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1.  Inhibition of the AKT pathway in cholangiocarcinoma by MK2206 reduces cellular viability via induction of apoptosis 
Cancer Cell International  2015;15(1):13.
Cholangiocarcinoma (CCA) is an aggressive disease with limited effective treatment options. The PI3K/Akt/mTOR pathway represents an attractive therapeutic target due to its frequent dysregulation in CCA. MK2206, an allosteric Akt inhibitor, has been shown to reduce cellular proliferation in other cancers. We hypothesized that MK2206 mediated inhibition of Akt would impact CCA cellular viability.
Study methods
Post treatment with MK2206 (0-2 μM), cellular viability was assessed in two human CCA cell lines—CCLP-1 and SG231—using an MTT assay. Lysates from the MK2206 treated CCA cells were then examined for apoptotic marker expression levels using Western blot analysis. Additionally, the effect on cellular proliferation of MK2206 treatment on survivin depleted cells was determined.
CCLP-1 and SG231 viability was significantly reduced at MK2206 concentrations of 0.5, 1, and 2 μM by approximately 44%, 53%, and 64% (CCLP-1; p = 0.01) and 32%, 32%, and 42% (SG231; p < 0.00005) respectively. Western analysis revealed a decrease in AKTSer473, while AKTThr308 expression was unchanged. In addition, cleaved PARP as well as survivin expression increased while pro-caspase 3 and 9 levels decreased with treatment. Depletion of survivin in CCLP-1 cells resulted in apoptosis as evidenced by increased cleaved PARP. In addition, survivin siRNA further enhanced the antitumor activity of MK2206.
This study demonstrates that by blocking phosphorylation of Akt at serine473, CCA cellular growth is reduced. The growth suppression appears to be mediated via apoptosis. Importantly, combination of survivin siRNA transfection and MK2206 treatment significantly decreased cell viability.
PMCID: PMC4324843
Cholangiocarcinoma; MK2206; PI3K/mTOR/AKT; Apoptosis
10.  Early Adaptations to Six Weeks of Non-Periodized and Periodized Strength Training Regimens in Recreational Males 
This study compared quadriceps muscle cross-sectional area (CSA) and maximum strength (1RM) after three different short-term strength training (ST) regimens (i.e. non-periodized [NP], traditional-periodization [TP], and undulating-periodization [UP]) matched for volume load in previously untrained individuals. Thirty-one recreationally active males were randomly divided into four groups: NP: n = 9; TP: n = 9; UP: n = 8 and control group (C): n = 5. Experimental groups underwent a 6-week program consisting of two training sessions per week. Muscle strength was assessed at baseline and after the training period. Dominant leg quadriceps CSA was obtained through magnetic resonance imaging (MRI) at baseline and 48h after the last training session.
The 1RM increased from pre to post only in the NP and UP groups (NP = 17.0 %, p = 0.002; UP = 12.9 %, p = 0.03), respectively. There were no significant differences in 1RM for LP and C groups after 6 weeks (TP = 7.7 %, p = 0.58, C = 1.2 %, p = 1.00). The CSA increased from pre to post in all of the experimental groups (NP = 5.1 %, p = 0.0001; TP = 4.6 %, p = 0.001; UP = 5.2 %, p = 0.0001), with no changes observed in the C group (p = 0.93).
Our results suggest that different ST periodization regimens over a short-term (i.e. 6 weeks), volume load equated conditions seem to induce similar hypertrophic responses regardless of the loading scheme employed. In addition, for those recreational males who need to develop muscle strength in the short-term, the training regimen should be designed properly.
Key pointsMuscle hypertrophy occurs within six weeks in recreationally active men regardless the ST training regimen employed.When the total volume is similar, training at greater intensities will demonstrate superior gains in the 1RM performance.Some caution should be exercised when interpreting our findings since long-term periodized regimens could produce different training-induced responses.
PMCID: PMC4126298  PMID: 25177188
Periodization; exercise prescription; training load; muscle hypertrophy
11.  L-leucine, beta-hydroxy-beta-methylbutyric acid (HMB) and creatine monohydrate prevent myostatin-induced Akirin-1/Mighty mRNA down-regulation and myotube atrophy 
The purpose of this study was to examine if L-leucine (Leu), β-hydroxy-β-methylbutyrate (HMB), or creatine monohydrate (Crea) prevented potential atrophic effects of myostatin (MSTN) on differentiated C2C12 myotubes.
