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1.  Acknowledgement of manuscript reviewers 
Contributing reviewers
We and the Editorial Board acknowledge and thank all reviewers for their active participation and contribution during 2013. We greatly appreciate their dedication and behind the scenes contribution. It is largely due to their support and expertise that we have been able to publish high-standard manuscripts. We would also like to thank authors for choosing Nutrition & Metabolism and contributing their cherished work.
doi:10.1186/1743-7075-11-7
PMCID: PMC3973956  PMID: 24620989
2.  Dietary intakes of fat and total mortality among Japanese populations with a low fat intake: the Japan Collaborative Cohort (JACC) Study 
Background
It may be useful to examine associations of fat intakes with total mortality as a basis for dietary recommendations. We aimed to elucidate associations between dietary fat and total mortality among Japanese populations with low fat intake.
Methods
We conducted a prospective study consisting of 58,672 men and women aged 40 to 79 years. Fat intakes were estimated using a food frequency questionnaire. Multivariate-adjusted hazard ratios (HRs) for mortality by sex were computed according to quintiles of energy-adjusted fat intakes.
Results
During the follow-up period (median duration, 19.3 years), 11,656 deaths were recorded. In men, we found no clear association between total fat and total mortality. HRs across quintiles of total fat intake were 1.00, 1.03 (95% confidence interval [CI], 0.95–1.12), 1.02 (0.94–1.10), 0.98 (0.90–1.07), and 1.07 (0.98–1.17). No significant association was detected in regard to types of fat. In women, HR was lowest in the fourth quintile of total fat intake followed by the top quintile; HRs across quintiles were 1.00, 1.03 (0.94–1.11), 1.00 (0.92–1.09), 0.88 (0.81–0.96), and 0.94 (0.86–1.03). Regarding types of fat in women, total mortality was inversely associated with intakes of saturated fatty acids (SFA), monounsaturated fatty acids (MUFA), and polyunsaturated fatty acids (PUFA); the lowest HR was in the top quintile of intake for SFA, MUFA, and PUFA: 0.91 (95% CI, 0.83–1.00), 0.91 (0.83–0.99) and 0.88 (0.80 - 0.97), respectively (trend P across quintiles, 0.020, 0.012, and 0.029, respectively). Causes of death other than cancer and cardiovascular disease contributed most to decreases in HRs for total and types of fat. In women, analysis with finer categories revealed that the lowest risk for total mortality appeared at total fat intake of 28% of energy.
Conclusions
Our findings from a large cohort study among populations with relatively low fat intake provide evidence regarding optimal levels of fat intakes.
doi:10.1186/1743-7075-11-12
PMCID: PMC3973975  PMID: 24597664
Fat; Fatty acids; Saturated fatty acids; Monounsaturated fatty acids; Polyunsaturated fatty acids; Total mortality; Cohort studies; Japan
3.  Retraction: Role of cytochrome P450 in drug interactions 
doi:10.1186/1743-7075-11-11
PMCID: PMC3924617  PMID: 24529076
4.  The pivotal role of pyruvate dehydrogenase kinases in metabolic flexibility 
Metabolic flexibility is the capacity of a system to adjust fuel (primarily glucose and fatty acids) oxidation based on nutrient availability. The ability to alter substrate oxidation in response to nutritional state depends on the genetically influenced balance between oxidation and storage capacities. Competition between fatty acids and glucose for oxidation occurs at the level of the pyruvate dehydrogenase complex (PDC). The PDC is normally active in most tissues in the fed state, and suppressing PDC activity by pyruvate dehydrogenase (PDH) kinase (PDK) is crucial to maintain energy homeostasis under some extreme nutritional conditions in mammals. Conversely, inappropriate suppression of PDC activity might promote the development of metabolic diseases. This review summarizes PDKs’ pivotal role in control of metabolic flexibility under various nutrient conditions and in different tissues, with emphasis on the best characterized PDK4. Understanding the regulation of PDC and PDKs and their roles in energy homeostasis could be beneficial to alleviate metabolic inflexibility and to provide possible therapies for metabolic diseases, including type 2 diabetes (T2D).
doi:10.1186/1743-7075-11-10
PMCID: PMC3925357  PMID: 24520982
PDC; PDK; Metabolic flexibility
5.  Lupin protein isolate versus casein modifies cholesterol excretion and mRNA expression of intestinal sterol transporters in a pig model 
Background
Lupin proteins exert hypocholesterolemic effects in man and animals, although the underlying mechanism remains uncertain. Herein we investigated whether lupin proteins compared to casein modulate sterol excretion and mRNA expression of intestinal sterol transporters by use of pigs as an animal model with similar lipid metabolism as humans, and cellular cholesterol-uptake by Caco-2 cells.
Methods
Two groups of pigs were fed cholesterol-containing diets with either 230 g/kg of lupin protein isolate from L. angustifolius or 230 g/kg casein, for 4 weeks. Faeces were collected quantitatively over a 5 d period for analysis of neutral sterols and bile acids by gas chromatographically methods. The mRNA abundances of intestinal lipid transporters were analysed by real-time RT-PCR. Cholesterol-uptake studies were performed with Caco-2 cells that were incubated with lupin conglutin γ, phytate, ezetimibe or albumin in the presence of labelled [4-14C]-cholesterol.
Results
Pigs fed the lupin protein isolate revealed lower cholesterol concentrations in total plasma, LDL and HDL than pigs fed casein (P < 0.05). Analysis of faeces revealed a higher output of cholesterol in pigs that were fed lupin protein isolate compared to pigs that received casein (+57.1%; P < 0.05). Relative mRNA concentrations of intestinal sterol transporters involved in cholesterol absorption (Niemann-Pick C1-like 1, scavenger receptor class B, type 1) were lower in pigs fed lupin protein isolate than in those who received casein (P < 0.05). In vitro data showed that phytate was capable of reducing the uptake of labelled [4-14C]-cholesterol into the Caco-2 cells to the same extend as ezetimibe when compared to control (−20.5% vs. −21.1%; P < 0.05).
