Low-dose Supplementation Research Articles

Analytical strategy for the detection of ecdysterone and its metabolites in vivo in uPA(+/+)‐SCID mice with humanized liver, human urine samples, and estimation of prevalence of its use in anti‐doping samples

Ecdysteroids are of interest as potential sport performance enhancers, due to their anabolic effects. The current study aimed to analyze levels of the most abundant ecdysteroid, ecdysterone (20‐hydroxyecdysone, 20‐OHE) in easily available dietary supplements, and, outline an analytical strategy for its detection, and that, of its metabolites, (1) following administration of pure 20‐OHE to uPA(+/+)‐SCID mice with humanized liver, (2) in a human volunteer after ingestion of two supplements, one with a relatively low, and the other a high, concentration of 20‐OHE, and, (3) to estimate the prevalence of use of 20‐OHE in elite athletes (n = 1000). Of the 16 supplements tested, only five showed detectable levels of 20‐OHE, with concentrations ranging from undetectable up to 2.3 mg per capsule. Urine of uPA(+/+)‐SCID urine showed the presence of 20‐OHE and its metabolite, 14 deoxy ecdysterone, within 24 hours (hr) of ingestion. In humans, both the parent and the metabolite were detectable within 2 to 5 hr of ingestion, with the metabolite being detectable for longer than the parent. After ingestion of a low dose supplement, the parent and metabolite were detectable for 70 and 48 hr, while following the higher dose it was 96 and 48 hr, respectively. Analysis of urines from athletes (n = 1000) confirmed four positives for 20‐OHE, suggesting a prevalence of use of 0.4%. Prevalence of its use by elite athletes was relatively low, however, this needs to be confirmed in other populations, and with other related ecdysteroids.

Low‐dose lithium supplementation augments mitochondrial biogenesis in murine skeletal muscle after high fat feeding

Promotion of oxidative metabolism in skeletal muscle improves muscle performance, fatigue resistance, and may help combat the obesogenic effects of a high fat diet. Lithium is a well-known glycogen synthase kinase (GSK3) inhibitor and we have recently shown that low-dose lithium supplementation (10 mg kg-1 day-1) augments skeletal muscle oxidative capacity in mice. In the soleus muscle, lithium mediated GSK3 inhibition increased the expression of oxidative markers such as peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1a) and myosin heavy chain I (MHCI) leading to improvements in muscle contractility and fatigue resistance. Interestingly, this same dose of lithium (10 mg kg-1 day-1) has been previously shown to attenuate high fat diet induced weight gain and metabolic efficiency (weight gained per calories consumed). However, the impact of lithium supplementation on muscle oxidative phenotype after high fat feeding has yet to be investigated. In this study, 36 wild-type male C57BL/6J mice were randomly assigned to low-fat standard chow diet (LFD, 4% kcal fat), high-fat diet (HFD, 60% kcal fat), or HFD with lithium chloride (HFD + Li; 10 mg kg-1 day-1) treatment groups for 12 weeks. Soleus muscles were collected at the end for Western blot analysis of total and phosphorylated GSK3 (inhibitory sites serine9 for GSK3b and serine21 for GSK3a), PGC-1a, cytochrome c oxidase subunit IV (COXIV), and MHCI protein content. Our results showed that the level of phosphorylated GSK3a and GSK3b (relative to total GSK3) were significantly lower after the HFD (-41 and -44%, respectively, p < 0.05), but in the HFD + Li group levels were similar to the LFD group. Therefore, the HFD enhanced soleus muscle GSK3 activation, and lithium supplementation was able to reduce this effect. No significant changes in MHCI content were observed. When examining PGC-1a, we found that the HFD + Li group had protein levels that were nearly 2-fold higher vs LFD, albeit only trending towards significance (p = 0.06). Further, COXIV content progressively increased from LFD, to HFD, and to HFD + Li (linear trend, r2=0.26, p = 0.002) with both HFD and HFD + Li groups having significantly higher COXIV content when compared to LFD. Altogether, our data shows that GSK3 inhibition via low dose lithium supplementation can augment mitochondrial biogenesis in the presence of a HFD. Future studies will further examine whether GSK3 inhibition via lithium can augment muscle oxidative metabolism after high fat feeding.

