Plasma kinetics of a cholesterol-rich emulsion in subjects with or without coronary artery disease

A cholesterol-rich emulsion (LDE) that resembles the LDL lipidic structure is taken-up by LDL receptors after intravenous injection by means of apolipoprotein E it acquires in the circulation and can be used to probe LDL metabolism. In this study, LDE was labeled with [14C]cholesteryl oleate and [3H]cholesterol and injected into 19 patients with coronary artery disease (CAD) and into 14 subjects without CAD to verify whether the kinetic behavior of the radioactive lipids is different in CAD. Blood was sampled over 24 h for radioactivity measurement after lipid extraction and separation by thin-layer chromatography. Fractional clearance rate (FCR, in h-1) of [14C]cholesteryl ester was not different in CAD and nonCAD expressed as median (25%; 75%): 0.08 (0.062; 0.134) h-1 versus 0.06 (0.04; 0.083) h-1, P = 0.167. However, [3H]cholesterol FCR was greater in CAD than in nonCAD (mean +/- SEM): 0.163 +/- 0.016 h-1 versus 0.077 +/- 0.014 h-1, P < 0.001. Esterification of the LDE [3H]cholesterol was also greater in CAD subjects than nonCAD at 10 h and 24 h after emulsion injection (P = 0.029 and 0.024 respectively). In conclusion, both removal from the plasma and esterification of the LDE-cholesterol were increased in CAD. These findings may contribute for unraveling pro-atherogenic mechanisms and the establishment of novel CAD markers.     

Induction of sorbitol dehydrogenase by sorbitol in Aspergillus niger

Summary Evidence is presented for the simultaneous induction of sorbitol dehydrogenase along with fructokinase and repression of glucokinase by sorbitol in Aspergillus niger. Fructose is the first product of sorbitol catabolism.     

Inflammation and immunity in diabetic vascular complications

PURPOSE OF REVIEW: Diabetes is associated with an increased risk for cardiovascular disease. The purpose of this review is to discuss possible mechanisms through which diabetes can contribute to a more aggressive atherosclerotic disease process with a particular focus on the role of innate and adaptive immunity. RECENT FINDINGS: The observation that adaptive immune responses to oxidized LDL modulate atherosclerotic plaque development has led to development of pilot vaccines that inhibit atherosclerosis in experimental animals. Recent studies have shown that similar immune responses operate against self-antigens modified by glycation in diabetes. Diabetes has also been shown to activate proinflammatory innate immune receptors and intracellular oxidative stress. SUMMARY: There are many similarities between the autoimmune responses against oxidized LDL and proteins modified by glycation. The role of autoimmune responses against modified self-antigens in the development of diabetic vascular complications represents a relatively unexplored concept that potentially could provide significant new mechanistic insight into the underlying disease process and identify novel targets for intervention.     

Biomarkers of diabetes-associated oxidative stress and antioxidant status in young diabetic patients with or without subclinical complications

The aims of the study were to ascertain the potential role of oxidative stress in the onset of disease-related pathophysiological complications in young type 1 diabetes patients. Indicative parameters of lipoperoxidation, protein oxidation, and changes in antioxidant defense system status were measured in blood samples from 26 young diabetic patients with recently diagnosed (< 6 months) microangiopathy (+DC), 28 diabetic patients without complications (−DC), and 40 healthy age-matched controls (CR). Both diabetic groups presented similar fructosamine and glycated hemoglobin (HbA1c) values. Results showed erythrocyte glutathione peroxidase activity, glutathione content, and plasma β-carotene to be significantly lower in diabetic patients compared with control subjects, but with no significant differences between −DC and +DC groups. Antioxidant enzyme superoxide dismutase activity was significantly higher in the erythrocytes of diabetic patients independently of the presence of microvascular complications. However, the plasma -tocopherol/total lipids ratio was significantly diminished in +DC group compared with −DC (p = .008). Lipid peroxidation indices measured in plasma included malondialdehyde, lipid hydroperoxides, and lipoperoxides, which were significantly elevated in our diabetic patients regardless of the presence of complications. Evidence of oxidative damage to proteins was shown both through the quantification of plasma protein carbonyl levels, which were significantly higher in −DC (0.61 ± 0.09 mmol/mg prot), and higher still in the +DC patients (0.75 ± 0.09 mmol/mg prot) compared with those of controls (0.32 ± 0.03 mmol/mg prot; p < .01) and immunoblot analysis of protein-bound carbonyls. Additionally, a marked increase in protein oxidation was observed in +DC patients through assessment of advanced oxidation protein products (AOPP) considered to be an oxidized albumin index; AOPP values were significantly higher in +DC than in −DC patients (p < .01) and CR (p < .0001). These results point to oxidatively modified proteins as a differential factor possibly related to the pathogenesis of diabetic complications.     

