atg7 and autophagy, autophagy slows down metabolism

Riboflavin functions as part of metabolic systems concerned with the oxidation of carbohydrates and amino acids, the constituents of proteins. http://www.britannica.com/eb/article-9075551  

niacin functions as part of a coenzyme involved in the metabolism of carbohydrates and acts to catalyze the oxidation of sugar derivatives and other substances. http://www.britannica.com/eb/article-9055669


https://answers.yahoo.com/question/index?qid=20060801071443AAtdDZn

Human epithelial cells are very sensitive to damage from low concentrations of unsaturated cis-configured fatty acids in vitro such as linoleic acid and oleic acid. Human epithelial cells are not as sensitive to saturated fatty acids. Various factors indicate that fatty acid binding proteins in the cytoplasm help fatty acid uptake in human lens cells, and that the uptake of fatty acids is influenced by concentrations of albumin in physiological solutions. This study measured the concentration of albumin in aqueous humour and showed that there was a significant age-dependent increase in albumin from approximately 2 μmol/L (<40 data-blogger-escaped-...="" data-blogger-escaped-...www.ncbi.nlm.nih.gov
www.journalofanimalscience.org

Calcium as a secondary messenger ... Important physiological roles for calcium signaling range widely. These include muscle contraction, neuronal transmission as in an excitatory synapse, cellular motility (including the movement of flagella and cilia), fertilisation, cell growth or proliferation, learning and memory as with synaptic plasticity, and secretion of saliva.[1] Other biochemical roles of calcium include regulating enzyme activity, permeability of ion channels, activity of ion pumps, and components of the cytoskeleton.[2] The resting concentration of Ca2+ in the cytoplasm is normally maintained in the range of 10–100 nM. To maintain this low concentration, Ca2+ is actively pumped from the cytosol to the extracellular space and into the endoplasmic reticulum (ER), and sometimes in the mitochondria. Certain proteins of the cytoplasm and organelles act as buffers by binding Ca2+. Signaling occurs when the cell is stimulated to release calcium ions (Ca2+) from intracellular stores, and/or when calcium enters the cell through plasma membrane ion channels.[3] Specific signals can trigger a sudden increase in the cytoplasmic Ca2+ level up to 500–1,000 nM by opening channels in the endoplasmic reticulum or the plasma membrane. The most common signaling pathway that increases cytoplasmic calcium concentration is the phospholipase C pathway. Many cell surface receptors, including G protein-coupled receptors and receptor tyrosine kinases activate the phospholipase C (PLC) enzyme. PLC hydrolyses the membrane phospholipid PIP2 to form IP3 and diacylglycerol (DAG), two classical second messengers. DAG activates the protein kinase C enzyme, while IP3 diffuses to the endoplasmic reticulum, binds to its receptor (IP3 receptor), which is a Ca2+ channel, and thus releases Ca2+ from the endoplasmic reticulum. Depletion of calcium from the endoplasmic reticulum will lead to Ca2+ entry from outside the cell by activation of "Store-Operated Channels" (SOCs). This inflowing calcium current that results after stored calcium reserves have been released is referred to as Ca2+-release-activated Ca2+ current (ICRAC). The mechanisms through which ICRAC occurs are currently still under investigation, although two candidate molecules, Orai1 and STIM1, have been linked by several studies, and a model of store-operated calcium influx, involving these molecules, has been proposed. Recent studies have cited the phospholipase A2 beta,[4] nicotinic acid adenine dinucleotide phosphate (NAADP),[5] and the protein STIM 1[6] as possible mediators of ICRAC. Many of Ca2+-mediated events occur when the released Ca2+ binds to and activates the regulatory protein calmodulin. Calmodulin may activate calcium-calmodulin-dependent protein kinases, or may act directly on other effector proteins. Besides calmodulin, there are many other Ca2+-binding proteins that mediate the biological effects of Ca2+. In neurons, concominant increases in cytosolic and mitochondrial calcium are important for the synchronization of neuronal electrical activity with mitochondrial energy metabolism. Mitochondrial matrix calcium levels can reach the tens of micromolar levels, which is necessary for the activation of isocitrate dehydrogenase, one of the key regulatory enzymes of the Kreb's cycle.[7][8] http://en.wikipedia.org/wiki/Calcium_signaling


The cAMP binding protein Epac modulates Ca2+ sparks by a Ca2+/calmodulin kinase signalling pathway in rat cardiac myocytes cAMP is a powerful second messenger whose known general effector is protein kinase A (PKA). The identification of a cAMP binding protein, Epac, raises the question of its role in Ca2+ signalling in cardiac myocytes. In this study, we analysed the effects of Epac activation on Ca2+ handling by using confocal microscopy in isolated adult rat cardiomyocytes. [Ca2+]i transients were evoked by electrical stimulation and Ca2+ sparks were measured in quiescent myocytes. Epac was selectively activated by the cAMP analogue 8-(4-chlorophenylthio)-2′-O-methyladenosine-3′,5′-cyclic monophosphate (8-CPT). Patch-clamp was used to record the L-type calcium current (ICa), and Western blot to evaluate phosphorylated ryanodine receptor (RyR). [Ca2+]i transients were slightly reduced by 10 μm 8-CPT (F/F0: decreased from 4.7 ± 0.5 to 3.8 ± 0.4, P < 0.05), an effect that was boosted when cells were previously infected with an adenovirus encoding human Epac. ICa was unaltered by Epac activation, so this cannot explain the decreased [Ca2+]i transients. Instead, a decrease in the sarcoplasmic reticulum (SR) Ca2+ load underlies the decrease in the [Ca2+]i transients. This decrease in the SR Ca2+ load was provoked by the increase in the SR Ca2+ leak induced by Epac activation. 8-CPT significantly increased Ca2+ spark frequency (Ca2+ sparks s−1 (100 μm)−1: from 2.4 ± 0.6 to 6.9 ± 1.5, P < 0.01) while reducing their amplitude (F/F0: 1.8 ± 0.02 versus 1.6 ± 0.01, P < 0.001) in a Ca2+/calmodulin kinase II (CaMKII)-dependent and PKA-independent manner. Accordingly, we found that Epac increased RyR phosphorylation at the CaMKII site. Altogether, our data reveal a new signalling pathway by which cAMP governs Ca2+ release and signalling in cardiac myocytes. http://jp.physoc.org/content/583/2/685 Recent studies demonstrated that the calcium/calmodulin dependent kinase 2 (CaMKII) is involved in the regulation of proliferation and survival of epithelial cells, were it phosphorylates RAF-1 and modulates MAPK pathway. A endogenous CaMKII inhibitor (hCaKIINα) is expressed in some cell types. It is down-expressed in colon and in ovarian cancer where it inversely correlates with the disease extension. Inhibition of CaMKII in these cells induced a reduction of ERK phosphorylation and cell proliferation. Then, the expression of hCaKIINα RNA was determined by real-time PCR in 24 primary MTCs and was correlated with some clinicopathological parameters. Gender and age at diagnosis did not correlate with hCaKIINα RNA expression. Serum calcitonin, (R2=0.032, P=0.017 by Spearman rank correlation), tumor volume (P=0.0094 by ANOVA), lymph node metastasis (P=0.0297 by t-test) and staging (P=0.0043 by ANOVA) were negatively correlated with the hCaMKIINα mRNA expression. http://www.endocrine-abstracts.org/ea/0032/ea0032oc3.5.htm

