Here’s what I personally get from this.
Pepsin is the way iron is taken into the system, Vitamin C and Lysine? Help with absorption.
IL-10 upregulates pepsin. Iron is needed for TPO, which gets the thyroid moving.
Vitamin C reduces bile? And IL-6. And Zn-MT.
MT needs zinc. Metallothioneins upregulate TNFR2 and IL-10.
Biles block pepsin that splits insulin, right? Without pepsin, the body goes into insulin overload which can tire you out. HCL can’t work by itself, but it may kill off stomach bugs.
GLUTAMATE DEHYDROGENASE P.1-5
DOPAMINE P.5
HISTAMINE P.5-6
GABA P.5-7
A1AR P.7
IL-10 UPREGULATES TNFR2 P.7
STOMACH ACID P.8
PEPSIN ON INSULIN P.10
HYPERINSULINEMIA DROPS STOMACH ACID P.10
INSULIN DEGRADING ENZYME p.10
THYROID = PEPSIN P.11
NITRIC OXIDE/CGMP BLOCKS TPO P.12
QUERCETIN INHIBITS INTESTINAL IRON ABSORPTION AND FERROPORTIN TRANSPORTER EXPRESSION ETHANOL-INDUCED IRON OVERLOAD BY REGULATING HEPCIDIN THROUGH THE BMP6/SMAD4 SIGNALING PATHWAY P.13
HYPERGLYCEMIA REGULATES HYPOXIA-INDUCIBLE FACTOR-1.P.14
15D-PGJ2 INHIBITED EXPRESSION OF LPS INDUCED IL-10 P.15
PGA1 INCREASED LPS-INDUCED IL-10 EXPRESSION. P.15
Potassium increases Pepsin p.18
SFCA decreases Pepsin p.18
GABA p/19
Lysine vs. bile p.21
Metallothioneins upregulate IL-10 p.22-23
IL-6 blocks IL-10 p.23
GLUD1 (Glutamate dehydrogenase 1) is a mitochondrial matrix enzyme, with a key role in the nitrogen and glutamate (Glu) metabolism and the energy homeostasis. GLUD1 is expressed at high levels in liver, brain, pancreas and kidney, but not in muscle. In the pancreatic cells, GLUD1 is thought to be involved in insulin secretion mechanisms. In nervous tissue, where Glu is present in concentrations higher than in the other tissues, GLUD1 appears to function in both the synthesis and the catabolism of Glu and perhaps in ammonia detoxification.
GLUD1 exsone/introne structure. The color scheme is as follows: Glu-BD, NAD(P)-BD, antena, the pivot helix
There is evidence that GLUD1 has been retro-posed to the X chromosome, where it gave rise to the intronless GLUD2 through random mutations and natural selection. GLUD2 have adapted to the particular needs of the nervous system where it is specifically expressed.[1]
Protein ---The domain structure of GLUD1-Each domain is colored differently - Glu-BD, NAD(P)-BD, antenna, the pivot helix. The allosteric regulators are shown as sphere models. This particular structure of GLUD1 is a combination of two X-ray structures - one with a bound GTP (1HWZ) and the second one with a bound ADP (1NQT). Although not real, this structure shows the relative position of the allosteric effectors when bound to GLUD1. NADPH and Glu are shown as well.
GLUD1 is a hexamer. The monomer unit has:
1. N-terminal Glu-BD(Binding domain) that is composed mostly of β-strands.
2. NAD-BD - can bind either NAD+ or NADP+.
3. 48-residue antenna-like projection that extends from the top of each NAD-BD. The antenna consists of an ascending helix and a descending random coil strand that contains a small α-helix toward the C-terminal end of the strand.
NAD-BD sits on the top of Glu-BD. NAD-BD and Glu-BD form the catalytic cleft. During substrate binding, the NAD-BD moves significantly. This movement has two components, rotating along the long axis of a helix at the back of the NAD-BD, called "the pivot helix", and twisting about the antenna in a clockwise fashion. A comparison of the open and closed conformations of GLUD1 reveals changes in the small helix of the descending strand of the antenna, which seems to recoil as the catalytic cleft opens.[2] Closure of one subunit is associated with distortion of the small helix of the descending strand that is pushed into the antenna of the adjacent subunit. R496 is located on this small helix (see Mutations).
The core structure of the hexamer is a stacked dimer of trimers. Glu-BDs of the monomers are mainly responsible in the build up of the core. The relative position of the monomers is such that the rotation about the pivot helix in each monomer is not restricted. The antennae from three subunits within the trimers wrap around each other and undergo conformational changes as the catalytic cleft opens and closes. The antenna serves as an intersubunit communication conduit during negative cooperativity and allosteric regulation.
Alignment of GLUD1 from various sources, shows that the antenna probably evolved in the protista prior to the formation of purine regulatory sites. This suggests that there is some selective advantage of the antenna itself and that animals evolved new functions for GLUD1 through the addition of allosteric regulation.[3]
GLUD1 can form long fibers by end to end association of the hexamers. The polimerization is unrelated to the catalytic activity, but probably has an important role such as formation of multienzyme comolexes.
GLUD1 has two co-enzyme binding sites: one in the NAD-BD that is able to bind ether NAD+ or NADP+ and is directly involved in the catalytic process, and a second one, that has regulatory function, lying directly under the pivot helix, that can bind ADP, NAD+, or NADH, but does not bind NADPH well.[4]
Function- GLUD1 catalyses the oxidative deamination of Glu to 2-oxoglutarate and free NH4+ using either NAD+ or NADP+ as a co-factor. The reaction occurs with the transfer of a hydride ion from Glu's Cα to NAD(P)+, thereby forming 2-iminoglutarate, which is hydrolyzed to 2-oxoglutarate and NH4+. The reaction's equilibrium under standard circumstances greatly favors Glu formation over NH4+ (Go' ~ 30 kJ.mol-1) formation. For this reason, it was thought that the enzyme played an important role in ammonia detoxification, because since high [NH4+] are toxic, this equilibrium position would be physiologically important; it would help to maintain low [NH4+]. However, in individuals with a certain form of hyperammonemia resulting from a form of hyperinsulinism, the enzyme's activity is increased due to decreased GTP sensitivy, a negative regulator. These individual's blood ammonia levels are raised significantly, which would not be expected if the enzyme did indeed operate at equilibrium.
ADP[edit]ADP binds behind the NAD-BD, just beneath the pivot helix - the second coenzyme binding site. The adenosine moiety binds down into a hydrophobic pocket with the ribose phosphate groups pointing up toward the pivot helix.
ADP can also bind to the second, inhibitory, NADH-site yet causes activation.
GTP[edit]GTP binding is antagonized by Pi and ADP but is synergistic with NADH bound in the noncatalytic allosteric site. The majority of the contacts between GTP and the enzyme are via the triphosphate moiety. The GTP-binding site is considered to be the "sensor" that turns the enzyme off when the cell is at a high energy state. GTP binds at the junction between the NAD-BD and the antenna.[4][5]
Whereas most of the GLUD1-GTP interactions are via β- and γ-phosphate interactions, there are specific interactions with E346 and K343 that favour guanosine over adenosine.
In the open conformation, the GTP binding site is distorted such that it can no longer bind GTP.[2]
Regulation[edit]When GLUD1 is highly saturated with the active site ligands (substrates), an inhibitory abortive complex forms in the active site: NAD(P)H.Glu in the oxidative deamination reaction at high pH, and NAD(P)+.2-oxoglutarate in the reductive amination reaction at low pH. GLUD1 assumes its basal state configuration in the absence of allosteric effectors, regardless of whether the allosteric sites are functional. The allosteric regulators of GLUD1 - ADP, GTP, Leu, NAD+ and NADH - exert their effects by changing the energy required to open and close the catalytic cleft during enzymic turnover, in other words by destabilizing or stabilizing, respectively, the abortive complexes. Activators are not necessary for the catalytic function of GLUD1, as it is active in the absence of these compounds (basal state). It has been suggested that GLUD1 assumes in its basal state a configuration (open catalytic cleft) that permits catalytic activity regardless of whether the allosteric sites are functional. GLUD regulation is of particular biological importance as exemplified by observations showing that regulatory mutations of GLUD1 are associated with clinical manifestations in children.
ADP[edit]ADP being one of the two major activators (NAD+ being the other one), acts by destabilizing the abortive complexes, and abrogating the negative cooperativity. In the absence of substrates, and with bound ADP, the catalytic cleft is in the open conformation, and the GLUD1 hexamers form long polymers in the crystal cell with more interactions than found in the abortive complex crystals (1NQT). This is consistent with the fact that ADP promotes aggregation in solution. When the catalytic cleft opens, R516 is rotated down on to the phosphates of ADP.[4] The opening of the catalytic cleft is roughly correlated with distance between R516 and phosphates of ADP. In this way, ADP activates GLUD1 by facilitating the opening of the catalytic cleft which decreases product affinity and facilitates product release.[2][6] thus allowing GLUD1 to reconcile the non-catalytic abortive complexes.[5]
Inhibition by high [ADP] has been suggested previously to be due to competition between ADP and the adenosine moiety of the coenzyme at the active site1. At least it is known that the effect is relatively unaffected by either H507Y or R516A.
· Low [ATP] - inhibition, mediated through the GTP-binding site, since it is eliminated by H507Y. The affinity of ATP for the GTP site appears to be 1000-fold lower than for GTP, since the β- and γ-phosphate interactions are the major determinant of binding at the GTP site.
· Intermediate [ATP] - activation, mediated through the ADP effector site, since it is almost completely eliminated by R516A. At this site the nucleotide group is the major determinant of binding.
· High [ATP] - inhibition, mediated by weak binding at a third site, which is relatively specific for the adenine nucleotides. This effect is relatively unaffected by either H507Y or R516A. As suggested for ADP it could be due to a competition between ATP and the adenosine moiety of the coenzyme at the active site.[7]
GTP[edit]GTP inhibits enzyme turnover over a wide range of conditions by increasing the affinity of GLUD1 for the reaction product, making product release rate limiting under all conditions in the presence of GTP. GTP acts by keeping the catalytic cleft in a closed conformation thus stabilizing the abortive complexes. GTP effects on GLUD1 are not localized solely to the subunit to which it is binding and that the antenna plays an important role in communicating this inhibition to other subunits.
Leu[edit]Leu activates GLUD1 independently of the ADP site by binding elsewhere, perhaps directly within the catalytic cleft. The enhanced responses of HI/HA patients (see HI/HA syndrom) to Leu stimulation of INS release3, which result from their impaired sensitivity to GTP inhibition, emphasize the physiological importance of inhibitory control of GLUD1.[7]
NAD+[edit]NAD(P)(H) can bind to a second site on each subunit. This site binds NAD(H) ~ 10-fold better than NADP(H) with the reduced forms better than the oxidized forms. Although it has been suggested that binding of the reduced coenzyme at this site inhibits the reaction, while oxidized coenzyme binding causes activation, the effect is still unclear.
Phosphate[edit]Phosphate and other bivalent anions stabilize GLUD1. Recent structural studies have shown that phosphate molecules bind to the GTP site.[4]
Clinical significance[edit]Familial hyperinsulinism, linked to mutations in GLUD1, is characterized by hypoglycemia that ranges from severe neonatal-onset, difficult-to-manage disease to childhood-onset disease with mild symptoms and difficult-to-diagnose hypoglycemia. Neonatal-onset disease manifests within hours to two days after birth. Childhood-onset disease manifests during the first months or years of life. In the newborn period, presenting symptoms may be nonspecific, including seizures, hypotonia, poor feeding, and apnea. In severe cases, serum glucose concentrations are typically extremely low and thus easily recognized, whereas in milder cases, variable and mild hypoglycemia may make the diagnosis more difficult. Even within the same family, disease manifestations can range from mild to severe. Individuals with autosomal recessive familial hyperinsulinism, caused by mutations in either ABCC8 or KCNJ11 (FHI-KATP), tend to be large for gestational age and usually present with severe refractory hypoglycemia in the first 48 hours of life; affected infants usually respond only partially to diet or medical management (i.e., diazoxide therapy) and thus may require pancreatic resection. Individuals with autosomal dominant FHI-KATP tend to be appropriate for gestational age at birth, to present at approximately age one year (range: 2 days - 30 years), and to respond to diet and diazoxide therapy. Exceptions to both of these generalities have been reported. FHI-GCK, caused by mutations in GCK, may be much milder than FHI-KATP; however, some persons have severe, diazoxide-unresponsive hypoglycemia. FHI-HADH, caused by mutations in HADH, tends to be relatively mild, although severe cases have been reported. Individuals with FHI-HNF4A, caused by mutations in HNF4A, are typically born large for gestational age and have mild features that respond to diazoxide treatment. FHI-UCP2, caused by mutations in UCP2, is a rare cause of diazoxide-responsive FH1. Hyperammonemia/hyperinsulinism (HA/HI) is associated with mild-to-moderate hyperammonemia and with relatively mild, late-onset hypoglycemia; most but not all affected individuals have mutations in GLUD1.[8]
Clinical characteristics[edit]FHI is characterized by hypoglycemia that ranges from severe neonatal-onset, difficult-to-manage disease to childhood-onset disease with mild symptoms and difficult-to-diagnose hypoglycemia. Neonatal-onset disease manifests within hours to two days after birth. Childhood-onset disease manifests during the first months or years of life. [9] In the newborn period, presenting symptoms may be nonspecific, including seizures, hypotonia, poor feeding, and apnea. In severe cases, serum glucose concentrations are typically extremely low and thus easily recognized, whereas in milder cases, variable and mild hypoglycemia may make the diagnosis more difficult. Even within the same family, disease manifestations can range from mild to severe.[10]
Diagnosis/testing[edit]Approximately 45% of affected individuals have mutations in either ABCC8, which encodes the protein SUR1, or KCNJ11, which encodes the protein Kir6.2. In the Ashkenazi Jewish population, two ABCC8 founder mutations are responsible for approximately 97% of FHI. Other ABCC8 founder mutations are present in the Finnish population (p.Val187Asp and p.Asp1506Lys). Mutations in GLUD1 and HNF4A each account for approximately 5% of individuals with FHI.[11][12] Activating mutations in GCK or inactivating mutations in HADH occur in fewer than 1% of individuals with FHI. Mutations in UCP2 have been reported in only two families to date. Approximately 40% of individuals with FHI do not have an identifiable mutation in any of the genes known to be associated with FHI.
