The role of menaquinones (vitamin K2) in human health
British Journal of Nutrition   FirstView Article, pp 1-12     2013   Joline W. J. Beulens

Recent reports have attributed the potential health benefits of vitamin K beyond its function to activate hepatic coagulation factors. Moreover, several studies have suggested that menaquinones, also known as vitamin K2, may be more effective in activating extra-hepatic vitamin K-dependent proteins than phylloquinone, also known as vitamin K1. Nevertheless, present dietary reference values (DRV) for vitamin K are exclusively based on phylloquinone, and its function in coagulation. The present review describes the current knowledge on menaquinones based on the following criteria for setting DRV: optimal dietary intake; nutrient amount required to prevent deficiency, maintain optimal body stores and/or prevent chronic disease; factors influencing requirements such as absorption, metabolism, age and sex. Dietary intake of menaquinones accounts for up to 25 % of total vitamin K intake and contributes to the biological functions of vitamin K. However, menaquinones are different from phylloquinone with respect to their chemical structure and pharmacokinetics, which affects bioavailability, metabolism and perhaps impact on health outcomes. There are significant gaps in the current knowledge on menaquinones based on the criteria for setting DRV. Therefore, we conclude that further investigations are needed to establish how differences among the vitamin K forms may influence tissue specificities and their role in human health. However, there is merit for considering both menaquinones and phylloquinone when developing future recommendations for vitamin K intake.

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Dihydrotestosterone is elevated following sprint exercise in healthy young men
Alan A. Smith             Journal of Applied Physiology May 15, 2013 vol. 114 no. 10 1435-1440

Dihydrotestosterone (DHT) exerts both functional and signaling effects extending beyond the effects of testosterone in rodent skeletal muscle. As a primer for investigating the role of DHT in human skeletal muscle function, this study aimed to determine whether circulating DHT is acutely elevated in men following a bout of repeat sprint exercise and to establish the importance of training status and sprint performance to this response.

Fourteen healthy active young men (V̇o2max 61.0 ± 8.1 ml·kg body mass−1·min−1) performed a bout of repeat sprint cycle exercise at a target workload based on an incremental work-rate maximum (10 × 30 s at 150% Wmax with 90-s recovery). Venous blood samples were collected preexercise and 5 and 60 min after exercise.

Five minutes after exercise, there were significant elevations in total testosterone (TT; P < 0.001), free testosterone (FT; P < 0.001), and DHT (P = 0.004), which returned to baseline after 1 h. Changes in DHT with exercise (5 min postexercise − preexercise) correlated significantly with changes in TT (r = 0.870; P < 0.001) and FT (r = 0.914; P < 0.001). Sprinting cadence correlated with changes in FT (r = 0.697; P = 0.006), DHT (r = 0.625; P = 0.017), and TT (r = 0.603; P = 0.022), and habitual training volume correlated with the change in TT (r = 0.569, P = 0.034). In conclusion, our data demonstrate that DHT is acutely elevated following sprint cycle exercise and that this response is influenced by cycling cadence. The importance of DHT in the context of exercise training and sports performance remains to be determined.

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Dietary inorganic nitrate reduces basal metabolic rate in man
Nitric Oxide Volume 31, Supplement 1, 15 April 2013, Pages S46   Tomas Schiffer

The integration of the rate-of-living and oxidative damage theory of aging predicts that lifespan extension is linked to low energy metabolism, low reactive oxygen species production rates and a slow aging rate. Recent studies show that inorganic nitrate, an inorganic anion abundant in vegetables, can reduce oxygen consumption during physical exercise and attenuate oxidative stress in animal models of disease. Bioactivation of nitrate involves its active accumulation in saliva and reduction to nitrite by oral bacteria. In a double-blind, randomized cross over designed study we examined the effects of dietary nitrate on resting energy expenditure and markers of oxidative stress in man. Basal metabolic rate (BMR) was measured by indirect calorimetry in 15 young healthy male volunteers after a three day dietary intervention with sodium nitrate (NaNO3, 0.1 mmol/kg/day) or placebo (NaCl). This amount of nitrate corresponds to what is found in 100–300 g of nitrate-rich vegetables such as spinach or beetroot. After the nitrate intervention BMR was 4.3% lower compared to placebo (p < 0.02). The change in BMR correlated strongly to the degree of nitrate accumulation in saliva (r2 = 0.72, p < 0.002). Plasma levels of Malondialdehyde (MDA), a marker of oxidative stress, were lower after nitrate supplementation while thyroid hormone status was unaffected. Vegetables figure prominently in the cuisines of cultures known for their longevity. Future studies will reveal if such life span extension in any way is linked to the high nitrate content of this food group.