Broiler welfare is preserved by long-term low-dose oral exposure to zinc oxide nanoparticles: preliminary study

The potential public health risk through utilizing of zinc oxide nanoparticles (ZnO NPs) in food constitutes the major obstacle to the expansion of nanoparticle (NP) in food industry. Liver histology, bone marrow and liver genotoxicity, immunity, and oxidant status were investigated upon long-term ZnO NPs feed supplementation. One hundred and sixty male IR (Indian River) chicks were randomly allocated to one of the four dietary treatments: control, ZnO NPs at 10, 20, or 40 mg/kg for 42 days. This study revealed non-significant hepatic histopathological alterations and DNA damage and the treatment had no influence on body and organ weights, liver enzymes, lipid peroxidation (MDA), IgG, IgM, and interferon gamma (IFN-γ). This study suggests that low-dose (< 40 mg/kg diet) long-term ZnO NPs supplementation to broiler chicks has no observed potential adverse effects on normal histology of the liver, blood physiology, immune system, and DNA damage of liver and bone marrows, which are critical features for validating ZnO NPs for use in food. Further studies are required to evaluate the probable withdrawal period of ZnO NPs before approval as a dietary supplement in broiler or livestock diets.

Preventing Recurrent Preeclampsia by Tailored Treatment of Nonphysiologic Hemodynamic Adjustments to Pregnancy

Preeclampsia is often preceded by abnormal hemodynamic changes with heterogeneous patterns in the first half of pregnancy. We assessed the effect of timely tailored correction of nonphysiological hemodynamic changes on preventing preeclampsia in a high-risk population. Primiparous women with a history of preeclampsia were invited to participate in a longitudinal program in their next pregnancy, including repeated hemodynamic assessments at 12-, 16-, 20- and 30-week gestation additional to regular pregnancy checkups. When at least 2 of the hemodynamic variables were not within physiological reference values, the hemodynamic imbalance between cardiac output and peripheral vascular resistance was counteracted with either labetalol, methyldopa, or nifedipine using a simple treatment algorithm. Normogram-guided women (n=157) were matched to 157 women receiving care as usual (power, 80%; α=0.05). Risk of recurrent preeclampsia was analyzed with logistic regression adjusted for daily low-dose aspirin or calcium supplementation. Hemodynamic changes were considered nonphysiological in 90% of women in the normogram-guided group. Twelve percent of these women developed recurrent preeclampsia compared with 22% in the care-as-usual group (adjusted odds ratio, 0.47 [95% CI, 0.25–0.88]). There were no differences between groups in gestational age at delivery (38 1 and 38 2 weeks in the normogram-guided and care-as-usual groups, respectively) and neonatal birth weight (3148 and 3180 g in the normogram-guided and care-as-usual groups, respectively). Tailored circulatory normalization of nonphysiological hemodynamic changes during pregnancy halves the risk of recurrent preeclampsia, without disadvantageous effects on offspring outcome. This simple and innovative treatment strategy may also be beneficial to other women at increased risk for preeclampsia in pregnancy. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04216706.

Early closure mechanisms of the ductus arteriosus in immature infants.

According to experimental studies, cardiopulmonary distress decreases after closure of patent ductus arteriosus. However, early closure of the ductus using ibuprofen or indomethacin has failed to increase survival without serious morbidity. We review relevant data aiming to define optimal early management strategies that promote early closure of ductus arteriosus without serious adverse effects. Literature in English was searched selectively focusing on the potential of using acetaminophen for early closure of the ductus. Prophylactic ibuprofen or indomethacin intended to close the ductus, predisposes infants to ischaemia, bleeding and immune dysfunction. Acetaminophen appears to have a similar efficacy as indomethacin or ibuprofen, and all three dose-dependently constrict the ductus. Ibuprofen and indomethacin cause non-specific inhibition of prostaglandin synthesis, while acetaminophen predominantly inhibits prostaglandin E synthesis. Owing to low CYP450 activity in infancy, acetaminophen toxicity has been rarely evident. However, increasing the dosage increases the oxidative stress. We review prophylactic treatments that may increase the safety and efficacy of acetaminophen. These include vitamin A, cysteine and glutamine, and low-dose corticosteroid supplementation. The current challenge is to define a safe perinatal management practice that promotes cardiorespiratory adaptation in immature infants, particularly the seamless closure of the ductus before significant cardiopulmonary distress develops.

The effect of calcium supplementation on blood pressure in non-pregnant women with previous pre-eclampsia: A randomized placebo-controlled study.

