Carbonic anhydrase inhibition boosts the antitumor effects of Imatinib mesylate via potentiating the antiangiogenic and antimetastatic machineries.

Carbonic anhydrase inhibitors have emerged in the past few years as an interesting candidate for the development of novel unconventional strategies. Despite their effect in tumor regression via inhibition of tumor acidification, their potential role is not yet fully elucidated. Herein, we investigated whether acetazolamide (AZ) could modulate imatinib (IM) anticancer activity, both in breast cancer cells (T47D) and in isolated tumor specimens of Ehrlich ascites carcinoma (EAC). The impact of this combination on angiogenesis was evidenced by decreasing PDGF-A expression and enhancing that of TSP-1. In the meantime, AZ significantly suppressed IM-induced attenuation of VEGF secretion in T47D cells, most probably due to NO inhibition. The combination also dramatically decreased the metastatic activity of T47D cells by mitigating the protein levels of MMP-2 and -9 and phosphorylation of p38 MAPK, while increasing the expression of TIMP-1 and -2. In addition, a strong proapoptotic effect was observed in T47D cells after combining AZ and IM in terms of increased caspase-9 and -3 activities. Interestingly, these results were confirmed by the reduction in the isolated tumor volume, MVD, Ki-67 and VEGF expression. Eventually, the study provides a new therapeutic strategy for treating cancer.

Neuroprotective effect of EGb761® and low-dose whole-body γ-irradiation in a rat model of Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. The present study was undertaken to investigate the pretreatment effects of standardized Ginkgo biloba extract (EGb761(®)) and low-dose whole-body γ-irradiation on the neurological dysfunction in the reserpine model of PD. Male Wistar rats were pretreated orally with EGb761 or fractionated low-dose whole-body γ-irradiation or their combination, then subjected to intraperitoneal injection of reserpine (5 mg/kg body weight) 24 h after the final dose of EGb761 or radiation. Reserpine injection resulted in the depletion of striatal dopamine (DA) level, increased catalepsy score, increased oxidative stress indicated via depletion of glutathione (GSH), increased malondialdehyde (MDA) and iron levels, decreased DA metabolites metabolizing enzymes; indicated by inhibition by glutathione-S-transferase, and nicotinamide adenine dinucleotide phosphate (NADPH)-quinone oxidoreductase (NQO) activities, mitochondrial dysfunction; indicated by declined complex I activity, and adenosine triphosphate (ATP) level and increased apoptosis; indicated by decreased mitochondrial B cell lymphoma-2 (Bcl-2) protein level and by transmission electron microscope. EGb761 and low-dose γ-radiation ameliorated the reserpine-induced state of oxidative stress, mitochondrial dysfunction, and apoptosis in brain. It can be concluded that EGb761, a widely used herbal medicine and low dose of γ-irradiation have protective effects for combating Parkinsonism possibly via replenishment of GSH levels.

Differential microRNAs expression in serum of patients with lung cancer, pulmonary tuberculosis, and pneumonia.

MicroRNAs (miRNAs) play critical regulatory roles in the physiological and pathological processes. The high stability of miRNAs in human serum represents attractive novel diagnostic biomarkers of clinical conditions. Several studies have shown that aberrant expression of miRNAs in human cancer including lung cancer, but little is known about their effects on some infectious lung diseases such as pulmonary tuberculosis (TB) and pneumonia. In this study, we investigated miRNA expression pattern in serum of Egyptian patients with lung cancer, TB, and pneumonia compared with matched healthy controls. Using microarray-based expression profiling followed by real-time quantitative polymerase chain reaction validation, we compared the levels of a series of circulating miRNAs (miR-21, miR-155, miR-182, and miR-197) in serum from patients with lung cancer (n = 65), pulmonary tuberculosis (n = 29), pneumonia (n = 29), and transudate (n = 16) compared with matched healthy controls (n = 37). MiRNA SNORD68 was the housekeeping endogenous control. We found that the serum levels of miR-21, miR-155, and miR-197 were significantly elevated in the patients with lung cancer and pneumonia whereas miR-182 and miR-197 levels were increased only in patients with lung cancer and TB, respectively, compared with controls. Receiver operating characteristic analysis revealed that miR-182, miR-155, and miR-197 have superior diagnostic potential in discriminating patients with lung cancer, pneumonia, and TB, respectively, from controls. Our results conclude that the differential expression of the four studied miRNAs can be potential non-invasive biomarkers for patients with lung cancer, TB and pneumonia.

Possible role of vitamin E, coenzyme Q10 and rutin in protection against cerebral ischemia/reperfusion injury in irradiated rats.

PURPOSE: To investigate the possible role of vitamin E, coenzyme Q10 and rutin in ameliorating the biochemical changes in brain and serum induced by cerebral ischemia/reperfusion (I/R) in whole body γ-irradiated rats. MATERIALS AND METHODS: Cerebral ischemia was induced in male Wistar rats (either irradiated or non-irradiated) followed by reperfusion. RESULTS: I/R increased brain content of malondialdehyde (MDA) and depleted its glutathione (GSH) content with a compensatory elevation in cytosolic activities of glutathione peroxidase (GPx) and glutathione reductase (GR) enzymes. It also raised brain cytosolic lactate dehydrogenase (LDH) activity and calcium (Ca(2+)) level. Furthermore, I/R provoked an inflammatory response reflected by an increment in serum levels of the proinflammatory cytokines tumour necrosis factor-α (TNF-α) and interlukin-1ß (IL-1ß). Moreover, induction of I/R in irradiated rats resulted in a further increase in brain oxidative stress and cytosolic LDH activity, disturbed brain Ca(2+) homeostasis and exaggerated the inflammatory reaction. During irradiation, administration of each of vitamin E, coenzyme Q10 (CoQ10) and rutin to irradiated rats before induction of I/R, alleviated the brain oxidative stress. Moreover, these antioxidants caused attenuation of the rise of the cytosolic activities of GPx and GR. A lowering effect of the cytosolic LDH activity and Ca(2+) level were caused by treatment with antioxidants. Each of vitamin E and rutin revealed an anti-inflammatory action of these antioxidants, while CoQ10 had no effect on serum levels of TNF-α and IL-1ß. CONCLUSION: These findings indicate that supplementation with either vitamin E, CoQ10 or rutin ameliorated most of the biochemical changes induced by I/R in irradiated rat brain and serum.