Effects of Single and Repeated Oral Doses of Ochratoxin A on the Lipid Peroxidation and Antioxidant Defense Systems in Mouse Kidneys

Ochratoxin-A (OTA) is a carcinogenic and nephrotoxic mycotoxin, which may cause health problems in humans and animals, and it is a contaminant in foods and feeds. The purpose of the present study is to evaluate the effect of oral OTA exposure on the antioxidant defense and lipid peroxidation in the kidney. In vivo administration of OTA in CD1, male mice (1 or 10 mg/kg body weight in a single oral dose for 24 h and repeated daily oral dose for 72 h or repeated daily oral dose of 0.5 mg/kg bodyweight for 21 days) resulted in a significant elevation of OTA levels in blood plasma. Some histopathological alterations, transcriptional changes in the glutathione system, and oxidative stress response-related genes were also found. In the renal cortex, the activity of the glutathione-system-related enzymes and certain metabolites of the lipid peroxidation (conjugated dienes, trienes, and thiobarbituric reactive substances) also changed.

Prevention of Lung Complications following Paraquat Poisoning by Silymarin, N-acetyl Cysteine and Hydrocortisone: An Experimental Study

Background: Paraquat poisoning results in multi-organ failure, primarily pulmonary fibrosis, acute renal failure, and hepatic impairment. The present study was designed to evaluate three treatment regimens, such as N-Acetyl cysteine (NAC), silymarin and hydrocortisone in the prevention of lung fibrosis after ingestion of toxic doses of paraquat in rats. Methods: Male Sprague-Dawley rats (N=20) were randomly divided into four groups of five each. The drugs and paraquat were given to the rats orally. All rat groups received one oral dose of paraquat (10 mg/kg) once daily for 1 week. The first group received a daily oral dose of silymarin (600 mg/kg) for 2 weeks. The second group received a daily oral dose of NAC (500 mg/kg) for 2 weeks. The third group was given daily oral doses of NAC (500 mg/kg) and hydrocortisone (50 mg/kg) for 2 weeks. The fourth group (controls) received no drugs other than paraquat. The experiment continued for 4 weeks. After the experiment, autopsy was performed on all rats and the lungs were examined histopathologically. Results: The results of histopathology examinations for peribronchial inflammation in the groups were shown that NAC plus hydrocortisone and silymarin had notable effects in the prevention of lung inflammation. Septal widening in the lungs was also observed in group three less than that in the other groups. Conclusion: Based on the results, silymarin, NAC and hydrocortisone may be used as a palliative treatment in paraquat poisoning specifically aimed at preventing the acute and chronic lung injuries as the worst complication of the poisoning.

Mouse model of metformin-induced diarrhea

ObjectiveMetformin, an oral medication used for type 2 diabetes mellitus, is the most commonly prescribed drug with less economic burden of patients. Although metformin’s efficacy and safety have long been recognized, approximately 5% of the patients treated with this drug develop severe diarrhea as an adverse effect and have to abandon treatment. Because there is no animal model to study metformin-induced diarrhea, it is hard to develop methods to maintain quality of life of patients prescribed with metformin.Research design and methodsUsing mouse models, we tried to develop an evaluation system for metformin-induced diarrhea to improve diarrheal symptoms in patients with diabetes. Healthy (C57BL/6J) and diabetic obese (db/db) mice were subjected to a stepwise dose escalation of metformin (250 mg/kg/day (125 mg/kg twice daily oral dose)—1000 mg/kg/day (500 mg/kg twice daily oral dose)), and fecal moisture contents and their score were monitored. To evaluate anti-diarrheal medications, wood creosote (a traditional medicine) was tested. Several groups of enterobacteria in fresh feces were examined by using PCR.Results1000 mg/kg/day (four times maximal effective dose) of metformin significantly increased fecal moisture content. Although no symptoms of diarrhea were observed in healthy C57BL/6J mice, the same dose of metformin induced severe diarrhea in diabetic obese db/db mice. A reduction in PCR signals for the Firmicutes group was associated with metformin-induced diarrhea. Wood creosote reduced diarrhea (high water-content) without affecting metformin’s efficacy or enterobacterial flora levels.ConclusionsWe have created the first animal model of metformin-induced diarrhea using db/db mice, which will provide better quality of life for patients suffering from diarrhea caused by metformin.

