Protective mechanisms of coenzyme-Q10 may involve up-regulation of testicular P-glycoprotein in doxorubicin-induced toxicity

The anticancer drug; doxorubicin (DOX), causes testicular toxicity as an adverse effect. P-glycoprotein (P-gp) is a multidrug resistance efflux transporter expressed in blood-testis barrier, which extrudes DOX from the testis. We investigated whether DOX-induced gonadal injury could be prevented by the use of antioxidant; coenzyme-Q10 (CoQ10). The involvement of P-gp expression, as a possible protective mechanism, was also investigated. CoQ10 was administered orally for 8 days, and DOX toxicity was induced via a single i.p. dose of 15 mg/kg at day 4. Concomitant administration of CoQ10 with DOX significantly restored testicular oxidative stress parameters and the distorted histopathological picture, reduced the up-regulation of caspase 3 caused by DOX, and increased P-gp expression. We show for the first time that CoQ10 up-regulates P-gp as a novel mechanism for gonadal protection. In conclusion, CoQ10 protects against DOX-induced testicular toxicity in rats via ameliorating oxidative stress, reducing apoptosis and up-regulating testicular P-gp.     

In vitro metabolism of cis- and trans-permethrin by rat liver microsomes,and its effect on estrogenic and anti-androgenic activities

Permethrin is a widely applied broad-spectrum pyrethroid insecticide that consists of a mixture of cis- and trans-isomers. We examined the changes of estrogenic and anti-androgenic activities resulting from metabolism of the isomers. Both cis- and trans-permethrin were hydrolyzed to 3-phenoxybenzyl alcohol (PBAlc) by rat liver microsomes, but the extent of hydrolysis of trans-permethrin was much greater than that of the cis-isomer. In the presence of NADPH, PBAlc was further transformed to 4′-hydroxylated PBAlc (4′-OH PBAlc), 3-phenoxybenzaldehyde (PBAld) and 3-phenoxybenzoic acid (PBAcid). cis-Permethrin, but not trans-permethrin, also afforded its 4′-hydroxylated derivative (4′-OH cis-permethrin). trans-Permethrin was an anti-androgen, but also showed weak estrogenic activity, while cis-permethrin was a weak estrogen and a weak anti-androgen. After incubation with rat liver microsomes in the presence of NADPH, cis-permethrin but not trans-permethrin was metabolically activated for estrogenic activity. On the other hand, estrogenic activity of trans-permethrin was not changed, but its anti-androgenic activity was enhanced after incubation. 4′-OH PBAlc and PBAlc showed estrogenic activity, while PBAld and PBAlc showed anti-androgenic activity. PBAcid showed neither activity. 4′-OH cis-permethrin showed both estrogenic and anti-androgenic activities. Overall, our results indicate that permethrin is metabolically activated for estrogenic and anti-androgen activities, and the microsomal transformation of permethrin to 4′-OH cis-permethrin, 4′-OH PBAlc and PBAlc contributes to the both metabolic activations.     

Age-related differences in kidney injury biomarkers induced by cisplatin

Acute kidney injury (AKI) occurs in a half of cisplatin (CDDP)-treated patients. Traditional biomarkers including blood urea nitrogen (BUN) and serum creatinine (SCr) are still used for detection of CDDP-induced AKI, but these biomarkers are not specific or sensitive. The aim of this study was to identify the specific and sensitive biomarkers against CDDP-induced renal injury between young (3-week-old) and old (20-week-old) rats. All animals were intraperitoneally injected once with CDDP (6 mg/kg). After 3 days, all animals were sacrificed and serum, urine, and kidney tissues were collected. Urinary and serum biomarkers as well as histological changes were measured. CDDP-induced proximal tubular damage was apparent from histopathological examination, being more severe in 3-week-old rats accompanied by increased number of TUNEL-positive apoptotic cells. This was associated with elevated urinary kidney injury molecule-1 (KIM-1), glutathione-S-transferase alpha (GST-α), vascular endothelial growth factor (VEGF), and tissue inhibitor of metalloproteinases-1 (TIMP-1). In contrast, the levels of neutrophil gelatinase-associated lipocalin (NGAL) and osteopontin were significantly increased in 20-week-old rats after CDDP treatment. These results indicate that the use of age-specific urinary biomarkers is necessary to diagnosis of CDDP-induced AKI. Especially, urinary KIM-1, GST-α, TIMP-1, and VEGF levels may help in the early diagnosis of young patients with CDDP-induced AKI.     

