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Liver ischemia-reperfusion (IR) injury is inevitable in surgical procedures such as hepatic resection and liver transplantation. It represents a leading cause of liver graft dysfunction and primary nonfunction after transplantation. Phosphodiesterase (PDE) inhibitors are emerging as effective drugs able to reduce IR damage. The aim of this study was to investigate the effect of selective PDE-3 inhibitor olprinone (Olp) against liver IR injury. Male Wistar rats were subjected to 1 h of partial warm ischemia (70%) followed by 6 h of reperfusion. Before ischemia, rats were treated with saline (IR group), Olp (Olp group), or Olp with Akt inhibitor LY294002 (Olp plus LY group). After reperfusion, hepatic injury (transaminase activities), mitochondrial damage (glutamate dehydrogenase activity), oxidative stress (malondialdehyde and glutathione concentrations and catalase and superoxide dismutase activities), and protein kinase Akt activation were evaluated. Rat treatment with Olp reduced liver injury, prevented mitochondrial damage, decreased lipid peroxidation, and enhanced antioxidant enzymes. Also, Olp induced a significant activation in protein kinase Akt. Inhibition of Akt with LY294002 abolished all of the protective effects of Olp. In conclusion, Olp treatment may be an effective strategy in reducing liver IR injury through oxidative stress prevention and Akt activation.

The aim of the study was to compare the effect of sodium arsenate (AsV) on two different cell types: 158N murine oligodendrocytes and HepG2 human hepatoma cells. Exposure of 158N cells to AsV (0.1-400 µM; 48 h) induced a biphasic cytoxic effect defined as hormesis. Thus, low concentrations of AsV stimulate cell proliferation, as shown by phase-contrast microscopy, cell counting with trypan blue, and crystal violet assay, whereas high concentrations induce cell death associated with a loss of cell adhesion. These side effects were confirmed by staining with propidium iodide and cell cycle analysis, characterized by the presence of a subG1 peak, a criterion of apoptosis. The effects of AsV on mitochondrial function, as determined by the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay, the measurement of mitochondrial transmembrane potential with 3,3'-dihexyloxacarbocyanine iodide, and the rate of mitochondrial adenosine triphosphate confirm the impact of AsV on the mitochondria. In contrast to 158N cells, HepG2 cells were susceptible to all AsV concentrations as shown by microscopic observations, by counting with trypan blue. However, no alteration is noted in the cell membrane integrity, which indicated an apoptotic mode of cell death, and this side effect is confirmed by the cycle analysis, which revealed a subG1 peak. Of note, there was a loss of MTT, suggesting that AsV induces mitochondrial complex II dysfunction. Altogether, our data show that the cytotoxic characteristics of AsV depend on the cell type considered.

The treatment of microglial BV-2 cells with sodium arsenate (As(V): 0.1-400μmol/L - 48hr) induces a dose-dependent response. The neurotoxic effects of high concentrations of As(V) (100, 200 and 400μmol/L) are characterized by increased levels of mitochondrial complexes I, II, and IV followed by increased superoxide anion generation. Moreover, As(V) triggers an apoptotic mode of cell death, demonstrated by an apoptotic SubG1 peak, associated with an alteration of plasma membrane integrity. There is also a decrease in transmembrane mitochondrial potential and mitochondrial adenosine triphosphate ATP. It is therefore tempting to speculate that As(V) triggers mitochondrial dysfunction, which may lead to defective oxidative phosphorylation subsequently causing mitochondrial oxidative damage, which in turn induces an apoptotic mode of cell death., (Copyright © 2016. Published by Elsevier B.V.)

Exposure of human neuronal SK-N-BE cells to sodium arsenate (AsV 0.1-400 μM; 48 h) induced a biphasic toxic effect evoking hormesis. Indeed, at low concentrations, AsV stimulates cell proliferation visualized by phase contrast microscopy, whereas at high concentrations, an induction of cell death associated with a loss of cell adhesion was observed. These side effects were confirmed with crystal violet test, cell cycle analysis, evaluation of the percentage of Ki67 positive cells, and staining with propidium iodide. The impact of AsV on mitochondrial functions, which was determined by the MTT assay, the measurement of mitochondrial transmembrane potential with DiOC6(3), and the rate of mitochondrial ATP, also support an hormesis process. In addition, in the presence of high concentrations of AsV, a significant decrease of the protein expression of OXPHOS complexes of the respiratory chain was observed by western blot supporting that AsV-induced cell death is associated with mitochondrial alterations. Therefore, there are some evidences of hormesis on AsV-treated SK-N-BE cells, and at high concentrations, the mitochondria are a target of toxicity induced by AsV.

