Amelioration of bleomycin-induced lung fibrosis in hamsters by dietary supplementation with taurine and niacin: biochemical mechanisms.

Interstitial pulmonary fibrosis induced by intratracheal instillation of bleomycin (BL) involves an excess production of reactive oxygen species, unavailability of adequate levels of NAD and ATP to repair the injured pulmonary epithelium, and an overexuberant lung collagen reactivity followed by deposition of highly cross-linked mature collagen fibrils resistant to enzymatic degradation. In the present study, we have demonstrated that dietary supplementation with taurine and niacin offered almost complete protection against the lung fibrosis in a multidose BL hamster model. The mechanisms for the protective effect of taurine and niacin are multifaceted. These include the ability of taurine to scavenge HOCl and stabilize the biomembrane; niacin's ability to replenish the BL-induced depletion of NAD and ATP; and the combined effect of taurine and niacin to suppress all aspects of BL-induced increases in the lung collagen reactivity, a hallmark of interstitial pulmonary fibrosis. It was concluded from the data presented at this Conference that the combined treatment with taurine and niacin, which offers a multipronged approach, will have great therapeutic potential in the intervention of the development of chemically induced interstitial lung fibrosis in animals and humans

Chronic cocaine enhances release of neuroprotective amino acid taurine: a microdialysis study

Cocaine inhibits high-affinity neurotransmitter uptake at the presynaptic nerve terminals to increase synaptic levels of dopamine, norepinephrine and serotonin^1^. This increase of synaptic dopamine may cause neurotoxicity^2,3^. At least two different mechanisms have been proposed for the development of dopamine-related neurotoxicity: 1) dopamine produces a free radical that may induce cell toxicity^2,3^ and 2) dopamine reduces glutamate transport at its presynaptic sites to increase synaptic levels of this amino acid^4^ and augments glutamate transmission by activating dopamine D1 receptors in different areas of the brain^5-7^. Increase in glutamatergic transmission mediated by the activation on N-methyl dextro-aspartate (NMDA) receptors has been shown to cause excitotoxicity and neuro-degeneration^8^. Others and we have reported protection against different psychotropic drug-induced neurotoxicity that may be achieved by prior or simultaneous administration of various pharmacological agents. For example, repeated treatment of rats with haloperidol induced neuronal damage that is ameliorated by prior administration of either GM1 ganglioside^9^ or the endogenous amino acid, taurine^10^. Similarly, chronic gestational cocaine exposure causes neurotoxicity that could be prevented by co-administration of clozapine^11^. To our knowledge, there is no information if chronic cocaine would enhance release of endogenous protective agents that may oppose the over activation of glutamatergic system. Here we show that repeated cocaine treatment increased synaptic levels of the neuroprotective amino acid taurine that opposes the excessive excitatory actions of the glutamatergic system in the rat brain. Thus, mammalian brain has an auto-protective mechanism to counter excitotoxicity and taurine or its synthetic derivative may be useful in the management and treatment of cocaine addiction and its neurotoxic effect

Transsulfuration pathway thiols and methylated arginines: the hunter community study

Background: Serum homocysteine, when studied singly, has been reported to be positively associated both with the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine [ADMA, via inhibition of dimethylarginine dimethylaminohydrolase (DDAH) activity] and with symmetric dimethylarginine (SDMA). We investigated combined associations between transsulfuration pathway thiols, including homocysteine, and serum ADMA and SDMA concentrations at population level. Methods: Data on clinical and demographic characteristics, medication exposure, C-reactive protein, serum ADMA and SDMA (LC-MS/MS), and thiols (homocysteine, cysteine, taurine, glutamylcysteine, total glutathione, and cysteinylglycine; capillary electrophoresis) were collected from a sample of the Hunter Community Study on human ageing [n = 498, median age (IQR) = 64 (60–70) years]. Results: Regression analysis showed that: a) age (P = 0.001), gender (P = 0.03), lower estimated glomerular filtration rate (eGFR, P = 0.08), body mass index (P = 0.008), treatment with beta-blockers (P = 0.03), homocysteine (P = 0.02), and glutamylcysteine (P = 0.003) were independently associated with higher ADMA concentrations; and b) age (P = 0.001), absence of diabetes (P = 0.001), lower body mass index (P = 0.01), lower eGFR (P&lt;0.001), cysteine (P = 0.007), and glutamylcysteine (P&lt;0.001) were independently associated with higher SDMA concentrations. No significant associations were observed between methylated arginines and either glutathione or taurine concentrations. Conclusions: After adjusting for clinical, demographic, biochemical, and pharmacological confounders the combined assessment of transsulfuration pathway thiols shows that glutamylcysteine has the strongest and positive independent associations with ADMA and SDMA. Whether this reflects a direct effect of glutamylcysteine on DDAH activity (for ADMA) and/or cationic amino acid transport requires further investigations.</br