Plasma 24S-hydroxycholesterol levels in elderly subjects with late onset Alzheimer's disease or vascular dementia: a case-control study

Background  

In central nervous system cholesterol cannot be degraded but is secreted into circulation predominantly in the form of its polar metabolite 24(S)-hydroxycholesterol (24S-OH-Chol). Some studies suggested an association between 24S-OH-Chol metabolism and different neurological diseases including dementia. A possible decrease in 24S-OH-Chol plasma levels has been reported late onset Alzheimer's disease (LOAD) and vascular dementia (VD), but results of previous studies are partially contradictory.     

Zinc environment in sheep liver sorbitol dehydrogenase

The extended X-ray absorption fine structure (EXAFS) associated with the zinc K-absorption edge has been recorded for sorbitol dehydrogenase. It is interpreted in terms of one cysteine sulfur among the ligands to the active site zinc atom. Simulations of the EXAFS based on the presence of two such sulfurs are less satisfactory, and comparison with the EXAFS of such systems points to the presence of only one sulfur ligand in sorbitol dehydrogenase. These results provide evidence that sorbitol dehydrogenase does not have the characteristic one water, one His, two Cys arrangement of ligands to the active site zinc found in the homologous alcohol dehydrogenases and are consistent with the one water, one His, one Cys, one Glu ligand arrangement of the proposed model of sorbitol dehydrogenase [Eklund, H., Horjales, E., J?rnvall, H., Br?ndén, C.-I., & Jeffery J. (1985) Biochemistry 24, 8005-8012]. Evidence for the correctness of the model is also evidence for validity of predictive techniques used in constructing the model, i.e., computer graphics fitting of the amino acid sequence to the crystallographically derived structure of a different but homologous protein.     

Red blood cell sorbitol dehydrogenase deficiency in a family with cataracts

Summary Sorbitol dehydrogenase (SORD) was quantitatively assayed in a family in which four out of five brothers and their father had bilateral cataracts. Three sibs (two of them with cataracts) and both their father and paternal grandfather had SORD activity of about 25% of the reference values; of the other two affected sibs one had about 50% and the other had 75%; the mother and two paternal uncles had about 75%. These results do not define a clear cataract-SORD deficiency etiopathogenic relationship, nevertheless, they strongly suggest activity polymorphism in human red cell SORD, which would be highly relevant not only to the study of cataracts but of other major complications in diabetes.     

Metabolic syndrome and diabetic atherothrombosis: implications in vascular complications

Metabolic syndrome is characterized by the clustering of a number of metabolic abnormalities in the presence of underlying insulin resistance with a strong association with diabetes and cardiovascular disease morbidity and mortality. The disorder is defined in different ways, but the pathophysiology is attributable to insulin resistance. An increased release of free fatty acids (FFAs) from adipocytes block insulin signal transduction pathway, induce endothelial dysfunction due to increased reactive oxygen species (ROS) generation and oxidative stress. Dyslipidemia, associated with high levels of triglycerides and low concentrations of high density lipoproteins (HDLs), contributes to a proinflammatory state. Inflammation, the key pathogenic component of atherosclerosis, promotes thrombosis, a process that underlies acute coronary event and stroke. Tissue factor, a potent trigger of the coagulation cascade, is increased in diabetes with poor glycemic control. Therapeutic lifestyle changes (weight loss and physical activity) along with pharmacological interventions are recommended to prevent the complications of metabolic syndrome. In addition to statins, metformin, blood pressure lowering medications, interventions to increase HDLs are other important approaches to decrease the risk of cardiovascular disease. Furthermore, the peroxisome proliferator activated receptor (PPAR)-alpha and gamma agonists are potent anti-inflammatory and anti-atherogenic agents that could both improve insulin sensitivity and the long-term cardiovascular risk. In this review we focus on the molecular and pathophysiological basis of metabolic syndrome, which augments diabetes (insulin resistance) and the contribution of neovascularization in the plaque progression in diabetes, leading to rupture and coronary thrombosis.     

Chlorpropamide-alcohol flushing,aldehyde dehydrogenase activity,and diabetic complications.

