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 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Because the role of elemental sulfur in human nutrition has not been studied extensively, it is the purpose of this article to emphasize the importance of this element in humans and discuss the therapeutic applications of sulfur compounds in medicine. Sulfur is the sixth most abundant macromineral in breast milk and the third most abundant mineral based on percentage of total body weight. The sulfur-containing amino acids (SAAs) are methionine, cysteine, cystine, homocysteine, homocystine, and taurine. Dietary SAA analysis and protein supplementation may be indicated for vegan athletes, children, or patients with HIV, because of an increased risk for SAA deficiency in these groups. Methylsulfonylmethane (MSM), a volatile component in the sulfur cycle, is another source of sulfur found in the human diet. Increases in serum sulfate may explain some of the therapeutic effects of MSM, DMSO, and glucosamine sulfate. Organic sulfur, as SAAs, can be used to increase synthesis of S-adenosylmethionine (SAMe), glutathione (GSH), taurine, and N-acetylcysteine (NAC). MSM may be effective for the treatment of allergy, pain syndromes, athletic injuries, and bladder disorders. Other sulfur compounds such as SAMe, dimethylsulfoxide (DMSO), taurine, glucosamine or chondroitin sulfate, and reduced glutathione may also have clinical applications in the treatment of a number of conditions such as depression, fibromyalgia, arthritis, interstitial cystitis, athletic injuries, congestive heart failure, diabetes, cancer, and AIDS. Dosages, mechanisms of action, and rationales for use are discussed. The low toxicological profiles of these sulfur compounds, combined with promising therapeutic effects, warrant continued human clinical trails.
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PMID:Sulfur in human nutrition and applications in medicine. 1189 44

Long-term changes in excitatory synapse strength are thought to reflect changes in synaptic abundance of AMPA receptors mediated by receptor trafficking. AMPA receptor-binding protein (ABP) and glutamate receptor-interacting protein (GRIP) are two similar PDZ (postsynaptic density 95/Discs large/zona occludens 1) proteins that interact with glutamate receptors 2 and 3 (GluR2 and GluR3) subunits. Both proteins have proposed roles during long-term potentiation and long-term depression in the delivery and anchorage of AMPA receptors at synapses. Here we report a variant of ABP-L (seven PDZ form of ABP) called pABP-L that is palmitoylated at a cysteine residue at position 11 within a novel 18 amino acid N-terminal leader sequence encoded through differential splicing. In cultured hippocampal neurons, nonpalmitoylated ABP-L localizes with internal GluR2 pools expressed from a Sindbis virus vector, whereas pABP-L is membrane targeted and associates with surface-localized GluR2 receptors at the plasma membrane in spines. Mutation of Cys-11 to alanine blocks the palmitoylation of pABP-L and targets the protein to intracellular clusters, confirming that targeting the protein to spines is dependent on palmitoylation. Non-palmitoylated GRIP is primarily intracellular, but a chimera with the pABP-L N-terminal palmitoylation sequence linked to the body of the GRIP protein is targeted to spines. We suggest that pABP-L and ABP-L provide, respectively, synaptic and intracellular sites for the anchorage of AMPA receptors during receptor trafficking to and from the synapse.
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PMID:Differential palmitoylation directs the AMPA receptor-binding protein ABP to spines or to intracellular clusters. 1197 26

Novel statistical methods have been developed and used to quantitate and annotate the sequence diversity within combinatorial peptide libraries on the basis of small numbers (1-200) of sequences selected at random from commercially available M13 p3-based phage display libraries. These libraries behave statistically as though they correspond to populations containing roughly 4.0+/-1.6% of the random dodecapeptides and 7.9+/-2.6% of the random constrained heptapeptides that are theoretically possible within the phage populations. Analysis of amino acid residue occurrence patterns shows no demonstrable influence on sequence censorship by Escherichia coli tRNA isoacceptor profiles or either overall codon or Class II codon usage patterns, suggesting no metabolic constraints on recombinant p3 synthesis. There is an overall depression in the occurrence of cysteine, arginine and glycine residues and an overabundance of proline, threonine and histidine residues. The majority of position-dependent amino acid sequence bias is clustered at three positions within the inserted peptides of the dodecapeptide library, +1, +3 and +12 downstream from the signal peptidase cleavage site. Conformational tendency measures of the peptides indicate a significant preference for inserts favoring a beta-turn conformation. The observed protein sequence limitations can primarily be attributed to genetic codon degeneracy and signal peptidase cleavage preferences. These data suggest that for applications in which maximal sequence diversity is essential, such as epitope mapping or novel receptor identification, combinatorial peptide libraries should be constructed using codon-corrected trinucleotide cassettes within vector-host systems designed to minimize morphogenesis-related censorship.
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PMID:Quantitative assessment of peptide sequence diversity in M13 combinatorial peptide phage display libraries. 1236 27