Management[edit]At initial diagnosis, hypoglycemia is corrected with intravenous glucose to normalize plasma glucose concentration and prevent brain damage.[13] Long-term medical management includes the use of diazoxide, somatostatin analogs, nifedipine, glucagon, recombinant IGF-I, glucocorticoids, human growth hormone, dietary intervention, or combinations of these therapies.[14] In individuals in whom aggressive medical management fails to maintain plasma glucose concentration within safe limits, or in whom such therapy cannot be safely maintained over time, pancreatic resection is considered.[15 https://en.wikipedia.org/wiki/Glutamate_dehydrogenase_1
ALDM; ALDHI; ALDH-E2
Summary
This protein belongs to the aldehyde dehydrogenase family of proteins. Aldehyde dehydrogenase is the second enzyme of the major oxidative pathway of alcohol metabolism. Two major liver isoforms of aldehyde dehydrogenase, cytosolic and mitochondrial, can be distinguished by their electrophoretic mobilities, kinetic properties, and subcellular localizations. Most Caucasians have two major isozymes, while approximately 50% of Orientals have the cytosolic isozyme but not the mitochondrial isozyme. A remarkably higher frequency of acute alcohol intoxication among Orientals than among Caucasians could be related to the absence of a catalytically active form of the mitochondrial isozyme. The increased exposure to acetaldehyde in individuals with the catalytically inactive form may also confer greater susceptibility to many types of cancer. This gene encodes a mitochondrial isoform, which has a low Km for acetaldehydes, and is localized in mitochondrial matrix. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[provided by RefSeq, Mar 2011]
Deficiency in mitochondrial aldehyde dehydrogenase (ALDH2), a tetrameric enzyme, results from inheriting one or two ALDH2*2 alleles. This allele encodes a protein subunit with a lysine for glutamate substitution at position 487 and is dominant over the wild-type allele, ALDH2*1. The ALDH2*2-encoded subunit (ALDH2K) reduces the activity of ALDH2 enzyme in cell lines expressing the wild-type subunit (ALDH2E). In addition to this effect on the enzyme activity, we now report that ALDH2*2 heterozygotes had lower levels of ALDH2 immunoreactive protein in autopsy liver samples. The half-lives of ALDH2 protein in HeLa cell lines expressing ALDH2*1, ALDH2*2, or both were determined by the rate of loss of immunoreactive protein after inhibition of protein synthesis with puromycin and by pulse-chase experiments. By either measure, ALDH2E enzyme was very stable, with a half-life of at least 22 h. ALDH2K enzyme had an enzyme half-life of only 14 h. In cells expressing both subunits, most of the subunits assemble as heterotetramers, and these enzymes had a half-life of 13 h. Thus, the effect of ALDH2K on enzyme turnover is dominant. These studies indicate that the ALDH2*2 allele exerts its dominant effect both by interfering with the catalytic activity of the enzyme and by increasing its turnover. This represents the first example of a dominantly acting allele with this effect on a mitochondrial enzyme's turnover. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC507646/
A conserved lysine residue, Lys36p, on the prosegment of pepsinogen was replaced with a positively charged arginine (K36pR), a negatively charged glutamic acid (K36pE), and a neutral side chain methionine (K36pM). K36pM and K36pE mutants were extremely unstable and degraded rapidly, especially K36pE, which was inactivated during purification. This instability was confirxmed by microcalorimetry where the denaturing temperatures for K36pM and K36pE were 6 degrees C and 10 degrees C lower than the wild-type, respectively. As a function of pH, K36pM and K36pR were activated over a broader range of pH as compared with wild-type. The mutant pepsinogens were activated faster than wild-type with K36pM being activated approximately 10 times faster. The activated pepsins from the various mutant pepsinogens showed lower kinetic efficiency than wild-type enzyme. Catalytic rate constants were reduced by half. The results suggested Lys36p is important for the correct folding of the active-centre residues. The molecular modeling calculation suggested that the position of Asp215 was substantially altered. In conclusion, the above results would suggest that Lys36p was important not only for stability of the prosegment and pepsinogen, but also for the correct alignment of the active-centre residues. http://www.ncbi.nlm.nih.gov/pubmed/10215892
Two genetic forms of hyperinsulinemic hypoglycemia caused by dysregulation of glutamate dehydrogenase. Glutamate dehydrogenase (GDH) has recently been shown to be involved in two genetic disorders of hyperinsulinemic hypoglycemia in children. These include the hyperinsulinism/hyperammonemia syndrome caused by dominant activating mutations of GLUD1 which interfere with inhibitory regulation by GTP and hyperinsulinism due to recessive deficiency of short-chain 3-hydroxy-acyl-CoA dehydrogenase (SCHAD, encoded by HADH1). The clinical manifestations of the abnormalities in pancreatic ß-cell insulin regulation include fasting hypoglycemia, as well as protein-sensitive hypoglycemia. The latter is due to abnormally increased sensitivity of affected children to stimulation of insulin secretion by the amino acid, leucine. In patients with GDH activating mutations, mild hyperammonemia occurs in both the basal and protein-fed state, possibly due to increased renal ammoniagenesis. Some patients with GDH activating mutations appear to be at unusual risk of developmental delay and generalized epilepsy, perhaps reflecting consequences of increased GDH activity in the brain. Studies of these two disorders have been carried out in mouse models to define the mechanisms of insulin dysregulation. In SCHAD deficiency, the activation of GDH is due to loss of a direct inhibitory protein-protein interaction between SCHAD and GDH. These two novel human disorders demonstrate the important role of GDH in insulin regulation and illustrate unexpectedly important reasons for the unusually complex allosteric regulation of GDH.http://www.ncbi.nlm.nih.gov/pubmed/21130127
Identification of lysine residue involved in inactivation of brain glutamate dehydrogenase isoproteins by o-phthalaldehyde.
Incubation of two types of glutamate dehydrogenase (GDH) isoproteins from bovine brain with o-phthalaldehyde resulted in a time-dependent loss of enzyme activity. The inactivation was partially prevented by preincubation of the GDH isoproteins with 2-oxoglutarate or NADH. Spectrophotometric studies indicated that the inactivation of GDH isoproteins with o-phthalaldehyde resulted in isoindole derivatives characterized by typical fluorescence emission spectra with a stoichiometry of one isoindole derivative per molecule of enzyme subunit. There were no differences between the two GDH isoproteins in sensitivities to inactivation by o-phthalaldehyde indicating that the microenvironmental structures of the GDH isoproteins are very similar to each other. Tryptic peptides of the isoproteins, modified with and without protection, identified a selective modification of one lysine as in the region containing the sequence L-Q-H-G-S-I-L-G-F-P-X-A-K for both GDH isoproteins. The symbol X indicates a position for which no phenylthiohydantoin-amino acid could be assigned. The missing residue, however, can be designated as an o-phthalaldehyde-labeled lysine since the sequences including the lysine residue in question have a complete identity with those of the other mammalian GDHs. Also, trypsin was unable to cleave the labeled peptide at this site. Both amino acid sequencing and compositional analysis identified Lys-306 as the site of o-phthalaldehyde binding within the brain GDH isoproteins. http://www.ncbi.nlm.nih.gov/pubmed/10607407
Glioblastoma Cells Require Glutamate Dehydrogenase to Survive Impairments of Glucose Metabolism or Akt Signaling Oncogenes influence nutrient metabolism and nutrient dependence. The oncogene c-Mycstimulates glutamine metabolism and renders cells dependent on glutamine to sustain viability (“glutamine addiction”), suggesting that treatments targeting glutamine metabolism might selectively kill c-Myc–transformed tumor cells. However, many current or proposed cancer therapies interfere with the metabolism of glucose, not glutamine. Here, we studied how c-Myc–transformed cells maintained viability when glucose metabolism was impaired. In SF188 glioblastoma cells, glucose deprivation did not affect net glutamine utilization but elicited a switch in the pathways used to deliver glutamine carbon to the tricarboxylic acid cycle, with a large increase in the activity of glutamate dehydrogenase (GDH). The effect on GDH resulted from the loss of glycolysis because it could be mimicked with the glycolytic inhibitor 2-deoxyglucose and reversed with a pyruvate analogue. Furthermore, inhibition of Akt signaling, which facilitates glycolysis, increased GDH activity whereas overexpression of Akt suppressed it, suggesting that Akt indirectly regulates GDH through its effects on glucose metabolism. Suppression of GDH activity with RNA interference or an inhibitor showed that the enzyme is dispensable in cells able to metabolize glucose but is required for cells to survive impairments of glycolysis brought about by glucose deprivation, 2-deoxyglucose, or Akt inhibition. Thus, inhibition of GDH converted these glutamine-addicted cells to glucose-addicted cells. The findings emphasize the integration of glucose metabolism, glutamine metabolism, and oncogenic signaling in glioblastoma cells and suggest that exploiting compensatory pathways of glutamine metabolism can improve the efficacy of cancer treatments that impair glucose utilization. [Cancer Res 2009;69(20):7986–93]
Introduction Tumor cells display enhanced, autonomous, or otherwise unusual metabolic activities compared with differentiated cells ( 1). Since Warburg's experiments in the 1920s, the metabolic idiosyncrasies of tumors have been proposed to hold therapeutic opportunities in cancer, and many studies have focused on identifying pathways supporting tumor cell survival and growth. Thus far, enhanced rates of glucose and glutamine utilization are best established as hallmarks of tumor metabolism ( 2– 4). The central roles of these nutrients derive from their abundance in vivo, their use as bioenergetic substrates, and especially from the fact that they provide precursors for the synthesis of lipids, proteins, and nucleic acids. Metabolic flux analysis in proliferating glioblastoma cells showed that the coordinated metabolism of glucose and glutamine enabled a metabolic platform supporting both bioenergetics and biosynthesis ( 5). These observations suggest that a better understanding of the relationships between glucose and glutamine metabolism will lead to novel approaches to curb tumor growth.
Consistent with the importance of glucose and glutamine for tumor growth, many studies have shown that tumor suppressors and oncogenes influence the metabolism of these nutrients. The phosphatidylinositol 3′-kinase/Akt pathway, which is enhanced in a large fraction of human tumors, positively regulates glucose uptake, glycolysis, and the use of glucose as a macromolecular precursor during cell growth ( 6, 7). The oncogene c-Myc facilitates glutamine metabolism by increasing the expression of surface transporters and enzymes ( 8, 9). In glioblastoma cells with enhanced c-Myc activity, Akt inhibition decreases glycolysis without affecting glutamine consumption, whereas suppression of c-Myc reduced the uptake and mitochondrial processing of glutamine ( 9). Thus, whereas many tumor cells exhibit high rates of glucose and glutamine consumption, distinct oncogenic pathways regulate discrete aspects of the metabolic phenotype.
A surprising consequence of transformation is that it can limit metabolic flexibility in vitro. For example, Akt increases not only glucose metabolism but also sensitivity to glucose withdrawal ( 10). This effect is due to an impaired ability to activate β-oxidation, which normally supports bioenergetics during glucose starvation ( 10, 11). Similarly, cells with enhanced c-Myc activity cannot survive glutamine withdrawal because they cannot maintain pools of tricarboxylic acid (TCA) cycle intermediates in the absence of glutamine ( 9, 12). These nutrient “addiction” studies suggest that targeting intermediary metabolism will be selectively toxic to cancer cells, with therapeutic specificity defined by the tumor genotype. This might be particularly useful in glucose addiction, because many current cancer therapies alter tumor glucose uptake and are correlated with reduced signal on18fluorodeoxyglucose positron emission tomography (18FDG-PET; ref. 13).
Importantly, however, tumor cells may retain the capacity for metabolic compensation in vivo to survive periods of diminished glucose metabolism. Recent studies have documented that a decrease in 18FDG-PET signal during cancer therapy does not necessarily predict histopathologic resolution or improved patient outcome ( 14, 15). These studies imply that glycolytic tumors survive stress by activating alternative metabolic pathways and that defining and targeting these pathways will improve cancer treatment. Given the complementary roles of glucose and glutamine in intermediary metabolism, we studied how glutamine-addicted glioblastoma cells survived glucose deprivation.
Results Glucose withdrawal stimulates mitochondrial glutamine metabolism. We previously determined that SF188 glioblastoma cells metabolized carbon from glutamine in the TCA cycle and secreted ammonia in the process ( 5). To understand how the cells converted glutamine into the TCA cycle intermediate α-ketoglutarate (α-KG), we compared the activities of glutaminase (GLS) and GDH. These two enzymes generate ammonia from the γ and α nitrogens of glutamine, respectively, and their sequential activity produces α-KG (Fig. 1A ). We cultured cells with glutamine that was labeled with 15N in either the γ- or α-position and followed production of 15NH4+ by GC/MS ( Fig. 1B). After 8 hours, more than 90% of the ammonia in the medium was derived from these two nitrogens ( Fig. 1B). More than half (58 ± 1%) of the glutamine consumed by the cells was metabolized by GLS, and thus this enzyme outpaced all other glutamine-consuming systems combined. Furthermore, the GDH flux was approximately 10% of the GLS flux, consistent with the known contribution of other glutamate-consuming enzymes [e.g., alanine aminotransferase (ALT), aspartate aminotransferase] under glucose-replete conditions ( 5).
Glutamine metabolism in glioblastoma cells. A, glutamine (Gln) is a precursor for synthesis of nucleotides, proteins, and glucosamine. It can also be metabolized in the mitochondria, providing carbon to the TCA cycle as α-ketoglutarate (α-KG). Downstream metabolism converts glutamine carbon into OAA and/or acetyl-CoA (Ac-CoA), although the latter is predominantly formed from glucose. B, glioblastoma cells were cultured in medium supplemented with unlabeled glucose and either L-[α-15N]glutamine or L-[γ-15N]glutamine. GLS and GDH activities were followed by measuring transfer of 15N to 15NH4+. The time course shows the average and SD at each time point for three parallel cultures. The pie graph shows relative contributions of the γ and α nitrogens of glutamine to the total NH4+ pool after 8 h. The small amount of unlabeled ammonium (gray wedge) mostly resulted from metabolism of unlabeled glutamate by GDH. Glc, glucose; Pyr, pyruvate; Lac,lactate; Cit, citrate; Glu, glutamate; Succ, succinate; Fum, fumarate; Mal,malate; Asp, aspartate; NH4+, ammonium.
Because these cells normally use carbon from both glucose and glutamine to operate the TCA cycle ( Fig. 1A), we tested whether glucose availability influenced glutamine metabolism. Cells were cultured in 10 or 0 mmol/L glucose, and the medium was analyzed to measure the consumption of glutamine and the secretion of by-products of glutamine catabolism (ammonia, alanine and glutamate). Under both conditions, the cells consumed glutamine at a rate at least 10-fold higher than any other amino acid, and alanine and glutamate were by far the most rapidly secreted amino acids (Supplementary Table S1). ATP levels were maintained over the time course (Supplementary Fig. S1). Surprisingly, glucose deprivation did not affect the net utilization of glutamine or of any other amino acid, suggesting that the cells did not enhance amino acid consumption rates to compensate for the loss of glucose (Supplementary Table S1; Fig. 2A ). However, glucose deprivation doubled total ammoniagenesis ( Fig. 2A), implying an increased allocation of glutamine into ammonia-generating mitochondrial reactions.
Glucose withdrawal increases mitochondrial glutamine metabolism. A, glutamine-dependent metabolic rates in the presence and absence of glucose. Averages and SDs of three independent cultures are shown. *:P < 0.005. B, 13C NMR spectra of metabolites from cells cultured in medium containing L-[3-13C]glutamine plus or minus unlabeled glucose. Inset, an enlargement of the glutamate C4 resonance at 34 ppm. The doublet (d) corresponds to glutamate labeled both at C4 (from acetyl-CoA) and at C3 (from glutamine-derived OAA), and the singlet (s) corresponds to glutamate molecules labeled at C4 but not C3. The experiment was performed twice for each condition. Ala, alanine.
Mitochondrial metabolism of glutamine follows two divergent pathways ( Fig. 1A). In one, glutamine carbon is used to produce oxaloacetate (OAA) in the TCA cycle. In the other, glutamine-derived malate leaves the mitochondria to be used as a minor source of pyruvate and acetyl-CoA, both of which are predominantly formed from glucose carbon (5). To determine how glucose withdrawal affected these pathways, we cultured cells in L-[3-13C]glutamine in the presence or absence of 10 mmol/L glucose and analyzed intracellular metabolites by 13C NMR. In the presence of glucose, glutamine enriched the OAA pool as shown by the labeling in aspartate carbons 2 and 3 ( Fig. 2B, top). Glutamine was only a minor source of acetyl-CoA, as shown by the minimal labeling in glutamate carbon 4, which arises from acetyl-CoA ( Fig. 2B, top). When glucose was withdrawn, glutamine not only enriched the OAA pool but also contributed carbon to pyruvate/acetyl-CoA, because the labeling in glutamate carbon 4 (C4) increased 5-fold ( Fig. 2B, bottom). Labeling in glutamate C5, also derived from acetyl-CoA, was similarly increased (data not shown). To confirm increased enrichment of the pyruvate pool, we measured 13C content in secreted lactate. In the presence of glucose, less than 5% of the lactate was derived from glutamine, but this percentage gradually increased as the glucose concentration in the medium declined (Supplementary Fig. S2A). However, the total abundance of 13C-labeled lactate fell during glucose deprivation (Supplementary Fig. S2B), as would be expected if more of the glutamine-derived pyruvate was converted to acetyl-CoA and oxidized in the TCA cycle. Thus, these cells use glutamine to produce OAA, pyruvate, and acetyl-CoA and to maintain the TCA cycle function in the absence of glucose.
Glucose withdrawal stimulates GDH activity. We next studied the mechanism by which glucose deprivation increased total ammoniagenesis. Glucose withdrawal caused a gradual increase in ammonia production ( Fig. 3A ). This could be reversed with CH3-Pyr ( Fig. 3B), a pyruvate analogue metabolized in the mitochondria ( 18), suggesting that the increased ammonia production resulted from reduced delivery of pyruvate to the mitochondria. Surprisingly, glucose deprivation only marginally increased GLS activity ( Fig. 3C). Instead, the excess ammonia was due to a large increase in GDH activity, which was completely reversed by CH3-Pyr ( Fig. 3D). The opposite trend was observed for alanine secretion ( Fig. 3D). Thus, glucose withdrawal caused a 12-fold increase in the ratio of GDH to ALT activity. This effect was not specific for glioblastoma cells because withdrawal of glucose from mouse embryonic fibroblasts also increased ammonia production and GDH activity (Supplementary Fig. S3).
Figure 3.Glucose withdrawal activates GDH.A, cells were cultured in decreasing glucose concentrations, and the rates of glucose consumption and ammonia production were measured. B, total ammoniagenesis was measured in cells cultured with or without glucose and with increasing concentrations of methyl-pyruvate (CH3-Pyr). The average and SD of three independent cultures are shown. C, GLS activity was measured by following transfer of 15N from L-[γ-15N]glutamine to 15NH4+ in the presence or absence of glucose and CH3-Pyr. The average and SD of three independent cultures are shown. #, P < 0.05. D, cells were cultured in L-[α-15N]glutamine and the accumulation of 15NH4+ (GDH activity) and of 15N-alanine (ALT activity) was measured in the presence or absence of glucose and CH3-Pyr. The average and SD of three independent cultures are shown. *, P < 0.0005.
