Exercise training increases mitochondria and GLUT4 in skeletal muscles. Recent studies indicate that an increased expression of the transcriptional coactivator peroxisome proliferator-activated receptor ␥ coactivator 1␣ (PGC-1␣) by exercise may promote mitochondrial biogenesis and fatty acid oxidation. To examine whether increased PGC-1␣ expression was also responsible for an increase of GLUT4 expression, transgenic mice that overexpress PGC-1␣ in skeletal muscles driven by a human ␣-skeletal actin promoter were made. PGC-1␣ was overexpresssed in skeletal muscles including type I and II fiber-rich muscles but not in the heart. With an increase of PGC-1␣ mRNA, type II fiber-rich muscles were redder, and genes of mitochondrial oxidative metabolism were up-regulated in skeletal muscles, whereas the expression of GLUT4 mRNA was unexpectedly downregulated. In parallel with a decrease of GLUT4 mRNA, an impairment of glycemic control after intraperitoneal insulin administration was observed. Thus, an increase of PGC-1␣ plays a role in increasing mitochondrial biogenesis and fatty acid oxidation but not in increasing GLUT4 mRNA in skeletal muscles.Endurance exercise training improves physical performance by an enhancement of skeletal muscle respiratory capacity (1) and decreases the incidence rate of diabetes mellitus (2). These effects might be related to increased numbers of mitochondria and the GLUT4 isoform of the glucose transporter in skeletal muscles, respectively. GLUT4, the insulin-responsive glucose transporter, is expressed in skeletal muscles, heart, and adipose tissues, and the number of GLUT4 on plasma membrane becomes a rate-limiting step for whole-body glucose clearance under physiological conditions (3-5). Thus, exercise training modifies the skeletal muscle to metabolize more fatty acids and glucose.As for mitochondrial biogenesis, two transcription factors, nuclear respiratory factor (NRF)-1 1 and NRF-2, were the key transcriptional activators of nuclear genes encoding mitochondrial enzymes (6, 7). NRFs up-regulate mitochondrial transcription factor A, which stimulates mitochondrial DNA transcription and replication (8). Recently, as a regulator of NRFs, peroxisome proliferator-activated receptor ␥ coactivator-1 (PGC-1␣) was found. PGC-1␣ is an inducible coactivator of nuclear receptors cloned from brown fat cell cDNA library because of its interaction with peroxisome proliferator-activated receptor ␥ (PPAR␥) (9). Overexpression of PGC-1␣ increased expression of mitochondrial enzymes in 3T3 adipocytes, stimulated mitochondrial biogenesis in C2C12 myocytes (9, 10), and induced the expression of nuclear and mitochondrial genes involved in multiple mitochondrial energy production pathways, including PPAR␣ target genes encoding the mitochondrial fatty acid ␤-oxidation in neonatal cardiac myocytes (11). In vivo cardiac-specific overexpression of PGC-1␣ in transgenic mice resulted in uncontrolled massive proliferation of mitochondria (11). Also, evidence that PGC-1␣ co-activated PPAR␣ (12) and NRF-1 (10) le...

Although lycopene, a major carotenoid component of tomatoes, has been suggested to attenuate the risk of breast cancer, the underlying preventive mechanism remains to be determined. Moreover, it is not known whether there are any differences in lycopene activity among different subtypes of human breast cancer cells. Using ER/PR positive MCF-7, HER2-positive SK-BR-3 and triple-negative MDA-MB-468 cell lines, we investigated the cellular and molecular mechanism of the anticancer activity of lycopene. Lycopene treatment for 168 consecutive hours exhibited a time-dependent and dose-dependent anti-proliferative activity against these cell lines by arresting the cell cycle at the G0/G1 phase at physiologically achievable concentrations found in human plasma. The greatest growth inhibition was observed in MDA-MB-468 where the sub-G0/G1 apoptotic population was significantly increased, with demonstrable cleavage of PARP. Lycopene induced strong and sustained activation of the ERK1/2, with concomitant cyclin D1 suppression and p21 upregulation in these three cell lines. In triple negative cells, lycopene inhibited the phosphorylation of Akt and its downstream molecule mTOR, followed by subsequent upregulation of proapoptotic Bax without affecting anti-apoptotic Bcl-xL. Taken together, these data indicate that the predominant anticancer activity of lycopene in MDA-MB-468 cells suggests a potential role of lycopene for the prevention of triple negative breast cancer.