After four days of differentiation, myotubes were treated with MSTN (10 ng/ml) for two additional days and four treatment groups were studied: 1) 3x per day 10 mM Leu, 2) 3x per day 10 mM HMB, 3) 3x per day 10 mM Crea, 4) DM only. Myotubes treated with DM without MSTN were analyzed as the control condition (DM/CTL). Following treatment, cells were analyzed for total protein, DNA content, RNA content, muscle protein synthesis (MPS, SUnSET method), and fiber diameter. Separate batch treatments were analyzed for mRNA expression patterns of myostatin-related genes (Akirin-1/Mighty, Notch-1, Ski, MyoD) as well as atrogenes (MuRF-1, and MAFbx/Atrogin-1).
MSTN decreased fiber diameter approximately 30% compared to DM/CTL myotubes (p < 0.001). Leu, HMB and Crea prevented MSTN-induced atrophy. MSTN did not decrease MPS levels compared to DM/CTL myotubes, but MSTN treatment decreased the mRNA expression of Akirin-1/Mighty by 27% (p < 0.001) and MyoD by 26% (p < 0.01) compared to DM/CTL myotubes. shRNA experiments confirmed that Mighty mRNA knockdown reduced myotube size, linking MSTN treatment to atrophy independent of MPS. Remarkably, MSTN + Leu and MSTN + HMB myotubes had similar Akirin-1/Mighty and MyoD mRNA levels compared to DM/CTL myotubes. Furthermore, MSTN + Crea myotubes exhibited a 36% (p < 0.05) and 86% (p < 0.001) increase in Akirin-1/Mighty mRNA compared to DM/CTL and MSTN-only treated myotubes, respectively.
Leu, HMB and Crea may reduce MSTN-induced muscle fiber atrophy by influencing Akirin-1/Mighty mRNA expression patterns. Future studies are needed to examine if Leu, HMB and Crea independently or synergistically affect Akirin-1/Mighty expression, and how Akirin-1/Mighty expression mechanistically relates to skeletal muscle hypertrophy in vivo.
PMCID: PMC4134516  PMID: 25132809
Myostatin; GDF8; Akirin-1; Atrophy; Skeletal muscle
12.  Phosphatidic acid enhances mTOR signaling and resistance exercise induced hypertrophy 
The lipid messenger phosphatidic acid (PA) plays a critical role in the stimulation of mTOR signaling. However, the mechanism by which PA stimulates mTOR is currently unknown. Therefore, the purpose of this study was to compare the effects of various PA precursors and phospholipids on their ability to stimulate mTOR signaling and its ability to augment resistance training-induced changes in body composition and performance.
In phase one, C2C12 myoblasts cells were stimulated with different phospholipids and phospholipid precursors derived from soy and egg sources. The ratio of phosphorylated p70 (P-p70-389) to total p70 was then used as readout for mTOR signaling. In phase two, resistance trained subjects (n = 28, 21 ± 3 years, 77 ± 4 kg, 176 ± 9 cm) consumed either 750 mg PA daily or placebo and each took part in an 8 week periodized resistance training program.
In phase one, soy-phosphatidylserine, soy-Lyso-PA, egg-PA, and soy-PA stimulated mTOR signaling, and the effects of soy-PA (+636%) were significantly greater than egg-PA (+221%). In phase two, PA significantly increased lean body mass (+2.4 kg), cross sectional area (+1.0 cm), and leg press strength (+51.9 kg) over placebo.
PA significantly activates mTOR and significantly improved responses in skeletal muscle hypertrophy, lean body mass, and maximal strength to resistance exercise.
PMCID: PMC4066292  PMID: 24959196
Supplementation; Skeletal muscle; Protein synthesis; Phospholipid; Ergogenic aid
13.  Oral adenosine-5’-triphosphate (ATP) administration increases blood flow following exercise in animals and humans 
Extracellular adenosine triphosphate (ATP) stimulates vasodilation by binding to endothelial ATP-selective P2Y2 receptors; a phenomenon, which is posited to be accelerated during exercise. Herein, we used a rat model to examine how different dosages of acute oral ATP administration affected the femoral blood flow response prior to, during, and after an exercise bout. In addition, we performed a single dose chronic administration pilot study in resistance trained athletes.