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Nitrite influences proliferation of myoblasts via its reduction to nitric oxide in skeletal muscle tissue
Nitric Oxide Volume 31, Supplement 1, 15 April 2013, Pages S25     Ulrike B. Hendgen-Cotta

Skeletal muscle regeneration is governed by complex cellular signaling processes. Proliferation of skeletal myoblasts is a key initial event in muscle regeneration and has been largely related to mammalian target of rapamycin (mTOR) signal transduction mechanisms. Although the precise underlying signaling remains incompletely understood, the role of nitric oxide (NO) in cell cycle regulation is well-appreciated. Nitrite, the oxidation product of NO, is regarded as a stable source for NO-like bioactivity in cases when the oxygen-dependent NO-synthases become dysfunctional. Whether nitrite itself has the potential to affect myoblast proliferation and metabolic activity under normoxic conditions with or without activation of the NO/cyclic guanosine monophosphate (cGMP) pathway is not known.

Methods

The influence of nitrite and NO on C2C12 myoblast proliferation was observed in cultures grown in DMEM + 10% FCS at 37 °C/5% CO2, with or without sodium nitrite, NO-donor DETA-NONOate, NO-scavenger cPTIO, soluble guanylatecyclase (sGC) inhibitor ODQ, or mTOR inhibitor rapamycin. Neutral red staining, propodium iodide staining for cell cycle analysis, WST-8 viability assay, mTOR phosphorylation activity assay and intracellular cGMP measuerements were performed according to modified manufacturer’s protocols.

Results

We here show that nitrite increases proliferation and metabolic activity of murine cultured myoblasts dose-dependently in normoxia. This effect is not abolished by the NO scavenger 2-(4-carboxy-phenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (cPTIO) and does not affect intracellular cGMP levels, implicating a cGMP-independent mechanism. Nitrite circumvents the rapamycin induced attenuation of myoblast proliferation and enhances mTOR phosphorylation activity.

Conclusion

Our results provide evidence for a novel potential physiological and therapeutic approach of nitrite in skeletal muscle regeneration processes under normoxia independent of NO and cGMP.

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Higher levels of endogenous nitrite are associated with superior vascular function and lactate anaerobic threshold in athletes
Matthias TotzeckNitric Oxide Volume 31, Supplement 1, 15 April 2013, Pages S17–S18

Nitrate and nitrite as oxidative derivates of nitric oxide have been suggested to both modulate and reflect exercise capacity in humans. The failure to increase endogenous nitrite has been related to decreased maximum exercise capacity, while a diet rich in nitrate improved exercise performance. The modulation of nitrate/nitrite levels has furthermore been related to an improvement of vascular functions. It remains unresolved to date whether baseline endogenous levels are associated with a superior vascular function and if this is also related to an improved exercise capacity.

Objective

To determine whether higher baseline nitrite levels are associated with a superior vascular function and whether this also relates to an advantage in exercise capacity as measured by lactate anaerobic threshold (LAT).

Methods

12 male athletes with an average age of 25 ± 2 years, a body weight of 79 ± 4 kg, a height of 185 ± 5 cm and trained 5 ± 1 times per week (means ± SD) were enrolled in this study. Each participant reported twice to the testing facility (n = 22 observations). Blood was drawn from the left cubital vein and the resulting plasma was used to determine the circulating levels of nitrate and nitrite via HPLC (ENO-20). 15 min later, vascular function was assessed on the contralateral arm (brachial artery) by measuring flow-mediated vasodilation (FMD) using a 12 MHz ultrasound probe. Participants were hereafter asked to complete a stepwise ergometric test starting at 100 W with increasing workloads (+50 W) every 5 min on a stationary bicycle ergometer (Lode Excalibur Sport). Blood was drawn from the ear lope and used to determine the levels of lactate at the end of each incremental steP Heart rate was measured continuously and the LAT (4 mM) in relation to heart rate was calculated using non-linear regression models.