Loss of GDH activity limits the use of glutamine carbon in the TCA cycle and sensitizes glioblastoma cells to glucose withdrawal. The abrupt increase in GDH activity during glucose withdrawal raised the possibility that GDH compensates for glucose deprivation and allows cells to maintain viability. To test this, we used siRNAs targeting the two GDH isoforms, encoded by the genes GLUD1 and GLUD2. An siRNA directed againstGLUD2 did not affect GDH abundance (data not shown), whereas two siRNAs directed against the GLUD1 transcript reduced GDH protein abundance and enzyme activity ( Fig. 4A ). Cells containing either of these siRNAs were indistinguishable from cells transfected with a control siRNA when glucose was present, but they lost viability in the absence of glucose for 24 hours ( Fig. 4B and C). CH3-Pyr completely rescued the viability of the glucose-deprived cells, as did dm-αKG, an analogue of α-KG ( Fig. 4B and C), which like CH3-Pyr suppressed GDH activity (Supplementary Fig. S4). To determine the effect of GDH knockdown on the TCA cycle, we generated a cell line with stable short hairpin RNA (shRNA)–mediated suppression of GDH (Supplementary Fig. S5A,B). Compared with cells expressing a control shRNA, GDH knockdown cells lost viability in the absence of glucose unless supplemented with CH3-Pyr (Supplementary Fig. S5C). We cultured these cells inL-[3-13C]glutamine and analyzed intracellular metabolites with 13C NMR. Suppression of GDH activity impaired the conversion of glutamine to acetyl-CoA, as shown by decreased labeling in glutamate C4 ( Fig. 4D). This effect was not due to global metabolic defects because labeling in aspartate was similar between the two cell lines (Supplementary Fig. S5D).
Figure 4.Glioblastoma cells require GDH to survive glucose deprivation. A,cells were transfected with a control siRNA or siRNAs directed against the GLUD1 transcript. The effect on GDH protein abundance (top) and flux (bottom) was determined in the presence and absence of glucose. The average and SD of three independent cultures are shown. B and C, cells transfected with the control orGLUD1 siRNAs were subjected to glucose withdrawal, and the effects on morphology and viability were determined. The metabolites CH3-Pyr and dm-αKG were tested for their ability to rescue viability in glucose-deprived cells. The average and SD of three independent cultures are shown for each condition. D, glucose-deprived cells expressing a control (NC) shRNA or a shRNA against the GLUD1 transcript (GLUD1-A) were cultured with L-[3-13C]glutamine. Labeling in carbon 4 of glutamate was analyzed by 13C NMR.
Inhibition of glycolysis or Akt signaling stimulates GDH activity. We next tested whether inhibitors of glycolysis could influence GDH activity. First, we treated cells with 2-DG, a competitive hexokinase inhibitor. Addition of 2-DG suppressed lactate production and increased ammoniagenesis ( Fig. 5A ). The drug also increased GDH activity, and this effect was reversed by CH3-Pyr ( Fig. 5B). Next, we treated cells with an Akt inhibitor previously reported to reduce glycolysis in these cells ( 9). Similar to the effects of glucose withdrawal, the Akt inhibitor suppressed alanine secretion and mildly increased GLS activity (data not shown), whereas GDH activity was significantly enhanced ( Fig. 5C). Addition of CH3-Pyr suppressed GDH activity during treatment with the Akt inhibitor ( Fig. 5C). Furthermore, mouse astrocytes expressing a constitutively active Akt allele displayed chronically suppressed GDH activity compared with parental cells ( Fig. 5D). Together, these data show that pharmacologic impairment of glycolysis enhances GDH activity, and that Akt suppresses GDH activity through its effects on glucose metabolism.
Inhibition of glycolysis or Akt signaling activates GDH. A,glioblastoma cells were cultured in increasing concentrations of 2-DG and the release of lactate (○) and NH4+ (•) was measured. B, cells were cultured in 4 mmol/L L-[α-15N]glutamine and the accumulation of 15NH4+ was measured in the presence or absence of 2-DG and CH3-Pyr. C,cells were cultured with an Akt inhibitor previously shown to suppress glycolysis in these cells ( 9). The effect on GDH activity in the absence and presence of CH3-Pyr was determined. D, GDH activity was compared between immortalized mouse astrocytes lacking or containing a constitutively active Akt allele (myr-Akt1). In all experiments, the average and SD of three independent cultures are shown for each condition. #, P < 0.05; *,P < 0.005.
A GDH inhibitor sensitizes glioblastoma cells to drugs that suppress glycolysis. We next tested whether we could recapitulate the effects of GDH knockdown using EGCG, an abundant green tea polyphenol that inhibits GDH in vitro ( 19). EGCG blunted maximal GDH activity in glucose-deprived cells ( Fig. 6A ). Like the effect of GDH knockdown, EGCG enhanced cell death in the absence of glucose, and addition of either CH3-Pyr or dm-αKG rescued viability ( Fig. 6B). Finally, to test whether EGCG could enhance the effect of drugs that limit glucose metabolism, we cultured cells in the presence of glucose with EGCG and either the Akt inhibitor or 2-DG. EGCG increased the effect of both these inhibitors on cell death ( Fig. 6C).
A GDH inhibitor sensitizes glioblastoma cells to glucose withdrawal and to inhibitors of glycolysis and Akt signaling. A, the effect of EGCG on GDH activity was determined in glucose-deprived cells. B, glioblastoma cells were cultured in the presence or absence of glucose, EGCG, CH3-Pyr, and dm-αKG. The effects of these treatments, alone or in combination, were determined on cell viability at 8 and 16 h. C,glioblastoma cells were cultured in the presence or absence of EGCG, an Akt inhibitor, or 2-DG, alone or in combination. After 24 h, viability was determined by trypan blue staining. In all experiments, the average and SD of three independent cultures are shown for each condition. *, P ≤ 0.005.
DiscussionThis decade has seen renewed interest in understanding the metabolic activities that support tumor cell survival and growth. The abundance of data showing that mutations in oncogenes and tumor suppressors influence glucose metabolism, coupled with the utility of18FDG-PET, have raised the expectation that metabolic therapies directed against glycolysis will be effective in cancer. However, recent studies showing imperfect correlation between improvement on 18FDG-PET and patient survival have tempered this hope. Such studies suggest that tumors are capable of surviving periods of reduced glucose metabolism by using alternative metabolic pathways. Finding and targeting these survival pathways may ultimately improve the long-term efficacy of treatments that interfere with tumor glucose metabolism. Here, we identified such a survival pathway catalyzed by GDH in a highly glycolytic gliobastoma cell line.
The emerging picture of tumor cell metabolism is that a complex network links signal transduction with the metabolism of glucose, glutamine, and other nutrients. Understanding this network will enhance efforts to develop metabolically targeted cancer therapies. This work emphasizes how distinct signaling pathways can influence glucose and glutamine metabolism in the same cells. In the glioblastoma cells we studied, Akt facilitates glucose metabolism but exerts no effect on total glutamine consumption ( 9). Rather, c-Myc stimulates glutamine metabolism by increasing the expression of amino acid transporters and GLS, resulting in increased glutamine catabolism and increased sensitivity to glutamine withdrawal ( 8, 9, 12). c-Myc activates a metabolic program in which glucose-replete cells require transamination reactions to produce α-KG ( 9). Thus, whereas Akt directs the delivery of glucose-derived acetyl-CoA to the TCA cycle, c-Myc directs the delivery of glutamine-derived α-KG and ultimately OAA for anaplerosis and cell growth. Glucose-replete cells can tolerate suppression of GDH because there are other sources of both α-KG and acetyl-CoA.
The current work adds to this picture by describing an alternative pathway that is activated in glucose-starved cells. The new pathway involves a large increase in GDH activity compared with ALT, which is the most active transaminase when glucose is present ( 5). Unlike transamination reactions, GDH has the advantage of delivering α-KG to the TCA cycle without the expenditure of a keto-acid, which could otherwise be oxidized to supplement ATP production. For example, the cells we studied displayed aspartate aminotransferase activity during glucose withdrawal, as shown by the transfer of 13C from glutamine to aspartate ( Fig. 2B). This reaction converts glutamate to α-KG but consumes OAA in the process. Thus, the pathway serves as a “minicycle” that generates aspartate but does not produce OAA for traditional TCA cycling ( 20). The concomitant induction of GDH would yield net OAA and therefore support ongoing citrate synthesis and function of the TCA cycle. Moreover, under these conditions, glutamine metabolism also generated acetyl-CoA for the TCA cycle in a GDH-dependent manner. This may explain how the cells maintained their ATP content in the absence of glycolysis (Supplementary Fig. S1).
The effects of glucose withdrawal on both ALT and GDH were reversed by CH3-Pyr ( Fig. 3D). Presumably, this molecule stimulates ALT by supplying a large intracellular pyruvate pool for transamination. Because both ALT and GDH consume glutamate, competition between the two enzymes might contribute to the negative effect of CH3-Pyr on GDH. However, the large discrepancy between GDH suppression (∼60 nmol/h/million cells) and ALT induction (only ∼10 nmol/h/million cells) suggests the involvement of additional mechanisms.
GDH has not received much attention in cancer cell metabolism, probably because its activity is suppressed during robust glycolysis in vitro. GDH is a widely expressed homohexameric enzyme localized to the mitochondrial matrix, where it coordinates carbon and nitrogen metabolism. It determines the rate of oxidative degradation of glutamate and other nonessential amino acids and thus is uniquely poised to respond to glucose deprivation. The regulation of GDH activity is extremely complex and involves allosteric effects, posttranslational modifications, and other levels of control ( 21, 22). Suppression of GDH activity by glucose is not restricted to glioblastoma because we also observed it in mouse embryonic fibroblasts (Supplementary Fig. S3) and another study observed it in myeloma and hybridoma cells ( 23). The mechanism for GDH activation during glucose withdrawal is independent of changes in mRNA and protein levels (data not shown andFig. 4A). Because the forward reaction (oxidative deamination of glutamate) uses NAD+ as a cofactor, it is possible that the low cellular NAD+/NADH ratio of highly glycolytic cells holds GDH activity in check. A similar phenomenon has been observed in brain slices where glucose deprivation increased the cytoplasmic and mitochondrial NAD+/NADH ratio and ammoniagenesis ( 24). It is significant that in the cells studied here, there was no toxicity associated with the increased production of ammonia when glucose was withdrawn. Rather, the additional GDH activity sustained cell viability. GDH serves a similar compensatory role in plants. Mutant strains of Arabidopsis lacking GDH activity grew normally in carbon-replete conditions, but could not survive carbon starvation induced by prolonged growth in the dark. Viability was restored to the mutants simply by providing an exogenous carbohydrate source ( 25). Thus, we conclude that derepression of GDH is necessary for some cells to adapt to and survive low-glucose conditions.
It is not known to what extent the metabolism of cultured tumor cells parallels tumor metabolism in vivo, but evidence suggests that many core metabolic activities are shared between settings. First, 18FDG-PET and 1H magnetic resonance spectroscopy reveal robust glucose consumption and lactate production in aggressive tumors. Second, expression studies have shown that enzymes involved in glucose and glutamine metabolism are abundantly expressed in tumor tissues and in some cases predict patient outcome ( 26– 29). Third, the inhibition of some of these enzymes impairs tumor growth in animal models ( 30– 33). Fourth, some mechanisms of metabolic compensation, particularly autophagy, allow cells to survive nutrient stress in vitro and in vivo ( 34– 36). Likewise, GDH inhibition may increase the efficacy of treatments that interfere with glucose metabolism. There are many such treatments already in use that could benefit from concomitant blockade of GDH. Alkylators and other DNA-damaging agents suppress glycolysis in vitro and in vivo through poly(ADP-ribose) polymerase–dependent depletion of cytoplasmic NAD ( 37– 39). The kinase inhibitors imatinib and rapamycin inhibit glycolysisin vitro by reversing the effects of oncogenic signaling pathways on glucose metabolism; they also suppress 18FDG-PET signal in some tumors ( 15, 40– 42).
A major challenge in cancer therapeutics is to develop strategies that antagonize tumor cell survival without causing dose-limiting toxicity. Previous efforts to inhibit tumor glutamine metabolism were complicated by nausea, mucositis, and pancytopenia ( 43). In this regard, tea polyphenols are intriguing because they are consumed in large quantities by millions of people worldwide and because a number of epidemiologic studies have shown the benefits of green tea in preventing the initiation or progression of cancer ( 44). EGCG in particular has a number of pharmacologic properties that could independently suppress tumor cell growth ( 45). The relevance of the activity of EGCG as a GDH inhibitor is unknown, although this has been proposed as a mechanism to explain the protective effect of green tea against diabetes ( 19). In the glioblastoma cells we studied, the effect of EGCG perfectly mimicked GDH knockdown in that it was enhanced during decreased glucose metabolism and reversed by providing GDH-dependent nutrients. Thus, it will be interesting to test whether genetic or pharmacologic impairment of GDH activity can suppress tumor growth or enhance the effect of conventional cancer therapies.
DOPAMINE
…Like all histamine receptors the H3 receptor is a G-protein coupled receptor. The H3 receptor is coupled to the Gi G-protein, so it leads to inhibition of the formation of cAMP. Also, the β and γ subunits interact with N-type voltage gated calcium channels, to reduce action potential mediated influx of calcium and hence reduce neurotransmitter release. H3 receptors function as presynaptic autoreceptors on histamine-containing neurons.[2]
The diverse expression of H3 receptors throughout the cortex and subcortex indicates its ability to modulate the release of a large number of neurotransmitters.
…The H3 receptor has also been shown to presynaptically inhibit the release of a number of other neurotransmitters (i.e. it acts as an inhibitory heteroreceptor) including, but probably not limited to dopamine, GABA, acetylcholine, noradrenaline, histamine and serotonin.
https://en.wikipedia.org/wiki/Histamine_H3_receptor
Pentylenetetrazole inhibits glutamate dehydrogenase and aspartate aminotransferase, and stimulates GABA aminotransferase in homogenates from rat cerebral cortex.
The mechanism by which pentylenetetrazole provokes convulsions in animals has been investigated by measuring its influence in vitro on the activities of several enzymes of glutamate metabolism in rat brain homogenates. Pentylenetetrazole does not affect the specific activities of glutamine synthetase, glutaminase, or glutamate decarboxylase; IT INHIBITS THOSE OF GLUTAMATE DEHYDROGENASE AND ASPARTATE AMINOTRANSFERASE, AND STIMULATES THAT OF GAMMA-AMINOBUTYRIC ACID (GABA) AMINOTRANSFERASE. The overall consequence of the action of pentylenetetrazole on the activities of these enzymes should be an increase in the concentration of glutamate and a decrease in that of GABA. This modulation of glutamate and GABA metabolism by pentylenetetrazole could contribute to the triggering of convulsions. http://www.ncbi.nlm.nih.gov/pubmed/3219659
Rapid induction of enterochromaffinlike cell tumors by ...-Rapid induction of enterochromaffinlike celltumors by histamine2-receptor blockade.
Histamine H1 and H2 receptor activation stimulates ACTH ...www.ncbi.nlm.nih.gov/...
Histamine H1 and H2 receptor activation stimulates ACTH and beta-endorphin secretion by increasing corticotropin-releasing hormone in the hypophyseal ...Histamine H2 receptor activates adenylate cyclase and PLC ...www.ncbi.nlm.nih.gov/...
Histamine H2 receptor activatesadenylate cyclase and PLC via separate GTP-dependent pathways. Wang L(1) ...Histamine H(2) receptor activated chloride conductance in ...
www.ncbi.nlm.nih.gov/...J Neurophysiol. 2000 Apr;83(4):1809-16. Histamine H(2) receptor activated chloride conductance in myenteric neurons from guinea pig small intestine.
Histamine H(2) receptor activated chloride conductance in myenteric neurons from guinea pig small intestine.
Whole cell perforated patch-clamp methods were used to investigate ionic mechanisms underlying histamine-evoked excitatory responses in small intestinal AH-type myenteric neurons. When physiological concentrations of Na(+), Ca(2+), and Cl(-) were in the bathing medium, application of histamine significantly increased total conductance as determined by stepping to 50 mV from a holding potential of -30 mV. The current reversed at a membrane potential of -30 +/- 5 (SE) mV and current-voltage relations exhibited outward rectification. The reversal potential for the histamine-activated current was unchanged by removal of Na(+) and Ca(2+) from the bathing medium. Reduction of Cl(-) from 155 mM to 55 mM suppressed the current when the neurons were in solutions with depleted Na(+) and Ca(2+). Current-voltage curves in solutions with reduced Cl(-) were linear and the reversal potential was changed from -30 +/- 5 mV to 7 +/- 4 mV. Niflumic acid, but not anthracene-9-carboxylic acid (9-AC) nor 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), suppressed the histamine-activated current. A membrane permeable analogue of cAMP evoked currents similar to those activated by histamine. A selective histamine H(2) receptor agonist (dimaprit) mimicked the action of histamine and a selective histamine H(2) receptor antagonist (cimetidine) blocked the conductance increase evoked by histamine. A selective adenosine A(1) receptor agonist (CCPA) reduced the histamine-activated current and a selective adenosine A(1) receptor antagonist (CPT) reversed the inhibitory action. The results suggest that histamine acts at histamine H(2) receptors to increase Cl(-) conductance in AH-type enteric neurons. Cyclic AMP appears to be a second messenger in the signal transduction process. Results with a selective adenosine A(1) receptor agonist and antagonist add to existing evidence for co-coupling of inhibitory adenosine A(1) receptors and histamine H(2) receptors to adenylate cyclase in AH-type enteric neurons. http://www.ncbi.nlm.nih.gov/pubmed/10758093
Adenosine A1 receptor stimulation enhances osteogenic differentiation of human dental pulp-derived mesenchymal stem cells via WNT signaling.In this study, mesenchymal stem cells deriving from dental pulp (DPSCs) of normal human impacted third molars, previously characterized for their ability to differentiate into osteoblasts, were used. We observed that: i) DPSCs, undifferentiated or submitted to osteogenic differentiation, express all four subtypes of adenosine receptors (AR) and CD73, corresponding to 5'-ecto-nucleotidase; and ii) AR stimulation with selective agonists elicited a greater osteogenic cell differentiation consequent to A1 receptor (A1R) activation. Therefore, we focused on the activity of this AR. The addition of 15-60nM 2-chloro-N(6)-cyclopentyl-adenosine (CCPA), A1R agonist, to DPSCs at each change of the culture medium significantly increased the proliferation of cells grown in osteogenic medium after 8days in vitro (DIV) without modifying that of undifferentiated DPSCs.
