Guinea Pig Liver Research Articles

Ameliorative properties of Iranian Trigonella foenum-graecum L. seeds and Punica granatum L. peel extracts in streptozotocin-induced experimental diabetic guinea pigs

ObjectiveTo assess the ameliorative properties of Iranian Trigonella foenum-graecum L. (T. foenum-graecum) seeds and Punica granatum L. (P. granatum) peel extracts against streptozotocin-induced diabetes in male guinea pigs. MethodsSixty guinea pigs were divided into six groups (10 guinea pigs per group). Group 1 consisted of normal animals. Groups 2 and 3 were treated with Iranian T. foenum-graecum seeds and P. granatum peel extract alone, respectively. Group 4 was treated with streptozotocin only; whereas Groups 5 and 6 receiving streptozotocin were treated with Iranian T. foenum-graecum seeds and P. granatum peel extract, respectively. All animals were treated for 30 days, and the body weight, blood and liver biochemical parameters were measured. ResultsGuinea pigs exposed to streptozotocin showed an alteration in body weight gain, fasting glucose level, kidney function parameters (blood urea nitrogen and creatinine) as well as decreased serum and hepatic total protein level. In addition, it increased the cholesterol and triglyceride level, while decreasing the hepatic glucose-6 phosphate dehydrogenase activity, glycogen, glutathione content and hepatic catalase activity. Oral treatment with T. foenum-graecum seeds and P. granatum peel extracts revealed significant protective properties with respect to body weight gain and other biochemical parameters studied. ConclusionsThe Iranian T. foenum-graecum seeds and P. granatum peel extracts are significantly potent in ameliorating diabetic condition induced by streptozotocin and improving various biochemical parameters in serum and liver of guinea pigs.

Albiflorin Granule significantly decreased the cholesterol gallstone formation by the regulation of insulin transduction signal.

To study the mechanism of insulin resistance in the cholesterol gallstone formation from insulin signal transduction pathway so as to reveal the possible mechanism and the effective role of Albiflorin Granule on preventing the cholesterol gallstones. Serum triglycerides (TG), free fatty acid (FFA), and total cholesterol (TC) from different groups were measured and liver cells InsR, PKB, IKK-β protein expression levels were detected by western blotting. Albiflorin significantly decreased the cholesterol gallstone formation rate, increased glucose infusion rate in gallstone guinea pigs and improved insulin resistance. Compared with the normal group, insulin receptor and PKB protein expression in GS group were significantly reduced. IKK-β protein in the GS group increased significantly and Albiflorin could reduce IKK-β protein expression in guinea pig liver cells. The model of insulin resistance in cholesterol gallstone guinea pig was successfully established, which plays an important role in the cholesterol gallstone formation. All aspects of insulin signaling pathway are involved in gallstone formation. Albiflorin can regulate various aspects of insulin signal transduction pathway to prevent the formation of gallbladder.

Bioluminescence Imaging of Colonization and Clearance Dynamics of Brucella Suis Vaccine Strain S2 in Mice and Guinea Pigs.

The goal of this study was to develop a plasmid-based lux bio-reporter for use to obtain in vivo images of Brucella suis vaccine strain 2 (B.suis S2) infection with high resolution and good definition. The pBBR-lux (pBBR1MCS-2-lxCDABE) plasmid that carries the luxCDABE operon was introduced into B. suis S2 by electroporation yielding B. suis S2-lux. The spatial and temporal transit of B. suis S2 in mice and guinea pigs was monitored by bioluminescence imaging. The plasmid pBBR-lux is stable in vivo and does not appear to impact the virulence or growth of bacteria. This sensitive luciferase reporter could represent B. suis S2 survival in real time. B. suis S2 mainly colonized the lungs, liver, spleen, and uterus in mice and guinea pigs as demonstrated by bioluminescence imaging. The plasmid-based lux bioreporter strategy can be used to obtain high resolution in vivo images of B. suis S2 infection in mice and guinea pigs.

