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Dissecting the interaction between COVID-19 and diabetes mellitus.
Chee, YJ, Tan, SK, Yeoh, E
Journal of diabetes investigation. 2020;11(5):1104-1114
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Several countries have reported higher death rates and more severe cases of covid-19 amongst individuals with chronic diseases such as type 2 diabetes. This review of 100 papers aimed to investigate the interconnecting factors which may contribute to poorer prognosis in individuals with covid-19 and type 2 diabetes. Although the evidence suggests that patients with type 2 diabetes have poorer outcomes after contracting covid-19, they are not more susceptible to infection. The paper reported that mechanisms which may increase severity in type 2 diabetics are abnormal immune function, increased susceptibility to inflammation, the increased adherence of the virus to target cells and reduced ability to fight infection. It is important to manage blood sugars when suffering from covid-19. The paper reviewed the use of several medications such as metformin, dipeptidyl peptidase-4 inhibitors (DPP4), glucagon-like peptide-1 agonists and insulin in the context of individuals suffering from covid-19, with insulin being the treatment of choice in the acutely ill patient. Current treatments of covid-19 were also reviewed such as chloroquine and hydroxychloroquine, Lopinavir-ritonavir, IL-6 receptor agonists, type 1 interferon and remdesivir. It was concluded that clinicians should be aware of the risks in patients with type 2 diabetes and covid-19. However as new data is made available, the chronic and long-term implications will become clearer. This study could be used by health care professionals to ensure that patients with type 2 diabetes do everything they can to avoid covid-19 infection and that if contracted these patients are closely monitored for severe disease.
Abstract
Coronavirus disease 2019 (COVID-19) is a global pandemic that is caused by a novel coronavirus, severe acute respiratory syndrome coronavirus-2. Data from several countries have shown higher morbidity and mortality among individuals with chronic metabolic diseases, such as diabetes mellitus. In this review, we explore the contributing factors for poorer prognosis in these individuals. As a significant proportion of patients with COVID-19 also have diabetes mellitus, this adds another layer of complexity to their management. We explore potential interactions between antidiabetic medications and renin-angiotensin-aldosterone system inhibitors with COVID-19. Suggested recommendations for the use of antidiabetic medications for COVID-19 patients with diabetes mellitus are provided. We also review pertinent clinical considerations in the management of diabetic ketoacidosis in COVID-19 patients. In addition, we aim to increase clinicians' awareness of the metabolic effects of promising drug therapies for COVID-19. Finally, we highlight the importance of timely vaccinations for patients with diabetes mellitus.
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The Long Haul of COVID-19 Recovery: Immune Rejuvenation versus Immune Support.
Bland, JS
Integrative medicine (Encinitas, Calif.). 2020;19(6):18-22
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Following Covid-19 infection, sufferers have reported various residual symptoms, which have been likened to those experienced by chronic fatigue sufferers and those with Gulf War syndrome. This review paper aimed to assess whether the body has a similar immune response to these diseases during Covid-19, and if so, what therapies could be used. It also reviewed any diet and lifestyle factors that may be affecting the immune response. The paper stated that Covid-19 infection is associated with inflammation, which can damage immune cells and inflammation prior to Covid-19 infection may contribute to severity of the infection. Prior research in seemingly healthy individuals indicates that environment, diet, and lifestyle factors can all contribute to differing “immune identities” and eliminating immune cells which carry the imprint of memories should be a therapy focus in Covid-19 patients. Fasting, diets low in refined sugars and high in omega-3 and plant chemicals were discussed as ways for the body to clear out immune cells. It was concluded that personalising therapy strategies based on an individual’s immune identity to reduce inflammation could ultimately support the immune system. This paper could be used by healthcare professionals to understand the importance of diet and lifestyle changes to reduce inflammation and support the immune system.
Abstract
With the COVID-19 pandemic still affecting communities all over the world and "Long Haul" chronic health issues emerging, it is time for us to look back at past multi-symptom health conditions that required a different approach to their treatment, beyond just managing symptoms. It is important for us to consider how to apply what we have learned about immune rejuvenation and its impact on conditions associated with chronic immune dysfunction. We know more than we ever have before about how to reduce chronic inflammation at its source through the support of selective immune cell autophagy/mitophagy and improved immune cell mitochondrial activity, followed by remodeling of the immune epigenome, and-ultimately-a reset of immune function.
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Vitamin B12 Status Upon Short-Term Intervention with a Vegan Diet-A Randomized Controlled Trial in Healthy Participants.
