Hepato-protective effect of rutin via IL-6/STAT3 pathway in CCl4-induced hepatotoxicity in rats

BACKGROUND: Carbon tetrachloride (CCl4) induces hepatotoxicity in animal models, including the increased blood flow and cytokine accumulation that are characteristic of tissue inflammation. The present study investigates the hepato-protective effect of rutin on CCl4-induced hepatotoxicity in rats. RESULTS: Forty male Wistar rats were divided into four groups. Group I (control group) received 1 mL/kg of dimethyl sulfoxide intragastrically and 3 mL/kg olive oil intraperitoneally twice a week for 4 weeks. Group II received 70 mg/ kg rutin intragastrically. Groups III and IV received CCl4 (3 mL/kg, 30 % in olive oil) intraperitoneally twice a week for 4 weeks. Group IV received 70 mg/kg rutin intragastrically after 48 h of CCl4 treatment. Liver enzyme levels were determined in all studied groups. Expression of the following genes were monitored with real-time PCR: interleukin-6 (IL-6), dual-specificity protein kinase 5 (MEK5), Fas-associated death domain protein (FADD), epidermal growth factor (EGF), signal transducer and activator of transcription 3 (STAT3), Janus kinase (JAK), B-cell lymphoma 2 (Bcl2) and B-cell lymphoma-extra-large (Bcl-XL). The CCl4 groups showed significant increases in biochemical markers of hepatotoxicity and up-regulation of expression levels of IL-6, Bcl-XL, MEK5, FADD, EGF, STAT3 and JAK compared with the control group. However, CCl4 administration resulted in significant down-regulation of Bcl2 expression compared with the control group. Interestingly, rutin supplementation completely reversed the biochemical markers of hepatotoxicity and the gene expression alterations induced by CCl4. CONCLUSION: CCl4 administration causes alteration in expression of IL-6/STAT3 pathway genes, resulting in hepatotoxicity. Rutin protects against CCl4-induced hepatotoxicity by reversing these expression changes.

Synthesis and investigation of novel shelf-stable, brain - specific chemical delivery system

A 1,4-dihydropyridine - pyridinium salt type redox system is described as a general and flexible method for site-specific and sustained delivery of drugs into the brain. Monoamine oxidase inhibitors [MAOIs] were used as a model example to be delivered into the brain. Chemical and biological oxidations of these compounds were investigated. The prepared 1,4-dihydropyridines were subjected to various chemical and biological oxidation to evaluate their ability to cross blood brain barrier [BBB], and to be oxidized biologically into their corresponding quaternary compounds. 1-[Ethoxy-carbonylmethyl]-3,5-bis[N-[2-fluoro-benzylideneamino] carbamoyl]-1,4-dihydropyridine [31] proved to cross BBB in adequate rate and converted by the oxidizing enzymes into the corresponding quaternary salt N-[ethoxycarbonylmethyl]-3,5-bis [N-[2-fluorobenzylideneamino] carbamoyl] pyridinium bromide [20]. Stability studies of the synthesized chemical delivery systems [CDSs] at various pH values and temperatures showed that the shelf life time of a solution containing compound 31 is 20.53 days at 5°C, which recommend a lower storage temperature for such solutions. The prepared CDSs proved to be fairly stable for powder form storage. The stability of the prepared compounds is attributed to the conjugation of the two carboxylic functions at C3 and C5 of the pyridine ring with their adjacent double bonds. These results are in consistency with the original rationale design

Effect of valproic acid on food intake and nociception in morphine dependent mice

