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R Poulsom

Publications and source records attributed to R Poulsom.

125 records · Page 7Linked to original sources
PubMed1990

Effects of long-term diabetes and galactosaemia upon lens and retinal mRNA levels in the rat.

The levels of mRNAs encoding the alpha 1 chain of collagen IV and the B1 chain of laminin were assayed in the lenses and retinas of long-term (28-week) diabetic and galactosaemic rats in order to gain some insight into the effects on basement membrane (BM) synthesis in these tissues. mRNAs coding for beta-actin, glucose transporter protein and the alpha 2 catalytic subunit of Na+,K(+)-ATPase were also assayed to determine whether any effects on BM-coding mRNA levels were specific. Long-term diabetes had no significant effect on the levels of alpha 1 (IV) collagen mRNA but caused a significant reduction in the laminin B1 message in the lens. In the same samples, the level of the glucose transporter protein mRNA was found to be elevated significantly in the diabetic tissue, whereas the mRNAsen coding beta-actin and alpha 2 Na+,K(+)-ATPase were unaffected in comparison with age-matched controls. Long-term galactosaemia resulted in significant increases in the levels of all mRNAs assayed when expressed per micrograms total RNA used for each analysis. However, this effect appeared to be due to a specific loss of ribosomal RNA from these severely cataractous lenses. When related to the beta-actin mRNA internal control, the levels of mRNA in the galactosaemic lenses were very similar to that found in the diabetics. Laminin B1 mRNA levels were decreased significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

Actins↗
PubMed1990

Streptozotocin-diabetes but not galactose-feeding increases the serum concentration of type IV collagen antigens in rats.

Serum concentrations of NC-1 (antigens related to the carboxy-terminal non-collagenous domain of type IV procollagen) were found to be increased significantly above normal in short-term (up to eight weeks duration) streptozotocin diabetic rats despite normal steady-state levels of the alpha 1 (IV) collagen mRNA previously reported in the kidneys of the same animals. The effect of long-term (11 and 28 weeks) diabetes on serum NC-1 was compared to the effects of galactose feeding (50% w/w) with and without aldose reductase inhibition (Statil). Serum concentrations in long-term diabetic animals remained significantly elevated above control levels at both time points. Normal NC-1 levels were found in galactosemic rats although this treatment is known to lead to capillary basement membrane thickening. Statil was proven to be effective in preventing polyol accumulation in sciatic nerve samples from diabetic rats but did not decrease the elevated serum NC-1 concentrations. These results suggest etiological heterogeneity in the development of different aspects of diabetic late complications and demonstrate no involvement of the polyol pathway in the events leading to increased serum NC-1 levels in diabetes.

Aging↗
PubMed1988

Increased steady-state levels of laminin B1 mRNA in kidneys of long-term streptozotocin-diabetic rats. No effect of an aldose reductase inhibitor.

The steady-state levels of mRNAs coding for two components of basement membranes, the alpha 1 chain of type IV collagen and the B1 chain of laminin, were measured in the kidneys of male CDF rats following the induction of diabetes with streptozotocin for periods of between 2 days and 28 weeks. The concentration of mRNA for the alpha 1 chain of type IV collagen/microgram of RNA decreased markedly with age in control and diabetic rats. The diabetic level was significantly lower than control after 2 and 11 weeks of diabetes. After 28 weeks, however, there was no significant difference from the levels in control animals. Treatment of control and diabetic rats with the aldose reductase inhibitor Statil (350 mg/kg diet) did not affect the levels of the mRNA for the alpha 1 chain of type IV collagen. In contrast to the continuous decline in the concentration of mRNA for the alpha 1 chain of type IV collagen, the level of mRNA for the B1 chain of laminin increased two-fold between 11 and 28 weeks after induction of diabetes. This increase occurred as aging of control rats reduced the level of laminin B1 mRNA by approximately 50%. Treatment with Statil had no effect on laminin B1 mRNA levels. In control rats there was no change in the ratio of the levels of mRNAs for laminin B1: alpha 1 (IV) collagen with age. The mean ratio was 0.97 +/- 0.10 at 19 weeks and 1.0 +/- 0.10 at 36 weeks of age. In diabetic rats there was a marked increase in the ratio from 0.85 +/- 0.11 at 19 weeks to 3.2 +/- 1.2 at 36 weeks of age. The increased abundance of mRNA for laminin B1 raises the possibility that increased synthesis of laminin contributes to the thickening and abnormal function of renal basement membranes in streptozotocin-diabetic rats.

Aging↗
PubMed1988

Congenital retinal folds in Sheffield-Wistar rats.