Conclusions
Data reveal that the cholesterol-lowering effect of lupin protein isolate is attributable to an increased faecal output of cholesterol and a reduced intestinal uptake of cholesterol. The findings indicate phytate as a possible biofunctional ingredient of lupin protein isolate.
doi:10.1186/1743-7075-11-9
PMCID: PMC3922606  PMID: 24490902
Lupin protein isolate; Faecal cholesterol output; Intestinal sterol transporters; Cholesterol-uptake; Pigs; Caco-2 cells
6.  Beneficial effects of the nutritional supplements on the development of diabetic retinopathy 
Purpose
Increased oxidative stress and inflammatory mediators are implicated in the development of diabetic retinopathy, and in rats, its development can be prevented by antioxidants. Carotenoids are some of the powerful antioxidants, and diabetes decreases lutein and zeaxanthin levels in the serum and retina. The aim of this study is to investigate the effect of carotenoid containing nutritional supplements (Nutr), which is in clinical trials for ‘Diabetes Vision Function’, on diabetic retinopathy.
Methods
Streptozotocin-induced diabetic rats (Wistar, male) were fed Purina 5001 supplemented with nutritional supplements containing zeaxanthin, lutein, lipoic acid, omega-3 fatty acids and other nutrients, or without any supplementation. Retinal function was analyzed at ~4 months of diabetes by electroretinography. After 11 months of diabetes, capillary cell apoptosis (TUNEL-staining) and histopathology (degenerative capillaries) were quantified in trypsin-digested retinal vasculature. Retina was also analyzed for mitochondrial damage (by quantifying gene expressions of mtDNA-encoded proteins of the electron transport chain), VEGF and inflammatory mediators, interleukin-1β and NF-kB.
Results
Diabetes impaired retinal function decreasing the amplitudes of both a- and b-waves. In the same animals, retinal capillary cell apoptosis and degenerative capillaries were increased by 3–4 fold. Gene expressions of mtDNA encoded proteins were decreased, and VEGF, interleukin-1β and NF-kB levels were elevated. Supplementation with the nutrients prevented increased capillary cell apoptosis and vascular pathology, and ameliorated these diabetes-induced retinal abnormalities.
Conclusions
Nutritional supplementation prevents diabetic retinopathy, and also maintains normal retinal function, mitochondrial homeostasis and inflammatory mediators. Thus, this supplementation could represent an achievable and inexpensive adjunct therapy to also inhibit retinopathy, a slow progressing disease feared most by diabetic patients.
doi:10.1186/1743-7075-11-8
PMCID: PMC3937140  PMID: 24479616
Carotenoids; Diabetic retinopathy; Macular pigment; Mitochondria; Nutritional supplements; Zeaxanthin
7.  Novel regulatory roles of omega-3 fatty acids in metabolic pathways: a proteomics approach 
Background
Omega-3 polyunsaturated fatty acids (n-3 PUFA) have been shown to alleviate the symptoms of metabolic disorders, such as heart disease, diabetes, obesity and insulin resistance. Several putative mechanisms by which n-3 PUFA elicit beneficial health effects have been proposed; however, there is still a shortage of knowledge on the proteins and pathways that are regulated by n-3 PUFA.
Methods
Using two dimensional polyacrylamide gel electrophoresis (2D-PAGE) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis, we investigated the effects of diets high or low in n-3 PUFA on hepatic proteomic profile of C57BL/6 mice.
Results
The findings show for the first time that high dietary n-3 PUFA reduced the expression of regucalcin, adenosine kinase and aldehyde dehydrogenase. On the other hand, diets high in n-3 PUFA increased the expression of apolipoprotein A-I, S-adenosylmethionine synthase, fructose-1, 6-bisphosphatase, ketohexokinase, malate dehydrogenase, GTP-specific succinyl CoA synthase, ornithine aminotransferase and protein disulfide isomerase-A3.
Conclusions
Our findings revealed for the first time that n-3 PUFA causes alterations in several novel functional proteins involved in regulating lipid, carbohydrate, one-carbon, citric acid cycle and protein metabolism, suggesting integrated regulation of metabolic pathways. These novel proteins are potential targets to develop therapeutic strategies against metabolic disorders.
doi:10.1186/1743-7075-11-6
PMCID: PMC3898484  PMID: 24438320
8.  Bioavailability of tocotrienols: evidence in human studies 
As a minor component of vitamin E, tocotrienols were evident in exhibiting biological activities such as neuroprotection, radio-protection, anti-cancer, anti-inflammatory and lipid lowering properties which are not shared by tocopherols. However, available data on the therapeutic window of tocotrienols remains controversial. It is important to understand the absorption and bioavailability mechanisms before conducting in-depth investigations into the therapeutic efficacy of tocotrienols in humans. In this review, we updated current evidence on the bioavailability of tocotrienols from human studies. Available data from five studies suggested that tocotrienols may reach its target destination through an alternative pathway despite its low affinity for α-tocopherol transfer protein. This was evident when studies reported considerable amount of tocotrienols detected in HDL particles and adipose tissues after oral consumption. Besides, plasma concentrations of tocotrienols were shown to be higher when administered with food while self-emulsifying preparation of tocotrienols was shown to enhance the absorption of tocotrienols. Nevertheless, mixed results were observed based on the outcome from 24 clinical studies, focusing on the dosages, study populations and formulations used. This may be due to the variation of compositions and dosages of tocotrienols used, suggesting a need to understand the formulation of tocotrienols in the study design. Essentially, implementation of a control diet such as AHA Step 1 diet may influence the study outcomes, especially in hypercholesterolemic subjects when lipid profile might be modified due to synergistic interaction between tocotrienols and control diet. We also found that the bioavailability of tocotrienols were inconsistent in different target populations, from healthy subjects to smokers and diseased patients. In this review, the effect of dosage, composition and formulation of tocotrienols as well as study populations on the bioavailability of tocotrienols will be discussed.