Results indicated that the calcium supplements depressed fecal copper losses and improved body copper retention as did potassium supplements. Magnesium and selenium supplementation of diets resulted in increased apparent fecal losses of copper while no effect of manganese supplementation was found. It may be that the unexpected positive effect of calcium on copper utilization was due to its neutralizing effect on the relatively high level of ascorbic acid provided by the constant background diet. Ascorbic acid is known to inhibit the absorption of copper.  http://www.ncbi.nlm.nih.gov/pubmed/2697140

A pathway activators (IBMX and forskolin) and inhibitors (H-89) and Ca2+/calmodulin pathways appeared to play important roles in the regulation of riboflavin uptake in Y-79 cells through significant reduction in V(max) (39%) and significant increase in K(m) (112%) of the uptake process. These studies demonstrated, for the first time, the existence of a specialized carrier-mediated system for riboflavin uptake in human-derived retinoblastoma cells. http://www.ncbi.nlm.nih.gov/pubmed/16117691

Originally, CREB was identified by Gonzalez and Montminy [55] as a factor induced in a cAMP-dependent process which could be activated by PKA-dependent phosphorylation. Later studies provided evidence that this transcription factor could also be activated in a Ca2+-dependent manner [45] and [46]. Numerous studies demonstrated that all kinases activating CREB phosphorylated the transcription factor at the same serine residue: Ser133[25], [26], [46] and [54]. First studies investigating which CaM-dependent kinase could play a role as a CREB-kinase suggested that this may be CaMKII [46], but subsequent investigations provided evidence that CaMKIV is the true CREB-Kinase inducing Ca2+-dependent gene expression [29] and [54]. In fact, Sun et al. [54] demonstrated in a detailed phosphopeptide analysis that CaMKII not only phosphorylated CREB at Ser133, but also at Ser142, and that the latter phosphorylation had an inhibitory influence on gene expression, and was dominant over Ser133 phosphorylation. IEGs such as c-fos are a group of genes which are rapidly and transiently activated by growth factors and other stimulatory mechanisms. A number of IEGs code for transcription factors like members of the fos and jun families, which dimerize to form the transcription regulatory complex AP-1. There is ample evidence that several signal transduction pathways can enhance the expression of c-fos, the best characterized system modulating the expression through the transcription factor CREB [56]. Recently, we provided evidence that CaMKIV could be involved in the regulation of c-fos expression in a primary fetal brain tissue culture system through THE PHOSPHORYLATION OF CREB, SINCE CAMKIV WAS PRESENT IN THOSE TISSUES ONLY AFTER INDUCTION BY THE THYROID HORMONE T3 (see below) [57], and Ca2+-dependent stimulation of c-fos expression was downregulated in the absence of CaMKIV, i.e., in the absence of T3 [58]. In this context it is also of interest that Matthews et al. [25] provided evidence that in transfected cells only CaMKIV, but not CaMKII, was able to transactivate a CRE-containing reporter gene in transient expression assays through the phosphorylation of CREB, since only CaMKIV could translocate to the nucleus [25]. On the other hand, phosphorylation of CREB by CaMKII could have an inhibitory effect on CREB-dependent gene expression, as suggested by Sun et al. [54], which could explain the recent finding of Nghiem et al. [59] who reported that in Jurkat T cells transfected with a constitutively active mutant of CaMKII, expression of interleukin-2 (IL-2) was downregulated by more than 90%. Since IL-2 expression is mainly controlled via the transcription factors NFAT and AP-1, the latter being a heterodimer of c-Fos and c-Jun, it could be suggested that downregulation of IL-2 could occur through inhibition of CREB controlling c-Fos expression. It is interesting that Nghiem et al. [59] indeed found that CaMKII significantly decreased stimulated transcription from AP-1. In Fig. 2 a schematic view of the different possible signal transduction pathways is provided, which may converge at the phosphorylation and subsequent activation or inhibition of CREB and possible consequences for the regulation of gene expression. 5. Induction of CaMKIV during development Thyroid hormones such as 3,3′,5-triiodo-l-thyronine (T3) have been shown to be required for normal growth and differentiation of the mammalian brain [60] and [61]. T3 acts through a specific receptor recognizing regulatory elements of the expressed gene, as has been described for other members of the superfamily of steroid/thyroid hormone receptors [62]. In a recent report we provided evidence for the specific induction of CaMKIV by T3 in a time- and concentration-dependent manner at a very early stage of brain differentiation, using a fetal rat telencephalon primary cell culture system which can grow and differentiate under chemically defined conditions [57]. The induction was T3-specific, i.e., the expression of the enzyme could not be induced by either reverse T3 (rT3) or retinoic acid. The expression of CaMKIV was regulated on both, the transcriptional and the translational level, since both the addition of actinomycin D as well as cycloheximide to the cultural medium could prevent the T3-dependent induction of the enzyme. Whether this T3-dependent regulation is due to a direct interaction of the T3-receptor with a responsive element of the CaMKIV gene or whether the effect is indirect remains to be determined, but since the T3-specific induction of CaMKIV could also be observed on the mRNA level, this observation could be indicative for a T3-receptor dependent regulation. In this respect it is of interest that in a recent abstract [63] it was reported that in a mouse embryonic stem cell derived neuronal culture system the expression of CaMKIV was strictly dependent on the presence of the thyroid hormone receptor, i.e., such a T3-dependent response was not observable in embryonic stem cells derived from TRα−/− mice (during embryonal development only TRα is expressed)…… In this respect it is interesting to note that in a recent communication CREB−/− mice were reported to exhibit a defect in T-cell development [67] which also showed a characteristic reduction in thymic cellularity. Thymocytes of these CREB deficient cells accumulate at the immature double-negative stage (CD25−44−), unable to progress into the double-positive stage (CD25+44+), i.e., the transition during which CaMKIV reaches its highest expression during T-cell development [65]. Thus it appears that the transcription factor CREB and its activating kinase CaMKIV are essential elements for T-cell development. http://www.sciencedirect.com/science/article/pii/S0167488998001426 Calcium chloride treatment results in higher total T4 and lower total T3 levels in serum, liver and kidneys in rats indicating the possibly lesser conversion of T4 to T3 (Etling et al., 1986).