We evaluated the contribution of peroxynitrite to the fatal cardiovascular depression induced by overproduction of nitric oxide (NO) after activation of inducible NO synthase (iNOS) in the rostral ventrolateral medulla (RVLM), the origin of sympathetic vasomotor tone. In Sprague-Dawley rats maintained under propofol anesthesia, microinjection of E. coli lipopolysaccharide (LPS) bilaterally into the RVLM elicited significant hypotension, bradycardia, reduction in sympathetic vasomotor tone and mortality. There was also a discernible elevation of iNOS expression in the ventrolateral medulla, followed by a massive production of nitrotyrosine, an experimental index for peroxynitrite. Co-administration bilaterally into the RVLM of the selective iNOS inhibitor, S-methylisothiourea (50, 100 or 250 pmol), an active peroxynitrite decomposition catalyst, 5,10,15,20-tetrakis- (N-methyl-4'-pyridyl)-porphyrinato iron (III) (10 or 50 pmol), a peroxynitrite scavenger, L-cysteine (5, 50 or 100 pmol), or a superoxide dismutase mimetic, Mn(III)-tetrakis-(4-benzoic acid) porphyrin (1 or 10 pmol), significantly prevented mortality, reduced nitrotyrosine production and reversed the NO-induced cardiovascular suppression after application of LPS into the RVLM. We conclude that the formation of peroxynitrite by a reaction between superoxide anion and NO is primarily responsible for the fatal cardiovascular depression induced by overproduction of NO after activation of iNOS at the RVLM.
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PMID:Contribution of peroxynitrite to fatal cardiovascular depression induced by overproduction of nitric oxide in rostral ventrolateral medulla of the rat. 1238 74

Oxidative and reductive mechanisms are important in Wilson's disease. In this study, we sought to evaluate tissue levels of glutathione and cysteine, an important detoxification system, and of malondialdehyde, a marker of lipoperoxidation, in patients with Wilson's disease receiving penicillamine or zinc treatment, in comparison with patients with chronic liver disease of different origin. Concentrations of cysteine, reduced/oxidized glutathione, malondialdehyde, zinc, and copper were determined (with the use of high-pressure liquid chromatography, fluorimetry and atomic-absorption spectrophotometry) in liver-biopsy specimens from 24 patients with Wilson's disease (18 treated with zinc, 6 with penicillamine), 34 patients with chronic viral hepatitis, and 10 patients with alcoholic liver disease. In patients with Wilson's disease, the concentration of reduced glutathione was lower than that in patients with viral hepatitis and as high as that in subjects with alcoholic liver damage. The cysteine level was significantly lower than those in the control groups, and the percentage of oxidized glutathione/total glutathione was higher than that in viral or alcoholic disease. Malondialdehyde levels were low, but when zinc- and penicillamine-treated patients were considered separately, only the former had low malondialdehyde levels. Zinc-treated patients had higher concentrations of reduced glutathione and a lower percentage of oxidized glutathione. In summary, patients with Wilson's disease have relevant glutathione depression, with low levels of reduced glutathione and cysteine and high concentrations of oxidized glutathione: This is prevented by zinc administration, which inhibits lipid peroxidation and increases glutathione availability.
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PMID:Zinc treatment prevents lipid peroxidation and increases glutathione availability in Wilson's disease. 1281 34

Monoamine oxidase (MAO) is an enzyme that oxidizes various physiologically and pathologically important monoamine neurotransmitters and hormones such as dopamine, noradrenaline, adrenaline, and serotonin. Two types of MAO, i.e. type A (MAO-A) and type B (MAO-B), were first discovered pharmacologically. MAO-A is inhibited by clorgyline; and MAO-B, by deprenyl. cDNAs MAO-A and MAO-B were cloned and their structures determined. MAO-A and MAO-B are made of similar but different polypeptides and encoded by different nuclear genes located on the X chromosome (Xp11.23). MAO-A and MAO-B genes consist of 15 exons with identical intron-exon organization, suggesting that they were derived from a common ancestral gene. Both enzymes require a flavin cofactor, flavin adenine dinucleotide (FAD), which binds to the cysteine residue of a pentapeptide sequence (Ser-Gly-Gly-Cys-Tyr). Both enzymes exist on the outer membrane of mitochondria of various types of cells in various tissues including the brain. In humans, MAO-A is abundant in the brain and liver, whereas the liver, lungs and intestine are rich in MAO-B. MAO-A oxidizes noradrenaline and serotonin; and MAO-B, mainly beta-phenylethylamine. In the human brain, MAO-A exists in catecholaminergic neurons, but MAO-B is found in serotonergic neurons and glial cells. MAO-A knockout mice exhibit increased serotonin levels and aggressive behavior, whereas MAO-B knockout mice show little behavioral change. The gene knockout mice of MAO-A or MAO-B, together with the observation that some humans lack MAO-A, MAO-B, or both have contributed to our understanding of the function of MAO-A and MAO-B in health and disease. MAO-A and MAO-B may be closely related to various neuropsychiatric disorders such as depression and Parkinson's disease, and inhibitors of them are the subject of drug development for such diseases.
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PMID:Progress in monoamine oxidase (MAO) research in relation to genetic engineering. 1469 76

