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)

Diabetic nephropathy is now the commonest cause of end stage renal disease and accounts for 30-40% of all patients requiring renal replacement therapy. Furthermore, the incidence of diabetic nephropathy continues to increase, in part due to the improved survival of type 2 diabetic patients as the cardiovascular mortality in this group declines (Ritz and Stefanski, 1996). Clinically incipient nephropathy is first manifest by the onset of persistent microalbuminuria, after which, overt diabetic nephropathy is heralded by the appearance of persistent proteinuria. Subsequently, there is a progressive decline in glomerular filtration rate (GFR) resulting, within 5 years, in end stage renal disease in 50% of patients (Hasslacher et al., 1989). The pathology of the renal lesions are similar in type I and II diabetes (Taft et al., 1994), although it has been suggested that there is more heterogeneity in type II diabetes (Chihara et al., 1986). Studies analysing structural-functional relationships have demonstrated that the development of proteinuria correlates with the degree of mesangial expansion (Mauer et al., 1984; White and Bilous, 2000). Although diabetic nephropathy was traditionally considered a primarily glomerular disease, it is now widely accepted that the rate of deterioration of function correlates best with the degree of renal tubulointerstitial fibrosis (Mauer et al., 1984, Bohle et al., 1991). This suggests that although in the majority of patients the primary event is a condition manifest by glomerular changes resulting in proteinuria, the long-term outcome is determined by events in the renal interstitium. With the increasing awareness of the importance of these pathological interstitial changes, interest has focused on the role of cells, such as the epithelial cells of the proximal tubule (PTC) or the interstitial myofibroblast, in the initiation of fibrosis. The aim of the present review is to analyse the available data supporting the role for the PTC in orchestrating renal interstitial fibrosis in diabetic nephropathy as a result of glucose-dependent alterations in PTC function. The potential for subsequent effects on PTC-fibroblast cross-talk will also be considered.
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PMID:Diabetic nephropathy: the central role of renal proximal tubular cells in tubulointerstitial injury. 1181 75

[Reaction: see text]. Asymmetric glycolate alkylation using a protected acetophenone surrogate under solid-liquid phase-transfer conditions is a new approach to the synthesis of 2-hydroxy esters and acids. Diphenylmethyloxy-2,5-dimethoxyacetophenone 1 with a trifluorobenzyl cinchonidinium bromide catalyst 9 (10 mol %) and cesium hydroxide provided S-alkylation products 2 at -35 degrees C in high yield (80-99%) and with excellent enantioselectivities using a wide range of electrophiles (80-90% ee). Alkylated products were elaborated to useful alpha-hydroxy intermediates 3 using bis-TMS peroxide Baeyer-Villiger conditions and selective transesterification reactions. The ester products have been enantioenriched by simple recrystallization from ether to give a single isomer (99% ee). A tight ion-pair model is proposed for the observed S-stereoinduction that includes van der Waals contacts between the extended enolate and the isoquinoline of the catalyst. To demonstrate the utility of the new methodology, the anti-diabetes drug (-)-ragaglitazar 24 was synthesized in six steps from a key 2-alkoxy-3-p-phenoxypropionic acid 26 that was made using PTC glycolate alkylation.
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PMID:Asymmetric phase-transfer catalyzed glycolate alkylation, investigation of the scope, and application to the synthesis of (-)-ragaglitazar. 1626 22

In PTC, it is clear that TGF-beta1 synthesis may be controlled independently at the levels of transcription and translation. In the context of diabetic nephropathy glucose is a potent stimulus of TGF-beta1 promoter activity. The resultant transcript is however poorly translated such that stimulation of PTC with glucose does not increase de novo TGF-beta1 protein synthesis. Although diabetes is a "metabolic" disease, in the kidney, nephropathy is associated with an inflammatory cell infiltrate. For example using the GK rat model of type II diabetes, we have demonstrated that progressive renal disease is associated with a prominent macrophage influx. This led us to examine TGF-beta1 regulation when the effects of macrophage derived cytokines such as platelet derived growth factor and interleukin-1 are combined with exposure to elevated glucose concentrations. These studies have demonstrated that such cytokines specifically facilitate translation of glucose induced TGF-beta1 transcripts. In addition, direct interaction between monocyte-macrophage CD18 and PTC cell surface ICAM-1 stimulates TGF-beta1 synthesis. Recent data from numerous experimental systems have suggested that the extracellular matrix component hyaluronan (HA) may be involved in the regulation of the inflammatory process. We have now identified HA based structures synthesised on the surface of PTC, which act to prevent PTC-macrophage interaction through ICAM-1 thus preventing macrophage driven TGF-beta1 synthesis. Disease promoting cytokines such as IL-1beta down-regulate these structures whilst potential therapeutic agents such as BMP-7 increase their assembly, that HA may possess disease limiting activity.
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PMID:The role of proximal tubular cells in interstitial fibrosis: understanding TGF-beta1. 1747 23