Inhibition of guinea pig aldehyde oxidase activity by different flavonoid compounds: An in vitro study

Aldehyde oxidase (AO), a cytosolic molybdenum-containing hydroxylase, is predominantly active in liver and other tissues of mammalian species and involved in the metabolism of extensive range of aldehydes and nitrogen-containing compounds. A wide range of natural components including polyphenols are able to interfere with AO-catalyzed reactions. Polyphenols and flavonoids are one of the extensive secondary plant metabolites ubiquitously present in plants considered an important part of the human diet. The aim of the present study was to investigate inhibitory effect of selected phenolic compounds from three subclasses of aurone, flavanone and phenolic lactone compounds on the activity of AO, spectrophotometrically. AO enzyme was partially purified from liver of guinea pig. Then, inhibitory effects of 10 flavonoid compounds including 8 derivatives of 2-benzylidenebenzofuran-3(2H)-ones, as well as naringenin and ellagic acid on the activity of aldehyde oxidase were assessed compared with the specific inhibitor of AO, menadione. Among the phenolic compounds with inhibitory effects on the enzyme, ellagic acid (IC50=14.47μM) was the most potent agent with higher inhibitory action than menadione (IC50=31.84μM). The mechanisms by which flavonoid compounds inhibit AO activity have been also determined. The inhibitory process of the assessed compounds occurs via either a non-competitive or mixed mode. Although flavonoid compounds extensively present in the nature, mainly in dietary regimen, aurones with promising biological properties are not widely distributed in nature, so synthesis of aurone derivatives is of great importance. Additionally, aurones seem to provide a promising scaffold in medicinal chemistry for the skeleton of new developing drugs, so the results of the current study can be valuable in order to better understanding drug–food as well as drug–drug interaction and also appears to be worthwhile in drug development strategies.

L-dehydroascorbic acid can substitute l-ascorbic acid as dietary vitamin C source in guinea pigs

Vitamin C deficiency globally affects several hundred million people and has been associated with increased morbidity and mortality in numerous studies. In this study, bioavailability of the oxidized form of vitamin C (l-dehydroascorbic acid or DHA)—commonly found in vitamin C containing food products prone to oxidation—was studied. Our aim was to compare tissue accumulation of vitamin C in guinea pigs receiving different oral doses of either ascorbate or DHA. In all tissues tested (plasma, liver, spleen, lung, adrenal glands, kidney, muscle, heart, and brain), only sporadic differences in vitamin C accumulation from ascorbate or DHA were observed except for the lowest dose of DHA (0.25mg/ml in the drinking water), where approximately half of the tissues had slightly yet significantly less vitamin C accumulation than from the ascorbate source. As these results contradicted data from rats, we continued to explore the ability to recycle DHA in blood, liver and intestine in guinea pigs, rats and mice. These investigations revealed that guinea pigs have similar recycling capacity in red blood cells as observed in humans, while rats and mice do not have near the same ability to reduce DHA in erythrocytes. In liver and intestinal homogenates, guinea pigs also showed a significantly higher ability to recycle DHA compared to rats and mice. These data demonstrate that DHA in guinea pigs—as in humans—is almost as effective as ascorbate as vitamin C source when it comes to taking up and storing vitamin C and further suggest that the guinea pig is superior to other rodents in modeling human vitamin C homeostasis.

Specificity of transglutaminase-catalyzed peptide synthesis

Biocatalytic methods for peptide synthesis are of high value due to the rapidly increasing approval of peptide-based therapeutics and the need to develop new analogs. Guinea pig liver transglutaminase (gTG2) catalyzes the cross-linking of peptides and proteins via the formation of γ-glutamyl-ϵ-lysyl isopeptide bonds. In this study, we investigate gTG2-catalyzed peptide bond formation between various amino acid-derived donor and acceptor substrates. Using LC–MS analysis, we demonstrate that gTG2 forms Gly-Xaa and d-Ala-Gly dipeptide products, confirming that its natural transamidation activity can be co-opted for peptide synthesis. An aromatic ester of Gly was the most efficient acyl-donor substrate tested; aromatic esters of d-Ala and l-Ala showed 50-fold lower reactivity or no reactivity, respectively. A computational strategy combining computational protein design algorithms and molecular dynamics simulations was developed to model the binding modes of donor substrates in the gTG2 active site. We show that the inability of gTG2 to efficiently catalyze peptide synthesis from donors containing alanine results from the narrow substrate binding tunnel, which prevents bulkier donors from adopting a catalytically productive binding mode. Our observations pave the way to future protein engineering efforts to expand the substrate scope of gTG2 in peptide synthesis, which may lead to useful biocatalysts for the synthesis of desirable bioactive molecules.