Better characterizing the effect of A1R stimulation on the osteogenic differentiation capability of these cells, we found that CCPA increased the: i) expression of two well known and early osteogenic markers, RUNX-2 and alkaline phosphatase (ALP), after 3 and 7DIV; ii) ALP enzyme activity at 7DIV and iii) mineralization of extracellular matrix after 21DIV. These effects, abolished by cell pre-treatment with the A1R antagonist 8-cyclopentyl-1,3-dipropyl-xanthine (DPCPX), involved the activation of the canonical Wnt signaling as, in differentiating DPSCs, CCPA significantly increased dishevelled protein and inhibited glycogen synthase kinase-3β, both molecules being downstream of Wnt receptor signal pathway. Either siRNA of dishevelled or cell pre-treatment with Dickkopf-1, known inhibitor of Wnt signaling substantially reduced either DPSC osteogenic differentiation or its enhancement promoted by CCPA. Summarizing, our findings indicate that the stimulation of A1R MAY STIMULATE DPSC DUPLICATION ENHANCING THEIR OSTEOGENIC DIFFERENTIATION EFFICIENCY. These effects may have clinical implications possibly facilitating bone tissue repair and remodeling. http://www.ncbi.nlm.nih.gov/pubmed/23651584
Basal (nonstimulated) gastric acid output was determined in conscious rats fitted with indwelling gastric cannulae. The adenosine deaminase resistant analog of adenosine, R-phenylisopropyladenosine, elevated intraluminal pH beyond 7.0 and decreased gastric acid secretion when given at doses of 0.10 or 1.0 mg/kg, while S-phenylisopropyladenosine at similar doses did not affect either gastric acid output or pH. The potent adenosine receptor antagonist, 8-phenyltheophylline, given at doses of 0.1, 1.0, and 2.5 mg/kg augmented gastric acid output and, at doses of 0.01, 0.1,1.0, and 2.5 mg/kg, blocked the acid-reducing effect of R-phenylisopropyladenosine (0.1 mg/kg). These data suggest that adenosine systems may be important regulators of gastric function. http://www.nrcresearchpress.com/doi/abs/10.1139/y87-186#.VlklSfmrTIU
Adenosine A1 receptors control dopamine D1-dependent [(3)H]GABA release in slices of substantia nigra pars reticulata and motor behavior in the rat.--Abnormalities in dopaminergic control of basal ganglia function play a key role in Parkinson's disease. Adenosine appears to modulate the dopaminergic control in striatum, where an inhibitory interaction between adenosine and dopamine receptors has been demonstrated. However the interaction has not been established in substantia nigra pars reticulata (SNr) where density of both receptors is high. Here we have explored the interaction between A1/D1 receptors in SNr. In SNr slices, SKF 38393, a selective D1 receptor agonist, produced a stimulation of depolarization-induced Ca(2+)-dependent [(3)H]GABA release that was inhibited by adenosine. The adenosine inhibition was abolished by 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a selective adenosine A1 receptor antagonist. DPCPX per se enhanced GABA release, indicating inhibition of the release by endogenous adenosine. When D1 receptors were blocked with SCH 23390 or the slices were depleted of dopamine, the effect of DPCPX was suppressed, showing that ACTIVATION OF DOPAMINE RECEPTORS WAS NECESSARY FOR THE ADENOSINE INHIBITION. In normal slices, 2-chloro-n(6)-cyclopentyladenosine (CCPA), a selective A1 agonist, inhibited GABA release, but the inhibition was prevented by the blockade of D1 receptors with SCH 23390.
Superperfusion with 8-bromo-cAMP produced a stimulation of GABA release that was not blocked by CCPA: this finding indicates that the blockade of D1 effects caused by activation of A1 receptors is specific. To see if these actions on GABA release were correlated with changes in motor behavior we studied the effect of unilateral intranigral injections of modifiers of adenosine A1 and dopamine D1 receptors in rats challenged with systemic methamphetamine. Both the A1 agonist CCPA and the D1 antagonist SCH 23390 produced ipsilateral turning whereas the A1 antagonist DPCPX caused contralateral turning. These motor effects are consistent with the findings on GABA release. The results indicate the presence of an inhibitory A1/D1 receptor interaction in SNr. The inhibition exerted by A1 adenosine receptors on GABAergic striatonigral transmission would be due exclusively to blockade of the facilitation resulting from activation of D1 dopamine receptors. The data permit to better understand the action of adenosine antagonists in the treatment of Parkinson's disease.http://www.ncbi.nlm.nih.gov/pubmed/12435413
A1AR HAS IRON, HEPCIDIN = A2AR
Basal and K+ -evoked GABA release in the hippocampus were depressed by adenosinergic compounds. Under normal conditions activation of both adenosine A1 and A2A receptors by the agonists R(-)N6-(2-phenylisopropyl)adenosine and CGS 21680 INHIBITED THE K+ -EVOKED RELEASE… The excitatory glutamatergic neurons in the hippocampus are modulated by inhibitory GABA-releasing interneurons. The neuromodulator adenosine is known to inhibit the presynaptic release of neurotransmitters and to hyperpolarize postsynaptic neurons in the hippocampus, which would imply that it is an endogenous protective agent against cerebral ischemia and excitotoxic neuronal damage. Interactions of the GABAergic and adenosinergic systems in regulating neuronal excitability in the hippocampus is of crucial importance, particularly under cell-damaging conditions. We now characterized the effects of adenosine receptor agonists and antagonists on the release of preloaded [3H]GABA from hippocampal slices prepared from adult (3-month-old) mice, using a superfusion system. The effects were tested both under normal conditions and in ischemia induced by omitting glucose and oxygen from the superfusion medium. Basal and K+ -evoked GABA release in the hippocampus were depressed by adenosinergic compounds. Under normal conditions activation of both adenosine A1 and A2A receptors by the agonists R(-)N6-(2-phenylisopropyl)adenosine and CGS 21680 inhibited the K+ -evoked release, which effects were blocked by their specific antagonists, 8-cyclopentyl-1,3-dipropyl-xanthine and 3,7-dimethyl-1-propargylxanthine, respectively. Under ischemic conditions the release of both GABA and adenosine is markedly enhanced. The above receptor agonists then depressed both the basal and K+ -evoked GABA release, only the action of A2A receptors being however receptor-mediated. The demonstrated depression of GABA release by adenosine in the hippocampus could be deleterious to neurons and contribute to excitotoxicity.http://www.ncbi.nlm.nih.gov/pubmed/16076017
The role of adenosine A2a receptors in regulating GABAergic synaptic transmission in striatal medium spiny neurons.
We demonstrated an adenosine A2a receptor-mediated disinhibition of medium spiny projection neurons using intracellular recording and the whole-cell patch-clamp recording applied to these cells, visually identified in thin rat striatal slices. The A2a receptor agonist 2-[p-(2-carboxyethyl) phenylethylamino]-5'-N- ethylcarboxamido adenosine (CGS-21680; 0.3-10 microM) suppressed GABAergic synaptic transmission onto these cells in a manner inhibited by the A2a receptor-selective antagonist (E)-8-(3,4-dimethoxystyryl)-1,3-dipropyl-7-methylxanthine (0.1-1.0 microM). The A1 receptor antagonists had no effect on the CGS-21680-induced suppression. Analysis of spontaneous miniature inhibitory synaptic currents indicated that suppression of intrastriatal GABAergic synaptic transmission was attributable to presynaptic, but not postsynaptic, A2a receptors. Therefore, the A2a receptor may regulate striatal output activity by relieving GABA-mediated inhibition of the medium spiny projection neurons, which explains the ability of purinergic agents to affect motor control. http://www.ncbi.nlm.nih.gov/pubmed/8551344
Adenosine tonically inhibits synaptic transmission through actions at A(1) receptors. It also facilitates synaptic transmission, but it is unclear if this facilitation results from pre- and/or postsynaptic A(2A) receptor activation or from indirect control of inhibitory GABAergic transmission. The A(2A) receptor agonist, CGS 21680 (10 nM), facilitated synaptic transmission in the CA1 area of rat hippocampal slices (by 14%), independent of whether or not GABAergic transmission was blocked by the GABA(A) and GABA(B) receptor antagonists, picrotoxin (50 microM) and CGP 55845 (1 microM), respectively. CGS 21680 (10 nM) also inhibited paired-pulse facilitation by 12%, an effect prevented by the A(2A) receptor antagonist, ZM 241385 (20 nM). These effects of CGS 21680 (10 nM) were occluded by adenosine deaminase (2 U/ml) and were made to reappear upon direct activation of A(1) receptors with N(6)-cyclopentyladenosine (CPA, 6 nM). CGS 21680 (10 nM) only facilitated (by 17%) the K(+)-evoked release of glutamate from superfused hippocampal synaptosomes in the presence of 100 nM CPA. This effect of CGS 21680 (10 nM), in contrast to the isoproterenol (30 microM) facilitation of GLUTAMATE RELEASE, WAS PREVENTED BY THE PROTEIN KINASE C INHIBITORS, chelerythrine (6 microM) and bisindolylmaleimide (1 microM), but not by the protein kinase A inhibitor, H-89 (1 microM). Isoproterenol (30 microM), but not CGS 21680 (10-300 nM), enhanced synaptosomal cAMP levels, indicating that the CGS 21680-induced facilitation of glutamate release involves a cAMP-independent protein kinase C activation. To discard any direct effect of CGS 21680 on adenosine A(1) receptor, we also show that in autoradiography experiments CGS 21680 only displaced the adenosine A(1) receptor antagonist, 1,3-dipropyl-8-cyclopentyladenosine ([(3)H]DPCPX, 0.5 nM) with an EC(50) of 1 microM in all brain areas studied and CGS 21680 (30 nM) failed to change the ability of CPA to displace DPCPX (1 nM) binding to CHO cells stably transfected with A(1) receptors. Our results suggest that A(2A) receptor agonists facilitate hippocampal synaptic transmission by attenuating the tonic effect of inhibitory presynaptic A(1) receptors located in glutamatergic nerve terminals. This might be a fine-tuning role for adenosine A(2A) receptors to allow frequency-dependent plasticity phenomena without compromising the A(1) receptor-mediated neuroprotective role of adenosine. http://www.ncbi.nlm.nih.gov/pubmed/12044450
Blood Journal | Interleukin-10 Upregulates Tumor Necrosis ...www.bloodjournal.org/content/90/10/4162 IL-10 upregulates and IFN-γ downregulates expression of mTNF-RII in LPS-stimulated monocytes. To compare the effects of IFN-γ and IL-10 on surface ...
Interleukin-10 Upregulates Tumor Necrosis Factor Receptor ...www.bloodjournal.org/content/90/10/4162.full.pdfOct 16, 1997 - The ability of IL-10 to upregulate TNF-RII gene expression was transcriptionally mediated because actino- of cytokines such as tumor necrosis .
Phosphorylation of CRTC3 by the salt-inducible kinases controls the interconversion of classically activated and regulatory macrophages. Macrophages acquire strikingly different properties that enable them to play key roles during the initiation, propagation, and resolution of inflammation. Classically activated (M1) macrophages produce proinflammatory mediators to combat invading pathogens and respond to tissue damage in the host, whereas regulatory macrophages (M2b) produce high levels of anti-inflammatory molecules, such as IL-10, and low levels of proinflammatory cytokines, like IL-12, and are important for the resolution of inflammatory responses. A central problem in this area is to understand how the formation of regulatory macrophages can be promoted at sites of inflammation to prevent and/or alleviate chronic inflammatory and autoimmune diseases. Here, we demonstrate that the salt-inducible kinases (SIKs) restrict the formation of regulatory macrophages and that their inhibition induces striking increases in many of the characteristic markers of regulatory macrophages, greatly stimulating the production of IL-10 and other anti-inflammatory molecules. We show that SIK inhibitors elevate IL-10 production by inducing the dephosphorylation of cAMP response element-binding protein (CREB)-regulated transcriptional coactivator (CRTC) 3, its dissociation from 14-3-3 proteins and its translocation to the nucleus where it enhances a gene transcription program controlled by CREB. Importantly, the effects of SIK inhibitors on IL-10 production are lost in macrophages that express a drug-resistant mutant of SIK2. These findings identify SIKs as a key molecular switch whose inhibition reprograms macrophages to an anti-inflammatory phenotype. The remarkable effects of SIK inhibitors on macrophage function suggest that drugs that target these protein kinases may have therapeutic potential for the treatment of inflammatory and autoimmune diseases. http://www.ncbi.nlm.nih.gov/pubmed/23033494 https://www.wikigenes.org/e/gene/e/17691.htm
Patient and Methods The criteria for this case study was that the mother had to be exclusively breast feeding, the infant had symptoms of colic and reflux, both the patient and her infant were not on any medications for indigestion, the patient had to be compliant with dietary changes and be compliant with taking any supplements. A patient for the case study was recruited from a local lactation specialist. The patient was 26 years old with a 15 day old infant son. A medical history of the patient revealed a past episode of hyperthyroidism, migraine headaches, seasonal allergies to mold and tree and grass pollen, a latex and betadine allergy, a tonsillectomy in 1999, and sinus surgery in 2006. When questioned about her digestive symptoms the patient revealed daily nausea, gas, acid reflux, stomach pains, and vomiting 7-8 times a month. The patient rated the severity of her initial digestive symptoms at 8/10. The patient’s typical diet consisted of eggs or cereal for breakfast, sandwich, pizza, or soup for lunch and for dinner baked chicken, green vegetables or pasta. She also consumes one cup of half caffeinated coffee per day. A medical history of the pregnancy revealed acid reflux, dehydration, constant nausea, lung infection, sinus infection, gum swelling and possible infection and 3-4 weeks of left sided trigeminal neuralgia. The patient took 3 courses of antibiotics for the infection of the lung, sinuses, and gums as well as intravenous antibiotics during the birthing process because she had tested Strep B positive. During the birth process the patient was also given pitocin, pain medication and had an epidural. The baby was delivered vaginally and began breast feeding 30 minutes after being born. No formula was given. At the age of one week the infant started to experience symptoms of colic and reflux including gurgling, coughing, hiccups, an inability to be soothed and inability to lay flat without crying. Over the course of the week the patient noted the infant’s symptoms were increasing. The patient rated the severity of her infant’s symptoms as 6/10. The patient also related that her 19 month old son followed the same progression of symptoms and had severe colic and reflux that did not stop until he was weaned. Initial manual muscle testing was performed bilaterally on the patient including the pectoralis major clavicular, pectoralis major sternal, quadriceps as a group, abdominals, popliteus, tensor fascia lata and quadratus lumborum. Muscles were chosen for their organ correlation to the digestive tract. The procedure for testing foods was having the patient taste and chew the individual food and then testing the muscles associated with the digestive tract. (1) All foods were organic when possible and were prepared as simply as possible by boiling, heating in a pan or leaving in their natural state when indicated. Foods, listed in Table 1, were chosen based on common foods mothers are told to avoid by lactation specialists and past experience in the office. If after tasting and chewing a food any muscle associated with the digestive tract became inhibited, the patient was told to avoid eating that food as much as possible. If a muscle became inhibited while tasting, the food the patient then tasted various digestive supports including betaine HCL and broad spectrum enzyme products to see if one negated the muscle inhibition. If a supplement negated the muscle inhibition, the patient was instructed to take that digestive aid when they were eating similar foods to the one that caused the inhibition. For example, if beef caused muscle inhibition and betaine HCL negated it, then the patient would be instructed to avoid beef but take the betaine HCL if the patient was eating other dense proteins. The patient was to return weekly until it could be determined if progress was being made. All initially positive tests were repeated for the duration of the case study. If a food tested negative initially it was not repeated due to time constraints. The patient was also tested for ileocecal valve disturbances. If positive the ileocecal valve was tested against broad spectrum anti-microbial and antifungals that would be allowed during breast feeding (2) and various types of probiotics. http://drspietrantone.com/wp-content/uploads/2011/09/Colic-Case-Study-for-the-ICAK.pdf
LEPTIN-MEDIATED MCP-1 SECRETION has been shown in immune cells such as eosinophils [38]. However, no studies addressed whether leptin injection into leptin deficient ob/ob mice increases plasma MCP-1 concentration.