Retinal folds are described in male rats of a Wistar-derived strain, which occasionally shows microphthalmia and cataract. The less severe lesions mainly affect the outer retinal layers and contain microretinal detachment, cell rosettes, phagocytic cells and lipid debris. More severe folds involve all the retinal layers, exhibit subretinal haemorrhage, and photoreceptor outer segment debris throughout the lesion and on the vitreal surface. The lesions are discussed in relation to previous observations of retinal folds.

Animals↗
PubMed1987

Comparison of aldose reductase inhibitors in vitro. Effects of enzyme purification and substrate type.

Aldose reductase (EC 1.1.1.21) was purified approximately 5000-fold from bovine lens by ammonium sulphate fractionation and chromatography on DEAE-Sephacel and Matrex OA. Inhibition of this enzyme was found to depend upon the assay substrate. Tested against the purest form of enzyme, the inhibitor Sorbinil gave IC50 values of approximately 100 microM with the model substrate 4-nitrobenzaldehyde (4NB) and 0.4-1.4 microM with the physiological substrate glucose. A similar effect of substrate was found for the inhibitor Statil (IC50 450-750 nM with 4NB, 26-71 nM with glucose substrate). The implications of these results towards the assessment of aldose reductase inhibitors in vitro are discussed.

Aldehyde Reductase↗
PubMed1987

Inhibition of aldose reductase from human retina.

Aldose reductase was prepared from a pool of 21 male and 16 female human retinas by ammonium sulphate fractionation (40-75% saturation) and chromatography on DEAE-Sephacel and Matrex-OA. The overall purification was 132-fold with 50% recovery of enzyme activity. The concentrations of the aldose reductase inhibitors Sorbinil, Statil and M79175 required to give 50% inhibition (IC50 value) of enzyme activity with the model substrate 4-nitrobenzaldehyde (4NB) were 3.4 microM, 2.3 microM and 0.22 microM respectively. This indicated that M79175 was the most effective inhibitor tested of aldose reductase with 4NB in vitro. These inhibitors were more effective when tested against aldose reductase activity with glucose, the substrate which might play a role in the pathogenesis of diabetic complications. Sorbinil gave an IC50 (glucose) of 0.40 microM; M79175 and Statil were more effective. At an inhibitor concentration of 0.1 microM the %-inhibitions observed were: Sorbinil 20% M79175 55%, Statil 76%. Thus Statil was the most potent compound tested against human retinal enzyme using the more physiological substrate in vitro. This report provides the first direct evidence that human retinal aldose reductase is susceptible to inhibition by compounds designed for chemotherapy of diabetic complications, and indicates that the concentrations of inhibitor required for a substantial block of activity in vitro are lower than those attained in plasma in man.

Aged↗
PubMed1986

Inhibition of hexonate dehydrogenase and aldose reductase from bovine retina by sorbinil, statil, M79175 and valproate.

Aldose reductase inhibitors (A.R.I.s), developed as potentially therapeutic agents for the treatment of complications of long-term diabetes, were found to be potent inhibitors of aldose reductase (ALR2) partially purified from bovine retina (IC50 values: Statil 0.89 microM, Sorbinil 2 microM, M79175 greater than 1 microM). These compounds varied, however, in their ability to inhibit hexonate dehydrogenase (ALR1), a closely related enzyme isolated from the same source (IC50 values: Statil greater than 1 microM, Sorbinil 3.9 microM, M79175 0.18 microM). Statil and Sorbinil were active against ALR2 at very low concentrations (approx. 5% inhibition at 100 pM), but did not inhibit ALR1 at less than or equal to 10 nM. In contrast, M79175 (structurally very similar to Sorbinil) and M7HEQ (a flavonoid) were preferential inhibitors of ALR1. Valproate, a compound of value in the treatment of epilepsies, was a poor inhibitor of ALR2 (18% at 1 mM). Furthermore, valproate was found to be a relatively poor inhibitor of ALR1, particularly in comparison with M79175.

Aldehyde Reductase↗
PubMed1983

Inhibition of aldose reductase in five tissues of the streptozotocin-diabetic rat.

For 22 days, streptozotocin-diabetic and normal rats were intubated once daily with ICI 105552 (1-(3,4-dichlorobenzyl)-3-methyl-1,2-dihydro-2-oxoquinol-4-ylacetic acid, sodium salt: 50 mg/kg body weight) an inhibitor of aldose reductase (EC 1.1.1.21), the first enzyme of the sorbitol pathway. Treatment with ICI 105552 affected neither glycaemia nor tissue glucose nor inositol concentrations yet reduced significantly the abnormal accumulations in diabetes of sorbitol in the lens (70% reduction), sciatic nerve (86%) and seminal vesicles with coagulating glands (S.V.C.G., 55%). ICI 105552 had no effect upon sorbitol accumulated in the diabetic kidney but it reduced the level in controls by 43%. The compound reduced the accumulation of sorbitol in diabetic retina by 58% although variation was too great for the decrease to be significant statistically. Treatment with ICI 105552 produced small (less than or equal to 11%) yet statistically significant increases in the weights of the kidneys, and both liver and kidney weight/100 g residual body weight but did not affect the weights of the body, lens, retina or S.V.C.G. The importance of these findings for the development of potentially chemotherapeutic aldose reductase inhibitors is discussed.

