Chemoprotective effects of captopril against cyclophosphamide-induced genotoxicity in mouse bone marrow cells

The protective effects of captopril (CAP) against toxicity induced by cyclophosphamide (CP) in mice were investigated using the micronucleus assay for anticlastogenic activity in mouse bone marrow cells and liver glutathione (GSH) content. A single intraperitoneal (i.p.) injection of CAP at 50, 100, and 200 mg/kg 1 h prior to cyclophosphamide (50 mg/kg) reduced the frequency of micronucleated polychromatic erythrocytes (MnPCEs). All three doses of CAP significantly reduced the frequency of MnPCEs in mouse bone marrow compared to the group treated with CP alone (P<0.0001–0.01). CP significantly depleted the GSH content in liver but the application of CAP at a dose of 100 mg/kg 1 h before CP treatment repleted the GSH content. CAP exhibited concentration-dependent antioxidant activity, scavenging >96% of the 1,1-diphenyl-2-picryl hydrazyl free radicals when used at a concentration of 0.2 mM. It appears that CAP, due to its antioxidant activity and by increasing GSH levels, can modulate the reduced cellular thiol content induced by CP and reduce the genotoxicity of CP in bone marrow cells.     

Citrus extract modulates genotoxicity induced by cyclophosphamide in mice bone marrow cells

The protective effect of citrus extract was investigated by using the micronucleus assay for anticlastogenic activity in mouse bone marrow cells; liver glutathione (GSH) content was determined against toxicity induced by cyclophosphamide. Mice were orally (gavage) pretreated with solutions of citrus peel extract (Citrus aurantium var. amara) prepared at three different doses (100, 200 and 400 mg kg(-1;) body weight) for 7 consecutive days. Then mice were injected intraperitoneally on the seventh day with cyclophosphamide (50 mg kg(-1)) and after 24 h killed for the evaluation of micronucleated polychromatic erythrocytes (MnPCEs) in bone marrow cells. Non-protein thiol levels in liver were estimated in mice injected with citrus extract with or without cyclophosphamide treatment. Administration of citrus extract before cyclophosphamide treatment significantly reduced the frequency of MnPCEs in mice bone marrow compared with the group treated with cyclophosphamide alone (P<0.0001-0.05). Citrus extract at a dose of 400 mg kg(-1) reduced MnPCEs 2.8 fold against genotoxicity induced by cyclophosphamide. Administration of cyclophosphamide depleted the GSH level in liver. Citrus extract showed excellent scavenging effects on 1,1-diphenyl-2-picryl hydrazyl radical (DPPH) at a concentration of 1.6 mg mL(-1). Application of citrus extract 1 h before cyclophosphamide treatment allowed GSH content to reach the normal level. It appeared that citrus extract, particularly flavonoids constituents with antioxidative activity, may return the GSH level to normal in stress conditions and reduces genotoxicity induced by cyclophosphamide in bone marrow cells.     

Improved identification of von Hippel-Lindau gene alterations in clear cell renal tumors

PURPOSE: To provide a comprehensive, thorough analysis of somatic mutation and promoter hypermethylation of the von Hippel-Lindau (VHL) gene in the cancer genome, unique to clear cell renal cancer (ccRCC). Identify relationships between the prevalence of VHL gene alterations and alteration subtypes with patient and tumor characteristics. EXPERIMENTAL DESIGN: As part of a large kidney cancer case-control study conducted in Central Europe, we analyzed VHL mutations and promoter methylation in 205 well-characterized, histologically confirmed patient tumor biopsies using a combination of sensitive, high-throughput methods (endonuclease scanning and Sanger sequencing) and analysis of 11 CpG sites in the VHL promoter. RESULTS: We identified mutations in 82.4% of cases, the highest VHL gene mutation prevalence reported to date. Analysis of 11 VHL promoter CpG sites revealed that 8.3% of tumors were hypermethylated and all were mutation negative. In total, 91% of ccRCCs exhibited alteration of the gene through genetic or epigenetic mechanisms. Analysis of patient and tumor characteristics revealed that certain mutation subtypes were significantly associated with Fuhrman nuclear grade, metastasis, node positivity, and self-reported family history of RCC. CONCLUSION: Detection of VHL gene alterations using these accurate, sensitive, and practical methods provides evidence that the vast majority of histologically confirmed ccRCC tumors possess genetic or epigenetic alteration of the VHL gene and support the hypothesis that VHL alteration is an early event in ccRCC carcinogenesis. These findings also indicate that VHL molecular subtypes can provide a sensitive marker of tumor heterogeneity among histologically similar ccRCC cases for etiologic, prognostic, and translational studies.     