Low dietary calcium is associated with the hypertensive disorders of pregnancy, and evidence suggests that the risks associated with pre-eclampsia are reduced by calcium supplementation. In the general (non-pregnant) population, low dietary calcium intake is associated with hypertension with inconsistent evidence that calcium supplementation may reduce blood pressure. Women with pre-eclampsia are also at risk of hypertension later in life. An exploratory sub-study among early participants enrolled in the WHO long-term calcium supplementation in women at high risk of pre-eclampsia (CAP) study reported a trend to more blood pressure reduction with calcium in non-pregnant women with previous severe as opposed to non-severe pre-eclampsia. The current study reports the effects of low-dose calcium supplementation in non-pregnant women in the complete trial cohort. The CAP Study was a multi-country randomized, double-blind placebo-controlled clinical trial to test the hypothesis that calcium deficiency may play a role in the genesis of pre-eclampsia in early pregnancy. From 2011 to 2016, non-pregnant women who had pre-eclampsia or eclampsia in their most recent pregnancy were randomized to receive either 500mg/day elemental calcium or placebo. In this sub-study we compared the change in blood pressure from baseline to the 12-week visit between participants receiving calcium versus placebo for those not pregnant at the 12-week visit. Of 1355 women randomized, 810 attended a 12-week visit without being pregnant, of whom 791 had blood pressure measurements available for both baseline and 12-week visits. There was a greater reduction in blood pressure in the calcium group compared with the placebo group for systolic pressure (difference 3.1mmHg, 95% CI 0.8 to 5.4) and mean arterial pressure (MAP) (difference 2.0mmHg, 95% CI 0.1 to 3.8). The difference in diastolic blood pressure reduction (1.4mmHg, 95% CI -0.5 to 3.3) was not statistically significant (p=0.140). For women with previous pre-eclampsia with severe features (n=447), there was significantly greater reduction in blood pressure in the calcium than the placebo group (difference for systolic 4.0, 95% CI 0.7 to 7.3; diastolic 3.0, 95% CI 0.5 to 5.5 and mean arterial pressure 3.3, 95% CI 0.8 to 5.9mmHg). For women with previous pre-eclampsia without severe features (n=344), there were no significant differences between calcium and placebo groups. ANOVA analysis found no statistically significant interaction between previous pre-eclampsia severity and treatment, for systolic (p=0.372), diastolic (p=0.063) or mean blood pressure (p=0.103). Low-dose calcium supplementation significantly reduced systolic and mean arterial pressure in non-pregnant women with previous pre-eclampsia. We did not confirm a greater calcium effect in women with previous pre-eclampsia with severe versus non-severe features. The effect of low-dose calcium is of importance since even modest blood pressure reductions at a population level may have important benefits in terms of reduced major complications of hypertension. This study adds to the mounting evidence of health benefits which could be achieved for populations with low dietary calcium through strategies to increase calcium intake, particularly among women at high risk due to previous pre-eclampsia. The trial was registered with the Pan-African Clinical Trials Registry, registration number PACTR201105000267371 (https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=267).

High-dose versus low-dose ergocalciferol for correcting hypovitaminosis D after fragility hip fracture: a randomized controlled trial

BackgroundHypovitaminosis D can be observed in most fragility hip fracture patients. However, measurement of 25-hydroxyvitamin D (25(OH)D) level is costly and may not be available in some centers. Without the baseline serum 25(OH)D level, the appropriate dose of vitamin D supplementation is not known. The aim of this study was to evaluate the effectiveness and safety of vitamin D supplementation in fragility hip fracture patients compared between high- and low-dose vitamin D supplementation.MethodsA total of 140 patients diagnosed with fragility hip fracture were randomly allocated to either the high-dose (60,000 IU/week) or low-dose (20,000 IU/week) vitamin D2 supplementation group for 12 weeks. The number of patients who achieved optimal vitamin D level (serum 25(OH)D > 30 ng/mL), the proportion of patients who developed hypercalcemia, and the functional outcome were compared between groups.ResultsOf the 140 patients who were enrolled, 21 patients were lost to follow-up during the study period. The remaining 119 patients (58 and 61 in the high- and low-dose groups, respectively) were included in the final analysis. The high-dose group had a higher rate of serum 25(OH)D restoration to optimal level than the low-dose group (82.8% vs 52.5%, respectively; p < 0.001). Approximately 3.4 and 1.6% of patients in the high- and low-dose groups, respectively, had mild transient hypercalcemia, but none developed moderate, severe, or symptomatic hypercalcemia. There were no differences in functional outcome scores between groups.ConclusionsIn treatment settings where baseline serum 25(OH)D level can’t be evaluated in older adults with fragility hip fracture, we recommend high-dose vitamin D2 of approximately 60,000 IU/week for 12 weeks, with subsequent switch to a maintenance dose. This regimen effectively restored serum vitamin D to an optimal level in 82.8% of patients without causing symptomatic hypercalcemia.Trial registrationThe protocol of this study was retrospectively registered in the Thai Clinical Trials Registry database no. TCTR20180302007 on 20 February 2018.

