Protective effects of nigella sativa against gentamicin-induced nephrotoxicity in rats

The aim of this study was focused on investigating the possible protective effect of NS against GS-induced nephrotoxicity. Twenty four Wistar-albino rats were divided into four equal groups as follows: control group, GS group (100 mg/kg intraperitoneal – i.p.), NSL+GS group (0.2 ml/kg+100 mg/kg i.p.) and NSH+GS group (0.4 ml/kg+100 mg/kg i.p.). Plasma creatinine and urea levels significantly increased as a result of nephrotoxicity in the GS group. Also, creatinine and urea levels significantly decreased in NSL+GS and NSH+GS groups. In the GS group, plasma MDA and NO levels increased significantly (p<0.05) and erythrocyte SOD and GSH-Px activities decreased significantly (p<0.05) when compared with control group. NS administration with GS injection resulted in significantly decreased MDA and NO generation and increased SOD and GSH-Px activities when compared with GS group. Proximal tubular necrosis, vacuolation, desquamation and degeneration in epithelial cells of the proximal tubules, hyaline casts in tubular lumen, mononuclear cell infiltration, glomerular and basement membrane alterations were histopathologically detected in the kidneys of the GS group. Co-treatments with NS (low and high dose) considerably decreased the renal damage when compared with the GS group. In conclusion, NS acts in the kidney as a potent scavenger of free radicals to prevent the toxic effects of GS both in the biochemical and histopathological parameters.     

Comparison of the protective effects of various antiulcer agents alone or in combination on indomethacin-induced gastric ulcers in rats

The aim of this study which was structured with the objective of determination of the optimum protective therapy against the long term NSAID therapy-induced ulcers was to compare the gastro-protective effects of various antiulcer drugs (ranitidine, omeprazole, bismuth and misoprostol) alone or in combination with each other in different doses on indomethacin-induced gastric ulcers in rats.In this experimental study the protective effect of misoprostol (100 μg/kg/day and 10 μg/kg/day i.g.), omeprazole (5 mg/kg/day and 1.5 mg/kg/day i.p.), ranitidine (40 mg/kg/day and 10 mg/kg/day i.p.), bismuth (70 mg/kg/day and 15 mg/kg/day i.g.), combinations of misoprostol (10 μg/kg/day i.g.) plus omeprazole (1.5 mg/kg/day i.p.) and misoprostol (10 μg/kg/day i.g.) plus ranitidine (10 mg/kg/day i.p.) are investigated on indomethacin (50 mg/kg/day s.c.) induced gastric ulcers. Half an hour before indomethacin administration, each group received the above treatment regimens for 5 days. After 5-day treatment, the rats were sacrificed and histopathological and hematological examinations were performed. The following regimens were found to be effective in the prevention of indomethacin-induced gastric lesions: 100 μg/kg misoprostol, 10 μg/kg misoprostol, 5 mg/kg omeprazole, combination of 10 μg/kg misoprostol plus 1.5 mg/kg omeprazole and 10 μg/kg misoprostol plus 10 mg/kg ranitidine. The prevention rates achieved by these treatments were 71.4%, 50%, 47.6%, 52.4% and 50%, respectively. As a result of this study, misoprostol and omeprazol were found to be effective in protection against NSAID-induced gastric problems; while, ranitidine and bismuth were not. Also, the combinations of these agents were not found to have additive or synergistic effects.     

Immunohistochemical and histological evaluations of cyclophosphamide-induced acute cardiotoxicity in wistar rats: The role of turmeric extract (curcuma)

