Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To understand hydrazone formation in hydralazine metabolism, the reaction of hydralazine with various biogenic aldehydes and ketones (acetone, pyruvic acid, acetoacetic acid, formaldehyde, and acetaldehyde) in pH 7.4 buffer was studied for potential alterations in hydralazine pharmacokinetics secondary to alcoholism and diabetes. The corresponding hydrazones were isolated, and their structures were characterized. High-performance liquid chromatography was used to monitor the reactions. An aqueous solvent reversed-phase liquid chromatographic system was used to separate hydralazine and its derivatives. Reaction of hydralazine with formaldehyde or acetaldehyde produced the corresponding hydrazones. Formation of an s-triazolo ring system yielded the known s-triazolo[3,4-alpha]phthalazine and 3-methyl-s-triazolo[3,4-alpha]phthalazine metabolites, which also were isolated and characterized and suggested nonenzymatic metabolism.
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PMID:High-performance liquid chromatographic studies of reaction of hydralazine with biogenic aldehydes and ketones. 52 44

These studies were designed to investigate the cytologic localization and topographic distribution of insulin receptors in human placental villi. Biochemical studies showed placental villi to specifically bind 125I-insulin. Radioautographic studies showed the specific binding to be localized to the surface of the syncytial trophoblast. Topographic distribution of insulin binding was determined with ferritin-insulin. Initial studies using ferritin-insulin containing some oligomers of ferritin revealed the insulin receptors to be specifically associated with the glycocalyx region of the surface membranes of microvilli. No insulin receptors were detectable in association with the intermicrovillous plasma membrane even though its glycocalyx is in direct continuity with the glycocalyx of microvilli. Monomeric ferritin-insulin showed the same nonuniform distribution of the insulin receptor, which suggests that there is not complete freedom of lateral mobility of the insulin receptors in the surface membrane of this tissue. The insulin receptors were found to occur as singletons or in groups of two or more. Incubations with monomeric ferritin-insulin at 4 degrees or with tissue prefixed with formaldehyde showed that the groups of insulin receptors were naturally occurring, i.e., they are present prior to and independent of insulin binding and thus not secondary to ligand-induced aggregation. The physiologic meaning of the nonuniform distribution and the groups of insulin receptors is unclear at present.
Diabetes 1978 May
PMID:Nonuniform distribution and grouping of insulin receptors on the surface of human placental syncytial trophoblast. 64 42

The capacity of the vascular enzyme, semicarbazide-sensitive amine oxidase (SSAO), to metabolize methylamine to the potentially toxic product, formaldehyde, was tested using rat aortic homogenates and purified porcine aortic SSAO. Formaldehyde production in incubations of enzyme source with methylamine (1 mM) was detected by high performance liquid chromatography and product was confirmed by desorption chemical ionization mass spectrometry (DCI-MS). Inhibitor studies using the specific SSAO inhibitor semicarbazide and the monoamine oxidase inhibitor pargyline indicate that SSAO is responsible for metabolism of methylamine to formaldehyde. These results suggest the possibility that elevated methylamine found in several pathologic states (such as uremia and diabetes mellitus), or generated from exogenous sources, could result in overproduction of formaldehyde in tissues with high SSAO activity, especially blood vessels.
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PMID:Methylamine metabolism to formaldehyde by vascular semicarbazide-sensitive amine oxidase. 163 2

Previous assays for nonenzymatic advanced glycosylation end products (AGEs) formed in tissues and/or circulating in blood are unsatisfactory. Based on our earlier identification of AGE-specific receptors on the macrophagelike tumor cell line RAW 264.7, a new assay system for AGEs has been devised. RAW 264.7 cells were used in competitive radioreceptor assays (RRA) after a 3-day culture in 96-well plates with 1 mu CI/ml [3H]glycine. Bovine serum albumin (BSA), modified extensively by incubation with glucose-6-phosphate in vitro to form AGE-BSA, was labeled with 125I and was used as a model ligand at a concn of 10 micrograms/ml. One unit of AGE was defined as the amount of test protein required to inhibit 50% of the specific binding of [125I]-labeled AGE-BSA to the AGE-receptors of intact RAW 264.7 cells. Nonlabeled AGE-BSA was used as a specific competitor to construct standard curves. The reproducibility of the assay was assessed at AGE levels equivalent to mean, maximum, and minimum levels of sensitivity for assays run on a single day and over an extended period, and the RRA had a reproducibility (coefficient of variation) between 5.9 and 14.7%. Protease hydrolysis of in vitro glycosylated proteins before assay increases the competitive ability of these proteins in proportion to their glycosylation. Little or no AGE cross-reactivity was detected in native BSA, Amadori-BSA, maleylated BSA, formaldehyde-treated BSA, palmitic acid-BSA, and acetylated low-density lipoproteins (acetyl-LDL). Polyanions such as heparin or fucoidan strongly interfere with this receptor binding assay.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1991 Dec
PMID:Radioreceptor assay for advanced glycosylation end products. 166 95