Besides, hypo and hypercalcemia reportedly influence T4, T3, TSH levels in human and animals (Gillet et al., 1990; Sakai et al., 1991). Uptake of iodide in thyroid tissue in vitro was found to increase in studies with calcium administration (Gandra and John, 1961). Calcium mediated triggering of TRH-dependent TSH secretion in vitro has also been reported (Murao et al., 2004). It has repressing effect on transcription factors, namely TTF-1, TTF-2, Pax-8, etc. and TPO and TG gene expressions in vitro (Suzuki et al., 1998) Conversely, in vitro studies with FRTL-5 cell line had shown thyroid hyperactivity following calcium treatment (Gaberscek et al., 1998). In some studies hypercalcemia has been associated with hyperthyroidism (Franklin et al., 1958; Charles et al., 1966). Oral calcium supplementation is k Iodothyronine 5_-deiodinases (DI, DII and DIII), the membrane-bound seleno-proteins expressed in tissue-specific patterns, are vital for the conver- sion of the prohormone thyroxine (T4), into the active form triiodothyronine (T3), in thyroid as well as extra-thyroidal tissues like liver, kidney, etc. ( nown to result in improved health status after thyroidectomy (Moore, 1994).

All these suggest that relatively high calcium exposures may cause thyroid hyperactivities. A Rise in Ionized Calcium Activates the Neutrophil NADPH-Oxidase ... link.springer.com/.../10.1023%2FA%3...‎ Springer Science+Business Media by C Movitz - ‎1997 - ‎Cited by 10 - ‎Related articles Oct 1, 1997 -

A Rise in Ionized Calcium Activates the Neutrophil NADPH-Oxidase But Is Not Sufficient to Directly Translocate Cytosolic p47 phox or p67 phox ... Serum calcium slope predicts hypocalcaemia following thyroid surgery. 2007 International journal of surgery (London, England) Sphingosylphosphorylcholine enhances calcium entry in thyroid FRO cells by a mechanism dependent on protein kinase C. 2006 Cellular signalling Differential effect of thyroid-stimulating hormone (TSH) on intracellular free calcium and cAMP in cells transfected with the human TSH receptor. 1998 The Journal of endocrinology Prevention of postoperative hypocalcemia with routine oral calcium and vitamin D supplements in patients with differentiated papillary thyroid carcinoma undergoing total thyroidectomy plus central neck dissection. 2009 Cancer Tumor necrosis factor-alpha, sphingomyelinase, and ceramide inhibit store-operated calcium entry in thyroid FRTL-5 cells. 1999 The Journal of biological chemistry Serum calcium in thyroid disease. 2001 Wiener klinische Wochenschrift http://science.naturalnews.com/C/Calcium_and_thyroid.html Tumor necrosis factor-alpha, sphingomyelinase, and ceramide inhibit store-operated calcium entry in thyroid FRTL-5 cells. 1999 The Journal of biological chemistry http://scholar.google.com/scholar_url?hl=en&q=http://www.researchgate.net/publication/229080539_Dietary_calcium_induced_cytological_and_biochemical_changes_in_thyroid/file/79e415144d8a323246.pdf&sa=X&scisig=AAGBfm2tDNG1T3yY9xQOFQ49oq94ZBsG5g&oi=scholarr

Synthesis Thrombin is produced by the enzymatic cleavage of two sites on prothrombin by activated Factor X (Xa). The activity of factor Xa is greatly enhanced by binding to activated Factor V (Va), termed the prothrombinase complex. Prothrombin is produced in the liver and is post-translationally modified in a vitamin K-dependent reaction that converts ten glutamic acids on prothrombin to gamma-carboxyglutamic acid (Gla). In the presence of calcium, the Gla residues promote the binding of prothrombin to phospholipid bilayers (see the picture). Deficiency of vitamin K or administration of the anticoagulant warfarin inhibits the production of gamma-carboxyglutamic acid residues, slowing the activation of the coagulation cascade. In human adults, the normal blood level of antithrombin activity has been measured to be around 1.1 units/mL. Newborn levels of thrombin steadily increase after birth to reach normal adult levels, from a level of around 0.5 units/mL 1 day after birth, to a level of around 0.9 units/mL after 6 months of life.[5] Mechanism of action In the blood coagulation pathway, thrombin acts to convert factor XI to XIa, VIII to VIIIa, V to Va, fibrinogen to fibrin, and XIII to XIIIa. Factor XIIIa is a transglutaminase that catalyzes the formation of covalent bonds between lysine and glutamine residues in fibrin. The covalent bonds increase the stability of the fibrin clot. Thrombin interacts with thrombomodulin.[6][7] As part of its activity in the coagulation cascade, thrombin also promotes platelet activation and aggregation via activation of protease-activated receptors on the cell membrane of the platelet. Negative feedback Thrombin bound to thrombomodulin activates protein C, an inhibitor of the coagulation cascade. The activation of protein C is greatly enhanced following the binding of thrombin to thrombomodulin, an integral membrane protein expressed by endothelial cells. Activated protein C inactivates factors Va and VIIIa. Binding of activated protein C to protein S leads to a modest increase in its activity. Thrombin is also inactivated by antithrombin, a serine protease inhibitor. http://en.wikipedia.org/wiki/Thrombin AMP-activated protein kinase (AMPK) is a heterotrimeric serine/threonine kinase composed of a catalytic α subunit and regulatory β and γ subunits (6, 16). AMPK has been shown to function as a sensor of the energy state of the cell. It is activated by a rise in the AMP/ATP ratio following a fall of intracellular ATP and initiates a series of changes aimed at regulating energy balance at the cellular level. These processes include the inhibition of ATP-requiring anabolic pathways and the stimulation of ATP-generating catabolic pathways as well as changes in gene and protein expression (6, 16). Additionally, AMPK acts as a regulator of the whole-body energy metabolism by mediating the effects of hormones such as adiponectin, leptin, or ghrelin (28). AMPK activation requires phosphorylation of threonine 172 in the activation loop of the α subunit (18). Two AMPK-activating kinases have been identified recently. LKB1, a tumor suppressor kinase, in complex with two accessory subunits, STRAD and MO25, has been shown to phosphorylate AMPK (19, 23, 38, 46). Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ) has also been identified as an AMPK kinase (20, 25, 45).