The current study tested whether adipose tissue mass, numbers of adipose tissue SVF cells and MSC numbers are altered with obesity in the ob/ob model. The current study also tested whether leptin injection to ob/ob mice increased plasma and adipose MCP-1expression and further dissected the intracellular signaling pathways involved in adipose MCP-1expression. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3559810/
Stomach acid is not something most people think about. Yet it’s one of the most important aspects of your digestive system!
Stomach acid, also called Gastric Acid, is made on demand when you eat via the parietal cells that line your stomach. Those parietal cells use various minerals to help make stomach acid–the latter which is mainly composed of hydrochloric acid, potassium and sodium, and will usually have a pH of 1.35 to 3.5 (Wiki), i.e. it’s all highly regulated. It’s purpose is to keep your pH levels down. Other cells in your stomach produce bicarbonate to help buffer the acidity, as well as mucus to help protect your stomach lining from the aciditiy.
What does stomach acid do for me?
Two key benefits: absorption and protection. When food hits your stomach, it’s your stomach’s gastric acid that begins the breakdown of protein and most minerals with pepsin to prepare for the important absorption of key nutrients (like iron B12, Vit. D and MORE) in those foods for your health and well-being. It also helps knock out bad or dangerous bacteria.
Low stomach acid also leads to non-optimal levels of neurotransmitters/amino acids (chemicals which transmit signals from one cell to another and play a huge role in your health and well-being).
How hypothyroidism negatively affects your stomach acid levels
Just as hypothyroidism can result in the drying out of your skin and hair, it also seems to lower the levels of stomach acid in many thyroid patients, possibly by lowering your amount of parietel cells or lowering their ability to produce gastric acid. The result? The absorption of important nutrients is reduced, and you can find yourself with non-optimal or low levels of iron, B12, Vitamin D and more. And you won’t have the protection you once had against bad forms of bacteria, causing their over-growth (dysbyosis). Symptoms can include delayed excessive gas as that bacteria enters your intestine. (Long term antibiotic use can also cause the same overgrowth.)
Those low levels also cause the diagnosis of “gastritis”–when the stomach becomes inflamed and irritated DUE to the low stomach acid causing food or supplements to sit too long, thus irritation of the stomach lining.
Acid reflux (GERD), heartburn, and indigestion–high levels of stomach acid? Nope.
Turns out that it’s our low levels of stomach acid which cause the Big 3: acid reflux (where our undigested stomach contents press up into our esophagus via a now-relaxed esophagus value and we feel the small amount of acid), heartburn (the burning sensation in our esophagus) and indigestion (impaired digestion due to poor breakdown of bad bacteria).
And sadly, our doctors have been putting us on Proton-pump inhibitors (PPIs) like Omeprazole (Prilosec) or Lansoprazole (Prevacid) or Esomepraxole (Nexium) and more, all acid suppressors…and as if our symptoms come from excess acid! Or we head to our local pharmacy or grocery store and load up on antacids like Rolaids, Tums or others. So though they can mask symptoms, we are now made even worse.
You can even have diarrhea from low stomach acid due to the inadequate digestion and pH issue of low stomach acid. Some speculate that inflammatory bowel disease is the result of low levels of stomach acid.
Aging and low stomach acid
Research has found that the older your body gets, the lower your secretion of stomach acid can become. This happened to the elderly mother-in-law of the creator of this site, even without being hypothyroid, and she did much better with her digestion once she added Apple Cider Vinegar to her morning and bedtime water.
Low stomach acid and Candida
Patients have discovered that increasing the acidic level of their stomachs can slow the growth of candida. (By the way, if you have candida, do an internet search for “baking soda candida”)
Low stomach acid, Lactose and/or Gluten Intolerance
Many patients are surprised to discover that their intolerance to milk products, called lactose intolerance, is actually a symptom of poor levels of stomach acid. And as happened to the husband of the creator of this site, his lactose intolerance completely went away once he started to give himself Apple Cider Vinegar (see below) in his morning drink.
Even many cases of gluten intolerance can be connected to low stomach acid for some individuals. They have found that when they improve their acid levels, they are less sensitive to gluten to some degree.
The solution?
o Treating one’s hypothyroidism, especially with natural desiccated thyroid (NDT), has helped reverse the problem of low stomach acid. It can also be important to treat low cortisol/low aldosterone to return stomach acid levels to normal.
o Swallowing daily supplements with healthy acids added to water or your favorite juice, such as one tablespoon Apple Cider Vinegar (ACV) or lemon juice, has helped many. Preferable brands of ACV are unfiltered, unheated, and unpasteurized (Braggs is one, but there are others). You can also disguise the ACV in water with flavored stevia, or Vitamin C packets, or more. Do NOT drink ACV by itself–it can burn your esophagus. Two notes: 1) if you have high potassium, you might want to avoid ACV and use lemon juice or Betaine below instead. 2) If you have a peptic ulcer, you’ll need to first work on healing that. Cabbage Juice can help, says this study. Other forms of healthy acids may do the trick as well.
o Over-the-counter hydrochloric acid, often known by the brand name Betaine, has helped. (Note: if you get diarrhea with Betaine, it may reveal that you also have h-pylori)
o The herb called Swedish Bitters may be worth a try, as it’s stated to help raise hydrochloric acid levels. It’s been recommended in the treatment of Candida, as well.
o Restoring your iodine levels may improve stomach acid production as well, as some articles suggest.
As you give yourself back the acid you need, absorption of key nutrients returns, which helps your parietal cells produce acid better all over again.
Many patients also turn to using a quality Probiotic along with their healthy acid supplements. Probiotics contain healthy bacteria as a way to start balancing out the abundance of bad bacteria.
Note: If you have been on Proton-pump inhibitors (PPIs) like Prilosec or over-the-counter digestive aids like Rolaids or Tums etc for an extended period, and want to get off, it’s recommended not to stop cold turkey, but to wean off to avoid some side-effects of withdrawal. Janie’s husband went off cold turkey, and had heartburn for a week and poor tolerance for acids . It eventually subsided, and he returned to using ACV until he could get his hypothyroidism better treated.
Ways to test if you have low stomach acid (even though it’s a given for most thyroid patients if you find yourself with low nutrients like iron, B12, Vit. D or more)
1. Baking Soda test (non-scientific): After you have gotten up in the morning, and before eating or drinking, mix about 1/4 tsp baking soda in a cup of water and drink it down. Watch to see if you have burped in the next 2 – 3 minutes (stomach acid and baking soda react to form carbon dioxide gas). If you do NOT, you probably have low stomach acid. NOTE: one test is not definitive. You have to do this test at least 3 mornings and see if you have more “No, I didn’t burp in 2-3 minutes”, then Yes, I did. This test is only a rough indication.
2. Betaine HCl Challenge Test (non-scientific and not to be done if you have peptic ulcers): You will need to purchase Betaine, preferably the 600 mg pills, at your local health food store–a man-made hydrochloric acid. Your goal is to find out how many tablets it takes to feel a warmth or burning in your stomach. Patients with normal stomach acid levels would feel this with one, or sometimes two pills. On the first day, take one right before or at the beginning of large meal. On the second day, take two before or at the beginning of a large meal. On the third day, take three before or at the beginning of a large meal….etc up to the 7th day and 7 tablets, if needed (some versions of this test go up to ten days and 10 tablets). The more tablets you have to take to feel that warmth, the more likely you have low stomach acid. NOTE: if this test produces excess burning in the beginning, it’s a sign you have too much stomach acid and this test should immediately stop. Otherwise, this test is only meant to be used until you feel that burn/warmth, which could happen before the seventh day.
3. The Heidelberg Stomach Acid test (scientific): This is a test you’ll have to ask your doctor about, and thus, is far more exact than the above, but can be costly–more than $300 US. You are instructed to drink a baking soda solution (sodium bicarbonate) as well as swallow a capsule with a tiny pH meter and radio transmitter (radiotelemetry). It will analyze the pH of your stomach acid.NOTE: you will need to be off any Proton Pump Inhibitors or over-the-counter stomach aides for about five days. This test takes about an hour or slightly more time.
P.S. Low aldosterone, which causes low levels of sodium, can promote low stomach acid, since the acid needs salt to exist! http://www.stopthethyroidmadness.com/stomach-acid/
Relationships of weight gain and behavior to digestive organ weight and enzyme activities in piglets.
Organ weights and digestive enzyme contents of the pancreas, stomach and duodenum were measured in 75 nursing piglets at 21 d of age. Piglets were given creep feed from 10 d of age. Creep feed intake was less than 1.5 g.d-1.piglet-1 up to d 18; on d 19 and 20 it averaged 15 g.d-1.piglet-1. On d 10, piglets went to the feeder more frequently than on the following days. Feeding bouts were longer on d 16, 17 and 18 just prior to the increase in creep feed consumption. Means and SE for the parameters studied at 21 d of age were 7.01 +/- .18 mg for pancreas weight; 61,499 +/- 4,091 units of amylase (UA) and 1,510 +/- 110 UA/mg DNA; 2,962 +/- 189 units of chymotrypsin (UC) and 68.94 +/- 3.92 UC/mg DNA; 8.76 +/- .35 g for fundic mucosa weight; 558,875 +/- 49,287 units of pepsin (UP) and 12,338 +/- 1,175 UP/mg DNA; 1.75 +/- .06 g for duodenum weight; 1.39 +/- .07 units of maltase (UM) and .14 +/- .006 UM/mg DNA. Day-0 weight was not correlated with 21-d gain. Feeding behaviors were correlated positively with 21-d gains. Feeding behaviors and behaviors were correlated positively to pancreas total and specific enzyme contents as well as to stomach and duodenum weights, RNA/DNA ratios of the pancreas and the stomach and protein/DNA of the pancreas but were correlated negatively with specific and total pepsin and maltase activities. Variation was large in enzyme activities (cv = 35 to 82%).(ABSTRACT TRUNCATED AT 250 WORDS) http://www.ncbi.nlm.nih.gov/pubmed/2480340
Betaine is a natural substance produced by the body and found it some foods. It's purpose is to convert homocysteine back to methionine, which is good because high homocysteine levels are bad. It shouldn't cause problems, as far as I know. http://forums.phoenixrising.me/index.php?threads/liquid-betaine-hydrochloride.14356/
That's a different form of betaine Valentijn. I think you're talking about Betaine Anhydrous, which is also known as TMG, or trimethylglycine.
She's talking about betaine hydrochloride, or hydrochloric acid, produced in the stomach if one has sufficient levels of zinc, histidine, and some of the b vitamins, but also available as a supplement until one can produce sufficient amounts naturally.
I agree w/Caledonia's recommendations.
Hyperglycemia also has secretory effects in the stomach, including decreased secretion of hydrochloric acid.13 The net result of these changes is a reduction in effective emptying, starting first with indigestible solids, then progressing to digestible solids, and eventually to liquids.14 The myoelectric and neuroanatomic consequences of hyperglycemia may be accentuated by abnormal secretion of various hormones, including glucagon, gastrin, cholecystokinin, and gastric inhibitory peptide in patients with diabetes.3 http://journal.diabetes.org/diabetesspectrum/00v13n1/pg11.htm
In six out of eight patients with portocaval shunts, rises of plasma insulin concentrations could be demonstrated following the intraduodenal administration of hydrochloric acid. Since intraduodenal acidification is a potent stimulus for the release of endogenous secretin, and since similar changes of plasma insulin levels may be produced by administration of exogenous secretin, it is suggested that the β-cytotropic effect of intraduodenal acidification may be mediated through liberation of endogenous secretin. It appears that in normal subjects, plasma insulin response to the same measures is obliterated by intrahepatic insulin clearance and by the dilution, in the peripheral circulation, of hepatic vein plasma. http://www.sciencedirect.com/science/article/pii/0026049570900545
Insulin-degrading enzyme (IDE) is a neutral Zn2+ peptidase that degrades short peptides based on substrate conformation, size and charge. Some of these substrates, including amyloid β (Aβ) are capable of self-assembling into cytotoxic oligomers. Based on IDE recognition mechanism and our previous report of the formation of a stable complex between IDE and intact Aβ in vitro and in vivo, we analyzed the possibility of a chaperone-like function of IDE. A proteolytically inactive recombinant IDE with Glu111 replaced by Gln (IDEQ) was used. IDEQ blocked the amyloidogenic pathway of Aβ yielding non-fibrillar structures as assessed by electron microscopy. Measurements of the kinetics of Aβ aggregation by light scattering showed that 1) IDEQ effect was promoted by ATP independent of its hydrolysis, 2) end products of Aβ-IDEQ co-incubation were incapable of “seeding” the assembly of monomeric Aβ and 3) IDEQ was ineffective in reversing Aβ aggregation. Moreover, Aβ aggregates formed in the presence of IDEQ were non-neurotoxic. IDEQ had no conformational effects upon insulin (a non-amyloidogenic protein under physiological conditions) and did not disturb insulin receptor activation in cultured cells. Our results suggest that IDE has a chaperone-like activity upon amyloid-forming peptides. It remains to be explored whether other highly conserved metallopeptidases have a dual protease-chaperone function to prevent the formation of toxic peptide oligomers from bacteria to mammals. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0059113
· CALHM1 ion channel elicits amyloid-{beta} clearance by insulin-degrading enzyme in cell lines and in vivo in the mouse brainJ. Cell Sci. 2015 128 (13) 2330-2338
· The Last Enzyme of the De Novo Purine Synthesis Pathway 5-aminoimidazole-4-carboxamide Ribonucleotide Formyltransferase/IMP Cyclohydrolase (ATIC) Plays a Central Role in Insulin Signaling and the Golgi/Endosomes Protein NetworkMCP 2015 14 (4) 1079-1092
· Highly Amyloidogenic Two-chain Peptide Fragments Are Released upon Partial Digestion of Insulin with PepsinJ Biol Chem 2015 290 (10) 5947-5958
THE ACTION OF PEPSIN ON INSULIN.
---ALBERT A. EPSTEINFROM THE LABORATORY OF PHYSIOLOGICAL CHEMISTRY, PATHOLOGICAL DEPARTMENT, MT. SINAI HOSPITAL, NEW YORK CITY.
SUMMARY
1. PEPSIN'INACTIVATES'INSULIN BUT DOES NOT DIGEST IT.
2. LIBERATION OR DISSOCIATION OF INSULIN FROM PEPSIN TAKES PLACE, EVEN AFTER PROLONGED CONTACT, AT A PROPERLY ADJUSTED PH. HTTP://EBM.SAGEPUB.COM/CONTENT/22/1/9.ABSTRACT
Highly Amyloidogenic Two-chain Peptide Fragments Are Released upon Partial Digestion of Insulin with Pepsin*♦
Results: Limited proteolysis of bovine insulin dimers with pepsin releases highly fibrillation-prone two-chain fragments.
Conclusion: Dynamics of the disulfide-bonded N-terminal fragments of A- and B-chains may strongly contribute to insulin amyloidogenesis.
Significance: Highly aggregation-prone regions of protein molecules may be revealed by partial proteolysis of the native state.http://www.jbc.org/content/290/10/5947.abstract
Background: Thyroid hormones are known to influence acid and pepsin secretion, though the exact mechanism is not fully understood. In this study, distension-stimulated acid and pepsin secretions in hypo- and hyperthyroid rats were compared with controls.
Results: Acid secretions, which were measured by automatic titrator in the:
RATS
|
DISTENSION-STIMULATED ACID x µmol/15 min
|
PEPSIN SECRETION x mg/15 min
|
HYPOTHYROID
|
8±0.2
|
4.4±0.5
|
HYPERTHYROID
|
14.6±1.9
|
9.09 ±0.4
|
CONTROL GROUPS
|
10.2±0.1
|
6.1±0.1
|
There were statistically significant differences in both series between control and the other two groups.
Conclusion: The results from the measurements of thyroid-stimulating hormones and T4
hormones showed that INCREASED OR DECREASED THYROID FUNCTION CAN SIGNIFICANTLY AFFECT GASTRIC DISTENSION-INDUCED ACID AND PEPSIN SECRETION. Ann Saudi http://www.kfshrc.edu.sa/annals/old/225_226/01-272.pdf
Iron and Zinc are also essential for normal thyroid hormone metabolism. Iron deficiency hinders the making of thyroid hormone by reducing activity of HEME-DEPENDENT THYROID PEROXIDASE. Iron-deficiency anemia decreases and iron supplementation improves the beneficial effects of iodine supplementation. Treating iron deficient hypothyroid patients with T4 also improves their iron deficiency anemia. Iodine, selenium, and zinc levels in the thyroid gland vary with TSH levels. In one study 29.8% of the hypothyroid women had low iron while only 16 % of the control group did.