Six groups of rats (n = 10 per group) were exposed to 1 and 10 mg/l of sodium arsenate for 45 and 90 days. Kidneys from treated groups exposed to arsenic showed higher levels of trans isomers of oleic and linoleic acids as trans C181n-9, trans C18:1n-11, and trans C18:2n-6 isomers. However, a significant decrease in eicosenoic (C20:1n-9) and arachidonic (C20:4n-6) acids were observed in treated rats. Moreover, the "Δ5 desaturase index" and the saturated/polyunsaturated fatty acids ratio were increased. There was a significant increase in the level of malondialdehyde at 10 mg/l of treatment and in the amount of conjugated dienes after 90 days (p < 0.05). Significant kidney damage was observed at 10 mg/l by increase of plasma marker enzymes. Histological studies on the ultrastructure changes of kidney supported the toxic effect of arsenate exposure. Arsenate intoxication activates significantly the superoxide dismutase at 10 mg/l for 90 days, whereas the catalase activity was markedly inhibited in all treated groups (p < 0.05). In addition, glutathione peroxidase activity was significantly increased at 45 days and dramatically declined after 90 days at 10 mg/l (p < 0.05). A significant increase in the level of glutathione was marked for the groups treated for 45 and 90 days at 1 mg/l followed by a significant decrease for rats exposed to 10 mg/l for 90 days. An increase in the level of protein carbonyl was observed in all treated groups (p < 0.05). In conclusion, the present study provides evidence for a direct effect of arsenate on fatty acid (FA) metabolism which concerns the synthesis pathway of n-6 polyunsaturated fatty acids and leads to an increase in the trans FAs isomers. Therefore, FA-induced arsenate kidney damage could contribute to trigger kidney cancer.

The present study aimed to evaluate the effect of arsenic on liver fatty acids (FA) composition, hepatotoxicity and oxidative status markers in rats. Male rats were randomly devised to six groups (n=10 per group) and exposed to sodium arsenate at a dose of 1 and 10 mg/l for 45 and 90 days. Arsenate exposure is associated with significant changes in the FA composition in liver. A significant increase of saturated fatty acids (SFA) in all treated groups (p<0.01) and trans unsaturated fatty acids (trans UFA) in rats exposed both for short term for 10 mg/l (p<0.05) and long term for 1 and 10 mg/l (p<0.001) was observed. However, the cis UFA were significantly decreased in these groups (p<0.05). A markedly increase of indicator in cell membrane viscosity expressed as SFA/UFA was reported in the treated groups (p<0.001). A significant increase in the level of malondialdehyde by 38.3 % after 90 days of exposure at 10 mg/l was observed. Compared to control rats, significant liver damage was observed at 10 mg/l of arsenate by increasing plasma marker enzymes after 90 days. It is through the histological investigations in hepatic tissues of exposed rats that these damage effects of arsenate were confirmed. The antioxidant perturbations were observed to be more important at groups treated by the high dose (p<0.05). An increase in the level of protein carbonyls was observed in all treated groups (p<0.05). The present study provides evidence for a direct effect of arsenite on FA composition disturbance causing an increase of SFA and TFAs isomers, liver dysfunction and oxidative stress. Therefore, arsenate can lead to hepatic damage and propensity towards liver cancer.

Objective: We evaluated the metabolic and the nutritional aspects of 134 urolithiasic children, in order to outline the risk factors that contribute to idiopathic stone formation in children., Material and Methods: In this prospective study 134 children (56 females, 78 males) with renal calculi were evaluated. The age of the patients ranged 6 months to 16 years. A dietary survey was performed on every child. All patients were investigated with respect to stone localization, serum and urine risk factors. Statistical analysis of data was carried out using software SPSS 11.0 for Windows. Statistical significance was determined using chi-square test., Results: Hypercalciuria was the commonest risk factor detected in this group (28.3%). A decrease of water intake was noted in all age group specially in the rural area (549.6 vs 1150.6 ml/day), and an increase in animal protein intake in 17 cases (mean 1.9 g/kg). In addition, increased intake of starchy foods and food with high oxalate content (sorgum) was observed in our 10-16 years group (51%). Calcium oxalate monohydrate represents the principal component of idiopathic stone (58.2%), which is more frequent in children (68%) than infants (51.7%) (P < 0.02)., Conclusions: The high frequency of idiopathic urolithiasis highlights the influence of dietary habit in stone formers in our country. The increase in calcium oxalate stones in school-age children confirms the change in the etiology of urolithiasis according to age.

