Adverse Effects In Rats Research Articles

Prevention of Heat Stress Adverse Effects in Rats by Bacillus subtilis Strain.

This study was designed to evaluate the protective effect of the Bacillus subtilis strain against complications related to heat stress. Thirty-two Sprague-Dawley rats were used in this study. Animals were orally treated twice a day for two days with B. subtilis BSB3 strain or PBS. The next day after the last treatment, each group was divided and two experimental groups (one treated with PBS and one treated with B. subtilis) were placed at 45 (o)C for 25 min. Two control groups stayed for 25 min at room temperature. All rats were euthanized and different parameters were analyzed in all groups. Adverse effects of heat stress are registered by the decrease of villi height and total mucosal thickness in the intestinal epithelium; translocation of bacteria from the lumen; increased vesiculation of erythrocytes and elevation of the lipopolysaccharides (LPS) level in the blood. The protective efficacy of treatment is evaluated by prevention of these side effects. The protocol was set up for the oral treatment of rats with bacteria for prevention of heat stress complications, but this protocol can be modified and used for other routes of administration and for analysis of different compounds.

A safety assessment of Coriolus versicolor biomass as a food supplement

BackgroundCoriolus versicolor (CV) is a common mushroom with antitumor, anti-inflammatory, antioxidant, antiviral, antibacterial, and immunomodulatory properties. The existence of these properties has been extensively proven mainly using CV extract; research on the biomass form is scarce. ObjectiveThe aim of this study was to investigate the safety of the CV biomass form, as it is commonly used as a food supplement.DesignCV biomass powder was dissolved in distilled water and administered daily (2.5, 5.0, and 7.5 g/kg live weight) in single doses by gavage to both female and male Charles River albino rats.ResultsNo adverse or lethal effects were observed as a consequence of the daily administration of CV biomass. In addition, compared with the control group, no abnormal findings were observed at necropsy and histopathological examination.ConclusionsA safe profile of CV biomass for human consumption can be inferred from the absence of any remarkable adverse effects in rats.

Effect of Chokeberry Juice on N-Nitrosodiethylamine-Induced Rat Liver Carcinogenesis.

Because humans commonly consume chokeberry, especially as a nutritional supplement, it must be checked to determine whether its excessive ingestion can cause adverse effects, in particular, in the case of simultaneous exposure to some xenobiotics. From this point of view, we examined the impact of long-term cotreatment of rats with chokeberry juice and hepatic carcinogen N-nitrosodiethylamine (NDEA) on oxidative damages and neoplastic lesions in the liver of rats. Daily exposure to chokeberry juice in a concentration of 10 g/kg feed via diet for 13 wk led to an intensified hepatotoxic effect of NDEA (0.01% in drinking water for 13 wk), as evidenced by changes in histopathological architecture of liver tissue, increased lipid peroxidation, protein carbonyl formation, and DNA degradation. Moreover, we noticed an increase in relative liver weight and a decrease in body weight in this group in comparison to NDEA-alone treated animals. Chokeberry juice applied alone did not cause any adverse effects in rats. On the basis of these findings, it can be concluded that high doses and longterm administration of chokeberry juice may enhance tumor-promoting action of some chemical carcinogens.

Herb–drug interactions between Scutellariae Radix and mefenamic acid: Simultaneous investigation of pharmacokinetics, anti-inflammatory effect and gastric damage in rats