Lederer, AK, Hannibal, L, Hettich, M, Behringer, S, Spiekerkoetter, U, Steinborn, C, Gründemann, C, Zimmermann-Klemd, AM, Müller, A, Simmet, T, et al
Nutrients. 2019;11(11)
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Veganism is growing in western societies and with it comes an increased risk of vitamin B12 deficiency which is principally found in animal products. Vitamin B12 is essential for multiple biological functions including DNA synthesis, digestive function and detoxification processes. It can take 2-5 years to exhaust natural stores of B12 within the body so deficiency risk is considered safe. This 2017 randomised control trial compared vitamin B12 status in 53 healthy omnivore subjects with 26 participants following an unsupplemented vegan diet for 4 weeks and the remaining 27 participants a meat-rich diet. The aim of the study was to answer two questions; (a) Do vitamin B12 markers respond to short-term dietary intervention with a meat-rich or a plant-based diet? and (b) Do meat-rich and vegan diets have an impact on plasma markers of inflammation and cardiovascular disease? Blood and urine samples were taken before and after the 4-week dietary protocol to also measure vitamin D status, Folate and Homocysteine levels as a marker for inflammation. The serum vitamin B12 levels (indicative of dietary B12) dropped significantly from 362.9 +/- 110.9 ng/mL to 296.1 +/- 94.1 ng/mL in the Vegan Diet group (p < 0.001) and remained stable in the Meat Diet group. Other markers measuring cellular B12 metabolism did not significantly vary. The short-term nature of the trial demonstrated rapid decrease in holo-TC, the bioactive form of vitamin B12 in plasma. The other blood and urinary markers demonstrated benefits to plant-based eating including reduced cholesterol intake and adequate profiles of nutrient and micronutrient status.
Abstract
Vegans are at an increased risk for certain micronutrient deficiencies, foremost of vitamin B12. Little is known about the short-term effects of dietary change to plant-based nutrition on vitamin B12 metabolism. Systemic biomarkers of vitamin B12 status, namely, serum vitamin B12 and holotranscobalamin, may respond quickly to a reduced intake of vitamin B12. To test this hypothesis, 53 healthy omnivore subjects were randomized to a controlled unsupplemented vegan diet (VD, n = 26) or meat-rich diet (MD, n = 27) for 4 weeks. Vitamin B12 status was examined by measurement of serum vitamin B12, holotranscobalamin (holo-TC), methylmalonic acid (MMA) and total plasma homocysteine (tHcy). Holo-TC decreased significantly in the VD compared to the MD group after four weeks of intervention, whereas metabolites MMA and tHcy were unaffected. Body weight remained stable in both groups. VD intervention led to a significant reduction of cholesterol intake, and adequate profiles of nutrient and micronutrient status. Lower intake of vitamin B12 was observed in VD, which was mirrored by a lower concentration of serum vitamin B12 and reduced holo-TC after 4 weeks. Plasma holo-TC may be a fast-responding biomarker to monitor adequate supply of vitamin B12 in plant-based individuals.
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Sorting out the Value of Cruciferous Sprouts as Sources of Bioactive Compounds for Nutrition and Health.
Abellán, Á, Domínguez-Perles, R, Moreno, DA, García-Viguera, C
Nutrients. 2019;11(2)
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Vegetable sprouts are naturally rich in nutrients and other beneficial compounds. The sprouts of cruciferous vegetables, such as broccoli, kale, radish and pak choi, stand out due to their high contents of glucosinolates and phenolic compounds. The aim of this review was to compile and update the available knowledge on the production, nutritional composition, and health benefits of cruciferous sprouts. A number of studies have found that compounds found in cruciferous sprouts have anti-cancer, anti-inflammatory, and antioxidant capacities. Consumption of cruciferous sprouts contributes to healthy glucose, insulin and fat levels in the blood, and may be beneficial for the treatment of some metabolic disorders, such as type 2 diabetes. There is evidence that compounds in cruciferous sprouts are a useful tool for enhancing phase II enzymes in the liver, and benefit levels of interleukine-6, C-reactive protein, and tumour necrosis factor-α, and inhibition of NF-κB, among others. The active compounds in these sprouts have an influence on several cardiovascular processes, potentially reducing the risk of several diseases. The lack of consistency between studies with regard to sampling schedules, doses, sample size, etc. means that it is not possible at this time to state the effective dose of sprouts or their active compounds needed in order to achieve health benefits. Further research is needed in this area.