doi:10.1186/1743-7075-11-5
PMCID: PMC3895660  PMID: 24410975
Tocotrienols; Bioavailability; Human; Metabolism; Absorption; Vitamin E; Palm oil
9.  Silicon balance in human volunteers; a pilot study to establish the variance in silicon excretion versus intake 
Background
Accumulating evidence suggests a role for silicon in optimal connective tissue health. Further proof of its importance/essentiality may be provided by studies involving imposed depletion followed by 29Si challenge to estimate metabolic balance. Prior to conducting these expensive studies, we first established the variance of estimating normal Si excretion versus intake using a single oral dose of typical dietary Si, orthosilicic acid.
Methods
Healthy volunteers were recruited from Loei Rajabhat University, separated into two matched groups (three males and three females/group) and maintained on a standardized diet for the three study days. One group ingested 500 ml water containing orthosilicic acid (28.9 mg Si) and the other group received 500 ml water alone, all on a fasted stomach. Blood samples and total urine and faeces were collected over the 48 h post-dose period and 24 h before-hand (baseline) and analysed for silicon by inductively coupled plasma optical emission spectrometry.
Results
Serum Si analysis confirmed the ready absorption of silicon from the orthosilicic acid solution. Mean total urinary and faecal Si excretions over the 24 h post-dose period accounted for 57 ± 9.5% and 39 ± 9.4% of the ingested dose, respectively. Thus in total 96.3 ± 5.8% of the ingested dose was recovered in faecal plus urinary excretions over the 24 h post-dose period.
Conclusions
We report that in healthy subjects (presumably in Si balance), the ingestion of a soluble dose of dietary Si results in the same quantity (within analytical error) being excreted within 24 h. It is currently not known if this all originated from the dose solution or if there was some exchange with the body Si pool but, given the low variance in these silicon balance data, isotopic studies are now merited.
doi:10.1186/1743-7075-11-4
PMCID: PMC3912935  PMID: 24405738
Silicon; Orthosilicic acid; Absorption; Balance studies; Urine; Faeces
10.  Effects of gastrointestinal motility on obesity 
Background
Changes of gastrointestinal motility, which are important related to the food digestion and absorption in the gastrointestinal tract, may be one of the factors in obesity-formation.
Aims
The changes of gastrointestinal motility were explored in the rats from diet-induced obesity (DIO), diet-induced obese resistant (DR) or control (CON) by diet intervention.
Methods
After fed with a high fat diet (HFD), 100 male Sprague–Dawley rats were divided into DIO, DR and CON groups. The rats from DIO and DR groups were fed with HFD, and CON with a basic diet (BD) for 6 weeks. Body weight, energy intake, gastric emptying, intestinal transit, motility of isolated small intestine segments and colon’s function were measured in this study. Expression of interstitial cells of Cajal (ICCs) and enteric nervous system (ENS) - choline acetyltransferase (ChAT), vasoactive intestinal peptides (VIP), substance P (SP) and NADPH-d histochemistry of nitric oxide synthase (NOS) were determined by immunohistochemistry.
Results
Body weight and intake energy in the DIO group were higher than those in the DR group (p < 0.05). Gastric emptying of DIO group rats (78.33 ± 4.95%) was significantly faster than that of DR group (51.79 ± 10.72%) (p < 0.01). The peak value of motility in rat’s duodenum from the DR group was significantly higher than that in the DIO group (p < 0.05). In addition, the expression of interstitial cells of Cajal (ICC), choline acetyltransferase (ChAT), substance P (SP), vasoactive intestinal peptides (VIP) and neuronal nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) in the intestine of rats were significantly increased in the DIO group when compared to the DR group (p < 0.05).
Conclusion
A faster gastric emptying, a weaker contraction of duodenum movement, and a stronger contraction and relaxation of ileum movement were found in the rats from the DIO group. It indicated that there has effect of gastrointestinal motility on obesity induced by HFD.
doi:10.1186/1743-7075-11-3
PMCID: PMC3891996  PMID: 24398016
Gastrointestinal motility; ICC; Enteric nervous system; Obesity
11.  Oleanolic acid attenuates renal fibrosis in mice with unilateral ureteral obstruction via facilitating nuclear translocation of Nrf2 
Background
Renal interstitial fibrosis is a common final pathological process in the progression of kidney disease. This is primarily due to oxidative stress, which contributes to renal inflammation and fibrosis. Nuclear factor-erythroid-2-related factor 2 (Nrf2) is known to coordinate induction of genes that encode antioxidant enzymes. We investigated the effects of oleanolic acid, a known Nrf2 activator, on oxidative stress-induced renal inflammation and fibrosis.
Methods
One day before unilateral ureteral obstruction (UUO) performed in C57BL/6 mice, oleanolic acid treatment was initiated and was continued until 3 and 7 days after UUO. Renal inflammation and fibrosis, markers of oxidative stress, and changes in Nrf2 expression were subsequently evaluated.
