Association of PON1, TNF-α and TGF-ß gene polymorphisms with prognosis in oral and oropharyngeal squamous cell carcinoma.

OBJECTIVE: The oral and oropharyngeal squamous cell carcinoma (OOSCC) accounts for 90-95% of tumours in the oral cavity. Single nucleotide polymorphism (SNP) in the coding region of PON1, tumour necrosis factor-alpha (TNF-α) and transforming growth factor-beta (TGF-ß) have been associated with to development of different cancers. Our aim was to investigate the prognostic value of PON1 (rs854560 and rs662), TNF-α (rs1800629 and rs361525) and TGF-ß (rs1800469) SNPs in OOSCC. MATERIALS AND METHODS: We genotyped 163 OOSCC patients and 146 patients from group of control for PON1 (rs854560 and rs662), TNF-α (rs1800629 and rs361525) and TGF-ß (rs1800469) SNPs by real-time polymerase chain reaction (PCR). RESULTS: TNF-α (rs1800629) GG genotype was significantly more frequent in intraoral lesions and clinical stages III and IV, while the polymorphic AA genotype in lip lesion and clinical stages I and II. Moreover, TGF-ß (rs1800469) AG and AA genotypes were significantly more frequent in larger tumours (T3 e T4). TNF-α (rs1800629) AG genotype had poor survival and patients carrying the PON1 (rs662) TT genotype tended to poor survival. CONCLUSIONS: Results suggest that the rs1800629 and rs1800469 could exert influence in the more aggressive behaviour of OOSCC and the genotypes AG of rs1800629, and TT of rs662 could be markers with prognostic value in OOSCC.

Nerol Attenuates Ouabain-Induced Arrhythmias.

Nerol (C10H18O) is a monoterpene found in many essential oils, such as lemon balm and hop. In this study, we explored the contractile and electrophysiological properties of nerol and demonstrated its antiarrhythmic effects in guinea pig heart preparation. Nerol effects were evaluated on atrial and ventricular tissue contractility, electrocardiogram (ECG), voltage-dependent L-type Ca2+ current (ICa,L), and ouabain-triggered arrhythmias. Overall our results revealed that by increasing concentrations of nerol (from 0.001 to 30 mM) there was a significant decrease in left atrium contractile force. This effect was completely and rapidly reversible after washing out (~ 2 min). Nerol (at 3 mM concentration) decreased the left atrium positive inotropic response evoked by adding up CaCl2 in the extracellular medium. Interestingly, when using a lower concentration of nerol (30 µM), it was not possible to clearly observe any significant ECG signal alterations but a small reduction of ventricular contractility was observed. In addition, 300 µM nerol promoted a significant decrease on the cardiac rate and contractility. Important to note is the fact that in isolated cardiomyocytes, peak ICa,L was reduced by 58.9 ± 6.31% after perfusing 300 µM nerol (n=7, p<0.05). Nerol, at 30 and 300 µM, delayed the time of onset of ouabain-triggered arrhythmias and provoked a decrease in the diastolic tension induced by the presence of ouabain (50 µM). Furthermore, nerol preincubation significantly attenuated arrhythmia severity index without changes in the positive inotropism elicited by ouabain exposure. Taken all together, we may be able to conclude that nerol primarily by reducing Ca2+ influx through L-type Ca2+ channel blockade lessened the severity of ouabain-triggered arrhythmias in mammalian heart.

Geraniol blocks calcium and potassium channels in the mammalian myocardium: useful effects to treat arrhythmias.

Geraniol is a monoterpene present in several essential oils, and it is known to have a plethora of pharmacological activities. In this study, we explored the contractile and electrophysiological properties of geraniol and its antiarrhythmic effects in the heart. The geraniol effects on atrial contractility, L-type Ca(2+) current, K(+) currents, action potential (AP) parameters, ECG profile and on the arrhythmia induced by ouabain were evaluated. In the atrium, geraniol reduced the contractile force (~98%, EC = 1,510 ± 160 µM) and diminished the positive inotropism of CaCl2 and BAY K8644. In cardiomyocytes, the IC a,L was reduced by 50.7% (n = 5) after perfusion with 300 µM geraniol. Moreover, geraniol prolonged the AP duration (APD) measured at 50% (n = 5) after repolarization, without changing the resting potential. The increased APD could be attributed to the blockade of the transient outward K(+) current (Ito ) (59.7%, n = 4), the non-inactivation K(+) current (Iss ) (39.2%, n = 4) and the inward rectifier K(+) current (IK 1 ) (33.7%, n = 4). In isolated hearts, geraniol increased PRi and QTi without affecting the QRS complex (n = 6), and it reduced both the left ventricular pressure (83%) and heart rate (16.5%). Geraniol delayed the time to onset of ouabain-induced arrhythmias by 128%, preventing 30% of the increase in resting tension (n = 6). Geraniol exerts its negative inotropic and chronotropic responses in the heart by decreasing both L-type Ca(2+) and voltage-gated K(+) currents, ultimately acting against ouabain-induced arrhythmias.