Sub-acute toxicity of lantadenes isolated from Lantana camara leaves in guinea pig animal model

The sub-acute toxicity of lantadenes isolated from Lantana camara leaves was studied in guinea pig laboratory animal model. A total of 20 guinea pigs of either sex were divided into five groups. Group I served as control, while groups II, III, IV, and V were orally administered lantadenes at the dose rate of 100, 50, 25, and 12.5 mg/kg body weight (bw), respectively for 28 days. The levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, acid phosphatase, total bilirubin, blood urea nitrogen, and creatinine were estimated in serum. The effect of lantadenes on lipid peroxidation, superoxide dismutase, reduced glutathione, and catalase was monitored in liver homogenate. The lantadenes at the dose rate of 25 mg/kg bw in animals of group IV did not result in mortality, produced gross and histopathological changes characteristic of sub-acute toxicity in liver and kidneys, and resulted in the highest levels of serum liver marker enzymes. Elevated lipid peroxidation levels and decreased levels of superoxide dismutase and catalase in group IV indicated free-radical-induced damage by lantadenes. It was concluded that lantadenes produced a dose-dependent toxicity and the dose level of 25 mg/kg bw was the sub-acute toxic dose which induced significant fibrosis and necrosis in liver of guinea pigs. To the best of our knowledge, this is the first report on the study of sub-acute toxicity of lantadenes in guinea pig animal model which mimic the actual livestock lantana toxicity cases in field conditions.

The guinea-pig expresses functional CYP2C and P-glycoprotein: further validation of its usefulness in drug biotransformation/transport studies.

The guinea-pig is an excellent animal model for studying cardiopulmonary physiology/pharmacology. Interestingly, it also possesses a number of drug-metabolizing enzymes found in humans, such as CYP1A, CYP2D and CYP3A. To evaluate the hypothesis that the guinea-pig also expresses a functional CYP2C drug-metabolizing enzyme and the P-glycoprotein (P-gp) drug transporter in various tissues. cDNAs encoding CYP2C and P-gp were obtained from guinea-pig liver or small intestine and sequenced. Western blotting was performed to confirm the expression of CYP2C and P-gp. The functional enzymatic activity of guinea-pig CYP2C was evaluated with microsomal preparations using diclofenac and tolbutamide as specific drug substrates in HPLC analyses. To further study both P-gp and CYP2C functional activities, the guinea-pig ABCB1/MDR1 and CYP2C genes were cloned. The recombinant plasmids were then transfected in HEK293 (human embryonic kidney) cells and either calcein-acetoxymethyl ester (AM) accumulation assays or 14,15-EET/DHET formation experiments were performed to evaluate either P-gp transport activity or CYP2C epoxygenase activity, respectively. The guinea-pig tissue distribution of P-gp was studied by Western blotting. Functional expression of CYP2C was demonstrated in guinea-pig liver microsomal preparations. CYP2C-mediated biotransformation of diclofenac and tolbutamide were shown. Expression of P-gp protein was detected in guinea-pig liver and small intestine. Functional activity of guinea-pig P-gp was demonstrated in ABCB1/MDR1-transfected cells. GP-CYP2C-transfected cells also showed functional epoxygenase activity. The guinea-pig expresses functional CYP2C and P-gp, thus suggesting its usefulness for further validating data obtained with other animal models in drug biotransformation/transport studies.

