Factors Affecting the Vitamin C Dose-Concentration Relationship: Implications for Global Vitamin C Dietary Recommendations.

Vitamin C status is known to be associated with several demographic and lifestyle factors. These include gender, age, ethnicity, pregnancy/lactation, body weight, smoking status and dietary habits. In the present study, our aim was to investigate the National Health and Nutrition Examination Survey (NHANES) 2017-2018 datasets to assess the impact of these factors on vitamin C dose-concentration relationships to establish if there are higher requirements for vitamin C in certain subpopulations, and the possible extent of these additional requirements. The final cohort comprised 2828 non-supplementing adult males and females (aged 18-80+ years) with both vitamin C serum concentrations and dietary intake data available. The data were subsequently stratified by gender, age tertiles (≤36, 37-58, ≥59 years), ethnicity (non-Hispanic white, non-Hispanic black, and total Hispanic), socioeconomic tertiles (poverty income ratios: ≤1.35, 1.36-3.0, >3.0), weight tertiles (<72, 72-91, >91 kg), BMI tertiles (<26, 26-32, >32 kg/m2) and smoking status. Sigmoidal (four parameter logistic) curves with asymmetrical 95% confidence intervals were fitted to the dose-concentration data. We found that males required vitamin C intakes ~1.2-fold higher than females to reach 'adequate' serum vitamin C concentrations of 50 µmol/L. Males had both higher body weight and a higher prevalence of smoking than females. Smokers required vitamin C intakes ~2.0-fold higher than non-smokers to reach adequate vitamin C concentrations. Relative to adults in the lighter weight tertile, adults in the heavier weight tertile required ~2.0-fold higher dietary intakes of vitamin C to reach adequate serum concentrations. We did not observe any impact of ethnicity or socioeconomic status on the vitamin C dose-concentration relationship, and although no significant difference between younger and older adults was observed at vitamin C intakes > 75 mg/day, at intakes < 75 mg/day, older adults had an attenuated serum response to vitamin C intake. In conclusion, certain demographic and lifestyle factors, specifically gender, smoking and body weight, have a significant impact on vitamin C requirements. Overall, the data indicate that the general population should consume ~110 mg/day of vitamin C to attain adequate serum concentrations, smokers require ~165 mg/day relative to non-smokers, and heavier people (100+ kg) require ~155 mg/day to reach comparable vitamin C concentrations. These findings have important implications for global vitamin C dietary recommendations.

Does Aging Affect Vitamin C Status Relative to Intake? Findings from NHANES 2017-2018.

The aging population is growing and fueling a global increase in chronic diseases and healthcare expenditure. In this study, we examine vitamin C dose-concentration relationships based on data from the National Health and Nutrition Examination Survey (NHANES) 2017-2018 to identify a possible age-dependent change in intake vs. concentration relationship among non-supplemented individuals (n = 2828). The vitamin C intake was similar between the younger (18-36 years), middle (37-58 years) and older (59-80+ years) age groups; however, circulating vitamin C concentrations were significantly lower in the middle and older age groups (p < 0.001). For intakes above 75 mg/day, no significant difference in the intake vs. serum concentration relationship was identified between younger and older individuals. However, for intakes below 75 mg/day, we found significantly lower serum concentrations relative to intake for the older compared to younger individuals, despite smoking being more prevalent in the younger compared to older adults (p < 0.001). This effect persisted among non-smokers and was further exacerbated by smoking in older people. Collectively, the present study suggests that healthy aging in non-institutionalized individuals does not increase requirements for vitamin C. In contrast, the lower serum concentrations relative to intake observed in older individuals at intakes < 75 mg/day may suggest that older individuals are more sensitive to a low vitamin C intake, perhaps due to the increased impact of long-term smoking and increased chronic disease prevalence in older adults. This finding may have implications for future intake guidelines in countries with low RDAs and for WHO/FAO, but requires further investigation.

Differential Effects of Dietary Components on Glucose Intolerance and Non-Alcoholic Steatohepatitis.