Results
In the obstructed kidneys of UUO mice, oleanolic acid significantly attenuated UUO-induced collagen deposition and fibrosis on day 7. Additionally, significantly less inflammatory cell infiltration, a lower ratio of Bax to Bcl-2 expression, and fewer apoptotic cells on TUNEL staining were observed in the obstructed kidneys of oleanolic acid-treated mice. Oleanolic acid increased the expression of nuclear Nrf2, heme oxygenase-1, NAD(P)H:quinone oxidoreductase 1 and heat shock protein 70, and decreased lipid peroxidation in the obstructed kidney of UUO mice. There were no changes in the expression of total Nrf2 and Kelch-like ECH-associated protein 1, indicating that oleanolic acid enhanced nuclear translocation of Nrf2.
Conclusions
These results suggest that oleanolic acid may exert beneficial effects on renal fibrosis by increasing nuclear translocation of Nrf2 and subsequently reducing renal oxidative stress.
doi:10.1186/1743-7075-11-2
PMCID: PMC3896758  PMID: 24393202
12.  Disintegration of wheat aleurone structure has an impact on the bioavailability of phenolic compounds and other phytochemicals as evidenced by altered urinary metabolite profile of diet-induced obese mice 
Background
Phenolic acids are covalently bound to the arabinoxylan fibre matrix of wheat aleurone layer. In order to be bioavailable they need to be released by endogenous or bacterial enzymes and absorbed within the intestinal lumen. The intestinal microbiota can metabolize phenolic acids and other food-born phytochemicals. However, the effect of structure of the cereal bran or aleurone layer on these processes is not comprehensively studied.
Methods
The structure of aleurone layer was modified either by dry-grinding or by enzymatic treatments with xylanase alone or in combination with feruloyl esterase. Diet induced obese C57BL6/J mice were fed with high-fat diets containing either pure ferulic acid, or one of the four differentially treated aleurone preparations for 8 weeks. The diets were designed to be isocaloric and to have similar macronutrient composition. The urinary metabolite profiles were investigated using non-targeted LC-qTOF-MS-metabolomics approach.
Results
The different dietary groups were clearly separated in the principal component analysis. Enzymatic processing of aleurone caused increased excretion of ferulic acid sulfate and glycine conjugates reflecting the increase in unbound form of readily soluble ferulic acid in the diet. The urinary metabolite profile of the diet groups containing native and cryo-ground aleurone was more intense with metabolites derived from microbial processing including hippuric acid, hydroxyl- and dihydroxyphenylpropionic acids. Furthermore, aleurone induced specific fingerprint on the urinary metabolite profile seen as excretion of benzoxazinoid metabolites, several small dicarboyxlic acids, and various small nitrogen containing compounds.
Conclusions
The structural modifications on wheat aleurone fraction resulted in altered metabolism of aleurone derived phenolic acids and other phytochemicals excreted in urine of diet-induced obese mice.
doi:10.1186/1743-7075-11-1
PMCID: PMC3891979  PMID: 24383425
Arabinoxylan; Ferulic acid; Microbial metabolism; Non-targeted metabolomics; LC-MS; Metabolite profiling
13.  ApoC-III and visceral adipose tissue contribute to paradoxically normal triglyceride levels in insulin-resistant African-American women 
Background
African-Americans are more insulin-resistant than whites but have lower triglyceride (TG) concentrations. The metabolic basis for this is unknown. Our goal was to determine in a cross-sectional study the effect of insulin resistance, visceral adipose tissue (VAT) and the apolipoproteins, B, C-III and E, on race differences in TG content of very low density lipoproteins (VLDL).
Methods
The participants were 31 women (16 African-American, 15 white) of similar age (37 ± 9 vs. 38 ± 11y (mean ± SD), P = 0.72) and BMI (32.4 ± 7.2 vs. 29.3 ± 6.0 kg/m2, P = 0.21). A standard diet (33% fat, 52% carbohydrate, 15% protein) was given for 7 days followed by a test meal (40% fat, 40% carbohydrate, 20% protein) on Day 8. Insulin sensitivity index (SI) was calculated from the minimal model. VAT was measured at L2-3. The influence of race, SI, VAT and apolipoproteins on the TG content of VLDL was determined by random effects models (REM).
Results
African-Americans were more insulin-resistant (SI: 3.6 ± 1.3 vs. 5.6 ± 2.6 mU/L-1.min-1, P < 0.01) with less VAT (75 ± 59 vs. 102 ± 71 cm2, P < 0.01). TG, apoB and apoC-III content of light and dense VLDL were lower in African-Americans (all P < 0.05 except for apoC-III in light VLDL, P = 0.11). ApoE content did not vary by race. In REM, VAT but not SI influenced the TG concentration of VLDL. In models with race, SI, VAT and all apolipoproteins entered, race was not significant but apoC-III and VAT remained significant determinants of TG concentration in light and dense VLDL.
Conclusions
Low concentrations of apoC-III and VAT in African-Americans contribute to race differences in TG concentrations.
Trial registration
ClinicalTrials.gov Identifier: NCT00484861
doi:10.1186/1743-7075-10-73
PMCID: PMC3878037  PMID: 24365086
ApoC-III; Visceral adipose tissue; Triglyceride; Apoliprotein C-III; Visceral adiposity; Insulin resistance; African-Americans; Health disparities
14.  Acidic retinoids in small amounts promote retinyl ester formation in neonatal lung, with transient increases in retinoid homeostatic gene expression 
Background
Mixing a small proportion, 10%, of retinoic acid (RA) into an oral dose of vitamin A (VA) has been shown to markedly increase retinol uptake and retinyl ester (RE) formation in the neonatal lung, as compared to VA given alone. Concomitantly, several retinoid homeostatic genes, lecithin:retinol acyltransferase (LRAT), RA-4-hydroxylase (CYP26B1), and stimulated by retinoic acid gene-6 (STRA6) were upregulated. However, whether multiple doses may act accumulatively and whether less than 10% RA can be used has not been determined.