Thyroid peroxidase or thyroperoxidase (TPO) is an enzyme expressed mainly in the thyroid where it is secreted into colloid. Thyroid peroxidase oxidizes iodide ions to form iodine atoms for addition onto tyrosine residues on thyroglobulin for the production of thyroxine (T4) or triiodothyronine (T3), the thyroid hormones.[1] In humans, thyroperoxidase is encoded by the TPO gene.[2]
Catalyzed reaction[edit]
+ I− + H+ + H2O2 ⇒ + 2 H2O
Iodide is oxidized to iodine radical which immediately reacts with tyrosine.
+ I− + H+ + H2O2 ⇒ + 2 H2O
The second iodine atom is added in similar manner to the reaction intermediate 3-iodotyrosine.
Thyroid hormone synthesis, with thyroid peroxidase performing the oxidation step seen at center-left in the image.[3]
Inorganic iodine enters the body primarily as iodide, I−. After entering the thyroid follicle (or thyroid follicular cell) via a Na+/I− symporter (NIS) on the basolateral side, iodide is shuttled across the apical membrane into the colloid via pendrin, after which thyroid peroxidase oxidizes iodide to atomic iodine (I) or iodinium (I+). The "organification of iodine," the incorporation of iodine into thyroglobulin for the production of thyroid hormone, is nonspecific; that is, there is no TPO-bound intermediate, but iodination occurs via reactive iodine species released from TPO.[4] The chemical reactions catalyzed by thyroid peroxidase occur on the outer apical membrane surface and are mediated by hydrogen peroxide.
Stimulation and inhibition---TPO is stimulated by TSH, which upregulates gene expression. --TPO is inhibited by the thioamide drugs, such as propylthiouracil and methimazole.[5] In laboratory rats with insufficient iodine intake, genistein has demonstrated inhibition of TPO.[6]
Clinical significance -Thyroid peroxidase is a frequent epitope of autoantibodies in autoimmune thyroid disease, with such antibodies being called anti-thyroid peroxidase antibodies (anti-TPO antibodies). This is most commonly associated with Hashimoto's thyroiditis. Thus, an antibody titer can be used to assess disease activity in patients that have developed such antibodies.[7][8]
Diagnostic use[edit]In diagnostic immunohistochemistry, the expression of thyroid peroxidase (TPO) is lost in papillary thyroid carcinoma.[9]
.
https://en.wikipedia.org/wiki/Thyroid_peroxidase Pathogenesis[edit]
The production of antibodies in Graves' disease is thought to arise by activation of CD4+ T-cells, followed by B-cell recruitment into the thyroid. These B-cells produce antibodies specific to the thyroid antigens. In Hashimoto's thyroiditis, activated CD4+ T-cells produce interferon-γ, causing the thyroid cells to display MHC class II molecules. This expands the autoreactive T-cell repertoire and prolongs the inflammatory response.[14]
While anti-thyroid antibodies are used to track the presence of autoimmune thyroiditis, they are generally not considered to contribute directly to the destruction of the thyroid.[9]
Effect on human reproduction[edit]
The presence of anti-thyroid antibodies is associated with an increased risk of unexplained subfertility (odds ratio 1.5 and 95% confidence interval 1.1–2.0), miscarriage (odds ratio 3.73, 95% confidence interval 1.8–7.6), recurrent miscarriage (odds ratio 2.3, 95% confidence interval 1.5–3.5), preterm birth (odds ratio 1.9, 95% confidence interval 1.1–3.5) and maternal Postpartum thyroiditis (odds ratio 11.5, 95% confidence interval 5.6–24).[15]
Nitric oxide enhances thyroid peroxidase activity in primary ...www.ncbi.nlm.nih.gov/.../9...Nitric oxide enhances thyroid peroxidase activity in primary human thyrocytes. ... onthyroid peroxidase (TPO) activity in monolayer cultures of primary human ...
Nitric oxide/cGMP signaling inhibits TSH-stimulated iodide ...www.ncbi.nlm.nih.gov/...Nitric oxide/cGMP signaling inhibits TSH-stimulated iodide uptake and expression of ... SNP inhibited thyroperoxidase (TPO) and thyroglobulin (TG) mRNA ...
IRON DEFICIENCY ANEMIA REDUCES THYROID PEROXIDASE ACTIVITY IN ...www.ncbi.nlm.nih.gov/...The objective of this study was to investigate whether iron (Fe) deficiency lowersthyroid peroxidase (TPO) activity. TPO is a heme-containing enzyme catalyzing ..
Iron deficiency anemia reduces thyroid peroxidase activity in rats.ct
Studies in animals and humans have shown that iron deficiency anemia (IDA) impairs thyroid metabolism. However, the mechanism is not yet clear. The objective of this study was to investigate whether iron (Fe) deficiency lowers thyroid peroxidase (TPO) activity. TPO is a heme-containing enzyme catalyzing the two initial steps in thyroid hormone synthesis. Male weanling Sprague-Dawley rats (n = 84) were randomly assigned to seven groups. Three groups (ID-3, ID-7, ID-11) were fed an Fe-deficient diet containing 3, 7 and 11 microg Fe/g, respectively. Because IDA reduces food intake, three control groups were pair-fed Fe-sufficient diets (35 microg Fe/g) to each of the ID groups and one control group consumed food ad libitum. After 4 wk, hemoglobin, triiodothyronine (T(3)) and thyroxine (T(4)) were lower in the Fe-deficient groups than in the ad libitum control group (P < 0.001). By multiple regression, food restriction had a significant, independent effect on T(4) (P < 0.0001), but not on T(3). TPO activity (by both guaiacol and iodine assays) was markedly reduced by food restriction (P < 0.05). IDA also independently reduced TPO activity (P < 0.05). Compared with the ad libitum controls, TPO activity per thyroid determined by the guaiacol assay in the ID-3, ID-7 and ID-11 groups was decreased by 56, 45 and 33%, respectively (P < 0.05). These data indicate that Fe deficiency sharply reduces TPO activity and suggest that decreased TPO activity contributes to the adverse effects of IDA on thyroid metabolism. http://www.ncbi.nlm.nih.gov/pubmed/12097675
Type of dietary carbohydrate affects thyroid hormone deiodination in iron-deficient rats.
The interactive effect of iron deficiency and dietary carbohydrate type on growth and thyroid hormone status of Sprague-Dawley rats was studied. Rats were fed either an iron-adequate (approximately 35 micrograms Fe/g) or an iron-deficient (less than 3 micrograms Fe/g) diet that contained 70% carbohydrate. The carbohydrate sources were 100% cornstarch (STARCH), 85.7% cornstarch and 14.3% sucrose (STARCH/SUCR), 71.4% cornstarch, 14.3% sucrose and 14.3% dextrin (DEXTRIN), or 100% sucrose (SUCROSE). After 4 wk, iron-deficient rats weighed less than the iron-adequate rats and were severely anemic. Total food intake was lower in iron-deficient than in iron-adequate animals; it was also significantly lower in SUCROSE-fed animals relative to other carbohydrate groups.
Plasma glucose concentrations were significantly higher in iron-deficient rats than in iron-adequate rats, but plasma thyroid hormones, thyroxine and triiodothyronine, and liver thyroxine monodeiodinase activity were lower.
Deiodination of reverse triiodothyronine in liver was unaffected by iron deficiency regardless of carbohydrate treatment. The STARCH-fed animals had higher rates of hepatic thyroxine monodeiodinase activity than rats fed the other dietary carbohydrates. The two main conclusions from this study are that thyroid hormone metabolism is altered by iron deficiency regardless of food intake and that the best purified rodent diet for this type of study would contain a mixture of carbohydrate types to avoid the stimulation of thyroxine monodeiodinase by a 70% cornstarch diet. http://www.ncbi.nlm.nih.gov/pubmed/1564571
https://books.google.com/books?id=5W5DAAAAQBAJ&lpg=PA83&ots=lbaOrUL-XD&dq=how%20to%20block%20hepcidin&pg=PA83#v=onepage&q=how%20to%20block%20hepcidin&f=false
Iron overload is frequently observed in type 2 diabetes mellitus (DM2), but the underlying mechanisms remain unclear. We hypothesize that hepcidin may be directly regulated by insulin and play an important role in iron overload in DM2. We therefore examined the hepatic iron content, serum iron parameters, intestinal iron absorption, and liver hepcidin expression in rats treated with streptozotocin (STZ), which was given alone or after insulin resistance induced by a high-fat diet. The direct effect of insulin on hepcidin and its molecular mechanisms were furthermore determined in vitro in HepG2 cells. STZ administration caused a significant reduction in liver hepcidin level and a marked increase in intestinal iron absorption and serum and hepatic iron content. Insulin obviously upregulated hepcidin expression in HepG2 cells and enhanced signal transducer and activator of transcription 3 protein synthesis and DNA binding activity. The effect of insulin on hepcidin disappeared when the signal transducer and activator of transcription 3 pathway was blocked and could be partially inhibited by U0126. In conclusion, the current study suggests that hepcidin can be directly regulated by insulin, and the suppressed liver hepcidin synthesis may be an important reason for the iron overload in DM2. http://www.ncbi.nlm.nih.gov/pubmed/24379355
Quercetin prevents ethanol-induced iron overload by regulating hepcidin through the BMP6/SMAD4 signaling pathway.
Emerging evidence has demonstrated that chronic ethanol exposure induces iron overload, enhancing ethanol-mediated liver damage. The purpose of this study was to explore the effects of the naturally occurring compound quercetin on ethanol-induced iron overload and liver damage, focusing on the signaling pathway of the iron regulatory hormone hepcidin. Adult male C57BL/6J mice were pair-fed with isocaloric-Lieber De Carli diets containing ethanol (accounting for 30% of total calories) and/or carbonyl iron (0.2%) and treated with quecertin (100 mg/kg body weight) for 15 weeks. Mouse primary hepatocytes were incubated with ethanol (100 mM) and quercetin (100 μM) for 24 h. Mice exposed to either ethanol or iron presented significant fatty infiltration and iron deposition in the liver; these symptoms were exacerbated in mice cotreated with ethanol and iron. Quercetin attenuated the abnormity induced by ethanol and/or iron. Ethanol suppressed BMP6 and intranuclear SMAD4 as well as decreased hepcidin expression. These effects were partially alleviated by quercetin supplementation in mice and hepatocytes. Importantly, ethanol caused suppression of SMAD4 binding to the HAMP promoter and of hepcidin messenger RNA expression. These effects were exacerbated by anti-BMP6 antibody and partially alleviated by quercetin or human recombinant BMP6 in cultured hepatocytes. In contrast, co-treatment with iron and ethanol, especially exposure of iron alone, activated BMP6/SMAD4 pathway and up-regulated hepcidin expression, which was also normalized by quercetin in vivo. Quercetin prevented ethanol-induced hepatic iron overload different from what carbonyl iron diet elicited in the mechanism, by regulating hepcidin expression via the
BMP6/SMAD4 signaling pathway.http://www.ncbi.nlm.nih.gov/pubmed/24746831
http://www.frontiersin.org/files/Articles/88368/fphar-05-00104-HTML/image_m/fphar-05-00104-g001.jpg
http://jpet.aspetjournals.org/content/337/1/16/F6.large.jpg
Quercetin Inhibits Intestinal Iron Absorption and Ferroportin Transporter Expression In Vivo and In Vitro
Acute exposure of rat duodenal mucosa to quercetin increased apical iron uptake but decreased subsequent basolateral iron efflux into the circulation. Quercetin binds iron between its 3-hydroxyl and 4-carbonyl groups and methylation of the 3-hydroxyl group negated both the increase in apical uptake and the inhibition of basolateral iron release, suggesting that the acute effects of quercetin on iron transport were due to iron chelation. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0102900
REACTIVE OXYGEN SPECIES REGULATE HYPOXIA-INDUCIBLE ...mcb.asm.org/content/28/16/5106.full Molecular and Cellular Biology In exercise, as well as cancer and ischemia, hypoxia-inducible factor 1 (HIF1) .....Where [Fe2+]0 and [Asc]0 were upregulated, the peak amount of HIF1α ...
HYPERGLYCEMIA REGULATES HYPOXIA-INDUCIBLE FACTOR-1 ... diabetes.diabetesjournals.org/content/53/12/3226.full.pdf Chronic kidney disease affects 40% of adults aged 65 and older. Anemia of CKD is present in 30% of patients with CKD and is associated with increased cardiovascular risk, decreased quality of life, and increased mortality. Hepcidin-25 (hepcidin), the key iron regulating hormone, prevents iron egress from macrophages and thus prevents normal recycling of the iron needed to support erythropoiesis. Hepcidin levels are increased in adults and children with CKD. Vitamin D insufficiency is highly prevalent in CKD and is associated with erythropoietin hyporesponsiveness. Recently, hepcidin levels were found to be inversely correlated with vitamin D status in CKD. The aim of this study was to investigate the role of vitamin D in the regulation of hepcidin expression in vitro and in vivo. This study reports that 1,25-dihydroxyvitamin D3(1,25(OH)2D3), the hormonally active form of vitamin D, is associated with decreased hepcidin and increased ferroportin expression in lipopolysaccharide (LPS) stimulated THP-1 cells. 1,25(OH)2D3 also resulted in a dose-dependent decrease in pro-hepcidin cytokines, IL-6 and IL-1β, release in vitro. Further, we show that high-dose vitamin D therapy impacts systemic hepcidin levels in subjects with early stage CKD. These data suggest that improvement in vitamin D status is associated with lower systemic concentrations of hepcidin in subjects with CKD. In conclusion, vitamin D regulates the hepcidin-ferroportin axis in macrophages which may facilitate iron egress. Improvement in vitamin D status in patients with CKD may reduce systemic hepcidin levels and may ameliorate anemia of CKD. http://www.jctejournal.com/article/S2214-6237(14)00004-0/abstract
Regulation of HIF-1 {alpha} activity in adipose tissue by ...www.ncbi.nlm.nih.gov/......” In adipose tissue, both HIF-1α mRNA and protein were increased by obesity. The underlying mechanism was investigated in 3T3-L1 adipocytes. HIF-1α mRNA and protein were augmented by adipocyte differentiation. In differentiated adipocytes, insulin further enhanced HIF-1α in both levels. Hypoxia enhanced only HIF-1α protein, not mRNA. PI3K and mTOR activities are required for the HIF-1α expression. Function of HIF-1α protein was investigated in the regulation of VEGF gene transcription. ChIP assay shows that HIF-1α binds to the proximal hypoxia response element in the VEGF gene promoter, and its function is inhibited by a corepressor composed of HDAC3 and SMRT. These observations suggest that of the three obesity-associated factors, all of them are able to augment HIF-1α protein levels, but only two (adipogenesis and insulin) are able to enhance HIF-1α mRNA activity. Adipose tissue HIF-1α activity is influenced by multiple signals, including adipogenesis, insulin, and hypoxia in obesity. The transcriptional activity of HIF-1α is inhibited by HDAC3-SMRT corepressor in the VEGF gene promoter.”
Increased adipocyte O2 consumption triggers HIF-1α ...www.ncbi.nlm.nih.gov/... Increased adipocyte O2 consumption triggers HIF-1α, causing inflammation and insulin ... Fatty Acids/metabolism; Hypoxia-Inducible Factor 1, alpha Subunit/genetics
BACKGROUNDS:Hepcidin modulates the de novo absorption of iron from the duodenum and the recycling of iron released from the reticuloendothelial system. In patients with chronic renal failure, administration of higher doses of ERYTHROPOIETIN (EPO) OR VITAMIN C (VIT C) CAN CORRECT THE FUNCTIONAL IRON DEFICIENCY. While EPO-regulated hepcidin expression within hepatocytes has been recently identified, the relation between vitamin C with hepcidin expression is still uncertain.
METHODS: HEPCIDIN-PRODUCING HEPG2 CELLS (a human liver carcinoma cell line) were cultured with 50- to 100-μg/mL vitamin C or 0.25- to 1.0-U/mL EPO for 6 hours. Reverse transcription polymerase chain reaction was performed for quantitative measurements of hepcidin, EPO, and EPO receptor (EPOR) expression.
RESULTS:EPO AND VITAMIN C INHIBITED HEPCIDIN EXPRESSION WITHIN HEPG2 CELLS; the EPO effect was dose dependent. EPO downregulated EPOR and vitamin C and upregulated EPOR. However, vitamin C had little effect on the expression of EPO.
CONCLUSIONS:EPO is capable of downregulating EPOR when it acts early. Vitamin C directly inhibits hepcidin expression within HepG2 cells. Moreover, by enhancing EPOR production, vitamin C may correct the downregulating EPOR from EPO, which has additional effect with EPO in treating anemia.