Speciation of arsenic in environmental samples gains increasingly importance, as the toxic effects of arsenic are related to its oxidation state. A method was developed for the determination of trace amounts of arsenic (III) and total arsenic by flow injection hydride generation coupled with an in-house made non-dispersive AAS device. The total arsenic is determined after prereduction of arsenic (V) to arsenic (III) with L-cysteine in a low concentration of hydrochloric, acetic or nitric acid. The conditions for the prereduction, hydride generation and atomization were systematically investigated. A quartz tube temperature of 800 degrees C was found to be optimum in view of peak shape and baseline stability. Pb(II), Ni(II), Fe(III), Cu(II), Ag(I), Al(III), Ga(II), Se(IV), Bi(III) were checked for interfering with the 2 microg/L As(V) signal. A serious signal depression was only observed for Se(IV) and Bi(III) at a 150-fold excess. With the above system, arsenic was determined at a sampling frequency of about 1/min with a detection limit (3sigma) of 0.01 microg/L using a 0.5 mL sample. The reagent blank was 0.001+/-0.0003 absorbance units and the standard deviation of 10 measurements of the 2 microg/l As signal was found to be 1.2%. Results obtained for standard reference materials and water samples are in good agreement with the certified values and those obtained by ICP-MS
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PMID:Differential determination of arsenic (III) and total arsenic with L-cysteine as prereductant using a flow injection non-dispersive atomic absorption device. 1504

HIV-1 encodes for one of the human glutathione peroxidases. As a consequence, as it is replicated, its genetic needs cause it to deprive HIV-1 seropositive individuals not only of glutathione peroxidase, but also of the four basic components of this selenoenzyme, namely selenium, cysteine, glutamine, and tryptophan. Eventually this depletion process causes severe deficiencies of all these substances. These, in turn, are responsible for the major symptoms of AIDS which include immune system collapse, greater susceptibility to cancer and myocardial infarction, muscle wasting, depression, diarrhea, psychosis and dementia. As the immune system fails, associated pathogenic cofactors become responsible for a variety of their own unique symptoms. Any treatment for HIV/AIDS must, therefore, include normalization of body levels of glutathione, glutathione peroxidase, selenium, cysteine, glutamine, and tryptophan. Although various clinical trials have improved the health of AIDS patients by correcting one or more of these nutritional deficiencies, they have not, until the present, been addressed together. Physicians involved in a selenium and amino-acid field trial in Botswana, however, are reporting that this nutritional protocol reverses AIDS in 99% of patients receiving it, usually within three weeks.
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PMID:How HIV-1 causes AIDS: implications for prevention and treatment. 1505 Jan 5

The serotonin transporter (SERT) belongs to a family of sodium-chloride-dependent transporters responsible for uptake of amino acids and biogenic amines from the extracellular space. SERT represents a major pharmacological target in the treatment of several clinical conditions, including depression and anxiety. In the present study we have undertaken a mutational scanning of human SERT in order to identify residues that are responsible for individual differences among related monoamine transporters. One mutant, G100A, was inactive in transport. However, ligand binding affinity was similar to wild-type, suggesting that G100A amongst different possible SERT conformations is restrained to a binding conformation. We suggest that the main role of glycine-100 is to confer structural flexibility during substrate translocation. For the two single mutants, T178A and F263C, uptake rates and K(m) values were both several-fold higher than wild-type while binding affinities and inhibitory potencies decreased considerably for several drugs. Ion dependency increased and only at hyperosmotic concentrations were K(m) values partly restored. For the double mutant, T178A/F263C, shifts in uptake kinetics and ligand affinities, as well as ion dependencies, were drastic. Effects were synergistic compared to the corresponding single mutants. In conclusion, we suggest that mutating threonine-178 to an alanine and phenylalanine-263 to a cysteine mainly alter the overall uptake kinetics of SERT by affecting the conformational equilibrium of different transporter conformations.
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PMID:Mutational scanning of the human serotonin transporter reveals fast translocating serotonin transporter mutants. 1506 48

A recombinant Chinese hamster ovary (CHO) cell line was used to express a humanized antibody. Product quality analysis of this humanized antibody showed the presence of free thiol, due to unpaired cysteine residues in the Fab region. Decreased potency of this thiol Fab made it critical to minimize the levels of free thiol. In an effort to do this, we evaluated the effect of copper sulfate addition to the cell culture production medium. As a component of the production medium, copper sulfate can act as an oxidizing agent, thereby facilitating disulfide bond formation. Four concentrations of copper sulfate were added at the beginning of 2-L benchtop production cultures of the recombinant CHO cell line: 0, 5, 50, and 100 microM. We found that these copper sulfate additions had no effect on cell growth or antibody production. However, a slight dose-dependent depression in culture viability was observed. Analysis of the purified antibody showed that either the 50 or 100 microM copper sulfate additions reduced the level of free thiol by more than 10-fold.
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PMID:Effect of copper sulfate on performance of a serum-free CHO cell culture process and the level of free thiol in the recombinant antibody expressed. 1580 97


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