Magnetic resonance imaging of the response of a mouse model of non-small cell lung cancer to tyrosine kinase inhibitor treatment

Mutational activation of the gene for epidermal growth factor receptor (EGFR) is 1 of the main ways by which this receptor induces non-small cell lung cancers (NSCLC). Variant III EGFR (EGFRvIII) is a potential therapeutic target in NSCLC treatment because of the high frequency of deletion mutations in this protein. This study used noninvasive magnetic resonance imaging (MRI) to investigate the role of an EGFRvIII mutant in lung tumorigenesis and tumor maintenance as well as its response to the EGFR small molecule inhibitor erlotinib (Tarceva) on bitransgenic mice. Both spin-echo and gradient-echo sequences with and without cardiac and respiratory gating were performed to image the invasive mouse lung tumor driven by EGFRvIII mutation. Tumor volumes were measured based on 2-dimensional axial MRI; 3-dimensional rendering of the images were obtained to demonstrate the spatial location and distribution of the tumor in the lung. The MRI results indicated that the tumor driven by the EGFRvIII mutation was generated and maintained in the bitransgenic mice with the use of doxycycline. Tumor monitoring via MRI showed that Erlotinib can significantly inhibit the growth of tumor in vivo. MRI has the ability to image mouse lung tumor with different sequences focusing on tissue contrasts between tumor and surroundings. The MRI approaches in this work can be applied on other antitumor drug treatment evaluation in vivo when appropriate sequences are chosen.     

Metformin inhibits mTOR–HIF-1α axis and profibrogenic and inflammatory biomarkers in thioacetamide-induced hepatic tissue alterations

The potential inhibitory effect of the antidiabetic and anti-inflammatory drug, metformin on thioacetamide (TAA)-induced hepatotoxicity associated with the inhibition of mammalian target of rapamycin (mTOR)–hypoxia-inducible factor-1α (HIF-1α) axis has not been investigated before. Therefore, we tested whether metformin can protect against liver injuries including fibrosis induced by TAA possibly via the downregulation of mTOR–HIF-1α axis and profibrogenic and inflammatory biomarkers. Rats either injected with TAA (200 mg/kg; twice a week for 8 weeks) before being killed after 10 weeks (model group) or were pretreated with metformin (200 mg/kg) daily for 2 weeks before TAA injections and continued receiving both agents until the end of the experiment, at Week 10 (protective group). Using light and electron microscopy examinations, we observed in the model group substantial damage to the hepatocytes and liver tissue such as collagen deposition, infiltration of inflammatory cells, and degenerative cellular changes with ballooned mitochondria that were substantially ameliorated by metformin. Metformin also significantly ( p < 0.05) inhibited TAA-induced HIF-1α, mTOR, the profibrogenic biomarker α-smooth muscle actin, tissue inhibitor of metalloproteinases-1, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), alanine aminotransferase (ALT) and aspartate aminotransferase in harvested liver homogenates and blood samples. In addition, a significant ( p < 0.01) positive correlation between hypoxia scoring (HIF-1α) and the serum levels of TNF-α ( r = 0.797), IL-6 ( r = 0.859), and ALT ( r = 0.760) was observed. We conclude that metformin protects against TAA-induced hepatic injuries in rats, which is associated with the inhibition of mTOR–HIF-1α axis and profibrogenic and inflammatory biomarkers; thus, may offer therapeutic potential in humans.     

Acute exposure to Catha edulis depresses contractility and induces myocardial infarction in spontaneously contracting,isolated rabbit’s heart

Khat chewing is a recreational habit known to pose major socio-economic and medical problems in countries of Southern Arabia and the Horn of Africa. Among other adverse health effects, khat chewing has been associated with an increased risk of myocardial infarction (MI) in heavy consumers. This study was carried out to examine the direct effects of Catha edulis extract on contractility of spontaneously contracting, isolated rabbit heart and to investigate its mechanism of action. Isolated six rabbit’s hearts attached to a Langendorff apparatus were perfused with extract at a constant flow rate and continuously bubbled with a 95% O₂/5% CO₂ gas mixture. Each heart served as its own control, as responses were recorded before and after administration of C. edulis extract. Varying concentrations of extract (50, 100 and 250 mg/ml) were loaded in the perfusate, their effects recorded and effluent fluid collected for assay of cardiac enzymes. Histological examination of the cardiac tissue was performed at the end of perfusion with 250 mg/ml extract. This study revealed that acute exposure to C. edulis extract exerted negative inotropic and chronotropic effects on isolated hearts. The extract also had a vasoconstrictor effect on coronary vessels, independent of α₁ adrenergic receptor stimulation. Histological examination of hearts perfused with 250 mg/ml C. edulis extract revealed the presence of histological changes unique to myocardial infarction, a finding consistent with observed increased levels of cardiac enzymes in perfusates. Thus, we have demonstrated experimentally a direct cardiac depressant- and MI inducing effects of C. edulis extract. These results are consistent with the earlier reported deleterious effects of khat on cardiovascular function among khat chewers.