Effects of long-term taurine supplementation on age-related changes in skeletal muscle function of Sprague-Dawley rats.

Taurine (2-aminoethanesulfonic acid) is a free amino acid found abundantly in mammalian tissues. Increasing evidence suggests that taurine plays a role in the maintenance of skeletal muscle function and increase of exercise capacity. Most energy drinks contain this amino acid; however, there is insufficient research on the effects of long-term, low-dose supplementation of taurine. In this study, we investigated the effects of long-term administration of taurine at low doses on aging in rodents. In Experiment 1, we examined age-related changes in aging Sprague-Dawley (SD) rats (32-92weeks old) that O2 consumption and spontaneous activity decreased significantly with aging. In Experiment 2, we examined the effects of long-term (21-week) administration of taurine on healthy aging SD rats. SD rats were stabilized for 32-34weeks and divided into three groups, administrated water (control), 0.5% taurine (25mg/kg body weight (BW)/day), or 1% taurine (50mg/kg BW/day) from age 34 to 56weeks (5 days/week, 5mL/kg BW). Our findings suggest that long-term administration of taurine at relatively low dose could attenuate the age-related decline in O2 consumption and spontaneous locomotor activity. Upon intestinal absorption, taurine might modulate age-related changes in respiratory metabolism and skeletal muscle function via peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), succinate dehydrogenase (SDH), cytochrome c (Cycs), myocyte enhancer factor 2A (MEF2A), glucose transporter 4 (GLUT4), and myoglobin, which are regulated by the activation of AMP-activated protein kinase (AMPK). This article examines the mechanism underlying the effects of taurine on age-related changes, which may have potential clinical implications.

Effects of Dose and Duration of Zinc Interventions on Risk Factors for Type 2 Diabetes and Cardiovascular Disease: A Systematic Review and Meta-Analysis

ABSTRACTNo meta-analysis has examined the effect of dose and duration of zinc interventions on their impact on risk factors for type 2 diabetes (T2D) or cardiovascular disease (CVD). This study aimed first to compare the effects of zinc interventions dichotomized as low versus high dose (<25 mg/d and ≥25 mg/d, respectively) and short versus long duration (<12 wk and ≥12 wk, respectively) on risk factors for T2D and CVD. Second, it discusses the results from the low-dose and long-duration meta-analyses as a foundation for understanding what impact a zinc-biofortification intervention could have on these risk factors. The PubMed and Cochrane Review databases were searched through January 2020 for full-text, human studies providing zinc supplements (alone) at doses ≤75 mg/d and a placebo. Data on study and sample characteristics and several T2D and CVD risk factors were extracted. There were 1042 and 974 participants receiving zinc and placebo, respectively, from 27 studies. Low-dose zinc supplementation (<25 mg/d) significantly benefited fasting blood glucose, insulin resistance, triglycerides, total cholesterol, and LDL cholesterol. High-dose zinc supplementation (≥25 mg/d) benefited glycated hemoglobin and insulin resistance. Short-duration interventions (<12 wk) benefited fasting blood glucose, insulin resistance, and triglycerides, while long-duration studies (≥12 wk) benefited fasting blood glucose, triglycerides, and total and LDL cholesterol. Effect sizes for low-dose and long-duration interventions were of equal or greater magnitude to those from high-dose or short-duration interventions. Low-dose and long-duration zinc supplementation each improved more risk factors for T2D and CVD than high-dose and short-duration interventions, respectively. It is currently unknown whether low doses of zinc delivered over long durations via a biofortified crop would similarly impact these risk factors. However, this review suggests that low-dose, long-duration zinc intake from supplements, and potentially biofortification, can benefit risk factors for T2D and CVD.

