Mohamed M. Elseweidy

Glycation as an atherogenic modification of LDL

Purpose of review To highlight the potential importance of glycation as an atherogenic modification of LDL in both diabetic and nondiabetic people. Recent findings Small dense LDL which is known to be most closely associated with atherogenesis is more susceptible to glycation than more buoyant LDL. Glycation and oxidation of LDL appear to be intimately associated. Summary Glycation of LDL occurs chiefly due to the nonenzymatic reaction of glucose and its metabolites with the free amino groups of lysine in which LDL is rich. Higher concentrations of glycated LDL are present in diabetic than in nondiabetic individuals, but even in the latter, there is generally more circulating glycated LDL than oxidatively modified LDL. Probably, oxidation and glycation of LDL are at least partially interdependent, but both prevent LDL receptor-mediated uptake and promote macrophage scavenger receptor uptake. The recognition that LDL glycation is at least as important as oxidation in atherogenesis may lead to improvements in our understanding of its mechanism and how to prevent it.

Role of sulfurous mineral water and sodium hydrosulfide as potent inhibitors of fibrosis in the heart of diabetic rats

This study examined the downstream signaling whereby hyperglycemia may lead to myocardial fibrosis and apoptosis in the left ventricle of diabetic rats. The effects of sulfurous mineral water or sodium hydrosulfide (NaHS) as possible modulators were also examined. Sulfurous mineral water (as drinking water) and NaHS (14μmol/kg/day, IP) were administered for 7 week to rats with streptozotocin (STZ)-induced diabetes. Hyperglycemia, overproduction of glycated hemoglobin (HbA1C) and serum decline in insulin, C-peptide and insulin like growth factor-I (IGF-I) were observed in diabetic rats. Up-regulation of gene expressions of nuclear factor (NF-κB), profibrogenic growth factor such as transforming growth factor-β1 (TGF-β1), matrix metalloproteniase-2 (MMP-2), procollagen-1 and Fas ligand (Fas-L) were observed in the left ventricle of diabetic rats. A linear positive correlation between TGF-β1 and MMP-2 was also detected in diabetic group. An increase in hydroxyproline level and a disturbance in oxidative balance were detected in heart of diabetic rats. Sulfurous mineral water and NaHS treatment possibly, by improving cardiac GSH level, counteracted the enhanced expression of NF-κB, the profibrogenic and apoptotic parameters. Histopathological examination was in accordance with the biochemical and molecular findings of this study. We suggest a novel therapeutic approach of sulfurous mineral water and exogenous supplementation of H(2)S in diabetic cardiomyopathy.

Small-dense LDL and LDL glycation in metabolic syndrome and in statin-treated and non-statin-treated type 2 diabetes:

Small-dense LDL (SD-LDL) has been particularly implicated in atherosclerosis. It has previously been reported that in non-diabetic people SD-LDL is preferentially glycated. The distribution of glycated apolipoprotein B (glyc-apoB) in lipoproteins in metabolic syndrome (MS) and in type 2 diabetes has not previously been studied. Plasma apoB and glyc-apoB were determined in different apoB-containing lipoproteins including buoyant and SD-LDL in MS (n=18) and type 2 diabetes (DM) [n=48; 12 statin-untreated (DM−S) and 36 statin-treated (DM+S)]. Plasma glyc-apoB was 5.6 ± 0.9, 3.5 ± 0.5 and 4.0 ± 0.2 mg/dl in DM−S, DM+S and MS, respectively. The glycated proportion of SD-LDL-apoB was greater than buoyant LDL in all groups. SD-LDL contributed most to plasma glyc-apoB in DM−S, because SD-LDL-apoB was higher in DM−S than in MS and DM+S (p < 0.001). Plasma glyc-apoB correlated with SD-LDL-apoB (r=0.74, p < 0.0001 in diabetes and r=0.53, p < 0.001 in MS), but not with HbA1c. SD-LDL is preferentially glycated in type 2 diabetes and MS. Its concentration is a stronger determinant of plasma glycapoB than glycaemia. Statin-induced changes in its level may be important in decreasing apoB glycation in diabetes. These findings may explain the small effect of improving glycaemia relative to statin treatment in reducing atherosclerosis risk in type 2 diabetes and the increased risk in MS even before the onset of type 2 diabetes.