The effects of N-acetylcysteine and epigallocatechin-3-gallate on liver tissue protein oxidation and antioxidant enzyme levels after the exposure to radiofrequency radiation

Purpose: The widespread and sustained use of mobile and cordless phones causes unprecedented increase of radiofrequency radiation (RFR). The aim of this experimental study was to investigate the effect of 900 MHz Global System for Mobile Communications (GSM)-modulated RFR (average whole body Specific Absorption Rate (SAR) of 0.4 W/kg, 10 or 20 min daily for consecutive 7 days) to the liver tissue of guinea pigs and the protective effects of antioxidant treatments.Materials and methods: Adult male guinea pigs were randomly divided into nine groups as: Group I (sham/saline), Group II (sham/EGCG), Group III (sham/NAC), Group IV (10-min RF-exposure/saline), Group V (20-min RF-exposure/saline), Group VI (10-min RF-exposure/EGCG), Group VII (20-min RF-exposure/EGCG), Group VIII (10-min RF-exposure/NAC), and Group IX (20-min RF-exposure/NAC). Protein oxidation (PCO), advanced oxidation protein products (AOPP) and antioxidant enzyme activities of superoxide dismutase (SOD) were evaluated after the exposure and the treatments with N-acetylcysteine (NAC) and (-)-epigallocatechin-3-gallate (EGCG).Results and conclusions: Significant decreases in the activities of SOD were observed in the liver of guinea pigs after RFR exposure. Protein damage did not change due to RFR exposure. On the other hand, only NAC treatment induced increased PCO levels, whereas EGCG treatment alone elevated the level of AOPP. Due to antioxidants having pro-oxidant behavior, the well decided doses and treatment timetables of NAC and ECGC are needed.

Protective Effects of CYP2E1 Inhibitors on Metabolic Syndrome-induced Liver Injury in Guinea Pigs

The present work reports the effects of CYP2E1-inhibitors (quercetin, 4methylpyrazole and disulfiram) on the indices characterizing state of the liver in guinea pigs with metabolic syndrome (MS) induced by protamine sulfate repeated administrations. The investigation of quercetin, 4-methylpyrazole and disulfiram effects on hepatic cytochrome P450 2E1 (CYP2E1) protein and activity changes was conducted. Simultaneously, the content of reactive oxygen species (ROS) and markers of liver damage were determined in experimental animals’ blood. The link between increased hepatic expression of CYP2E1, prominent ROS generation and liver damage in animals with MS has been discovered. It has been demonstrated that CYP2E1 protein content and activity in guinea pigs with MS rose almost 3 times compared to intact animals. These events were accompanied by increase in ROS generation and metabolism Original Research Article Rushchak et al.; BBJ, 7(2): 57-67, 2015; Article no.BBJ.2015.046 58 and liver disturbances symptoms: increase in serum glucose and cholesterol contents (2 and 2.6 times respectively), alanine aminotransferase (2.8 times), aspartate aminotransferase (6.4 times), and alkaline phosphatase (1.8 times) elevations. Our investigation suggests that administration of quercetin, 4-methylpyrazole, and disulfiram in guinea pigs with MS caused decrease in this isoenzyme protein expression (2.5, 1.7 and 2.4 respectively) as well as its enzymatic activity in liver (6.6, 1.1, and 1.7 respectively). The content of blood ROS was partially restored or normalized by all three CYP2E1 inhibitors. In turn, suppression of CYP2E1 activity and ROS generation led to decrease in hepatic MS manifestation. It is apparent from the present observation that quercetin has the highest efficiency among the investigated substances. Further studies on various quercetin doses and administration regimens could provide relevant information for the development of MSrelated nonalcoholic fatty liver disease treatment.

English

Aim: Tamoxifen, once praised for its importance in preventing breast cancer recurrence, is now implicated in dangerous side-effects. The authors are not aware of studies on the effect of tamoxifen on the histomorphological and biochemical components of the liver of guinea pig, hence the present one. Methods: Thirty guinea pigs weighing between 650g and 700g were assigned randomly into 6 groups of five and were separately given 0.70 and 7.0mg/kg body weight (b.w) tamoxifen for 2 and 4 weeks. Liver function tests and conventional tissue processing haematoxylin and eosin staining method were used in the study. Results: The results showed a significant loss in body weight (p<0.05) of the guinea pigs administered with low and high doses of the tamoxifen for 4 weeks when compared with the controls. The mean serum levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin and conjugated bilirubin increased significantly than the controls in high dose groups exposed for 2 weeks and 4 weeks respectively (p<0.05). Similarly, histomorphological changes such as enlargement and sclerotic condition of central vein, enlargement and non-hexagonal radiating arrangement of sinusoids were observed in the liver of guinea pigs in the high dose tamoxifen Key words: Tamoxifen, Liver, Breast cancer