Preliminary Guidelines for the Use of IVIg during COVID-19

Infection with the severe acute respiratory syndrome novel type-2 novel coronavirus (SARS-CoV-2) responsible for the 2019 coronavirus disease (COVID-19) shows a highly heterogeneous clinical presentation and age affliction in children and adults, ranging from asymptomatic or mild disease to severe involvement, with potentially fatal respiratory failure and multiple organ dysfunction. As susceptibility to severe COVID-19 depends upon comorbid factors including immune competence, optimizing the latter through low-dose supplementation or high dose treatment with immune globulin therapy in those with primary immune deficiency and post-infectious immune sequelae of SARS-CoV-2 and existing autoimmune disorders is essential. There are no existing guidelines hence; this paper provides a framework for considering preliminary guidelines for the use of immune globulin therapy during COVID-19.

Low Dose of β-Carotene Regulates Inflammation, Reduces Caspase Signaling, and Correlates with Autophagy Activation in Cardiomyoblast Cell Lines.

BackgroundExcessive reactive oxygen species (ROS) stimulate mitochondrial damage that causes degenerative diseases such as cardiovascular disease (CVD). β-carotene (BC), a natural antioxidant able to counteract free radicals, acts as a cytoprotective agent. However, knowledge of the role of BC on cardiomyoblasts is limited. In this study, we explored its role on COX4, Tom20, Nfr1, Nrf2, Nf-κB, LC3, p62, caspase 3, and caspase 9 and its association with cardiomyoblast viability and survival.Material/MethodsH9C2 cell lines were seeded, cultivated until 90% to 100% confluency, and treated with various doses of BC: 10 μM, 1 μM, 0.1 μM, and 0.01 μM. After 24 h, the cells were harvested, lyzed, and tested for specific related protein expressions from each dose.ResultsLow-dose BC induced autophagy most effectively at 1 μM, 0.1 μM, and 0.01 μM, as indicated by a decrease of LC3II and p62 levels. We observed that Nf-κB protein levels were suppressed; Nrf2 was stimulated, but Nrf1 was not altered significantly. Further, low-dose BC might stimulate cell viability by reducing apoptotic signals of caspase 3 and 9. Notably, low-dose BC also showed potential to increase Tom20 protein levels.ConclusionsLow-dose BC supplementation shows beneficial effects, especially at 0.01 μM, by reducing inflammation through the suppression of Nf-κB and increase of Nrf2 level. Autophagy as a cellular maintenance mechanism was also stimulated, and the amount of the mitochondria marker Tom20 increased. Taken together, results showed that specific low-dose BC is effective and might improve cell viability by stimulating autophagy, inhibiting proinflammatory factors, and suppressing apoptosis.

The Impact of Low-Level Iron Supplements on the Faecal Microbiota of Irritable Bowel Syndrome and Healthy Donors Using In Vitro Batch Cultures.

Ferrous iron supplementation has been reported to adversely alter the gut microbiota in infants. To date, the impact of iron on the adult microbiota is limited, particularly at low supplementary concentrations. The aim of this research was to explore the impact of low-level iron supplementation on the gut microbiota of healthy and Irritable Bowel Syndrome (IBS) volunteers. Anaerobic, pH-controlled in vitro batch cultures were inoculated with faeces from healthy or IBS donors along with iron (ferrous sulphate, nanoparticulate iron and pea ferritin (50 μmol−1 iron)). The microbiota were explored by fluorescence in situ hybridisation coupled with flow cytometry. Furthermore, metabolite production was assessed by gas chromatography. IBS volunteers had different starting microbial profiles to healthy controls. The sources of iron did not negatively impact the microbial population, with results of pea ferritin supplementation being similar to nanoparticulate iron, whilst ferrous sulphate led to enhanced Bacteroides spp. The metabolite data suggested no shift to potentially negative proteolysis. The results indicate that low doses of iron from the three sources were not detrimental to the gut microbiota. This is the first time that pea ferritin fermentation has been tested and indicates that low dose supplementation of iron is unlikely to be detrimental to the gut microbiota.

The role of vitamin D in metabolic and reproductive disturbances of polycystic ovary syndrome: A narrative mini-review.

