Non-melanoma skin cancer (NMSC) is the most common cancer world-wide and the incidence continues to rise, in part due to increasing numbers in high-risk groups such as organ transplant recipients and those taking photosensitizing medications. The most significant risk factor for NMSC is ultraviolet radiation (UVR) from sunlight, specifically UVB, which is the leading cause of DNA damage, photoaging, and malignant transformation in the skin. Activation of apoptosis following UVR exposure allows the elimination of irreversibly damaged cells that may harbor oncogenic mutations. However, UVR also activates signaling cascades that promote the survival of these potentially cancerous cells, resulting in tumor initiation. Thus, the UVR-induced stress response in the skin is multi-faceted and requires coordinated activation of numerous pathways controlling DNA damage repair, inflammation, and kinase-mediated signal transduction that lead to either cell survival or cell death. This review focuses on the central signaling mechanisms that respond to UVR and the subsequent cellular changes. Given the prevalence of NMSC and the resulting health care burden, many of these pathways provide promising targets for continued study aimed at both chemoprevention and chemotherapy.
Monahan KD, Feehan RP, Kunselman AR, Preston AG, Miller DL, Lott ME. Dose-dependent increases in flow-mediated dilation following acute cocoa ingestion in healthy older adults. J Appl Physiol 111: 1568 -1574. First published September 8, 2011 doi:10.1152/japplphysiol.00865.2011.-An inverse relation exists between intake of flavonoid-rich foods, such as cocoa, and cardiovascular-related mortality. Favorable effects of flavonoids on the endothelium may underlie these associations. We performed a randomized, double-blind, placebo-controlled study to test the hypothesis that acute cocoa ingestion dose dependently increases endothelium-dependent vasodilation, as measured by an increase in brachial artery flow-mediated dilation (FMD), in healthy older adults. Measurements were obtained before (preingestion) and after (1-and 2-h postingestion) ingestion of 0 (placebo), 2, 5, 13, and 26 g of cocoa in 23 adults (63 Ϯ 2 yr old, mean Ϯ SE). Changes in brachial artery FMD 1-and 2-h postingestion compared with preingestion were used to determine the effects of cocoa. FMD was unchanged 1 (⌬Ϫ0.3 Ϯ 0.2%)-and 2-h (⌬0.1 Ϯ 0.1%) after placebo (0 g cocoa). In contrast, FMD increased both 1-h postingestion (2 g cocoa ⌬0.0 Ϯ 0.2%, 5 g cocoa ⌬0.8 Ϯ 0.3%, 13 g cocoa ⌬1.0 Ϯ 0.3%, and 26 g cocoa ⌬1.6 Ϯ 0.3%: P Ͻ 0.05 compared with placebo for 5, 13, and 26 g cocoa) and 2-h postingestion (2 g cocoa ⌬0.5 Ϯ 0.3%, 5 g cocoa ⌬1.0 Ϯ 0.3%, 13 g cocoa ⌬1.4 Ϯ 0.2%, and 26 g cocoa ⌬2.5 Ϯ 0.4%: P Ͻ 0.05 compared with placebo for 5, 13, and 26 g cocoa) on the other study days. A serum marker of cocoa ingestion (total epicatechin) correlated with increased FMD 1-and 2-h postingestion (r ϭ 0.44 -0.48; both P Ͻ 0.05). Collectively, these results indicate that acute cocoa ingestion dose dependently increases brachial artery FMD in healthy older humans. These responses may help to explain associations between flavonoid intake and cardiovascular-related mortality in humans.flavonoid; flavanol; chocolate; endothelium; endothelial function THE ENDOTHELIUM CONTRIBUTES critically to cardiovascular homeostasis by influencing factors such as vascular tone, vascular permeability, platelet aggregation, and thrombosis. As abnormal function of the endothelium is a key event in the atherosclerotic process (15), it is not surprising that endothelial dysfunction is a hallmark feature of many cardiovascular disease states (33). Moreover, it is not surprising that aging, which is a primary risk factor for the development of cardiovascular disease and atherosclerosis (29,36), is associated with marked endothelial dysfunction. Specifically, in response to stimulation of the vascular endothelium via pharmacological substances, such as acetylcholine, or physiological stimuli, such as increases in vascular shear stress, a reduced endothelium-dependent vasodilatory response occurs in healthy older adults compared with healthy young adults (7,11,12,41). As low levels of brachial artery flow-mediated dilation (FMD), a commonly used method to assess endothelium-dependent vasodi...