Enantiospecific Effects of Ketoconazole on Aryl Hydrocarbon Receptor

Azole antifungal ketoconazole (KET) was demonstrated to activate aryl hydrocarbon receptor (AhR). Since clinically used KET is a racemic mixture of two cis-enantiomers (2R,4S)-(+)-KET and (2S,4R)-(−)-KET, we examined the effects of KET enantiomers on AhR signaling pathway. (+)-KET dose-dependently activated AhR in human gene reporter cell line AZ-AHR, and displayed 5–20× higher agonist activity (efficacy), as compared to (−)-KET; both enantiomers were AhR antagonists with equal potency (IC50). Consistently, (+)-KET strongly induced CYP1A1 mRNA and protein in human HepG2 cells, while (−)-KET exerted less than 10% of (+)-KET activity. In primary human hepatocytes, both enantiomers preferentially induced CYP1A2 over CYP1A1 mRNA and protein, and the potency of (+)-KET was slightly higher as compared to (−)-KET. Ligand binding assay with guinea pig liver cytosols revealed that both (+)-KET and (−)-KET are weak ligands of AhR that displaced [3H]-TCDD with comparable potency. Similarly, both enantiomers weakly transformed AhR to DNA-binding form with similar potency, as showed by EMSA, in guinea pig liver cytosolic extracts and nuclear extracts from mouse Hepa-1 cells. We also examined effects of KET on glucocorticoid receptor (GR), a regulator of AhR activity. Both KET enantiomers antagonized GR with similar potency, as revealed by gene reporter assay in AZ-GR cell line and down-regulation of tyrosine aminotransferase mRNA in human hepatocytes. Finally, we demonstrate enantiospecific antifungal activities of KET enantiomers in six Candida spp. strains. In conclusion, the significance of current study is providing the first evidence of enatiospecific effects of cis-enantiomers of ketoconazole on AhR-CYP1A pathway.

Distribution and excretion of 2,2′,3,4′,5,5′,6-heptachlorobiphenyl (CB187) and its metabolites in rats and guinea pigs

4-Hydroxy (OH)-2,2′,3,4′,5,5′,6-heptachlorobiphenyl (CB187) is a polychlorinated biphenyl (PCB) metabolite present in human serum at the highest concentration of the PCB metabolites. Our previous study demonstrated that CB187 was metabolized by rat and guinea pig liver microsomes to the major metabolite 4′-OH-2,2′,3,3′,5,5′,6-heptachlorobiphenyl (CB178), and the two minor metabolites 4-OH-CB187 and 4′-OH-2,2′,3,5,5′,6-hexachlorobiphenyl (CB151). In this study, the distribution of these metabolites in serum, liver and kidney, and their fecal excretion, were examined in rats and guinea pigs intraperitoneally dosed with CB187. Similarly to the in vitro study, 4′-OH-CB178 was a major metabolite in the liver, serum and feces of both animal species on day 4 after CB187 injection, and the level in the liver was about 20 times higher in untreated guinea pigs than in untreated rats. In addition, 4-OH-CB187, a minor metabolite, was detected in the serum and kidneys, but not in the feces, of both guinea pigs and rats. Another minor metabolite, 4′-OH-CB151, was detected at a lower level only in guinea pig feces; little was found in the serum or liver of either animals. Over the 30d following CB187 injection into guinea pigs, 4′-OH-CB178 and 4-OH-CB187 in the serum was observed at higher level on day 4 and day 16 after injection, respectively. The majority of the 4′-OH-CB178 was rapidly excreted to the feces following unmetabolized CB187, whereas 4-OH-CB187 was not found in guinea pig feces and liver during 30d. These results support previous reports that 4-OH-CB187 is retained persistently in animal blood.

