RESUMEN
PURPOSE: Dietary nitrate (NO3 (-)) supplementation reduces the O2 cost of fixed-workload tasks performed in temperate environments but has not been examined in the heat. If this effect were retained it could reduce heatstroke risk in military personnel that are deployed for desert combat. METHODS: Nine men completed three 45 min loaded battle marches at a standard cadence (4.83 km h(-1)/1.5 % grade) while wearing full combat gear [BDU, boots, body armor (8 kg), NBC suit] and carrying a loaded rucksack (16 kg). The 1st March (FAM) commenced in a temperate environment. The 2nd and 3rd commenced in simulated dry desert conditions (41 °C/20 % RH) and required subjects to ingest the beetroot juice equivalent of 8.4 mmol NO3 (-) (BRJ) or a NO3 (-) depleted placebo (PLA) for 6 days prior. VO2, VCO2, V E, core (T re), skin (T sk), and mean body (T b) temperatures, HR, and physiological strain index (PSI) were measured continuously. Thermal sensation, generalized discomfort, and perceived exertion (RPE) were measured at 5 min intervals. Heat storage (HS) was calculated. Blood markers of gastrointestinal permeability (TNF, Il-6, HO-1) were measured before and after exercise. RESULTS: VO2 in BRJ was lower than PLA from 1 to 12; 16 to 26; and 29 to 45 min of exercise (p < 0.05). VCO2 in BRJ was lower than PLA from 1 to 12 min (p < 0.05). V E in BRJ was lower than PLA from 1 to 20 min of exercise (p < 0.05). T re and T b in BRJ exceeded PLA from 16 to 45 min (p < 0.05). TNF, Il-6, and HO-1 were reduced in BRJ (p < 0.05) while HR, PSI, Tsk, and HS were not altered (p > 0.05). Thermal sensation, generalized discomfort, and RPE were elevated in BRJ from 40 to 45, 25 to 45, and 10 to 45 min, respectively (p < 0.01). CONCLUSION: Metabolic efficiency was improved in BRJ. Paradoxically, body temperatures rose more. This was not due to gut permeability. Therefore, we speculate that based on elimination of other possibilities, blood redistribution from skin to skeletal muscle may have contributed to impaired heat exchange.
Asunto(s)
Temperatura Corporal/efectos de los fármacos , Clima Desértico/efectos adversos , Ejercicio Físico , Golpe de Calor/prevención & control , Nitratos/uso terapéutico , Oxígeno/metabolismo , Adulto , Suplementos Dietéticos , Humanos , Masculino , Personal Militar , Nitratos/administración & dosificación , Nitratos/farmacologíaRESUMEN
Omental adipose stromal cells (O-ASC) are a multipotent population of mesenchymal stem cells contained in the omentum tissue that promote endometrial and ovarian tumor proliferation, migration, and drug resistance. The mechanistic underpinnings of O-ASCs' role in tumor progression and growth are unclear. Here, we propose a novel nitric oxide (NO)-mediated metabolic coupling between O-ASCs and gynecologic cancer cells in which O-ASCs support NO homeostasis in malignant cells. NO is synthesized endogenously by the conversion of l-arginine into citrulline through nitric oxide synthase (NOS). Through arginine depletion in the media using l-arginase and NOS inhibition in cancer cells using N(G)-nitro-l-arginine methyl ester (l-NAME), we demonstrate that patient-derived O-ASCs increase NO levels in ovarian and endometrial cancer cells and promote proliferation in these cells. O-ASCs and cancer cell cocultures revealed that cancer cells use O-ASC-secreted arginine and in turn secrete citrulline in the microenvironment. Interestingly, citrulline increased adipogenesis potential of the O-ASCs. Furthermore, we found that O-ASCs increased NO synthesis in cancer cells, leading to decrease in mitochondrial respiration in these cells. Our findings suggest that O-ASCs upregulate glycolysis and reduce oxidative stress in cancer cells by increasing NO levels through paracrine metabolite secretion. Significantly, we found that O-ASC-mediated chemoresistance in cancer cells can be deregulated by altering NO homeostasis. A combined approach of targeting secreted arginine through l-arginase, along with targeting microenvironment-secreted factors using l-NAME, may be a viable therapeutic approach for targeting ovarian and endometrial cancers.