Ethnopharmacological relevanceScutellariae Radix (SR), the dried root of Scutellariae baicalensis Georgi, has a lot in common with non-steroidal anti-inflammatory drugs (NSAIDs). Their similarities in therapeutic action (anti-inflammation) and metabolic pathways (phase II metabolisms) may lead to co-administration by patients with the potential of pharmacokinetic and/or pharmacodynamic interactions. The current study aims to investigate the potential interactions between SR and an NSAID, mefenamic acid (MEF), on the overall pharmacokinetic dispositions, anti-inflammatory effects and adverse effects in rats. Materials and methodsThe current study simultaneously monitored the pharmacokinetic and pharmacodynamic interactions in a single animal. Four groups of Sprague-Dawley rats (n=7 each) received oral doses of a standardized SR extract (300mg/kg, twice daily), MEF (40mg/kg, daily), combination of SR extract and MEF, and vehicle control, respectively, for 5 days. On Day 5, blood samples were collected after first dose over 24h for the determination of (1) plasma concentrations of SR bioactive components, MEF and its metabolites by LC-MS/MS, and (2) prostaglandin E2 (PGE2) production and cyclooxygenase-2 (COX-2) gene expression by ex vivo analyses using LPS-stimulated RAW264.7 macrophage cells, ELISA and real time-PCR. After the rats were sacrificed, stomachs were isolated to assess their gross mucosal damage. Statistical comparisons were conducted using ANOVA and t-test. ResultsMinimal pharmacokinetic interaction between SR extract and MEF was observed. Co-administration of SR extract and MEF did not significantly alter the plasma concentration–time profile or the pharmacokinetic parameters such as Cmax, AUC0→24, Tmax or clearance. Pharmacodynamic interaction via the COX-2 pathway was observed. The PGE2 level in LPS-stimulated RAW264.7 cells treated with plasma collected from control group over the 24h sampling (AUC0→24[PGE2]) was 191981±8789pg/mlhr, which was significantly reduced to 174,780±6531 and 46,225±1915pg/mlhr by plasma collected from rats administered with SR extract and MEF, respectively. Co-administration of SR extract and MEF further potentiated the PGE2 inhibition, with an AUC0→24[PGE2] of 37013±2354pg/mlhr (p<0.05, compared to SR or MEF group). By analyzing the COX-2 gene expression, SR extract significantly prolonged the COX-2 inhibitory effect of MEF over the 24h (p<0.05). Furthermore, the MEF-induced stomach ulcer after the 5-day treatment, as evidenced by the increased gross ulcer index and sum of lesion length (p<0.05, compared to control), could be alleviated by co-administration with SR extract (p<0.05). ConclusionsCo-administration of SR extract and MEF potentiated the anti-inflammatory effects, alleviated the MEF-induced stomach adverse effect while having minimal pharmacokinetic interactions. Our findings provide insight for combination therapy of SR extract and MEF against inflammatory diseases.

Repeated Dose 90-Day Feeding Study of Whole Fruits of Genetically Modified Papaya Resistant to Papaya Ringspot Virus in Rats.

Genetically modified (GM) papaya plants resistant to infection by Papaya ringspot virus (PRSV) have been successfully generated by cloning the coat protein (CP) gene of PRSV to increase fruit production. In this study, the GM papaya line 823-2210 was used to conduct a 90-day feeding toxicity study and compared to its parent plant of non-GM papaya, Tainung-2 (TN-2) based on the experimental guidance reported by the European Food Safety Authority.1 Ten male and 10 female Sprague-Dawley albino rats were gavaged at low (1 g/kg bw) and high (2 g/kg bw) doses of non-GM and GM lyophilized papaya fruits for 90 days. Hematology, coagulation, biochemistry, urinalysis, and pathology were examined in all animals. Although some differences were found in feed consumption, hematology, and serum chemistry examinations between non-GM and GM papaya, the results were within historical control values and not considered biologically significant in rats. In addition, there were no treatment-related gross or microscopic lesions in male or female rats attributable to the non-GM or GM papaya fruit. This 90-day feeding study of GM papaya fruit did not reveal adverse effects in rats and indicates that GM papaya fruits may be substantially equivalent to their non-GM parent plants.

Histopathological alterations kidney in adult male rats that prenatally exposed to diclofenac sodium: A histopathological study

In this study, we investigated the morphometric and histological alterations of the kidney in adult male rats that they were exposed to diclofenac sodium (DS) during pregnancy. For this purpose, pregnant rats were divided into two groups: the control and drug-treated groups. DS (Voltaren 75 mg/3 ml, Novartis, Turkey) was intraperitoneally injected to rats of the treated group beginning from the 5 th day after mating through the 15 th day of pregnancy. No injection was given to the rats in the control group. After spontaneous delivery, male offspring were obtained. Twelve weeks after from birth, kidney samples were removed from all animals. Following dissection and routine histological preparation, histopathological study was carried out. Our results indicate that DS application leads to pathological alterations in the kidney. Light microscopic investigation showed a dilatation in blood vessels and Bowman’s space, degeneration in nephrons, including glomerulosclerosis and tubular defects, and an increase in the connective tissue in the kidneys of the DS treated group. We suggested that diclofenac sodium usage may lead to renal deformities as a result of histopathological changes such as dilatation, tubular defects, inflammation and connective tissue enlargement of the kidney. Finally, in light of our findings, we may suggest that DS may lead to adverse effects in rats that are prenatally subjected to this drug.