The Hepatoprotective Effect of Olive Leaf Extract on Diabetic Pregnant Mice and Their Fetuses

Gestational diabetes mellitus (GDM) defined as is a disease with hyperglycemia, insulin resistance and fetal abnormality development. This study was designed to evaluate the hypoglycemic effect and hepatoprotective properties of olive leaves extract.The experimental mice divided into, the control group GI (not diabetic group), and the diabetic pregnant mice groups were divided into: the diabetic pregnant group (GII) single intraperitoneal injected by streptozotocine (STZ, 240mg/Kg b.wt.). The pregnant mice were given a daily oral dose of olive leaf extract (OLE) only (100 mg/kg) from day 1 to 18 of gestation group (GIII). The diabetic pregnant mice were given daily oral dose of olive leaf extract from day 1 to day 18 of gestation, group (GIV). The STZ-induced diabetic group(GII) exhibited a significant (p<0.05) hyperglycemia, accompanied with a significant increase in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT), enzyme activitieswhen compared with control group. This result is confirmed with extreme histopathological changes in liver tissues and decreased in glutathione peroxidase (GPx) expression. A significant improvement in glucose level, serum AST and ALT enzyme activities showed in (GIV). Also, OLE succeeded to minimize the severe changes in liver tissues of diabetic pregnant mice and their fetuses. Furthermore, level of (GPx) was returned to near normal level. The findings suggest that OLE have a hepatoprotective effect on pregnant diabetic mice and their fetus.

The Hepatoprotective Effect of Olive Leaf Extract on Diabetic Pregnant Mice and Their Fetuses

Gestational diabetes mellitus (GDM) is a disease with hyperglycemia, insulin resistance and fetal abnormality development. This study was designed to evaluate the hypoglycemic effect and hepatoprotective properties of olive leaves extract.The experimental mice divided into not diabetic group, the control group (GI), and the diabetic pregnant mice were divided into: the diabetic pregnant group (GII) single intraperitoneal injected by streptozotocine (STZ, 240mg/Kg b.wt.). The pregnant mice were given a daily oral dose of olive leaf extract (OLE) only (100 mg/kg) from day 1 to 18 of gestation group (GIII). The diabetic pregnant mice were given daily oral dose of olive leaf extract from day 1 to day 18 of gestation, group (GIV). The STZ-induced diabetic group(GII) exhibited a significant (p<0.05) hyperglycemia, accompanied with a significant increase in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT), enzyme activitieswhen compared with control group. This result is confirmed with extreme histopathological changes in liver tissues and decreased in glutathione peroxidase (GPx) expression. A significant improvement in glucose level, serum AST and ALT enzyme activities showed in (GIV). Also, OLE succeeded to minimize the severe changes in liver tissues of diabetic pregnant mice and their fetuses. Furthermore, level of (GPx) was returned to near normal level. The findings suggest that OLE have a hepatoprotective effect on pregnant diabetic mice and their fetus.

Aflatoxins and Saccharomyces cerevisiae: yeast modulates the intestinal effect of aflatoxins, while aflatoxin B1 influences yeast ultrastructure

The gastrointestinal tract (GIT) is the main site where absorption of food components takes place and the first system coming into contact with mycotoxins of dietary origin. The aim of this work was to study the effect of probiotic Saccharomyces cerevisiae RC016 on intestinal villi of rats exposed to aflatoxins for 60 days. Moreover, the effect of in vitro aflatoxin B1 (AFB1) exposure on yeast cell ultrastructure was evaluated. Six treatments were applied (n=6) to inbred male Wistar rats: (1) uncontaminated feed control (F); (2) yeast control; (3) F + 40 μg/kg AFB1 + 20 μg/kg aflatoxin G1 (AFG1); (4) F + 100 μg/kg AFB1 + 50 μg/kg AFG1; (5) F + 40 μg/kg AFB1 + 20 μg/kg AFG1 + daily oral dose 108 viable S. cerevisiae cells; and (6) F + 100 μg/kg AFB1 + 50 μg/kg AFG1 + daily oral dose 108 viable S. cerevisiae cells. Morphometric measurements (villus length and width, crypt depth, quantification of goblet cells) were assessed using image analysis. S. cerevisiae RC016 cells were exposed to 20 μg/ml of AFB1 in intestinal solutions or in phosphate buffered saline and cells processed for transmission electron microscopy and high resolution light microscopy studies. Dietary exposure to the yeast did not induce significant differences in villus width but increased villus length and crypt depth. Aflatoxin-contaminated diets induced an increase in villus length, width and crypt depth and a significant decrease in the number of goblet cells which were improved by the addition of S. cerevisiae RC016. A significant increase in the yeast cell diameter was observed when RC016 was exposed to aflatoxins, suggesting this as an advantage since a larger cell would be able to adsorb mycotoxins more efficiently. The ability of this strain to act as probiotic and aflatoxin binder makes it a candidate for the formulation of new additives to improve animal performance.

