Sahar E. El-Swefy

Hyperhomocysteinaemia and cardiovascular risk in female ovariectomized rats: role of folic acid and hormone replacement therapy

Hyperhomocysteinaemia is an independent risk factor for arteriosclerosis, recurrent thromboembolic complications and osteoporosis. After menopause, a high level of total homocysteine seems to be secondary to the altered hormonal status. Hormone replacement therapy (HRT) limits the development of coronary artery disease through a variety of mechanisms. One such mechanism is through affecting homocysteine metabolism. Folate and vitamin B12 deficiencies are considered to be major risks for hyperhomocysteinaemia. This study, therefore, was undertaken to examine whether lowering homocysteine with HRT or folic acid in ovariectomized rats could attenuate cardiovascular complications. Sixty sexually mature female Wistar rats were ovariectomized. Three weeks later, they were treated with estradiol (15 μg kg−1 every two weeks, i.m.) or folic acid (90 μg daily, orally), either alone or in a combined form for four weeks. In addition, groups of ovariectomized rats (positive control) and healthy rats (negative control) were given cottonseed oil. Blood samples were then collected for serum and plasma separation. Serum total homocysteine, folate, estradiol, plasma nitric oxide (NO), lipid profile, and susceptibility of non‐high‐density‐lipoprotein cholesterol (non HDLC) contentto oxidation were determined. In ovariectomized rats, hyperhomocysteinaemia was established and associated with significant increments of both atherogenic indexes (total cholesterol/HDLC, low‐density‐lipoprotein cholesterol (LDLC)/HDLC) and susceptibility of their non HDLC to oxidation. However, plasma NO, serum folate, and estradiol levels significantly decreased. HRT and folic acid significantly reduced total homocysteine and susceptibility of non HDLC to oxidation and increased plasma NO content. Moreover, a significant negative correlation was found between total homocysteine versus folate and estradiol (r = − 0.5, P< 0.01; r = − 0.25, P< 0.05, respectively). Meanwhile, a positive correlation with the susceptibility of lipoprotein to oxidation was observed (r = 0.85, P< 0.001). In conclusion, a low folate level is found to be associated with elevated total homocysteine. Folic acid supplementation, either individually or in a combined form with HRT, has a beneficial effect in low estrogen status subsequent to ovariectomy.

Effect of erythropoietin therapy on the progression of cisplatin induced renal injury in rats

Cisplatin is one of the most important chemotherapeutic agents useful in the treatment of a variety of solid tumors; however, it has several side effects such as nephrotoxicity. In the present study, the effect of rhEPO on acute kidney injury induced by i.p. injection of rats with 9.0 mg/kg cisplatin was studied. It was observed that EPO treated group showed a significantly lower rate in the extent and severity of the histological signs of kidney injury than untreated one. This is attributed to (i) a decrease in the elevated oxidative and nitrosative stress markers, (ii) reduction of the expression of VEGF, HO-1 and iNOS as well as (iii) improvement of Bcl2 immunoreaction in most tubular cells. Thus, EPO may be one of the futures therapeutic possibilities to overcome the side effects of anti-cancer drugs induced acute renal injury through various mechanisms including down regulation of vascular endothelial growth factor (VEGF), hemeoxygenase-1 (HO-1) and inducible nitric oxide synthase (iNOS) expressions in addition to stimulation of tubular cell regeneration.

Dietary fatty acid unsaturation levels, lipoprotein oxidation and circulating chemokine in experimentally induced atherosclerotic rats