Many nitrosamines are metabolized by cytochromes P450, one of which (P450IIE1) has received much attention because of its role in the metabolic activation of N-nitrosodimethylamine. This enzyme exists in man, rat, mouse, hamster and other animal species. It is inducible by fasting, diabetes and exposure to ethanol, acetone, isoniazid, benzene and other chemicals. P450IIE1 is responsible for the low Km form of N-nitrosodimethylamine demethylase and is the major enzyme catalysing the metabolic activation of this carcinogen. In addition, P450IIE1 is the most active P450 species known in the metabolism of N-nitrosoethylmethylamine and N-nitrosopyrrolidine. In the metabolism of N-nitrosobutylmethylamine, P450IIE1 preferentially oxidizes the methyl group over the butyl group, whereas P450IIB1 efficiently oxidizes both the methyl and butyl groups. P450IIB1 also catalyses the alpha-oxygenation of both the pentyl and methyl groups of N-nitrosopentylmethylamine, forming pentaldehyde and formaldehyde at a rate ratio of 2:1, as well as oxygenation at other carbons of the pentyl group. Many nitrosamines are effectively activated in nonhepatic target tissues. The metabolism of 4-(N-nitroso-methylamino)-1-(3-pyridyl)-1-butanone in lung and nasal microsomes is discussed.
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PMID:Enzyme mechanisms in the metabolism of nitrosamines. 185 65

NDMA, one of the most widely occurring carcinogenic compounds in the environment, is present in human food (meat, vegetables, cheese and alcohol beverages), in drinking water, in drugs, in cosmetics, in tobacco and its smokes. Furthermore NDMA may be synthesized from nitrates and nitrites and endogen or exogen amines. Since the first observations of MAGEE and BARNES in 1956 on the carcinogenicity of NDMA, this compound was reported to be carcinogenic in a large number of animal species including mammals, birds, amphibia and fish. NDMA requires metabolic activation for its cytotoxic and carcinogenic actions. The major activation step is believed to be the oxygenation of the alpha-carbon catalysed by a Cytochrome P-450-dependent enzyme system commonly know as NDMA-demethylase. Studies on the enzymology of NDMA metabolism show that some Cytochrome P-450 isozymes exhibit significant NDMA-demethylase activity only at high NDMA concentrations. The form of P-450 inducible by factors such as, fasting, diabetes, ethanol consumption and pretreatment with acetone, pyrazole or isopropanol has the higher affinity for NDMA. The gene coding for this isozyme belongs tho the P-450 II E subfamily. Because NDMA-demethylase activity is decreased by monoamine oxidase inhibitors, some authors have suggested a possible role of MAO in NDMA demethylation. This view is not supported by others who don't find evidence for an involvement of MAO in NDMA metabolism. Likewise, there are contradictory reports about the existence of some NDMA demethylase activity in cytosol, nuclei and mitochondria. NDMA demethylation, followed by nonenzymatic cleavage of the hydroxylated methyl group gives formaldehyde and methyldiazohydroxide and then leads to the formation of, a methonium ion, which is able to methylate nucleophilic sites of cellular macromolecules such as, proteins, RNA and DNA. A lot of studies suggest the existence of an alternative pathway to the formation of a methylating agent, denitrosation. Although the nature of mechanisms of denitrosation is not completely known, authors think that the formation of nitrite may represent a detoxification pathway rather than an activation pathway.
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PMID:[Biotransformation of dimethylnitrosamine]. 207 89

Adrenergic innervation of tibial and vagus nerves was studied after 1-16 weeks duration of streptozotocin (STZ)-induced diabetes in rats. Sucrose-phosphate glyoxylic acid (SPG) histochemistry and the formaldehyde-induced fluorescence (FIF) method were used to demonstrate adrenergic nerve fibers in the epi-perineurial and endoneurial compartments. Densities of innervation were quantitated with fluorescence microscopy. The density of periarteriolar adrenergic innervation in the epi-perineurium of the tibial and vagus nerves was increased 5 and 12 weeks after STZ injections as compared with control. At 16 weeks, mean densities of periarteriolar innervation in epi-perineurium had returned to or below control levels in both nerve types. In the endoneurium, however, the mean density of adrenergic nerve fibers decreased gradually at 5 weeks after induction of diabetes in both nerves, and was totally absent at 12 weeks. At 16 weeks no sign of recovering innervation in the endoneurium was seen. In conclusion, adrenergic innervation goes through similar pathological alterations both in tibial and vagus nerves shortly after the induction of streptozotocin diabetes. These changes may contribute to diabetic peripheral neuropathy by impairing the regulation of nerve blood flow.
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PMID:Adrenergic innervation in the tibial and vagus nerves of rats with streptozotocin-induced diabetes. 214 Sep 50

