Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Carnosine and related dipeptides such as anserine are naturally-occurring histidine-containing compounds. They are found in several tissues most notably in muscle where they represent an appreciable fraction of the total water-soluble nitrogen-containing compounds. The biological role of these dipeptides are conjectural but they are believed to act as cytosolic buffering agents. Numerous studies have demonstrated, both at the tissue and organelle level, that they possess strong and specific antioxidant properties. Carnosine and related dipeptides have been shown to prevent peroxidation of model membrane systems leading to the suggestion that they represent water-soluble counterparts to lipid-soluble antioxidants such as alpha-tocopherol in protecting cell membranes from oxidative damage. Other roles ascribed to these dipeptides include actions as neurotransmitters, modulation of enzymic activities and chelation of heavy metals. Many claims have been made in respect of therapeutic actions of carnosine and histidine-containing dipeptides. These include antihypertensive effects, actions as immunomodulating agents, wound healing and antineoplastic effects. Many of these claims have not been convincingly documented nor subject to rigorous clinical evaluation. Nevertheless, there are examples where studies have shown considerable promise. One is the treatment of senile cataract in dogs and another is in acceleration of healing of surface wounds and burns to the skin. It is clear from this review that many of the effects of these histidine-containing dipeptides, especially in regard to claims for their therapeutic effects, need to be subjected to critical experimental and clinical examination. Several applications do, however, show clear evidence of being useful therapeutic agents.
Mol Aspects Med 1992
PMID:Carnosine: its properties, functions and potential therapeutic applications. 976 90

Classical galactosemia, characterized clinically by acute hepatic dysfunction, sepsis, cataract, and failure to thrive, is caused by deficiency of galactose-1-phosphate uridyltransferase (GALT). Galactose restriction normalizes these acute symptoms; however, long-term complications such as intellectual deficits and ovarian failure are conspicuous in the majority of patients. Here we report two Turkish siblings with classical galactosemia. The clinical course of the two children differed markedly: only the older girl suffered from severe acute symptoms during the neonatal period, and she developed greater mental retardation than her younger affected brother. The functional activity of GALT was virtually absent in each affected children. The mother and two healthy siblings exhibited approximately 50% normal GALT activity and the father approximately 25%. Molecular analysis revealed that these two galactosemic siblings were homozygous for a stop codon mutation of E340X in GALT exon 10. Moreover, two additional mutations, a neutral polymorphism L218L and N314D, which are typical for the Duarte-I variant, were found in the same GALT allele. The two healthy siblings and the parents were heterozygous for these combinations of mutations. In addition, the father's second GALT allele revealed three intron mutations at nucleotide position 1105 (G-->C), 1323 (G-->A) and 1391 (G-->A) and the N314D mutation, which correspond to the mutations of Duarte-2 variant. Our findings indicate that in classical galactosemia several distinct mutations can be present in one allele (in cis) of the GALT gene. Therefore it seems to be necessary to examine all introns and exons of the GALT gene in galactosemic patients who do not carry the Q188R mutation or another frequent mutation in the GALT gene.
J Mol Med (Berl) 1998 Sep
PMID:Simultaneous occurrence of various mutations and polymorphisms in cis and in trans of the galactose-1-phosphate uridyltransferase gene in a Turkish family with classical galactosemia. 976 50

Previous study has supposed a possible mechanism of exacerbating cataract formation in cataractous human lens capsules induced by hypertension or glaucoma. To clarify the glaucoma-induced cataract formation of the eyes lens, changes in the human lens lipid and protein structures of immature cataractous patients with or without glaucoma were investigated. Two normal lenses, ten immature cataractous lenses without any complication and four immature cataractous lenses with glaucoma were used after surgical operation. Each de-capsulated human lens sample was sliced with a number 15 surgical blade. The intact nuclear lens regions were used for non-destructive analysis. The lens lipid and protein structures, as well as compositions of these lens samples, were determined using a Fourier transform infrared (FTIR) microspectroscopy with second-derivative, de-convolution and curve-fitting methods. The results indicate that the IR spectrum of glaucomatous lenses appeared as a shoulder only at 2853 cm-1, thus the composition of the symmetric CH2 stretching band at 2853 (2852) cm-1 decreased more significantly in glaucomatous lens to only one half of that in normal and immature cataractous lenses. The composition of the asymmetric CH3 stretching band at 2965 cm-1 for normal lens decreases markedly from 32 to 20% for immature cataractous lenses with or without glaucoma. The compositional ratio of component at 2965 cm-1 to component at 2928 (2930) cm-1 for normal lenses was about 0.702, and that ratio for cataractous lenses without glaucoma was 0.382 but for glaucomatous lenses was 0.377. The maximum peak position of amide I band for IR spectra of the normal lens, immature cataractous lenses without complications or glaucomatous lenses appeared respectively at 1632, 1630 or 1622 cm-1, assigned to beta sheet structure. A marked difference in peak intensity of amide I band for the normal lenses and immature cataractous human lenses with or without glaucoma was observed. The peak intensity ratio of amide I/amide II (1632/1545 cm-1) for normal lenses was in the range of 2.20-2.33, whereas in the spectra of immature cataractous lenses without glaucoma this ratio (1630/1545 cm-1) was 1.28-1.41 but was 1.04-1.13 for glaucomatous lens in the intensity ratio of 1622/1545 cm-1. The intensity of the glycogen bands in the wavenumber region 1135-1076 and 1069-1032 cm-1 was found to increase for the immature cataractous lenses with or without glaucoma, as compared with the normal ones. The peaks ranging from 1633 to 1610 cm-1 assigned to beta-sheet structure also exhibited a pronounced compositional difference, particularly in glaucomatous lenses. The human lens lipid and protein secondary structures were more affected by glaucoma. Higher protein side chains and reduced lipid content contributed predominantly to the CH stretching vibrations of normal lens structure, whereas high lipid content and less protein side chains dominated the CH stretching vibrations of cataractous lenses with or without glaucoma. Decrease alpha-helix and random coil structures but enhanced beta-sheet structure in the immature cataractous human lens induced by glaucoma might result from the formation of intermolecular hydrogen-bonding insoluble protein aggregates that modify the secondary structure of protein in lenses.
Spectrochim Acta A Mol Biomol Spectrosc 1998 Sep
PMID:Non-destructive analysis of the conformational changes in human lens lipid and protein structures of the immature cataracts associated with glaucoma. 980 41