Objectives: To study the effect of a vitamin A supplemented diet on calcium-oxalate stone formation in rats and to test its expected action in the dissolution of renal calculi., Material and Methods: Twenty-four male Wistar rats were randomly divided into three groups of eight rats each. The first group (group A) received a normal diet for six weeks. The second group (group B) was fed a lithogenic diet by the addition of ethylene glycol 0.5% to drinking water for three weeks then a normal diet for three weeks. The third group (group C) received the same lithogenic diet for three weeks then a vitamin A supplemented diet 20 times the normal amount (5.1mg/100g of diet) at the three last weeks. One day before the end of treatment, each animal was placed for 24h in metabolic cage in order to collect urine samples and determine the urinary parameters., Results: The glomerular filtration rate and the urinary excretion of citric acid which fell in group B have been restored in group C., Conclusions: This study shows that a vitamin A supplemented diet at the rate of 20 times standard ration could improve the renal function by restoring the glomerular filtration rate and by increasing the urinary pH and excretion of citric acid., ((c) 2009 Elsevier GmbH. All rights reserved.)

The aim of this study was to examine the accumulation of cadmium (Cd) incorporated in radish bulb and its effects on testes function in male rats. Control animals were given diet containing ordinary radish bulb for 4, 8 and 12 weeks, while contaminated animals were given diet containing Cd-polluted radish bulb (1.1 microg Cd/g of diet) for the same periods as in controls. At each time point, rats were killed and plasma was collected, and the testes and epididymides were removed. The findings indicated that the ratio of testes weight to body weight of contaminated rats was identical to that of control rats. Cd concentration in the testes significantly and gradually increased from the 4th to the 12th week of treatment. After 12 weeks of treatment, plasma testosterone levels significantly increased, while epididymal sperm concentration significantly decreased in contaminated rats as compared to correspondent controls.

The aim of this study was to examine the accumulation of cadmium (Cd) incorporated in radish bulb and its effects on liver and kidney functions in male rats. Control animals were given diet containing ordinary radish bulb for 4, 8 and 12 weeks, while contaminated animals were given diet containing Cd-polluted radish bulb (1.1 microg Cd/g of diet) for the same periods as in controls. At each time point, rats were killed and plasma was collected, and the liver and the kidneys were removed. Results indicated that body weight gain of contaminated rats was identical to that of control rats. Cd concentration in the liver and the kidney increased significantly and gradually from the 4th to the 12th week of treatment. Plasma alanine aminotrasfase (ALT) and lactate dehydrogenase (LDH) activities increased significantly after 8 and 12 weeks of treatment, while plasma alkaline phosphatase (ALP) activity was increased significantly only after 12 weeks. Plasma urea concentration was comparable in the two groups during the experimental period, while plasma creatinine concentration increased significantly after 12 weeks of treatment.

Objective: To test whether increasing dietary calcium intake prevents calcium oxalate stone formation when the diet is oxalate-rich. Material and methods. Four groups, eight rats in each, were subjected to a lithogenic diet by the addition of 0.5% ethylene glycol to drinking water for 3 weeks. The first group, used as a control, simultaneously received a standard diet. The second group was supplemented with calcium at 500 mg/100 g of diet and the third group with oxalate at 3 g/100 g of diet. The diet given to the last group was supplemented with similar doses of calcium and oxalate. One day before the end of treatment, each animal was placed in a metabolic cage to collect 24-h urine samples and determine urinary parameters. The kidneys were removed to determine calcium oxalate deposits and for histological examination., Results: The number of calcium oxalate crystals in renal tissue was highest in the oxalate group and calcium oxalate deposits were also found to be elevated in this group. Hyperoxaluria and hypocitraturia, induced by a oxalate-rich diet, seemed to be the major causes contributing to aggravated renal stone formation. The protective effect of dietary calcium supplementation, which was clear in the calcium + oxalate group, was probably due to intestinal binding of oxalate by calcium, thereby reducing urinary oxalate excretion., Conclusion: Increased dietary calcium intake can prevent calcium oxalate stone formation only when the diet is oxalate-rich.