In addition to phosphorylation, AMPK is allosterically activated by binding of AMP, and this can also promote phosphorylation of threonine 172 (21). However, AMPK can be activated in an AMP-independent manner as shown with hyperosmotic stress or with the antidiabetic drug metformin (14). The finding that CaMKKβ acts upstream of AMPK suggests that in addition to changes of the AMP/ATP ratio an increase of intracellular Ca2+ may act as a second pathway to activate AMPK. AMPK is ubiquitously expressed and has also been reported in endothelial cells of different origins. Endothelial AMPK has been shown to be activated by hypoxic stress (33), peroxynitrite (49, 50), hormones including adiponectin (7, 35) and estradiol (37), metformin (51), and vascular mediators such as bradykinin (32) and histamine or thrombin (40). Several studies have suggested that AMPK may play a role in endothelial cell energy supply (10); protection from apoptosis (26); and regulation of inflammation, angiogenesis, and maintenance of perfusion (5, 33, 35, 36). Recently, a link between AMPK and endothelial nitric oxide synthase (eNOS) activation has garnered considerable interest, and NO formation has been thought to be implicated in angiogenic and anti-inflammatory effects of AMPK (7, 31, 33, 35, 37, 40, 49, 50, 51). Accordingly, AMPK has been reported to phosphorylate eNOS at its serine residue 1177 (7, 8, 31, 33, 35, 40, 49, 50) or to enhance the interaction between eNOS and heat shock protein 90 (37). Thrombin, one of the stimuli shown to induce AMPK phosphorylation, is a multifunctional serine protease that is generated at the sites of vascular injury. It mediates the final step of the coagulation cascade and additionally activates vascular cells via G-protein-coupled protease-activated receptors (PARs) (9). Endothelial cell responses to thrombin include shape and permeability changes and expression of adhesion molecules as well as synthesis of cytokines and autocoids such as NO and are often related to an increase of intracellular Ca2+ (3, 15, 30, 42). So far, the upstream kinase that is mediating AMPK activation upon thrombin stimulation of endothelial cells is not known. Moreover, it is not fully understood under which conditions AMPK mediates the phosphorylation of its putative downstream target eNOS and whether AMPK and eNOS activation are linked in thrombin-treated cells. The aim of our study was to investigate the signaling mechanisms leading to AMPK activation and the functional relevance of AMPK in endothelial cells stimulated with thrombin. The results presented here demonstrate that thrombin activates AMPK in endothelial cells via its receptor PAR-1 in a Gq-protein/phospholipase C- and Ca2+-dependent and ATP-independent manner. Our study identifies CaMKKβ as the upstream kinase responsible for AMPK phosphorylation upon thrombin stimulation. Thrombin also induced the phosphorylation of acetyl coenzyme A carboxylase (ACC), a well-known downstream target of AMPK, and of eNOS at serine 1177. Inhibition of either CaMKKβ or AMPK by two different approaches (pharmacological inhibition or protein downregulation using RNA interference) showed, however, that only thrombin-induced ACC but not eNOS phosphorylation was mediated by the CaMKKβ/AMPK pathway. Thrombin activation of AMPK is independent of the cellular AMP/ATP ratio.Because the cellular AMP/ATP ratio is one of the major determinants of AMPK activity, the effect of thrombin on this ratio was measured at time points where AMPK was maximally stimulated by thrombin. Stimulation of HUVEC by thrombin for 0 (control), 0.5, 1, and 2 min resulted in AMP/ATP ratios of 0.037 ± 0.003, 0.034 ± 0.002, 0.037 ± 0.003, and 0.041 ± 0.002, respectively (data are means ± SEMs of three experiments). As can be seen, there was no significant change in the AMP/ATP ratio upon thrombin stimulation, indicating that AMPK activation occurred independently of changes in the levels of adenine nucleotides. In contrast, dinitrophenol (500 μM, 15 min), an uncoupler of the mitochondrial electron transport known to activate AMPK, clearly increased the AMP/ATP ratio from 0.033 ± 0.001 to 0.119 ± 0.006 (n = 2). Thrombin activates AMPK via PAR-1 and Gq-protein-mediated phospholipase C activation.Thrombin exerts its effects on endothelial cells through G-protein-coupled PARs via a tethered ligand mechanism. This includes proteolytic cleavage at the amino terminus of the receptor and an intramolecular binding of the newly exposed tethered ligand to the activation site of the receptor (9). We used TFLLR, a peptide analogue of the new N terminus of PAR-1, to examine whether PAR-1, the predominant thrombin receptor expressed in HUVEC (34), was involved in AMPK activation. TFLLR (10 μM, 0.25 to 15 min) mimicked the effect of thrombin and induced a time-dependent increase of AMPK phosphorylation at threonine 172 (Fig. 2A). http://mcb.asm.org/content/26/16/5933.full The kinase triad, AMPK, mTORC1 and ULK1, maintains energy and nutrient homoeostasis. Dunlop EA1, Tee AR. Author information Abstract In order for cells to divide in a proficient manner, they must first double their biomass, which is considered to be the main rate-limiting phase of cell proliferation. Cell growth requires an abundance of energy and biosynthetic precursors such as lipids and amino acids. Consequently, the energy and nutrient status of the cell is acutely monitored and carefully maintained. mTORC1 [mammalian (or mechanistic) target of rapamycin complex 1] is often considered to be the master regulator of cell growth that enhances cellular biomass through up-regulation of protein translation. In