In previous studies stereospecific protection against lens opacity was consistent with specific reduction of R-alpha-lipoic acid(R-alpha-LA) in mitochondria of the vulnerable cells at the lens equator where the first globular degeneration is seen in glucose cataract. In this study two further possible explanations of this effect were investigated: (1) increased glucose uptake by the lens, leading to increased glycolysis and release of lactate into the incubation medium and/or (2) maintenance of glutathione levels by the R-alpha-LA. The data did not support 1, but was consistent with 2, after 24 hr incubation. The concentrations of glutathione in normal lenses or lenses incubated with R- or racemic alpha-LA were not significantly different, but the concentration of glutathione in lenses incubated with S-alpha-LA was significantly lower than the R-alpha-LA-incubated lenses.
Biochem Mol Biol Int 1998 Oct
PMID:Modelling cortical cataractogenesis XX. In vitro effect of alpha-lipoic acid on glutathione concentrations in lens in model diabetic cataractogenesis. 981 98

The incidence of certain ageing sequelae such as lung and cardiovascular disease and cataract are higher in smokers than in non-smokers. We recently proposed that certain components of mainstream cigarette smoke can react with plasma and extracellular matrix proteins to form covalent adducts with many of the properties of advanced glycation endproducts (AGE). AGEs have been implicated previously in the pathogenesis of the end-organ complications of diabetes and ageing, including cataract, atherosclerosis and renal insufficiency. In these circumstances, AGEs arise in vivo from the non-enzymatic reaction of reducing sugars with amino groups. Over time the initial Schiff base and Amadori products that form gradually undergo dehydration and rearrangement to produce reactive, carbonyl containing compounds with characteristic fluorescence and covalent crosslinking properties. Recent studies indicate that in smokers, tobacco-derived AGEs accumulate on plasma low density lipoprotein (LDL), structural proteins present within the vascular wall, and the lens proteins of the eye. These data point to a new and significant source of Maillard products in the human environment, significantly broaden the role of Maillard chemistry in pathological processes, and provide new insight into the pathogenesis of atherosclerosis and other diseases associated with tobacco usage.
Cell Mol Biol (Noisy-le-grand) 1998 Nov
PMID:Advanced glycation endproducts and cigarette smoking. 984 84

Cataract, the major cause of blindness world-wide, is associated with conformational changes and unfolding of proteins in the lens, which can arise directly as a result of post-translational modifications, induced by the Maillard reaction. In the lens, the stress protein alpha-crystallin, which is related to small heat-shock proteins and forms GroEL-like functional aggregates, can act as a chaperone-like protein to maintain transparency, sequestering unfolded protein, and inhibiting subsequent aggregation and insolubilisation. There are a number of criteria which enable the classification of cataract as a conformational disease, including not only the protein conformational change itself, resulting in aggregation and tissue deposition, but also the mechanisms for preventing such unfolding and aggregation. Post-translational modification of alphabeta-crystallin results in loss of chaperone-like activity, and aspirin, ibuprofen and paracetamol can inhibit in vitro cross-linking events responsible for the loss of this activity. Of the many avenues available to block protein aggregation, common analgesics--and vitamin C--may provide a cost-effective route to explore further in the treatment of a range of conformational diseases.
Cell Mol Biol (Noisy-le-grand) 1998 Nov
PMID:Cataract as a conformational disease--the Maillard reaction, alpha-crystallin and chemotherapy. 984 86