Cadmium (Cd) was given to Meriones shawi shawi dams in the diet (1 g CdCl2/1.5 kg of diet) from day 1 to day 21 of lactation. Pups were killed at 5, 10, 14 and 21 days of lactation. Thereafter, liver, kidney, femur and stomach content were removed and plasma was collected to element analyses. Cd in stomach content, kidney, liver and femur and calcium (Ca) in stomach content, femur and plasma were determined in pups by atomic absorption spectrophotometer. The results indicate that Cd was transferred to the suckling and it was detected in the liver, the kidney and the femur from the 5th, the 10th and the 14th days of age, respectively. Stomach content of Ca was increased significantly from the 10th day to the end of lactation, whereas Ca levels increase in plasma and femur only at day 10 of lactation., (Copyright (c) 2005 S. Karger AG, Basel.)

The purpose of our study is to compare the status of vitamin A and E enters a group of male patients aged 30-40 years and having idiopathic lithiasis in the other whose origin of the lithiasis is awarded to a hypercalciuria and/or hypercalciuria and/or hyperoxaluria. Reference values were established from a normal subjects aged 30-40 years and having no history of nephrolithiasis. Our results showed that the mean levels of vitamin A was significantly lower in idiopathic renal stone-formers than metabolic stone-formers (p < 0.001). Compared to control group, the status of vitamin A was found lower only in idiopathic renal stone patients (p < 0.05). On the contrary, the mean levels of vitamin E were found similar in the two patient groups, but significantly lower compared to control group. These results suggested that idiopathic renal stone genesis could be generated by vitamin A deficiency.

Seventy two male Wistar-strain rats were fed lithogenic diet with ethylene-glycol within three weeks. At the end of this treatment, six rats were killed in order to determine the oxalate and calcium concentrations in renal tissue. Remained rats was randomly divided in four series, each series consisting of three groups. In first series (T), the animals were treated with distilled water; in the second (D1Zn), the animals were treated intramuscularly with the zinc at the rate of 24 micrograms per 100 grams of body weight and per day; in the third (D2Zn), 240 micrograms of zinc were administrated to animals and in the last series (D2Cu), the animals were treated at the same dose as the previous series, but with the copper. The groups which making up each series were killed successively at the 5th, 10th and 15th day after ending treatment with ethyleneglycol in order to determine urinary pH, percentage of water in renal tissue, uremia and concentrations of oxalate and calcium in renal tissue. Then, the comparisons of means were carried out, at each time, between different treated groups and reference group which was treated with distilled water. Litholytic effect was found in all series, including that which had been treated with distilled water. However, compared to reference animals, no acceleration of litholytic process was induced by zinc or copper. The high doses used in these experimentations proved therefore that calcium oxalate calculi were insoluble by zinc and copper.

Oxalate lithiasis was induced in control rats and rats previously given a vitamin A supplement for one week at the dose for 200 UI/d/kg body weight. Oxalate and calcium deposits in renal tissue measured 24 hours after the induction of lithiasis were found to be significantly lower in the vitamin A supplemented rats (p < 0.001 and p < 0.01) respectively). Renal function in these animals was also improved as compared with controls (p < 0.05). However, when vitamin A supplements were given for the same period and at the same dose, but after the induction of oxalate lithiasis, no difference regarding oxalate and calcium deposits was found between the two groups of animals. The same applied to renal function, which showed no improvement in the supplemented animals as compared with controls. These results suggest that vitamin A supplements have an inhibitory effect on lithogenesis but probably no litholytic action as such. The effect of vitamin A is probably related to its action on tubular cellular repair or an inhibitory effect on necrosis of these cells.

The addition of sucrose to drinking water of rats at the rate of 2.5 or 5 grams per 100 ml, for one month, induced hypercalciuria which appeared to be dependent on the degree of supplementation. In spite of these disorders, calcium deposits were not observed in treated animals. This protection against renal calculi was probably due to high urinary excretions of magnesium, phosphorus, zinc and copper. These lithogenesis inhibitors varied, like oxaluria and calciuria, in parallel with dietary sucrose intake.

