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Androgen deprivation therapy (ADT) decreases muscle mass and function but no human studies have investigated the underlying genetic or cellular effects. We tested the hypothesis that ADT will lead to changes in skeletal muscle gene expression, which may explain the adverse muscle phenotype seen clinically. We conducted a prospective cohort study of 9 men with localised prostate cancer who underwent a vastus lateralis biopsy before and after 4 weeks of ADT. Next-generation RNA sequencing was performed and genes differentially expressed following ADT underwent gene ontology mining using Ingenuity Pathway Analysis. Differential expression of genes of interest was confirmed by quantitative PCR (Q-PCR) on gastrocnemius muscle of orchidectomised mice and sham controls (n=11/group). We found that in men, circulating total testosterone decreased from 16.5±4.3nmol/L at baseline to 0.4±0.15nmol/L post-ADT (p<0.001). RNA sequencing identified 19 differentially expressed genes post-ADT (all p<0.05 after adjusting for multiple testing). Gene ontology mining identified 8 genes to be of particular interest due to known roles in androgen-mediated signalling; ABCG1, ACTC1, ANKRD1, DMPK, THY1, DCLK1, CST3 were upregulated and SLC38A3 was downregulated post-ADT. Q-PCR in mouse gastrocnemius muscle confirmed that only one gene, Actc1 was concordantly upregulated (p<0.01) in orchidectomised mice compared with controls. In conclusion, given that ACTC1 upregulation is associated with improved muscle function in certain myopathies, we hypothesise that upregulation of ACTC1 may represent a compensatory response to ADT-induced muscle loss. Further studies will be required to evaluate the role and function of ACTC1., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Ang II has been involved in the pathogenesis of cardiovascular diseases, and matrix metalloproteinase-9 (MMP-9) induced migration of human aortic smooth muscle cells (HASMCs) is the most common and basic pathological feature. Carbon monoxide (CO), a byproduct of heme breakdown by heme oxygenase, exerts anti-inflammatory effects in various tissues and organ systems. In the present study, we aimed to investigate the effects and underlying mechanisms of carbon monoxide releasing molecule-2 (CORM-2) on Ang II-induced MMP-9 expression and cell migration of HASMCs. Ang II significantly up-regulated MMP-9 expression and cell migration of HASMCs, which was inhibited by transfection with siRNA of p47 phox , Nox2, Nox4, p65, angiotensin II type 1 receptor (AT1R) and pretreatment with the inhibitors of NADPH oxidase, ROS, and NF-κB. In addition, Ang II also induced NADPH oxidase/ROS generation and p47 phox translocation from the cytosol to the membrane. Moreover, Ang II-induced oxidative stress and MMP-9-dependent cell migration were inhibited by pretreatment with CORM-2. Finally, we observed that Ang II induced IL-6 release in HASMCs via AT1R, but not AT2R, which could further caused MMP-9 secretion and cell migration. Pretreatment with CORM-2 reduced Ang II-induced IL-6 release. In conclusion, CORM-2 inhibits Ang II-induced HASMCs migration through inactivation of suppression of NADPH oxidase/ROS generation, NF-κB inactivation and IL-6/MMP-9 expression. Thus, application of CO, especially CORM-2, is a potential countermeasure to reverse the pathological changes of various cardiovascular diseases. Further effects aimed at identifying novel antioxidant and anti-inflammatory substances protective for heart and blood vessels that targeting CO and establishment of well-designed in vivo models properly evaluating the efficacy of these agents are needed., (Copyright © 2017. Published by Elsevier B.V.)

Human fibroblast-like synoviocytes (FLSs) play a role in joint synovial inflammation in rheumatoid arthritis (RA). Some evidence indicates that particulate matter (PM) in air pollution could contribute to the progression of RA. However, more research is needed to clarify this relationship. Up-regulation of cyclooxygenase (COX)-2 and its metabolite prostaglandin E 2 (PGE 2 ) are implicated in various inflammatory diseases. Resveratrol, a polyphenol found mainly in grapes and red wine, has antioxidant and anti-inflammatory activities. In the present study, we demonstrated that resveratrol reduced PM-induced COX-2/PGE 2 expression in human FLSs, and attenuated PM-enhanced NADPH oxidase activity and ROS generation. In addition, PM induced Akt, ERK1/2, or p38 MAPK activation, which was inhibited by resveratrol. Finally, we demonstrated that PM enhanced NF-κB p65 phosphorylation and the NF-κB promoter activity, which were reduced by pretreatment with a ROS inhibitor or resveratrol. Thus, we concluded that resveratrol functions as a suppressor of PM-induced inflammatory signaling pathways by inhibiting COX-2/PGE 2 expression., (Copyright © 2017. Published by Elsevier Ltd.)