Abstract
Edible sprouts with germinating seeds of a few days of age are naturally rich in nutrients and other bioactive compounds. Among them, the cruciferous (Brassicaceae) sprouts stand out due to their high contents of glucosinolates (GLSs) and phenolic compounds. In order to obtain sprouts enriched in these phytochemicals, elicitation is being increasing used as a sustainable practice. Besides, the evidence regarding the bioavailability and the biological activity of these compounds after their dietary intake has also attracted growing interest in recent years, supporting the intake of the natural food instead of enriched ingredients or extracts. Also, there is a growing interest regarding their uses, consumption, and applications for health and wellbeing, in different industrial sectors. In this context, the present review aims to compile and update the available knowledge on the fundamental aspects of production, enrichment in composition, and the benefits upon consumption of diverse edible cruciferous sprouts, which are sources of phenolic compounds and glucosinolates, as well as the evidence on their biological actions in diverse pathophysiological situations and the molecular pathways involved.
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A Systematic Review of Organic Versus Conventional Food Consumption: Is There a Measurable Benefit on Human Health?
Vigar, V, Myers, S, Oliver, C, Arellano, J, Robinson, S, Leifert, C
Nutrients. 2019;12(1)
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The demand for organic products has risen rapidly over the last decades. The reasons why consumers may favour organic over conventional products are varied. They may be for personal health and wellbeing, environmental considerations, animal welfare or perceived higher nutritional profile - which is true for some, but not all components. While the long-term safety of pesticide consumption through conventional food production has been questioned, organic foods clearly show lower levels of toxic metabolites, like heavy metals and synthetic fertilizer and pesticide residues. This systematic review aimed to assess the current evidence of organic diet consumption and human health compared to conventionally produced foods. Included were 35 papers on clinical trials and observational studies. The clinical trials studied pesticide and phytochemical excretion, antioxidant capacity, body composition, lipids and inflammatory markers. The observational studies were focused on fertility, foetal and childhood development, pregnancy, lactation and levels of pesticides in children and adults, as well as nutritional biomarkers and cancer risk in adults. An increased intake of organic produce in long-term studies appeared to reduce the incidence of infertility, birth defects, allergies, middle ear infection, pre-eclampsia, metabolic syndrome, high BMI, and non-Hodgkin lymphoma. Organic intake was also linked to reduced urinary levels of organophosphorus pesticides and herbicides. Yet, the author highlighted that organic consumers are more likely to be health conscious, physically active, eat a more plant-based diet, have higher education levels and income, and therefore are not representative of the general population. They also argue that the possible benefits from an organic diet may be partially due to the quality and composition of the diet rather than a direct effect of organic food consumption. Whereby a growing number of findings demonstrate the health benefits of organic food consumption, according to the authors, the current evidence does not yield a solid and definitive answer.
Abstract
The current review aims to systematically assess the evidence related to human health outcomes when an organic diet is consumed in comparison to its conventional counterpart. Relevant databases were searched for articles published to January 2019. Clinical trials and observational research studies were included where they provided comparative results on direct or indirect health outcomes. Thirty-five papers met the criteria for inclusion in the review. Few clinical trials assessed direct improvements in health outcomes associated with organic food consumption; most assessed either differences in pesticide exposure or other indirect measures. Significant positive outcomes were seen in longitudinal studies where increased organic intake was associated with reduced incidence of infertility, birth defects, allergic sensitisation, otitis media, pre-eclampsia, metabolic syndrome, high BMI, and non-Hodgkin lymphoma. The current evidence base does not allow a definitive statement on the health benefits of organic dietary intake. However, a growing number of important findings are being reported from observational research linking demonstrable health benefits with organic food consumption. Future clinical research should focus on using long-term whole-diet substitution with certified organic interventions as this approach is more likely to determine whether or not true measurable health benefits exist.
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A Khorasan Wheat-Based Replacement Diet Improves Risk Profile of Patients With Nonalcoholic Fatty Liver Disease (NAFLD): A Randomized Clinical Trial.