Diabetes induces osteopenia, which is characterized by a deficiency of osteoid and decreased activity of osteoblasts. We recently found that tetracyclines prevent the loss of osteoid and bone matrix and the degeneration of osteoblasts in diabetic rats by a mechanism independent of their antimicrobial efficacy. However, bone remodeling requires the activity of osteoclasts as well as osteoblasts. To determine the in vivo effects of tetracycline on osteoclasts in long bones, either a tetracycline (minocycline, TC) or its chemically modified non-antibiotic analogue (CMT), 4-de-dimethylaminotetracycline, was administrated daily to streptozotocin-induced diabetic rats by oral intubation. After 21 days, the rats were perfusion-fixed with a mixture of formaldehyde and glutaraldehyde, and the humeri were dissected and processed for ultracytochemical demonstration of acid trimetaphosphatase (ACPase) activity. In untreated non-diabetic (control) rats, the osteoclasts at the zone of provisional ossification exhibited abundant mitochondria and cisterns of rough endoplasmic reticulum (RER) throughout the cytoplasm, prominent stacks of Golgi membranes, and lysosomes in the perinuclear cytoplasm, and numerous various pale vacuoles in the cytoplasmic area adjacent to well-developed ruffled border. Intense ACPase activity was observed in the Golgi saccules, lysosomes, pale vacuoles, and the extracellular canals of ruffled border. The reaction products were also noted along the resorbing bone surfaces associated with the osteoclast ruffled border. The osteoclasts in the untreated diabetic rats showed a cytoplasmic organization similar to that of the non-diabetic control rats, but showed little or no ruffled border which was replaced by a broad clear zone in some of these cells. However, most of the osteoclasts on bone matrix in the diabetics were devoid of both a ruffled border and a clear zone. ACPase activity was detected in the osteoclast cytoplasm of diabetic rat, as in the controls, but to a much lesser extent along the broad clear zone facing the resorbing bone surfaces. The osteoclasts in TC-treated diabetic rats possessed both a clear zone and a small ruffled border. However, in some cases, they lacked both structures reminiscent of the untreated diabetic cells. The osteoclasts of CMT-treated diabetic rats exhibited structural and enzymatic features essentially identical to those of the non-diabetic control rats. These results suggest that the diabetes-induced osteopenia results, at least in part, from degeneration of osteoclasts (as well as atrophic osteoblasts) and that tetracyclines may be effective in preventing these abnormalities by a mechanism not dependent on the drugs' antimicrobial properties.
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PMID:Tetracycline administration normalizes the structure and acid phosphatase activity of osteoclasts in streptozotocin-induced diabetic rats. 216 33

Hepatocytes and bile duct epithelium express several types of cytokeratins, the characteristic intermediate-filament proteins of epithelial cells. The cytokeratin antigen expression was studied in normal and diseased livers, intrahepatic cholangiocarcinomas, and hepatocellular carcinomas by immunohistochemical methods using a panel of polyclonal and monoclonal antibodies to cytokeratins. Ten percent formaldehyde solution-fixed, paraffin-embedded sections obtained from ten patients without liver disease, 18 patients without liver disease, 18 patients with different stages of primary biliary cirrhosis, 14 patients with alcoholic hepatitis, ten patients with fatty liver hepatitis secondary to diabetes mellitus or morbid obesity, five patients with hepatocellular carcinomas, and five patients with cholangiocarcinomas were examined. The results suggested that hepatocytes and bile duct epithelium retain their distinct cytokeratin profiles in liver disease, including malignant transformation. Therefore, demonstration of cytokeratins in the liver is useful in establishing the cellular origin of neoplasms and understanding the pathogenesis of liver diseases.
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PMID:Expression of cytokeratins in normal and diseased livers and in primary liver carcinomas. 246 75

Nonenzymatic glycation by glucose (glucation) was compared with glycation by fructose (fructation). The rate and extent of protein-bound fluorescence generation upon fructation was about 10 times that upon glucation. In contrast, nonenzymatically glucated bovine serum albumin (BSA) released about twice as much formaldehyde upon periodate oxidation as did nonenzymatically fructated BSA. However, the rate of blocking of amino groups was similar in both proteins. Periodate oxidation of borohydride-reduced glycated BSA led to regeneration of amino groups with preservation of fluorescence. From the ratio between the decrease in formaldehyde-releasing ability and the regenerated amino groups, formaldehyde molar yields of 0.47 and 0.8 were computed for fructose- and glucose-derived Amadori groups, respectively. This is consistent with participation of both carbon 1 and carbon 3 in the Amadori rearrangement from fructose. The formaldehyde releasing ability of nonenzymatically fructated BSA attains asymptotic maximum values earlier than that of nonenzymatically glucated BSA. Thus, the higher rate of fluorescence generation in nonenzymatically fructated BSA could be explained by a faster conversion of its Amadori groups. Since fluorescence generation through the Maillard reaction has been correlated with long term complications of diabetes mellitus, the participation of nonenzymatic fructation in this pathological state deserves further exploration. This is especially relevant in tissues where fructose levels increase in diabetes as a result of the operation of the sorbitol pathway.
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PMID:Nonenzymatic glycation of bovine serum albumin by fructose (fructation). Comparison with the Maillard reaction initiated by glucose. 253 88


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