Vitamin D is a secosteroid hormone that plays a pivotal role in several metabolic and reproductive pathways in humans. Increasing evidence supports the role of vitamin D deficiency in metabolic disturbances and infertility in women with polycystic ovary syndrome (PCOS). Indeed, supplementation with vitamin D seems to have a beneficial role on insulin resistance (IR) and endometrial receptivity. On the other hand, exceedingly high levels of vitamin D appear to play a detrimental role on oocytes development and embryo quality. In the current review, we summarize the available evidence about the topic, aiming to suggest the best supplementation strategy in women with PCOS or, more generally, in those with metabolic disturbances and infertility. Based on the retrieved data, vitamin D seems to have a beneficial role on IR, insulin sensitivity and endometrial receptivity, but high levels and incorrect timing of administration seem to have a detrimental role on oocytes development and embryo quality. Therefore, we encourage a low dose supplementation (400-800IU/day) particularly in vitamin D deficient women that present metabolic disturbances like PCOS. As far as the reproductive health, we advise vitamin D supplementation in selected populations, only during specific moments of the ovarian cycle, to support the luteal phase. However, ambiguities about dosage and timing of the supplementation still emerge from the clinical studies published to date and further studies are required.

A 2-Year Randomized Controlled Trial With Low-Dose B-Vitamin Supplementation Shows Benefits on Bone Mineral Density in Adults With Lower B12 Status.

Folate, vitamins B12, B6, and riboflavin are required for one-carbon metabolism and may affect bone health, but no previous randomized trial has investigated all four nutrients in this context. We investigated the effect of low-dose B-vitamins for 2 years on bone mineral density (BMD) in a dual-centered, 2-year randomized controlled trial (RCT) in adults aged ≥50 years. Eligible participants not consuming B-vitamin supplements or fortified foods >4times weekly were randomized to receive daily either combined folic acid (200 μg), vitamin B12 (10 μg), vitamin B6 (10 mg), and riboflavin (5mg), or "active" placebo, whereby both the intervention and placebo groups received vitamin D (10 μg). BMD was assessed before and after intervention using dual-energy X-ray absorptiometry (DXA) scanning of the total hip, femoral neck, and lumbar spine (L1 to L4). Of 205 eligible participants randomized, 167 completed the trial in full. B-vitamin intervention resulted in increases in serum folate (p < 0.001), serum B12 (p < 0.001), and plasma pyridoxal-5-phosphate (p < 0.001) and decreases in functional biomarkers of B-vitamin status, erythrocyte glutathione reductase activation coefficient (p < 0.001), serum methylmalonic acid (MMA; p < 0.001), and serum total homocysteine (p < 0.001). B-vitamin intervention had no overall effect on BMD, which declined in both treatment groups by approximately 1% (ranging from -0.7% to -1.4%). However, in participants with lower baseline B12 status (serum B12 <246 pmol/L or MMA ≥0.22 μmol/L), B-vitamin intervention reduced the 2-year BMD decline versus placebo: adjusted mean (95% confidence interval [CI]) change of -0.003 (-0.008, 0.002) versus -0.015 (-0.021, -0.010)g/cm2 at the total hip and -0.004 (-0.010, 0.001) versus -0.013 (-0.018, -0.007)g/cm2 at the femoral neck. In conclusion, the findings indicate that although low-dose B-vitamin intervention for 2 years had no overall effect on BMD, improving B-vitamin status appears to have specific benefits for bone health in adults with lower B12 status. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Cardiac Arrhythmia Prevention in Ischemia and Reperfusion by Low-Dose Dietary Fish Oil Supplementation in Rats