Chemotherapy-induced cardiac derangement is a major concern in health sector. Cyclophosphamide as a chemotherapeutic agent induces acute cardiotoxicity through its toxic metabolite, acrolein. This study evaluated the effect of ethanol extract of turmeric on cyclophosphamide-induced acute cardiotoxicity in Wistar rats. Thirty-five healthy Wistar rats, weighing 200–250 g were randomly assigned into 7 groups (Groups A, B, C, D, E, F and G) N = 5. Group A was the control, group B was negative control, and group C was administered 200 mg/kg of turmeric extract (orally) only. While groups B, D, E, F and G were all administered 100 mg/kg cyclophosphamide (i.p) for 10 days. Groups D and E were administered 100 mg/kg and 200 mg/kg of turmeric extract (orally) respectively for 72 hours before cyclophosphamide administration. Groups F and G were concomitantly administered 100 mg/kg cyclophosphamide (i.p) with doses of 100 mg/kg and 200 mg/kg of turmeric extract (orally) respectively. The rats were sacrificed under ketamine anesthesia (30 mg/kg i.m). The left ventricle of the heart was excised. One-way ANOVA was used to analyze data. Results revealed that there was statistically significant (P < 0.05) difference in body weight change, CK–MB, and LDH across all experimental groups; which were significantly lower in cyclophosphamide group. Histology and Immunohistochemistry revealed that there were morphological alterations in the myocardium of the left ventricle in group B while turmeric extract ameliorated cyclophosphamide-induced damage in the myocardium in other experimental groups. In conclusion, cyclophosphamide-induced myocardial alterations were significantly ameliorated through administration of ethanol extract of turmeric.     

A therapeutic approach to treat cardiovascular dysfunction of diabetes

Diabetes greatly increases risk of cardiovascular dysfunction and interruptions of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) have been shown to reduce the risk by alteration in extracellular matrix. We hypothesized that minocycline induced MMP-2 and MMP-9 inhibition can be enhanced by aspirin (through its COX and tPA inhibitory action) and this combination can reduce cardiovascular dysfunction of diabetes. Four weeks after diabetes induction (streptozotocin, 55 mg/kg, i.p.), rats were treated with minocycline (50 mg/kg, p.o.), aspirin (50 mg/kg, p.o.), or minocycline (50 mg/kg, p.o.) plus aspirin (50 mg/kg, p.o.) for a period of next four weeks. At the end of eighth week arterial pressure, heart rate and left ventricular pressure were recorded. Contractile response to phenylephrine (10^?5 M) and relaxation responses to acetylcholine (10^?9–10^?4 M) were obtained from aortic rings of diabetic rats. Gel zymography was performed to evaluate MMP-2 and MMP-9 levels. Heart rate, mean arterial pressure, dp/dt_max and dp/dt_min were found significantly decreased in STZ diabetic rats when compared with normoglycemic group. Treatment with combination of minocycline and aspirin significantly ameliorate these compared to vehicle treated diabetic group. Endothelium-dependent relaxation responses induced by acetylcholine were decreased in diabetic rats and significantly higher in combination treated group. Collagen, MMP-2 and MMP-9 levels were significantly decreased in combined treated group when compared with diabetic control. Present study revealed that aspirin potentate minocycline induced MMP-2 and MMP-9 inhibition to ameliorate cardiovascular dysfunction of diabetes and this combination can be an approach for the treatment.     

The effects of royal jelly on liver damage induced by paracetamol in mice

The present study was undertaken to investigate the protective effect of royal jelly against paracetamol-induced liver damage. The study was conducted in 90 female Swiss Albino mice, and six groups were established. While the first group was maintained as control, Groups 2–6 were administered 200 mg/kg RJ for 1 day, 200 mg/kg RJ for 7 days, 400 mg/kg PAR for 1 day, 200 mg/kg RJ plus 400 mg/kg PAR for 1 day and 200 mg/kg RJ for 7 days and then second 400 mg/kg PAR on the 7th day, orally, respectively. It was shown that PAR significantly increased serum ALT, AST, ALP, liver MDA levels and significantly decreased liver GSH-Px activity, when compared to the control group (Group 1). On the other hand, meaningful changes were observed in the biochemical parameters of the group which was administered long-term RJ (Group 6). The aforementioned parameters which were statistically significant were determined to have drawn closer to values of the control group, and among these, the existing statistical differences for MDA level and GSH-Px activity between the trial group (Group 6) and the control group disappeared (Group 1). Compared to the pathological changes observed in the liver parenchyma, remark cords, sinusoids and hepatocytes in the group which was administered paracetamol alone (Group 4), lesions were determined to be less severe particularly in the group (Group 6) which received royal jelly for 7 days prior to paracetamol. In conclusion, the administration of royal jelly as a hepatoprotective agent for 7 days against paracetamol-induced liver damage was determined to exhibit marked protective effect on liver tissue.     