Diagnosis and therapy of Capillaria plica infection: report and literature review

Worldwide, data on Capillaria (Pearsonema) plica infections of the urinary tract in domestic carnivores are limited. Nevertheless, cystitis with hematuria, dysuria or pollakiuria may suggest a C. plica infection. A three-year old dog from Poland showing pollakiuria and hematuria was presented. At urine analysis, C. plica eggs were found in the urine sediment. The dog was unsuccessfully treated with a daily oral dose of fenbendazole 50 mg/kg BW for 5 days, while a single subcutaneous administration of ivermectin 0.2 mg/kg BW once effectively eliminated C. plica infection.

Kibdelomycin Is a Potent and Selective Agent against Toxigenic Clostridium difficile

ABSTRACTClostridium difficileis the causative agent ofC. difficile-associated diarrhea (CDAD), with increased risk in elderly populations. Kibdelomycin, a novel natural-product inhibitor of type II topoisomerase enzymes, was evaluated for activity againstC. difficileand gastrointestinal anaerobic organisms. ToxigenicC. difficileisolates (n= 168) from U.S. hospitals and anaerobic Gram-positive and Gram-negative organisms (n= 598) from Chicago-area hospitals were tested. Kibdelomycin showed potent activity against toxigenicC. difficile(MIC90= 0.25 μg/ml) and most Gram-positive aerobic organisms but had little activity againstBacteroidesspecies (MIC50> 32 μg/ml;n= 270). Potent anti-C. difficileactivity was also observed in the hamster model ofC. difficilecolitis. Dosing at 1.6 mg/kg (twice-daily oral dose) resulted in protection from a lethal infection and a 2-log reduction inC. difficilececal counts. A 6.25-mg/kg twice-daily oral dose completely eliminated detectableC. difficilecounts in cecal contents. A single 6.25-mg/kg oral dose showed that cecal contents were exposed to the drug at >2 μM (eightfold higher than the MIC), with no significant plasma exposure. These findings support further exploration of kibdelomycin for development of an anti-C. difficileagent.

Safety and Pharmacokinetics of the Anti-Orthopoxvirus Compound ST-246 following a Single Daily Oral Dose for 14 Days in Human Volunteers

ABSTRACTST-246 is being evaluated as a treatment for pathogenic orthopoxvirus infections in humans. To this end, a phase 2, double-blind, randomized, placebo-controlled, multicenter trial was conducted to assess the safety, tolerability, and pharmacokinetics (PK) of ST-246 when administered as a single daily oral dose (400 mg or 600 mg) for 14 days in fed adult volunteers. ST-246 was safe and well tolerated, with no deaths or serious adverse events reported during the study. There was a low incidence of treatment-emergent adverse events (TEAEs), the most common of which were mild nausea and headache. There were no clinically significant results from laboratory assessments, vital sign measurements, physical examinations, or electrocardiograms. The PK and dose proportionality of ST-246 were determined. The PK analysis showed that steady state was achieved by day 5 for the ST-246 400-mg treatment group and by day 6 for the 600-mg group. The dose proportionality analysis showed that the 400- and 600-mg ratio of dose-normalized peak drug concentration in plasma (Cmax) and relative exposure for each dosing interval (AUCτ) ranged from 80% to 85%. However, the 90% confidence intervals did not include 1.0, so dose proportionality could not be concluded. Overall, ST-246 was shown to be safe, and the PK was predictable. These results support further testing of ST-246 in a multicenter pivotal clinical safety study for licensure application.