Animal study: Male Wistar rats were gavage-fed the body surface area, species adjusted human equivalent dose (HED) of either 100 mg (n=4), 400 mg (n=4), 1,000 mg (n=5) or 1,600 mg (n=5) of oral ATP as a disodium salt (Peak ATP®, TSI, Missoula, MT). Rats that were not gavage-fed were used as controls (CTL, n=5). Blood flow was monitored continuously: a) 60 min prior to, b) during and c) 90 min following an electrically-evoked leg-kicking exercise. Human Study: In a pilot study, 12 college-aged resistance-trained subjects were given 400 mg of ATP (Peak ATP®, TSI, Missoula, MT) daily for 12 weeks, and prior to an acute arm exercise bout at weeks 1, 4, 8, and 12. Ultrasonography-determined volumetric blood flow and vessel dilation in the brachial artery was measured at rest, at rest 30 minutes after supplementation, and then at 0, 3, and 6 minutes after the exercise.
Animal Study: Rats fed 1,000 mg HED demonstrated significantly greater recovery blood flow (p < 0.01) and total blood flow AUC values (p < 0.05) compared to CTL rats. Specifically, blood flow was elevated in rats fed 1,000 mg HED versus CTL rats at 20 to 90 min post exercise when examining 10-min blood flow intervals (p < 0.05). When examining within-group differences relative to baseline values, rats fed the 1,000 mg and 1,600 mg HED exhibited the most robust increases in blood flow during exercise and into the recovery period. Human study: At weeks 1, 8, and 12, ATP supplementation significantly increased blood flow, along with significant elevations in brachial dilation.
Oral ATP administration can increase post-exercise blood flow, and may be particularly effective during exercise recovery.
PMCID: PMC4086998  PMID: 25006331
14.  The effects of 12 weeks of beta-hydroxy-beta-methylbutyrate free acid supplementation on muscle mass, strength, and power in resistance-trained individuals: a randomized, double-blind, placebo-controlled study 
European Journal of Applied Physiology  2014;114(6):1217-1227.
Studies utilizing beta-hydroxy-beta-methylbutyrate (HMB) supplementation in trained populations are limited. No long-term studies utilizing HMB free acid (HMB-FA) have been conducted. Therefore, we investigated the effects of 12 weeks of HMB-FA supplementation on skeletal muscle hypertrophy, body composition, strength, and power in trained individuals. We also determined the effects of HMB-FA on muscle damage and performance during an overreaching cycle.
A three-phase double-blind, placebo- and diet-controlled randomized intervention study was conducted. Phase 1 was an 8-week-periodized resistance-training program; Phase 2 was a 2-week overreaching cycle; and Phase 3 was a 2-week taper. Muscle mass, strength, and power were examined at weeks 0, 4, 8, and 12 to assess the chronic effects of HMB-FA; and assessment of these, as well as cortisol, testosterone, and creatine kinase (CK) was performed at weeks 9 and 10 of the overreaching cycle.
HMB-FA resulted in increased total strength (bench press, squat, and deadlift combined) over the 12-week training (77.1 ± 18.4 vs. 25.3 ± 22.0 kg, p < 0.001); a greater increase in vertical jump power (991 ± 168 vs. 630 ± 167 W, p < 0.001); and increased lean body mass gain (7.4 ± 4.2 vs. 2.1 ± 6.1 kg, p < 0.001) in HMB-FA- and placebo-supplemented groups, respectively. During the overreaching cycle, HMB-FA attenuated increases in CK (−6 ± 91 vs. 277 ± 229 IU/l, p < 0.001) and cortisol (−0.2 ± 2.9 vs. 4.5 ± 1.7 μg/dl, p < 0.003) in the HMB-FA- and placebo-supplemented groups, respectively.
These results suggest that HMB-FA enhances hypertrophy, strength, and power following chronic resistance training, and prevents decrements in performance following the overreaching.
Electronic supplementary material
The online version of this article (doi:10.1007/s00421-014-2854-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4019830  PMID: 24599749
Leucine metabolite; Resistance training; Overreaching; Recovery; Sports supplements
15.  Comparative absorption of curcumin formulations 
Nutrition Journal  2014;13:11.
