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)

Wolfram syndrome is an autosomal recessive neuro-degenerative disorder associated with juvenile onset non-autoimmune diabetes mellitus and progressive optic atrophy. The disease has been attributed to mutations in the WFS1 gene, which codes for a protein predicted to possess 9-10 transmembrane segments. Little is known concerning the function of the WFS1 protein (wolframin). Endoglycosidase H digestion, immunocytochemistry, and subcellular fractionation studies all indicated that wolframin is localized to the endoplasmic reticulum in rat brain hippocampus and rat pancreatic islet beta-cells, and after ectopic expression in Xenopus oocytes. Reconstitution of wolframin from oocyte membranes into planar lipid bilayers demonstrated that the protein induced a large cation-selective ion channel that was blocked by Mg2+ or Ca2+. Inositol triphosphate was capable of activating channels in the fused bilayers that were similar to channel components induced by wolframin expression. Expression of wolframin also increased cytosolic calcium levels in oocytes. Wolframin thus appears to be important in the regulation of intracellular Ca2+ homeostasis. Disruption of this function may place cells at risk to suffer inappropriate death decisions, thus accounting for the progressive beta-cell loss and neuronal degeneration associated with the disease.
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PMID:Wolframin expression induces novel ion channel activity in endoplasmic reticulum membranes and increases intracellular calcium. 1452 44

Advanced glycation end products (AGEs) appear to contribute to the diabetic complications. This study reports the inhibitory effect of OPB-9195 (OPB), an inhibitor of AGEs formation, and the role of a collagen-specific molecular chaperone, a 47-kDa heat shock protein (HSP47) in diabetic nephropathy. Transgenic mice carrying nitric-oxide synthase cDNA fused with insulin promoter (iNOSTg) leads to diabetes mellitus. The iNOSTg mice at 6 months of age represented diffuse glomerulosclerosis, and the expression of HSP47 was markedly increased in the mesangial area in parallel with increased expression of types I and IV collagens. OPB treatment ameliorated glomerulosclerosis in the iNOSTg mice associated with the decreased expression of HSP47 and types I and IV collagens. The expression of transforming growth factor-beta (TGF-beta) was increased in glomeruli of iNOSTg mice and decreased after treatment with OPB. To confirm these mechanisms, cultured mesangial cells were stimulated with AGEs. AGEs significantly increased the expression of HSP47, type IV collagen, and TGF-beta mRNA. Neutralizing antibody for TGF-beta inhibited the overexpression of both HSP47 and type IV collagen in vitro. In conclusion, AGEs increase the expression of HSP47 in association with collagens, both in vivo and in vitro. The processes may be mediated by TGF-beta.
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PMID:Advanced glycation end products increase collagen-specific chaperone protein in mouse diabetic nephropathy. 1500 23

Human Forkhead-box (FOX) gene family consists of at least 43 members, including FOXA1, FOXA2, FOXA3, FOXB1, FOXC1, FOXC2, FOXD1, FOXD2, FOXD3, FOXD4, FOXD5 (FOXD4L1), FOXD6 (FOXD4L3), FOXE1, FOXE2, FOXE3, FOXF1, FOXF2, FOXG1 (FOXG1B), FOXH1, FOXI1, FOXJ1, FOXJ2, FOXJ3, FOXK1, FOXK2, FOXL1, FOXL2, FOXM1, FOXN1, FOXN2 (HTLF), FOXN3 (CHES1), FOXN4, FOXN5 (FOXR1), FOXN6 (FOXR2), FOXO1 (FOXO1A), FOXO2 (FOXO6), FOXO3 (FOXO3A), FOXO4 (MLLT7), FOXP1, FOXP2, FOXP3, FOXP4, and FOXQ1. FOXE3-FOXD2 (1p33), FOXQ1-FOXF2-FOXC1 (6p25.3), and FOXF1-FOXC2-FOXL1 (16q24.1) loci are FOX gene clusters within the human genome. Members of FOX subfamilies A-G, I-L and Q were grouped into class 1 FOX proteins, while members of FOX subfamilies H and M-P were grouped into class 2 FOX proteins. C-terminal basic region within the FOX domain was the common feature of class 1 FOX proteins. FOXH1 and FOXO1 mRNAs are expressed in human embryonic stem (ES) cells. FOXC1, FOXC2, FOXE1, FOXE3, FOXL2, FOXN1, FOXP2 and FOXP3 genes are mutated in human congenital disorders. FOXA1 gene is amplified and over-expressed in esophageal and lung cancer. FOXM1 gene is up-regulated in pancreatic cancer and basal cell carcinoma due to the transcriptional regulation by Sonic Hedgehog (SHH) pathway. FOXO1 gene is fused to PAX3 or PAX7 genes in rhabdomyosarcoma. FOXO3 and FOXO4 genes are fused to MLL gene in hematological malignancies. Deregulation of FOX family genes leads to congenital disorders, diabetes mellitus, or carcinogenesis. Expression profiles, genetic alterations and epigenetic changes of FOX family genes as well as binding proteins and target genes of FOX family transcription factors should be comprehensively investigated to develop novel therapeutics and preventives for human diseases.
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PMID:Human FOX gene family (Review). 1549 44