Dual effects of l-3,4-dihydroxyphenylalanine on aromatic l-amino acid decarboxylase,dopamine release and motor stimulation in the reserpine-treated rat: evidence that behaviour is dopamine independent

The comparative effects of l-3,4-dihydroxphenylalanine (L-DOPA) on dopamine synthesis, release and behaviour were studied in the reserpine-treated rat. Acute administration of L-DOPA (25–200 mg/kg) dose-dependently inhibited the activity of aromatic l-amino acid decarboxylase (AADC) in the substantia nigra and corpus striatum. The antiparkinsonian drugs budipine (10 mg/kg) and amantadine (40 mg/kg) enhanced AADC activity in these regions, and prevented or reversed AADC inhibition by L-DOPA. Dual probe dialysis revealed that low doses of L-DOPA (25–50 mg/kg) dose-dependently stimulated the release of dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) in nigra and striatum, whilst high doses of L-DOPA (100–200 mg/kg) completely suppressed the release of dopamine, but not DOPAC. Sulpiride (50 μM) administered via the probes antagonized dopamine release in response to 25 mg/kg L-DOPA, but greatly facilitated release by 200 mg/kg L-DOPA. Dopamine release was blocked by the centrally acting AADC inhibitor NSD 1015, but facilitated by the central AADC activator budipine. In behavioural tests L-DOPA (plus benserazide, 50 mg/kg) only reversed akinesia at 200 mg/kg, and not at 25–100 mg/kg. Pretreatment with either NSD 1015 (100 mg/kg) or budipine (10 mg/kg) markedly potentiated the motor stimulant action of a threshold dose of L-DOPA (100 mg/kg). A combination of NSD 1015 (100 mg/kg) and benserazide (50 mg/kg) potentiated L-DOPA behaviour more effectively than either inhibitor alone. NSD 1015-facilitated L-DOPA behaviour was antagonized by sulpiride (100 mg/kg) and not by SCH 23390 (1 mg/kg), whereas budipine-facilitated L-DOPA behaviour was fully antagonized by SCH 23390 and only partially by sulpiride.These results show that behaviourally active doses of L-DOPA in the reserpinized rat are not accompanied by significant increases in extracellular dopamine and are therefore probably not dopamine mediated. We propose that L-DOPA is capable of directly stimulating dopamine D₂ and possibly non-dopamine receptors, thereby inhibiting dopamine efflux presynaptically and promoting motor activation postsynaptically. A stimulant action of L-DOPA on motor behaviour, preferentially mediated by D₁>D₂ receptors, suggests that L-DOPA may also be capable of yielding a dopamine-like response in the absence of detectable dopamine release. These findings are incorporated into a new model of L-DOPA's actions in the reserpinized rat, and their possible implications for our understanding of L-DOPA in Parkinson's disease are discussed.     

Role of connexin 32 in acetaminophen toxicity in a knockout mice model

Gap junctional intercellular communication (GJIC), by which glutathione (GSH) and inorganic ions are transmitted to neighboring cells, is recognized as being largely involved in toxic processes of chemicals. We examined acetaminophen (APAP)-induced hepatotoxicity clinicopathologically using male wild-type mice and mice lacking the gene for connexin32, a major gap junction protein in the liver [knockout (Cx32KO) mice]. When APAP was intraperitoneally administered at doses of 100, 200, or 300 mg/kg, hepatic centrilobular necrosis with elevated plasma aminotransferase activities was observed in wild-type mice receiving 300 mg/kg, and in Cx32KO mice given 100 mg/kg or more. At 200 mg/kg or more, hepatic GSH and GSSG contents decreased significantly and the effect was more severe in wild-type mice than in Cx32KO mice. On the other hand, markedly decreased GSH staining was observed in the hepatic centrilobular zones of Cx32KO mice compared to that of wild-type mice. These results demonstrate that Cx32KO mice are more susceptible to APAP hepatotoxicity than wild-type mice, and indicate that the distribution of GSH of the centrilobular zones in the hepatic lobules, rather than GSH and GSSG contents in the liver, is important in APAP hepatotoxicity. In conclusion, Cx32 protects against APAP-induced hepatic centrilobular necrosis in mice, which may be through the GSH transmission to neighboring hepatocytes by GJIC.     