Detection of Metabolites by Proton Ex Vivo NMR, in Vivo MR Spectroscopy Peaks and Tissue Content Analysis: Biochemical-Magnetic Resonance Correlation: Preliminary Results

*Aim*: Metabolite concentrations by in vivo magnetic resonance spectroscopy and ex vivo NMR spectroscopy were compared with excised normal human tissue relaxation times and tissue homogenate contents.&#xd;&#xa;&#xd;&#xa;*Hypothesis*: Biochemical analysis combined with NMR and MR spectroscopy defines better tissue analysis.&#xd;&#xa;&#xd;&#xa;*Materials and Methods*: Metabolites were measured using peak area, amplitude and molecular weights of metabolites in the reference solutions. In normal brain and heart autopsy, muscle and liver biopsy tissue ex vivo NMR peaks and spin-lattice (T1) and spin-spin (T2) relaxation times, were compared with diseased tissue NMR data in meningioma brain, myocardial infarct heart, duchene-muscular-dystrophy muscle and diffused-liver-injury liver after respective in vivo proton MR spectroscopy was done. NMR data was compared with tissue homogenate contents and serum levels of biochemical parameters.&#xd;&#xa;&#xd;&#xa;*Results*: The quantitation of smaller NMR visible metabolites was feasible for both ex vivo NMR and in vivo MR spectroscopy. Ex vivo H-1 NMR and in vivo MRS metabolite characteristic peaks (disease/normal data represented as fold change), T1 and T2, and metabolites in tissue homogenate and serum indicated muscle fibrosis in DMD, cardiac energy depletion in MI heart, neuronal dysfunction in meningioma brain and carbohydrate-lipid metabolic crisis in DLI liver tissues.&#xd;&#xa;&#xd;&#xa;*Conclusion*: This preliminary report highlights the biochemical-magnetic resonance correlation as basis of magnetic resonance spectroscopic imaging data interpretation of disease

Meta-Analysis of Mitochondrial DNA Reveals Several Population Bottlenecks during Worldwide Migrations of Cattle

Several studies have investigated the differentiation of mitochondrial DNA in Eurasian, African and American cattle as well as archaeological bovine material. A global survey of these studies shows that haplogroup distributions are more stable in time than in space. All major migrations of cattle have shifted the haplogroup distributions considerably with a reduction of the number of haplogroups and/or an expansion of haplotypes that are rare or absent in the ancestral populations. The most extreme case is the almost exclusive colonization of Africa by the T1 haplogroup, which is rare in Southwest Asian cattle. In contrast, ancient samples invariably show continuity with present-day cattle from the same location. These findings indicate strong maternal founder effects followed by limited maternal gene flow when new territories are colonized. However, effects of adaptation to new environments may also play a rol

Conformational variability of the glycine receptor M2 domain in response to activation by different agonists