order for cells to control cellular homoeostasis during growth, there is close signalling interplay between mTORC1 and two other protein kinases, AMPK (AMP-activated protein kinase) and ULK1 (Unc-51-like kinase 1). This kinase triad collectively senses the energy and nutrient status of the cell and appropriately dictates whether the cell will actively favour energy- and amino-acid-consuming anabolic processes such as cellular growth, or energy- and amino-acid-generating catabolic processes such as autophagy. The present review discusses important feedback mechanisms between these three homoeostatic protein kinases that orchestrate cell growth and autophagy, with a particular focus on the mTORC1 component raptor (regulatory associated protein of mammalian target of rapamycin), as well as the autophagy-initiating kinase ULK1.http://www.ncbi.nlm.nih.gov/pubmed/23863160 Autophagy is a catabolic cellular process involving the degradation of the cell's own components. Although the role of autophagy of diverse tissues in body metabolism has been investigated, the importance of autophagy in hypothalamic proopiomelanocortin (POMC) neurons, key regulators of energy balance, has not been addressed. The role of autophagy in leptin sensitivity that is critical for the control of body weight and appetite has also not been investigated. We produced mice with specific deletion of autophagy-related 7 (Atg7), an essential autophagy gene, in hypothalamic POMC neurons (Atg7ΔPOMC mice). Atg7 expression was deficient in the arcuate nucleus of the hypothalamus of Atg7ΔPOMC mice. p62, a specific substrate of autophagy, accumulated in the hypothalamus of Atg7ΔPOMC mice, which colocalized with ubiquitin. Atg7ΔPOMC mice had increased body weight due to increased food intake and decreased energy expenditure. Atg7ΔPOMC mice were not more prone to diet-induced obesity compared with control mice but more susceptible to hyperglycemia after high-fat diet. The ability of leptin to suppress fasting-elicited hyperphagia and weight gain during refeeding was attenuated in Atg7ΔPOMC mice. Deficient autophagy did not significantly affect POMC neuron number but impaired leptin-induced signal transducer and activation of transcription 3 activation. Our findings indicate a critical role for autophagy of POMC neurons in the control of energy homeostasis and leptin signaling. http://press.endocrine.org/doi/abs/10.1210/en.2011-1882 he essential autophagy gene Atg7 functions to promote BrafV600E-driven lung tumorigenesis by preserving mitochondrial glutamine metabolism. This suggests that inhibiting autophagy is a novel approach to treating BrafV600E-driven cancers. Cancer Discov; 3(11); 1272–85. ©2013 AACR. http://cancerdiscovery.aacrjournals.org/content/3/11/1272.long An inhibition of autophagy blocks 3T3-L1 cell TG accumulation and differentiation. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2769174/ LEPTIN = B Cells- Macroautophagy Regulates Energy Metabolism during Effector T Cell Activation Blockade of macroautophagy inhibits T cell activation Our previous results showed that stimulated T cells activated macroautophagy. To clarify the role of macroautophagy in the regulation of T cell activity, we determined the effect of blocking macroautophagy in activation-induced cytokine production and proliferation. Leupeptin and NH4Cl were used to block lysosomal proteolysis and 3-methyladenine to inhibit autophagosome formation. Inhibition of autophagy resulted in a dramatic decrease in IL-2 and IFN-γ production and profoundly impaired T cell proliferation (Fig. 2) in the absence of any increase in cell death (Supplemental Fig. 2). … blocking autophagy through deletion of Atg7 resulted in decreased activation-induced cytokine production http://www.jimmunol.org/content/185/12/7349.long • Molecular Cancer | Full text | Rottlerin-induced autophagy leads to ... www.molecular-cancer.com/content/12/1/171‎ by D Kumar - ‎2013 - ‎Related articles Dec 23, 2013 - Several anti-apoptotic signals such as the Akt/mTOR signaling pathway, and ... Calcium mediated autophagy is regulated by AMP activated protein kinase ..... Carlsbad, CA) containing mammary epithelial growth supplement ... • [PDF] Dynamical Modeling of the Interaction between Autophagy ... - arXiv arxiv.org/pdf/1312.7149‎ arXiv by I Tavassoly - ‎2013 - ‎Related articles BCL2 family proteins in the ER function as anti-autophagy proteins though their ... that regulation can be accomplished by controlling calcium signaling from the endoplasmic .... In general, our equations take the form proposed in Refs. 42, 43. • Saikosaponin-d, a novel SERCA inhibitor, induces autophagic cell ... www.nature.com › Journal home › Archive › July 11 2013‎ Nature by VKW Wong - ‎2013 - ‎Cited by 2 - ‎Related articles Jul 11, 2013 - (d) Calcium chelator blocks the Ssd-induced autophagy and diminishes ... supplementation of the glycolytic intermediate (methyl pyruvate, MP) was .... Although some anti-cancer agents can induce autophagy in various types ... We are currently studying the first generation of this therapy, chloroquine, which disrupts autophagy, as a neoadjuvant therapy for DCIS and ADH (NCT01023477). The outcome of this trial should be known within the next 2 years. If we are successful in showing that chloroquine a) will reduce the radiologic size of the DCIS lesions, or b) reduce proliferation, and perhaps increase apoptosis, of the intraductal neoplastic cells, after the 30 day treatment course, then this will set the stage for wider confirmatory studies by others. http://europepmc.org/articles/PMC3779365/reload=0;jsessionid=gJAgal7Ozj1JD5OkZ53m.18

