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Functional and morphological alterations were generated by p.o. (per os) administration of a single oral dose of carbon tetrachloride (CCl4; 0.125 mL/kg b.w., equivalent to 293 mg/kg) to adult male Wistar rats. CCl4 significantly increased (p < 0.05) the serum activities of alanine aminotransferase (ALT; 7478 ± 1044%) and aspartate aminotransferase (AST; 6964 ± 833%), compared to control rats; CCl4 also significantly decreased serum concentration of albumin (23 ± 5.5%) and increased the concentration of malondialhdeyde (MDA) in liver (300 ± 33%). Furthermore, CCl 4 down-regulated the mRNA steady-state level of tumor necrosis factor a(TNF-a). CCl4 produced necrosis in the central lobe area, extended to the periphery, nuclear alterations (pycnosis, karyolysis and karyorrhexis), and cytoplasmic acidophilia. The pretreatment with 4 mg/kg (p.o.) of Ginkgo biloba extract (GbE), for 5 days, prevented most of the damage caused by CCl4: significantly decreased the serum activities of ALT and AST (54 and 65%, respectively), compared to CCl4-treated rats; GbE partially prevented the increase of liver MDA (55 ± 14%) and the decrease of albumin concentration to 12 ± 0.2%. This pretreatment prevented the down-regulation of TNF-a and up-regulated the interleukine 6 (IL-6) mRNA steady-state level. Moreover, the GbE reduced the amount of necrotic areas in the central lobe area, compared to CCl4-treated rats. [ABSTRACT FROM PUBLISHER]

Over-the-counter (OTC) analgesics are among the most widely prescribed and purchased drugs around the world. Most analgesics, including non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen, are metabolized in the liver. The hepatocytes are responsible for drug metabolism and detoxification. Cytochrome P450 enzymes are phase I enzymes expressed mainly in hepatocytes and they account for ≈75% of the metabolism of clinically used drugs and other xenobiotics. These metabolic reactions eliminate potentially toxic compounds but, paradoxically, also result in the generation of toxic or carcinogenic metabolites. Cumulative or overdoses of OTC analgesic drugs can induce acute liver failure (ALF) either directly or indirectly after their biotransformation. ALF is the result of massive death of hepatocytes induced by oxidative stress. There is an increased interest in the use of natural dietary products as nutritional supplements and/or medications to prevent or cure many diseases. The therapeutic activity of natural products may be associated with their antioxidant capacity, although additional mechanisms may also play a role (e.g., anti-inflammatory actions). Dietary antioxidants such as flavonoids, betalains and carotenoids play a preventive role against OTC analgesics-induced ALF. In this review, we will summarize the pathobiology of OTC analgesic-induced ALF and the use of natural pigments in its prevention and therapy., Competing Interests: The authors declare no conflict of interest.

Little information is apparently available regarding the nephrotoxic effects induced by pesticides. The aim of this study was to examine the influence of low doses of methyl parathion (MP) on the structure and function of the kidney of male Wistar rats. A corn oil (vehicle) was administered to control rats, whereas treated rats received MP at 0.56 mg/kg orally (1/25 of LD 50 ), every third day, for 8 weeks. At the end of each week following MP exposure, creatinine and glucose levels were measured in plasma, while glucose, inorganic phosphate, total proteins, albumin, and activity of γ-glutamyltranspeptidase (GGT) were determined in urine. Kidney histological study was also performed. Compared with control rats, MP significantly increased plasma glucose and creatinine levels accompanied by decreased urinary flow rate and elevated urinary excretion rates of glucose, phosphate, and albumin. Further, the activity of GGT in urine was increased significantly. The proximal cells exhibited cytoplasmic vacuolization, positive periodic acid Schiff inclusions, and brush border edge loss after 2 or 4 weeks following MP treatment. Finally, renal cortex samples were obtained at 2, 4, 6, and 8 weeks of MP treatment, and the concentrations of reduced glutathione (GSH) and glutathione peroxidase (GPx) activity were measured. The mRNA expression levels of BAX and tumor necrosis factor-α (TNF-α) were also determined (RT-PCR). MP significantly decreased renal GSH levels, increased GPx activity, as well as downregulated the mRNA expression of TNF-α and BAX. Densitometry analysis showed a significant reduction in TNF-α and BAX mRNA expression levels at 2 and 4 weeks following MP treatment. Low doses of MP produced structural and functional damage to the proximal tubules of male rat kidney.