Pharmacological treatment modalities for non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) are scarce, and discoveries are challenged by lack of predictive animal models adequately reflecting severe human disease stages and co-morbidities such as obesity and type 2 diabetes. To mimic human NAFLD/NASH etiology, many preclinical models rely on specific dietary components, though metabolism may differ considerably between species, potentially affecting outcomes and limiting comparability between studies. Consequently, understanding the physiological effects of dietary components is critical for high translational validity. This study investigated the effects of high fat, cholesterol, and carbohydrate sources on NASH development and metabolic outcomes in guinea pigs. Diet groups (n = 8/group) included: low-fat low-starch (LF-LSt), low-fat high-starch (LF-HSt), high-fat (HF) or HF with 4.2%, or 8.4% sugar water supplementation. The results showed that caloric compensation in HF animals supplied with sugar water led to reduced feed intake and a milder NASH phenotype compared to HF. The HF group displayed advanced NASH, weight gain and glucose intolerance compared to LF-LSt animals, but not LF-HSt, indicating an undesirable effect of starch in the control diet. Our findings support the HF guinea pig as a model of advanced NASH and highlights the importance in considering carbohydrate sources in preclinical studies of NAFLD.

The role of vitamin C in epigenetic cancer therapy.

The role of vitamin C in the treatment of cancer has been subject to controversy for decades. Within the past 10 years, mechanistic insight into the importance of vitamin C in epigenetic regulation has provided a new rationale for its potential anti-cancer effects. At physiological concentrations, vitamin C is a potent antioxidant and thereby co-factor for a range of enzymes including the Fe(II)- and α-ketoglutarate-dependent dioxygenases that represent some of the most important epigenetic regulators; the ten-eleven translocation (TET) methylcytosine dioxygenases and the Jumonji-C domain-containing histone demethylases. Epigenetic deregulation is a hallmark of many cancers and reduced activity of these enzymes or somatic loss-of-function mutations in the genes encoding them, are observed in many cancer types. The present review outlines the growing literature on the role of vitamin C in epigenetic therapy of cancer. In the vast majority of in vitro, animal and clinical studies included in this review, vitamin C showed ability across cancer types to increase the hydroxylation of 5-methylcytosine to 5-hydroxymethylcytosine catalyzed by the TET enzymes - the first step in DNA demethylation. Most consistently, vitamin C in combination with the class of epigenetic drugs, DNA methyltransferase inhibitors, has demonstrated efficacy in the treatment of hematological malignancies in both preclinical and the limited number of available clinical studies. Yet, the pertinent question of what is the optimal dose of vitamin C in cancer studies remains to be answered. High-quality randomized placebo-controlled trials are needed to determine whether supplementation with vitamin C may benefit subgroups of patients with (pre-)cancer.

Vitamin C Deficiency May Delay Diet-Induced NASH Regression in the Guinea Pig.

Oxidative stress is directly linked to non-alcoholic fatty liver disease (NAFLD) and the progression to steaotohepatitis (NASH). Thus, a beneficial role of antioxidants in delaying disease progression and/or accelerating recovery may be expected, as corroborated by recommendations of, e.g., vitamin E supplementation to patients. This study investigated the effect of vitamin C deficiency-often resulting from poor diets low in fruits and vegetables and high in fat-combined with/without a change to a low fat diet on NAFLD/NASH phenotype and hepatic transcriptome in the guinea pig NASH model. Vitamin C deficiency per se did not accelerate disease induction. However, the results showed an effect of the diet change on the resolution of hepatic histopathological hallmarks (steatosis, inflammation, and ballooning) (p < 0.05 or less) and indicated a positive effect of a high vitamin C intake when combined with a low fat diet. Our data show that a diet change is important in NASH regression and suggest that a poor vitamin C status delays the reversion towards a healthy hepatic transcriptome and phenotype. In conclusion, the findings support a beneficial role of adequate vitamin C intake in the regression of NASH and may indicate that vitamin C supplementation in addition to lifestyle modifications could accelerate recovery in NASH patients with poor vitamin C status.