Many diabetics who take chlorpropamide (a sulphonylurea compound) experience facial flushing after drinking even small amounts of alcohol. These flushers have a noticeably lower prevalence of late complications of diabetes (microangiopathy, macroangiopathy, and neuropathy) than non-flushers. This flush reaction is accompanied by increased blood acetaldehyde concentrations, suggesting an inhibition of aldehyde dehydrogenase activity. In the present study the activity of this enzyme in erythrocytes was assessed in the absence of chlorpropamide. Erythrocyte homogenates obtained from flushers and non-flushers were incubated with acetaldehyde and the rate of metabolism studies. Flushers eliminated acetaldehyde more slowly at a low range of concentrations (0--30 mumol/l), suggesting a difference in aldehyde dehydrogenase activity. Further studies are needed to clarify the role of this enzyme in the pathogenesis of diabetic complications.     

Advanced glycation end-products and the progress of diabetic vascular complications

Epidemiological studies have confirmed that hyperglycemia is the most important factor in the onset and progress of vascular complications, both in Type 1 and 2 diabetes mellitus. The formation of advanced glycation end-products (AGEs) correlates with glycemic control. The AGE hypothesis proposes that accelerated chemical modification of proteins by glucose during hyperglycemia contributes to the pathogenesis of diabetic complications including nephropathy, retinopathy, neuropathy and atherosclerosis. Recent studies have shown that increased formation of serum AGEs exists in diabetic children and adolescents with or without vascular complications. Furthermore, the presence of diabetic complications in children correlates with elevated serum AGEs. The level of serum AGEs could be considered as a marker of later developments of vascular complications in children with Type 1 and 2 diabetes mellitus. The careful metabolic monitoring of young diabetics together with monitoring of serum AGEs can provide useful information about impending AGE-related diabetic complications. It is becoming clear that anti-AGE strategies may play an important role in the treatment of young and older diabetic patients. Several potential drug candidates such as AGE inhibitors have been reported recently.     

Intravitreal bevacizumab with or without triamcinolone for refractory diabetic macular oedema

We evaluate the effect of intravitreal injections of Bevacizumab (IVB) alone or combined with triamcinolone (IVT) in the first injection for treatment of refractory diabetic macular oedema (DME). Sixty eyes of sixty patients with refractory DME were included. Half of the receive injections of IVB (1.25 mg/0.05 mL) or combined IVB and IVT (1.25 mg/0.05 mL and 2 mg/0.05 mL respectively). The primary outcome measure was change in central macular thickness (CMT). Secondary outcome measures were change in best-corrected logMAR visual acuity (BCVA) and incidence of potential adverse events. Central macular thickness was reduced significantly in both the IVB and IVB/IVT groups. At week 24, CMT change compared to the baseline was -95.7 microm (95% CI, -172.2 to -19.26) in the IVB group and -92.1 pm (95% CI, -154.4 to -29.7) in the IVB/IVT group. There was not a significant difference between the IVB and the IVB/IVT groups (p = 0.022). Improvement of BCVA was initiated at weeks 6 and 12 in the IVB/IVT and IVB groups respectively. In terms of BCVA change compared to the baseline at 24 weeks, the differences between the IVB and the IVB/IVT groups (p = 0.006) were significant. Anterior Chamber reaction was noticed in six (20%) and six (20%) eyes respectively in the IVB and IVB/IVT groups the day after injection, and it resolved with no sequel. Elevation of IOP occurred in two eyes (6%) in the IVB/ IVT group. Intravitreal injections of Bevacizumab had a beneficial effect on refractory DME in terms of CMT reduction and BCVA improvement. Addition of triamcinolone in the injection seemed to induce earlier visual improvement; however, it did not show any significant additive effect later during follow-up.     