Acetaminophen (APAP)-induced acute liver failure (ALF) is a serious health problem in developed countries. N-acetyl-L-cysteine (NAC), the current therapy for APAP-induced ALF, is not always effective, and liver transplantation is often needed. Opuntia spp. fruits are an important source of nutrients and contain high levels of bioactive compounds, including antioxidants. The aim of this study was to evaluate the hepatoprotective effect of Opuntia robusta and Opuntia streptacantha extracts against APAP-induced ALF. In addition, we analyzed the antioxidant activities of these extracts. Fruit extracts (800mg/kg/day, orally) were given prophylactically to male Wistar rats before intoxication with APAP (500 mg/kg, intraperitoneally). Rat hepatocyte cultures were exposed to 20mmol/LAPAP, and necrosis was assessed by LDH leakage. Opuntia robusta had significantly higher levels of antioxidants than Opuntia streptacantha. Both extracts significantly attenuated APAP-induced injury markers AST, ALT and ALP and improved liver histology. The Opuntia extracts reversed APAP-induced depletion of liver GSH and glycogen stores. In cultured hepatocytes, Opuntia extracts significantly reduced leakage of LDH and cell necrosis, both prophylactically and therapeutically. Both extracts appeared to be superior to NAC when used therapeutically. We conclude that Opuntia extracts are hepatoprotective and can be used as a nutraceutical to prevent ALF., Competing Interests: The authors declare no conflict of interest.

Objectives: We determined the seroprevalence and correlates of Toxoplasma gondii infection in pregnant women in Aguascalientes City, Mexico., Design: A cross-sectional survey., Setting: Pregnant women were enrolled in the central Mexican city of Aguascalientes., Participants: We studied 338 pregnant women who attended prenatal care in 3 public health centres., Primary and Secondary Outcome Measures: Women were examined for IgG/IgM antibodies to T. gondii by using commercially available enzyme immunoassays, and an avidity test. Multiple analyses were used to determine the association of T. gondii seropositivity with the characteristics of the pregnant women., Results: Of the 338 pregnant women studied, 21 (6.2%) had IgG antibodies to T. gondii, and 1 (4.8%) of them was also positive for IgM antibodies to T. gondii. Avidity of IgG antibodies to T. gondii was high in the IgM-positive sample. Logistic regression analysis of sociodemographic, behavioural and housing variables showed that T. gondii seropositivity was associated with white ethnicity (OR=149.4; 95% CI 10.8 to 2054.1; p<0.01), not washing hands before eating (OR=6.41; 95% CI 1.73 to 23.6; p=0.005) and use of latrine (OR=37.6; 95% CI 4.63 to 306.31; p=0.001)., Conclusions: Results demonstrate that pregnant women in Aguascalientes City have a low seroprevalence of T. gondii infection. However, this low prevalence indicates that most pregnant women are at risk for a primary infection. Factors associated with T. gondii exposure found in this study, including food hygiene, may be useful to determine preventive measures against T. gondii infection and its sequelae., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

The Ginkgo biloba extract (GbE) is a commercial product used as a nutraceutic herbal remedy in Europe and US. It contains 27% of the polyphenols isorhamnetin, kaempferol, and quercetin, as antioxidants. We used male adult Wistar rats (200-300 g), divided into four groups: control group (treated with 5.0 mg/kg of sodium chloride, intravenous), titanium dioxide nanoparticles (TiO2-NPs) group (5.0 mg/kg, intravenous), GbE group (10 mg/kg, intraperitoneal), and GbE + TiO2-NPs group (treated 24 h before with 10 mg/kg of GbE, intraperitoneal), followed, 24 h later, by 5.0 mg/kg of TiO2-NPs intravenously. The statistical analysis was performed using Student's t-test for grouped data with ANOVA posttest. The GbE protected renal cells against the effects of TiO2-NPs because it reversed the increased activity of γ-glutamyltranspeptidase and the enzymatic activity of dipeptidylaminopeptidase IV at all times tested (0-5, 5-24, 24-48, and 48-72 h). Also it reversed the glucosuria, hypernatriuria, and urine osmolarity at three times tested (5-24, 24-48, and 48-72). Thus, we conclude that GbE has a beneficial activity in the cytoplasmic membranes of brush border cells on the renal tubules, against the adverse effects that can be produced by some xenobiotics in this case the TiO2-NPs, in experimental rats.

