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•The role of miRNA-376a-3p in colorectal cancer (CRC) resistant to CPT-11 was investigated.•Resistance to CPT-11 is associated with increased migratory behavior and a shift toward a mesenchymal phenotype in CRC cells.•Co-treatment with CPT-11 and miRNA-376a-3p significantly improved the therapeutic effectiveness of CPT-11.•Transfection of miRNA-376a-3p along with CPT-11 reversed the migratory behavior and mesenchymal phenotype in CRC cells.•The combination of CPT-11 and miRNA-376a-3p effectively inhibited tumor progression.

Ginsenoside Rg1 has been shown to clear senescence-associated beta-galactosidase (SA-β-gal) in cultured cells. It remains unknown whether Rg1 can influence SA-β-gal in exercising human skeletal muscle.

Exercise inevitably induces damages and triggers a brief inflammation in challenged tissues of the human body. Nevertheless, regular exercise is associated with improved physical fitness and lower all-cause mortality among adults in a dose-dependent manner. The paradox between destructive nature of exercise and its anti-aging benefit can be best explained by decreasing aged cell population of the human body in a Darwinian natural selection fashion, resulting in tissue renewal. In this concept, the unfit-to-fit cell ratio of a multicellular system increases during growth (expansion of cell population and size) and decreases after exercise challenges. Inflammation serves as an innate mechanism to recognize cells in danger and triggers clearance mechanism to eliminate unhealthy cells followed by regeneration. A recent finding of decreased p16INK4a+senescent cells together with CD68+macrophage infiltration in human skeletal muscle after resistance exercise supports this concept. The senescent cells are mostly stem cells located in capillaries surrounding myofibers, functioning to replace short-lived endothelial cells. They can be found in young men aged 20–25 years. In this context, exercise controls weight gain (i.e. cell number and size) and decrease senescent cell proportion in capillaries of the human body, providing benefits in physical fitness and increasing life expectancy.

Tissue damage is regarded as an unwanted medical condition to be avoided. However, introducing tolerable tissue damages has been used as a therapeutic intervention in traditional and complementary medicine to cure discomfort and illness. Eccentric exercise is known to cause significant necrosis and insulin resistance of skeletal muscle. The purpose of this study was to determine the magnitude of muscle damage and blood glucose responses during an oral glucose tolerance test (OGTT) after eccentric training in 21 young participants. They were challenged by 5 times of 100-meter downhill sprinting and 20 times of squats training at 30 pounds weight load for 3 days, which resulted in a wide spectrum of muscle creatine kinase (CK) surges in plasma, 48 h after the last bout of exercise. Participants were then divided into two groups according the magnitude of CK increases (low CK: +48% ± 0.3; high CK: +137% ± 0.5, P < 0.05). Both groups show comparable decreases in blood glucose levels in OGTT, suggesting that this muscle-damaging exercise does not appear to decrease but rather improve glycemic control in men. Conclusion: The result of the study rejects the hypothesis that eccentric exercise decreases glucose tolerance. Improved glucose tolerance with CK increase implicates a beneficial effect of replacing metabolically weaker muscle fibers by eccentric exercise in Darwinian natural selection fashion.

Objectives This study investigates the molecular mechanisms by which Alpiniae oxyphyllae fructus (AOF) promotes neuron regeneration.Methods A piece of silicone rubber was guided across a 15 mm gap in the sciatic nerve of a rat. This nerve gap was then filled with different concentrations of AOF extract (0-200 mg/ml). We investigated the role of MAPK (ERK1/2, JNK and p38) pathways for AOF-induced matrix-degrading proteolytic enzyme (PAs and MMP2/9) production in RSC96 Schwann cells.Results The results showed that AOF increased the expressions of uPA, tPA, MMP-9, and MAPKs in vivo. In vitro, our results show that treatment with AOF extract induces ERK1/2, JNK, and p38 phosphorylation to activate the downstream PAs and MMPs signaling expression. AOF-stimulated ERK1/2, JNK, and p38 phosphorylation attenuated by individual pretreatment with siRNAs or inhibitors (U0126, SP600125 and SB203580), resulting in migration and uPA-related signal pathway inhibition.Conclusions Taken together our data suggests the MAPKs (ERK1/2, JNK and p38), PAs (uPA, tPA), MMP (MMP2, MMP9) regenerative and migration signaling pathway of Schwann cells regulated by AOF extract might play a major role in Schwann cell migration and damaged peripheral nerve regeneration.