Results

Baseline plasma nitrite levels correlated with LATs (r = 0.65; p = 0.001, n = 22) and with endothelial function as assessed by FMD (r = 0.71; p = 0.0002). Cor-relation coefficients from both testing days did not differ. Multiple linear regressions showed that base-line plasma nitrite level but not endothelial function was an independent predictor of exercise capacity. No such correlations were determined for plasma nitrate levels.

Conclusion

Higher baseline levels of nitrite are associated with a superior vascular function and lactate anerobic threshold.

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Basic evidence for epidermal H2O2/ONOO−-mediated oxidation/nitration in segmental vitiligo is supported by repigmentation of skin and eyelashes after reduction of epidermal H2O2 with topical NB-UVB-activated pseudocatalase PC-KUS
Karin U. Schallreuter     The FASEB Journal   Published online before print April 29, 2013

Nonsegmental vitiligo (NSV) is characterized by loss of inherited skin color. The cause of the disease is still unknown despite accumulating in vivo and in vitro evidence of massive epidermal oxidative stress via H2O2 and peroxynitrite (ONOO−) in affected individuals. The most favored hypothesis is based on autoimmune mechanisms. Strictly segmental vitiligo (SSV) with dermatomal distribution is a rare entity, often associated with stable outcome. Recently, it was documented that this form can be associated with NSV (mixed vitiligo). We here asked the question whether ROS and possibly ONOO− could be players in the pathogenesis of SSV. Our in situ results demonstrate for the first time epidermal biopterin accumulation together with significantly decreased epidermal catalase, thioredoxin/thioreoxin reductase, and MSRA/MSRB expression. Moreover, we show epidermal ONOO− accumulation. In vivo FT-Raman spectroscopy reveals the presence of H2O2, methionine sulfoxide, and tryptophan metabolites; i.e., N-formylkynurenine and kynurenine, implying Fenton chemistry in the cascade (n=10). Validation of the basic data stems from successful repigmentation of skin and eyelashes in affected individuals, regardless of SSV or segmental vitiligo in association with NSV after reduction of epidermal H2O2 (n=5). Taken together, our contribution strongly supports H2O2/ONOO-mediated stress in the pathogenesis of SSV. Our findings offer new treatment intervention for lost skin and hair color.

Senile hair graying: H2O2-mediated oxidative stress affects human hair color by blunting methionine sulfoxide repair
  The FASEB Journal vol. 23 no. 7 2065-2075   J. M. Wood

Senile graying of human hair has been the subject of intense research since ancient times. Reactive oxygen species have been implicated in hair follicle melanocyte apoptosis and DNA damage. Here we show for the first time by FT-Raman spectroscopy in vivo that human gray/white scalp hair shafts accumulate hydrogen peroxide (H2O2) in millimolar concentrations. Moreover, we demonstrate almost absent catalase and methionine sulfoxide reductase A and B protein expression via immunofluorescence and Western blot in association with a functional loss of methionine sulfoxide (Met-S=O) repair in the entire gray hair follicle. Accordingly, Met-S=O formation of Met residues, including Met 374 in the active site of tyrosinase, the key enzyme in melanogenesis, limits enzyme functionality, as evidenced by FT-Raman spectroscopy, computer simulation, and enzyme kinetics, which leads to gradual loss of hair color. Notably, under in vitro conditions, Met oxidation can be prevented by l-methionine. In summary, our data feed the long-voiced, but insufficiently proven, concept of H2O2-induced oxidative damage in the entire human hair follicle, inclusive of the hair shaft, as a key element in senile hair graying, which does not exclusively affect follicle melanocytes. This new insight could open new strategies for intervention and reversal of the hair graying process.

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http://www.tandfonline.com/doi/abs/10.1080/02640414.2013.771958

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