The dietary balance of long‐chain fatty acids may influence processes involving leukocyte endothelial interactions, such as atherogenesis and inflammation. The relationship between proatherogenic lipoproteins and chemotactic motility is still controversial. However, the interaction of the former can increase recruitment of monocytes to the vessel walls and accelerate the events of atherogenesis. The current study examined the effects of unsaturated fatty acid levels on the oxidative susceptibility of lipoprotein, chemokine expressions and their relationship to atherosclerotic lesion development in experimental rats. Male Wistar rats were fed an atherogenic diet for 4 months and the diet was then supplemented with 10% v/w of virgin olive oil (OO group), sunflower oil (SO group) or fish oil (FO group) for 4 and 8 weeks. Blood samples were collected at four time points: at baseline, after feeding with the atherogenic diet and during the dietary regimen (4 and 8 weeks). Plasma lipid profile and lipoprotein oxidative susceptibility (LOS), C‐reactive protein (CRP), monocyte chemoattractant protein (MCP‐1), and regulated upon activation normal T‐cell expressed and secreted (RANTES) were measured. The superoxide dismutase (SOD) and reduced glutathione (GSH) antioxidant activities were also studied in aortic segments. Histological assessment of the aortic segment was determined. Compared to baseline data, the high‐fat and cholesterol‐enriched diet increased atheroma formation, plasma LOS and inflammatory indexes (CRP, MCP‐1, RANTES). However, it dramatically reduced aortic SOD and GSH contents. Dietary treatment of atherosclerotic rats with OO greatly reduced LOS and remarkably increased aortic SOD and GSH contents as compared to the SO‐ and FO‐treated groups. The FO‐supplemented diet had a more pronounced lowering effect on MCP‐1 and RANTES compared to the OO and SO diets. In conclusion, this study demonstrated a strong relationship between LOS and circulating levels of chemokines. OO is a potent antioxidant and moderate anti‐inflammatory, which effectively reduced aortic atherosclerotic lesions more than the SO‐ or FO‐treated groups in male Wistar rats.

Biochemical effect of a ketogenic diet on the brains of obese adult rats

Excess weight, particularly abdominal obesity, can cause or exacerbate cardiovascular and metabolic disease. Obesity is also a proven risk factor for Alzheimers disease (AD). Various studies have demonstrated the beneficial effects of a ketogenic diet (KD) in weight reduction and in modifying the disease activity of neurodegenerative disorders, including AD. Therefore, in this study we examined the metabolic and neurodegenerative changes associated with obesity and the possible neuroprotective effects of a KD in obese adult rats. Compared with obese rats fed a control diet, obese rats fed a KD showed significant weight loss, improvement in lipid profiles and insulin resistance, and upregulation of adiponectin mRNA expression in adipose tissue. In addition, the KD triggered significant downregulation of brain amyloid protein precursor, apolipoprotein E and caspase-3 mRNA expression, and improvement of brain oxidative stress responses. These findings suggest that a KD has anti-obesity and neuroprotective effects.

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.

Inflammation, oxidative stress and apoptosis cascade implications in bisphenol A-induced liver fibrosis in male rats

Bisphenol A (BPA) is a key monomer in the production of plastics. It has been shown to be hepatotoxic. Inflammation and oxidative stress are closely linked with liver fibrosis, the major contributing factor to hepatic failure. Therefore, the aim of this study was to evaluate the impact of chronic exposure to BPA on the development of hepatic fibrosis in male rats and to determine the cross‐talk between the hepatic cytokine network, oxidative stress and apoptosis. For this purpose, 30 male Wistar albino rats were divided into three equal groups as follows: the first group was given no treatment (normal control group); the second group was given corn oil once daily by oral gavage for 8 weeks (vehicle control group); and the third group received BPA (50 mg/kg body weight/day, p.o.) for 8 weeks. BPA administration induced liver fibrosis as reflected in an increase in serum hepatic enzymes activities, hepatic hydroxyproline content and histopathological changes particularly increased collagen fibre deposition around the portal tract. In addition, there was inflammation (as reflected in increase in interleukin‐1beta ‘IL‐1β’, decrease in interleukin‐10 ‘IL‐10′ serum levels and increase in IL‐1β/IL‐10 ratio), oxidative stress (as reflected in increase in malondialdehyde (MDA) level, reduction in reduced glutathione (GSH) content and inhibition of catalase (CAT) activity) and apoptosis [as reflected in an increase in caspase‐3 level and a decrease in numbers of B‐cell lymphoma 2 (BCL2)‐immunopositive hepatocytes]. Interestingly, BPA had an upregulating effect on an extracellular matrix turnover gene [as reflected in matrix metalloproteinase‐9 (MMP‐9)] and a downregulating effect on its inhibitor gene [as reflected in tissue inhibitor of matrix metalloproteinase‐2 (TIMP‐2)] expression. Thus, the mechanism by which BPA induced liver fibrosis seems to be related to stimulation of the inflammatory response, along with oxidative stress, the apoptotic pathway and activation of extracellular matrix turnover.