Models describing the structural changes mediating cys-loop receptor activation generally give little attention to the possibility that different agonists may promote activation via distinct M2 pore-lining domain structural rearrangements. We investigated this question by comparing the effects of different ligands on the conformation of the external portion of the homomeric α1 glycine receptor M2 domain. Conformational flexibility was assessed by tethering a rhodamine fluorophore to cysteines introduced at the 19’ or 22’ positions and monitoring fluorescence and current changes during channel activation. During glycine activation, fluorescence of the label attached to R19’C increased by ~20% and the emission peak shifted to lower wavelengths, consistent with a more hydrophobic fluorophore environment. In contrast, ivermectin activated the receptors without producing a fluorescence change. Although taurine and β-alanine were weak partial agonists at the a1R19’C GlyR, they induced large fluorescence changes. Propofol, which drastically enhanced these currents, did not induce a glycine-like blue-shift in the spectral emission peak. The inhibitors, strychnine and picrotoxin, elicited fluorescence and current changes as expected for a competitive antagonist and an open channel blocker, respectively. Glycine and taurine (or β-alanine) also produced an increase and a decrease, respectively, in the fluorescence of a label attached to the nearby L22’C residue. Thus, results from two separate labelled residues support the conclusion that the GlyR M2 domain responds with distinct conformational changes to activation by different agonists

Ethane-beta-Sultam Modifies the Activation of the Innate Immune System Induced by Intermittent Ethanol Administration in Female Adolescent Rats

Intermittent ethanol abuse or ‘binge drinking’ during adolescence induces neuronal damage, which may be associated with cognitive dysfunction. To investigate the neurochemical processes involved, rats were administered either 1 g/kg or 2 g/kg ethanol in a ‘binge drinking’ regime. After only 3 weeks, significant activation of phagocytic cells in the peripheral (alveolar macrophages) and the hippocampal brain region (microglia cells) was present,as exemplified by increases in the release of pro-inflammatory cytokines in the macrophages and of iNOS in the microglia. This was associated with neuronal loss in the hippocampus CA1 region. Daily supplementation with a taurine prodrug, ethane-β-sultam, 0.028 g/kg, during the intermittent ethanol loading regime, supressed the release of the pro-inflammatory cytokines and of reactive nitrogen species, as well as neuronal loss, particularly in the rats administered the lower dose of ethanol, 1 g/kg. Plasma, macrophage and hippocampal taurine levels increased marginally after ethane-β-sultam supplementation. The ‘binge drinking’ ethanol rats administered 1 g/kg ethanol showed increased latencies to those of the control rats in their acquisition of spacial navigation in the Morris Water Maze, which was normalised to that of the controls values after ethane-β-sultam administration. Such results confirm that the administration of ethane-β-sultam to binge drinking rats reduces neuroinflammation in both the periphery and the brain, suppresses neuronal loss, and improved working memory of rats in a water maze study

Increased amino acid turnover and myofibrillar protein breakdown in advanced cancer are associated with muscle weakness and impaired physical function

Muscle wasting in cancer negatively affects physical function and quality of life. This study investigates amino acid metabolism and the association with muscle mass and function in patients with cancer.In 16 patients with advanced cancer undergoing chemotherapy and 16 healthy controls, we administered an intravenous pulse and prime of stable amino acid tracers. We took blood samples to measure the Rate of appearance (Ra), whole body production (WBP), clearance (Cl), and post absorptive whole body net protein breakdown (WBnetPB). Plasma amino acid concentrations and enrichments were analysed by LC-MS/MS. We assessed muscle mass, handgrip/leg/respiratory muscle strength and reported physical activity, quality of life, and physical function.Muscle strength was lower in cancer patients than in healthy controls. Total and limb muscle mass, reported physical activity and WBnetPB were comparable. WBP and Cl of tau-methylhistidine, leucine, glutamine and taurine were higher in cancer patients as well as glycine Cl. Amino acid metabolism was correlated with low muscle mass, strength, physical function and quality of life.Myofibrillar protein breakdown and production of amino acids involved in muscle contractility are up regulated in patients with cancer undergoing chemotherapy and related to muscle weakness and reduced physical outcomes

One-electron oxidation and reduction of glycosaminoglycan chloramides: a kinetic study.