β-Caryophyllene,a natural sesquiterpene,modulates carbohydrate metabolism in streptozotocin-induced diabetic rats

The study was designed to evaluate the antihyperglycemic effects of β-caryophyllene (BCP), a natural sesquiterpene from spices on streptozotocin (STZ) induced diabetic rats. Diabetes mellitus was induced by a single intraperitoneal injection of STZ (40 mg/kg b.w.) in adult male Wistar rats. Diabetic rats exhibited an increase in glucose and HbA_1c with a significant fall in insulin and hemoglobin levels. Aberrations in carbohydrate metabolic enzymes were noticed in liver, kidney and skeletal muscle of diabetic rats. A fall in liver and skeletal muscle glycogen with alterations in glycogen synthase and phosphorylase activities was also observed. Oral administration of BCP in dose dependent manner and glibenclamide (600 μg/kg b.w.), a standard oral hypoglycemic drug to diabetic rats for 45 days significantly decreased glucose with increased plasma insulin levels and ameliorated the altered activities of carbohydrate metabolic enzymes to near normal. The insulinotropic effect of BCP was supported by immunohistochemical studies. BCP at a dose of 200 mg/kg b.w. exerted significant antidiabetic effects than other two doses (100 and 400 mg/kg b.w.). We conclude that administration of BCP has beneficial effects in glucose homeostasis in diabetic rats.     

The effects of grape seed and colchicine on carbon tetrachloride induced hepatic damage in rats

This study aims to determine the effects of grape seed and colchicine on carbon tetrachloride (CCl₄) induced hepatic damage and on some serum biochemical parameters. Sixty male Wistar albino rats (200–250 g) were randomly divided into six groups (ten rats/group) and included the control group the group were given isotonic sodium chloride (1 mL/kg b.w) intraperitonealy (i.p.), group 2 the group treated i.p. injection of CCl₄ (1.0 mL/kg b.w) in corn oil twice in the first week, Groups 3 and 4 injected with CCl₄ as described for group 2 and the rats were orally given (100 mg/kg b.w) GSE and i.p. injected (10 μg/rat) with colchicine for four weeks, respectively and groups 5 and 6 were the grape seed and colchicine control groups in which rats were orally given grape seed (100 mg/kg b.w) and i.p. injected with colchicine (10 μg/rat), respectively. Anorexia, weight loss, motionlessness and hepatic colour variation at necropsy were observed in groups 2, 3, and 4. Hyperemia, focal bleeding, fat degeneration, changes ranging from degenerative to necrotic, increase in connective tissue elements, pronounced in portal sites in particular, and infiltration of lymphoid series cell observed in the livers of the rats in group 2, treated with CCl₄. Histological hepatic changes in the rats in group 3 and 4 were similar to those in group 2. The levels of serum total protein, albumin and globulin decreased in groups 2, 3, and 4, compared with groups 1, 5 and 6; aspartate transaminase (ALT) activities increased. The lowest alkaline phosphatase (ALP) activities were in groups 4 and 5. We concluded that GSE and colchicine have not sufficient ameliorative effects to CCl₄ induced acute hepatic damage.     

New insight in colistin induced neurotoxicity with the mitochondrial dysfunction in mice central nervous tissues