The effect of acetylsalicylic acid and pentoxifylline in guinea pigs with non-alcoholic steatohepatitis.

Therapeutic options are urgently needed for non-alcoholic fatty liver disease (NAFLD), but development is time-consuming and costly. In contrast, drug repurposing offers the advantages of re-applying compounds that are already approved, thereby reducing cost. Acetylsalicylic acid (ASA) and pentoxifylline (PTX) have shown promise for treatment of NAFLD, but have not yet been tested in combination. Guinea pigs were fed a high-fat diet for 16 weeks and then continued on the diet while being treated with ASA, PTX or ASA+PTX for 8 weeks. Chow-fed animals served as healthy controls. Guinea pigs were CT scanned before intervention start and at intervention end. Animals without steatosis (ie NAFLD) at week 16 were excluded from the data analysis. ASA and PTX alone or in combination did not improve hepatic steatosis, ballooning, inflammation or fibrosis nor did the treatments affect liver enzymes (aminotransferases and alkaline phosphatase) or circulating lipids. Liver triglyceride levels, relative liver weight and hepatic mRNA expression of monocyte chemoattractant protein 1, interleukin 8 and platelet-derived growth factor b were nominally decreased. Thus, in the current study, treatment with ASA and PTX alone or in combination for 8 weeks did not ameliorate NASH or hepatic fibrosis in guinea pigs.

Dietary Intervention Accelerates NASH Resolution Depending on Inflammatory Status with Minor Additive Effects on Hepatic Injury by Vitamin E Supplementation.

Despite the lack of effective pharmacotherapy against nonalcoholic steatohepatitis (NASH) and liver fibrosis, vitamin E (vitE) supplementation and lifestyle modifications are recommended for the management of NASH due to promising clinical results. We recently reported a positive effect of supplementation with 800 IU vitE and atorvastatin on NASH resolution in guinea pigs. In the present study, we investigated the effect of high-dose vitE therapy combined with dietary intervention against progressive NASH and advanced fibrosis in the guinea pig model. Sixty-six guinea pigs received either high-fat (HF) or standard guinea pig chow diet (Control) for 25 weeks. Prior to eight weeks of intervention, HF animals were allocated into groups; dietary intervention (Chow) or dietary intervention with 2000 IU/d vitE supplementation (CvitE). Both Chow and CvitE reduced dyslipidemia, hepatic lipid accumulation and liver weight (p < 0.05), while CvitE further decreased hepatocellular ballooning (p < 0.05). Subanalyses of individual responses within intervention groups showed significant correlation between the hepatic hallmarks of NASH and lipid accumulation vs. inflammatory state (p < 0.05). Collectively, our results indicate that individual differences in sensitivity towards intervention and inflammatory status determine the potential beneficial effect of dietary intervention and high-dose vitE supplementation. Moreover, the study suggests that inflammation is a primary target in NASH treatment.

Ascorbate maintains a low plasma oxygen level.

In human blood, oxygen is mainly transported by red blood cells. Accordingly, the dissolved oxygen level in plasma is expected to be limited, although it has not been quantified yet. Here, by developing dedicated methods and tools, we determined that human plasma pO2 = 8.4 mmHg (1.1% O2). Oxygen solubility in plasma was believed to be similar to water. Here we reveal that plasma has an additional ascorbate-dependent oxygen-reduction activity. Plasma experimental oxygenation oxidizes ascorbate (49.5 µM in fresh plasma vs < 2 µM in oxidized plasma) and abolishes this capacity, which is restored by ascorbate supplementation. We confirmed these results in vivo, showing that the plasma pO2 is significantly higher in ascorbate-deficient guinea pigs (Ascorbateplasma < 2 µM), compared to control (Ascorbateplasma > 15 µM). Plasma low oxygen level preserves the integrity of oxidation-sensitive components such as ubiquinol. Circulating leucocytes are well adapted to these conditions, since the abundance of their mitochondrial network is limited. These results shed a new light on the importance of oxygen exposure on leucocyte biological study, in regards with the reducing conditions they encounter in vivo; but also, on the manipulation of blood products to improve their integrity and potentially improve transfusions' efficacy.