Studies on the effect of sodium arsenate on the enzymes of carbohydrate metabolism,brush border membrane,and oxidative stress in the rat kidney

Arsenic is an environmental pollutant and its contamination in drinking water poses serious world wide environmental health threats. It produces multiple adverse effects in various tissues, including the kidney. However, biochemical mechanism and renal response to its toxic insult are not completely elucidated. We hypothesized that sodium arsenate (ARS) induces oxidative stress and alters the structure and metabolic functions of kidney. Male Wistar rats were administered ARS (10 mg/kg body weight/day), intraperitoneally daily for 10 days. ARS administration increased blood urea nitrogen, serum creatinine, cholesterol, glucose, and phospholipids but decreased inorganic phosphate, indicating kidney toxicity. The activity of brush border membrane (BBM) enzymes significantly lowered in both cortex and medulla. Activity of hexokinase, lactate dehydrogenase, glucose-6-phosphate dehydrogenases, and NADP-malic enzyme significantly increased whereas malate dehydrogenase, glucose-6-phosphatase, and fructose 1,6 bis phosphatase decreased by ARS exposure. The activity of superoxide dismutase, GSH-peroxidase, and catalase were selectively altered in renal tissues along with an increase in lipid peroxidation. The present results indicated that ARS induced oxidative stress caused severe renal damage that resulted in altered levels of carbohydrate metabolism and BBM enzymes.     

Downregulation of cytochrome P450scc as an initial adverse effect of adult exposure to diethylstilbestrol on testicular steroidogenesis

Reproductive toxicities and endocrine disruptions caused by chemicals in adult males are still poorly understood. It is our objectives to understand further details of the initial adverse effects leading severe testicular toxicities of a pharmaceutical endocrine disruptor, diethylstilbestrol (DES). Downregulations of both testicular regulatory proteins, such as the steroidogenic acute regulatory protein (StAR) and the peripheral benzodiazepine receptor (PBR), which play important roles in the transport of cholesterol into the mitochondria, and cytochrome P450 mediating the cholesterol side chain cleavage reaction (P450scc), were observed in the rat orally administered DES (340 μg/kg/2 days) for 2 weeks. We found that after only 1 week treatment with DES, the blood and testicular testosterone (TS) levels were drastically decreased without abnormalities of the StAR and PBR; however, the protein and mRNA levels of P450scc were diminished. Decrease in the conversion rate of cholesterol to pregnenolone was delayed in the in vitro assay using the testicular mitochondrial fraction from the rat treated with DES for 1 week. When the precursors in TS biosynthesis containing the testis were identified and determined by liquid chromatography‐mass spectrometry analysis, decreased levels of all precursors except cholesterol were observed. In conclusion, suppressed cytochrome P450scc expression in adult male rat was identified as an initial target of DES in testicular steroidogenesis disorder leading reproductive toxicities. © 2013 Wiley Periodicals, Inc. Environ Toxicol 29: 1452–1459, 2014.     

Mechanisms Underlying the Effect of Acupuncture on Cognitive Improvement: A Systematic Review of Animal Studies

Acupuncture has been reported to be beneficial in treating cognitive impairment in various pathological conditions. This review describes the effort to understand the signaling pathways that underlie the acupunctural therapeutic effect on cognitive function. We searched the literature in 12 electronic databases from their inception to November 2013, with full text available and language limited to English. Twenty-three studies were identified under the selection criteria. All recruited animal studies demonstrate a significant positive effect of acupuncture on cognitive impairment. Findings suggest acupuncture may improve cognitive function through modulation of signaling pathways involved in neuronal survival and function, specifically, through promoting cholinergic neural transmission, facilitating dopaminergic synaptic transmission, enhancing neurotrophin signaling, suppressing oxidative stress, attenuating apoptosis, regulating glycometabolic enzymes and reducing microglial activation. However, the quality of reviewed studies has room for improvement. Further high-quality animal studies with randomization, blinding and estimation of sample size are needed to strengthen the recognition of group differences.     

Predicción de resultados de cistoscopias en la práctica

ObjectiveOur objective was to elaborate a predictive model of bladder cancer, in an unselected clinical population submitted to cystoscopy.Materials and methodsWe recruited consecutive patients that underwent cystoscopy due to suspicion of bladder cancer or surveillance of a previously diagnosed bladder cancer. Urine cytology and a BTA-stat® (BTA) test were carried out for all patients. To avoid an assessment bias, the BTA-tests, cytologies and cystoscopies were conducted in a blinded fashion. We used logistic regression to predict cystoscopy results from cytology, BTA-test and clinical variables.ResultsFrom August 2011 to July 2012, we recruited 244 patients and 237 were valid for analysis. Newly diagnosed and surveillance cases were 13% and 87% respectively. Cytology and BTA-test sensitivities were 57.9% (CI 95: 42.2-72.1) and 63.2% (CI 95: 47.3-76.6) with specificities of 84.4% (CI 95: 78.7-88.8) and 82.9% (CI 95: 77.1-87.5). The predictive model included the BTA-test, cytology, time since previous tumour, and treatment with mitomicin or BGC during the last three months. The model predictive accuracy (AUC) was .85 (.78-.92), and dropped to 0.79 when excluding the BTA-test (P = .026). For the surveillance of bladder cancer, a 10% threshold on the model predicted probabilities resulted in an overall negative predictive value of 95.7%, and 95.0% in low grade tumours.ConclusionIn a cost containment environment, our prediction model could be used to space out cystoscopies in patients with previous, low grade tumours, resulting in a more efficient use of resources in the healthcare system.