Dinu, M, Whittaker, A, Pagliai, G, Giangrandi, I, Colombini, B, Gori, AM, Fiorillo, C, Becatti, M, Casini, A, Benedettelli, S, et al
Journal of the American College of Nutrition. 2018;37(6):508-514
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Non-alcoholic fatty liver disease (NAFLD) is prevalent, however early intervention with lifestyle modifications such as weight loss, dietary therapy and physical activity may reverse it. Previous studies have shown that the Mediterranean diet, which includes a large proportion of grains, may reduce NAFLD. However no prior studies have assessed grains in isolation on these individuals. This randomised double blind parallel arm study aimed to assess the effects of a replacement diet with ancient khorasan wheat products on patients with NAFLD. 40 people with mild- moderate NAFLD were assigned to either khorasan wheat diet or a modern wheat grain diet for three months. This comparatively small study found that a khorasan wheat based diet improved liver function and inflammation. However regardless of the diet, measures of oxidative stress, which assesses the imbalance of free radicals and antioxidants in the body, was significantly reduced and some individuals were shown to regress from moderate to mild NAFLD. Nutrition practitioners who have clients with mild-moderate NAFLD may recommend a khorasan wheat based diet in the short term to improve biochemical and inflammatory markers and to potentially reverse disease development.
Abstract
OBJECTIVE KAMUT khorasan is an ancient grain with widely acclaimed health benefits. The aim of this study was to investigate the effects of a replacement diet with ancient khorasan wheat products in patients with NAFLD, in comparison to a similar replacement diet with control products made from organic semi-whole-grain modern wheat. METHODS Forty NAFLD patients (12 M/28 F; age 55.2 ± 10.4 years) with mild to moderate liver steatosis were included. The experimental design was a randomized, double-blind, parallel-arm study with 20 participants assigned to consume either KAMUT khorasan or control wheat products (pasta, bread, crackers, biscuits) over a 3-month period. Anthropometric measurements, blood analyses, and ultrasonography examination were performed at both the beginning and end of each dietary intervention. RESULTS After the implementation of a general linear model for repeated measurements adjusted for baseline demographic details, risk factors, and medication, alanine aminotransferase (ALT) was significantly reduced by 12%, aspartate aminotransferase (AST) by 14%, alkaline phosphatase (ALP) by 8%, and cholesterol by 6% only in the khorasan group (p < 0.05 for all). Similarly, significant reductions in circulating proinflammatory tumor necrosis factor-alpha by 50%, interleukin l-receptor antagonist-alpha by 37%, interleukin-8 by 24%, and interferon gamma by 24% were evident only in participants who consumed the khorasan products (p < 0.05 for all). Finally, significant improvements in the liver steatosis grading, Doppler perfusion index values, and reactive oxygen species (ROS) production were evident after consumption of both the khorasan and control products. CONCLUSIONS This study suggests that a short-term replacement diet with ancient KAMUT khorasan products is most effective in reducing metabolic risk factors and ameliorating the liver profile in patients with NAFLD.
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Impact of Consuming Extra-Virgin Olive Oil or Nuts within a Mediterranean Diet on DNA Methylation in Peripheral White Blood Cells within the PREDIMED-Navarra Randomized Controlled Trial: A Role for Dietary Lipids.
Arpón, A, Milagro, FI, Razquin, C, Corella, D, Estruch, R, Fitó, M, Marti, A, Martínez-González, MA, Ros, E, Salas-Salvadó, J, et al
Nutrients. 2017;10(1)
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Our genes are not fixed. They interact constantly with the environment through dietary and lifestyle factors, which affect whether genes are expressed or not. This is often referred to as epigenetic modulation. DNA methylation is an epigenetic mechanism that adds a methyl group to DNA, thereby modifying the function of the genes and affecting gene expression. Epigenetic alterations have been associated with conditions, such as obesity, type 2 diabetes, cardiovascular disease and immunological conditions. It is suggested that epigenetic marks are reversible and can be modulated by nutrient status and certain dietary components. The aim of the current study was to explore methylation changes in genes of peripheral white blood cells in a subset of participants from the PREDIMED-Navarra randomised controlled trial. 36 participants were allocated to three groups, all consuming a Mediterranean diet. In the first group, the diet was supplemented with extra virgin olive oil (EVOO), in the second group, with mixed nuts, and the third group, which served as the control group, were advised to consume a low-fat diet. Changes in DNA methylation were analysed from blood samples at baseline and at five-year follow-up. The authors observed methylation changes in several genes, related to metabolism, glucose and energy regulation, diabetes and inflammation, after the consumption of EVOO and nuts. They concluded that the beneficial effects of Mediterranean diets that include EVOO and nuts, may, at least in part, be mediated via epigenetic mechanisms. As these foods are high in monounsaturated and polyunsaturated fats, the quality of fat may be playing an important role in this mediation.