On the effect of vitamin C intake on human health: How to (mis)interprete the clinical evidence.

For decades, the potential beneficial effect of vitamin C on human health-beyond that of preventing scurvy-has been subject of much controversy. Hundreds of articles have appeared either in support of increased vitamin C intake through diet or supplements or rejecting the hypothesis that increased intake of vitamin C or supplementation may influence morbidity and mortality. The chemistry and pharmacology of vitamin C is complex and has unfortunately rarely been taken into account when designing clinical studies testing its effect on human health. However, ignoring its chemical lability, dose-dependent absorption and elimination kinetics, distribution via active transport, or complex dose-concentration-response relationships inevitably leads to poor study designs, inadequate inclusion and exclusion criteria and misinterpretation of results. The present review outlines the differences in vitamin C pharmacokinetics compared to normal low molecular weight drugs, focusses on potential pitfalls in study design and data interpretation, and re-examines major clinical studies of vitamin C in light of these.

Hypophosphatemic Hypovitaminosis D Induces Osteomalacia in the Adult Female Rat.

Osteomalacia is a bone-demineralizing disease of adulthood, often caused by hypovitaminosis D. Current animal models of the disease mimic osteomalacia as a consequence of gastric bypass or toxic exposure to metals, but a relevant model of diet-induced osteomalacia is lacking. For that purpose, 7-month-old female Sprague Dawley rats were randomly assigned into 2 weight-stratified groups and maintained for 4 months on synthetic diets containing negligible or normal levels of vitamin D. The dietary regimen resulted in vitamin D deficiency as measured by 25-hydroxyvitamin D serum levels; however, hypovitaminosis D per se did not affect biomarkers of calcium metabolism and bone turnover, nor did it result in increased osteoid. Thus, vitamin D depletion through the diet was found to be insufficient to induce an osteomalacia-like phenotype in the adult rat. After 4 months, the phosphate content of the vitamin D-depleted diet had decreased to 0.16% (calcium:phosphorus ratio of 5.85), resulting in an osteomalacic-like condition (trabecular osteoid surface/bone surface constituted 33%; CI, 26-40). The diet change also affected both metabolic and bone turnover biomarkers, including significantly suppressing serum fibroblast growth factor 23. Furthermore, decreased dietary phosphate in a vitamin D-depleted diet led to microarchitectural changes of trabecular and cortical bone, lower bone mass density, lower bone mass content and decreased bone strength, all indicating reduced bone quality. Taken together, our results show that osteomalacia can be induced in the adult female rat by depleting vitamin D and lowering phosphate content in the diet.

Oral vitamin C supplementation to patients with myeloid cancer on azacitidine treatment: Normalization of plasma vitamin C induces epigenetic changes.

BACKGROUND: Patients with haematological malignancies are often vitamin C deficient, and vitamin C is essential for the TET-induced conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), the first step in active DNA demethylation. Here, we investigate whether oral vitamin C supplementation can correct vitamin C deficiency and affect the 5hmC/5mC ratio in patients with myeloid cancers treated with DNA methyltransferase inhibitors (DNMTis). RESULTS: We conducted a randomized, double-blinded, placebo-controlled pilot trial (NCT02877277) in Danish patients with myeloid cancers performed during 3 cycles of DNMTi-treatment (5-azacytidine, 100 mg/m2/d for 5 days in 28-day cycles) supplemented by oral dose of 500 mg vitamin C (n = 10) or placebo (n = 10) daily during the last 2 cycles. Fourteen patients (70%) were deficient in plasma vitamin C (< 23 µM) and four of the remaining six patients were taking vitamin supplements at inclusion. Global DNA methylation was significantly higher in patients with severe vitamin C deficiency (< 11.4 µM; 4.997 vs 4.656% 5mC relative to deoxyguanosine, 95% CI [0.126, 0.556], P = 0.004). Oral supplementation restored plasma vitamin C levels to the normal range in all patients in the vitamin C arm (mean increase 34.85 ± 7.94 µM, P = 0.0004). We show for the first time that global 5hmC/5mC levels were significantly increased in mononuclear myeloid cells from patients receiving oral vitamin C compared to placebo (0.037% vs - 0.029%, 95% CI [- 0.129, - 0.003], P = 0.041). CONCLUSIONS: Normalization of plasma vitamin C by oral supplementation leads to an increase in the 5hmC/5mC ratio compared to placebo-treated patients and may enhance the biological effects of DNMTis. The clinical efficacy of oral vitamin C supplementation to DNMTis should be investigated in a large randomized, placebo-controlled clinical trial. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02877277 . Registered on 9 August 2016, retrospectively registered.