Intravitreal Bevacizumab with or without triamcinolone for refractory diabetic macular oedema

We evaluate the effect of intravitreal injections of Bevacizumab (IVB) alone or combined with triamcinolone (IVT) in the first injection for treatment of refractory diabetic macular oedema (DME). Sixty eyes of sixty patients with refractory DME were included. Half of them received injections of IVB (1.25 mg/0.05 ml) or combined IVB and IVT (1.25 mg/0.05 ml and 2 mg/0.05 ml respectively). The primary outcome measure was change in central macular thickness (CMT). Secondary outcome measures were change in best-corrected logMAR visual acuity (BCVA) and incidence of potential adverse events. Central macular thickness was reduced significantly in both the IVB and IVB/IVT groups. At week 24, CMT change compared to the baseline was -93.7 microm (95% CI, -172.2 to -19.26) in the IVB group and -93.1 microm (95% CI, -154.4 to -29.7) in the IVB/IVT group. There was not a significant difference between the IVB and the IVB/IVT groups. Improvement of BCVA was initiated at weeks 6 and 12 in the IVB/IVT and IVB groups respectively. Anterior chamber reaction was noticed in six (20%) and six (20%) eyes respectively in the IVB and IVB/IVT groups the day after injection, and it resolved with no sequel. Elevation of intraocular pressure (IOP) occurred in two eyes (6%) in the IVB/IVT group. Intravitreal injections of Bevacizumab had a beneficial effect on refractory DME in terms of CMT reduction and BCVA improvement. Addition of triamcinolone in the injection seemed to induce earlier visual improvement; however, it did not show any significant additive effect later during follow-up.     

Polymorphism of sorbitol dehydrogenase and 6-phosphogluconate dehydrogenase in swine (Sus scrofa)

More than 300 kidneys from the local bacon factory were investigated and it was shown that the enzyme sorbitol dehydrogenase (EC 1.1.1.14) exhibits a genetically determined polymorphism. While homozygous individuals yield only a single enzyme band after starch gel electrophoresis, heterozygotes show multiple bands.
On the same material also 6-phosphogluconate dehydrogenase (EC 1.1.1.44) and lactate dehydrogenase were investigated, the former showed also clear genetic variants while the latter appeared only in one form.
Gene frequencies for different breeds and types of pigs are given and the results discussed.     

Aldose reductase and sorbitol dehydrogenase distribution in rat kidney.

The sorbitol pathway catalyzes the conversion of glucose to fructose via the intermediate sorbitol. It consists of aldose reductase (AR) and sorbitol dehydrogenase (SDH). In adult (44 day) kidney zones, AR was highest in the outer medulla. In substructures AR was highest in distal convoluted tubule. The AR was greatest in newborn and 8-day zones of developing rat kidney. Acute alloxan diabetes was associated with decreased AR in small arteries, but not glomeruli. The SDH was lowest in outer medulla. It was most active in glomeruli and distal convoluted tubules. The diabetic state leads to no change of SDH in arteries but an increase in glomeruli. SDH increased with development. This study demonstrates AR and SDH in substructures of the kidney. The pathway is present in developing kidney. In diabetes the enzymatic changes would tend to decrease accumulation of sorbitol.     

Effect of experimental cryptorchism on testis L-iditol: NAD oxidoreductase (sorbitol dehydrogenase or ketose-reductase)

Summary The histochemioal distribution of sorbitol dehydrogenase in normal and cryptorchid rat testis has been studied. In the normal testis sorbitol dehydrogenase is localized in the spermatids, increases during their differentiation and is maximal in those spermatids attached to the Sertoli cells (stages V–VII). In the cryptorchid testis, sorbitol dehydrogenase activity of the spermatids, similarly to that of the Sertoli cells, is completely abolished. Therefore, we conclude that sorbitol dehydrogenase activity of the Sertoli cells depends on the spermatid differentiation.Abbreviations used SBDH sorbitol dehydrogenase - NAD nicotinamide adenine dinucleotide - NBT m-nitroneotetrazolium chloride - PMS phenazine methosulfate - Tris tris (hydroxymethyl) aminomethane     

Studies on isozymes of sorbitol dehydrogenase in some vertebrate species

Summary In swine, the enzyme sorbitol dehydrogenase exhibits a genetically determined polymorphism as identified by multiple electrophoretic bands suggesting a tetrameric structure (Op't Hof, 1969). In order to obtain further information on the genetics of this polymorphism, a number of other vertebrate species were examined. Multiple alleles at the SDH gene locus were found in the Cyprinid fishes Leuciscus and Rutilus, and in the Salmonid fish Salmo trutta. The electrophoretic patterns found in these species are compatible with the model of a tetrameric structure of the enzyme. This model was further verified by dissociation-reassociation studies with the homomeric enzymes of swine and Leuciscus. Since in the heterozygote an intensity gradient of the isozymes was seen, the three phenotypes observed in swine were further characterized by means of activity measurements and application of different substrates. The results point to a differential activity of the two different homomeres.Supported by the Deutsche Forschungsgemeinschaft.