Small dense LDL is more susceptible to glycation than more buoyant LDL in Type 2 diabetes

Glycation of apoB (apolipoprotein B) of LDL (low-density lipoprotein) increases its atherogenicity. Concentrations of both serum glyc-apoB (glycated apoB) and SD-LDL (small dense LDL) (syn LDL3; D=1.044-1.063 g/ml) are increased in diabetes and are closely correlated. We studied whether SD-LDL is more susceptible to glycation in vitro than more buoyant LDL in statin- and non-statin-treated Type 2 diabetes mellitus. Serum SD-LDL apoB and glyc-apoB on statins was 20±2 (means±S.D.) and 3.6±0.41 compared with 47±3 and 5.89±0.68 mg/dl in those not receiving statins (P<0.001 and <0.01, respectively). There was a dose-dependent increase in glycation on incubation of LDL subfractions with glucose, which was accompanied by an increase in LPO (lipid peroxide) and electrophoretic mobility and a decrease in free amino groups. SD-LDL was more susceptible to these changes than more buoyant LDL. Both SD-LDL and more buoyant LDL from statin-treated patients were less susceptible to glycation. There were fewer free amino groups on LDL subfractions from statin-treated patients, which may contribute to this resistance. In conclusion, greater susceptibility of SD-LDL to glycation is likely to contribute to the raised levels of circulating glyc-apoB in diabetes. Statins are associated with lower levels of both SD-LDL and glyc-apoB.

High-density lipoprotein impedes glycation of low-density lipoprotein

Glycation of low-density lipoprotein (LDL) increases its atherogenicity, but whether high-density lipoprotein (HDL) can protect LDL against glycation is not known. LDL and HDL were isolated from 32 volunteers with serum HDL cholesterol concentrations ranging from 0.76 to 2.01 (mean = 1.36) mmol/L. Glycation of LDL was induced by incubation with 0–80 mmol/L glucose for 7 days at 37°C under nitrogen in the presence of and absence of human HDL. Glycation of LDL apolipoprotein B (apoB) doubled at glucose 50 and 80 mmol/L (both p < 0.001), and this increase was ameliorated by HDL. In the absence of glucose, 0.11 (0.01) [mean (standard error, SE)] mg apoB/mg LDL protein was glycated increasing to 0.22 (0.02) mg/mg at glucose 80 mmol/L in the absence of HDL, but remaining at 0.13 (0.01) mg/mg when autologous HDL was present. Heterologous HDL from a further study of 12 healthy participants was similarly effective in impeding LDL apoB glycation. HDL impeded not only glycation but also the lipid peroxidation, free amino group consumption and increased electrophoretic mobility of LDL which accompanied glycation. HDL from participants with higher serum paraoxonase1 (PON1) was more effective in impeding glycation and the related processes. In conclusion, HDL can impede the glucose-induced glycoxidation of LDL. PON1 may be important for this function of HDL.

Frequent inadequate supply of micronutrients in fast food induces oxidative stress and inflammation in testicular tissues of weanling rats.

Fast food is high in energy density and low in essential micronutrient density, especially zinc (Zn), of which antioxidant processes are dependent. We have tested the hypothesis that frequent fast food consumption could induce oxidative damage associated with inflammation in weanling male rats in relevance to Zn deprivation, which could adversely affect testis function. Zn and iron (in plasma and testicular tissue), plasma antioxidant vitamins (A, E, and C), as well as testicular superoxide dismutase (SOD) and reduced glutathione (GSH), lipid peroxidation indexes (thiobarbituric acid reactive substances (TBARS) and lipoprotein oxidation susceptibility (LOS)), and inflammatory markers (plasma C‐reactive protein (CRP) and testicular tumour necrosis factor‐alpha (TNF‐α)) were determined. Serum testosterone and histological examination of the testis were performed also. We found a severe decrease in antioxidant vitamins and Zn, with concomitant iron accumulation. Zinc deficiency correlated positively with SOD, GSH, anti‐oxidant vitamins and testosterone, and negatively with TBARS, LOS, CRP and TNF‐α, demonstrating a state of oxidative stress and inflammation. We concluded that micronutrient deficiency, especially Zn, enhanced oxidative stress and inflammation in testicular tissue leading to under‐development of testis and decreased testosterone levels.

Pyridoxamine, an inhibitor of protein glycation, in relation to microalbuminuria and proinflammatory cytokines in experimental diabetic nephropathy

Diabetic nephropathy (DN) is one of the major complications that develop as consequence of chronic and uncontrolled hyperglycaemia. Hyperglycaemia initiates various processes, one of which is protein glycation, leading to the formation of advanced glycation end products. Alteration of intracellular signalling, gene expression, release of proinflammatory molecules and free radicals are examples of such changes and they contribute to the initiation of diabetic complications. In the current manuscript, we studied the effect of pyridoxamine (PM) on protein glycation, oxidative stress, interleukin-1α (IL-1α), IL-6, C-reactive protein (CRP), gene expression of tumour necrosis factor-α (TNF-α) and transforming growth factor-β1 (TGF-β1) in relation to microalbuminuria and kidney functions in a model of alloxan-induced diabetic rats. We have observed that onset of microalbuminuria has preceded the gradual increase of blood sugar level in diabetic rats. In diabetic rats, gene expression of TNF-α and TGF-β1 recorded a gradual increase and marked increase was observed after one and two weeks of alloxan administration, in comparison with normal rats. PM induced significant decrease in kidney malondialdehyde content and the gene expression of TNF-α and TGF-β1, in addition to levels of serum glucose, fructosamine, urea, creatinine, IL-1α, IL-6, CRP and urine microalbumin. Histopathological examination of kidney tissues showed certain improvements as compared with diabetic control. In conclusion, our results may provide a supporting evidence for the therapeutic benefit of PM in DN.

