Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.2.1.20 (alpha-glucosidase)
4,237 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glycosidases play a pivotal role in processing of various glycoproteins and glycolipids. It is well known that glycosidases are also involved in a variety of degenerative metabolic disorders such as cancer and AIDS. In order to develop potent alpha-glucosidase inhibitors, we first screened 2,2-diphenyl-1-picrylhydrazyl hydrate as a candidate. 2,2-Diphenyl-1-picrylhydrazyl hydrate was found to inhibit alpha- and beta-glucosidases as well as alpha- and beta-mannosidases. It was also shown to be a non-competitive inhibitor of yeast alpha-glucosidase with a Ki value of 1.1 x 10(-6) M. Taken together, we anticipate that 2,2-diphenyl-1-picrylhydrazyl hydrate may be a potent inhibitor for some incurable metabolic disorders including AIDS.
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PMID:2,2-Diphenyl-1-picrylhydrazyl hydrate, a stable free radical, is an alpha-glucosidase inhibitor. 1141 71

Normal somatic cells undergo a finite number of divisions and then cease dividing whereas cancer cells are able to proliferate indefinitely. To identify the underlying mechanisms that limit the mitotic potential, a two-dimensional differential proteome analysis of replicative senescence in serially passaged rat embryo fibroblasts was undertaken. Triplicate independent two-dimensional gels containing over 1200 spots each were run, curated, and analyzed. This revealed 49 spots whose expression was altered more than 2-fold. Of these, 42 spots yielded positive protein identification by mass spectrometry comprising a variety of cytoskeletal, heat shock, and metabolic proteins, as well as proteins involved in trafficking, differentiation, and protein synthesis, turnover, and modification. These included gelsolin, a candidate tumor suppressor for breast cancer, and alpha-glucosidase II, a member of the family of glucosidases that includes klotho; a defect in klotho expression in mice results in a syndrome that resembles human aging. Changes in expression of TUC-1, -2, -4, and -4 beta, members of the TUC family critical for neuronal differentiation, were also identified. Some of the identified changes were also shown to occur in two other models of senescence, premature senescence of REF52 cells and replicative senescence of mouse embryo fibroblasts. The majority of these candidate proteins were unrecognized previously in replicative senescence. They are now implicated in a new role.
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PMID:Differential proteome analysis of replicative senescence in rat embryo fibroblasts. 1209 10

The full-scale commercial appearance of antibiotics in the 1950s caused a shift in the nature of lethal diseases from infectious and acute to noninfectious and chronic. In this situation, biological response modifiers (BRMs), which are not based on selective toxicity, could be expected to be useful. Several types of BRM exist, including retinoids, which act directly on cells at the level of gene expression, and thalidomide and related molecules, which modulate the production of various cytokines. We have been engaged in medicinal, chemical, and structural development studies based on these bioactive compounds. Retinoids include all- trans-retinoic acid (ATRA), a major active form of vitamin A (retinol), and its bioisosters, which elicit their biological effects by binding to their nuclear receptors, retinoic acid receptors (RARs). ATRA has been used in differentiation therapy, typically for the treatment of acute promyelocytic leukemia, and the treatment of dermatological diseases. Our structural development studies of retinoids, including computer-assisted molecular design, have yielded class/subtype-selective agonists, synergists, and antagonists of RARs and their partner nuclear receptors, retinoid X receptors. Among them, the benzanilide-type compounds, Am80 and TAC101, are under phase II and I/II clinical studies in Japan and the USA, respectively. Thalidomide is a hypnotic/sedative drug that was withdrawn from the market because of teratogenicity. However, thalidomide has been established to be useful in the treatment of various diseases including cancer. Thalidomide elicits a wide range of pharmacological effects, including anticachexia, anti-tumor-promoting, antiangiogenic, immunosuppressing, antiviral, hypoglycemic, and antimetastatic activities. We have found that thalidomide is a multitarget drug. Hypothetical target events/molecules of thalidomide include tumor necrosis factor-alpha production, nuclear androgen receptor, cyclooxygenases, aminopeptidases, and alpha-glucosidase. Specific and potent compounds for each of these target phenomena/molecules have been prepared by appropriate modification of the thalidomide structure, and are expected to be superior lead compounds for novel immunomodulators, antiangiogenic agents, and anti-tumor-promoting agents.
Cancer Chemother Pharmacol 2003 Jul
PMID:Structural development of synthetic retinoids and thalidomide-related molecules. 1281 30