Supplementing animal diets with fish oil increases myocardial omega-3 polyunsaturated fatty acids [ω-3 (n-3) PUFA], lowers heart rate, and prevents malignant cardiac arrhythmias. In contrast to epidemiological reports, results of some human clinical trials and of unphysiologically high doses employed in animal studies call into question the application of dietary ω-3 PUFA for cardioprotection. This study tested the hypothesis that low ω-3 PUFA dietary thresholds for myocardial incorporation in rats, equivalent in dose to what humans derive from eating fish, can reduce heart rate and arrhythmia vulnerability. Male Sprague-Dawley rats (12-15 wk old) were fed isoenergetic diets containing 10% fat for 4-5 wk. The control diet (CON) contained 5.5% beef tallow, 2.5% sunflower seed oil, and 2% olive oil. Fish oil diets contained high-DHA tuna oil, exchanged for olive oil: 0.31% [fish oil group 1 (FO1)] (human equivalent EPA+DHA 570 mg/d); 1.25% [fish oil group 2 (FO2)] (equivalent EPA+DHA 2.3 g/d). Anaesthetized rats (pentobarbital, 60 mg/kg intraperitoneally) were subjected in vivo to 15-min cardiac ischemia by left coronary artery occlusion and then reperfusion, with arrhythmias detected by electrocardiogram. Fish oil dose dependently modulated myocardial membrane fatty acids (DHA mean±SEM: CON, 5.0±0.2%; FO1, 13.1±0.9%; FO2, 18.3±0.4%; n=4-5; P-trend<0.001 ANOVA); resting heart rate (CON, 453±6; FO1, 432±4; FO2, 422±5 bpm; n=15-18; P-trend<0.001); reduced ventricular fibrillation (VF) (CON, 89%; FO1, 60%; P=0.052; FO2, 50%; n=15-18; P=0.013 chi square); and total arrhythmia severity (arrhythmia score: CON, 6.1±0.4; FO1, 4.6±0.5; FO2, 3.1±0.7; n=15-18; P-trend<0.01) during ischemia and reperfusion (VF: Con, 86%; FO1, 22% P=0.011; FO2, 8% P=0.001; n=7-12); (arrhythmia score: CON, 4.6±0.3; FO1, 3.1±0.3; FO2, 1.3±0.3; n=7-12; P-trend<0.001). Ventricular arrhythmias were prevented and heart rate was slowed by lower ω-3 PUFA intake in rats than previously reported, equivalent to human fish consumption and associated with increased myocardial DHA. The efficacy of low-dose fish oil demonstrates biological plausibility for nutritional ω-3 fatty acid-mediated cardioprotection and suggests that effectiveness in human clinical trials may be obscured by failure to exclude fish eaters.

Effects of low-dose spirulina and turmeric supplementation on executive functions in university students

Effects of low-dose spirulina and turmeric supplementation on executive functions in university students

Replicating Randomized Trial Results with Observational Data Using the Parametric g-Formula: An Application to Intravenous Iron Treatment in Hemodialysis Patients.

BackgroundReproducibility of clinical and epidemiologic research is important to generalize findings and has increasingly been scrutinized. A recently published randomized trial, PIVOTAL, evaluated high vs low intravenous iron dosing strategies to manage anemia in hemodialysis patients in the UK. Our objective was to assess the reproducibility of the PIVOTAL trial findings using data from a well-established cohort study, the Dialysis Outcomes and Practice Patterns Study (DOPPS).MethodsTo overcome the absence of randomization in the DOPPS, we applied the parametric g-formula, an extension of standardization to longitudinal data. We estimated the effect of a proactive high-dose vs reactive low-dose iron supplementation strategy on all-cause mortality (primary outcome), hemoglobin, two measures of iron concentration (ferritin and TSAT), and erythropoiesis-stimulating agent dose over 12 months of follow-up in 6325 DOPPS patients.ResultsComparing high- vs low-iron dose strategies, the 1-year mortality risk difference was 0.020 (95% CI: 0.008, 0.031) and risk ratio was 1.20 (95% CI: 1.07, 1.33), compared with null 1-year findings in the PIVOTAL trial. Differences in secondary outcomes were directionally consistent but of lesser magnitude than in the PIVOTAL trial.ConclusionOur findings are somewhat consistent with the recent PIVOTAL trial, with discrepancies potentially attributable to model misspecification and differences between the two study populations. In addition to the importance of our results to nephrologists and hence hemodialysis patients, our analysis illustrates the utility of the parametric g-formula for generalizing results and comparing complex and dynamic treatment strategies using observational data.

Excessive vitamin B6 during treatment is related to poor prognosis of patients with nasopharyngeal carcinoma: A U-shaped distribution suggests low dose supplement

Several studies explored the association of vitamin B6 intake with the risk of cancers. However, it is unclear whether different doses of vitamin B6 have distinct effects on the prognosis of nasopharyngeal carcinoma (NPC) patients. This study investigated the relationship between different doses of B6 intake and the prognosis of NPC patients. This retrospective cohort analysis included 792 newly diagnosed NPC patients with a median follow-up of 62.05 months. Restricted cubic spline and maximally selected rank statistics were performed to determine the cut-off value of vitamin B6 during treatment (VB6DT). Kaplan-Meier method and log-rank tests were performed to analyze survival outcomes. A multivariable Cox proportional hazard model was performed to determine the independent prognostic factors. NPC patients were divided into three groups according to the cut-off value of VB6DT: non-users (0mg/d), VB6DT>8.6mg/d, and VB6DT≤8.6mg/d. Patients with VB6DT>8.6mg/d had significantly lower 5-year overall survival (OS) (83.5% vs. 90.8%, p=0.006), distant metastasis-free survival (DMFS) (83.5% vs. 91.0%, p=0.004), and progression-free survival (PFS) (73.7% vs. 81.7%, p=0.011) and slightly but not significantly lower 5-year local recurrence-free survival (LRFS) (87.7% vs. 90.7%, p=0.214) than the non-users. Patients with VB6DT≤8.6mg/d had slightly but not significantly better 5-year OS (93.3% vs. 90.8%, p=0.283) than the non-users, while all other primary endpoints were similar (p>0.50). Multivariable analyses confirmed that VB6DT>8.6mg/d was an independent negative prognostic factor of OS (p=0.010), DMFS (p=0.017), and PFS (p=0.030) but not of LRFS (p=0.428). Excessive VB6DT higher than the cut-off value is an independent negative prognostic factor for NPC patients. Additionally, low dose intake improved OS only slightly but not significantly.