The purpose of these studies was to evaluate the possible role of serotonin on pepsin secretion. The results of our data suggest that serotonin is a stimulator of pepsin secretion since (a) pretreatment with reserpine (which depletes serotonin stores) abolished the stimulatory effect of histamine on pepsin secretion; (b) pretreatment with UML-491 (a serotonin blocking agent at the effector level) augmented the pepsin inhibition induced by the intraduodenal infusion of fat, and (c) 5-hydroxytryptophan (a serotonin precursor) caused a significant stimulation of pepsin secretion. The mode of action of serotonin is probably by a direct hormonal action on the gastric chief cells. http://www.ncbi.nlm.nih.gov/pubmed/329778
ALDOSTERONE IS INCREASED BY H2 RECEPTOR. The effect of aldosterone on recovery in arteries from wild-type mice and the SNP-mediated dilatation in arteries from eNOS−/− mice was inhibited by the histamine H2 receptor antagonist cimetidine. RT-PCR showed expression of mast cell markers in mouse mesenteric arteries.http://ajpheart.physiology.org/content/304/8/H1094
Secretion of aldosterone in response to histamine in hypophysectomized-nephrectomized dogs. ---In hypophysectomized-nephrectomized dogs after intravenous injection of histamine, a marked increase was observed in the rate of secretion of aldosterone, although it was smaller than that in intact dogs. Hypophysectomy plus bilateral nephrectomy greatly impaired the secretion of corticosterone and cortisol in the dog in response to histamine. However, a small yet significant increase in corticosterone and cortisol secretion was observed in hypophysectomized-nephrectomized dogs after intravenous injection of histamine. Additional experiments showed that plasma concentrations of potassium and sodium in hypophysectomized-nephrectomized dogs remained unchanged after intravenous injection of histamine. These results suggest that histamine stimulates aldosterone secretion in the dog partly by a direct effect on the adrenal cortical cells, whereas the effect of histamine on corticosterone and cortisol secretion is mediated mainly, but not totally, by pituitary release of ACTH.http://www.ncbi.nlm.nih.gov/pubmed/224133
IL-10 Diseases Associated With Lower IL-10 Levels This is a partial list
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Dendritic cells (DCs) require costimulatory molecules such as CD86 to efficiently activate T cells for the induction of adaptive immunity. DCs maintain minimal levels of CD86 expression at rest, but upregulate levels upon LPS stimulation. LPSstimulated DCs produce the immune suppressive cytokine IL-10 that acts in an autocrine manner to regulate CD86 levels. Interestingly, the underlying molecular mechanism behind the tight control of CD86 is not completely understood. In this study, we report that CD86 is ubiquitinated in DCs via MARCH1 E3 ubiquitin ligase and that this ubiquitination plays a key role in CD86 regulation. Ubiquitination at lysine 267 played the most critical role for this regulation. CD86 is ubiquitinated in MARCH1-deficient DCs to a much lesser degree than in wild-type DCs, which also correlated with a significant increase in CD86 expression. Importantly, CD86 is continuously ubiquitinated in DCs following activation by LPS, and this was due to the autocrine IL-10 inhibition of MARCH1 downregulation. Accordingly, DCs lacking MARCH1 and DCs expressing ubiquitination-resistant mutant CD86 both failed to regulate CD86 in response to autocrine IL-10. DCs expressing ubiquitination-resistant mutant CD86 failed to control their T cellactivating abilities at rest as well as in response to autocrine IL-10. These studies suggest that ubiquitination serves as an important mechanism by which DCs control CD86 expression and regulate their Ag-presenting functions. One potential mechanism is that IL-10 may inhibit LPS signaling, which downregulates MARCH1 expression in DCs (12, 28). Alternatively but not exclusively, IL-10 may upregulate MARCH1 expression independently of LPS signaling. By any means, MARCH1-mediated ubiquitination plays an essential role for DCs to regulate CD86 in their response to autocrine IL-10. This finding is consistent with the recent report that MARCH1 is important for DCs to suppress CD86 expression in response to recombinant IL-10 (11). http://www.jimmunol.org/content/early/2011/08/17/jimmunol.1101643.full.pdf
. Rather, reduced basophil responsiveness, which required the presence of live helminths, was found to be dependent on host IL-10 and was accompanied by decreases in key IgE signaling molecules known to be downregulated by IL-10… Like allergic diseases, helminths induce type 2 immune responses characterized by eosinophilia, elevated IgE levels, and CD4+ T-cell production of IL-4, IL-5, and IL-13. In people with infrequent exposures to helminths, this immune response is often associated with allergic symptoms such as rash and pruritus during acute infection (1). …n terms of acute effector function, basophils release histamine and leukotriene C4 after becoming activated. These molecules induce classic allergy symptoms by increasing vascular permeability, mucus secretion, and smooth muscle contraction (52, 53). While the contribution basophils make to acute inflammatory responses likely varies between different diseases, a recent clinical study demonstrated that basophils may be responsible for the majority of allergic symptoms that occur after intranasal allergen challenge of individuals with cat allergy (54). Similarly, two murine studies have identified basophils as the principal effector cells of chronic allergic inflammation (18, 22). One of the mysteries regarding helminth infections and allergy has been the observation that, in contrast to its utility in developed countries, allergen-specific IgE has poor predictive value for allergic disease in developing countries with high rates of helminth disease (55). Our discovery that chronic helminth infections can suppress IgE-mediated activation of basophils provides an explanation for this finding. Given the many differences between human and mouse FcεRI expression and basophil properties (56, 57),… n terms of acute effector function, basophils release histamine and leukotriene C4 after becoming activated. These molecules induce classic allergy symptoms by increasing vascular permeability, mucus secretion, and smooth muscle contraction (52, 53). While the contribution basophils make to acute inflammatory responses likely varies between different diseases, a recent clinical study demonstrated that basophils may be responsible for the majority of allergic symptoms that occur after intranasal allergen challenge of individuals with cat allergy (54). Similarly, two murine studies have identified basophils as the principal effector cells of chronic allergic inflammation (18, 22). One of the mysteries regarding helminth infections and allergy has been the observation that, in contrast to its utility in developed countries, allergen-specific IgE has poor predictive value for allergic disease in developing countries with high rates of helminth disease (55). Our discovery that chronic helminth infections can suppress IgE-mediated activation of basophils provides an explanation for this finding. Given the many differences between human and mouse FcεRI expression and basophil properties (56, 57),…http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3331970/
The cyclopentenone prostaglandins (cyPGs) prostaglandin A1 (PGA1) and 15-deoxy-12,14-prostaglandin J2 (15d-PGJ2) have been reported to exhibit antiinflammatory activity in activated monocytes/macrophages. However, the effects of these two cyPGs on the expression of cytokine genes may differ. In this study, we investigated the mechanism of action of PGA1 in lipopolysaccharide (LPS)-induced expression of interleukin (IL)-10 mRNA in mouse peritoneal macrophages.
15d-PGJ2 inhibited expression of LPS induced IL-10,
PGA1 increased LPS-induced IL-10 expression.
This synergistic effect of PGA1 on LPS-induced IL-10 expression reached a maximum as early as 2 h after simultaneous PGA1 and LPS treatment (PGA1/LPS), and did not require new protein synthesis.
The synergistic effect of PGA1 was inhibited by GW9662, a specific peroxisome proliferator-activated receptor (PPAR) antagonist, and Bay-11-7082, a NF-kappaB inhibitor.
The extracellular signalregulated kinases (ERK) inhibitor PD98059 increased the expression of PGA1/LPS-induced IL-10 mRNA, rather than inhibiting the IL-10 expression.
Moreover, PGA1 inhibited LPS-induced ERK phosphorylation.
The synergistic effect of PGA1 on LPS-induced IL-10 mRNA and protein production was inhibited by p38 inhibitor PD169316, and PGA1 increased LPS-induced p38 phosphorylation. In the case of stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK), the SAPK/JNK inhibitor SP600125 did not inhibit IL-10 mRNA synthesis but inhibited the production of IL-10 protein remarkably. These results suggest that the synergistic effect of PGA1 on LPS-induced IL-10 expression is NF-kappaB-dependent and mediated by mitogen-activated protein (MAP) kinases, p38, and SAPK/ JNK signaling pathways, and also associated with the PPARgamma pathway. Our data may provide more insight into the diverse mechanisms of PGA1 effects on the expression of cytokine genes. http://www.ncbi.nlm.nih.gov/pubmed/18600064
IgG and IBS
http://biomedfrontiers.org/allergy-2013-11-25/ dministration of vitamin C in vivo markedly reduced serum ...
www.researchgate.net/.../49713364_fig1_Administration-o...
Administration of vitamin C in vivo markedly reduced serum IgG1 titer. Mice were injected with nothing (control group), PBS, 0.625 mg, or 5 mg of vitamin C ...
Moderate alcohol intake in humans attenuates monocyte inflammatory responses: inhibition of nuclear regulatory factor kappa B and induction of interleukin 10. Mandrekar, P., Catalano, D., White, B., Szabo, G. Alcohol. Clin. Exp. Res. (2006) [Pubmed]
www.ncbi.nlm.nih.gov/.../1...IL-10 inhibits nitric oxide synthesis in murine uterus. ... of lipopolysaccharide (LPS; 8 mg/kg) significantly increased the conversion of arginine into citrulline.
Chemokine (C-C motif) ligand 5 (also CCL5) is a protein which in humans is encoded by the CCL5 gene.[1] It is also known as RANTES (regulated on activation, normal T cell expressed and secreted).
CCL5 is an 8kDa protein classified as a chemotactic cytokine or chemokine. CCL5 is chemotactic for T cells, eosinophils, and basophils, and plays an active role in recruiting leukocytes into inflammatory sites. With the help of particular cytokines (i.e., IL-2 and IFN-γ) that are released by T cells, CCL5 also induces the proliferation and activation of certain natural-killer (NK) cells to form CHAK (CC-Chemokine-activated killer) cells.[2] It is also an HIV-suppressive factor released from CD8+ T cells. This chemokine has been localized to chromosome 17 in humans.[1]
RANTES was first identified in a search for genes expressed "late" (3–5 days) after T cell activation. It was subsequently determined to be a CC chemokine and expressed in more than 100 human diseases. RANTES expression is regulated in T lymphocytes by Kruppel like factor 13 (KLF13).[3][4][5][6] RANTES, along with the related chemokines MIP-1alpha and MIP-1beta, has been identified as a natural HIV-suppressive factor secreted by activated CD8+ T cells and other immune cells.[7] Recently, the RANTES protein has been engineered for in vivo production by Lactobacillus bacteria, and this solution is being developed into a possible HIV entry-inhibiting topical microbicide.[8]https://en.wikipedia.org/wiki/CCL5
CCL5 increased IL-10 expression in the VSMCs of SHRs; the s.c. injection of CCL5 (1.5 μg kg−1, twice a day) for 3 weeks into SHRs with established hypertension upregulated IL-10 expression in both the thoracic aorta and the VSMCs and decreased systolic blood pressure. CCL5-induced the elevation of IL-10 expression, an effect mediated primarily via the activation of an Ang II subtype II receptor (AT2 R). Dimethylarginine dimethylaminohydrolase (DDAH)-1 activity also contributed to the elevation of IL-10 expression via CCL5 in the VSMCs of SHRs. Moreover, CCL5 partially mediated the inhibitory effects of IL-10 on Ang II-induced 12-lipoxygenase (LO) and endothelin (ET)-1 expression in the VSMCs of SHRs. Taken together, this study provides novel evidence that CCL5 plays a role in the upregulation of IL-10 activity in the VSMCs of SHRs.http://www.nature.com/hr/journal/v38/n10/full/hr201562a.html
INSULIN ACTIVATED AKT SIGNALING IN TREGS, LEADING TO INHIBITION OF BOTH IL-10 PRODUCTION AND THE ABILITY OF TREGS TO SUPPRESS THE PRODUCTION OF TNF-Α BY MACROPHAGES IN A CONTACT-INDEPENDENT MANNER. The effect of insulin on Treg suppression was limited to IL-10 production and it did not alter the expression of other proteins associated with Treg function, including CTLA-4, CD39, and TGF-β. In a model of diet-induced obesity, Tregs from the visceral adipose tissue of hyperinsulinemic, obese mice showed a similar specific decrease in IL-10 production, as well as a parallel increase in production of IFN-γ. These data suggest that hyperinsulinemia may contribute to the development of obesity-associated inflammation via a previously unknown effect of insulin on the IL-10–mediated function of Tregs. http://www.jimmunol.org/content/192/2/623.full
The collagen-induced arthritis model in DA rats induced with homologous rat type II collagen was chosen to determine the therapeutic capacity and effects on autoimmunity by IL-10. Systemic IL-10 treatment (100 or 10 μg/day) with mini-osmotic pumps during the periods of arthritis onset (days 12–20 after immunization) decreased the frequency of arthritis and delayed the onset and reduced the severity of arthritis in the few rats that eventually developed arthritis. Concomitantly, levels of autoantibodies to CII were reduced. To test the activity on established arthritis, IL-10 was administered subcutaneously in the paws. This treatment reduced the swelling but did not block the arthritis process. The effective treatment required 100 μg of IL-10 every 12th hour while 50 μg of IL-10 had little effect, although a tendency of reduced paw swelling was observed. Surprisingly, therapeutic IL-10 treatment led to higher serum levels of autoantibodies to CII. The highest doses of IL-10 (100 μg) did not show any apparent toxic effects when given locally or systematically. Taken together, this study suggests that IL-10 is a candidate for treatment of rheumatoid arthritis. http://onlinelibrary.wiley.com/doi/10.1046/j.1365-3083.1996.d01-355.x/abstract
http://www.nature.com/jidsp/journal/v8/n1/images/5640090f2.gif
Mg deficiency accelerates Fe accumulation in the liver, which may induce various metabolic disturbances. In the present study, we examined the gene expression of Hepcidin, a peptide hormone produced in the liver to regulate intestinal Fe absorption negatively, in Mg-deficient rats. Although liver Fe concentration was significantly higher in rats fed an Mg-deficient diet for 4 weeks than in rats fed a control diet, Hepcidin expression in the liver was comparable between the dietary groups. Previous studies revealed that Fe overload up-regulated Hepcidin expression through transcriptional activation by Fe-induced bone morphogenetic protein (Bmp) 6, a growth/differentiation factor belonging to the transforming growth factor-β family, in the liver. Mg deficiency up-regulated the expression of Bmp6 but did not affect the expression of inhibition of DNA binding 1, a sensitive Bmp-responsive gene. In addition, the expression of Bmp receptors such as activin receptor-like kinase 2 (Alk2), activin receptor type IIA (Actr2a), activin receptor type IIB (Actr2b) and Bmp type II receptor (Bmpr2) was lower in the liver of Mg-deficient rats than in that of control rats. The present study indicates that accumulation of hepatic Fe by Mg deficiency is a stimulant inducing Bmp6 expression but not Hepcidin expression by blunting Bmp signalling possibly resulting from down-regulation of the receptor expression. Unresponsive Hepcidin expression may have a role in Mg deficiency-induced changes related to increased liver Fe. Hepcidin expression in the liver of rats fed a magnesium-deficient diet (PDF Download Available). Available from: http://www.researchgate.net/publication/51474632_Hepcidin_expression_in_the_liver_of_rats_fed_a_magnesium-deficient_diet [accessed Nov 21, 2015].
Finally, we demonstrate a physical interaction between HJV.Fc and BMP6, and we show that BMP6 increases hepcidin expression and reduces serum iron in mice. These data support a key role for BMP6 as a ligand for hemojuvelin and an endogenous regulator of hepcidin expression and iron metabolism in vivo. http://www.ncbi.nlm.nih.gov/pubmed/19252486
The parathyroids, calcium and gastric secretion in man ... - Gut gut.bmj.com/content/5/2/173.full.pdf
Parathyroidectomy (partial or total and usually combined with thyroidectomy) has always been found to reduce the secretion of acid and of pepsin in animals ...
https://books.google.com/books?id=r4tAAAAAcAAJ&lpg=PA124&ots=m-mhvP6KW3&dq=pepsin%20vomiting&pg=PA124#v=onepage&q=pepsin%20vomiting&f=false
https://books.google.com/books?id=2T8cAQAAMAAJ&lpg=PA769&ots=XZlYTlkNXu&dq=pepsin%20vomiting&pg=PA769#v=onepage&q=pepsin%20vomiting&f=false
Factors that can contribute to GERD:
·The use of medicines such as prednisolone.
·Obesity: increasing body mass index is associated with more severe GERD.
·Scleroderma and systemic sclerosis, which can feature esophageal dysmotility.
·Hypercalcemia, which can increase gastrin production, leading to increased acidity.
·Hiatal hernia, which increases the likelihood of GERD due to mechanical and motility factors.
·Zollinger-Ellison syndrome, which can be present with increased gastric acidity due to gastrin production.
