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Cytochrome P450 isozyme 1A2 (CYP1A2) is one main xenobiotic metabolizing enzyme in humans. It has been associated with the bioactivation of procarcinogens, including ...4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco specific and potent pulmonary carcinogen. This work describes the computational design and in-silico screening of potential CYP1A2 inhibitors, their chemical synthesis, and enzymatic characterization with the ultimate aim of assessing their potential as cancer chemopreventive agents. To achieve this, a combined classifiers model was used to screen a library of quinazoline-based molecules against known CYP1A2 inhibitors, non-inhibitors, and substrates to predict which quinazoline candidates had a better probability as an inhibitor. Compounds with high probability of CYP1A2 inhibition were further computationally evaluated via Glide docking. Candidates predicted to have selectivity and high binding affinity for CYP1A2 were synthesized and assayed for their enzymatic inhibition of CYP1A2, leading to the discovery of novel and potent quinazoline-based CYP1A2 inhibitors.
This study examined the relationship between previous dietary adherence during a low‐calorie diet weight loss intervention and subsequent weight change during a 2‐year follow‐up for weight ...maintenance. One hundred and sixteen healthy, recently weight reduced (lost ∼12 kg, BMI 22–25 kg/m2) premenopausal women were studied. Dietary adherence was assessed by doubly labeled water (DLW) and body composition change. Comparisons were made between the upper and lower tertiles for previous dietary adherence and subsequent weight change at 1‐ and 2‐year follow‐up. Percent weight regained was significantly lower (30.9 ± 6.7% vs. 66.7 ± 9.4%; P < 0.05) in the upper compared to the lower adherence tertile for previous weight loss dietary adherence (49.9 ± 8.8% vs. 96.8 ± 12.8% P < 0.05) at 1‐ and 2‐year follow‐up, respectively. This difference was partly explained by increases in daily activity‐related energy expenditure (AEE) (+95 ± 45 kcal/day vs. −44 ± 42 kcal/day, P < 0.05) and lower daily energy intake (2,066 ± 71 kcal/day vs. 2,289 ± 62 kcal/day, P < 0.05) in the higher tertile for previous dietary adherence, compared to the lower. These findings suggest that higher adherence (i.e., higher tertile) to the previous low‐calorie diet predicts lower weight regain over 2‐year follow‐up for weight maintenance, which is explained by lower energy intake and higher physical activity. Finally, how well an individual adheres to a low‐calorie diet intervention during weight loss may be a useful tool for identifying individuals who are particularly vulnerable to subsequent weight regain.
Kava beverages are typically prepared from the root of Piper methysticum. They have been consumed among Pacific Islanders for centuries. Kava extract preparations were once used as herbal drugs to ...treat anxiety in Europe. Kava is also marketed as a dietary supplement in the U.S. and is gaining popularity as a recreational drink in Western countries. Recent studies suggest that kava and its key phytochemicals have anti-inflammatory and anticancer effects, in addition to the well-documented neurological benefits. While its beneficial effects are widely recognized, rare hepatotoxicity had been associated with use of certain kava preparations, but there are no validations nor consistent mechanisms. Major challenges lie in the diversity of kava products and the lack of standardization, which has produced an unmet need for quality initiatives. This review aims to provide the scientific community and consumers, as well as regulatory agencies, with a broad overview on kava use and its related research. We first provide a historical background for its different uses and then discuss the current state of the research, including its chemical composition, possible mechanisms of action, and its therapeutic potential in treating inflammatory and neurological conditions, as well as cancer. We then discuss the challenges associated with kava use and research, focusing on the need for the detailed characterization of kava components and associated risks such as its reported hepatotoxicity. Lastly, given its growing popularity in clinical and recreational use, we emphasize the urgent need for quality control and quality assurance of kava products, pharmacokinetics, absorption, distribution, metabolism, excretion, and foundational pharmacology. These are essential in order to inform research into the molecular targets, cellular mechanisms, and creative use of early stage human clinical trials for designer kava modalities to inform and guide the design and execution of future randomized placebo controlled trials to maximize kava's clinical efficacy and to minimize its risks.