Abstract
DNA methylation could be reversible and mouldable by environmental factors, such as dietary exposures. The objective was to analyse whether an intervention with two Mediterranean diets, one rich in extra-virgin olive oil (MedDiet + EVOO) and the other one in nuts (MedDiet + nuts), was influencing the methylation status of peripheral white blood cells (PWBCs) genes. A subset of 36 representative individuals were selected within the PREvención con DIeta MEDiterránea (PREDIMED-Navarra) trial, with three intervention groups in high cardiovascular risk volunteers: MedDiet + EVOO, MedDiet + nuts, and a low-fat control group. Methylation was assessed at baseline and at five-year follow-up. Ingenuity pathway analysis showed routes with differentially methylated CpG sites (CpGs) related to intermediate metabolism, diabetes, inflammation, and signal transduction. Two CpGs were specifically selected: cg01081346-CPT1B/CHKB-CPT1B and cg17071192-GNAS/GNASAS, being associated with intermediate metabolism. Furthermore, cg01081346 was associated with PUFAs intake, showing a role for specific fatty acids on epigenetic modulation. Specific components of MedDiet, particularly nuts and EVOO, were able to induce methylation changes in several PWBCs genes. These changes may have potential benefits in health; especially those changes in genes related to intermediate metabolism, diabetes, inflammation and signal transduction, which may contribute to explain the role of MedDiet and fat quality on health outcomes.
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Intake of red wine in different meals modulates oxidized LDL level, oxidative and inflammatory gene expression in healthy people: a randomized crossover trial.
Di Renzo, L, Carraro, A, Valente, R, Iacopino, L, Colica, C, De Lorenzo, A
Oxidative medicine and cellular longevity. 2014;2014:681318
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The traditional Mediterranean diet is known to reduce the risk of developing several chronic diseases including cardiovascular disease (CVD). The major underlying factors of CVD are oxidative stress and chronic inflammation, and oxidised low-density lipoprotein (ox-LDL) particles have been associated with increased CVD risk. The aim of this crossover trial was to evaluate the impact of various meal combinations on ox-LDL status and genetic expression of oxidative stress and inflammation. A total of 24 participants were analysed after consumption of four different meal combinations with washout periods in between: Mediterranean meal, McDonald’s meal, both with and without red wine. The findings of this study showed a significant reduction of ox-LDL depending on the quality of meal consumed, and found red wine to have a protective effect. The results of this study indicate that the antioxidant potential of nutrients found in the Mediterranean diet and red wine may be important for reducing inflammation and oxidative stress in chronic disease.
Abstract
Several studies have found that adherence to the Mediterranean Diet, including consumption of red wine, is associated with beneficial effects on oxidative and inflammatory conditions. We evaluate the outcome of consumption of a McDonald's Meal (McD) and a Mediterranean Meal (MM), with and without the additive effect of red wine, in order to ascertain whether the addition of the latter has a positive impact on oxidized (ox-) LDL and on expression of oxidative and inflammatory genes. A total of 24 subjects were analyzed for ox-LDL, CAT, GPX1, SOD2, SIRT2, and CCL5 gene expression levels, before and after consumption of the 4 different meal combinations with washout intervals between each meal. When red wine is associated with McD or MM, values of ox-LDL are lowered (P < 0.05) and expression of antioxidant genes is increased, while CCL5 expression is decreased (P < 0.05). SIRT2 expression after MM and fasting with red wine is significantly correlated with downregulation of CCL5 and upregulation of CAT (P < 0.001). GPX1 increased significantly in the comparison between baseline and all conditions with red wine. We highlighted for the first time the positive effect of red wine intake combined with different but widely consumed meal types on ox-LDL and gene expression. Trial Registration. This trial is registered with ClinicalTrials.gov NCT01890070.
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Silymarin in the prevention and treatment of liver diseases and primary liver cancer.
Féher, J, Lengyel, G
Current pharmaceutical biotechnology. 2012;13(1):210-7
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Non-alcoholic fatty liver disease (NAFLD) is a recognised health problem with no convincing interventions to date. This randomised trial aimed to examine the efficacy of silymarin plus vitamin E in the treatment of NAFLD. 36 patients were randomized to either group Ι or group ΙΙ. Group Ι was treated with 2 tablets of silymarin plus vitamin E per day, hypocaloric diet and exercise. Group ΙΙ was treated only with a hypocaloric diet. Study duration was 3 months for both groups. Diagnosis of NAFLD was confirmed for all participants by liver biopsy. Patients in group Ι showed significant decrease in anthropometric measurements. Both groups experienced reductions in markers of NAFLD, however in group I, these reductions were independent of weight loss, whereas in group II, those who failed to lose 5% of body weight didn’t show a change in biochemical markers. Authors conclude that intervention with silymarin plus vitamin E, alone or along with other treatments, can help NAFLD patients who fail to lose weight with diet.