10-Dehydrogingerdione raises HDL-cholesterol through a CETP inhibition and wards off oxidation and inflammation in dyslipidemic rabbits

OBJECTIVE To investigate the CETP suppression by 10-dehydrogingerdione, a compound in Zingiber officinale, and its effect on the progression of atherosclerosis in dyslipidemic rabbits and the underlying oxidative and inflammatory consequences. METHODS Twenty-four New Zealand male rabbits were fed either a normal diet or an atherogenic diet. The rabbits on the atherogenic diet received treatments of atorvastatin or 10-dehydrogingerdione and placebo concurrently (n = 6/group). Blood samples were collected after three and six weeks for biochemical analysis. RESULTS 10-Dehydrogingerdione-treated rabbits showed a significant improvement in serum lipids especially HDL-C in a time-dependant manner. This effect was correlated to its ability to lower CETP. Lp(a), ox-LDL, hsCRP, homocysteine and MMP9 decreased significantly in both 10-dehydrogingerdione- and atorvastatin-treated rabbits compared with placebo (p < 0.001). Lp(a) achieved normal values by both treatments, while homocysteine did not reach normal values by either treatments. Conversely, MMP9 returned below normal values by 10-dehydrogingerdione (p < 0.001), hsCRP and ox-LDL were slightly below normal values (hsCRP: p < 0.001; ox-LDL: p < 0.001 and p < 0.05 in 10-dehydrogingerdione and atorvastatin groups, respectively). The effect achieved by 10-dehydrogingerdione was similar to that of atorvastatin on hsCRP and Lp(a). However, 10-dehydrogingerdione exerted better effect than atorvastatin on homocysteine, MMP9 (p < 0.001) and ox-LDL (p < 0.05). CONCLUSIONS In a rabbit dyslipidemic model, 10-dehydrogingerdione lowers LDL-C and raises HDL-C by suppressing CETP; an effect that modulates inflammatory and oxidative risk factors of CVD. These findings suggested that the naturally occurring 10-dehydrogingerdione might be a potential CETP inhibitor for the treatment of atherosclerosis and residual risk in CVD.

The Antiapoptotic Effects of Sulphurous Mineral Water and Sodium Hydrosulphide on Diabetic Rat Testes

Background/Aims: It is well known that diabetes mellitus is associated with the impairment of testicular function. In the present study, we aimed to study the effects of sulphurous mineral water or sodium hydrosulphide (NaHS) on apoptotic testicular damage in rats with streptozotocin (STZ)-induced diabetes. Methods: Sulphurous mineral water (as drinking water) or NaHS (14 µmol/kg body weight/day, I.P.) was administered for 7 wks to rats with STZ-induced diabetes. Results: Hyperglycaemia, an overproduction of glycated haemoglobin (HbA1C) and a decline in serum insulin, C-peptide and insulin-like growth factor-I (IGF-I) were observed in diabetic rats. A decline in the serum testosterone level and an impairment of spermatogenesis, as indicated by a histopathological examination of diabetic rats, demonstrated significant testicular damage. Sulphurous mineral water and NaHS treatment may have improved the level of testicular GSH by blocking the overexpression of some apoptosis-related regulatory proteins such as Bax/Bcl-2, cytochrome c, caspase-9 and -3, and p53. This anti-apoptotic potential was associated with an increase in serum testosterone level and the amelioration of hyperglycaemia-related biochemical parameters. The histopathological examination was in harmony with the biochemical and molecular findings. Conclusion: Our study provides the first indication that sulphurous mineral water and NaHS may have a novel anti-apoptotic potential that could be a useful treatment in preventing diabetes-induced testicular dysfunction.

Atheroprotective potentials of curcuminoids against ginger extract in hypercholesterolaemic rabbits

The anti-atherogenic potentials of total ginger (Zingiber officinale) extract (TGE) or curcuminoids extracted from turmeric (Curcuma longa), members of family Zingiberaceae, were compared in hypercholesterolaemia. Rabbits were fed either normal or atherogenic diet. The rabbits on atherogenic diet received treatments with TGE or curcumenoids and placebo concurrently for 6 weeks (n = 6). The anti-atherogenic effects of curcuminoids and ginger are mediated via multiple mechanisms. This effect was correlated with their ability to lower cholesteryl ester transfer protein activity. Ginger extract exerted preferential effects on plasma lipids, reverse cholesterol transport, cholesterol synthesis and inflammatory status. Curcuminoids, however, showed superior antioxidant activity.