We have previously demonstrated that a number of rats fed a moderately high-fat diet (MHFD) become obese and hypertensive and had compromised sympathoinhibitory and vasodilator responses to the gut hormones cholecystokinin (CCK) and gastric leptin. This has implications for increased resistance in vascular beds that attract a large proportion of cardiac output after a meal and may be an important mechanism underlying the development of hypertension in obesity in which food consumption is greatly increased. The aim of this study was to determine whether swapping a MHFD for a low-fat diet (LFD) would induce weight loss in obese animals, reverse the signs of hypertension and restore sympathoinhibitory reflexes. Male Sprague-Dawley rats were placed on a LFD (controls; n = 8) or a MHFD (n = 24) for 11 weeks after which the latter displayed either an obesity-prone (OP) or obesity-resistant (OR) phenotype. All animals were fed a LFD for a further 6 weeks after which they were anaesthetised with isoflurane and artificially ventilated for evaluation of resting arterial pressure (AP) and renal sympathetic nerve responses to CCK (0.1-4 μg/kg) and leptin (15 μg/kg). Weight gain in OP animals remained higher than OR or controls following diet switch (P < 0.05 for both). Resting AP was not significantly different between OP (103 ± 4 mmHg), OR (102 ± 3 mmHg) or control (104 ± 3 mmHg) animals and sympathoinhibitory responses to CCK or leptin were not different between the groups (P > 0.05). These results demonstrate that diet modification can have beneficial effects on sympathetic function and restore normotension without the need for weight reduction., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The gut hormone cholecystokinin (CCK) acts at subdiaphragmatic vagal afferents to induce renal and splanchnic sympathoinhibition and vasodilatation, via reflex inhibition of a subclass of cardiovascular-controlling neurons in the rostroventrolateral medulla (RVLM). These sympathoinhibitory and vasodilator responses are blunted in obese, hypertensive rats and our aim in the present study was to determine whether this is attributable to (i) altered sensitivity of presympathetic vasomotor RVLM neurons, and (ii) aberrant peripheral or central signalling mechanisms. Using a diet-induced obesity model, male Sprague-Dawley rats exhibited either an obesity-prone (OP) or obesity-resistant (OR) phenotype when placed on a medium high fat diet for 13-15 weeks; control animals were placed on a low fat diet. OP animals had elevated resting arterial pressure compared to OR/control animals (P < 0.05). Barosensitivity of RVLM neurons was significantly attenuated in OP animals (P < 0.05), suggesting altered baroreflex gain. CCK induced inhibitory responses in RVLM neurons of OR/control animals but not OP animals. Subdiaphragmatic vagal nerve responsiveness to CCK and CCK1 receptor mRNA expression in nodose ganglia did not differ between the groups, but CCK induced significantly less Fos-like immunoreactivity in both the nucleus of the solitary tract and the caudal ventrolateral medulla of OP animals compared to controls (P < 0.05). These results suggest that blunted sympathoinhibitory and vasodilator responses in obesity-related hypertension are due to alterations in RVLM neuronal responses, resulting from aberrant central but not peripheral signalling mechanisms. In obesity, blunted sympathoinhibitory mechanisms may lead to increased regional vascular resistance and contribute to the development of hypertension.

Gastric leptin elicits its cardiovascular and splanchnic sympathoinhibitory responses via a vagal afferent mechanism, however the latter are blunted/abolished in animals fed a medium high fat diet (MHFD). In a diet-induced obesity model we sought to determine whether the renal sympathetic nerve discharge (RSND) and regional vasodilator responses to gastric leptin are also affected by diet and/or obesity. The diet induced obesity model was used in 2 separate studies. After 13 weeks on a MHFD the animals were classified as either obesity prone (OP) or obesity resistant (OR) depending on their weight gain. Control animals were fed a low fat diet for an equivalent period. Arterial pressure (AP) and heart rate (HR) were monitored in isoflurane-anaesthetised, artificially ventilated animals and RSND or regional vascular responses to leptin (15 μg/kg) administered close to the coeliac artery were evaluated. OP rats had higher baseline AP compared to control/OR rats (P<0.05). Close arterial leptin inhibited RSND in control animals but this response was abolished in OR and OP animals (P<0.01 for both). Leptin administration increased renal vascular conductance in control animals but this response was significantly attenuated only in OP animals (P<0.05). The vasodilator response in the superior mesenteric artery was not significantly different in any of the groups (P>0.05). Together these results suggest that, while the renal sympathoinhibitory responses to gastric leptin are affected by diet, the vasodilator responses to leptin in the renal vascular bed are only affected in OP animals. These changes may impact on cardiovascular homeostatic mechanisms in obesity., (Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.)