The anorectic and antinociceptive effects or valproic acid [VPA] were studied in morphine-dependent rnice in comparison with normal ones. For this purpose, the food intake of animals deprived of food for 24 hours and the hot plate reaction time, were studied. Morphine-dependency was induced by i.p. injections of morphine HC1 [40 mg /kg; twice daily for 3 days]. Morphine-dependent animals showed a significant decrease in food intake [p < 0.05], when compared with control mice [non-morphinized]. Acute administration of VPA [100, 200 and 300 mg /kg, i.p.] significantly potentiated the anorexia observed in morphine-dependent mice. VPA [200 and 300 mg /kg, i.p.] alone produced a significant decrease in food intake [p < 0.05] in non-morphinized animals, in the study of antinociception, a significant increase [p < 0.001] in hot-plate latency was observed in morphine-dependent animals, as compared to control mice. Treatment with VPA alone produced a significant increase [p < 0.05] in hot-plate latency in saline-pretreated animals in comparison with saline-pretreated control group. However, the administration of VPA [100 and 200 mg /kg, i.p.] to morphine-dependent animals significantly decreased [p < 0.05] their hot-plate latency as compared to the control group, in conclusion, VPA exhibited anorectic and antinociceptive activities in mice. VPA potentiated the anorexia seen in mice, which were rendered dependent to morphine, whereas the drug inhibited the antinociceptive activity observed in these mice. It seems from the present study that VPA is probably toxic in morphine-dependent subjects, since it might potentiate the anorectic and inhibit the analgesic effects

Reproductive, cytological and biochemical toxicity of Yohimbe in male Swiss albino mice / 亚洲男科学杂志(英文版)

<p><b>AIM</b>To study the effect of Corynanthe Yohimbe (Yohimbe) on germ cells in Swiss albino mice.</p><p><b>METHODS</b>Adult male mice were orally (gavage) treated with different doses (188, 375 and 750 mg/[kg x day]) of aqueous suspension of Yohimbe for 90 days. The following parameters were evaluated: (i) reproductive organ weight, (ii) motility and count of sperm, (iii) study on rate of pregnancy and mean implants, (iv) spermatozoa morphology, (v) cytology of the testes chromosomes, and (vi) biochemical study on estimation of proteins, RNA, DNA, malondialdehyde, nonprotein sulfhydryl (NP-SH) and hormones.</p><p><b>RESULTS</b>The treatment caused significant increase in the weight of seminal vesicles, motility and count of spermatozoa, pre- and post-implants. Male fertility was decreased. These results are confirmed by our data on spermatozoa abnormalities and chromosomal aberrations. The data on biochemical parameters showed increase of malondialdehyde and depletion of NP-SH, proteins, RNA and DNA in the testicular cells.</p><p><b>CONCLUSION</b>Our results elucidated the role of free radical species in cytological and reproductive changes, possibly, under the influence of yohimbine (principal constituent of Yohimbe) on neurotransmitters, including norephinephrine. These data warrant careful use of Yohimbe.</p>

Antinociceptive activity of vigabatrin in mice

Vigabatrin [an inhibitor of GABA catabolism] was examined for its antinociceptive activity, changes in locomotor activity and body temperature in mice after acute treatment over a period of 24 hours. Vigabatrin [125 and 500 mg/kg i.p] resulted in rapid antinociception within 15 min. At the low dose of vigabatrin this effect returned to normal after-45 min but persisted more than 12 hours at the high dose. With the same dose regimen, the locomotor activity declined significant, with persistence up to 24 hour of the treatment. The effect of this treatment on body temperature was dose related being significantly reduced at 15 min. It returned to normal after 6 hours of treatment with vigabatrin 500 mg/kg. Treatment with bicuculline [a specific GABA A-receptor antagonist] was found to be minimally effective to avert locomotor or body] temperature changes induced by vigabatrin. Picrotoxin [a GABA Aand GABA gated-chloride ion channel blocker] was also ineffective on the hot-plate latency, locomotion or body temperature. However, picrotoxin slightly though significantly [p<0.05] reversed the changes in locomotion and rectal temperature only at first observation [15 min]. On the other hand, naloxone did not antagonize the effect of vigabatrin on body temperature but caused a significant decline in hot-plate latency at 45 min, perhaps because of hepotentiation of naloxone by vigabatrin in the induction of hyperalgesic response. These effects are thought to be a result of neuromediator interactions with the probable involvement of GABA receptor mediated processes and a possible direct effect of drug

Genetic and biochemical effects of Ginkgo Biloba on somatic and germ cells of mice