Post-exercise elevations of cardiac troponin T (cTnT) and I (cTnI) are often used in isolation but interpreted interchangeably. Research suggests, however, that post-exercise cTn kinetic might differ ...with each isoform. In this cross-sectional observational study, we collected blood samples before, immediately after (5 minutes), and at 1-, 3-, 6-, 12-, and 24-hour post-exercise in a mixed cohort of 56 participants after a distance-trial of 60 min continuous swimming (age range from 14 to 22, 57.1% female). Cardiac troponin kinetics were modelled using Bayesian mixed-effects models to estimate time to peak (TTP) and peak concentration (PC) for each isoform, while controlling for participants sex, tanner stage and average relative heart rate during the test. Exercise induced an elevation of cTnT and cTnI in 93% and 75% of the participants, respectively. Cardiac troponin T peaked earlier, at 2.9 h (CI: 2.6 - 3.2 h) post-exercise, whereas cTnI peaked later, at 4.5 h (CI: 4.2 - 4.9 h). Peak concentrations for cTnT and cTnI were 2.5 ng/L, CI: 0 - 11.2 ng/L and 2.16 ng/L, CI: 0 - 22.7 ng/L, respectively. Additionally, we did not observe a systematic effect of sex and maturational status mediating cTn responses.
The purpose of this study was to determine what effect aerobic and resistance exercise training has on gain of visceral fat during the year following weight loss. After being randomly assigned to ...aerobic training, resistance training, or no exercise training, 45 European-American (EA) and 52 African-American (AA) women lost 12.3 ± 2.5 kg on a 800 kcal/day diet. Computed tomography was used to measure abdominal subcutaneous and visceral adipose tissue, whereas total fat and regional fat (leg, arm, and trunk) were measured by dual energy X-ray absorptiometry after weight loss and 1 year following the weight loss. Because not all the subjects adhered to the 2 time/week 40 min/day exercise training during the 1-year follow-up, subjects were divided into five groups for analysis: aerobic adherers, aerobic nonadherers, resistance adherers, resistance nonadherers, and no exercise. No significant differences were observed between the aerobic training and resistance training adherers for any variable. However, the aerobic (3.1 kg) and resistance (3.9 kg) exercise adherers gained less weight than any of the other three groups (all >6.2 kg). In addition, the two exercise adherence groups did not significantly increase visceral fat (<0.8%) as compared with the 38% increase for the two nonadhering exercise groups and the 25% for the nonexercise group. In conclusion, as little as 80 min/week aerobic or resistance training had modest positive effects on preventing weight regain following a diet-induced weight loss. More importantly, both aerobic and resistance training prevented regain of potentially harmful visceral fat.
This paper presents a “full green” version of a rubber tyre gantry (RTG) crane with a fuel cell (FC) unit and supercapacitors (SCs) as energy storage system (ESS), instead of using the conventional ...RTG powered by a diesel engine. The SCs provide the required high current peaks and power demands when accelerating the load in the hoisting-up movement. Once the power demand reaches a steady level (hoist up constant speed), the FC provides the energy needed for the rest of the movements. The SCs are also charged when the hoist down movement is taking place. In this case, the regenerative energy can be stored in the SCs instead of being burnt in the braking resistors as in the conventional RTG crane. The new hybrid powertrain based on FC and SCs is designed and evaluated from the real driving cycle of the RTG crane. Simulation results, which include a comparative study with the current configuration of the RTG crane (powered only by diesel engine), demonstrate the technical viability of the RTG crane powered by FC and SCs. This hybrid powertrain is more expensive than the diesel powertrain, but more energy-efficient, and a better solution from the environmental point of view.
•“Full green” version of a rubber tyre gantry crane with fuel cell and supercapacitors.•New configuration designed and evaluated from the real driving cycle of the crane.•Configuration technically feasible, more energy-efficient and better option for the environment.
Aging is associated with loss of endurance; however, aging is also associated with decreased fatigue during maximal isometric contractions. The aims of this study were to examine the relationship ...between age and walking endurance (WE) and maximal isometric fatigue (MIF) and to determine which metabolic/fitness components explain the expected age effects on WE and MIF. Subjects were 96 pre-menopausal women. Oxygen uptake (walking economy) was assessed during a 3-mph walk; aerobic capacity and WE by progressive treadmill test; knee extension strength by isometric contractions, MIF during a 90-s isometric plantar flexion (muscle metabolism measured by
31
P MRS). Age was related to increased walking economy (low
V
O
2
,
r
= −0.19,
P
< 0.03) and muscle metabolic economy (force/ATP, 0.34,
P
= 0.01), and reduced MIF (−0.26,
P
< 0.03). However, age was associated with reduced WE (−0.28,
P
< 0.01). Multiple regression showed that muscle metabolic economy explained the age-related decrease in MIF (partial
r
for MIF and age −0.13,
P
= 0.35) whereas walking economy did not explain the age-related decrease in WE (partial
r
for WE and age −0.25,
P
< 0.02). Inclusion of
V
O
2max
and knee endurance strength accounted for the age-related decreased WE (partial
r
for WE and age = 0.03,
P
> 0.80). In premenopausal women, age is related to WE and MIF. In addition, these results support the hypothesis that age-related increases in metabolic economy may decrease MIF. However, decreased muscle strength and oxidative capacity are related to WE.
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