TF (tissue factor) is the main trigger of the coagulation cascade; by binding Factor VIIa it activates Factor IX and Factor X, thereby resulting in fibrin formation. Various stimuli, such as cytokines, growth factors and biogenic amines, induce TF expression and activity in vascular cells. Downstream targets of these mediators include diverse signalling molecules such as MAPKs (mitogen-activated protein kinases), PI3K (phosphoinositide 3-kinase) and PKC (protein kinase C). In addition, TF can be detected in the bloodstream, known as circulating or blood-borne TF. Many cardiovascular risk factors, such as hypertension, diabetes, dyslipidaemia and smoking, are associated with increased expression of TF. Furthermore, in patients presenting with acute coronary syndromes, elevated levels of circulating TF are found. Apart from its role in thrombosis, TF has pro-atherogenic properties, as it is involved in neointima formation by inducing vascular smooth muscle cell migration. As inhibition of TF action appears to be an attractive target for the treatment of cardiovascular disease, therapeutic strategies are under investigation to specifically interfere with the action of TF or, alternatively, promote the effects of TFPI (TF pathway inhibitor).
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PMID:Tissue factor: beyond coagulation in the cardiovascular system. 1984 9

Berberine, an important natural isoquinoline alkaloid from traditional Chinese medicine, is reported to exhibit multiple pharmacological properties, including anti-microbial, anti-diabetes, anti-obesity, anti-inflammatory and anti-carcinogenic activities. Although studies have shown that a wide range of carcinoma cells could be inhibited by berberine, few studies involved thyroid carcinoma. We therefore examined the effect of berberine on papillary thyroid carcinoma (PTC, the most common subtype) and anaplastic thyroid carcinoma (ATC, the most malignant and aggressive subtype). Three thyroid carcinoma cell lines with different aberrant genotypes and one normal thyroid cell line were selected, including C643 (ATC, with H-RAS mutation), OCUT1 (ATC, with BRAFV600E and PIK3CA mutations), TPC1 (PTC, with RET/PTC1 rearrangement) and Htori3 (normal). We found that berberine inhibited the proliferation of C643, OCUT1 and TPC1 thyroid carcinoma cells in a dose- and time-dependent manner (p<0.01, compared with the control), while normal human thyroid cells showed less sensitivity to the cytotoxicity of berberine. Berberine-induced significant mitochondrial apoptosis, G0/G1 cell cycle arrest and inhibitive migration in thyroid carcinoma cells were also observed (p<0.05 or p<0.01, compared with the control). Increased Bax/Bcl-2, cleaved Caspase 3, P21 and decreased Cyclin E1, CDK2 and Vimentin were verified by western blot. Additionally, berberine caused markedly decreased p-AKT1 expression and disturbances in classic ERK MAPK as well as P38 and JNK MAPK pathways in diverse thyroid carcinoma cells. Therefore, berberine could modulate PI3K-AKT and MAPK signaling pathways in thyroid carcinoma cells, which leads to mitochondrial apoptosis, G0/G1 cell cycle arrest and suppressive migration. Berberine may represent a promising chemotherapy for the treatment of thyroid carcinoma.
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PMID:Berberine could inhibit thyroid carcinoma cells by inducing mitochondrial apoptosis, G0/G1 cell cycle arrest and suppressing migration via PI3K-AKT and MAPK signaling pathways. 2893 Dec 15