Ischemic heart damage usually triggers cardiomyopathological remodeling and fibrosis, thus promoting the development of heart functional failure. Mesenchymal stem cells (MSCs) are a heterogeneous group of cells in culture, with multipotent and hypoimmunogenic characters to aid tissue repair and avoid immune responses, respectively. Numerous experimental findings have proven the feasibility, safety, and efficiency of MSC therapy for cardiac regeneration. Despite that the exact mechanism remains unclear, the therapeutic ability of MSCs to treat ischemia heart diseases has been tested in phase I/II clinical trials. Based on encouraging preliminary findings, MSCs might become a potentially efficacious tool in the therapeutic options available to treat ischemic and nonischemic cardiovascular disorders. The molecular mechanism behind the efficacy of MSCs on promoting engraftment and accelerating the speed of heart functional recovery is still waiting for clarification. It is hypothesized that cardiomyocyte regeneration, paracrine mechanisms for cardiac repair, optimization of the niche for cell survival, and cardiac remodeling by inflammatory control are involved in the interaction between MSCs and the damaged myocardial environment. This review focuses on recent experimental and clinical findings related to cellular cardiomyoplasticity. We focus on MSCs, highlighting their roles in cardiac tissue repair, transdifferentiation, the MSC niche in myocardial tissues, discuss their therapeutic efficacy that has been tested for cardiac therapy, and the current bottleneck of MSC-based cardiac therapies.

From ancient times, Dǎngshēn (Codonopsis javanica) has been used in Chinese traditional medicine. In this study we investigated the anti-hyperinsulinemia and antioxidant properties of C. javanicaroot extracts in a rat model of insulin resistance (IR), induced by chronic fructose feeding. Twenty-four Sprague–Dawley rats were randomized into control, fructose-treated (10%, w/v), and fructose then C. javanica(Fru + Cod)-treated groups. After 8 weeks fructose feeding, increased fasting serum insulin levels (2.6 ± 0.45 μg/L) and insulin area under the curve confirmed the IR (p < 0.001). However, C. javanicatreatment to fructose-fed rats significantly attenuated the hyperinsulinemia with correspondingly improved glucose tolerance. Weight gain in Fru + Cod group was comparably (p < 0.01) lower than in the fructose-fed group. Furthermore, IR-induced increased hepatic lipid peroxidation, as demonstrated by elevated malondialdehyde levels, were significantly (p < 0.001) alleviated by C. javanicatreatment. These findings reveal that chronic fructose intake may facilitate IR and oxidative damage, which could be eradicated by improved antioxidant status. Accordingly, we found that C. javanicatreatment significantly improved the antioxidant enzyme activities, including superoxide dismutase, glutathione peroxidase and glutathione reductase in the liver. These findings that fructose-induced hyperinsulinemia and associated oxidative stress could be attenuated by C. javanicaroot extracts.

This study investigated the nephro-protective effect of ginger against chronic alcohol-induced oxidative stress and tissue damage.

Lee, Wen-Chih, Shu-Man Chen, Min-Chieh Wu, Chien-Wen Hou, Yu-Chiang Lai, Yi-Hung Laio, Chin-Hung Lin, and Chia-Hua Kuo. The role of dehydroepiandrosterone levels on physiologic acclimatization to chronic mountaineering activity. High Alt. Med. Biol. 7:228–236, 2006.—Previous studies have reported that glucose tolerance can be improved by short-term altitude living and activity. However, not all literature agrees that insulin sensitivity is increased at altitude. The present study investigated the effect of a 25-day mountaineering activity on glucose tolerance and its relation to serum levels of dehydroepiandrosterone-sulfate (DHEA-S) and tumor necrosis factor-α (TNF-α) in 12 male subjects. On day 3 at altitude, we found that serum DHEAS was reduced in the subjects with initially greater DHEA-S value, whereas the subjects with initially lower DHEA-S remained unchanged. To further elucidate the role of DHEA-S in acclimatization to mountaineering activity, all subjects were then divided into lower and upper halves according to their sea-level DHEA-S concentrations: low DHEA-S (n = 6) and high DHEA-S groups (n = 6). Glucose tolerance, insulin level, and the normal physiologic responses to altitude exposure, including hematocrit, hemoglobin, erythropoietin (EPO), and cortisol were measured. We found that glucose and insulin concentrations on an oral glucose tolerance test were significantly lowered by the mountaineering activity only in the high DHEA-S group. Similarly, hematocrit and hemoglobin concentration in altitude were increased only in the high DHEA-S group. In contrast, the low DHEA-S subjects exhibited an EPO value at sea level and altitude greater than the high DHEA-S group, suggesting an EPO resistance. The findings of the study imply that DHEA-S is essential for physiologic acclimatization to mountaineering challenge.