The potential health benefits of curcumin are limited by its poor solubility, low absorption from the gut, rapid metabolism and rapid systemic elimination. The purpose of this study was the comparative measurement of the increases in levels of curcuminoids (curcumin, demethoxycurcumin, bisdemethoxycurcumin) and the metabolite tetrahydrocurcumin after oral administration of three different curcumin formulations in comparison to unformulated standard.
The relative absorption of a curcumin phytosome formulation (CP), a formulation with volatile oils of turmeric rhizome (CTR) and a formulation of curcumin with a combination of hydrophilic carrier, cellulosic derivatives and natural antioxidants (CHC) in comparison to a standardized curcumin mixture (CS) was investigated in a randomized, double-blind, crossover human study in healthy volunteers. Samples were analyzed by HPLC-MS/MS.
Total curcuminoids appearance in the blood was 1.3-fold higher for CTR and 7.9-fold higher for CP in comparison to unformulated CS. CHC showed a 45.9-fold higher absorption over CS and significantly improved absorption over CP (5.8-fold) and CTR (34.9-fold, all p < 0.001).
A formulation of curcumin with a combination of hydrophilic carrier, cellulosic derivatives and natural antioxidants significantly increases curcuminoid appearance in the blood in comparison to unformulated standard curcumin CS, CTR and CP.
PMCID: PMC3918227  PMID: 24461029
Curcumin; Absorption; Bioavailability
22.  Effects of 8 weeks of Xpand® 2X pre workout supplementation on skeletal muscle hypertrophy, lean body mass, and strength in resistance trained males 
Xpand® 2X is a proprietary blend comprised of branched chain amino acids, creatine monohydrate, beta-alanine (CarnoSyn®), quercetin, coenzymated B-vitamins, alanyl-glutamine (Sustamine®), and natural nitrate sources from pomegranate and beet root extracts purported to enhance the neuromuscular adaptations of resistance training. However to date, no long-term studies have been conducted with this supplement. The purpose of this study was to investigate the effects of a multi-ingredient performance supplement (MIPS) on skeletal muscle hypertrophy, lean body mass and lower body strength in resistance-trained males.
Twenty resistance-trained males (21.3 ± 1.9 years) were randomly assigned to consume a MIPS or a placebo of equal weight and volume (food-grade orange flavors and sweeteners) in a double-blind manner, 30 minutes prior to exercise. All subjects participated in an 8-week, 3-day per week, periodized, resistance-training program that was split-focused on multi-joint movements such as leg press, bench press, and bent-over rows. Ultrasonography measured muscle thickness of the quadriceps, dual-energy X-ray absorptiometry (DEXA) determined lean body mass, and strength of the bench press and leg press were determined at weeks 0, 4, and 8 of the study. Data were analyzed with a 2 × 3 repeated measures ANOVA with LSD post hoc tests utilized to locate differences.
There was a significant group-by-time interaction in which the MIPS supplementation resulted in a significant (p < 0.01) increase in strength of the bench press (18.4% vs. 9.6%) compared with placebo after 4 and 8 weeks of training. There were no significant group by time interactions between MIPS supplementation nor the placebo in leg press strength (p = .08). MIPS supplementation also resulted in a significant increase in lean body mass (7.8% vs. 3.6%) and quadriceps muscle thickness (11.8% vs. 4.5%) compared with placebo (group*time, p <0.01).
These results suggest that this MIPS can positively augment adaptations in strength, and skeletal muscle hypertrophy in resistance-trained men.
PMCID: PMC3851572  PMID: 24107586
Pre-workout; Performance; Hypertrophy; Supplementation; Sports nutrition
23.  Effects of oral adenosine-5′-triphosphate supplementation on athletic performance, skeletal muscle hypertrophy and recovery in resistance-trained men 
Currently, there is a lack of studies examining the effects of adenosine-5′-triphosphate (ATP) supplementation utilizing a long-term, periodized resistance-training program (RT) in resistance-trained populations. Therefore, we investigated the effects of 12 weeks of 400 mg per day of oral ATP on muscular adaptations in trained individuals. We also sought to determine the effects of ATP on muscle protein breakdown, cortisol, and performance during an overreaching cycle.