Antioxidant supplementation for lung disease in cystic fibrosis.

BACKGROUND: Airway infection leads to progressive damage of the lungs in cystic fibrosis (CF) and oxidative stress has been implicated in the etiology. Supplementation of antioxidant micronutrients (vitamin E, vitamin C, beta-carotene and selenium) or N-acetylcysteine (NAC) as a source of glutathione, may therefore potentially help maintain an oxidant-antioxidant balance. Glutathione or NAC can also be inhaled and if administered in this way can also have a mucolytic effect besides the antioxidant effect. Current literature suggests a relationship between oxidative status and lung function. This is an update of a previously published review. OBJECTIVES: To synthesise existing knowledge on the effect of antioxidants such as vitamin C, vitamin E, beta-carotene, selenium and glutathione (or NAC as precursor of glutathione) on lung function through inflammatory and oxidative stress markers in people with CF. SEARCH METHODS: The Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register and PubMed were searched using detailed search strategies. We contacted authors of included studies and checked reference lists of these studies for additional, potentially relevant studies. We also searched online trials registries.Last search of Cystic Fibrosis Trials Register: 08 January 2019. SELECTION CRITERIA: Randomised and quasi-randomised controlled studies comparing antioxidants as listed above (individually or in combination) in more than a single administration to placebo or standard care in people with CF. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies, extracted data and assessed the risk of bias in the included studies. We contacted study investigators to obtain missing information. If meta-analysed, studies were subgrouped according to supplement, method of administration and the duration of supplementation. We assessed the quality of the evidence using GRADE. MAIN RESULTS: One quasi-randomised and 19 randomised controlled studies (924 children and adults) were included; 16 studies (n = 639) analysed oral antioxidant supplementation and four analysed inhaled supplements (n = 285). Only one of the 20 included studies was judged to be free of bias.Oral supplements versus controlThe change from baseline in forced expiratory volume in one second (FEV1) % predicted at three months and six months was only reported for the comparison of NAC to control. Four studies (125 participants) reported at three months; we are uncertain whether NAC improved FEV1 % predicted as the quality of the evidence was very low, mean difference (MD) 2.83% (95% confidence interval (CI) -2.16 to 7.83). However, at six months two studies (109 participants) showed that NAC probably increased FEV1 % predicted from baseline (moderate-quality evidence), MD 4.38% (95% CI 0.89 to 7.87). A study of a combined vitamin and selenium supplement (46 participants) reported a greater change from baseline in FEV1 % predicted in the control group at two months, MD -4.30% (95% CI -5.64 to -2.96). One study (61 participants) found that NAC probably makes little or no difference in the change from baseline in quality of life (QoL) at six months (moderate-quality evidence), standardised mean difference (SMD) -0.03 (95% CI -0.53 to 0.47), but the two-month combined vitamin and selenium study reported a small difference in QoL in favour of the control group, SMD -0.66 (95% CI -1.26 to -0.07). The NAC study reported on the change from baseline in body mass index (BMI) (62 participants) and similarly found that NAC probably made no difference between groups (moderate-quality evidence). One study (69 participants) found that a mixed vitamin and mineral supplement may lead to a slightly lower risk of pulmonary exacerbation at six months than a multivitamin supplement (low-quality evidence). Nine studies (366 participants) provided information on adverse events, but did not find any clear and consistent evidence of differences between treatment or control groups with the quality of the evidence ranging from low to moderate. Studies of ß-carotene and vitamin E consistently reported greater plasma levels of the respective antioxidants.Inhaled supplements versus controlTwo studies (258 participants) showed inhaled glutathione probably improves FEV1 % predicted at three months, MD 3.50% (95% CI 1.38 to 5.62), but not at six months compared to placebo, MD 2.30% (95% CI -0.12 to 4.71) (moderate-quality evidence). The same studies additionally reported an improvement in FEV1 L in the treated group compared to placebo at both three and six months. One study (153 participants) reported inhaled glutathione probably made little or no difference to the change in QoL from baseline, MD 0.80 (95% CI -1.63 to 3.23) (moderate-quality evidence). No study reported on the change from baseline in BMI at six months, but one study (16 participants) reported at two months and a further study (105 participants) at 12 months; neither study found any difference at either time point. One study (153 participants) reported no difference in the time to the first pulmonary exacerbation at six months. Two studies (223 participants) reported treatment may make little or no difference in adverse events (low-quality evidence), a further study (153 participants) reported that the number of serious adverse events were similar across groups. AUTHORS' CONCLUSIONS: With regards to micronutrients, there does not appear to be a positive treatment effect of antioxidant micronutrients on clinical end-points; however, oral supplementation with glutathione showed some benefit to lung function and nutritional status. Based on the available evidence, inhaled and oral glutathione appear to improve lung function, while oral administration decreases oxidative stress; however, due to the very intensive antibiotic treatment and other concurrent treatments that people with CF take, the beneficial effect of antioxidants remains difficult to assess in those with chronic infection without a very large population sample and a long-term study period. Further studies, especially in very young children, using outcome measures such as lung clearance index and the bronchiectasis scores derived from chest scans, with improved focus on study design variables (such as dose levels and timing), and elucidating clear biological pathways by which oxidative stress is involved in CF, are necessary before a firm conclusion regarding effects of antioxidants supplementation can be drawn. The benefit of antioxidants in people with CF who receive CFTR modulators therapies should also be assessed in the future.