In the present study, the mechanism of colistin-induced neurotoxicity was investigated with a focus on behavioral characters, mitochondrial ultrastructures and functions of the central nerve tissues in mice followed by administrating intravenously 15 (divided into two dose and 12 h apart), 7.5 and 5 mg/kg bw colistin sulfate for 1, 3 or 7 days successively. To assess the recoverability of colistin-induced neurotoxicity, the neurotoxicity was also examined on day 15 (8 post colistin sulfate administration for 7 days). The results showed that, the spontaneous activities of mice were significantly decreased on days 3 and 7 in the 15 mg/kg group compared with the correspondingly control group. The abnormal ultrastructure changes of mitochondria were presented in their nervous tissues and changed in a dose- and time-dependent manner, e.g. severe vacuolation and fission on days 3 and 7 in the 15 mg/kg group and more slight on day 7 in the 7.5 mg/kg group. In addition, mitochondrial permeability transition (MPT), membrane potential (Δψ_m) and activities of mitochondrial succinate dehydrogenase changed, showing that colistin affected the mitochondrial functions. The recoverability of colistin-induced neurotoxicity was showed and only slight injury occurred in the nerve tissues of mice on day 15 in the 15 mg/kg group and it had no abnormal changes in the behavioral and neuropathology characters in mice on day 15 in the 7.5 and 5 mg/kg groups. The results suggested that mitochondrial dysfunction might partly account for the mechanism of neurotoxicity induced by colistin sulfate.     

Characterization of liver toxicity in F344/N rats and B6C3F1 mice after exposure to a flame retardant containing lower molecular weight polybrominated diphenyl ethers

Lower molecular weight polybrominated diphenyl ethers (PBDEs), components of flame retardants, are found in the environment and in human and animal tissues. Toxicity studies were conducted in F344/N rats and B6C3F1 mice by administering a flame retardant containing these lower molecular weight PBDEs (BDE-47, BDE-99, BDE-100, and BDE153) by oral gavage 5 days/week for 13 weeks at doses of 0.01, 5, 50, 100 or 500 mg/kg/day. Liver was the primary target organ in rats and mice. Treatment-related increases in liver weights, liver cytochrome P450 (1A1, 1A2, 2B) and UDPGT (rats only) levels, and liver lesions were seen in both rats and mice. Hepatocyte hypertrophy and vacuolization increased in incidence and severity with treatment, and occurred at levels of 50 mg/kg and above in rats, and at 100 mg/kg and above in mice. Liver Cyp 1A1, 1A2, and 2B levels were increased at exposure levels of 50 mg/kg and above in rats and mice. In addition, treatment-related thyroid lesions occurred particularly in rats. The most sensitive parameter for PBDE toxicity was the increase in liver weights which occurred at 5 mg/kg above in rats and 50 mg/kg and above in mice. These results suggest that liver may be a target organ for carcinogenesis processes after long-term administration of PBDEs. A chronic PBDE study is currently being conducted by the National Toxicology Program.     

A modified model of gentamicin induced renal failure in rats: Toxicological effects of the iodinated X-ray contrast media ioversol and potential usefulness for toxicological evaluation of iodinated X-ray contrast media

Contrast-induced nephropathy (CIN) remains a serious complication in patients exposed to iodinated X-ray contrast media (ICM). Animal models of CIN are useful to further understand the mechanisms involved, identify novel biomarkers and evaluate potential differences between ICM. The current investigation was undertaken to modify the rat-gentamicin model for potential usefulness for toxicological evaluation of ICM. A dose-range finding study (50, 60 and 70 mg/kg body weight (bw)) of gentamicin was conducted over 4 consecutive days. Based on the kidney histopathology findings, a gentamicin dose of 70 mg/kg bw was chosen to investigate whether ICM would cause further renal damage. Following gentamicin treatment, this group was given a single administration of ioversol (6 g I/kg bw). Blood and urine samples were taken from all animals 3 days before the start of the study and at the end of treatment. Serum and urinary creatinine, urinary N-acetyl-β-d-glucosaminidase (NAG), γ-glutamyl transferase (GGT), total protein, and urine cytology were evaluated as biomarkers of renal damage. Histopathological examination of kidneys was performed. Histopathological examination of the kidneys revealed vacuolation, dilatation, and necrosis of the proximal tubules in the gentamicin–ioversol treatment group. These changes were not seen in the gentamicin-only treatment groups. Data on GGT and urinary epithelial cells show clear differences between rats treated with gentamicin alone versus gentamicin plus ioversol. These findings show that the modified rat-gentamicin model was able to demonstrate the nephrotoxic effect of ioversol.     