Laparoscopic Roux-en-Y gastric bypass in intestinal non-rotation

There are some incidental findings during bariatric surgery. Some of these findings may make the operation more challenging than routine surgery. Intestinal malrotation/non-rotation are rare congenital anomalies that may remain asymptomatic until bariatric surgery. Here we report a 30-year-old female patient with unknown intestinal congenital anomaly which was diagnosed during surgery and she underwent Roux-en-Y gastric bypass, which can be a challenging procedure in intestinal malrotation/non-rotation and conversion may be needed.     

Polymorphic CT dinucleotide repeat in the GATA3 gene and risk of breast cancer in Iranian women

8p21.3 deletion was recently characterized in B cell lymphoma suggesting that TRAIL-R1 and TRAIL-R2 may be the target of the deletion and act as dosage-dependent tumor suppressor genes. As multiple myeloma is a plasma cell malignancy originating from B-lineage clonogenic cells, the idea was why do not evaluate this deletion in this pathology. Thus, interphase FISH studies with two mixtures of probes spanning the 8p21.3 region were retrospectively performed in 37 French multiple myeloma patients. Surprisingly, deletion in this region was found in 8 (21.6 %) patients. Interestingly, this deletion was usually associated with a 13q14 deletion. In two among them, the patients showed also translocation (4;14)(p16;q32) and one other harbor also a deletion of the P53 gene. These results indicate that deletion of TRAIL-R1 and TRAIL-R2 may be relevant to the loss of 8p21.3 and may play an important role the pathogenesis of MM. The association of this deletion with other well-known chromosomal aberrations in multiple myeloma suggests, as previously described, that these anomalies are not randomly distributed, but strongly interconnected.     

Morphine sex-dependently induced place conditioning in adult Wistar rats

The present study was conducted to investigate the potential sex-differences in morphine-induced conditioned place preference. A 3-day unbiased conditioning procedure was used to establish conditioned place preference in adult male and female Wistar rats (weighing 200-250 g). The effect of morphine on locomotor activity of subjects was also studied. Naloxone (0.5-2 mg/kg, i.p.), a selective antagonist of mu-opioid receptor or sulpiride (0.5-2 mg/kg, s.c.), a selective antagonist of dopamine D(2) receptor was administered, during conditioning, to indicate the receptor-mediated mechanisms governing upon possible sex-differences to the opioid response. Results show that morphine (0.5-10 mg/kg, s.c.) differently produced a significant place preference in female and male Wistar rats. Although, the opioid maximum response in both sexes was observed at 7.5 mg/kg, but, it was found that female rats acquired conditioned place preference at a lower dose (0.5 mg/kg, s.c.) of morphine compared to male rats. Moreover, the increase in morphine-induced response at higher doses (5-10 mg/kg, s.c.) was more pronounced in females than the males, indicating that female Wistar rats are more sensitive to the place conditioning induced by morphine. Also, the females were more sensitive to locomotor activation induced by morphine at least at one dose (7.5 mg/kg). Animals' body-weight at 10 mg/kg of opioid was increased, the effect that was not dependent to sex. The results also demonstrate that naloxone (1 and 2 mg/kg, i.p.) induced a significant place preference in two sexes with no significant effect on animals' locomotor activity. The antagonist in males but not in females showed a significant effect on animals' body-weight. Naloxone (0.5-2 mg/kg, i.p.) prior-administration to morphine, during conditioning, attenuated the opioid response in two sexes. The attenuation of the morphine response was more pronounced in males than the other sex at the higher dose (2 mg/kg) of the antagonist. In addition, the preadministration of naloxone, during morphine conditioning, both attenuated the drug-induced hyperactivity in females and decreased the animals' body-weight, albeit more effectively in females than the males. Sulpiride injections (1 and 2 mg/kg s.c.), during the conditioning period, induced a significant aversion in males but not in females with no significant effect either on locomotor activity or body-weight in both sexes. When sulpiride (0.5-2 mg/kg, s.c.), during conditioning, was morphine pre-injected, the antagonist at higher doses significantly attenuated the opioid response in males, reflecting the involvement of dopamine D(2) receptor in sex-dependent morphine-conditioned place preference. Prior-injections of sulpiride to morphine produced a significant effect on locomotor activity of females. The effect of the antagonist preinjections on body-weight was also observed in males. Present results indicate sex-differences both in reinforcing and locomotor activity effects of morphine in Wistar rats.