Depletion of L-arginine induces autophagy as a cytoprotective ... www.ncbi.nlm.nih.gov/...‎ National Center for Biotechnology Information by R García-Navas - ‎2012 - ‎Cited by 2 - ‎Related articles Aug 9, 2012 - L-arginine (L-Arg) deficiency results in decreased T-cell proliferation and ... Inhibition of autophagy by ERN1, BECN1 and ATG7 silencing, or by ... Our data also show that the L-Arg depletion-induced ER stress response could lead to apoptosis when autophagy is blocked. http://www.ncbi.nlm.nih.gov/pubmed/22874569 •
 Autophagy: Turning Stress into Health - Caveman Doctor www.cavemandoctor.com/2012/04/.../autophagy-turning-stress-into-heal...‎ Apr 6, 2012 - This garbage is converted to amino acids, the building blocks of proteins, ... A healthy and naturally way to stress the body to elicit autophagy is ... • Antioxidants block cell repair — New information and what it may ... metamodern.com/2010/09/26/antioxidants-block-cell-repair/‎ Sep 26, 2010 - Abstract: Antioxidants inhibit basal autophagy and block the ... Trials of Antioxidant Supplements for Primary and Secondary Prevention: ... • Reconstitution of leucine-mediated autophagy via the mTORC1 ... www.ncbi.nlm.nih.gov/...‎ National Center for Biotechnology Information by X Yan - ‎2012 - ‎Cited by 3 - ‎Related articles Feb 1, 2012 - Supplementation of branched chain amino acids, especially leucine, ... cultured cells blocks Barkor puncta formation and autophagy activity. • Antioxidants can inhibit basal autophagy and enhance ... www.ncbi.nlm.nih.gov/...‎ National Center for Biotechnology Information Jun 21, 2010 - Figure 5. Vitamin E and over-expression of SOD can also inhibit autophagy. .... This is of significance, as supplements with putative antioxidant ... • [PDF] Autophagy - Molecular and Cell Biology mcb.berkeley.edu/.../Autophagy%20Fe...‎ University of California, Berkeley by X Yan - ‎2012 - ‎Cited by 3 - ‎Related articles suggesting an essential role of mTORC1 in autophagy inhibition in this cell free ... leucine supplementation in the cultured cells blocks Barkor puncta formation ... Our results suggest that insulin, but not glucose, is associated with short-term appetite regulation in healthy participants, but the relationship is disrupted in the overweight and obese. We conclude that the postprandial insulin response may be an important satiety signal, and that central nervous system insulin resistance in overweight might explain the blunted effect on appetite. http://www.ncbi.nlm.nih.gov/pubmed/17524176 http:/
 URL PLAY_LOOP=TRUE, or CONTROLS=FALSE> RC=&ltURL> The URL of the source document. http://www.lehman.edu/faculty/hoffmann/itc/techteach/embed/Embed_tag_syntax.html Curcumin induces autophagy to protect vascular endothelial cell ... www.ncbi.nlm.nih.gov/...‎ National Center for Biotechnology Information by J Han - ‎2012 - ‎Cited by 24 - ‎Related articles May 1, 2012 - Our study first proposed that curcumin could protect human ... of acetylated FOXO1 and ATG7, under the circumstance of oxidative stress. Caspases play a central role in apoptosis, a well-studied pathway of programmed cell death. Other programs of death potentially involving necrosis and autophagy may exist, but their relation to apoptosis and mechanisms of regulation remains unclear. We define a new molecular pathway in which activation of the receptor-interacting protein (a serine-threonine kinase) and Jun amino-terminal kinase induced cell death with the morphology of autophagy. Autophagic death required the genes ATG7 and beclin 1 and was induced by caspase-8 inhibition. Clinical therapies involving caspase inhibitors may arrest apoptosis but also have the unanticipated effect of promoting autophagic cell death. http://www.sciencemag.org/content/304/5676/1500 ABSTRACT RET/papillary thyroid carcinoma (PTC), TRK-T, or activating mutations of Ras and BRaf are frequent genetic alterations in PTC, all leading to the activation of the extracellular-regulated kinase (Erk) cascade. The aim of this study was to investigate the role of calmodulin-dependent kinase II (CaMKII) in the signal transduction leading to Erk activation in PTC cells. In normal thyroid cells, CaMKII and Erk were in the inactive form in the absence of stimulation. In primary PTC cultures and in PTC cell lines harboring the oncogenes RET/PTC-1 or BRaf(V600E), CaMKII was active also in the absence of any stimulation. Inhibition of calmodulin or phospholipase C (PLC) attenuated the level of CaMKII activation. Expression of recombinant RET/PTC-3, BRaf(V600E), or Ras(V12) induced CaMKII activation. Inhibition of CaMKII attenuated Erk activation and DNA synthesis in thyroid papillary carcinoma (TPC-1), a cell line harboring RET/PTC-1, suggesting that CaMKII is a component of the Erk signal cascade in this cell line. In conclusion, PTCs contain an active PLC/Ca(2+)/calmodulin-dependent signal inducing constitutive activation of CaMKII. This kinase is activated by BRaf(V600E), oncogenic Ras, and by RET/PTC. CaMKII participates to the activation of the Erk pathway by oncogenic Ras and RET/PTC and contributes to their signal output, thus modulating tumor cell proliferation. http://www.researchgate.net/publication/38080469_The_Ca2-calmodulin-dependent_kinase_II_is_activated_in_papillary_thyroid_carcinoma_%28PTC%29_and_mediates_cell_proliferation_stimulated_by_RETPTC Linus Pauling Macronutritent info center: Vitamin B6 Vitamin B6 is a water-soluble vitamin that was first isolated in the 1930s. There are three traditionally considered forms of vitamin B6: pyridoxal (PL), pyridoxine (PN), pyridoxamine (PM). The phosphate ester derivative pyridoxal 5'-phosphate (PLP) is the principal coenzyme form and has the most importance in human metabolism (1-3). Function Vitamin B6 must be obtained from the diet because humans cannot synthesize it. PLP plays a vital role in the function of approximately 100 enzymes that catalyze essential chemical reactions in the human body (1-5). For example, PLP functions as a coenzyme for glycogen phosphorylase, an enzyme that catalyzes the release of glucose from stored glycogen. Much of the PLP in the human body is found in muscle bound to glycogen phosphorylase. PLP is also a coenzyme for reactions used to generate glucose from amino acids, a process known as gluconeogenesis (4, 5). Nervous system function In the brain, the synthesis of the neurotransmitter, serotonin, from the amino acid, tryptophan, is catalyzed by a PLP-dependent enzyme. Other neurotransmitters, such as dopamine, norepinephrine and gamma-aminobutyric acid (GABA), are also synthesized using PLP-dependent enzymes (4). Red blood cell formation and function PLP functions as a coenzyme in the synthesis of heme, an iron-containing component of hemoglobin. Hemoglobin is found in red blood cells and is critical to their ability to transport oxygen throughout the body. Both PL and PLP are able to bind to the hemoglobin molecule and affect its ability to pick up and release oxygen. However, the impact of this on normal oxygen delivery to tissues is not known (4). Niacin formation The human requirement for another B vitamin, niacin, can be met in part by the conversion of the essential amino acid, tryptophan, to niacin, as well as through dietary intake. PLP is a coenzyme for a critical reaction in the synthesis of niacin from tryptophan; thus, adequate vitamin B6 decreases the requirement for dietary niacin (4). Hormone function Steroid hormones, such as estrogen and testosterone, exert their effects in the body by binding to steroid hormone receptors in the nucleus of the cell and altering gene transcription. PLP binds to steroid receptors in a manner that inhibits the binding of steroid hormones, thus decreasing their effects. The binding of PLP to steroid receptors for estrogen, progesterone, testosterone, and other steroid hormones suggests that the vitamin B6 status of an individual may have implications for diseases affected by steroid hormones, including breast cancer and prostate cancers (4). Nucleic acid synthesis PLP serves as a coenzyme for a key enzyme involved in the mobilization of single-carbon functional groups (one-carbon metabolism). Such reactions are involved in the synthesis of nucleic acids. The effect of vitamin B6 deficiency on the function of the immune system may be partly related to the role of PLP in one-carbon metabolism (see Disease Prevention). Deficiency Severe deficiency of vitamin B6 is uncommon. Alcoholics are thought to be most at risk of vitamin B6 deficiency due to low dietary intakes and impaired metabolism of the vitamin. In the early 1950s, seizures were observed in infants as a result of severe vitamin B6 deficiency caused by an error in the manufacture of infant formula. Abnormal electroencephalogram (EEG) patterns have been