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Although pterostilbene, a natural analog of resveratrol, has potent antitumor activity against several human cancer types, the possible inhibitory mechanisms against subtypes of human breast cancer with different hormone receptor and human epidermal growth factor receptor 2 (HER2) status remain unknown. We investigated the anticancer activity of pterostilbene using three subtypes of breast cancer cell lines. Pterostilbene treatment exhibited a dose-dependent antiproliferative activity, with the greatest growth inhibition observed in triple-negative MDA-MB-468 cells. Although pterostilbene arrested cell-cycle progression at the G/G phase regardless of breast cancer subtype, its apoptosis-inducing activity was highly apparent in MDA-MB-468 cells. Pterostilbene induced strong and sustained activation of extracellular signal-regulated kinase (ERK) 1/2, with concomitant cyclin D1 suppression and p21 up-regulation, and inhibited the phosphorylation of AKT and mammalian target of rapamycin (mTOR), followed by subsequent up-regulation of BAX without affecting B-cell lymphoma-extra large (BCL-xL). Oral administration of pterostilbene significantly suppressed tumor growth in nude mice xenotransplanted with MDA-MB-468 cells. These data suggest a potential role of pterostilbene for prevention and treatment of human breast cancer, especially of triple-negative breast cancer.

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The authors investigated interannual differences in the sodium excretion levels of young healthy Japanese women as estimated from spot urine analysis at Nakamura Gakuen University from 1995 to 2015. Participants included 4931 women aged 18 to 20 years who were classified into three time periods according to year of health check:first (1995-2001), second (2002-2007), and third (2008-2015). Estimated daily urinary sodium and potassium excretion levels and the sodium to potassium ratio were 120.6±31.9 mmol, 35.2±8.1 mmol, and 3.5±0.9, respectively. Adjusted for body weight, sodium excretion, and potassium excretion significantly decreased in the second and third period compared with the first period (P<.001). Systolic blood pressure also decreased in the same way between time periods (P<.001). Estimated urinary excretion levels of sodium and potassium in young Japanese women have decreased over the past 20 years independently of body weight. | INTRODUCTIONExcess sodium intake plays an important role in the development and progression of hypertension and the development of cardiovascular diseases.1-3 It has been reported that excess sodium intake from early stages of life contributes to population increases in blood pressure (BP), hypertension, and prehypertension. 4 Estimations of the mortality rates resulting from reductions in salt intake as a function of age suggest a greater attenuation of mortality rates for younger people. 5These reports suggest that reducing salt intake from a younger age is an important lifestyle modification when it comes to prophylactic and therapeutic issues of hypertension. Large-scale trends in sodium intake during recent decades have not yet been reported for young Japanese people. The Japanese National Health and Nutrition Survey provides information on interannual changes in the sodium intake of Japanese people. According to this survey, the sodium intake of young people has decreased during the past 20 years, but sodium intake corrected for energy intake was relatively unchanged during the past 10 years. 6,7 However, this survey has several limitations. For instance, the proportion of young people in the population surveyed was small, and sodium intake was calculated as a function of food consumed by a family and position in the family (eg, 35% intake for the father, 25%intake for the mother, and 40% intake for two children), 8 and thus the investigation underestimates the actual amount of diet. 9,10 Notably, the results of a salt intake study of 760 Japanese people aged 20 to 69 years with 24-hour urinary sodium excretion measurements taken at two time points differ from Japanese National Health and Nutrition Survey results, raising the question of whether salt intake did decline across these decades. 8 To better determine recent trends in the sodium intake of Japanese people, we need to evaluate changes in urinary sodium excretion levels and compare these values with the sodium intakes recorded by the Japanese National Health and Nutrition

Anticancer activities of soy isoflavones, such as genistein and equol, a bioactive metabolite of daidzein, have been extensively studied because of possible involvement in the prevention of breast cancer. However, their interactions still remain unclear. We investigated here whether cytotoxic activity of genistein was enhanced by equol, using estrogen receptor positive MCF-7, HER2-positive SK-BR-3, and triple-negative MDA-MB-468 cell lines. Although cytotoxicity of genistein did not significantly differ between three subtypes of breast cancer cells, cytotoxic activities of genistein were significantly enhanced in combination with 50 μM equol in MCF-7 cells, but not in SK-BR-3 and MDA-MB-468 cells. In fluorescence activated cell sorting (FACS) analyses, MCF-7 cells were arrested at the G2/M by genistein but at G1/S by equol. Combination treatment arrested cells at G2/M but abolished equol-induced G1 block, indicating an antagonistic activity of genistein against equol in cell-cycle progression. Although apoptosis was not so evident with genistein alone, the combination made a drastic induction of apoptosis, accompanied by the increase of Bax/Bcl-xL expression ratio, without affecting the activities of Akt and mTOR. Taken together, these data suggest that enhancement of genistein activity by equol would be mainly mediated by augmented induction of apoptosis rather than arrest or delay of the cell cycle.