Methods
Neonatal rats were treated once on postnatal day (PD) 4 or PD14 with VA alone or VA combined with 10% RA (VARA10%) or a stable analog, Am580 (VAAm10%), or they were treated with multiple doses on PD4, 7, 11, and 14.
Results
RE increased cumulatively with multiple dosing. However, LRAT, CYP26B1 and STRA6 mRNA levels were similar for single and multiple treatments, indicating a transient noncumulative impact on gene expression. Lung RE was elevated with as little as 0.5% RA (P < 0.05) in a single dosing study. Whereas all concentrations of VARA elevated lung RE in single dosing studies, only 10% RA increased lung RE after multiple dosing, suggesting an attenuation of RA action with repeated dosing. In contrast, VAAm10%, 2%, and 1% all significantly increased lung RE after multiple doses (P < 0.05), while also increasing the expression of LRAT and CYP26B1.
Conclusions
These results indicate that the neonatal lung is very sensitive to acidic retinoid exposure and suggest that a VA combined with a very small fraction of acidic retinoid could be effective in increasing the lung’s storage pool of VA.
doi:10.1186/1743-7075-10-72
PMCID: PMC3878245  PMID: 24351038
Vitamin A supplementation; Acidic retinoids; Neonates; Lung
15.  The effects of caffeine, nicotine, ethanol, and tetrahydrocannabinol on exercise performance 
Caffeine, nicotine, ethanol and tetrahydrocannabinol (THC) are among the most prevalent and culturally accepted drugs in western society. For example, in Europe and North America up to 90% of the adult population drinks coffee daily and, although less prevalent, the other drugs are also used extensively by the population. Smoked tobacco, excessive alcohol consumption and marijuana (cannabis) smoking are addictive and exhibit adverse health effects. These drugs are not only common in the general population, but have also made their way into elite sports because of their purported performance-altering potential. Only one of the drugs (i.e., caffeine) has enough scientific evidence indicating an ergogenic effect. There is some preliminary evidence for nicotine as an ergogenic aid, but further study is required; cannabis and alcohol can exhibit ergogenic potential under specific circumstances but are in general believed to be ergolytic for sports performance. These drugs are currently (THC, ethanol) or have been (caffeine) on the prohibited list of the World Anti-Doping Agency or are being monitored (nicotine) due to their potential ergogenic or ergolytic effects. The aim of this brief review is to evaluate the effects of caffeine, nicotine, ethanol and THC by: 1) examining evidence supporting the ergogenic or ergolytic effects; 2) providing an overview of the mechanism(s) of action and physiological effects; and 3) where appropriate, reviewing their impact as performance-altering aids used in recreational and elite sports.
doi:10.1186/1743-7075-10-71
PMCID: PMC3878772  PMID: 24330705
Common drugs; Doping; Performance enhancement; Anti-doping
16.  Zerumbone, a tropical ginger sesquiterpene, ameliorates streptozotocin-induced diabetic nephropathy in rats by reducing the hyperglycemia-induced inflammatory response 
Background
Zerumbone is one of the pungent constituents of Zingiber zerumbet (L) Smith (Zingiberaceae family). The aim of the present study was to examine the effects of zerumbone in rats with streptozotocin-induced diabetic nephropathy (DN).
Methods
Diabetic rats were treated orally with zerumbone (20 or 40 mg/kg/day) for 8 weeks. Changes in renal function-related parameters in plasma and urine were analyzed at the end of the study. Kidneys were isolated for pathology histology, immunohistochemistry, and Western blot analyses.
Results
Diabetic rats exhibited renal dysfunction, as evidenced by reduced creatinine clearance, increased blood glucose, blood urea nitrogen and proteinuria, along with marked elevation in the ratio of kidney weight to body weight, that were reversed by zerumbone. Zerumbone treatment was found to markedly improve histological architecture in the diabetic kidney. Hyperglycemia induced p38 mitogen-activated protein kinase activation, leading to increased infiltration of macrophages and increased levels of interleukin (IL)-1, IL-6 and tumor necrosis factor-α. All of the above abnormalities were reversed by zerumbone treatment, which also decreased the expression of intercellular adhesion molecule-1, monocyte chemoattractant protein-1, transforming growth factor-β1 and fibronectin in the diabetic kidneys.
Conclusions
The beneficial effect of zerumbone in rats with DN is at least in part through antihyperglycemia which was accompanied by inhibition of macrophage infiltration via reducing p38 mediated inflammatory response.
doi:10.1186/1743-7075-10-64
PMCID: PMC3818326  PMID: 24499158
17.  Mitochondrial-associated metabolic disorders: foundations, pathologies and recent progress 
Research in the last decade has revolutionized the way in which we view mitochondria. Mitochondria are no longer viewed solely as cellular powerhouses; rather, mitochondria are now understood to be vibrant, mobile structures, constantly undergoing fusion and fission, and engaging in intimate interactions with other cellular compartments and structures. Findings have implicated mitochondria in a wide variety of cellular processes and molecular interactions, such as calcium buffering, lipid flux, and intracellular signaling. As such, it does not come as a surprise that an increasing number of human pathologies have been associated with functional defects in mitochondria. The difficulty in understanding and treating human pathologies caused by mitochondrial dysfunction arises from the complex relationships between mitochondria and other cellular processes, as well as the genetic background of such diseases. This review attempts to provide a summary of the background knowledge and recent developments in mitochondrial processes relating to mitochondrial-associated metabolic diseases arising from defects or deficiencies in mitochondrial function, as well as insights into current and future avenues for investigation.
doi:10.1186/1743-7075-10-63
PMCID: PMC3853754  PMID: 24499129
Mitochondria; mtDNA; Metabolism; Disease
18.  Diet and cardiovascular health in asymptomatic normo- and mildly-to-moderately hypercholesterolemic participants – baseline data from the BLOOD FLOW intervention study 
Background
For decades in Finland, intensive population strategies and preventive activities have been used to lower the risk of atherosclerotic coronary heart disease (CHD). Lifestyle changes, with the emphasis on diet, play an important role in preventive strategies. The aim of this study was to evaluate arterial stiffness and endothelial function in asymptomatic free-living adults and to relate the results to CHD risk factors and lifestyle habits with the emphasis on diet.