Nutritional supplements in combination with chemotherapy or targeted therapy reduces tumor progression in mice bearing triple-negative breast cancer

The potential anti-cancer properties of selenium (Se) and eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA) have been documented. However, few studies have been conducted examining anti-tumor effects of nutritional supplements (NS) containing Se and EPA/DHA in combination with anti-cancer agents, such as taxol (Tax), adriamycin (Adr), and avastin (Ava). Compared with triple-negative breast cancer (TNBC)-bearing positive control (TB) mice, a low dose of Tax, Adr, and Ava decreased tumor size and the incidence of metastasis in TB-Tax, TB-Adr, and TB-Ava groups. Combination treatment with anti-cancer agent and NS (2.7 μg Se and 5.1 mg EPA/3.7 mg DHA/g) induced additional decreases in TB-Tax-NS, TB-Adr-NS, and TB-Ava-NS groups. Th1-associated cytokines were increased, and Th2-type cytokines were decreased significantly in TB mice with combination treatment than that of anti-cancer agent treatment alone. Combination treatment with anti-cancer agents and NS has also been shown to further increased tumor malondialdehyde (MDA) levels, lowered hypoxia-inducible factor (HIF)-1α, angiogenic markers (vascular endothelial growth factor [VEGF] and CD31) and metastatic potential, as well as reduced heat shock proteins, receptor tyrosine kinase AXL, and surface markers of cancer stem cells, and increased apoptotic proteins. For immune checkpoint molecules, combination treatment was associated with a greater decrease in programmed cell death ligand-1 (PD-L1) in both tumors and mammary glands, but PD-1 level in primary tumors was increased. Our results suggest that combination treatment with low-dose anti-cancer agents (Tax, Adr, and Ava) and oral supplementation of Se/ EPA/DHA significantly decreased tumor growth and metastatic progression in TNBC mice through multiple anti-tumor mechanisms.

Low caffeine dose improves intermittent sprint performance in hot and humid environments.

While the effects of caffeine have been evaluated in relation to endurance exercise, few studies have assessed the ergogenic effects of low caffeine doses on intermittent exercise performance in hot and humid environments. Thus, we aimed to determine the effects of low-dose caffeine supplementation on intermittent exercise performance under these conditions. Eight male soccer players (age, 19.9±0.3 years; height, 173.7±6.3cm; body mass, 65.1±5.5kg; V˙O2max, 50.0±3.1mL ⋅ kg-1⋅ min-1) participated in this double-blind, randomized, cross-over study. Caffeine was orally administered at 60min before exercise (dosage, 3mg ⋅kg-1). The participants completed a 90-min intermittent sprint cycling protocol under two conditions (after receiving caffeine and placebo) at 32°C and at 70% relative humidity. A significant improvement in the total amount of work was observed in the caffeine condition compared to the placebo condition (155.0±15.8 vs 150.8±14.5kJ, respectively; p<0.05, d=0.28). In contrast, the rectal temperature measured at the end of exercise showed no significant difference between the conditions (38.9±0.4°C and 38.7±0.5°C in the caffeine and placebo conditions, respectively; p>0.05, d=0.57). Other thermal responses, such as the mean skin temperature, heart rate, or sweat volume, were not significantly different between these conditions. These results suggested that a low caffeine dose improved the intermittent sprint performance and the reasons could be explained by the fact that a low caffeine dose ingestion did not affect the thermoregulatory responses compared to the placebo condition and, thus, did not attenuate its ergogenic effect on exercise in hot and humid environments.