Bone marrow-derived mesenchymal stem cells effectively regenerate fibrotic liver in bile duct ligation rat model

Mesenchymal stem cells (MSCs) have attracted lots of attention for the treatment of acute liver failure and end-stage liver diseases. This study aimed at investigating the fundamental mechanism by which bone marrow-derived MSCs (BM-MSCs) induce liver regeneration of fibrotic liver in rats. Rats underwent bile duct ligation (BDL) surgery and four weeks later they were treated with either BM-MSCs (3 × 106 cells /rat, once, tail vein injection) or silymarin (100 mg/kg, daily, orally) for four weeks. Liver function tests and hepatic oxidative stress were determined. Hepatic injury and fibrosis were assessed by H and E, Sirus red staining and immunohistochemical expression of α-smooth muscle actin (α-SMA). Hepatocyte growth factor (HGF) and the gene expression of cytokeratin-19 (CK-19) and matrix metalloproteinase-2 (MMP-2) in liver tissue were determined. BDL induced cholestatic liver injury characterized by elevated ALT and AST activities, bilirubin and decreased albumin. The architecture damage was staged as Metavir score: F3, A3. Fibrosis increased around proliferating bile duct as indicated by sirus red staining and α-SMA immunostaining. Fibrogenesis was favored over fibrolysis and confirmed by decreased HGF with increased expression of CK-19, but decreased MMP-2 expression. BM-MSCs treatment restored deteriorated liver functions and restored the histological changes, resolved fibrosis by improving liver regenerative capabilities (P < 0.001), increases in HGF and MMP-2 mRNA and downregulating CK-19 mRNA. Sliymarin, however, induced similar but less prominent effects compared to BM-MSCs. In conclusion, liver regenerative capabilities can be stimulated by BM-MSCs via augmentation of HGF that subsequently up-regulate MMP-2 mRNA while downregulating CK-19 mRNA.

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.

Vanillin as a new modulator candidate for renal injury induced by cisplatin in experimental rats

HighlightsCisplatin administration induced renal injury in experimental rats.The effect of vanillin was mediated through down regulation of oxidative stress.The protective effect of vanillin was mediated through down regulation of inflammation and fibrotic pathways. Abstract Cisplatin is commonly prescribed for the treatment of various solid tumors but its use is limited due to certain side effects and renal injury is a true example. Oxidative stress and inflammation may contribute to the cisplatin induced nephrotoxicity. Accordingly, we evaluated the effect of oral vanillin intake (100 mg/kg body weight) daily for 4 weeks to combat this hazard. The present results have demonstrated significant attenuation of oxidative stress and renal injury where reduced glutathione (GSH) showed significant increase along with malondialdehyde (MDA) decrease. Fibrotic markers like fibroblast growth factor‐23 (FGF‐23), transforming growth factor‐&bgr;1 (TGF‐&bgr;1), inflammatory mediators such as nuclear factor‐&kgr;B (NF‐&kgr;B) and tumor necrosis factor‐&agr; (TNF‐&agr;) showed also significant decrease in vanillin treated rats as compared with the control group. Renal function showed also significant improvement where urea and creatinine demonstrated significant decrease and the histopathological study presented a good support to the biochemical markers results. Our conclusion that vanillin is a potent antioxidant, anti‐inflammatory and anti‐fibrotic agent. Additionally, it is a good modulator candidate for the renal injury induced by cisplatin intake.

Obesity and neurodegeneration: effect of a Mediterranean dietary pattern

Abstract Obesity is a serious global health problem and is associated with a variety of chronic diseases. Increasing evidence suggests that obesity increases the risk of Alzheimers disease. Several studies have shown that a Mediterranean diet is effective in reducing weight and epidemiological data suggest that such a diet is associated with lower risk of neurodegenerative disorders, including Alzheimers disease. Therefore, we examined the relationship between obesity and neurodegeneration and the possible effects of Mediterranean diet on both in adult obese rats. Obese rats showed significant dyslipidaemia, insulin resistance, down-regulation of adiponectin mRNA expression in adipose tissue, up-regulation of brain amyloid precursor protein, apolipoprotein E and caspase-3 mRNA expression and a marked increase in brain oxidative stress. Treatment with Mediterranean diet induced significant weight loss and improvement in these various markers. The present study suggests that Mediterranean diet is a viable nutritional intervention in obesity and, more importantly, in the prevention and treatment of Alzheimers disease.