The Presence of Autoantibodies Against Vascular and Nervous Tissue in Sera From Patients with Neuro-Behçet's Disease.

Behçet's disease is a chronic inflammatory disease of unknown aetiology that affects multiple organ systems. Since the diagnosis of this disease mainly relies on clinical criteria, a diagnostic laboratory test is required especially for neuro-Behçet's patients without systemic involvement. In this study, we searched for the presence of autoantibodies against brain tissue, by means of indirect immunofluorescent staining technique in sera obtained from patients with neuro-Behçet's disease, based on reports that humoral immune dysregulation may play a role in susceptibility to Behçet's disease. After pre-absorbtion of sera with guinea pig liver powder to reduce nonspecific staining, serum samples were applied to mouse brain sections and immunoreactivity was detected with fluorescein (FITC)-conjugated goat antibody against human IgG. Ten sera from neuro-Behçet's patients and 10 age-matched control sera were screened for immunoreactivity. We detected specific immunoreactivity to both parenchymal and vascular brain structures in the patients' sera. Parenchymal vessel immunopositivity was detected in 8 of 10 patients, whereas only two of control sera showed no significant parenchymal vascular immunoreactivity (p=.025). In addition to vascular immunoreactivity, filamentous and reticular immunopositive structures were detected in brain sections of 5 out of 10 patients. No such immunoreactivity was detected in sections incubated with control sera (p=.016). We detected a specific immunoreactivity against vascular and parenchymal filamentous structures in neuro-Behçet patients' sera. Humoral autoimmunity may play a role in the pathogenesis of neuro-Behçet's disease in addition to cellular immune response. Findings of this preliminary study will be evaluated with a large number of patients and controls, to determine whether it is the cause or the result and, further studies are underway to disclose the nature of epitope to which the immunoreactivity was directed against and to develop a diagnostic laboratory method for investigating central nervous system involvement in Behçet's patients.

Effect of inhaled arsenic trioxide and moxa leaf oil on eosinophil in asthmatic guinea pigs

Objective The experiment was designed to observe the effect of inhaled arsenic trioxide（As2O3）and in combination with inhaled moxa leaf oil on eosinophils（EOS）and lung tissue’s morphology in asthmatic guinea pigs, and to explore its mechanism of relieving wheezing. Methods The ovalbumin（OVA）-induced asthmatic guinea pig model was established. Sixty guinea pigs were randomly divided into As2O3 atomization inhalation group B1 As2O3 low dose group：2.0 mg/（kg·d）, B2 As2O3 high dose group：4.0 mg/（kg·d）, combined treatment group C1 low dose group：2.0 mg/（kg·d）＋moxa leaf oil 0.05 ml, C2 high dose group： 4.0 mg/（kg·d）＋moxa leaf oil 0.10 ml, saline aerosol inhalation group（group A） asthma model group）and normal control group（group D）according to random permutation table method. After 7 days medicated, the EOS in bronchoalveolar lavage fluid（BALF）were compared. Guinea pig lung, heart, liver and kidney pathological specimens were prepared and the change of the lung tissue’s inflammation and heart, liver and kidney tissue were investigated. Lung tissue’s electron microscopy specimens were prepared and the apoptosis of acidophilic cells and repair of alveolar epithelial cells were observed. Results Compared with asthma model group’s EOS number[（58.08±19.01）×105], the difference in As2O3 low dose group、As2O3 high dose group、combined treatment low dose group、combined treatment high dose group and normal control＆amp;nbsp;group[（26.37±1.12）×105, （11.50±1.61）×105, （14.16±4.88）×105, （5.03±1.66）×105 and（0.35±0.16）×105, respectively] were statistically significant（P<0.01）; there was statistical difference between As2O3 low dose group and As2O3 high dose group（P<0.01）;There was statistical difference between As2O3 low dose group and combined treatment low dose group（P<0.01）;There was statistical difference between As2O3 high dose group and combined treatment high dose group（P<0.05）. Compared with combined treatment high dose group, difference in As2O3 low dose group、As2O3 high dose group and combined treatment low dose group was statistically significant（P<0.05）. The difference in B1, B2, C1, C2 and D group was statistically significant compared with group A （P<0.01）. The difference in B1 and B2, B1 and C1 group was statistically significant （P<0.01）. The difference between B2 and C2 group was statistically significant（P<0.05）. The difference in C2 group was statistically significant compared with group B1, B2 and C1（P<0.05）. Conclusion EOS abnormal apoptosis was an important pathogenesis of bronchial asthma. The mechanism of arsenic trioxide anti-asthma was that arsenic trioxide could reduce acidophil infiltration and promote acidophilic cell apoptosis. The mechanism of moxa leaf oil anti-asthma was it could reduce acidophil infiltration. Smaller doses of the combination of inhaled As2O3 and moxa leaf oil was safe and effective to achieve the effect of relieving wheezing and the combined use had synergy. Key words: Arsenic trioxide; Moxa leaf oil; Inhaled; Bronchial asthma; Guinea pig; Eosinophile