Glycemic Control during Pregnancy-A Predictor of Vitamin C Status at Labor in Type 1 Diabetic Women?

Several experimental studies have suggested that vitamin C (vitC) deficiency during pregnancy may be detrimental to fetal development, and observational studies have shown that vitC status is lower during pregnancy and in people with diabetes. A cross-sectional study in pregnant type 1 diabetic women found that poor maternal vitC status was a significant predictor for obstetric complications of pregnancy when measured within four weeks before labor. The plasma vitC concentration was significantly negatively correlated to HbA1c, the biomarker of glycemic control well-known to be associated with the outcome of the diabetic pregnancy. Here, we evaluated HbA1c during pregnancy in relation to the measured vitC levels in late pregnancy based on data from 46 women from the same cohort. Regression analysis showed that HbA1c of first trimester, the combined mean HbA1c of first and second trimester, mean HbA1c of the whole pregnancy (first, second and third trimester combined), and HbA1c of third trimester alone were all associated with vitC in late pregnancy (p = 0.03, n = 45; p = 0.034, n = 43; p = 0.017, n = 42; and p = 0.008, n = 46, respectively). In third trimester, when adjusted for creatinine clearance, the association between vitC and HbA1c persisted (p = 0.029). Women in third trimester with HbA1c above 7.0% had an increased risk of having poor vitC status compared to women with HbA1c below this level (11 out of 21 vs. 2 out of 25 women, p < 0.001). The results suggest that high HbA1c is associated with poor maternal vitC status and potentially inadequate supply of vitC for the neonate. HbA1c may thus be a relevant substitute biomarker for identifying pregnant women who might benefit from vitC supplementation.

Long term Westernized diet leads to region-specific changes in brain signaling mechanisms.

