and dengue. Moreover, HDIVC has been demonstrated to be very safe. Regarding COVID-19, vitamin C can suppress the cytokine storm, reduce thrombotic complications, and diminish alveolar and vascular damage, among other benefits. Due to these reasons, the use of HDIVC should be seriously considered in complicated COVID-19 patients. In this article, we will emphasize vitamin C's multiple roles in the most prominent pathophysiological processes presented by the COVID-19 disease.

Mitochondria, Energy and Cancer: The Relationship with Ascorbic Acid.

Ascorbic Acid (AA) has been used in the prevention and treatment of cancer with reported effectiveness. Mitochondria may be one of the principal targets of ascorbate's cellular activity and it may play an important role in the development and progression of cancer. Mitochondria, besides generating adenosine triphosphate (ATP), has a role in apoptosis regulation and in the production of regulatory oxidative species that may be relevant in gene expression. At higher concentrations AA may increase ATP production by increasing mitochondrial electron flux, also may induce apoptotic cell death in tumor cell lines, probably via its pro-oxidant action In contrast, at lower concentrations AA displays antioxidant properties that may prevent the activation of oxidant-induced apoptosis. These concentration dependent activities of ascorbate may explain in part the seemingly contradictory results that have been reported previously.