Genetically modified laboratory animals provide a powerful approach for studying gene expression and regulation and allow one to directly examine structure-function and cause-and-effect relationships in pathophysiological processes. Today, transgenic mice are available as a research tool in almost every research institution. On the other hand, the development of a relatively large mammalian transgenic model, transgenic rabbits, has provided unprecedented opportunities for investigators to study the mechanisms of human diseases and has also provided an alternative way to produce therapeutic proteins to treat human diseases. Transgenic rabbits expressing human genes have been used as a model for cardiovascular disease, AIDS, and cancer research. The recombinant proteins can be produced from the milk of transgenic rabbits not only at lower cost but also on a relatively large scale. One of the most promising and attractive recombinant proteins derived from transgenic rabbit milk, human alpha-glucosidase, has been successfully used to treat the patients who are genetically deficient in this enzyme. Although the pronuclear microinjection is still the major and most popular method for the creation of transgenic rabbits, recent progress in gene targeting and animal cloning has opened new avenues that should make it possible to produce transgenic rabbits by somatic cell nuclear transfer in the future. Based on a computer-assisted search of the studies of transgenic rabbits published in the English literature here, we introduce to the reader the achievements made thus far with transgenic rabbits, with emphasis on the application of these rabbits as human disease models and live bioreactors for producing human therapeutic proteins and on the recent progress in cloned rabbits.
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PMID:Transgenic rabbits as therapeutic protein bioreactors and human disease models. 1295 Nov 61

Research on cancer and other conditions has shown flavonoids and sphingolipids to be food components capable of exerting chemoprotective action. Nevertheless, little is known about their effects on healthy individuals and their potential usefulness as therapeutic agents. The present study examined the possible action of a dietary flavonoid, quercetin, and a sphingolipid, sphingomyelin, as functional foods in healthy animals. In particular, the effect on animal growth of supplementing a conventional diet with one or other of these substances (0.5 % quercetin and 0.05 % sphingomyelin) was considered. Possible action affecting intestinal physiology was also analysed by measuring the uptake of sugar and dipeptide, mediated by the Na(+)-dependent sugar transporter SGLT1 and the dipeptide Na(+)/H(+) exchanger PEPT1 respectively, and the activity of related intestinal enzymes such as sucrase, maltase and aminopeptidase N. Both substances seemed to modify small intestinal activity in healthy mice, altering intestinal enzymatic activity and nutrient uptake. These effects observed in the small intestine did not impair normal development of the animals, as no differences in serum biochemical parameters or in organ and body weights were found. The findings should help in elucidating the mechanisms of action of these food components with a view to their possible use in the prevention of certain pathological conditions.
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PMID:Effect of dietary quercetin and sphingomyelin on intestinal nutrient absorption and animal growth. 1651 30

Genetic aberrations at chromosome 7 are known to be related with diverse human diseases, including cancer and autism. In a number of cancer research areas involving gastric cancer, several comparative genomic hybridization studies employing metaphase chromosome or BAC clone microarrays have repeatedly identified human chromosome 7 as containing 'regions of changes' related with cancer progression. cDNA microarray-based comparative genomic hybridization can be used to directly identify individual target genes undergoing copy number variations. Copy number change analysis for 17,000 genes on a microarray format was performed with tumor and normal gastric tissues from 30 patients. A group of 90 genes undergoing copy number increases (gene amplification) at the p11 approximately p22 or q21 approximately q36 region of chromosome 7 is reported. The list of genes includes wingless-type MMTV integration site family member 2 (WNT2), a proto-oncogene and acyloxyacyl hydrolase (AOAH) that was amplified in >80% of the tested cases. The amplified genes are those functioning in the biological processes such as signal transduction pathways, cell proliferation, metabolism, transport, inflammatory response and protein folding or proteolysis. Also found in the list are genes that are targets for drug development, such as maltase-glucoamylase (MGAM), cyclin-dependent kinase 5 (CDK5), neuropeptide Y (NPY) and dopa decarboxylase (DDC). The current dataset can be used as one of the resources in understanding genetic aberrations of chromosome 7 in human gastric cancer.
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PMID:Gene amplifications at chromosome 7 of the human gastric cancer genome. 1761 41

Quercetin, a flavonol contained in various vegetables and herbal medicines, has various biological activities including anti-cancer, anti-allergic and anti-oxidative activities. However, low oral bioavailability of quercetin due to insolubility in water has limited its use as a food additive or dietary supplement. Since the water solubility is enhanced by glycosyl conjugation, in the present study, we evaluated the bioavailability of several quercetin glycosides with different sugar moieties in rats. Quercetin, quercetin-3-O-rutinoside (rutin), and quercetin-3-O-glucoside (isoquercitrin, IQC) in suspension, and quercetin-3-O-maltoside (Q3M), quercetin-3-O-gentiobioside (Q3G), alpha-monoglucosyl rutin (alphaMR), alpha-oligoglucosyl rutin (alphaOR), and enzymatically modified isoquercitrin (alpha-oligoglucosyl isoquercitrin, EMIQ) dissolved in water, were orally administered to rats under anesthesia. Bioavailability (F value) was calculated from the concentrations of total quercetin in plasma from 0 to 12 h after the administration. F value of quercetin was 2.0%, and those of IQC, Q3M and EMIQ were 12%, 30%, and 35%, respectively. Although Q3G, alphaMR and alphaOR have high water solubility, their F values were low (3.0%, 4.1%, 1.8%, respectively). In the in vitro study, the homogenate of rat intestinal epithelium rapidly hydrolyzed IQC, Q3M and EMIQ to quercetin, and alphaMR and alphaOR to rutin. However, it could not hydrolyze Q3G or rutin to quercetin. Elongation of alpha-linkage of glucose moiety in IQC enhances the bioavailability of quercetin, and intestinal epithelial enzymes such as lactase-phrolizin hydrolase or mucosal maltase-glucoamylase would play important roles in the hydrolysis and absorption of these flavonol glycosides.
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PMID:Enzymatically modified isoquercitrin, alpha-oligoglucosyl quercetin 3-O-glucoside, is absorbed more easily than other quercetin glycosides or aglycone after oral administration in rats. 1995 24