Effects of aqueous extract of Withania somnifera on some liver biochemical and histopathological parameters in male guinea pigs.

Organophosphorus (OP) insecticides constitute one of the most widely used classes of pesticides being employed for both agricultural and landscape pest control. The purpose of this study was to investigate the effect of dimethoate (DM), an organophosphorus insecticide, on some biochemical and histopathological parameters in liver of adult male guinea pigs as well as the possible role of Withania somnifera extract in attenuation of DM-induced hepatotoxicity. The animals were divided randomly into 5 groups and kept at 5 animals per group in an environmentally controlled condition with free access to food and water ad libitum. The first group was served as a control group and administered with olive oil orally; the group II received aqueous extract of W. somnifera (100 mg kg(-1) b.wt.) orally, group III, IV and V was administered with DM (14 mg kg(-1); 1/25LD50) for 21 days orally. Group IV and V received 100 mg kg(-1) of W. somnifera extract and silymarin, respectively half hour before DM administration for 21 days. DM caused a statistically significant increase in the serum level of liver enzymes (AST, ALT, ALP) when compared to control animals, whereas, W. somnifera and silymarin pre-treatment to the DM-intoxicated animals resulted in a significant normalization of the enzymes activities. On the other hand W. somnifera extract reduced the incidence of histopathological changes such as cytoplasmic vacuolization and degeneration in nuclei, rupture of epithelia lining the central vein, widened sinusoidal space and lymphocyte infiltration induced by DM treatment in guinea pigs. In conclusion, the results of this study suggest that W. somnifera aqueous extract could protect the liver against DM-induced oxidative damage.

Dietary α-tocopherol and atorvastatin reduce high-fat-induced lipid accumulation and down-regulate CD36 protein in the liver of guinea pigs

The increased uptake and storage of lipids in the liver are important features of steatotic liver diseases. The fatty acid translocase/scavenger receptor cluster of differentiation (CD)36 facilitates the hepatic uptake of lipids. We investigated if RRR-α-tocopherol (αT) alone or in combination with atorvastatin (ATV) is capable of preventing hepatic lipid accumulation via down-regulation of CD36. To this end, Dunkin Hartley guinea pigs were fed a control diet (5% fat); or a high-fat control diet (21% fat, 0.15% cholesterol); or a high-fat control diet fortified with αT (250 mg/kg diet), ATV (300 mg/kg diet) or both ATV+αT for 6 weeks. Hepatic triacylglycerols, hepatic protein and mRNA expression of CD36 as well as the mRNA expression of the controlling nuclear receptors LXRα, PXR and PPARγ were determined. Animals fed the high-fat control diet accumulated significantly more triacylglycerols in the liver than control animals. This was significantly reduced by ATV and numerically by αT and ATV+αT. Hepatic CD36 protein concentrations were significantly higher in the high-fat than in the control group, and both αT and ATV reduced CD36 expression to the level observed in the control group. However, no synergistic effect of the combined treatment was observed. Neither CD36 mRNA nor that of the nuclear receptors (LXRα, PXR and PPARγ) differed between groups, suggesting a posttranslational regulatory mechanism. Our results indicate that orally administered ATV and αT individually, but not synergistically, prevent diet-induced lipid accumulation in the liver of guinea pigs by down-regulation of hepatic CD36 protein.