TiO2 nanoparticles used as vectors for the delivery of drugs have shown greater effectiveness. However, TiO2 nanoparticles can cause oxidative stress in liver and kidney, so we analyzed if a previous or simultaneous quercetin treatment could counteract this in rats. Five groups of male Wistar rats (200-250 g) were included: (1) healthy controls, (2) TiO2 group, (3) quercetin group, (4) preventive group: quercetin for 5 days prior to exposure of TiO2, and (5) therapeutic group: TiO2 (5 mg/kg, i.v.) plus quercetin single dose for 5 days (5 mg/kg/day, i.p.). Hepatic and renal function tests were made. Five animals from each group were sacrificed (0, 14 and 28 days), and liver and kidney tissue were obtained. Malondialdehyde (MDA), reduced/oxidized glutathione, and activity of glutathione peroxidase/reductase were measured, as well as the level of gene expression by q-PCR. There were no significant changes in serum ALT and AST activities. More damage was observed at 14 versus 28 days, because TiO2 was excreted in urine. Quercetin indeed showed a renal protective effect by increasing glutathione reductase and peroxidase levels and reducing MDA levels. On the other hand, TiO2 liver damage was less pronounced with quercetin as therapeutic treatment. TiO2 induces significantly the glutathione reductase expression and it can be down-regulated by quercetin. Biochemical tests in serum and urine showed a better effect of quercetin administered in the therapeutic group. Care should be taken with the dose and time of administration of quercetin, because this antioxidant could also have a pro-oxidant effect.

It is well known that exposure to chromium (Cr) can lead to nephrotoxicity. Quercetin is a flavonoid of interest because of its proposed health-promoting effects. The aim of this work was to elucidate the role of quercetin against the nephrotoxicity caused by Cr in rats. Quercetin may have positive effects in combating, or helping to prevent, nephrotoxicity. It was observed that a single dose of potassium dichromate resulted in both an increase of systemic peroxidation of lipids and a decrease of the renal clearance of para-aminohippuric acid and inulin. Our results show that treatment with quercetin protected and prevented against these damaging effects.

It has been reported that potassium dichromate-induced nephrotoxicity is evidenced by diminution in creatinine clearance, increase in urinary protein, and structural damage to the proximal tubules. Damage to tissue often leads to the release of enzymes from the injured cells into the extracellular fluids. The aim of this study was to establish whether potassium dichromate induces changes in the urinary-specific activities of gamma-glutamyl transpeptidase and alanine aminopeptidase enzymes. Our results show that the administration of a single intraperitoneal dose of potassium dichromate decreased the activity of such enzymes in urine.

Relationship between cirrhosis and renal dysfunction is not yet fully understood. A model of cirrhosis with acute hepatic and renal damage (RF), produced by CCl4 in rats, with hemodynamic and renal functional alterations, similar to those observed in decompensated cirrhosis (DC) in man, was used to study chemical nephrotoxicity in animals. We performed in male Wistar rats hepatic and renal functional and hemodynamic studies in control, cirrhotic and decompensated cirrhotic (DC) groups. Cirrhosis was induced with carbon tetrachloride by chronic administration. Association between liver and renal functional alterations was detected in rats with decompensated cirrhosis, showing fall in mean arterial pressure and reduction of glomerular filtration rate and filtration fraction. Renal hemodynamics did not change in cirrhotic rats, similarly to what occurs in compensated cirrhotic patients. However, DC rats exhibited increased sodium, glucose and phosphate urinary excretions and decreased ATP in renal cortex. DC animals had severe hypoglycemia. There was an extensive liver fibrosis. Glomeruli had hypercellularity and tubules showed extensive vacuolization in cirrhotic and DC rats. The present study suggests that in this model, damage typical of acute tubular necrosis ensues in cirrhotic rats. We describe functional and morphological damage in liver and kidney in a model of cirrhosis that might predispose to the development of acute renal failure when an individual with hepatic damage is exposed in acute way to chemical toxicants.