Effects ofSaccharomyces boulardiion antibiotic induced orocecal transit in rats

Clarithromycin is an antibiotic widely used for Helicobacter pylori (H. pylori) eradication and together with amoxicillin and proton pump inhibitors they constitute the first line triple treatment regimen against H. pylori. Diarrhoea is one of the major drawbacks during H. pylori eradication and is majorly attributed to clarithromycin, while Saccharomyces boulardii is a probiotic and is shown to be effective in the treatment of antibiotic associated diarrhoea. We aimed to evaluate the effect of clarithromycin on orocecal transit in rats and to identify whether the supplementation with S. boulardii has a role on orocecal transit index. Adult rats of both sexes were divided into two groups to determine immediate or chronic effects of S. boulardii and clarithromycin on orocecal transit. The first group was given single dose of the test drug, while the second group received the test drugs for one week through orogastric intubation. Both groups were randomly distributed into four subgroups; the placebo group (group A), the S. boulardii group (group B), the clarithromycin group (group C), and the co-administration that is clarithromycin plus S. boulardii group (group D). Rats were given 20 mg kg−1 clarithromycin and 500 mg kg−1S. boulardii. We did not find any difference among the subgroups in group 1, where only single dose of the test drugs was administered. In chronic administration group, that is group 2, significant differences among the subgroups were observed (P=0.004). Post-hoc comparisons of orocecal transit index between group “2A and 2C” and “2C and 2D” were significantly different (P=0.013 and P=0.005, respectively). Our results show that long term clarithromycin administration leads to rapid orocecal transit index and S. boulardii supplementation to clarithromycin can abolish this adverse effect in rats. Those findings suggest the beneficial use of S. boulardii in H. pylori eradication regimens.

Oral administration of Bacillus subtilis strain BSB3 can prevent heat stress-related adverse effects in rats.

To determine the efficacy of Bacillus subtilis strain in prevention of heat stress-related complications in rats. Male Sprague-Dawley rats weighing 250-300 g were treated by oral gavage with B. subtilis BSB3 strain or PBS twice a day for 2 days. Half of the rats of each group were exposed to heat stress (45°C, relative humidity 55% for 25 min), while the remaining rats were placed at identical conditions but at 25°C. Bacterial translocation, histological changes in the intestine, cytokines profile, serum lipopolysaccharide level (LPS), as well as vesiculation of erythrocytes were analysed and compared between groups. Adverse effects of heat stress (morphological changes in intestine, bacterial translocation, elevated levels of LPS and IL-10, increased vesiculation of erythrocytes) were observed only in rats not protected with B. subtilis strain and exposed to heat. All registered parameters in rats pretreated with bacilli and exposed to heat were similar to control groups. Bacillus subtilis BS3B strain was effective in the prevention of complications related to heat stress in rats. This work will contribute towards better understanding of probiotics' mechanisms of action and will bring new approaches to characterize and use of beneficial bacteria.

Safety of Malaysian marine endophytic fungal extract S2 from a brown seaweed Turbinaria conoides

Objective: To evaluate the in vivo acute toxicity and antioxidant activity of the marine endophytic fungus extract S2 isolated from Turbinaria conoides. Methods: Two doses (100 mg/kg and 400 mg/kg) of the S2 extract were administered to rats orally for acute toxicity and antioxidant test. The body weight, relative weight of six organs, haematological, biochemical and antioxidant properties were investigated on Day 14. Results: A single oral dose treatment did not cause any mortality or observable adverse effects in rats. No significant variations in the body and organ weights between the control and the treated groups were observed. Heamatological analysis and clinical blood chemistry also did not reveal any toxic effects of the extract. The total white blood cell count and haemoglobin levels were increased. The levels of total serum cholesterol in males treated with 100 and 400 mg/kg were significantly (P<0.05) decreased (1.28 and 1.34 mmol/L respectively) compared to control (1.55 mmol/L) rats. Pathologically, neither gross abnormalities nor histopathological changes were observed. This study showed strong evidence of the non-toxic effects of S2 extract. Furthermore the extract exhibited significant (P<0.05) antioxidant activity through increased levels of superoxide dismutase and glutathione peroxidase enzymes in serum, liver and kidney. Conclusions: The research findings from the present study showed the potential of marine natural products particularly in Malaysia as a source of bioactive compounds. Marine endophytic fungi as a potential source of anticancer drugs with great potential as they are potent yet safe, thus deserving further extensive investigation.