The recombinant ferritin heavy chain (FTN-H) formed self-assembled spherical nanoparticles with the size comparable to native one. We tried to express the GAD65 COOH-terminal fragments, i.e., 448-585 (GAD65(448-585)), 487-585 (GAD65(487-585)), and 512-585 (GAD65(512-585)) amino acid fragments, using FTN-H as N-terminus fusion expression partner in Escherichia coli. All of recombinant fusion proteins (FTN-H::GAD65(448-585), FTN-H::GAD65(487-585), and FTN-H::GAD65(512-585)) also formed spherical nanoparticles due probably to the self-assembly function of the fused ferritin heavy chain. The antigenic epitopes within GAD65(448-585), GAD65(487-585), and GAD65(512-585) against insulin-dependent diabetes mellitus (IDDM) marker (autoantibodies against GAD65) were localized at the surface of the spherical protein nanoparticles so that anti-GAD65 Ab could recognize them. Protein nanoparticles like FTN-H seem to provide distinct advantages over other inorganic nanoparticles (e.g., Au, Ag, CdSe, etc.) in that through the bacterial synthesis, the active capture probes can be located at the nanoparticle surface with constant orientation/conformation via covalent cross-linking without complex chemistry. Also it is possible for the protein nanoparticles to have uniform particle size, which is rarely achieved in the chemical synthesis of inorganic nanoparticles. Thus, the recombinant ferritin particles can be used as a three-dimensional (spherical) and nanometer-scale probe structure that is a key component in ultra-sensitive protein chip for detecting protein-small molecule interactions and protein-protein interactions.
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PMID:Glutamate decarboxylase-derived IDDM autoantigens displayed on self-assembled protein nanoparticles. 1562 56

The arterial content of hyaluronan (HA) undergoes diffuse changes as part of the diabetic macroangiopathy. Because HA influences the phenotype of vascular cells in vitro such as proliferation, migration, and secretion, it is tempting to speculate that diabetes-induced hastened cardiovascular disease may be linked to the increased amount of HA. To explore the pathophysiological role of altered HA content in the arterial wall in vivo, we created transgenic (Tg) mice with HA overexpression in smooth muscle cells (SMCs) in large and small vessels, targeted by the alpha smooth-muscle-cell-actin (alphaSMA) promoter fused to the human hyaluronan synthase 2 (hHAS2) cDNA. RT-PCR demonstrated hHAS2 mRNA expression in the tunica media of large and small vessels. In situ hybridization confirmed that hHAS2 mRNA was targeted to the SMCs. The aortic HA content was elevated in the Tg mice, and by immunohistochemistry, it was seen that HA accumulated in the tunica media. The secretory profile of high- and low-molecular HA was similar in wild-type and Tg animals. Overproduction of HA in the aorta resulted in thinning of the elastic lamellae in Tg mice. Our data suggest that this may lead to increased mechanical stiffness and strength, as determined by controlled stretching until failure. Finally, overproduction of HA on the genetic background of the ApoE-deficient mouse strain promoted atherosclerosis development in the aorta. These results indicate that a single component of the diabetic macroangiopathy, diffuse accumulation of HA, accelerates the progression of atherosclerosis.
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PMID:Overexpression of hyaluronan in the tunica media promotes the development of atherosclerosis. 1570 63