The gut and kidney command >50% of cardiac output postprandially, highlighting the importance of these vascular beds in cardiovascular homeostasis. The gastrointestinal peptide cholecystokinin (CCK) induces vagally mediated splanchnic sympathoinhibition that is attenuated in animals fed a medium high-fat diet (MHFD); therefore, our aim was to determine whether renal sympathetic nerve discharge (RSND) responses to CCK are also affected by this diet, and whether these changes are associated with obesity and hypertension. Another aim was to determine whether regional vasodilator responses to CCK are affected in obesity-related hypertension. In two separate studies, Sprague-Dawley rats were fed either a low-fat diet (LFD; control) or a MHFD for 13 weeks, after which MHFD animals were classified as obesity prone (OP) or obesity resistant (OR) based on their weight gain falling into the upper or lower tertile, respectively. Arterial pressure and heart rate were monitored in isoflurane-anaesthetized, artificially ventilated animals, and either RSND or regional vascular responses to CCK (0.1-8 μg kg(-1)) were evaluated. The OP rats had higher baseline arterial pressure compared with control/OR rats (P < 0.05). Administration of CCK inhibited RSND and increased renal vascular conductance in control/OR rats, and these responses were significantly blunted in OP rats (P < 0.05 for all). Baseline arterial pressure was positively correlated with weight gain and inversely correlated with CCK-induced vasodilatation (P < 0.05 for both). We hypothesize that in obesity-related hypertension, disruption of the sympathoinhibitory signals elicited by CCK reduces vasodilatation in the splanchnic/renal regions, leading to increased postprandial vascular resistance.

Gastric leptin and cholecystokinin (CCK) act on vagal afferents to induce cardiovascular effects and reflex inhibition of splanchnic sympathetic nerve discharge (SSND) and may act cooperatively in these responses. We sought to determine whether these effects are altered in animals that developed obesity in response to a medium high-fat diet (MHFD). Male Sprague-Dawley rats were placed on a low-fat diet (LFD; n = 8) or a MHFD (n = 24) for 13 wk, after which the animals were anesthetized and artificially ventilated. Arterial pressure was monitored and blood was collected for the determination of plasma leptin and CCK. SSND responses to leptin (15 μg/kg) and CCK (2 μg/kg) administered close to the coeliac artery were evaluated. Collectively, MHFD animals had significantly higher plasma leptin but lower plasma CCK levels than LFD rats (P < 0.05), and this corresponded to attenuated or reversed SSND responses to CCK (LFD, -21 ± 2%; and MHFD, -12 ± 2%; P < 0.05) and leptin (LFD, -6 ± 2%; and MHFD, 4 ± 1%; P < 0.001). Alternatively, animals on the MHFD were stratified into obesity-prone (OP; n = 8) or obesity-resistant (OR; n = 8) groups according to their weight gain falling within the upper or lower tertile, respectively. OP rats had significantly higher resting arterial pressure, adiposity, and plasma leptin but lower plasma CCK compared with LFD rats (P < 0.05). The SSND responses to CCK or leptin were not significantly different between OP and OR animals. These results demonstrate that a high-fat diet is associated with blunted splanchnic sympathoinhibitory responses to gastric leptin and CCK and may impact on sympathetic vasomotor mechanisms involved in circulatory control.

Sleep deprivation leads to impairment in performance, loss of efficiency and deterioration in mood states such as tension, depression, aggression, fatigue, confusion and vigour. These can be detrimental to combat readiness and could contribute to "battle stress". In the present study, a homogeneous group of 20 seamen under total sleep deprivation was rated 6 hourly with the Stanford Sleepiness Scale (SSS), Profile of Mood States (POMS) and a battery of performance tests including the trail making, grooved peg board, digit span, digit symbol, sea-shore rhythm, flicker fusion, dynamometer and naval tasks. With the exception of the trail making test and naval tasks, the test performance was observed to correlate significantly (P < 0.05) with the SSS. A higher sleepiness score was associated with a poorer performance in test scores. On the time trends of sleep deprivation on the performance tests measured, a dip in performance was observed in all the tests at 42 hours of sleep deprivation and continuous deterioration of performance was observed after 72 hours of sleep deprivation. The cognitive, vigilance, mood and sleepiness tests were substantially affected by sleep deprivation. Greater effect was observed in tests that involved cognition, speed and precision and smaller effect was observed in routine tasks that involved gross manual movement. The decrease in performance observed at 42 hours of sleep deprivation was 5.9 standard deviation from initial values for SSS; 3.9 for sea-shore rhythm, 3.0 for grooved peg board; 2.6 for dynamometer; 2.4 for mood; 1.8 for digit span; 1.6 for trail making and digit symbol; 1.0 for naval tasks and addition; and 0.9 for flicker fusion.(ABSTRACT TRUNCATED AT 250 WORDS)