Abstract
In chronic liver diseases caused by oxidative stress (alcoholic and non-alcoholic fatty liver diseases, drug- and chemical-induced hepatic toxicity), the antioxidant medicines such as silymarin can have beneficial effect. Liver cirrhosis, non-alcoholic fatty liver and steatohepatitis are risk factors for hepatocellular carcinoma (HCC). Insulin resistance and oxidative stress are the major pathogenetic mechanisms leading the hepatic cell injury in these patients. The silymarin exerts membrane-stabilizing and antioxidant activity, it promotes hepatocyte regeneration; furthermore it reduces the inflammatory reaction, and inhibits the fibrogenesis in the liver. These results have been established by experimental and clinical trials. According to open studies the long-term administration of silymarin significantly increased survival time of patients with alcohol induced liver cirrhosis. Based on the results of studies using methods of molecular biology, silymarin can significantly reduce tumor cell proliferation, angiogenesis as well as insulin resistance. Furthermore, it exerts an anti-atherosclerotic effect, and suppresses tumor necrosis factor-alpha-induced protein production and mRNA expression due to adhesion molecules. The chemopreventive effect of silymarin on HCC has been established in several studies using in vitro and in vivo methods; it can exert a beneficial effect on the balance of cell survival and apoptosis by interfering cytokines. In addition to this, anti-inflammatory activity and inhibitory effect of silymarin on the development of metastases have also been detected. In some neoplastic diseases silymarin can be administered as adjuvant therapy as well.
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Partial purification and characterization of extrinsic pathway inhibitor (the factor Xa-dependent plasma inhibitor of factor VIIa/tissue factor).
Warn-Cramer, BJ, Maki, SL, Zivelin, A, Rapaport, SI
Thrombosis research. 1987;48(1):11-22
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Green tea (GT) consumption has been associated with the prevention and control of type 2 diabetes, cardiovascular and metabolic disease as well as having a positive effect on body weight and composition. However, the polyphenols in GT have been shown to interact with mineral distribution within the body and those minerals have been shown to be deficient in obesity. Studies to measure mineral status in obese subjects supplementing with GT have been inconclusive and this study aimed to measure the serum concentrations of minerals (calcium, copper, iron, zinc, magnesium), body mass index, total antioxidant status (TAS), lipid profile and glucose concentration. 46 obese patients were randomised into 2 groups, one group were supplemented with 279mg of green tea extract (GTE) and 208mg of the polyphenol epigallocatechin-3-gallate (EGCG) and the other group were issued with a placebo for 3 months. The study concluded that GTE improved Zn and Mg, however decreased levels of FE. The results confirmed a positive effect on body mass, lipid profile, glucose and TAS. It was concluded that more studies are required on a larger population over a longer period of time.
Abstract
We report a procedure to purify partially from plasma (approximately 1200 fold) the factor Xa-dependent inhibitor of factor VIIa/tissue factor (i.e., the extrinsic pathway inhibitor or EPI) and describe some of its properties. An assay for EPI was developed based upon inhibition of factor VIIa/tissue factor induced release of activation peptide from tritiated factor IX by a test sample in the presence but not in the absence of factor Xa. Approximately 50% of the total EPI activity in plasma was found in the lipoprotein fraction, which was used as the starting material for purification. Total lipoproteins (isolated by density ultracentrifugation) were delipidated and the urea soluble apoproteins gel filtered on Sephacryl S-200. The inhibitory activity co-eluted with the major protein peak, which primarily contained apoprotein A-I. Inhibitory activity was separated from apoprotein A-I by anion-exchange chromatography on Q-Sepharose and was further resolved from higher and lower molecular weight contaminating proteins by polypreparative disc gel electrophoresis in the presence of 0.1% SDS. Functional inhibitory activity eluted from the polypreparative disc gel in two discrete pools of different molecular weights (approximately 34,000 and approximately 43,000 D). Apoprotein E was identified by immunological techniques as the major protein present in both of these pools. However, incubation with a monospecific polyclonal antibody to human apoprotein E did not decrease EPI activity either in plasma or in the partially purified polypreparative disc gel fractions. A rabbit antiserum was prepared against material from the polypreparative disc gel. The IgG fraction neutralized approximately 95% of the total inhibitory activity present in plasma. Therefore, EPI in the lipoprotein fraction and in the non-lipoprotein fraction of plasma appears to be antigenically similar.