Stem cell technologies hold great potential for the treatment of type 1 diabetes, provided that functional transplantable beta-cells can be selectively generated in an efficient manner. Such a process should recapitulate, at least to a certain extent, the embryonic development of beta-cells in vitro. However, progress at identifying the transcription factors involved in beta-cell development has not been accompanied by a parallel success at unraveling the pattern of their instructive extracellular signals. Here we present proof of principle of a novel approach to circumvent this problem, based on the use of the HIV/TAT protein transduction domain. Neurogenin 3 (ngn3), a factor whose expression is essential for pancreatic endocrine differentiation, was fused to the TAT domain. Administration of TAT/ngn3 to cultured pancreatic explants results in efficient uptake, nuclear translocation, and stimulation of downstream reporter and endogenous genes. Consistent with the predicted activity of the protein, e9.5 and e13.5 mouse pancreatic explants cultured in the presence of TAT/ngn3 show an increased level of endocrine differentiation compared with control samples. Our results raise the possibility of sequentially specifying stem/progenitor cells toward the beta-cell lineage, by using the appropriate sequence and combination of TAT-fused transcription factors.
Diabetes 2005 Mar
PMID:TAT-mediated neurogenin 3 protein transduction stimulates pancreatic endocrine differentiation in vitro. 1573 48

Functional anatomy of the human penis involves various parameters: cavernous tissue, covering integument, prepuce foreskin, corpora cavernosa, corpus spongiosum, glans, facia, arterial supply, venous drainage, lymph drainage, musculature, and nerve supply. Several factors affect the expression/degree of erectile dysfunction (ED) endocrine profile, aging/senescence, demyelinating diseases, and surgery. Risk factors of ED are: age, vascular factors, metabolic diseases (diabetes mellitus), neurologic diseases, and HIV/AIDS. Several drugs are associated with ED: antiandrogenic, anticholinergic, antidepressants, antihypertensive, major tranquilizers, anxiolytics, and certain medicines/metabolites. The International Index of Erectile Function (IIEF) is a multidimensional scale for assessment of erectile dysfunction. The main structures mediating erection are the corpora cavernosa or "erectile bodies," which are fused distally for approximately three-quarters of their length. They separate proximally to fuse with each ischial tuberosity of the pelvis. On their ventral surface lies the corpus spongiosum, which surrounds the urethra. Coital dysfunction is classified into "erectile dysfunction" (psychosexual and endocrine/neuro-endocrine) and "ejaculatory dysfunction" (psychosexual, and genitourinary surgery). Vasculogenic impotence was evaluated by high-resolution ultrasonography and pulsed Doppler spectrum analysis. Cavernosal, alpha-blockade is a technique used to evaluate and treat ED. Another diagnostic procedure for ED involves color floro and spectural Doppler imaging after papaverine-induced erection in impotent men. Color Doppler and duplex ultrasonography are used to evaluate Peyronie's disease. Sildenafil cilrate (Viagra) is an effective therapy of ED in men. Vardenavil is a highly selective phosphodiesterase 5 (PDE5) inhibitor which improved ED. Prostagland E1, vasoactive intestinal polypeptide (VIP), and phentolamine mesylate (administered by autoinjectors) have been applied to treat ED in patients resistant to other intracavernosal agents. Clinical trials were conducted on self-injection of vasoactive drugs, apomorphine SL, and tadalafil in diabetic men. Medical therapy of ED includes: medicated urethral system for erection (MUSE), intravenous pharmacotherapy, arterial revascularization, vacuum devices, two- and three-component inflatable penile prosthesis, semi-rigid penile prosthesis in situ, and inflatable one-piece penile prosthesis. Surgical therapy include procedures to correct Peyronie's penile deformity and penile deformity, procedures to avoid inevitable shortening accompanying Nesbit's disease, and for penile lengthening.
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PMID:Erectile dysfunction: anatomical parameters, etiology, diagnosis, and therapy. 1576 14

