Design of Multi-Target drugs of HDACs and other Anti-Alzheimer related Targets: Current strategies and future prospects in Alzheimer's diseases therapy.

Alzheimer disease (AD) is the most prevalent form of dementia that develops spontaneously in the elderly. It's worth mentioning that as people age, the epigenetic profile of the central nervous system cells changes, which may speed up the development of various neurodegenerative disorders including AD. Histone deacetylases (HDACs) are a class of epigenetic enzymes that can control gene expression without altering the gene sequence. Moreover, a promising strategy for multi-target hybrid design was proposed to potentially improve drug efficacy and reduce side effects. These hybrids are monocular drugs that contain various pharmacophore components and have the ability to bind to different targets at the same time. The HDACs ability to synergistically boost the performance of other anti-AD drugs, as well as the ease with which HDACs inhibitor cap group, can be modified. This has prompted numerous medicinal chemists to design a novel generation of HDACs multi-target inhibitors. Different HDACs inhibitors and other ones such as acetylcholinesterase, butyryl-cholinesterase, phosphodiesterase 9, phosphodiesterase 5 or glycogen synthase kinase 3ß inhibitors were merged into hybrids for treatment of AD. This review goes over the scientific rationale for targeting HDACs along with several other crucial targets in AD therapy. This review presents the latest hybrids of HDACs and other AD target pharmacophores.

Comparison in Repetitions to Failure Between Concentric-Only and Eccentric-Only Dumbbell Arm Curl Exercise at Four Different Relative Intensities.

ABSTRACT: Shibata, K, Yamaguchi, T, Takizawa, K, and Nosaka, K. Comparison in repetitions to failure between concentric-only and eccentric-only dumbbell arm curl exercise at four different relative intensities. J Strength Cond Res 37(9): 1754-1760, 2023-The repetitions to failure (RF) were compared between concentric-only (CON) and eccentric-only (ECC) arm curl exercise for different intensities based on CON and ECC 1 repetition maximum (1RM), respectively, with 2 different inter-repetition rests. Sixteen healthy male, university students (19-22 years) participated in 6 sessions. In sessions 1 and 2, CON and ECC 1RM strength were determined. In sessions 3 to 6, CON and ECC dumbbell arm curl exercises were performed until momentary failure at the intensity of either 70, 80, 90 or 95% of CON and ECC 1RM, respectively, with the inter-repetition rest of 3 seconds (R3) for one arm and 6 seconds (R6) for the other arm in a pseudo-randomized order. A significant ( p < 0.01) muscle contraction type × intensity interaction effect was evident for both R3 and R6 conditions. RF was greater ( p < 0.01) in ECC than in CON at 70% (34.2 ± 13.3 vs 20.9 ± 5.4), 80% (22.0 ± 6.7 vs 11.6 ± 2.7), 90% (10.1 ± 3.1 vs 5.2 ± 1.3), and 95% (6.8 ± 2.1 vs 2.7 ± 0.8) for R3. RF was also greater ( p < 0.01) for ECC than for CON at 80% (24.5 ± 8.1 vs 15.6 ± 3.6), 90% (10.8 ± 2.8 vs 7.2 ± 1.8) and 95% (6.7 ± 2.4 vs 3.9 ± 1.5) for R6, with greater ( p < 0.05) RF for R6 than R3. Significant ( p < 0.01) correlations in RF were evident between CON and ECC for R3 ( r = 0.86) and R6 ( r = 0.76). Equations to estimate 1RM were derived for CON and ECC at R3 and R6 (e.g., ECC 1RM = Load × 110.0/[110.5-RF] for R3). These results suggest that fatigue is less in ECC than in CON performed at the same relative intensity.

Warm-Up Intensity and Time-Course Effects on Jump Height under Cold Conditions.

With this study, we aimed to investigate the effects of different warm-up intensities on counter-movement jump (CMJ) performance over time under cold conditions. Eleven male collegiate athletes volunteered. The participants performed high-intensity warm-up (HWU) at 80% VO2max and moderate-intensity warm-up (MWU) at 60% VO2max for 15 min on a bicycle ergometer in a laboratory room at 10 °C. CMJ height, vastus lateralis muscle temperature, heart rate, and perceived fatigue were measured before warm-up (Pre), immediately after (Post 0), 10 min after (Post 10), and 20 min after (Post 20). Significant main effects and interactions were found for CMJ height (time, p < 0.001 and ηp2 = 0.859; interaction, p = 0.007 and ηp2 = 0.327). HWU significantly increased CMJ height at Post 0 to Post 20 compared to that at Pre (p < 0.01), whereas MWU increased CMJ height at Post 0 only compared to that at Pre (p < 0.001). The results indicate that HWU achieved an increase in CMJ height for 20 min. MWU changed CMJ height instantly, but the change did not last compared to HWU in a cold environment.

Effects of Prolonging Eccentric Phase Duration in Parallel Back-Squat Training to Momentary Failure on Muscle Cross-Sectional Area, Squat One Repetition Maximum, and Performance Tests in University Soccer Players.

ABSTRACT: Shibata, K, Takizawa, K, Nosaka, K, and Mizuno, M. Effects of prolonging eccentric phase duration in parallel back-squat training to momentary failure on muscle cross sectional area, squat one repetition maximum, and performance tests in university soccer players. J Strength Cond Res 35(3): 668-674, 2021-This study aimed to compare 2 squat training programs repeated until momentary failure with different eccentric phase duration (2 seconds vs. 4 seconds) on the changes in muscle cross-sectional area, squat 1 repetition maximum (1RM), squat jump (SJ), and countermovement jump (CMJ) height, agility (T-test), and Yo-Yo intermittent recovery test (YY-IR2). Male university soccer players (19.9 ± 0.9 years, 172.2 ± 3.8 cm, 66.1 ± 6.6 kg) were randomly assigned to one of the 2 groups; CON for 2 seconds and ECC for 4 seconds (C2/E4, n = 11) or CON for 2 seconds and ECC for 2 seconds (C2/E2, n = 11). They performed parallel back-squat exercises twice a week for 6 weeks using 75% 1RM weight to momentary failure in each set for 3 sets with each protocol. Outcome measurements were taken before (Pre) and after 3 (Mid; 1RM, SJ, and CMJ only), and at 6 weeks (Post). One repetition maximum increased more (p < 0.05) for C2/E2 (Pre: 95.9 ± 12.2 kg, Mid: 108.2 ± 15.4 kg, Post: 113.6 ± 14.8 kg) than C2/E4 (95.5 ± 12.9 kg, 102.7 ± 15.6 kg, 105.5 ± 14.9 kg, respectively). Cross-sectional area (50% of the thigh length: 3.5 ± 2.8%), SJ (6.7 ± 8.9%) and CMJ height (6.3 ± 8.6%) increased similarly between C2/E2 and C2/E4, but no significant changes in T-test or YY-IR2 were evident in either group. These results suggest that increasing the ECC phase duration during squat exercises does not produce greater training effects when compared with a shorter ECC phase-duration program with momentary failure.

Comparison Between Two Volume-Matched Squat Exercises With and Without Momentary Failure for Changes in Hormones, Maximal Voluntary Isometric Contraction Strength, and Perceived Muscle Soreness.

ABSTRACT: Shibata, K, Takizawa, K, Tomabechi, N, Nosaka, K, and Mizuno, M. