Nicotinamide enhances repair of arsenic and ultraviolet radiation-induced DNA damage in HaCaT keratinocytes and ex vivo human skin.

Arsenic-induced skin cancer is a significant global health burden. In areas with arsenic contamination of water sources, such as China, Pakistan, Myanmar, Cambodia and especially Bangladesh and West Bengal, large populations are at risk of arsenic-induced skin cancer. Arsenic acts as a co-carcinogen with ultraviolet (UV) radiation and affects DNA damage and repair. Nicotinamide (vitamin B3) reduces premalignant keratoses in sun-damaged skin, likely by prevention of UV-induced cellular energy depletion and enhancement of DNA repair. We investigated whether nicotinamide modifies DNA repair following exposure to UV radiation and sodium arsenite. HaCaT keratinocytes and ex vivo human skin were exposed to 2µM sodium arsenite and low dose (2J/cm2) solar-simulated UV, with and without nicotinamide supplementation. DNA photolesions in the form of 8-oxo-7,8-dihydro-2'-deoxyguanosine and cyclobutane pyrimidine dimers were detected by immunofluorescence. Arsenic exposure significantly increased levels of 8-oxo-7,8-dihydro-2'-deoxyguanosine in irradiated cells. Nicotinamide reduced both types of photolesions in HaCaT keratinocytes and in ex vivo human skin, likely by enhancing DNA repair. These results demonstrate a reduction of two different photolesions over time in two different models in UV and arsenic exposed cells. Nicotinamide is a nontoxic, inexpensive agent with potential for chemoprevention of arsenic induced skin cancer.

Nicotinamide enhances repair of ultraviolet radiation-induced DNA damage in primary melanocytes.

Cutaneous melanoma is a significant cause of morbidity and mortality. Nicotinamide is a safe, widely available vitamin that reduces the immune suppressive effects of UV, enhances DNA repair in keratinocytes and has shown promise in the chemoprevention of non-melanoma skin cancer. Here, we report the effect of nicotinamide on DNA damage and repair in primary human melanocytes. Nicotinamide significantly enhanced the repair of oxidative DNA damage (8-oxo-7,8-dihydro-2'-deoxyguanosine) and cyclobutane pyrimidine dimers induced by UV exposure. It also enhanced the repair of 8-oxo-7,8-dihydro-2'-deoxyguanosine induced by the culture conditions in unirradiated melanocytes. A significant increase in the percentage of melanocytes undergoing unscheduled but not scheduled DNA synthesis was observed, confirming that nicotinamide enhances DNA repair in human melanocytes. In summary, nicotinamide, by enhancing DNA repair in melanocytes, is a potential agent for the chemoprevention of cutaneous melanoma.

Association between exercise hemodynamics and changes in local vascular function following acute exercise.

Skeletal muscle contractions are associated with physical stimuli that act upon muscle vasculature, including increased shear stress and blood pressure. It is unclear if acute dynamic exercise alters local vascular function. The purpose of this study was to examine the role of exercise hemodynamics on the effects of acute exercise on vascular function, as evaluated by brachial artery flow-mediated dilation (FMD). Healthy individuals (n = 14; age, 18-34 years) performed 30 min of handgrip exercise at fast and slow contractions. Blood pressure during exercise was measured using a Vasotrac system (Medwave Inc.), while shear rate during exercise and FMD at rest and after 30 min of recovery from exercise were measured in the brachial artery of the active arm using Doppler ultrasound. Estimated contractile work was correlated with blood pressure (r = 0.61, p < 0.01) and retrograde shear rate (r = -0.78, p < 0.01). As a result, blood pressure was higher (p < 0.05) and oscillatory shear index was lower (p < 0.05) during slow as compared with fast contractions. On average, FMD was unchanged following fast contractions (5.4 ± 3.4%dilation to 6.1 ± 3.8%dilation; p = 0.19), but significantly reduced following slow contractions (6.9 ± 4.2%dilation to 3.6 ± 2.5%dilation; p = 0.01). Within slow contractions, subgroup analysis revealed blood pressure to associate with the change in FMD; such that individuals with mean blood pressure >100 mm Hg (range, 102-139 mm Hg) during exercise had larger decreases in FMD than individuals with lower exercise blood pressure. These results indicate that impaired local vascular function following acute exercise with high contractile activity is associated with blood pressure stimuli in healthy individuals.

Vascular remodeling in response to 12 wk of upper arm unilateral resistance training.

UNLABELLED: Participation in regular aerobic exercise has been shown to increase arterial size and that exercise-induced vascular remodeling may be regional rather than systemic. However, these issues have been minimally investigated concerning resistance training. PURPOSES: To determine whether 1) resistance training of the nondominant arm elicits an increase in diameter of the brachial artery and 2) unilateral training induces arterial remodeling in the contralateral arm. METHODS: Twenty-four previously untrained participants, consisting of 18 females (aged 22.3 +/- 5.1 yr) and 6 males (aged 21.7 +/- 1.8 yr), participated in unilateral strength training of the biceps and triceps for 12 wk using their nondominant arm. Isotonic (one-repetition maximum, 1RM) and isometric (ISO) strength of the biceps were assessed before and after training on both arms. Brachial artery diameter and biceps muscle cross-sectional area (CSA) of both arms were also measured before and after training using magnetic resonance imaging (MRI). RESULTS: Brachial artery diameter increased 5.47% (P < 0.05) in the nondominant trained arm with no change observed in the dominant untrained arm. Biceps CSA increased 18.3% (P < 0.05) in the trained arm with no change (P > 0.05) in the untrained limb. Nondominant 1RM and ISO strength increased by 35.1% and 16.8%, respectively (P < 0.05 for both), although there were no significant changes (P > 0.05) in the contralateral arm. A modest correlation was found between the increases in CSA and in brachial artery diameter (r2 = 0.19, P = 0.039). CONCLUSIONS: These results indicate that upper arm vascular remodeling, manifesting as increased brachial artery diameter, can result from resistance training and that these changes are localized to the trained limb and associated with increases in CSA.

Exercise-induced shear stress is associated with changes in plasma von Willebrand factor in older humans.

Shear stress is the frictional force of blood against the endothelium, a stimulus for endothelial activation and the release of von Willebrand factor (vWF). This study tested the hypothesis that the increase in shear stress associated with exercise correlates with plasma vWF. Young (n = 14, 25.7 +/- 5.4 years) and older (n = 13, 65.6 +/- 10.7 years) individuals participated in 30 min of dynamic handgrip exercise at a moderate intensity. Brachial artery diameter and blood flow were measured using ultrasound Doppler and blood samples were collected before, immediately after, and following 30 min of recovery from exercise with plasma levels of vWF. Plasma levels of vWF increased (P < 0.05) by 6 +/- 2% in young individuals and 4 +/- 1% in older individuals immediately after exercise. The change in plasma vWF was linearly correlated with the increase in shear stress during exercise in older individuals (post-exercise: r = 0.78, 30 min recovery: r = 0.77, P < 0.01), but no association was found in the young individuals. These changes in plasma levels of vWF in humans suggest that aging influences endothelial activation and hemostasis.

Role of retrograde flow in the shear stimulus associated with exercise blood flow.

To test the hypothesis that retrograde flow influences the shear stimulus of exercise blood flow, eight healthy men [25.6+/-3.1 years (SD)] performed 20 min of single-leg knee-extension exercise at two contraction velocities: fast (FR, 1.5 m s(-1)) and slow (SR, 0.4 m s(-1)). Contraction frequency (30 cpm) and workload (5 kg) were kept constant resulting in a work rate of 15.25 W for both contraction velocities. Common femoral artery diameter and blood velocity were measured at rest and during exercise using ultrasound Doppler. Mean blood flow was not different between contraction velocities while antegrade (2012.4+/-379.9 versus 1745.6+/-601.5 ml min(-1); P=0.05) and retrograde (121.7+/-43.0 versus 11.2+/-6.6 ml min(-1); P<0.001) flows were higher during FR than SR contractions, respectively. Despite the similar mean blood flow response, vascular resistance was lower during FR than SR contractions (0.06+/-0.01 versus 0.08+/-0.03 units; P=0.03) and was closely related to shear rate (pooled data: r=-0.77, P<0.01). Retrograde flow was associated with a lower vascular resistance during exercise (pooled data: r=-0.48, P

Prior heavy knee extension exercise does not affect V̇O2 kinetics during subsequent heavy cycling exercise.