Platelets from healthy donors and insuline dependent patients with type 1 diabetes mellitus were examined for proteins specifically interacting in vitro with GST-fused constitutively active (Val12) forms of small GTPases of Rac, Rho and Cdc42. Differential changes in pattern of proteins which bind to these G-proteins in diabetic platelets have been revealed. Obtained results suggest that signalling pathways mediated by Rho GTPases are altered under type I diabetes mellitus. Such changes of actin cytoskeleton regulation may contribute to the higher level of platelet aggregation, which prove to be the etiological background of the late diabetes complications.
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PMID:[Changes in functional state of the low-molecular G-proteins of platelets in type 1 diabetes mellitus]. 1591 22

Many dipeptide boronic acids of the type H(2)N-X-Y-B(OH)(2) are potent protease inhibitors. Interest in these compounds as drugs for cancer, diabetes, and other diseases is growing. Because of the great mutual B-N affinity, cyclization through the N- and B-termini, forming six-membered rings, is a common occurrence at neutral pH and higher where the terminal amino group is unprotonated. Here we report the discovery that when X, the N-terminal amino acid, contains a side chain having a functional group with boron affinity and suitable geometry, additional cyclization in the form of bidentate intramolecular chelation or "autochelation" may occur, predominantly at mid pH. NMR studies of two compounds, l-Aspartyl-l-boroProline (Asp-boroPro) and l-Histidyl-l-boroProline (His-boroPro), are reported here from pH 0.5 to pH 12 by (1)H, (15)N, (13)C, and (11)B NMR. Both of these previously unreported autochelates contain two fused six-membered rings, cis-proline, chiral boron, and -NH(2)(+) protons in slow exchange with water, even at 25 degrees C and pH as high as 4. Using microscopic acid-base equilibrium constants, we show that at high pH (>8 for Asp-boroPro and >10 for His-boroPro) hydroxide competes with the side chains for boron, reducing the chelates from bidentate to monodentate. At low pH (<0.5), proton competition for N-terminal nitrogens causes both compounds to become noncyclic. High chelate stability causes a reduction of the apparent acidic dissociation constant of the protonated N-terminal amino group greater than eight units. In the His-boroPro autochelate, imidazolate anion is produced at the extraordinarily low pH value of approximately 9.
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PMID:Autochelation in dipeptide boronic acids: pH-dependent structures and equilibria of Asp-boroPro and His-boroPro by NMR spectroscopy. 1592 38

A fusion gene CTB-PROIN, in which Proinsulin gene was fused to the 3' end of CTB gene by a hinge peptide 'GPGP', was constructed and cloned into pET-30a(+) to obtain a prokaryotic expression vector pETCPI. Subsequently the recombinant plasmid pETCPI was transformed into E. coli stain BL21 (DE3). After induced by IPTG, the expression product was analyzed by sodium dodecyl sulphate-polyacrylamide gel (15%) electrophoresis (SDS-PAGE), and its result indicated that the recombinant protein CTB-PROIN was expressed and accumulated as inclusion bodies. The recombinant CTB-PROIN protein accumulated to the level of 25% of total bacterial proteins. After inclusion bodies was denaturalized and refolded in vitro, significant assembly of monomers had occurred, and the recombinant protein represented assembled pentamers. The results of western blotting analysis also demonstrated that the fusion protein could be recognized by the anti-CT and anti-insulin antibody, respectively. In addition, the result of the CTB-PROIN-GM1 binding assay, that the protein could bind to monosialoganglioside specifically, showed it possesed biological activity in vitro. These results provided the possibility of developing a cheaper and more efficient oral vaccine for type I diabetes using such constructs.
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PMID:[Cloning of CTB-PROIN fusion gene and its expression in Escherichia coli]. 1601 76


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