Niacin inhibits vascular inflammation via downregulating nuclear transcription factor-κB signaling pathway.

The study aimed to investigate the effect of niacin on vascular inflammatory lesions in vivo and in vitro as well as its lipid-regulating mechanism. In vivo study revealed that niacin downregulated the levels of inflammatory factors (IL-6 and TNF-α) in plasma, suppressed protein expression of CD68 and NF-κB p65 in arterial wall, and attenuated oxidative stress in guinea pigs that have been fed high fat diet. In vitro study further confirmed that niacin decreased the secretion of IL-6 and TNF-α and inhibited NF-κB p65 and notch1 protein expression in oxLDL-stimulated HUVECs and THP-1 macrophages. Moreover, niacin attenuated oxLDL-induced apoptosis of HUVECs as well. In addition, niacin significantly lessened lipid deposition in arterial wall, increased HDL-C and apoA levels and decreased TG and non-HDL-C levels in plasma, and upregulated the mRNA amount of cholesterol 7α-hydroxylase A1 in liver of guinea pigs. These data suggest for the first time that niacin inhibits vascular inflammation in vivo and in vitro via downregulating NF-κB signaling pathway. Furthermore, niacin also modulates plasma lipid by upregulating the expression of factors involved in the process of reverse cholesterol transport.

Interfacing of dextran coated ferrite nanomaterials with cellular system and delayed hypersensitivity on Guinea pigs

The study focused on the interfacing of dextran coated ferrite nanomaterials (DFNM) with the cellular system and delayed hypersensitivity on Guinea pigs. In vitro study investigated the cytotoxic potential of DFNM on L929 cells, effect on antioxidant enzymes and Lipid peroxides (LPO) production on rat brain homogenates. DFNM was also repeatedly exposed topically to Guinea pigs for the evidence of skin sensitization and toxicity at the molecular level. Biochemical and hematological parameters were estimated. Liver and brain of Guinea pigs were homogenized and evaluated for the induction of LPO, glutathione (GSH), glutathione reductase (GR), glutathione peroxidase (GPx), superoxide dismutase (SOD) and 8-hydroxyl-2-deoxyguanosine (8-OHdG). The results of the study demonstrated that there was no significant alternation in the level of antioxidant defense enzymes, LPO, hematological, biochemical or oxidative stress related DNA damage. Hence, it can be concluded that the synthesized DFNM was non-skin irritant or non-toxic at the molecular level under the laboratory conditions.

Sex Differences in Metabolism of Trichloroethylene and Trichloroethanol in Guinea Pigs

Trichloroethylene (TRI) has the potential to cause generalized dermatitis complicated with hepatitis. The guinea pig maximization test (GPMT) also suggests that both TRI and its metabolite trichloroethanol (TCE) exhibit immunogenicity and possible sex differences in guinea pigs. However, TRI and TCE metabolisms in guinea pigs have not been elucidated in detail. The first issue to clarify may be the sex differences in relation to the immunogenicity. We collected urine from Hartley male and female guinea pigs 24 hours after intracutaneous injection of TRI, TCE or trichloroacetic acid (TCA) during a GPMT and measured the urinary metabolites by gas chromatography-mass spectrometry. After TRI treatment, the amount of TCA was significantly greater in females than males, while there was no sex difference in the total amount (TCA + TCE). TCA was only detected in urine after TCA treatment. Interestingly, not only TCE but also TCA was detected in urine of both sexes after TCE treatment, and the amount of TCA was also greater in females than males. An additional experiment showed that TCE treatment did not result in the detection of urinary TCA in cytochrome P450 (CYP)2E1-null mice TCEbut did in wild-type mice, suggesting the involvement of CYP2E1 in the metabolism from TCE to TCA. The constitutive expression of CYP2E1 in the liver of guinea pigs was greater in females than males. The sex difference in urinary TCA excretion after TRI and TCE treatments may be due to variation of the constitutive expression of CYP2E1.