Aldehyde Reductase↗
PubMed1983

The effects of long-term treatment of streptozotocin-diabetic rats with an aldose reductase inhibitor.

To test the possible involvement of the sorbitol pathway in the pathogenesis of retinopathy in long-term experimentally-diabetic rats, streptozotocin-diabetic and normal rats were dosed orally (50 mg/kg body weight daily) for up to 373 days with an aldose reductase inhibitor (ICI 105552) or a placebo. Long-term treatment with ICI 105552 (1,(3,4-dichlorobenzyl)-3-methyl-1,2-dihydro-2-oxoquinol-4-ylaceti c acid; sodium salt) markedly reduced the normal accumulations of sorbitol and fructose in the sciatic nerves (86 and 69% reductions) and seminal vesicles with coagulating glands (75 and 49% reductions). Thus, by these criteria, the inhibitor was as effective after several months of dosing as after three weeks. There was no evidence that treatment with this aldose reductase inhibitor had any protective effect against the development of pathological changes in the retina and kidney of these rats.

Aldehyde Reductase↗
PubMed1983

The effects of an aldose reductase inhibitor upon the sorbitol pathway, fructose-1-phosphate and lactate in the retina and nerve of streptozotocin-diabetic rats.

UNLABELLED: To investigate the aetiology of complications secondary to experimental diabetes in the rat, the concentrations of glucose, sorbitol, fructose, fructose-1-phosphate, lactate and inositol were measured in the retina and sciatic nerve of streptozotocin-diabetic and normal rats treated for 22 days with ICI 105552 (1-(3,4-dichlorobenzyl)-3-methyl-1,2-dihydro-2-oxoquinol-4-ylacetic acid, sodium salt; 50 mg/kg body wt daily), an inhibitor of aldose reductase (E.C. 1.1.1.21) the first enzyme of the sorbitol pathway. In the diabetic nerve, where accumulation of sorbitol may be pathogenic, treatment with ICI 105552 reduced the accumulations of sorbitol (70%), fructose (47%) and lactate (34%) without affecting glucose, fructose-1-phosphate or inositol. In the nerves of controls, the inhibitor reduced both sorbitol (23%) and fructose (20%) levels without other effects. In the diabetic retina where accumulation of sorbitol or lactate might be pathogenic, treatment with ICI 105552 had no statistically significant effect upon the concentrations of glucose, sorbitol, fructose, fructose-1-phosphate or inositol. However, the inhibitor reduced the concentration of lactate to below the non-diabetic level. In the retinas of controls, dosage with ICI 105552 reduced the concentration of sorbitol by 36% without other effects. THE RESULTS: (1) demonstrated that ICI 105552 was a potent inhibitor of aldose reductase in sciatic nerve and suggested that a proportion of nerve lactate in diabetes could result from sorbitol pathway activity; (2) implied that flux through the sorbitol pathway, eventually to form lactate, increases in diabetic retina; and (3) indicated, by the drug's reduction of retinal lactate concentration, that inhibitors of aldose reductase might be of potential use in diabetic retinopathy.

Aldehyde Reductase↗
PubMedDate not supplied

Molecular aspects of restitution: functions of trefoil peptides.

Healing of mucosal damage takes place in two phases: restitution of mucosal integrity and remodeling towards recreating the original glandular arrangements. These processes can be observed in several experimental rodent models: e.g., cryoprobe or NSAID-generated ulcers in the gastric or duodenal mucosa and following surgical resection of the small or large bowel. In some studies, it has been possible to detect changes in the expression of peptides, either in the reparative epithelium or adjacent to the damage, that may contribute to the healing processes. Trefoil peptides are expressed constitutively by epithelial cells in specific regions of the gastrointestinal tract, in association with mucins. Several studies have shown that trefoil peptide expression is enhanced at sites of damage in man and rat, and experimental evidence supports their active participation in the healing process. Recombinant trefoil peptides are able to enhance the rate of epithelial cell migration in vitro and are able to protect against indomethacin-induced damage in vivo, yet they do not depend upon TGF-beta for enhancing cell migration and do not appear to affect acid secretion. The mode of action of trefoil peptides appears to be receptor-mediated but is not simple. There is good evidence that there are interactions between members of the trefoil family and the EGF family that are beneficial for mucosal defense and repair. This raises the possibility that combining trefoil peptides with other growth factors or small molecules may be advantageous for treatment of ulceration.

Animals↗