Calpain I (mu-calpain) and II (m-calpain) are well known calcium-activated neutral cysteine proteases. Many reports have shown that activation of calpain is related to cataract formation, neuronal degeneration, blood clotting, ischemic injuries, muscular dystrophy and cornified cell envelope (CE) formation. Here, we report that insoluble CE formation was reduced after treatment with calpain I inhibitor (N-acetyl-leucyl-leucyl-norleucinal) on normal human epidermal keratinocytes (NHEK), whereas serine and thiol protease inhibitors had no effect on the reduction of CE. When NHEK cells were confluent, keratinocytes were treated with various concentrations (0.5 microM-0.5 mM) of calpain I inhibitor or serine and thiol protease inhibitors under calcium induced differentiation. Insoluble CE formation was reduced about 90% in the 50 microM calpain inhibitor I treated group by day 9 of culture, whereas insoluble CE was reduced only 10% in the same condition. Interestingly TGase activity was blocked by 90% in the 0.5 mM calpain inhibitor treated group within 72 h, whereas TGase activity was retained by 80% in the 0.5 mM serine protease inhibitor treated group at 7 day treatment. Therefore it can be suggested that cysteine protease calpains might be responsible for the activation of the TGase 1 enzyme to complete insoluble CE formation during epidermal differentiation.
Exp Mol Med 1998 Dec 31
PMID:Calpain inhibitors reduce the cornified cell envelope formation by inhibiting proteolytic processing of transglutaminase 1. 989 58

Cataract formation in diabetic lenses has been attributed to polyol-osmotic pressure-generated influx of water. The ensuing swelling in the form of pocket and lake accumulations cause light scattering. The authors tested whether clear lenses of diabetic patients show different hydration properties than age matched normal lenses. Normal and diabetic human lenses were investigated for their nonfreezable water content by differential scanning calorimetry. The total water content of the lens sections were studied by thermogravimetric analysis. Non-cataractous diabetic lenses in all three regions showed a higher total water content than normal lenses. The nonfreezable water content, seems to increase with age in diabetic lenses and decrease with age in normal human lenses. Thus, hydration changes in human diabetic lenses precede cataract formation. While syneresis, the release of bound water into the bulk, is part of the normal aging process, it appears to occur in the younger diabetics only. In older diabetics syneresis is halted or even reversed. This may be due to the glycation of lens proteins in diabetic patients which tends to immobilize water and therefore, reverse the syneresis due to aging.
Res Commun Mol Pathol Pharmacol 1998 Oct
PMID:Do changes in the hydration of the diabetic human lens precede cataract formation? 992 Mar 42

Compounds capable of inhibiting protein aggregation may find pharmacological applications in the treatment of a number of diseases called protein condensation diseases [Benedek (1997)], which include cataract, biliary and urinary lithiasis and certain rheumatic diseases. We examined the effect of selected compounds on heat-induced aggregation human serum albumin (HSA), IgG and lysozyme. HSA (0.2% w/v in 0.066 M sodium phosphate pH 5.3 at 22 degrees C), IgG (0.5% w/v in 0.066 M Tris pH 8.0 at 22 degrees C), and L (0.2 % w/v in 0.066 M CAPS pH 11.0 at 22 degrees C) were heated for 30 min at 70 degrees C in the presence or absence of different concentrations of the substance under examination and heat-induced aggregation of 100 microl aliquots was evaluated by measuring the absorbance at 595 nm using an automatic microplate reader. In these conditions, inhibition of aggregation could be due to an anti-denaturant effect or to interferences with the aggregation of denatured molecules, as previously described [Saso, Casini et al. (1998)]. However, this distinction may not be pharmacologically relevant when the target of the therapy is the prevention of abnormal phenomena of protein aggregation. Inorganic salts like NaCl and CaCl2 were active on the three proteins (IgG > HSA > L) but many ligands of HSA such as tryptophan, N-acetyl-tryptophan, caprylic acid, capric acid, cholic acid, deoxycholic acid, chenodeoxycholic acid, lithocholic acid and bendazac were active on their carrier but not on IgG and L, indicating that the latter proteins are more difficult to protect and that specific anti-denaturant and/or anti-aggregant compounds should be developed.
Res Commun Mol Pathol Pharmacol 1998 Oct
PMID:Effect of selected substances on heat-induced aggregation of albumin, IgG and lysozyme. 992 Mar 43

Studies describe an attenuation of sugar cataract formation by topical administration of ethyl pyruvate. Cataract formation was induced by feeding young rats a 30% galactose diet. Mature cataracts appeared in about thirty days. Instillation of the eye drops containing 5% ethyl pyruvate decelerated the process significantly. Biochemically, the effect was reflected by lowering in the contents of dulcitol and glycated proteins. The ATP levels were also higher in comparison to the placebo treated group. The effects are hence attributable to the effect of pyruvate in inhibiting dulcitol synthesis and protein glycation, in addition to its antioxidant properties and metabolic support. The use of esterified pyruvate instead of the unesterified pyruvate was preferred because of its greater penetration through the cornea and consequently a higher concentration attained in the aqueous humor.
Mol Cell Biochem 1999 Oct
PMID:Attenuation of sugar cataract by ethyl pyruvate. 1056 89


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