noted in some studies of vitamin B6 deficiency. Other neurologic symptoms noted in severe vitamin B6 deficiency include irritability, depression, and confusion; additional symptoms include inflammation of the tongue, sores or ulcers of the mouth, and ulcers of the skin at the corners of the mouth (2). The Recommended Dietary Allowance (RDA) Because vitamin B6 is involved in many aspects of metabolism, several factors are likely to effect an individual's requirement for vitamin B6. Of those factors, protein intake has been the most studied. Increased dietary protein results in an increased requirement for vitamin B6, probably because PLP is a coenzyme for many enzymes involved in amino acid metabolism (6). Unlike previous recommendations, the Food and Nutrition Board (FNB) of the Institute of Medicine did not express the most recent RDA for vitamin B6 in terms of protein intake, although the relationship was considered in setting the RDA (7). The current RDA was revised by the Food and Nutrition Board (FNB) in 1998 and is presented in the table below. Recommended Dietary Allowance (RDA) for Vitamin B6 Life Stage Age Males (mg/day) Females (mg/day) Infants 0-6 months 0.1 (AI) 0.1 (AI) Infants 7-12 months 0.3 (AI) 0.3 (AI) Children 1-3 years 0.5 0.5 Children 4-8 years 0.6 0.6 Children 9-13 years 1.0 1.0 Adolescents 14-18 years 1.3 1.2 Adults 19-50 years 1.3 1.3 Adults 51 years and older 1.7 1.5 Pregnancy all ages - 1.9 Breast-feeding all ages - 2.0 Disease Prevention Homocysteine and cardiovascular disease Even moderately elevated levels of homocysteine in the blood have been associated with increased risk for cardiovascular disease, including heart disease and stroke (8). During protein digestion, amino acids, including methionine, are released. Homocysteine is an intermediate in the metabolism of methionine. Healthy individuals utilize two different pathways to metabolize homocysteine. One pathway converts homocysteine back to methionine and is dependent on folic acid and vitamin B12. The other pathway converts homocysteine to the amino acid cysteine and requires two vitamin B6(PLP)-dependent enzymes. Thus, the amount of homocysteine in the blood is regulated by at least three vitamins: folic acid, vitamin B12, and vitamin B6 (diagram). Several large observational studies have demonstrated an association between low vitamin B6 intake or status with increased blood homocysteine levels and increased risk of cardiovascular diseases. A large prospective study found the risk of heart disease in women who consumed, on average, 4.6 mg of vitamin B6 daily was only 67% of the risk in women who consumed an average of 1.1 mg daily (9). Another large prospective study found higher plasma levels of PLP were associated with a decreased risk of cardiovascular disease independent of homocysteine levels (10). Further, several studies have reported that low plasma PLP status is a risk factor for coronary artery disease (11-13). In contrast to folic acid supplementation, studies supplementing individuals with only vitamin B6 have not resulted in significant decreases in basal (fasting) levels of homocysteine. However, one study found that vitamin B6 supplementation was effective in lowering blood homocysteine levels after an oral dose of methionine (methionine load test) was given (14), suggesting vitamin B6 may play a role in the metabolism of homocysteine after meals. Immune function Low vitamin B6 intake and nutritional status have been associated with impaired immune function, especially in the elderly. Decreased production of immune system cells known as lymphocytes, as well as decreased production of an important immune system protein called interleukin-2, have been reported in vitamin B6 deficient individuals (15). Restoration of vitamin B6 status has resulted in normalization of lymphocyte proliferation and interleukin-2 production, suggesting that adequate vitamin B6 intake is important for optimal immune system function in older individuals (15, 16). However, one study found that the amount of vitamin B6 required to reverse these immune system impairments in the elderly was 2.9 mg/day for men and 1.9 mg/day for women; these vitamin B6 requirements are higher than the current RDA (15). Cognitive function A few studies have associated cognitive decline in the elderly or Alzheimer's disease with inadequate nutritional status of folic acid, vitamin B12, and vitamin B6 and thus, elevated levels of homocysteine (17). One observational study found that higher plasma vitamin B6 levels were associated with better performance on two measures of memory, but plasma vitamin B6 levels were unrelated to performance on 18 other cognitive tests (18). Similarly, a double-blind, placebo-controlled study in 38 healthy elderly men found that vitamin B6 supplementation improved memory but had no effect on mood or mental performance (19). Further, a placebo-controlled trial in 211 healthy younger, middle-aged, and older women found that vitamin B6 supplementation (75 mg/day) for five weeks improved memory performance in some age groups but had no effect on mood (20). Recently, a systematic review of randomized trials concluded that there is inadequate evidence that supplementation with vitamin B6, vitamin B12, or folic acid improves cognition in those with normal or impaired cognitive function (21). Because of mixed findings, it is presently unclear whether supplementation with B vitamins might blunt cognitive decline in the elderly. Further, it is not known if marginal B vitamin deficiencies, which are relatively common in the elderly, even contribute to age-associated declines in cognitive function, or whether both result from processes associated with aging and/or disease. Kidney stones A large prospective study examined the relationship between vitamin B6 intake and the occurrence of symptomatic kidney stones in women. A group of more than 85,000 women without a prior history of kidney stones were followed over 14 years and those who consumed 40 mg or more of vitamin B6 daily had only two thirds the risk of developing kidney stones compared with those who consumed 3 mg or less (22). However, in a group of more than 45,000 men followed over six years, no association was found between vitamin B6 intake and the occurrence of kidney stones (23). Limited data have shown that supplementation of vitamin B6 at levels higher than the tolerable upper intake level (100 mg/day) decreases elevated urinary oxalate levels, an important determinant of calcium oxalate kidney stone formation in some individuals. However, it is less clear that supplementation actually resulted in decreased formation of calcium oxalate kidney stones. Presently, the relationship between vitamin B6 intake and the risk of developing kidney stones requires further study before any recommendations can be made. Disease Treatment Vitamin B6 supplements at pharmacologic doses (i.e., doses much larger than those needed to prevent deficiency) have been used in an attempt to treat a wide variety of conditions, some of which are discussed below. In general, well designed, placebo-controlled studies have shown little evidence that large supplemental doses of vitamin B6 are beneficial (24). Side effects of oral contraceptives Because vitamin B6 is required for the metabolism of the amino acid tryptophan, the tryptophan load test (an assay of tryptophan metabolites after an oral dose of tryptophan) was used as a functional assessment of vitamin B6 status. Abnormal tryptophan load tests in women taking high-dose oral contraceptives in the 1960s and 1970s suggested that these women were vitamin B6 deficient. Abnormal results in the tryptophan load test led a number of clinicians to prescribe high doses (100-150 mg/day) of vitamin B6 to women in order to relieve depression and other side effects sometimes experienced with oral contraceptives. However, most other indices of vitamin B6 status were normal in women on high-dose oral contraceptives, and it is unlikely that the abnormality in tryptophan metabolism was due to vitamin B6 deficiency (24). A more recent placebo-controlled study in women on the lower dose oral contraceptives, which are commonly prescribed today, found that doses up to 150 mg/day of vitamin B6 (pyridoxine) had no benefit in preventing side effects, such as nausea, vomiting, dizziness, depression, and irritability (25). Premenstrual syndrome (PMS) The use of vitamin B6 to relieve the side effects of high-dose oral contraceptives led to the use of vitamin B6 in the treatment of premenstrual syndrome (PMS). PMS refers to a cluster of symptoms, including but not limited to fatigue, irritability, moodiness/depression, fluid retention, and breast tenderness, that begin sometime after ovulation (mid-cycle) and