Methods
Ninety-four asymptomatic participants were recruited by advertisements in four large companies and two research institutes employing mainly office workers. Arterial stiffness was assessed as the cardio-ankle vascular index in large arteries, and endothelial function as the reactive hyperemia index with peripheral arterial tonometry. The systematic Cardiovascular Risk Estimation (SCORE) was calculated.
Results
The data was collected in the spring of 2011. Anthropometric, dietary, and lipid data was available from 92 participants, blood pressure from 85 and vascular measurements from 86–88 subjects (38% males; 62% females; mean age of all 51). The majority (72%) had an elevated low density lipoprotein (LDL) cholesterol concentration and over half were overweight or obese. SCORE stated that 49% of the participants had a moderate risk of cardiovascular disease. When compared to general recommendations, half of the participants had too high intake of total fat and in 66% the consumption of saturated fat was too high. In contrast, the intake of carbohydrates was too low in 90% of the participants and for fiber 73% were below recommendations. There was evidence of borderline or increased arterial stiffness in 72% of the participants and endothelial function was impaired in 8%. Arterial stiffness was associated with LDL cholesterol concentration (p = 0.024), dietary cholesterol intake (p = 0.029), and SCORE (p < 0.001).
Conclusions
In a cross-sectional study of asymptomatic middle-aged participants, the half had a moderate risk for cardiovascular diseases manifested as increased arterial stiffness, elevated LDL cholesterol concentration, and poor dietary habits. The new observation that arterial stiffness was associated with dietary cholesterol intake and SCORE emphasizes the urgency of adequate lifestyle and dietary interventions to prevent future coronary events even in asymptomatic participants.
Trial registration
Clinical Trials Register # NCT01315964
doi:10.1186/1743-7075-10-62
PMCID: PMC3851521  PMID: 24499098
Diet; Saturated fatty acids; LDL cholesterol; Arterial stiffness; Endothelial function; Cardio-ankle vascular index; Reactive hyperemia index; Systematic cardiovascular risk estimation
19.  Coffee polyphenols exert hypocholesterolemic effects in zebrafish fed a high-cholesterol diet 
Background
Hypercholesterolemia is an important risk factor for the development of coronary artery disease. Some dietary polyphenols, such as coffee polyphenols (CPPs), reduce cholesterol levels. The mechanism of this cholesterol-lowering effect is not fully understood, although 5-CQA, a major component of CPPs, reportedly inhibits cholesterol biosynthesis. Here, we investigated the mechanism of the cholesterol-lowering effect of CPPs on the basis of cholesterol metabolism–related gene expression in the liver. We also examined the effects of CPPs on vascular lipid accumulation in zebrafish with high cholesterol diet–induced hypercholesterolemia.
Methods
Over 14 weeks, adult zebrafish were fed a control diet, a high-cholesterol diet, or the latter diet supplemented with CPPs. To measure the extent of vascular lipid accumulation, for 10 days larval zebrafish (which are optically transparent) were fed these same diets with the addition of a fluorescent cholesteryl ester.
Results
In adult zebrafish, addition of CPPs to a high-cholesterol diet significantly suppressed the increase in plasma and liver cholesterol levels seen when fish ingested the same diet lacking CPPs. Transcription levels of the liver genes hmgcra (encoding 3-hydroxy-3-methylglutaryl-coenzyme A reductase A, a rate-limiting enzyme in cholesterol biosynthesis) and mtp (encoding microsomal triglyceride transfer protein, a lipid transfer protein required for assembly and secretion of lipoproteins) were significantly lower in fish fed the CPP-containing diet than in fish fed the unsupplemented high-cholesterol diet. In contrast, the expression level of the liver gene cyp7a1a (encoding the cytochrome P450 polypeptide 1a of subfamily A of family 7, a rate-limiting enzyme for bile acid biosynthesis) increased significantly upon consumption of the CPP-containing diet. In larval fish, accumulation of fluorescently labeled cholesterol in the caudal artery was greatly reduced on the CPP-containing diet.
Conclusions
CPP ingestion suppressed cholesterol accumulation in the plasma, liver, and vascular system of zebrafish. Downregulation of cholesterol and lipoprotein synthesis and upregulation of bile acid synthesis in the liver may be the fundamental underlying mechanisms by which CPPs exert their hypocholesterolemic effects. CPP intake may help prevent and manage hypercholesterolemia in humans, and further investigations along these lines using a variety of CPP dose rates are warranted.
doi:10.1186/1743-7075-10-61
PMCID: PMC3871761  PMID: 24220226
Chlorogenic acids; Cholesterol diet; Coffee polyphenols; Cytochrome P450 7A1; 3-hydroxy-3- methylglutaryl-coenzyme A reductase; Hypercholesterolemia; Microsomal triglyceride transfer protein; Vascular lipid accumulation; Zebrafish
20.  Lower serum levels of total cholesterol are associated with higher urinary levels of 8-hydroxydeoxyguanosine 
Background
Lower serum total (TC), high-density lipoprotein (HDL-C) and low-density lipoprotein cholesterols (LDL-C) have been linked to an increased risk of cancer in various sites, but its underlying mechanism remains unclear. In an attempt to clarify the association between cholesterol levels and oxidative DNA damage, we investigated the relationship between serum cholesterol and urinary 8-hydroxydeoxyguanosine levels in a Japanese working population.