Glycosidases play an important role in a wide range of physiological and pathological conditions, and have become potential targets for the discovery and development of agents useful for the treatment of diseases such as diabetes, cancer, influenza, and even AIDS. In this study, several benzimidazole derivatives were prepared from o-phenylenediamine and aromatic and heteroaromatic carboxaldehydes in very good yields, using PdCl2(CH3CN)2 as the most efficient catalyst. Synthesized compounds were assayed for their activity on yeast and rat intestinal alpha-glucosidase inhibition and cytotoxic activity against colon carcinoma cell line HT-29. Compound 3e exhibited 95.6% and 75.3% inhibition of yeast and rat intestinal alpha-glucosidase enzyme, while showing 74.8% cytotoxic activity against the HT-29 cell line at primary screening concentrations of 2.1 mM for yeast and rat intestinal alpha-glucosidase enzyme and 0.2 mM for cytotoxic activity against the HT-29 cell line, respectively. Compound 3c displayed 76% and 34.4% inhibition of yeast and rat intestinal alpha-glucosidase enzyme, and 80.4% cytotoxic activity against the HT-29 cell line at similar primary screening concentrations. The IC50 value for the most potent intestinal alpha-glucosidase inhibitor compound 3e was found to be 99.4 microM. The IC50 values for the most active cytotoxic compounds 3c and 3e were 82 microM and 98.8 microM, respectively. Both compounds displayed significant antihyperglycemic activity in starch-induced postprandial hyperglycemia in rats. This is the first report assigning yeast and rat intestinal alpha-glucosidase enzyme inhibition, cytotoxic activity against the HT-29 cell line, and antihyperglycemic activity to benzimidazole compounds 3c and 3e.
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PMID:New antihyperglycemic, alpha-glucosidase inhibitory, and cytotoxic derivatives of benzimidazoles. 2003 May 12

Iminosugars are monosaccharide analogues that have been demonstrated to be specific inhibitors for glycosidases and are currently used therapeutically in several human disorders. N-alkylated derivatives of D-fagomine and (2R,3S,4R,5S)-2-(hydroxymethyl)-5-methylpyrrolidine-3,4-diol with aliphatic chains were tested in eight human cancer cell lines to analyze their cytotoxicity and the inhibitory effect in the activities of specific glycosidases. Results indicate that these compounds were more cytotoxic as the length of the alkyl chain increases. N-dodecyl-D-fagomine inhibited specifically the alpha-D-glucosidase activity in cell lysates, whereas no effect was detected in other glycosidases. The N-dodecyl derivative of (2R,3S,4R,5S)-2-(Hydroxymethyl)-5-methylpyrrolidine-3,4-diol induced specific inhibition against alpha-L-fucosidase in cell lysates. Our results indicated that the length of the alkyl chain linked to the iminosugars determine their cytotoxicity as well as the inhibitory effect on the enzymatic activities of specific glycosidases, in human cancer cell lines.
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PMID:Cytotoxicity and enzymatic activity inhibition in cell lines treated with novel iminosugar derivatives. 2004 Dec 92

In this era, major community worldwide is suffering from diabetes type II, cancer and neurodegenerative disorders. To overcome these diseases, in the screening of Korean medicinal plants, we studied the whole plant of Boehmeria nivea (B. nivea). The methanolic leaf, stem and root extracts of B. nivea and their respective n-hexane, methylene chloride (CH(2)Cl(2)), ethyl acetate (EtOAc), n-butanol (BuOH) and aqueous fractions were investigated for their total phenolic content (TPC), 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging activity, alpha-glucosidase, beta-glucosidase, alpha-galactosidase, beta-galactosidase, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzyme inhibition activities. Profound TPC and DPPH free radical scavenging activities were observed in the EtOAc and BuOH fractions of root, where the BuOH fraction showed high-pitched alpha-glucosidase inhibition and the EtOAc layer showed the maximum beta-glucosidase inhibition. Furthermore, the leaf extract demonstrated the highest beta-galactosidase inhibitory activity, but no alpha-galactosidase inhibition was seen in any of the plant parts. Notable BChE and moderate AChE inhibitory activity was found in whole plant. It can be suggested that whole plant of B. nivea provides a strong biochemical rationale as one of the good choices for the treatment of diabetes type II, cancer and neurodegenerative diseases (AD, etc).
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PMID:Evaluation of antiglycosidase and anticholinesterase activities of Boehmeria nivea. 2036 6


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