Western diets, high in fat and energy, are associated with cognitive deficits in humans and animal models, but the underlying mechanisms are not fully elucidated. This includes whether diet-induced dyslipidemia per se negatively impacts brain signaling. Here we investigate the effects of dyslipidemia induced by two high fat diets with or without high sucrose on hippocampal and frontal cortical oxidative stress, brain-derived neurotrophic factor (BDNF) and down-stream markers of synaptic plasticity, as well as alterations in monoaminergic neurotransmitter levels. A high fat diet was associated with decreased antioxidant status (vitamin C), increased serotonin in the frontal cortex, and increased ratio of phosphorylated Ca2+/calmodulin-dependent protein kinase II in the hippocampus, while a high fat and sucrose diet decreased levels of vitamin C in the frontal cortex and BDNF in the hippocampus. Markers of dyslipidemia correlated significantly with cerebral vitamin C levels, monoaminergic neurotransmitters and metabolites in the frontal cortex, but not in the hippocampus. Thus, a high fat diet caused regional alterations in antioxidant levels, neurochemistry and molecular markers in the non-obese dyslipidemic guinea pig.

Biochemical and cognitive effects of docosahexaenoic acid differ in a developmental and SorLA dependent manner.

Beneficial effects of omega-3 fatty acid intake on cognition are under debate as some studies show beneficial effects while others show no effects of omega-3 supplementation. These inconsistencies may be a result of inter-individual response variations, potentially caused by gene and diet interactions. SorLA is a multifunctional receptor involved in ligand trafficking including lipoprotein lipase and amyloid precursor protein. Decreased SorLA levels have been correlated to Alzheimer's disease, and omega-3 fatty acid supplementation is known to increase SorLA expression in neuronal cell lines and mouse models. We therefore addressed potential correlations between Sorl1 and dietary omega-3 in SorLA deficient mice (Sorl1-/-) and controls exposed to diets supplemented with or deprived of omega-3 during their entire development and lifespan (lifelong) or solely from the time of weaning (post weaning). Observed diet-induced effects were only evident when exposed to lifelong omega-3 supplementation or deprivation as opposed to post weaning exposure only. Lifelong exposure to omega-3 supplementation resulted in impaired spatial learning in Sorl1-/- mice. The vitamin C antioxidant capacity in the brains of Sorl1-/- mice was reduced, but reduced glutathione and vitamin E levels were increased, leaving the overall antioxidant capacity of the brain inconclusive. No gross morphological differences of hippocampal neurons were found to account for the altered behavior. We found a significant adverse effect in cognitive performance by combining SorLA deficiency with lifelong exposure to omega-3. Our results stress the need for investigations of the underlying molecular mechanisms to clarify the precise circumstances under which omega-3 supplementation may be beneficial.

Weekly ascorbic acid infusion in castration-resistant prostate cancer patients: a single-arm phase II trial.

BACKGROUND: Ascorbic acid (AA) has in vivo cytotoxic properties at concentrations that can only be achieved through intravenous (IV) administration in humans. Treatment with intravenous AA is widely and increasingly used in complementary medicine despite a lack of clinical evidence for the efficacy of this treatment. METHODS: This non-comparative, single-center, phase II trial included patients with chemotherapy-naïve, metastatic castration-resistant prostate cancer (mCRPC) from an outpatient clinic to evaluate the efficacy and safety of IV AA therapy. Patients received weekly infusions of AA (week 1, 5 g; week 2, 30 g; and weeks 3-12, 60 g) followed by efficacy evaluation at 12 weeks. The primary endpoint for efficacy was a 50% reduction in the prostate-specific antigen (PSA) level. The secondary endpoints included changes in health-related quality of life (HRQoL), biomarkers of bone metabolism, inflammation and bone scans. Clinicaltrials.gov identifier: NCT01080352. RESULTS: Twenty-three patients were enrolled in this study, and 20 completed the efficacy evaluation at 12 weeks. The mean baseline PSA level was 43 µg/L. No patient achieved a 50% PSA reduction; instead, a median increase in PSA of 17 µg/L was recorded at week 12. Among the secondary endpoints, no signs of disease remission were observed. In total, 53 adverse events (AEs) were recorded. Eleven were graded as "serious". Three AEs were directly related to AA, and all of which were related to fluid load. CONCLUSIONS: Infusion with 60 g of AA did not result in disease remission. This study does not support the use of intravenous AA outside clinical trials.