Synaptic degradation of cardiac autonomic nerves in streptozotocin-induced diabetic rats

Background: Cardiac autonomic neuropathy (CAN) is a common complication in type I diabetes mellitus (DM). Nevertheless, the relationship between functional and structural disturbances of cardiac autonomic nerves remains unclear. Methods and results: To clarify this relationship, we studied heart rate variability (HRV) and ultrastructural changes of cardiac autonomic nerves in streptozotocin (STZ)-induced DM in rats. STZ was injected (65 mg/kg intravenous) into the tail vein of male Wistar rats to destroy β cells in the pancreatic islets. After STZ injection, fasting blood sugar (FBS) increased from baseline values of 75 ± 3 mg/dl up to 328 ± 12 mg/dl within 1 week and it reached up to 353 ± 24 mg/dl within 17 weeks. HR in these rats was decreased within 20 days and low HR was maintained for the observation period. TP and HF power started decreasing 20 days after STZ injection, and this decrease progressed throughout the observation period. The L/H power ratio was decreased 80 days after STZ. Electron microscopic findings indicated a depletion of neurotransmitter vesicles and degradation of parasympathetic nerve endings but not of sympathetic ones in the SA node region of the heart in the early stages of DM. In the late stages of DM, the same region showed degradation of both sympathetic and parasympathetic nerve endings. Conclusion: Synaptic degradation in parasympathetic nerves immediately after the onset of DM, and in sympathetic nerves much later in the development of DM is consistent with functional derangements in cardiac autonomic nerve activities assessed by HRV analysis.     

Genotoxic and mutagenic effects of fipronil on mice

The toxic effects of several compounds on ecosystems are not restricted to ecological disturbances, and may also affect long-term human health. Fipronil is highly efficient in the control of pests, including those resistant to pyrethroid, organophosphate, and carbamate insecticides. Relatively little is known about the action of fipronil in vertebrates. This study was aimed to evaluate the genotoxic and mutagenic potential of this compound in mice exposed to different doses and demonstrates the damage caused by fipronil on non-target organisms in artificial conditions. Mice were divided into five groups: group I = 30% of DL₅₀ (15 mg/kg), group II = 50% of the DL₅₀ (25 mg/kg), group III = DL₅₀ (50 mg/kg), group IV = negative control, and group V = positive control. Peripheral blood was collected for the comet assay (24 h after exposure) and the micronucleus test (24, 48 and 72 h after exposure). Our findings revealed that doses of 15 mg/kg (group I) and 25 mg/kg (group II) of fipronil did not have genotoxic or mutagenic effects. Only the highest dose tested (50 mg/kg) induced DNA damage 24 h after exposure, indicating the mutagenic potential of fipronil. Therefore, this or higher doses are not recommended, as they may be toxic to non-target organisms.     

The potential role of combined antioxidant treatment on pancreas of STZ-diabetic mice

In diabetes, cells and tissues are damaged due to the imbalance between production of free radicals and removal of them. The effective biologic antioxidants for oxidative stress such as α-lipoic acid, vitamin E and selenium are effective in diminishing oxidative damage such as membrane lipid peroxidation. The experiment aimed to investigate the oxidative stress occurring in mitochondrial and cytoplasmic fraction of pancreatic tissues in streptozotocin-diabetic mice and the possible effects of α-lipoic acid + vitamin E + selenium combination on oxidative damage and antioxidative system by using microscopic and biochemical methods.The mice were divided into five groups. These groups were treated by citrate buffer, the solvents of the antioxidants, combined the antioxidants [α-lipoic acid (50 mg/kg), vitamin E (100 mg/kg), selenium (0.25 mg/kg)], streptozotocin (40 mg/kg × 5), combined the antioxidants and streptozotocin. The mice were sacrificed by cervical dislocation.In the experimental group given combined antioxidants following results were observed compared to diabetic group: increased percent insulin-positive cell area; decreased blood glucose levels; increased manganase superoxide dismutase activities and unsignificantly increased superoxide dismutase activities; unsignificantly decreased lipid peroxidase levels in both of fraction; unsignificantly decreased in mitochondrial fraction and unsignificantly increased in cytosolic fraction for catalase levels; not any alteration glutathione levels; not any activity in both of fraction for glutathione peroxidase.We can say that by taking the blood glucose levels and immunohistochemical results into account, the combination of triple antioxidants has a partly positive effect on diabetes. This positive effect could increase when trying different doses of combined antioxidant treatment.     