Chiu, Li-Ling, Ying-Lan Tsai, Wen-Chih Lee, Yu-Min Cho, Hsin-Yi Ho, Shu-Man Chen, Mu- Tsung Chen, and Chia-Hua Kuo. Acute effect of exercise–hypoxia challenge on GLUT4 protein expression in rat cardiac muscle. High Alt. Med. Biol. 6:256–267, 2005.—Altitude training is a frequently used method for enhancing endurance performance in athletes. But its acute effect on carbohydrate metabolism in cardiac muscle is unknown. In this study, we determined the acute effect of an exercise–hypoxia challenge on glycogen storage and GLUT4 protein expression in heart muscle. Sixteen male Sprague–Dawley rats were assigned to one of two groups: control (CTRL) and exercise–hypoxia (EX+HY). The exercise protocol consisted of swimming for 180 min twice, with a 45-min rest interval. Five hours after the exercise, the EX+HY rats were exposed to a 14% O2 systemic hypoxia under normobaric condition for 12 h. After this hypoxia exposure, the EX+HY and control rats were given glucose orally (1 g/kg body weight) with stomach tube and recovered under normal condition for 16 h. Ventricular portion of the heart was used to determine the levels of glycogen, GLUT4 mRNA, and GLUT4 protein after recovery. We found that myocardial glycogen level was lowered by the exercise–hypoxia challenge (51% below control, p < 0.05), while GLUT4 mRNA was dramatically elevated (approximately 400% of the control level, p < 0.05). The acute exercise–hypoxia treatment did not affect GLUT1 protein level in the same tissue. The novel finding of the study was that the exercise–hypoxia treatment significantly induced GLUT4 gene expression in the cardiac muscle. This acute response appears to be associated with a sustained glycogen depletion of the muscle.

The aim of this study was to investigate the effect of mountain living conditions and high altitude hiking activities on glucose tolerance. In study I, we performed an oral glucose tolerance test on nine untrained subjects before and after 3 days of mountain living. In study II, the same measurement was used to determine the effect of high altitude hiking in two distinct geographic environments; participants included 19 professionally trained mountaineers. We found that trained mountaineers displayed significantly better sea-level glucose tolerance than sedentary subjects of a similar age (p < 0.05). This result suggests that mountaineering training could produce a beneficial effect on glucose tolerance. More importantly, in study I we demonstrated that 3 days of high altitude living (altitude approximately 2400 m) was sufficient to improve glucose tolerance. Furthermore, hiking in a relatively flat plateau area (Pamirs highland area, China, altitude approximately 4000 m) generated significantly better improvement in glucose tolerance than hiking in a mountain that contained many rough hills at a similar altitude (Mountain Snow, Taiwan, altitude approximately 3800 m). In conclusion, we found that living at a high altitude for the short term can significantly improve glucose tolerance. Additionally, the improving effect of hiking at high altitudes on glucose tolerance appears to be influenced by the geographic environment. These preliminary results suggest that high altitude living conditions and activities may possibly be developed as potential natural medicines for the prevention and treatment of type II diabetes in the future.

The effect of carbohydrate supplementation on skeletal muscle glucose transporter GLUT-4 protein expression was studied in fast-twitch red and white gastrocnemius muscle of Sprague-Dawley rats before and after glycogen depletion by swimming. Exercise significantly reduced fast-twitch red muscle glycogen by 50%. During a 16-h exercise recovery period, muscle glycogen returned to control levels (25.0 ± 1.4 μmol/g) in exercise-fasted rats (24.2 ± 0.3 μmol/g). However, when carbohydrate supplementation was provided during and immediately postexercise by intubation, muscle glycogen increased 77% above control (44.4 ± 2.1 μmol/g). Exercise-fasting resulted in an 80% increase in fast-twitch red muscle GLUT-4 mRNA but only a 43% increase in GLUT-4 protein concentration. Conversely, exercise plus carbohydrate supplementation elevated fast-twitch red muscle GLUT-4 protein concentration by 88% above control, whereas GLUT-4 mRNA was increased by only 40%. Neither a 16-h fast nor carbohydrate supplementation had an effect on fast-twitch red muscle GLUT-4 protein concentration or on GLUT-4 mRNA in sedentary rats, although carbohydrate supplementation increased muscle glycogen concentration by 40% (35.0 ± 0.9 μmol/g). GLUT-4 protein in fast-twitch white muscle followed a pattern similar to fast-twitch red muscle. These results indicate that carbohydrate supplementation, provided with exercise, will enhance GLUT-4 protein expression by increasing translational efficiency. Conversely, postexercise fasting appears to upregulate GLUT-4 mRNA, possibly to amplify GLUT-4 protein expression on an increase in glucose availability. These regulatory mechanisms may help control muscle glucose uptake in accordance with glucose availability and protect against postexercise hypoglycemia.

Effects of the major ginsenoside Rg1 on mammalian longevity and physical vitality are rarely reported.

The 17 beta-estradiol (E2) is a sex hormone that is most abundant and most active estrogen in premenopausal women. The importance of E2 in providing cardioprotection and reducing the occurrence of heart disease in women of reproductive age has been well recognized. There are three subtype of estrogen receptors (ERs), including ERα, ERβ and GPR30 have been identified and accumulating evidence reveal their roles on E2-mediated genomic and nongenomic pathway in cardiomyocytes against various cardiac insults. In this review, we focus on the estrogen and ERs mediated signaling pathways in cardiomyocytes that determines cardio-protection against various stresses and further discuss the clinical implication of ERs and phytoestrogens. Further we provide some insights on phytoeostrogens which may play as alternatives in estrogen replacement therapies.