Effect of resveratrol on hematological and biochemical alterations in rats exposed to fluoride.

We investigated the protective effects of resveratrol on hematological and biochemical changes induced by fluoride in rats. A total of 28 rats were divided into 4 groups: control, resveratrol, fluoride, and fluoride/resveratrol (n = 7 each), for a total of 21 days of treatment. Blood samples were taken and hematological and biochemical parameters were measured. Compared to the control group, the fluoride-treated group showed significant differences in several hematological parameters, including decreases in WBC, RBC, and PLT counts and neutrophil ratio. The group that received resveratrol alone showed a decrease in WBC count compared to the control group. Furthermore, in comparison to the control group, the fluoride group showed significantly increased ALT enzyme activity and decreased inorganic phosphorus level. The hematological and biochemical parameters in the fluoride + resveratrol treated group were similar to control group. In the fluoride + resveratrol group, resveratrol restored the changes observed following fluoride treatment, including decreased counts of WBC, RBC, and PLT, decreased neutrophil ratio and inorganic phosphorus levels, and elevated ALT enzyme activity. The present study showed that fluoride caused adverse effects in rats and that resveratrol reduced hematological and biochemical alterations produced by fluoride exposure.

The urinary ratio of 3-hydroxykynurenine/3-hydroxyanthranilic acid is an index to predicting the adverse effects of D-tryptophan in rats.

The adverse effects of D-tryptophan and the possibility of it being a surrogate index for predicting adverse effects in rats were investigated. Male rats were fed one of several test diets (20% casein diets with 0% (control), 0.1%, 0.2%, 0.3%, 0.4%, and 0.5% D-tryptophan) for 21 d, and 24-h urine samples on the final day of the experiment were collected. Analyses of food intake and body-weight changes revealed adverse effects to be observed in the group fed the 0.3% D-tryptophan diet. We propose urinary levels of 3-hydroxykynurenine/3-hydroxyanthranilic acid to be surrogate indicators for predicting the adverse effects of D-tryptophan from the break point of body-weight gains and urinary levels of D-tryptophan metabolites. The reaction 3-hydroxykynurenine→3-hydroxyanthranilic acid is catalyzed by the pyridoxal phosphate-dependent enzyme kynureninase. Increasing urinary 3-hydrokykynurenine indicates kynureninase deficiency. Intake of D-tryptophan in rats fed the 0.3% D-tryptophan diet was 0.21 g/kg body weight and feeding of the 0.3% D-tryptophan diet did not elicit adverse effects. Thus, the safe level of D-tryptophan was less than 0.2% in the diet, 0.15 g/kg body weight, in rats.

Diverse effects of parenteral arginine on systemic and local oxidant–antioxidant homeostasis and nitrosative stress in rats with subacute peritonitis

BackgroundThe beneficial effects of arginine on oxidative stress have been previously reported; however, excess production of nitric oxide, an arginine metabolite, may cause hemodynamic instability and inflammatory response. Previous studies have demonstrated that parenteral arginine levels at 2%–4% of total calories may alleviate inflammation and enhance immunity, whereas greater than 6% of total calories may have adverse effects in rats with subacute peritonitis. Herein, we investigated the effects of parenteral arginine dose on lipid peroxidation (thiobarbituric acid reactive substances, TBARS) and antioxidant enzyme activities in the plasma and organs. Materials and methodsMale Wistar rats with cecal puncture–induced subacute peritonitis were infused with parenteral nutrition solutions containing 1.61% (CP group), 2.85% (LA group), 4.08% (MA group), and 6.54% (HA group) of total calories as arginine for 7 d. Healthy, orally fed rats (NC group) were used as references. ResultsSubacute peritonitis significantly elevated the levels of nitrate, nitrite and TBARS in the plasma and decreased glutathione peroxidase activity in the kidneys. These changes were significantly reversed in the MA and HA groups. The MA and HA groups had significantly increased nitrotyrosine levels in the plasma. The LA, MA, and HA groups had significantly increased glutathione peroxidase activity in the plasma, cytochrome P450 levels in the liver, and nitrotyrosine levels in the heart and had significantly decreased TBARS levels in the kidneys compared with the CP group. ConclusionsOur results suggest that parenteral arginine at a dose less than 4% of total calories may attenuate lipid peroxidation and increase antioxidant enzyme activities without leading to nitrosative stress in subacute peritonitis.