·Visceroptosis or Glenard syndrome, in which the stomach has sunk in the abdomen upsetting the motility and acid secretion of the stomach.
http://www.disabled-world.com/health/digestive/gerd/
PEPSIN AND SFCA
[The role of short chain fatty acids and lactate in regulation of the gastric secretion]. [Article in Ukrainian] The investigation was carried out in acute experiments by means of isolated stomach perfusion by Ghosh and Shild and in chronic experiments in dogs with fistula of the stomach and duodenum. In rats with intact nervous system lactulose as the source of short chain fatty acids (SCFAs) diminished basal and stimulated by insulin, pentagastrin and histamine gastric acid secretion. By contrast it did not influence carbachol gastric acid secretion. In dogs with intact nervous system lactulose also suppressed the intensity, debit of acid and pepsin of gastric juice stimulated by insulin and histamine. It suggests that the effect of lactulose does not dependent on kinds of animals. Truncal vagotomy removed the inhibitory action of lactulose on pentagastrin and histamine gastric acid secretion in rats. SCFAs and lactic acid suppressed pentagastrin gastric acid secretion in rats. Lactulose, propionate potassium, lactate potassium enhanced the blood glucose level. Truncal vagotomy did not influence the increase of the blood glucose level evoked by lactulose. It is concluded that SCFAs decreases gastric secretion in the third intestinal phase through central inhibition. The mechanism of inhibitory action of lactic and propionic acids depends on their role in the liver gluconeogenesis which leads to increase of the blood glucose level. Hyperglycemia as it is known suppress gastric secretion through diminishing of neural cholinergic activity of nerves vagus. (did they mean insulin?) http://www.ncbi.nlm.nih.gov/pubmed/16909755
Conclusions These findings suggest that the mechanism of action of the rare proarrhythmic effects of the nonsedating antihistamines appears to be secondary to potassium channel blockade. A significant voltage-dependent blockade of the IK1 channel was demonstrated, as well as additional inhibitory effects on Ito and IKchannels. These actions lead to delayed repolarization, QT interval prolongation, and enhanced susceptibility to the development of premature ventricular depolarizations. Caution is advised in the prescription of nonsedating antihistamines, particularly in patients at risk of elevated serum levels of the antihistamine or patients with existing repolarization abnormalities. http://circ.ahajournals.org/content/91/8/2220.full
Potassium Channel KCNJ15 is Required for Histamine Stimulated Gastric Acid Secretion
· Gastric acid secretion is mediated by the K+ dependent proton pump (H+,K+-ATPase), which requires a continuous supply of K+ at the luminal side of the apical membrane. Several K+channels are implicated in gastric acid secretion. However, the identity of the K+ channel(s) responsible for apical K+ supply is still elusive. Our previous studies have shown the translocation of KCNJ15 from cytoplasmic vesicles to the apical membrane upon stimulation, indicating its involvement in gastric acid secretion. In this study, the stimulation associated trafficking of KCNJ15 was observed in a more native context with a live cell imaging system. KCNJ15 molecules in resting live cells were scattered in cytoplasm, but exhibited apical localization after stimulation. Further, KNOCKING DOWN KCNJ15 EXPRESSION WITH A SHRNA ADENOVIRAL CONSTRUCT ABOLISHED HISTAMINE STIMULATED ACID SECRETION in rabbit primary parietal cells. Moreover, KCNJ15, like H+,K+-ATPase, was detected in all of the parietal cells by immunofluorescence staining, while only about half of the parietal cells were positive for KCNQ1 under the same condition. Consistently, the endogenous protein levels of KCNJ15, analyzed by Western blotting, were higher than KCNQ1 in the gastric mucosa of human, mouse, and rabbit. These results provide evidence for a major role of KCNJ15 in apical K+ supply during stimulated acid secretion. http://ajpcell.physiology.org/content/early/2015/06/18/ajpcell.00012.2015
Peripheral dopamine D2-like receptors have a regulatory effect on carbachol-, histamine- and pentagastrin-stimulated gastric acid secretion.It has been documented that dopamine, an important regulator of gastric function in the brain-gut axis, has an inhibitory effect on the gastric acid secretion. It has also been suggested that dopamine D1, D2 and D5 receptor proteins are present in the gastrointestinal tract from the stomach through to the distal colon. Therefore, we hypothesized that peripheral D2 receptors may be involved in the control of stimulated gastric acid secretion. To address this question, we examined the effect of quinpirole, a selective D2 receptor-like agonist, and domperidone, a peripheral D2 receptor antagonist, on rat gastric acid secretion. Quinpirole (0.0001-0.5 mg/kg, i.p.) was administered simultaneously with intravenous infusions of histamine, pentagastrin, and carbachol. In some experiments, domperidone (3 and 7 mg/kg) was administered 30 min before quinpirole injection. We found that intraperitoneal injection of quinpirole (0.0001-0.5 mg/kg) suppressed stimulated gastric acid secretion induced by histamine (0.08 mg/100 g per h), pentagastrin (1 microg/100 g per h) and carbachol (4 microg/100 g per h) in a dose-dependent manner. This inhibitory effect of quinpirole persisted until the end of the experiments (90-120 min) and was completely suppressed by domperidone (7 mg/kg). In conclusion, the results of the present study suggest that peripheral D2-like receptors have an inhibitory effect on histaminergic-, pentagastrin- and cholinergic-stimulated gastric acid secretion. This inhibitory effect may be mediated by enteric dopaminergic neurons and/or non-neuronal membranes.http://www.ncbi.nlm.nih.gov/pubmed/18505447
Effect of continuous infusion of GABA and baclofen on gastric secretion in anaesthetised rats.---Continuous infusion of gamma- aminobutyric acid (GABA) and baclofen (BAC) on gastric acid and pepsin secretion in perfused rat stomach showed that GABA (25-100 mg/kg/hr, i.v.) and BAC (1 mg/kg/hr, i.v.) increased the acid output which was blocked by bicuculline (Bicc, 1 mg/kg, i.v.) when given 30 min before their infusion. However, lower dose of GABA (5 mg/kg/hr) and hig her doses of BAC (5 or 10 mg/kg/hr) did not show any significant effect on acid secretion. GABA (5 and 25 mg/kg/hr) inhibited peptic output and again Bicc in the above dose inhibited the inhibitory effect of 25 mg/kg/hr of GABA on peptic output. The result indicate dichotomy on the effects of GABA on acid and pepsin secretion. As both the effects were blocked by Bicc, involvement of GABAA receptor may be a possibility. The antiulcer effect of GABA and BAC could not be due to their effect on gastric acid secretion, but may be due to inhibition of pepsin secretion by GABA or effects of GABA or BAC on mucosal defensive factors. http://www.ncbi.nlm.nih.gov/pubmed/9055649
GABA Effect of continuous infusion of GABA and baclofen on gastric secretion in anaesthetised rats. Continuous infusion of gamma- aminobutyric acid (GABA) and baclofen (BAC) on gastric acid and pepsin secretion in perfused rat stomach showed that GABA (25-100 mg/kg/hr, i.v.) and BAC (1 mg/kg/hr, i.v.) increased the acid output which was blocked by bicuculline (Bicc, 1 mg/kg, i.v.) when given 30 min before their infusion. However, lower dose of GABA (5 mg/kg/hr) and hig her doses of BAC (5 or 10 mg/kg/hr) did not show any significant effect on acid secretion. GABA (5 and 25 mg/kg/hr) inhibited peptic output and again Bicc in the above dose inhibited the inhibitory effect of 25 mg/kg/hr of GABA on peptic output. The result indicate dichotomy on the effects of GABA on acid and pepsin secretion. As both the effects were blocked by Bicc, involvement of GABAA receptor may be a possibility. The antiulcer effect of GABA and BAC could not be due to their effect on gastric acid secretion, but may be due to inhibition of pepsin secretion by GABA or effects of GABA or BAC on mucosal defensive factors.http://www.ncbi.nlm.nih.gov/pubmed/9055649
Molecular Basis of Vitamin E Action TOCOTRIENOL MODULATES 12-LIPOXYGENASE, A KEY MEDIATOR OF GLUTAMATE-INDUCED NEURODEGENERATION ... Vitamin E Treatment—Stock solutions (10 3 times the working concentration) of α-tocotrienol
was ... during flow cytometry, the viability of these cells was assessed by measuring lactate dehydrogenase leakage (23) from cells to the medium 24 h after glutamate treatment using ...
Most studies of the nutritional requirements for protein have been done for the agricultural industries, and so have been designed to find the cheapest way to get the maximum growth in the shortest time. The industry isn't interested in the longevity, intelligence, or happiness of their pigs, chickens, and lambs. The industry has used chemical growth stimulants in combination with the foods that support rapid growth at least expense. Antibiotics and arsenic and polyunsaturated fatty acids have become part of our national food supply because they produce rapid weight gain in young animals.
The amino acids in proteins have been defined as “essential” on the basis of their contribution to growth, ignoring their role in producing long life, good brain development, and good health. The amino acid and protein requirements during aging have hardly been studied, except in rats, whose short life-span makes such studies fairly easy. The few studies that have been done indicate that the requirements for tryptophan and cysteine become very low in adulthood.
Prostaglandin-A1 Delta-isomerase
From Wikipedia, the free encyclopedia
prostaglandin-A1 delta-isomerase
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In enzymology, a prostaglandin-A1 Delta-isomerase (EC 5.3.3.9) is an enzyme that catalyzes the chemical reaction
(13E)-(15S)-15-hydroxy-9-oxoprosta-10,13-dienoate (13E)-(15S)-15-hydroxy-9-oxoprosta-11,13-dienoate
Hence, this enzyme has one substrate, (13E)-(15S)-15-hydroxy-9-oxoprosta-10,13-dienoate (Prostaglandin A1 or PGA1), and one product, (13E)-(15S)-15-hydroxy-9-oxoprosta-11,13-dienoate (Prostaglandin C1).
This enzyme belongs to the family of isomerases, specifically those intramolecular oxidoreductases transposing C=C bonds. The systematic name of this enzyme class is (13E)-(15S)-15-hydroxy-9-oxoprosta-10,13-dienoate Delta10-Delta11-isomerase. This enzyme is also called prostaglandin A isomerase.
References[edit]
· Polet H, Levine L (1975). "Metabolism of prostaglandins E, A, and C in serum". J. Biol. Chem. 250 (2): 351–7. PMID 234423.
Prostaglandin A1 Prostanoid receptor ligand Biosynthesis from dihomo-γ-linolenic acid. Stimulates renin release. Antitumor activity. Inhibits NFκB activation in several human cell lines. Induces the synthesis of heat shock proteins. Activates PPARs in human osteosarcoma cells at 10μM.http://www.enzolifesciences.com/BML-PG001/prostaglandin-a1/
dihomo-γ-linolenic acid
Dihomo-γ-linolenic acid
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Other names
cis,cis,cis-8,11,14-Eicosatrienoic acid
DGLA
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C20H34O2
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Dihomo-γ-linolenic acid (DGLA) is a 20-carbon ω−6 fatty acid. In physiological literature, it is given the name 20:3 (ω−6). DGLA is a carboxylic acid with a 20-carbon chain and three cis double bonds; the first double bond is located at the sixth carbon from the omega end. DGLA is the elongation product of γ-linolenic acid (GLA; 18:3, ω−6). GLA, in turn, is a desaturation product of linoleic acid (18:2, ω−6). DGLA is made in the body by the elongation of GLA, by an efficient enzyme which does not appear to suffer any form of (dietary) inhibition. DGLA is an extremely uncommon fatty acid, found only in trace amounts in animal products.[1][2]
Biological effects[edit]
All of these effects are anti-inflammatory. This is in marked contrast with the analogous metabolites of arachidonic acid (AA), which are the series-2 thromboxanes and prostanoids and the series-4 leukotrienes. In addition to yielding anti-inflammatory eicosanoids, DGLA competes with AA for COX and lipoxygenase, inhibiting the production of AA's eicosanoids.
Taken orally in a small study, DGLA produced antithrombotic effects.[5] Supplementing dietary GLA increases serum DGLA, as well as serum AA levels.[6]Cosupplementation with GLA and EPA lowers serum AA levels by blocking Δ-5-desaturase activity, while also lowering leukotriene synthesis in neutrophils.[7]https://en.wikipedia.org/wiki/Dihomo-%CE%B3-linolenic_acid
Dihomo-γ-linolenic acid increased significantly in serum phospholipids only in the 4:2 and 4:4 groups; however, total n−3 fatty acids increased in all 4 groups. Eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and γ-linolenic acid (GLA)
Metabolism of γ-linolenic acid. In many animal tissues and cells, LA is converted to AA by an alternating sequence of Δ6 desaturation, chain elongation and Δ5 desaturation, in which hydrogen atoms are selectively removed to create new double bonds and then two carbon atoms are added to lengthen the fatty acid chain. Dietary GLA bypasses the rate-limited Δ6 desaturation step and is quickly elongated to DGLA by elongase, with only a very limited amount being desaturated to AA by Δ5 desaturase. DGLA can be converted to PGE1 via the cyclooxygenase pathway and/or converted to 15-HETrE via the 15-lipoxygenase pathway. 15-HETrE is capable of inhibiting the formation of AA-derived 5-lipoxygenase (proinflammatory) metabolites.
Model for stimulation of DGLA-derived PGE1 biosynthesis by macrophages. Dietary GLA, via its metabolic elongation to DGLA, can enhance macrophage synthesis of PGE1, an anti-proliferative cyclooxygenase product. PGE1 elicits an array of biological responses by binding to select G protein coupled surface receptors on smooth muscle cells, increasing intracellular cAMP levels. This in turn stimulates the expression of numerous genes through the PKA-mediated phosphorylation of the nuclear CREB binding proteins. The transcriptional co-activator, CBP, in turn, mediates PKA-induced transcription by binding to the PKA phosphorylated activation domain of CREB. CREB proteins can also heterodimerize with other members of the b-ZIP or basic zipper family of transcription factors, including Fos proteins (c-fos, Fosb, Fra-1, Fra-2), and Jun proteins (c-jun, JunB, JunD). Through this mechanism, PGE1 has been shown to inhibit vascular smooth muscle cell proliferation. Abbreviations: CBP, CREB adapter binding protein; CRE, cyclic AMP response element.
in pepsin it was decided to study the action of iodine on pepsin. Io- dine is supposed to ... 82 per cent of the total iodine was obtained from the iodinated pepsin.
www.ncbi.nlm.nih.gov/... Feb 27, 2015 - Farnesoid X receptor-induced lysine-specific histone demethylase reduces hepatic bile acid levels and protects the liver against bile acid ...
Effect of lysine acetylsalicylate on biliary lipid secretion in ...www.ncbi.nlm.nih.gov/.../1...The influence of lysineacetylsalicylate on bile flow, erythritol clearance and bile salt, phospholipid and ...
The development of antibodies to thyroid peroxidase (TPO) thyroglobulin (TG) and Thyroid stimulating ..... IL4, and IL-10 strongly up-regulate the expression of.
press.endocrine.org/doi/full/10.1210/jcem.82.11.4336
Antigen-specific TCC were reactive to thyroid peroxidase (TPO), ... IL-4 promotes the differentiation of Th2 cells and, similar to IL-10, inhibits cytokine secretion
www.ncbi.nlm.nih.gov/...
J Microbiol Biotechnol. 2007 Feb;17(2):348-58. Functions of metallothionein generatinginterleukin-10-producing regulatory CD4+ T cells potentiate suppression ...
Functions of metallothionein generating interleukin-10-producing regulatory CD4+ T cells potentiate suppression of collagen-induced arthritis.
METALLOTHIONEIN, A CYSTEINE-RICH STRESS RESPONSE PROTEIN THAT IS NATURALLY INDUCED BY A VARIETY OF IMMUNOLOGIC STRESSORS, HAS BEEN SHOWN TO SUPPRESS AUTOIMMUNE DISORDERS through mechanisms not yet fully defined. In the present study, we examined the underlying mechanisms by which metallothionein might mediate such regulation of autoimmunity. Naïve CD4+ T cells from metallothionein-deficient mice differentiated to produce significantly less IL-10, TGF-gamma, and repressor of GATA, but more IFN-gamma and T-bet, when compared with those from wild-type mice. The levels of IL-4 and GATA-3 production were not different between the two groups of mice. Conversely, treatment with exogenous METALLOTHIONEIN DURING THE PRIMING PHASE DROVE NAÏVE WILD-TYPE CD4+ T CELLS TO DIFFERENTIATE INTO CELLS PRODUCING MORE IL-10 AND TGF-BETA, BUT LESS IFN-GAMMA THAN UNTREATED CELLS. Metallothionein-primed cells were hyporesponsive to restimulation, and suppressive to T cell proliferation in an IL-10-dependent manner. Lymphocytes from metallothionein-deficient mice displayed significantly elevated levels of AP-1 and JNK activities in response to stimulation compared with those from wild-type controls. Importantly, transgenic mice overexpressing metallothionein exhibited significantly reduced susceptibility to collagen-induced arthritis and enhanced IL-10 level in the serum, relative to their nontransgenic littermates. Taken together, these data suggest that metallothionein is able to promote the generation of IL-10- and TGF-beta-producing type 1 regulatory T-like cells by downregulating JNK-dependent AP-1 activity. Thus, metallothionein may play an important role in the regulation of Th1-dependent autoimmune arthritis, and may represent both a potential target for therapeutic manipulation and a critical element in the diagnostic assessment of disease potential. http://www.ncbi.nlm.nih.gov/pubmed/18051768
www.ncbi.nlm.nih.gov/...
The level of each was increased within 3 hr after the addition of IL-6 at 10 ng/ml (10hepatocyte-stimulating factor units/ml). Maximal increases in metallothionein ...
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