Because of the diversity and importance of dietary factors in the pathogenesis of renal stones, a nutritional survey must be carried out in order to determine the quantity of protein, calcium, oxalate, sodium, sugar, vitamin D, vitamin C, ingested and the fluid intake and the quality of the drinking water. Although defects are observed in all parameters, it is essential to reduce the intake of protein, calcium, oxalate, sodium, vitamin D, vitamin C as well as increase the sucrose intake and recommend dietary therapy based on mineral water rich in bicarbonate.

Intraperitoneal injection of sodium oxalate, at the dose of 8 mg/100 g of body weight, induced into rats oxalate and calcium deposits in renal tissue, compared to animals which received distilled water (respectively P less than 0.05; P less than 0.05). However, when a zinc solution was administered previously, at the dose of 24 micrograms/100 g of body weight, oxalate and calcium accumulation was found to be significantly lower than in the group treated exclusively with sodium oxalate. Similar results were found when the metal used was copper, but oxalate accumulation was found to be significantly higher in this group than in the group treated with zinc (P less than 0.01). Compared to reference animals, which received distilled water, oxalate accumulation was found to be significantly decreased in the groups treated with both zinc (P less than 0.001) and copper (P less than 0.01), whereas calcium accumulation was found to be similar. Microscopic examination showed calcium crystals only in the group treated with sodium oxalate, preferentially localized in the renal papilla. These results suggest that zinc and copper, when administered at the dose of 24 mu/100 g of body weight, completely protect against experimental lithiasis induced by oxalic acid. However, the inhibitory effect of zinc was more pronounced than that of copper, especially against oxalate accumulation.

Sodium oxalate injected into young rats, via the intraperitoneal route, at a dose of 8 mg per 100 g of body weight, induced death in 50 p. cent of animals, and induced calcium oxalate crystals in renal tissue. When a zinc solution was administered prior to sodium oxalate, at the dose of 12 micrograms/100 g of body weight, the mortality rate decreased, and at the same time oxalate and calcium deposits were significant reduced (respectively P less than 0.01; P less than 0.01). The same results were found when zinc was administered at 24 micrograms/100 g of body weight, however, oxalic accumulation was found to be significantly lower in this group than in the group treated at 12 micrograms. This protection against calcium oxalate deposits was complete in the animals treated with various doses of zinc, because compared to reference animals, which received distilled water, calcium accumulation in these groups was not different and oxalate accumulation was also found to be lower (respectively P less than 0.05; P less than 0.001). Microscopic examination showed calcium crystals only in the group treated with sodium oxalate, localized preferentially in the renal papilla. All these experiments conclude on the total inhibitory effect of zinc on experimental lithiasis induced by oxalic acid, even though it was administered at a dose of only 12 micrograms/100 g of body weight.

Administration of ascorbic acid, at 150 mg/100 ml of water intake, for one month, induced hyperoxaluria in the rats (P less than 0.001) and decreased citraturia (P less than 0.001) magnesuria (P less than 0.001) and pyrophosphaturia (P less than 0.01). The same disorders were observed when the dose administered was 300 mg/100 ml, excepted that oxaluria was considerably enhanced in this group. Despite these variations, renal deposits were not observed, even in the animals receiving 300 mg of ascorbate/100 ml of water intake. This protection was due to decreased calcium excretion (P less than 0.01 in two groups) and probably to acidification of the urine.

Administration of high doses of vitamin D3 (2,600 IU/100 ml of drinking water) to adult rats, for one month, significantly altered renal function (P less than 0.01) and enhanced renal accumulation of oxalate (71.44 x 18.82 micrograms/g of tissue in treated rats vs 38.87 +/- 11.96 micrograms/g in untreated rats; P less than 0.001), phosphate (1.388 +/- 188 micrograms/g in treated rats vs 870 +/- 171 micrograms/g in untreated rats; P less than 0.01) and calcium (477 +/- 107 micrograms/g in treated rats vs 326 +/- 104 micrograms/g in untreated rats; P less than 0.01). Urinary analyses of principal promotors and inhibitors of lithogenesis revealed high calcium excretion (1,576 +/- 0.419 mg/24 hr in treated rats vs 0.969 +/- 0.214 mg/24 hr in untreated rats; p less than 0.01) and decreased magnesium excretion (0.330 +/- 0.135 mg/24 hr in treated rats vs 0.910 +/- 0.168 mg/24 hr in untreated rats; p less than 0.001). Microscopic calcium deposits were found in the medulla, especially in renal papilla. These results suggested that vitamin D3, when administered at high doses for a long time, may induce nephrocalcinosis and alter renal function.