The study was a 3-phase randomized, double-blind, and placebo- and diet-controlled intervention. Phase 1 was a periodized resistance-training program. Phase 2 consisted of a two week overreaching cycle in which volume and frequency were increased followed by a 2-week taper (Phase 3). Muscle mass, strength, and power were examined at weeks 0, 4, 8, and 12 to assess the chronic effects of ATP; assessment performance variables also occurred at the end of weeks 9 and 10, corresponding to the mid and endpoints of the overreaching cycle.
There were time (p < 0.001), and group x time effects for increased total body strength (+55.3 ± 6.0 kg ATP vs. + 22.4 ± 7.1 kg placebo, p < 0.001); increased vertical jump power (+ 796 ± 75 ATP vs. 614 ± 52 watts placebo, p < 0.001); and greater ultrasound determined muscle thickness (+4.9 ± 1.0 ATP vs. (2.5 ± 0.6 mm placebo, p < 0.02) with ATP supplementation. During the overreaching cycle, there were group x time effects for strength and power, which decreased to a greater extent in the placebo group. Protein breakdown was also lower in the ATP group.
Our results suggest oral ATP supplementation may enhance muscular adaptations following 12-weeks of resistance training, and prevent decrements in performance following overreaching. No statistically or clinically significant changes in blood chemistry or hematology were observed.
Trial registration NCT01508338
PMCID: PMC3849389  PMID: 24330670
Adenosine triphosphate; Exercise performance; Power; Strength; Muscle hypertrophy; Sports nutrition
24.  The effects of 8 weeks of whey or rice protein supplementation on body composition and exercise performance 
Nutrition Journal  2013;12:86.
Consumption of moderate amounts of animal-derived protein has been shown to differently influence skeletal muscle hypertrophy during resistance training when compared with nitrogenous and isoenergetic amounts of plant-based protein administered in small to moderate doses. Therefore, the purpose of the study was to determine if the post-exercise consumption of rice protein isolate could increase recovery and elicit adequate changes in body composition compared to equally dosed whey protein isolate if given in large, isocaloric doses.
24 college-aged, resistance trained males were recruited for this study. Subjects were randomly and equally divided into two groups, either consuming 48 g of rice or whey protein isolate (isocaloric and isonitrogenous) on training days. Subjects trained 3 days per week for 8 weeks as a part of a daily undulating periodized resistance-training program. The rice and whey protein supplements were consumed immediately following exercise. Ratings of perceived recovery, soreness, and readiness to train were recorded prior to and following the first training session. Ultrasonography determined muscle thickness, dual emission x-ray absorptiometry determined body composition, and bench press and leg press for upper and lower body strength were recorded during weeks 0, 4, and 8. An ANOVA model was used to measure group, time, and group by time interactions. If any main effects were observed, a Tukey post-hoc was employed to locate where differences occurred.
No detectable differences were present in psychometric scores of perceived recovery, soreness, or readiness to train (p > 0.05). Significant time effects were observed in which lean body mass, muscle mass, strength and power all increased and fat mass decreased; however, no condition by time interactions were observed (p > 0.05).
Both whey and rice protein isolate administration post resistance exercise improved indices of body composition and exercise performance; however, there were no differences between the two groups.
PMCID: PMC3698202  PMID: 23782948
Protein Quality; Leucine; Whey; Rice
25.  Predicting Body Composition in College Students Using the Womersley and Durnin Body Mass Index Equation 
Asian Journal of Sports Medicine  2013;4(2):153-157.
When assessing fitness levels, body composition is usually measured. The purpose of this study was to determine the overall efficacy of a body mass index (BMI) equation for predicting body composition with respect to college aged participants.
Body composition was measured using dual-energy x-ray absorptiometry (DXA) and was estimated using the Womersley and Durnin BMI prediction equation.
There was no significant (P=0.8) percent body fat (%BF) difference between the BMI prediction equation and DXA (BMI Predicted=25 (10) [min=6; max=52] %BF vs DXA=25 (6) [min=10; max=45] %BF). In addition, a significant correlation was found between the two approaches (r=0.791, P=0.001). However, both the standard error of estimate (6.32 %BF) and total error (6.63 %BF) were outside acceptable ranges for prediction equations.
The Womersley and Durnin equation for estimating %BF was not found to be a good estimate. Therefore, although the BMI predicted %BF has been previously found to predict skinfold estimated %BF, it does not appear valid in estimating %BF from DXA.
PMCID: PMC3690736  PMID: 23802058
Body Fat; Percent Fat; Fat Mass

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