This study examined the magnitude of the oxygen uptake slow component (VO(2) SC) during heavy exercise when preceded by heavy knee extension (KE) exercise. Nine males (26.6 +/- 1.7 years, +/-SE) performed repeated bouts of heavy exercise, each lasting 6 min with 6 min of recovery. Cycling-cycling trials (CYC(1), CYC(2)) involved step transitions to a workrate corresponding to 50% of the difference between peak VO(2) and the lactate threshold (Delta 50%). During bilateral KE-cycling trails (KE, CYC(3)), KE was performed at an intensity requiring twofold greater muscle activation relative to CYC(1) followed by a cycling transition to Delta 50%. VO(2) was measured breath-by-breath and was modeled using three exponentials to determinate the amplitudes (A (2)', A (3)') and time constants (tau (2), tau (3)) of the primary phase and VO(2) SC. Electromyography (EMG) recorded from the vastus lateralis and medialis was averaged and reported relative to maximal voluntary contraction (%MVC). EMG was higher (p < 0.05) during KE (37.6 +/- 8.1 %MVC) than CYC(1) (20.8 +/- 1.9 %MVC), CYC(2) (21.6 +/- 5.7 %MVC) and CYC(3) (19.8 +/- 6.3 %MVC). The amplitude of the VO(2) SC was lower (p < 0.05) in CYC(2) (197 +/- 120 ml min(-1)) and CYC(3) (163 +/- 51 ml min(-1)) compared to CYC(1) (325 +/- 126 ml min(-1)). No difference in VO(2) SC was observed between CYC(2) and CYC(3). Although the activation of additional motor units during KE exercise reduced the amplitude of the VO(2) SC, the decrease was similar to that observed following heavy cycling exercise. Thus, the activation of motor units in excess of those required for the activity does not alter the VO(2) response during a subsequent bout of exercise.

Forearm blood flow follows work rate during submaximal dynamic forearm exercise independent of sex.

To test the hypothesis that sex influences forearm blood flow (FBF) during exercise, 15 women and 16 men of similar age [women 24.3 +/- 4.0 (SD) vs. men 24.9 +/- 4.5 yr] but different forearm muscle strength (women 290.7 +/- 44.4 vs. men 509.6 +/- 97.8 N; P < 0.05) performed dynamic handgrip exercise as the same absolute workload was increased in a ramp function (0.25 W/min). Task failure was defined as the inability to maintain contraction rate. Blood pressure and FBF were measured on separate arms during exercise by auscultation and Doppler ultrasound, respectively. Muscle strength was positively correlated with endurance time (r = 0.72, P < 0.01) such that women had a shorter time to task failure than men (450.5 +/- 113.0 vs. 831.3 +/- 272.9 s; P < 0.05). However, the percentage of maximal handgrip strength achieved at task failure was similar between sexes (14% maximum voluntary contraction). FBF was similar between women and men throughout exercise and at task failure (women 13.6 +/- 5.3 vs. men 14.5 +/- 4.9 ml.min(-1).100 ml(-1)). Mean arterial pressure was lower in women at rest and during exercise; thus calculated forearm vascular conductance (FVC) was higher in women during exercise but similar between sexes at task failure (women 0.13 +/- 0.05 vs. men 0.11 +/- 0.04 ml.min(-1).100 ml(-1).mmHg(-1)). In conclusion, the similar FBF during exercise was achieved by a higher FVC in the presence of a lower MAP in women than men. Still, FBF remained coupled to work rate (and presumably metabolic demand) during exercise irrespective of sex.

Forearm blood flow responses to fatiguing isometric contractions in women and men.

Previous studies suggest that women experience less vascular occlusion than men when generating the same relative contractile force. This study examined forearm blood flow (FBF) in women and men during isometric handgrip exercise requiring the same relative force. Thirty-eight subjects [20 women and 18 men, 22.8 +/- 0.6 yrs old (means +/- SE)] performed low- and moderate-force handgrip exercise on two occasions. Subjects performed five maximum voluntary contractions (MVC) before exercise to determine 20% and 50% MVC target forces. Time to task failure (TTF) was determined when the subject could not maintain force within 5% of the target force. Mean blood velocity was measured in the brachial artery with the use of Doppler ultrasonography. Arterial diameter was measured at rest and used to calculate absolute FBF (FBFa; ml/min) and relative FBF (FBFr; ml.min(-1).100 ml(-1)). Women generated less (P < 0.05) absolute maximal force (208 +/- 10 N) than men (357 +/- 17 N). The TTF was longer (P < 0.05) at 20% MVC for women (349 +/- 32 s) than for men (230 +/- 23 s), but no difference between the sexes was observed at 50% MVC (women: 69 +/- 5 s; men: 71 +/- 8 s). FBFa and FBFr increased (P < 0.05) from rest to TTF in both women and men during 20% and 50% MVC trials. FBFr was greater in women than in men at > or =30% TTF during 50% MVC. At exercise durations > or =60% of TTF, FBFa was lower (P < 0.05) in women than in men during handgrip at 20% MVC. Despite the longer exercise duration for women at the lower contraction intensity, FBFr was similar between the sexes, suggesting that muscle perfusion is matched to the exercising muscle mass independent of sex.