Key points• The sympathetic nervous system is an important regulator of coronary blood flow.• How ageing may effect sympathetic nervous system regulation of coronary blood flow during physiological stress is unknown.• We measured coronary vascular responses to sympathetic activation before and during systemic α-and β-adrenergic receptor blockade in young and older healthy men.• Our results indicate that the normal coronary vascular response to sympathetic activation in young men is pronounced vasodilatation and that this effect is lost with advancing age, as the result of an apparent adrenergic mechanism.• These findings may help explain how acute sympathetic activation may trigger angina and coronary ischaemic events, particularly in older adults.Abstract The sympathetic nervous system is an important regulator of coronary blood flow. The cold pressor test (CPT) is a powerful sympathoexcitatory stressor. We tested the hypotheses that: (1) CPT-induced sympathetic activation elicits coronary vasodilatation in young adults that is impaired with advancing age and (2) combined α-and β-adrenergic blockade diminishes/abolishes these age-related differences. Vascular responses of the left anterior descending artery to the CPT were determined by transthoracic Doppler echocardiography before (pre-blockade) and during (post-blockade) systemic co-administration of α-and β-adrenergic antagonists in young (n = 9; 26 ± 1 years old, mean ± SEM) and older healthy men (n = 9; 66 ± 2 years old). Coronary vascular resistance (CVR; mean arterial pressure/coronary blood velocity) was used as an index of vascular tone. CPT decreased CVR (i.e. coronary vasodilatation occurred) in young ( -33 ± 6%), but not older men ( -3 ± 4%; P < 0.05 vs. young) pre-blockade. Adrenergic blockade abolished CPT-induced coronary vasodilatation in young men ( -33 ± 6% vs. 0 ± 6%, pre-blockade vs. post-blockade, respectively; P < 0.05) such that responses post-blockade mirrored those of older men ( -3 ± 4% vs. 8 ± 9%; both P > 0.05 compared to young pre-blockade). Impaired CPT-induced coronary vasodilatation could not be explained by a reduced stimulus for vasodilatation as group and condition effects persisted when CVR responses were expressed relative to myocardial oxygen demand (rate-pressure product). These data indicate that the normal coronary vascular response to sympathetic activation in young men is pronounced vasodilatation and this effect is lost with age as the result of an adrenergic mechanism. These findings may help explain how acute sympathoexcitation may precipitate angina and coronary ischaemic events, particularly in older adults.
Exposure to ultraviolet-B (UVB) irradiation, the principal cause of non-melanoma skin cancer (NMSC), activates both the rapamycin-sensitive mammalian target of rapamycin complex 1 (mTORC1) and the rapamycin-resistant mTORC2. We have previously reported that UVB-induced keratinocyte survival is dependent on mTORC2, though the specific mechanism is not well understood. FOXO3a is an important transcription factor involved in regulating cell survival. The activity of FOXO3a is reduced as a result of protein kinase B (AKT/PKB) activation, which is downstream of mTORC2; however, the specific function of FOXO3a during UVB-induced apoptosis is unclear. In this study, we establish that in cells with wild-type mTORC2 activity, FOXO3a is quickly phosphorylated in response to UVB and sequestered in the cytoplasm. In contrast, loss of mTORC2 causes FOXO3a to be localized to the nucleus and sensitizes cells to UVB-induced apoptosis. Furthermore, this sensitization is rescued by knockdown of FOXO3a. Taken together, these studies provide strong evidence that inhibition of mTORC2 enhances UVB-induced apoptosis in a FOXO3a-dependent manner, and suggest that FOXO3a activation by mTORC2 inhibitors may be a valuable chemopreventive target in NMSC.
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