Antidiabetic,antihyperlipidemic and antioxidant effects of the flavonoid rich fraction of Pilea microphylla (L.) in high fat diet/streptozotocin-induced diabetes in mice

The present study describes the antidiabetic effect of the flavonoid rich fraction of Pilea microphylla (PM1). HPLC characterization of PM1 revealed the presence of polyphenols viz., chlorogenic acid, rutin, luteolin-7-O-glucoside, isorhoifolin, apigenin-7-O-glucoside, and quercetin. PM1 inhibited dipeptidyl peptidase IV (DPP-IV) in vitro with an IC₅₀ of 520.4 ± 15.4 μg/ml. PM1, at doses of 300, 600 and 900 mg/kg i.p., also produced dose-dependent mean percent reductions of 9.9, 30.6 and 41.0 in glucose excursion (AUC_0–120 min) respectively in lean mice. However, even the highest dose of PM1 did not alter normoglycemic condition. PM1 at dose of 100 mg/kg/day, i.p. for 28 days produced significant (p < 0.05) reduction in body weight, plasma glucose (PG), triglycerides (TG) and total cholesterol (TC) content in high-fat streptozotocin-induced diabetic mice. PM1 also improved oral glucose tolerance significantly (p < 0.05) with mean percentage reduction of 48.0% in glucose excursion (AUC_0–120 min) and significantly (p < 0.05) enhanced the endogenous antioxidant status in mice liver compared to diabetic control. PM1 preserved islet architecture and prevented hypertrophy of hepatocytes as evident from the histopathology of pancreas and liver. PM1 did not show any detectable hematological toxicity at therapeutic doses. In conclusion, PM1 exhibits antidiabetic effect possibly by inhibiting DPP-IV and improving antioxidant levels in high fat diet/streptozotocin (HFD/STZ) diabetic mice.     

Furan-induced dose–response relationships for liver cytotoxicity,cell proliferation,and tumorigenicity (furan-induced liver tumorigenicity)

Rodent studies of furan are associated with liver cell necrosis, release of liver-associated enzymes, increased hepatocyte proliferation, and hepatocarcinogenesis. For carcinogens whose proposed mode of action is cytolethality, it is hypothesized that the dose–response curve for tumor development would parallel the dose–response curve for cell death with compensatory proliferation in the target organ. To prospectively test this hypothesis, female B6C3F₁ mice were exposed to furan at carcinogenic doses and lower for 3 weeks or 2 years. At 3 weeks and in the 2-year study, there were dose-dependent and significant increases in hepatic cytotoxicity at 1.0, 2.0, 4.0, and 8.0 mg furan/kg. For cell proliferation as measured by 5-bromo-2′-deoxyuridine (BrdU) labeling index (LI), there was a statistically significant trend with increasing dose levels of furan and increased LI at 8.0 mg/kg. There was an increased incidence of foci of altered hepatocytes, hepatocellular adenomas, and adenomas or carcinomas at 4.0 and 8.0 mg/kg and carcinomas at 8.0 mg/kg. The multiplicity of microscopic tumors was increased and latency was decreased in mice exposed to 8.0 mg/kg. Prevalence of hepatic nodules at necropsy was increased in mice exposed to 4.0 and 8.0 mg/kg. Data demonstrate an association among furan-induced hepatic cytotoxicity, compensatory cell replication, and liver tumor formation in mice; at high doses ?4.0 mg/kg, furan induced hepatotoxicity, compensatory cell replication and tumorigenesis in a dose-related manner, while furan did not produce tumors at cytotoxic doses of 1.0 and 2.0 mg/kg.     

