PubMed Health⌕ Search

PubMed · 2122421

Aldose reductase inhibitors.

Abstract

The present management of diabetes consists of attempting to control blood sugar tightly in the normal range and to treat individual complications such as neuropathy and retinopathy as they appear. Whereas these measures are perhaps effective in slowing the progress of diabetic complications, they do not cure the underlying process. The aldose reductase inhibitors have been investigated as possible remedies for various diabetic complications. Aldose reductase is an enzyme present in several human tissues that reduces glucose to sorbitol. In animal models there is evidence that the production of sorbitol is associated with the development of diabetic complications. Animal and human studies have tested the ability of aldose reductase inhibitors to halt or reverse diabetic complications. The weight of evidence leads to two conclusions: first, that aldose reductase inhibitors may bring significant relief to patients with certain diabetic complications; and second, that the current approach to proving clinical efficacy may not be adequate for these drugs.

Explore related subjects

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

W R Kirchain, M S Rendell. 1990. Aldose reductase inhibitors.. https://pubmed.ncbi.nlm.nih.gov/2122421/

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related citations

Exploring structural feature of aldose-reductase inhibition by 5-[[2-(omega-carboxyalkoxy)aryl]methylene]-4-oxo-2-thioxothiazolidine derivatives employing Fujita-Ban and Hansch approach.

Designing of a highly selective, potent and safe inhibitor of aldose reductase (ALR) capable of potentially blocking the excess glucose flux through the polyol pathway that prevails under diabetic condition has been a long standing challenge. In our study, we did quantitative structure-activity relationship (QSAR) analysis, based on Fujita-Ban and classical Hansch approach, on 5-[[2-(omega-carboxyalkoxy)aryl]methylene]-4-oxo-2-thioxothiazolidine derivatives. Study gave structural insight into the binding mode of the molecules to the aldose reductase enzyme. The Fujita-Ban approach revealed that benzylidene thiazolidine nucleus is more potent as compare to naphthyl-methylene thiazolidine analogs. The bulkierness of naphthyl-methylene might be inquisitive with receptor. Hansch approach suggested that electron-withdrawing groups are conducive to aldose reductase inhibitory activity.

Aldehyde Reductase↗

Mediation of aldose reductase in lipopolysaccharide-induced inflammatory signals in mouse peritoneal macrophages.

Aldose reductase (AR; AKR1B1) a member of aldo-keto reductase super family, that we had shown earlier mediates cytotoxic signals induced by high glucose, cytokines and growth factors, also mediates the inflammatory signals induced by Gram-negative bacterial endotoxin, lipopolysaccharide (LPS). Inhibition of AR by three distinct AR inhibitors sorbinil, tolrestat or zopolrestat suppressed the LPS-induced production of inflammatory cytokines such as TNF-alpha, IL-6, IL-1beta, IFN-gamma, and chemokine MCP-1 in murine peritoneal macrophages. Inhibition of AR also prevented the production of nitric oxide, and prostaglandin E2 and expression of iNOS and Cox-2 proteins. The LPS-induced DNA binding activity of NF-kappaB and AP1 were significantly inhibited by AR inhibitors, and this effect was mediated through the inhibition of phosphorylation of IkappaB-alpha, IKK alpha/beta and PKC. These results suggest the therapeutic use of AR inhibitors as anti-inflammatory drugs.

Aldehyde Reductase↗

Proteomic identification of proteins associated with the osmoregulatory transcription factor TonEBP/OREBP: functional effects of Hsp90 and PARP-1.

Hypertonicity (e.g., high NaCl) activates the transcription factor tonicity-responsive enhancer/osmotic response element-binding protein (TonEBP/OREBP), increasing transcription of protective genes. In the present studies, by stably expressing amino acids 1-547 of TonEBP/OREBP in HEK 293 cells and immunoprecipitating it plus associated proteins from the nuclei of cells exposed to high NaCl, we identify 14 proteins that are physically associated with TonEBP/OREBP. The associated proteins fall into several classes: 1) DNA-dependent protein kinase, both its catalytic subunit and regulatory subunit, Ku86; 2) RNA helicases, namely RNA helicase A, nucleolar RNA helicase II/Gu, and DEAD-box RNA helicase p72; 3) small or heterogeneous nuclear ribonucleoproteins (snRNPs or hnRNPs), namely U5 snRNP-specific 116 kDa protein, U5 snRNP-specific 200 kDa protein, hnRNP U, hnRNP M, hnRNP K, and hnRNP F; 4) heat shock proteins, namely Hsp90beta and Hsc70; and 5) poly(ADP-ribose) polymerase-1 (PARP-1). We confirm identification of most of the proteins by Western analysis and also demonstrate by electrophoretic mobility-shift assay that they are present in the large complex that binds specifically along with TonEBP/OREBP to its cognate DNA element. In addition, we find that PARP-1 and Hsp90 modulate TonEBP/OREBP activity. PARP-1 expression reduces TonEBP/OREBP transcriptional activity and the activity of its transactivating domain. Hsp90 enhances those activities and sustains the increased abundance of TonEBP/OREBP protein in cells exposed to high NaCl.

Aldehyde Reductase↗