Ginkgo biloba has immense folkloric significance in the treatment of Alzheimer's disease and age-related dementia. The present study on the genetic and biochemical effects of Ginkgo biloba was undertaken, in view of the reports on the carcinogenic effects of the dietary supplements containing Ginkgo biloba. the cytotoxic and mutagenic potentials of its constituents and a paucity of literature on the genotoxicity. The protocol included the oral treatment of mice with different doses [100. 200 and 400 mg/kg] of Ginkgo biloba for 7 consecutive days. The following experiments were conducted: [i] cytological studies on micronucleus test. [ii] cytological analysis of spermatozoa abnormalities, [iii] quantification of proteins and nucleic acids in hepatic and testicular cells and [iv] estimation of malondialdehyde [MDA] and nonprotein sulihydryl [NPSH] in hepatic and testicular cells. The results obtained in this study clearly demonstrate lack of any effect of Ginkgo biloba on the frequency of micronuclei, ratio of polychromatic erythrocytes [PCE]/normochromatic erythrocytes [NCE], spermatozoa abnormalities and hepatic concentrations of nucleic acids, while the nucleic acid levels of testicular cells were significantly depleted. The results on testicular nucleic acids failed to reflect our data on spermatozoa abnormality. The discordance might be related to the role of excurrent duct system in eliminating morphologically abnormal spermatozoa during transit from testis to vas deferens and caudac epididymis. The observation on MDA and NP-SH showed Ginkgo biloha to cause genesis of lipid peroxides. This study indicates that the changes observed in the somatic and germ cells were independent of the Ginkgo biloba-induced genesis of lipid peroxides. The observed changes of Ginkgo biloba might be related to its effect on the increase of MDA and depletion of NP-SH. In view of the observed oxidant potentials, our study warrants careful use of Ginkgo biloba

Renal cell carcinoma in children. Prognostic factors

To determine the outcome in childhood renal cell carcinoma and the role of surgical and radiation treatment. The records of 21 children with renal cell carcinoma were reviewed, 15 patients treated in the University of Toronto centers from 1959 through to 1997 and 6 patients treated in King Faisal Specialist Hospital, Riyadh, Kingdom of Saudi Arabia from 1975 through to 1998. The age was 3-17 [median 13] years. Systematic metastases were present at diagnosis in 5 patients. Regional nodal spread was present in 9 patients and 7 patients had localized disease alone. In the 16 M0 patients, the surgical treatment was radical nephrectomy [14 patients] partial nephrectomy [one patient] and wedge resection [one patient]. Postoperative radiation treatment was utilized in 8 [50%] of these patients. The 5 year survival rate for all patients was 52%, and for M0 patients was 70%. No patient with systematic metastases at diagnosis survived beyond 26 months. Four of 7 node negative patients and 8 of 9 node positive patients remained in first complete remission, with the duration of follow up 1-30 [Median 5] years. Seven of 8 M0 patients who did not receive adjuvant radiation therapy continued in first remission [3N0, 2NI, 2N2], compared with 5 of 8 patients who received postoperativeradiation treatment [1 N0, 2 NI, 2 N2]. The prognosis of localized renal cell carcinoma in childhood may be better than in the adult. Gross complete resection is required for long term survival. Elective postoperativeradiation treatment is not indicated

Protective effect of thymoquinone and aminoguanidine against paraquat induced cardiotoxicity: possible role of nitric oxide synthase

Paraquat induced cardiotoxicity is due to oxidative damage produced by free radicals generations. The present study was undertaken to investigate whether inhibition of nitric oxide synthase by aminoguanidine, an inhibitor of nitric oxide [NO] synthase, can protect against paraquat-induced cardiomyopathy and to investigate whether thymoquinone, a potent superoxide radical scavenger, can protect against paraquat-induced cardiotoxicity in rats. Administration of paraquat, 50 mg/kg I P induce cardiotoxicity as indicated by a significant increase in the level of lipid peroxide, significant depletion of the reduced glutathione in heart tissue and significant decrease in the activity of antioxidant enzymes glutathione peroxidase [EC 1.11.1.9] and catalase [EC 1.11.1.6]. Oral administration of aminoguanidine [50 mg/100 mL in drinking water] or thymoquinone [5 mg/100 mL in drinking water] for 5 days before 2 days after single injection of paraquat [50 mg/kg, IP] leads to return of lactate dehydrogenase [EC 1.1.1.27] and creatine phosphokinase [EC 2.7.3.2] to normal values