Protective effect of Tamarindus indica fruit pulp extract on collagen content and oxidative stress induced by sodium fluoride in the liver and kidney of rats

Fluorosis is a serious public health problem in many parts of the world. The generation of reactive oxygen species and lipid peroxidation has been considered to play an important role in the pathogenesis of chronic fluoride toxicity. The present study was undertaken to evaluate the protective effect of Tamarindus indica fruit pulp extract on the collagen content and oxidative stress in liver and kidney of fluoride-exposed rats. The first group served as control. The second group received 200 mg L−1 of sodium fluoride through drinking water. The third and fourth groups received T. indica fruit pulp extract (200 mg kg−1 body weight) alone and along with fluorinated drinking water respectively, daily by gavage for a period of 90 days. At the end of the experiment, blood samples were collected from all groups, and liver and kidney samples were taken concurrently. Levels of malondialdehyde and glutathione and the activities of superoxide dismutase and catalase were evaluated in the liver and kidney of experimental rats. Furthermore, level of hydroxyproline and histological examination of liver and kidney along with serum biochemical parameters were evaluated. In conclusion, fluoride was determined to cause adverse effects in rats, and the supplementation of tamarind to these animals alleviated the adverse effects of fluoride.

Sub-acute toxicity profile of a modified resveratrol supplement

Longevinex, a nutraceutical formulation containing Resveratrol as the main component along with other polyphenolics exhibits diverse health benefits but systemic safety studies are lacking. Hence, to test the safety of Longevinex use for therapeutic purposes, 50 Sprague Dawley rats were randomly divided into five groups (n=10; 5M, 5F) wherein group I as vehicle treated control, group II and group III received 50 mg and 100 mg of plain Resveratrol respectively and group IV and group V received 50 mg and 100 mg of Longevinex respectively for a period of 28 days. All toxicological parameters were analyzed as per OECD-407 guidelines. Results showed treatment with Resveratrol and Longevinex did not result in any mortality of rats neither did they exhibit any clinical signs of toxicity. Hematological and biochemical analysis of serum enzymes and metabolites were not significantly altered between Longevinex and control rats. Likewise, histopathological analysis for various organs did not reveal significant changes in the vital organs of the treated rats. The study revealed that there were no significant treatment related adverse effects in rats exposed to Longevinex for 28 days and considered safe at the given dose where compared to plain Resveratrol.

Stereological and histopathological evaluation of ovary and uterine horns of female rats prenatally exposed to diclofenac sodium

In this study, we investigated the morphometric and histological alterations of the ovary and uterine horns in 4-week-old rats that were prenatally exposed to diclofenac sodium (DS). For this purpose, pregnant rats were divided into two groups: the control and drug-treated groups. Beginning from the 5th day after mating through the 15th day of pregnancy, DS (1 mg/kg daily) was intraperitoneally injected in the treated group. No injection was given to the rats in the control group. After spontaneous delivery, male offspring were obtained. At the end of the 4th week, ovary and uterine horn samples were removed. Following dissection and routine histological preparation, histopathological and stereological investigations were carried out. Our results indicate that DS application leads to a decrease in the mean volume fraction of the uterine horn. Moreover, there was an increased volume fraction in some structures of the ovary; like the cortex, medulla and zona granulosa. There was no difference found between the two groups in terms of the mean volume of the antrum and the Graafian follicle fraction. Finally, in light of our findings, we may suggest that DS may lead to adverse effects in rats that are prenatally subjected to this drug.

