ABSTRACT
Background: Tumor angiogenesis is considered as a crucial pathologic feature of cancer with a key role in multidrug resistance (MDR). Adverse effects of the currently available drugs and the development of resistance to these remain as the hardest obstacles to defeat. Objetive: This work explores flora from Argentina as a source of new chemical entities with antiangiogenic activity. Methods: Tube formation assay using bovine aortic endothelial cells (BAECs) was the experiment of choice to assess antiangiogenic activity. The effect of the pure compound in cell invasiveness was investigated through the trans-well migration assay. The inhibitory effect of the pure compound on VEGFR-2 and PKC isozymes α and ß2 activation was studied by molecular and massive dynamic simulations. Cytotoxicity on peripheral blood mononuclear cells and erythrocyte cells was evaluated by means of MTT and hemolysis assay, respectively. In silico prediction of pharmacological properties (ADME) and evaluation of drug-likeness features were performed using the SwissADME online tool. Results: Among the plants screened, T. minuta, showed an outstanding effect with an IC50 of 33.6 ± 3.4 µg/ml. Bio-guided isolation yielded the terthiophene α-terthienylmethanol as its active metabolite. This compound inhibited VEGF-induced tube formation with an IC50 of 2.7 ± 0.4 µM and significantly impaired the invasiveness of bovine aortic endothelial cells (BAECs) as well as of the highly aggressive breast cancer cells, MDA-MB-231, when tested at 10 µM. Direct VEGFR-2 and PKC inhibition were both explored by means of massive molecular dynamics simulations. The results obtained validated the inhibitory effect on protein kinase C (PKC) isozymes α and ß2 as the main mechanism underlying its antiangiogenic activity. α-terthienylmethanol showed no evidence of toxicity against peripheral blood mononuclear and erythrocyte cells. Conclusion: These findings support this thiophene as a promising antiangiogenic phytochemical to fight against several types of cancer mainly those with MDR phenotype.
ABSTRACT
INTRODUCTION: Is the application of ultrasound effective on pain, the severity of the symptoms, physical function, strength, and neurophysiological parameters of the median nerve conduction in patients with carpal tunnel syndrome? EVIDENCE ACQUISITION: A systematic review and meta-analysis of randomized controlled trials was performed by using a structured search strategy in Scopus, CINAHL, Web of Science and PEDro databases. All the primary studies included samples with carpal tunnel syndrome treated by: ultrasound versus no treatment, therapeutic ultrasound versus sham ultrasound, ultrasound and usual care versus usual care, or ultrasound and other intervention versus the same intervention. The outcomes measures registered were pain, severity of symptoms, function, strength, and neurophysiological parameters (motor distal latency and sensory distal latency) of the median nerve. Methodological quality was evaluated by PEdro Scale. EVIDENCE SYNTHESIS: Ten clinical trials met the inclusion criteria for the systematic review. Eight trials were meta-analyzed, which included a total of 2069 patients with carpal tunnel syndrome. The methodological quality of the included studies ranged among limited (5 trials), moderate (3 trials), and high (2 trials). In one of the electrophysiological parameters (motor distal latency), a significant difference between groups after the use of ultrasound was observed (MD=-0.10; fixed 95% CI=-0.20, -0.01; P=0.04). No significant differences between groups were observed at post-treatment for pain (P=0.29), severity of symptoms (P=0.99), function (P=0.54), strength (P=0.27) and for the rest of the electrophysiological parameters evaluated (P>0.05). CONCLUSIONS: The use of ultrasound on patients with carpal tunnel syndrome seems to improve motor distal latency. This finding implies a partial improvement at the neurophysiological level, representing a reduction in the grade of clinical severity. Additional clinical trials with a high methodological quality are needed to investigate the doses at which ultrasound are most effective.