Does Glucagon-like Peptide-1 Ameliorate Oxidative Stress in Diabetes? Evidence Based on Experimental and Clinical Studies.

Glucagon-like peptide-1 (GLP-1) has shown to influence the oxidative stress status in a number of in vitro, in vivo and clinical studies. Well-known effects of GLP-1 including better glycemic control, decreased food intake, increased insulin release and increased insulin sensitivity may indirectly contribute to this phenomenon, but glucose-independent effects on ROS level, production and antioxidant capacity have been suggested to also play a role. The potential 'antioxidant' activity of GLP-1 along with other proposed glucose-independent modes of action related to ameliorating redox imbalance remains a controversial topic but could hold a therapeutic potential against micro- and macrovascular diabetic complications. This review discusses the presently available knowledge from experimental and clinical studies on the effects of GLP-1 on oxidative stress in diabetes and diabetes-related complications.

L-dehydroascorbic acid can substitute l-ascorbic acid as dietary vitamin C source in guinea pigs.

Vitamin C deficiency globally affects several hundred million people and has been associated with increased morbidity and mortality in numerous studies. In this study, bioavailability of the oxidized form of vitamin C (l-dehydroascorbic acid or DHA)-commonly found in vitamin C containing food products prone to oxidation-was studied. Our aim was to compare tissue accumulation of vitamin C in guinea pigs receiving different oral doses of either ascorbate or DHA. In all tissues tested (plasma, liver, spleen, lung, adrenal glands, kidney, muscle, heart, and brain), only sporadic differences in vitamin C accumulation from ascorbate or DHA were observed except for the lowest dose of DHA (0.25mg/ml in the drinking water), where approximately half of the tissues had slightly yet significantly less vitamin C accumulation than from the ascorbate source. As these results contradicted data from rats, we continued to explore the ability to recycle DHA in blood, liver and intestine in guinea pigs, rats and mice. These investigations revealed that guinea pigs have similar recycling capacity in red blood cells as observed in humans, while rats and mice do not have near the same ability to reduce DHA in erythrocytes. In liver and intestinal homogenates, guinea pigs also showed a significantly higher ability to recycle DHA compared to rats and mice. These data demonstrate that DHA in guinea pigs-as in humans-is almost as effective as ascorbate as vitamin C source when it comes to taking up and storing vitamin C and further suggest that the guinea pig is superior to other rodents in modeling human vitamin C homeostasis.

Distribution of vitamin C is tissue specific with early saturation of the brain and adrenal glands following differential oral dose regimens in guinea pigs.

Vitamin C (VitC) deficiency is surprisingly common in humans even in developed parts of the world. The micronutrient has several established functions in the brain; however, the consequences of its deficiency are not well characterised. To elucidate the effects of VitC deficiency on the brain, increased knowledge about the distribution of VitC to the brain and within different brain regions after varying dietary concentrations is needed. In the present study, guinea pigs (like humans lacking the ability to synthesise VitC) were randomly divided into six groups (n 10) that received different concentrations of VitC ranging from 100 to 1500 mg/kg feed for 8 weeks, after which VitC concentrations in biological fluids and tissues were measured using HPLC. The distribution of VitC was found to be dynamic and dependent on dietary availability. Brain saturation was region specific, occurred at low dietary doses, and the dose-concentration relationship could be approximated with a three-parameter Hill equation. The correlation between plasma and brain concentrations of VitC was moderate compared with other organs, and during non-scorbutic VitC deficiency, the brain was able to maintain concentrations from about one-quarter to half of sufficient levels depending on the region, whereas concentrations in other tissues decreased to one-sixth or less. The adrenal glands have similar characteristics to the brain. The observed distribution kinetics with a low dietary dose needed for saturation and exceptional retention ability suggest that the brain and adrenal glands are high priority tissues with regard to the distribution of VitC.