Evaluation of the novel USPIO GEH121333 for MR imaging of cancer immune responses

Tumor-associated macrophages (TAM) maintain a chronic inflammation in cancers, which is associated with tumor aggressiveness and poor prognosis. The purpose of this study was to: (1) evaluate the pharmacokinetics and tolerability of the novel ultrasmall superparamagnetic iron oxide nanoparticle (USPIO) compound GEH121333; (2) assess whether GEH121333 can serve as a MR imaging biomarker for TAM; and (3) compare tumor MR enhancement profiles between GEH121333 and ferumoxytol. Blood half-lives of GEH121333 and ferumoxytol were measured by relaxometry (n = 4 each). Tolerance was assessed in healthy rats injected with high dose GEH121333, vehicle or saline (n = 4 each). Animals were monitored for 7 days regarding body weight, complete blood counts and serum chemistry, followed by histological evaluation of visceral organs. MR imaging was performed on mice harboring MMTV-PyMT-derived breast adenocarcinomas using a 7 T scanner before and up to 72 h post-injection (p.i.) of GEH121333 (n = 10) or ferumoxytol (n = 9). Tumor R1, R2* relaxation rates were compared between different experimental groups and time points, using a linear mixed effects model with a random effect for each animal. MR data were correlated with histopathology. GEH121333 showed a longer circulation half-life than ferumoxytol. Intravenous GEH121333 did not produce significant adverse effects in rats. All tumors demonstrated significant enhancement on T1, T2 and T2*-weighted images at 1, 24, 48 and 72 h p.i. GEH121333 generated stronger tumor T2* enhancement than ferumoxytol. Histological analysis verified intracellular compartmentalization of GEH121333 by TAM at 24, 48 and 72 h p.i. MR imaging with GEH121333 nanoparticles represents a novel biomarker for TAM assessment. This new USPIO MR contrast agent provides a longer blood half-life and better TAM enhancement compared with the iron supplement ferumoxytol. Copyright © 2013 John Wiley & Sons, Ltd.Supporting information may be found in the online version of this paper

Hepatic, testicular and spermatozoa antioxidant status in rats chronically treated with Garcinia kolaseed

Ethnopharmacological relevanceGarcinia kola seed is commonly used in African Traditional Medicine as a remedy for liver disorders, hepatitis, bronchitis, throat infections as well as an aphrodisiac and fertility enhancing substance. Owing to the abundance of complex mixture of phenolic compounds in Garcinia kola seed, there is a growing safety concern on its long-term use in folklore medicine. The present study evaluated the hepatic, testicular and spermatozoa antioxidant status in rats chronically treated with Garcinia kolaseed. Materials and methodsAdult male Wistar rats were randomly assigned to four groups of 10 rats each and were orally administered with Garcinia kola at 0, 250, 500 and 1000mg/kg for 6consecutive weeks. Clinical observations, serum biochemistry, oxidative stress biomarkers, spermatozoa parameters and histopathological examination of the organs were assessed to monitor treatment-related adverse effects inrats. ResultsLong-term treatment of Garcinia kola had no adverse effect on the spermatozoa characteristics but significantly elevated testosterone concentration when compared to the control group. Improvement of antioxidant systems was accompanied by a significant decrease in malondialdehyde level in the liver, testes and spermatozoa of Garcinia kola-treated rats. Histological observation revealed that chronic administration of Garcinia kola had no effect on the liver and testes at all doses when compared with control. ConclusionGarcinia kola seed boosts the antioxidant status and exhibits no adverse effect on the liver, testes and spermatozoa after a long-term oral exposure inrats.

Evaluation of Oral Subchronic Toxicity of Soshiho-Tang Water Extract: The Traditional Herbal Formula in Rats

Soshiho-tang (Xiao-chai-hu-tang in Chinese and Sho-saiko-to in Japanese) has been widely used for its various pharmacological effects, which include anti-inflammatory, antioxidant, antihepatic fibrosis, and antitumor properties. To evaluate the safety of Soshiho-tang water extract (SST), we tested its subchronic toxicity in male and female Crl:CD (SD) rats. Rats were orally treated with four different doses (0, 500, 1000, and 2000 mg/kg/day) of SST administered for 13 weeks. Mortality, clinical signs, body weight changes, food and water consumption changes, ophthalmology, urinalysis, hematological and biochemical parameters, gross findings, organ weights, and histological markers were monitored during the study. The SST treatment did not result in any toxicologically significant changes in mortality, clinical signs, body weights, food and water consumption, ophthalmoscopy, urinalysis, hematological and serum biochemical parameters, gross findings, organ weights, or histopathology. Histological analysis did not show any liver or kidney alteration. We concluded that the 13-week repeated oral administration of SST did not cause any adverse effects in rats at dosage levels of ≤2000 mg/kg/day. Under these experimental conditions, the no-observed-adverse-effect level was concluded to be 2000 mg/kg/day for both sexes.