Methods
The study subjects were 294 men and 209 women aged 21-66 years in two Japanese municipal offices. Urinary 8-hydroxydeoxyguanosine (8-OHdG) was measured using an automated high-pressure liquid chromatography. Linear regression analysis was used to examine the associations of urinary 8-OHdG with TC, HDL-C and LDL-C levels with adjustment for sex, age, smoking and body mass index. Subgroup analyses were conducted by smoking status in men and age in women. Analysis of covariance was employed to estimate adjusted means of urinary 8-OHdG across TC category.
Results
After multivariate adjustment, urinary 8-OHdG levels were inversely associated with serum TC levels (β = −0.0015, p < 0.05) and LDL-C levels (β = −0.0012, p = 0.07). The inverse association with TC was apparent among smoking men (β = −0.0017, p < 0.05) and among women aged less than 48 years (β = −0.0040, p < 0.01). 8-OHdG decreased as TC increased (up to 219 mg/dL); subjects with TC levels of <160 mg/dL had a 17.4% higher adjusted mean of 8-OHdG than did those with TC levels of 200–219 mg/dL.
Conclusion
Results suggest that circulating low TC levels are associated with higher oxidative DNA damage.
doi:10.1186/1743-7075-10-59
PMCID: PMC3850899  PMID: 24499054
Oxidative stress; 8-hydroxydeoxyguanosine (8-OHdG); Epidemiologic studies; Cross-sectional studies; High-density lipoprotein (HDL-C); Low-density lipoprotein (LDL-C); Total cholesterol
21.  Metabolic effects of milk protein intake strongly depend on pre-existing metabolic and exercise status 
Milk protein intake has recently been suggested to improve metabolic health. This Perspective provides evidence that metabolic effects of milk protein intake have to be regarded in the context of the individual’s pre-existing metabolic and exercise status. Milk proteins provide abundant branched-chain amino acids (BCAAs) and glutamine. Plasma BCAAs and glutamine are increased in obesity and insulin resistance, but decrease after gastric bypass surgery resulting in weight loss and improved insulin sensitivity. Milk protein consumption results in postprandial hyperinsulinemia in obese subjects, increases body weight of overweight adolescents and may thus deteriorate pre-existing metabolic disturbances of obese, insulin resistant individuals.
doi:10.1186/1743-7075-10-60
PMCID: PMC3856498  PMID: 24225036
Adipogenesis; Body weight; Branched-chain amino acids; Glutaminolysis; Insulin resistance; Milk proteins; microRNA; mTORC1; Obesity; Prostate cancer
22.  The effect of a low-fat, plant-based lifestyle intervention (CHIP) on serum HDL levels and the implications for metabolic syndrome status – a cohort study 
Background
Low levels of high-density lipoproteins (HDL) are considered an important risk factor for cardiovascular disease and constitute one of the criteria for the Metabolic Syndrome (MetS). Lifestyle interventions promoting a low-fat, plant-based eating pattern appear to paradoxically reduce cardiovascular risk but also HDL levels. This study examined the changes in MetS risk factors, in particular HDL, in a large cohort participating in a 30-day lifestyle intervention that promoted a low-fat, plant-based eating pattern.
Methods
Individuals (n = 5,046; mean age = 57.3 ± 12.9 years; 33.5% men, 66.5% women) participating in a in a Complete Health Improvement Program (CHIP) lifestyle intervention within the United States were assessed at baseline and 30 days for changes in body mass index (BMI), blood pressure (BP), lipid profile and fasting plasma glucose (FPG).
Results
HDL levels decreased by 8.7% (p<0.001) despite significant reductions (p<0.001) in BMI (-3.2%), systolic BP (-5.2%), diastolic BP (-5.2%), triglycerides (TG; -7.7%), FPG (-6.3%), LDL (-13.0%), total cholesterol (TC, -11.1%), TC: HDL ratio (-3.2%), and LDL: HDL ratio (-5.3%). While 323 participants classified as having MetS at program entry no longer had this status after the 30 days, 112 participants acquired the MetS classification as a result of reduction in their HDL levels.
Conclusions
When people move towards a low-fat, plant-based diet, HDL levels decrease while other indicators of cardiovascular risk improve. This observation raises questions regarding the value of using HDL levels as a predictor of cardiovascular risk in populations who do not consume a typical western diet. As HDL is part of the assemblage of risk factors that constitute MetS, classifying individuals with MetS may not be appropriate in clinical practice or research when applying lifestyle interventions that promote a plant-based eating pattern.
doi:10.1186/1743-7075-10-58
PMCID: PMC3849684  PMID: 24283215
Metabolic Syndrome; Cardiovascular disease; HDL; Lipids; Lifestyle intervention; CHIP
23.  Effects of oral adenosine-5′-triphosphate supplementation on athletic performance, skeletal muscle hypertrophy and recovery in resistance-trained men 
Background
Currently, there is a lack of studies examining the effects of adenosine-5′-triphosphate (ATP) supplementation utilizing a long-term, periodized resistance-training program (RT) in resistance-trained populations. Therefore, we investigated the effects of 12 weeks of 400 mg per day of oral ATP on muscular adaptations in trained individuals. We also sought to determine the effects of ATP on muscle protein breakdown, cortisol, and performance during an overreaching cycle.
Methods
The study was a 3-phase randomized, double-blind, and placebo- and diet-controlled intervention. Phase 1 was a periodized resistance-training program. Phase 2 consisted of a two week overreaching cycle in which volume and frequency were increased followed by a 2-week taper (Phase 3). Muscle mass, strength, and power were examined at weeks 0, 4, 8, and 12 to assess the chronic effects of ATP; assessment performance variables also occurred at the end of weeks 9 and 10, corresponding to the mid and endpoints of the overreaching cycle.