The kidney's responsiveness to male sexual hormones has been often neglected. Renal secretion of organic anions is higher in male than in female individuals; as a consequence, most of the xenobiotics that are excreted from the organism through this pathway are eliminated more rapidly by males than by female animals. To gain further insight into this issue, we studied in vitro and in vivo characteristics of the transport of p-aminohippurate (PAH), a suitable marker for this system, in male and female rats, under different hormonal conditions. Kinetics of PAH showed a shorter elimination half-time in male than in female rats (t(1/2el): male = 16.2 +/- 2.1 min, female = 25.7 +/- 4.5 min, P < 0.05). Castration of male rats increased t(1/2el) to a value similar to that of female rats (t(1/2el): orchiectomized rat = 28.1 +/- 7.1 min). Testosterone treatment of female rats increased the elimination rate to a value similar to that of male rats. In vitro PAH uptake by renal cortical slices from intact male rats was higher than that by slices from orchiectomized rats. Kinetic analyses of PAH uptake suggest that the difference was caused by a lower number of transporting molecules in orchiectomized than in intact animals, whereas the transporting capacity for each carrier was similar in male and in orchiectomized rats. Our results suggest that testosterone increases the number of functional carriers for PAH in the kidney.

1. Acute effects of Karwinskia humboldtiana (Kh) were studied in some renal functions and structural patterns of renal tissue. 2. Haemodynamic changes were observed with decrements of the glomerular filtration rate, renal plasma flow and filtration fraction during acute intoxication. 3. A marked increment in the fractional excretion of sodium was observed in the rats treated with tullidora fruits (Kh). 4. Cloudy swelling and hydropic degeneration was seen 72 hr after intoxication, mainly in the proximal convoluted tubules.

The biotransformation of glycerol trinitrate (GTN), isosorbide dinitrate (ISD), pentaerythritol tetranitrate (PETN), erythritol tetranitrate (ETN), and mannitol hexanitrate (MHN) by extracts from human liver, small intestine mucosa, kidney, and blood serum was investigated. The glutathione-dependent organic nitrate ester reductase activity of the intestinal mucosa was 21, 4, 4, and 2 times higher than the liver activity for ISD, PETN, GTN, and ETN, respectively. The liver enzymatic activity for MHN was 35% higher than the intestinal activity and 56% higher than kidney enzyme activity. The order of increasing enzymatic rates was: ISD = PETN less than GTN less than ETN less than MHN in the intestinal mucosa; ISD less than PETN less than GTN less than ETN less than MHN in the liver; and ISD less than PETN = GTN less than ETN less than MHN in the kidney. Human serum also metabolized these organic nitrates at lower rates than the studied organs. Thus, the serum specific activities were 1/5 for MHN, 1/30 for ETN, 1/40 for GTN, 1/44 for ISD, and 1/2000 for PETN of the activity present in kidney. On the other hand, the activity of human albumin was lower than that of blood serum. The serum and albumin activities were not modified by reduced glutathione or sulfhydryl inhibitors. These results suggest that small intestine may play an important role in the biotransformation of these drugs at their absorption site, after oral administration. They also demonstrate the possible participation of various human tissues in the overall metabolism of organic nitrate esters.

The effects of ethyl parathion on the activities of various renal enzymes were studied in the offspring from dams treated with this insecticide during pregnancy. The enzymes tested were the (Na+-K+)- and the Mg2+-dependent ATPases, the glutathione S-transferases and carboxylesterases. The postnatal effects of parathion on kidney ATPases from undernourished rats were also assessed. The organophosphate was administered per os to pregnant rats at a dose of 1 mg kg-1 body weight per day throughout gestation, and suspended after delivery. The offspring were divided in groups of normally-fed and undernourished rats. In the undernourished group, food restriction produced a decrease of 43% in body weight as compared to the normally-fed group. Offspring were sacrificed 6 weeks after birth and the enzymatic activities were determined in kidney homogenates. We found a decrease in the enzymatic activity of total ATPases, at the expense of the Mg2+-dependent ATPase. However, the activities of the (Na+-K+)-dependent ATPase, the glutathione S-transferases and the carboxylesterases did not show significant changes. On the other hand, undernutrition did not potentiate the effects of parathion on the ATPases. Thus, this organophosphate administered during pregnancy produced a selective inhibition on the renal Mg2+-dependent ATPase from offspring, which was not potentiated by our undernutritional model.