Evaluation of oral subchronic toxicity of Pu-erh green tea (camellia sinensis var. assamica) extract in Sprague Dawley rats

Ethnopharmacological relevancePu-erh green tea, originally produced in the Yunnan province of P.R. China for about 1700 years, is believed to be beneficial to health in Asian countries. The potential toxicity of Pu-erh green tea when administered at high doses via concentrated extract, however, has not been completely investigated. The aim of the studyThe present study was aimed to evaluate the potential toxicity of Pu-erh green tea extract (PGTE) of sub-chronic administration to Sprague Dawley (SD) rats. Materials and methodsGrowing SD rats were administrated orally by gavage with PGTE at doses of 0, 1250, 2500, and 5000mg/kg/day for 91 consecutive days. Clinical observations, including survival, hematology, serum biochemistry, urinalysis and histopathological examination were measured to monitor treatment-related adverse effects in rats. ResultsThe results showed that oral administration of high dose of PGTE led to body weight gain suppression, liver and calcium deposition dysfunctions. ConclusionsIn conclusion, the no-observed-adverse-effect level for Pu-erh green tea extract derived from the results of the present study was 2500mg/kg/day for both genders.

Effects of dietary inulin, statin, and their co-treatment on hyperlipidemia, hepatic steatosis and changes in drug-metabolizing enzymes in rats fed a high-fat and high-sucrose diet

BackgroundRats fed a high-fat and high-sucrose (HF) diet develop hepatic steatosis and hyperlipidemia. There are several reports that a change in nutritional status affects hepatic levels of drug-metabolizing enzymes. Synthetic inulin is a dietary component that completely evades glucide digestion. Supplementing a HF diet with inulin ameliorates hypertriglycemia and hepatic steatosis, but not hypercholesterolemia. This study aimed at distinguishing the effects of synthetic inulin and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin), which inhibit cholesterol biosynthesis.MethodsWe examined effects of co-treatment with synthetic inulin (5%) and fluvastatin (0, 4, and 8 mg/kg, per os) on body weight, epidydimal white adipose tissue weight, serum and hepatic lipid profiles, and hepatic cytochrome P450 (CYP) mRNA and protein profiles in rats fed a standard diet or a HF diet for 3 weeks.ResultsTreatment with the synthetic inulin (5%) or fluvastatin at 4 mg/kg (lethal dose in rats fed the HF diet, 8 mg/kg) ameliorated the elevation in hepatic triacylglycerol and total cholesterol levels in rats fed the HF diet. Whereas co-treatment with the inulin (5%) and fluvastatin (4 mg/kg) had a tendency to more strongly suppress the elevation in serum levels of very low density lipoprotein triacylglycerol than either treatment alone, no additive or synergistic effect was found in decrease in hepatic lipid levels. Hepatic levels of CYP1A1/2 and CYP2E1 mRNA and protein and methoxyresorufin O-demethylase and ethoxyresorufin O-deethylase activities were reduced in rats fed the HF diet. The synthetic inulin alleviated the reduction in hepatic levels of CYP1A1/2 and CYP2E1 mRNA and protein more strongly than fluvastatin, and no synergistic effects were observed on co-treatment. Furthermore, hepatic levels of aryl hydrocarbon receptor mRNA were decreased in rats fed the HF diet and recovered to near normal values with the intake of dietary inulin, which correlated with change in CYP1A1/2.ConclusionsDietary inulin alone was effective to prevent the development of hepatic steatosis, ameliorate nutritional effects, and alleviate the hepatic change in the expression of CYP1A1/2 and CYP2E1, while co-treatment with statin did not have additive or synergistic effects and statin may cause adverse effects in rats fed the HF diet.