Protective effect of Moringa oleifera leaves against gentamicin-induced nephrotoxicity in rabbits

Oxidative stress due to abnormal production of reactive oxygen species has been implicated in the nephrotoxicity induced by gentamicin. The nephroprotective effect of aqueous-ethanolic extract of Moringa oleifera leaves (150 and 300 mg/kg) was evaluated against gentamicin-induced (80 mg/kg) renal injury in rabbits. Serum urea and creatinine levels were evaluated as the markers of renal nephrotoxicity. At the end of the experiment, the kidneys of rabbits were excised for histological examinations and determination of lipid peroxidation levels. Serum urea and creatinine levels were reduced in the M. oleifera (150 and 300 mg/kg) plus gentamicin treated groups. On histological examinations, kidney of intoxicated rabbits groups which received M. oleifera extract showed reparative tendencies. A highly significant (p < 0.01) elevation was observed in lipid peroxidation (LPO) level in the kidneys of gentamicin-intoxicated rabbits whereas combined treatment of M. oleifera and gentamicin group showed a highly significant (p < 0.01) depletion in LPO. The present study indicates that aqueous-ethanolic extract of M. oleifera leaves attenuates renal injury in rabbits treated with gentamicin, possibly by inhibiting lipid peroxidation.     

Crocus sativus L. (saffron) attenuates isoproterenol-induced myocardial injury via preserving cardiac functions and strengthening antioxidant defense system

Saffron (dried stigmas of Crocus sativus L.), a naturally derived plant product, has long been used as a traditional ancient medicine against various human diseases. The aim of the series of experiments was to systematically determine whether saffron exerts cardioprotection in isoproterenol-induced myocardial damage. Male Wistar rats (150–175 g) were divided into five groups: control, isoproterenol (ISO) and three saffron (200, 400 and 800 mg/kg) treatment groups. Aqueous extract of saffron or vehicle was administered orally to rats for four weeks. On days 28 and 29, the animals in ISO and saffron treatment groups were administered ISO (85 mg/kg, s.c.) at an interval of 24 h. On day 30, after recording hemodynamics and left ventricular functions, animals were sacrificed for biochemical, histopathological and electromicroscopical examinations. Isoproterenol challenged animals showed depressed hemodynamics and left ventricular functions as evident by decreased left ventricular rate of peak positive and negative pressure change and elevated left ventricular end-diastolic pressure. Structural and ultrastructural studies further confirmed the damage which was reconfirmed by increased thiobarbituric acid reactive substances (p < 0.001) and decreased creatine kinase-MB and lactate dehydrogenase (p < 0.001). In addition, significant reduction in superoxide dismutase and catalase (p < 0.001) was observed in ISO group. Our results suggested that saffron at all the doses exerted significant cardioprotective effect by preserving hemodynamics and left ventricular functions, maintaining structural integrity and augmenting antioxidant status. Among the different doses used, saffron at 400 mg/kg dose exhibited maximum protective effects which could be due to maintenance of the redox status of the cell reinforcing its role as an antioxidant.     

Effect of chlorpromazine on rat placenta development

We examined the sequential histopathological changes in the placentas from rats exposed to chlorpromazine. Chlorpromazine was intraperitoneally administered on GD 14 at 50 and 100 mg/kg and the placentas were sampled on GDs 14.5, 15, 17 and 21. The incidence of dams with complete fetal resorption was increased from GD 17 up to 20% at 50 mg/kg and 44.4% at 100 mg/kg. The embryo/fetal weights reduced on GDs 15 and 17 at 50 mg/kg and during GDs 15–21 at 100 mg/kg. The placental weights reduced on GD 17 at 50 mg/kg and during GDs 14.5–21 at 100 mg/kg. Histopathologically, in the labyrinth zone, apoptotic cells were scattered in the trophoblastic septa without inhibition of cell proliferation on GDs 14.5 and 15 at 50 and 100 mg/kg in a dose-dependent manner. A decrease in trophoblasts led to labyrinth zone hypoplasia. In the basal zone, apoptotic cells were scattered on GDs 14.5 and 15 at 100 mg/kg, and most of them appeared to be glycogen cells. A decrease in glycogen cells induced the delayed development of glycogen cell islands and the subsequent remaining glycogen cell islands, and led to the cystic degeneration of glycogen cells. In addition, failure of development of the glycogen cell islands led to the impaired interstitial invasion of the glycogen cells, and then metrial gland hypoplasia occurred.