subside with the onset of menstruation (the monthly period). A review of 12 placebo-controlled double-blind trials on vitamin B6 use for PMS treatment concluded that evidence for a beneficial effect was weak (26). A more recent review of 25 studies suggested that supplemental vitamin B6, up to 100 mg/day, may be of value to treat PMS; however, only limited conclusions could be drawn because most of the studies were of poor quality (27). Depression Because a key enzyme in the synthesis of the neurotransmitters serotonin and norepinephrine is PLP-dependent, it has been suggested that vitamin B6 deficiency may lead to depression. However, clinical trials have not provided convincing evidence that vitamin B6 supplementation is an effective treatment for depression (24, 28), though vitamin B6 may have therapeutic efficacy in premenopausal women (28). Morning sickness (nausea and vomiting in pregnancy) Vitamin B6 has been used since the 1940s to treat nausea during pregnancy. Vitamin B6 was included in the medication Bendectin, which was prescribed for the treatment of morning sickness and later withdrawn from the market due to unproven concerns that it increased the risk of birth defects. Vitamin B6 itself is considered safe during pregnancy and has been used in pregnant women without any evidence of fetal harm (29). The results of two double-blind, placebo-controlled trials that used 25 mg of pyridoxine every eight hours for three days (30) or 10 mg of pyridoxine every eight hours for five days (29) suggest that vitamin B6 may be beneficial in alleviating morning sickness. Each study found a slight but significant reduction in nausea or vomiting in pregnant women. A recent systematic review of placebo-controlled trials on nausea during early pregnancy found vitamin B6 to be somewhat effective (31). However, it should be noted that morning sickness also resolves without any treatment, making it difficult to perform well-controlled trials. Carpal tunnel syndrome Carpal tunnel syndrome causes numbness, pain, and weakness of the hand and fingers due to compression of the median nerve at the wrist. It may result from repetitive stress injury of the wrist or from soft tissue swelling, which sometimes occurs with pregnancy or hypothyroidism. Several early studies by the same investigator suggested that vitamin B6 status was low in individuals with carpal tunnel syndrome and that supplementation with 100-200 mg/day over several months was beneficial (32, 33). A recent study in men not taking vitamin supplements found that decreased blood levels of PLP were associated with increased pain, tingling, and nocturnal wakening, all symptoms of carpal tunnel syndrome (34). Studies using electrophysiological measurements of median nerve conduction have largely failed to find an association between vitamin B6 deficiency and carpal tunnel syndrome. While a few trials have noted some symptomatic relief with vitamin B6 supplementation, double-blind, placebo-controlled trials have not generally found vitamin B6 to be effective in treating carpal tunnel syndrome (24, 35). Sources Food sources Surveys in the U.S. have shown that dietary intake of vitamin B6 averages about 2 mg/day for men and 1.5 mg/day for women. A survey of elderly individuals found that men and women over 60 years old consumed about 1.2 mg/day and 1.0 mg/day, respectively; both intakes are lower than the current RDA. Certain plant foods contain a unique form of vitamin B6 called pyridoxine glucoside; this form of vitamin B6 appears to be only about half as bioavailable as vitamin B6 from other food sources or supplements. Vitamin B6 in a mixed diet has been found to be approximately 75% bioavailable (7). In most cases, including foods in the diet that are rich in vitamin B6 should supply enough to prevent deficiency. However, those who follow a very restricted vegetarian diet might need to increase their vitamin B6 intake by eating foods fortified with vitamin B6 or by taking a supplement. Some foods that are relatively rich in vitamin B6 and their vitamin B6 content in milligrams (mg) are listed in the table below. For more information on the nutrient content of specific foods, search the USDA food composition database. Food Serving Vitamin B6 (mg) Fortified cereal 1 cup 0.5-2.5 Banana 1 medium 0.43 Salmon, wild, cooked 3 ounces* 0.48 Turkey, without skin, cooked 3 ounces 0.39 Chicken, light meat without skin, cooked 3 ounces 0.51 Potato, Russet, baked, with skin 1 medium 0.70 Spinach, cooked 1 cup 0.44 Hazelnuts, dry roasted 1 ounce 0.18 Vegetable juice cocktail 6 ounces 0.26 *A 3-ounce serving of meat or fish is about the size of a deck of cards. Supplements Vitamin B6 is available as pyridoxine hydrochloride in multivitamin, vitamin B-complex, and vitamin B6 supplements (36). Safety Toxicity Because adverse effects have only been documented from vitamin B6 supplements and never from food sources, safety concerning only the supplemental form of vitamin B6 (pyridoxine) is discussed. Although vitamin B6 is a water-soluble vitamin and is excreted in the urine, long-term supplementation with very high doses of pyridoxine may result in painful neurological symptoms known as sensory neuropathy. Symptoms include pain and numbness of the extremities and in severe cases, difficulty walking. Sensory neuropathy typically develops at doses of pyridoxine in excess of 1,000 mg per day. However, there have been a few case reports of individuals who developed sensory neuropathies at doses of less than 500 mg daily over a period of months. Yet, none of the studies in which an objective neurological examination was performed reported evidence of sensory nerve damage at intakes below 200 mg pyridoxine daily (24). To prevent sensory neuropathy in virtually all individuals, the Food and Nutrition Board of the Institute of Medicine set the tolerable upper intake level (UL) for pyridoxine at 100 mg/day for adults (see table below) (7). Because placebo-controlled studies have generally failed to show therapeutic benefits of high doses of pyridoxine, there is little reason to exceed the UL of 100 mg/day. Tolerable Upper Intake Level (UL) for Vitamin B6 Age Group UL (mg/day) Infants 0-12 months Not possible to establish* Children 1-3 years 30 Children 4-8 years 40 Children 9-13 years 60 Adolescents 14-18 years 80 Adults 19 years and older 100 *Source of intake should be from food and formula only. Drug interactions Certain medications interfere with the metabolism of vitamin B6; therefore, some individuals may be vulnerable to a vitamin B6 deficiency if supplemental vitamin B6 is not taken. Anti-tuberculosis medications, including isoniazid and cycloserine, the metal chelator penicillamine, and antiparkinsonian drugs including L-dopa, all form complexes with vitamin B6 and thus create a functional deficiency. Additionally, the efficacy of other medications may be altered by high doses of vitamin B6. For instance, high doses of vitamin B6 have been found to decrease the efficacy of two anticonvulsants, phenobarbital and phenytoin, as well as L-dopa (4, 24). Linus Pauling Institute Recommendation Metabolic studies suggest that young women require 0.02 mg of vitamin B6 per gram of protein consumed daily (6, 37, 38). Using the upper boundary for acceptable levels of protein intake for women (100 grams/day), the daily vitamin B6 requirement for young women would be calculated at 2.0 mg daily. Older adults may also require at least 2.0 mg/day. For these reasons, the Linus Pauling Institute recommends that all adults consume at least 2.0 mg of vitamin B6 daily. Following the Linus Pauling Institute recommendation to take a daily multivitamin-mineral supplement containing 100% of the Daily Value for vitamin B6 will ensure an intake of at least 2.0 mg/day of vitamin B6. Although a vitamin B6 intake of 2.0 mg daily is slightly higher than the most recent RDA, it is 50 times less than the tolerable upper intake level (UL) set by the Food and Nutrition Board (see Safety). Older adults (> 50 years) Metabolic studies have indicated that the requirement for vitamin B6 in older adults is approximately 2.0 mg daily (39); this requirement could be even higher if the effect of marginally deficient vitamin B6 intakes on immune function and homocysteine levels are clarified. Despite evidence that the requirement for vitamin B6 may be slightly higher in older adults, several surveys have found that over half of individuals over age 60 consume less than the current RDA (1.7 mg/day for men and 1.5 mg/day for women). For these reasons, the Linus Pauling Institute recommends that older adults take a multivitamin/multimineral supplement, which generally provides at least 2.0 mg of vitamin B6 daily. http://lpi.oregonstate.edu/infocenter/vitamins/vitaminB6/