Results
There were time (p < 0.001), and group x time effects for increased total body strength (+55.3 ± 6.0 kg ATP vs. + 22.4 ± 7.1 kg placebo, p < 0.001); increased vertical jump power (+ 796 ± 75 ATP vs. 614 ± 52 watts placebo, p < 0.001); and greater ultrasound determined muscle thickness (+4.9 ± 1.0 ATP vs. (2.5 ± 0.6 mm placebo, p < 0.02) with ATP supplementation. During the overreaching cycle, there were group x time effects for strength and power, which decreased to a greater extent in the placebo group. Protein breakdown was also lower in the ATP group.
Conclusions
Our results suggest oral ATP supplementation may enhance muscular adaptations following 12-weeks of resistance training, and prevent decrements in performance following overreaching. No statistically or clinically significant changes in blood chemistry or hematology were observed.
Trial registration
ClinicalTrials.gov NCT01508338
doi:10.1186/1743-7075-10-57
PMCID: PMC3849389  PMID: 24330670
Adenosine triphosphate; Exercise performance; Power; Strength; Muscle hypertrophy; Sports nutrition
24.  Supplementary site interactions are critical for the regulation of microsomal triglyceride transfer protein by microRNA-30c 
Microsomal triglyceride transfer protein (MTTP) is an essential chaperone that assists in the assembly of apolipoprotein B-containing lipoproteins to transport lipids. We have shown that microRNA (miR)-30c regulates MTTP expression but other members of the same family do not. Further, we showed that interactions between miR-30c seed sequence and the 3΄-untranslated region (UTR) of the MTTP mRNA are critical for this regulation. The same seed sequence is shared by all the members of the miR-30 family. Therefore, it is unclear why only miR-30c regulates MTTP expression. Bioinformatics analysis revealed that, miR-30c interacts with MTTP mRNA involving supplementary site, besides seed sequence, forming an intervening loop. Here, we evaluated the importance of the supplementary site and the size of the intervening loop in miR-30c/MTTP mRNA interactions by cloning MTTP 3΄-UTR at the end of the luciferase gene and subjecting it to site-directed mutagenesis. Reducing the number of base pairs at the supplementary site abolished the ability of miR-30c to reduce luciferase activity. However, increasing the number of base pairs at the supplementary site, seed sequence or in the intervening loop enhanced the efficacy of miR-30c in reducing luciferase activity. These studies demonstrated that the supplementary site of miR-30c is, but the intervening loop is not, critical for binding to the MTTP mRNA. To our knowledge, this is the first demonstration that miRs might require both seed and supplementary interactions to regulate target mRNA specificity. Further, this study suggests that more potent miR-30c mimics could be synthesized by increasing base pairing in the loop region.
doi:10.1186/1743-7075-10-56
PMCID: PMC3856448  PMID: 24007526
MTTP; apoB; Lipoproteins; microRNA; miR-30; Hyperlipidemia; UTR
25.  ProAlgaZyme subfraction improves the lipoprotein profile of hypercholesterolemic hamsters, while inhibiting production of betaine, carnitine, and choline metabolites 
Background
Previously, we reported that ProAlgaZyme (PAZ) and its biologically active fraction improved plasma lipids in hypercholesterolemic hamsters, by significantly increasing the high density lipoprotein cholesterol (HDL-C) while reducing non-HDL cholesterol and the ratio of total cholesterol/HDL-C. Moreover, hepatic mRNA expression of genes involved in HDL/reverse cholesterol transport were significantly increased, while cholesteryl ester transfer protein (CETP) expression was partially inhibited. In the current study, we investigated the therapeutic efficacy of the biologically active fraction of PAZ (BaP) on the plasma lipid and plasma metabolomic profiles in diet induced hypercholesterolemic hamsters.
Methods
Fifty male Golden Syrian hamsters were fed a high fat diet for 4 weeks prior to randomization into 6 groups, based on the number of days they received subsequent treatment. Thus animals in T0, T3, T7, T10, T14, and T21 groups received BaP for 0, 3, 7, 10, 14, and 21 days, respectively, as their drinking fluid. Plasma lipids were assayed enzymatically, while real-time reverse transcriptase polymerase chain reaction (RT-PCR) provided the transcription levels of the Apolipoprotein (Apo) A1 gene. The plasma metabolomic profile was determined using 1H nuclear magnetic resonance (NMR) spectroscopy in conjunction with multivariate analysis.
Results
Plasma HDL-C was significantly increased in T3 (P < 0.05) and T21 (P < 0.001), while non-HDL cholesterol was significantly reduced in T3, T7, T10 (P < 0.001) and T14, T21 (P < 0.01). Moreover, the ratio of total cholesterol/HDL-C was significantly lower in all BaP treated groups (P < 0.001) as compared with T0. Quantitative RT-PCR showed an increase in Apo A1 expression in T10 (3-fold) and T21 (6-fold) groups. NMR data followed by multivariate analysis showed a clear separation between T0 and T21 groups, indicating a difference in their metabolomic profiles. Plasma concentrations of metabolites associated with a risk for atherosclerosis and cardiovascular disease, including choline, phosphocholine, glycerol-phosphocholine, betaine and carnitine metabolites were significantly lower in the T21 group.
Conclusion
Treatment with BaP significantly improved the plasma lipid profile by increasing HDL-C and lowering non-HDL cholesterol. In addition, BaP potentially improved the plasma metabolomic profile by reducing the concentration of key metabolites associated with risk for atherosclerosis and cardiovascular disease.
doi:10.1186/1743-7075-10-55
PMCID: PMC3844637  PMID: 23981691
Apolipoprotein A1; Betaine; Carnitine; Choline; HDL; 1H NMR; Lipid metabolism; Metabolomics; ProAlgaZyme

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