Hypochlorous acid and its acid-base counterpart, hypochlorite ions, produced under inflammatory conditions, may produce chloramides of glycosaminoglycans, these being significant components of the extracellular matrix (ECM). This may occur through the binding of myeloperoxidase directly to the glycosaminoglycans. The N-Cl group in the chloramides is a potential selective target for both reducing and oxidizing radicals, leading possibly to more efficient and damaging fragmentation of these biopolymers relative to the parent glycosaminoglycans. In this study, the fast reaction techniques of pulse radiolysis and nanosecond laser flash photolysis have been used to generate both oxidizing and reducing radicals to react with the chloramides of hyaluronan (HACl) and heparin (HepCl). The strong reducing formate radicals and hydrated electrons were found to react rapidly with both HACl and HepCl with rate constants of 1-1.7 x 108 and 0.7-1.2 x 108 M-1 s-1 for formate radicals and 2.2 x 109 and 7.2 x 10 8 M-1 s-1 for hydrated electrons, respectively. The spectral characteristics of the products of these reactions were identical and were consistent with initial attack at the N-Cl groups, followed by elimination of chloride ions to produce nitrogen-centered radicals, which rearrange subsequently and rapidly to produce C-2 radicals on the glucosamine moiety, supporting an earlier EPR study by M.D. Rees et al. (J. Am. Chem. Soc. 125: 13719-13733; 2003). The oxidizing hydroxyl radicals also reacted rapidly with HACl and HepCl with rate constants of 2.2 x 108 and 1.6 x 108 M-1 s-1, with no evidence from these data for any degree of selective attack on the N-Cl group relative to the N-H groups and other sites of attack. The carbonate anion radicals were much slower with HACl and HepCl than hydroxyl radicals (1.0 x 105 and 8.0 x 10 4 M-1 s-1, respectively) but significantly faster than with the parent molecules (3.5 x 104 and 5.0 x 10 4 M-1 s-1, respectively). These findings suggest that these potential in vivo radicals may react in a site-specific manner with the N-Cl group in the glycosaminoglycan chloramides of the ECM, possibly to produce more efficient fragmentation. This is the first study therefore to conclusively demonstrate that reducing radicals react rapidly with glycosaminoglycan chloramides in a site-specific attack at the N-Cl group, probably to produce a 100% efficient biopolymer fragmentation process. Although less reactive, carbonate radicals, which may be produced in vivo via reactions of peroxynitrite with serum levels of carbon dioxide, also appear to react in a highly site-specific manner at the N-Cl group. It is not yet known if such site-specific attacks by this important in vivo species lead to a more efficient fragmentation of the biopolymers than would be expected for attack by the stronger oxidizing species, the hydroxyl radical. It is clear, however, that the N-Cl group formed under inflammatory conditions in the extracellular matrix does present a more likely target for both reactive oxygen species and reducing species than the N-H groups in the parent glycosaminoglycans. © 2013 Elsevier Inc. All rights reserved

Methionine Restriction Extends Lifespan in Progeroid Mice and Alters Lipid and Bile Acid Metabolism

C.L.-O. is supported by grants from the European Union (ERC-2016-ADG, DeAge); Ministerio de Economía y Competitividad (MINECO/FEDER: SAF2014-52413-R and SAF2017-87655-R); Instituto de Salud Carlos III (RTICC); Progeria Research Foundation (PRF2016-66); and EDP Foundation. J.M.P.F. is supported by the Ministerio de Economía y Competitividad (MINECO/FEDER: SAF2015- 64157-R) and Gobierno del Principado de Asturias. G.M. is funded by the Ramón y Cajal Program (RYC-2013-12751) and supported by the Ministerio de Economía y Competitividad (MINECO/FEDER: BFU2015-68539) and BBVA Foundation (BBM_BIO_3105). G.K. is supported by the Ligue contre le Cancer (équipe labelisée); Agence National de la Recherche (ANR) – Projets Blancs; ANR under the frame of E-Rare-2; the ERA-Net for Research on Rare Diseases; Association pour la Recherche sur le Cancer (ARC); Canceropole Ile-de-France; Institut National du Cancer (INCa); Institut Universitaire de France; Fondation pour la Recherche Médicale (FRM); the European Commission (ArtForce); the European Research Council (ERC); the LeDucq Foundation; the LabEx Immuno-Oncology; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); the SIRIC Cancer Research and Personalized Medicine (CARPEM); and the Paris Alliance of Cancer Research Institutes (PACRI)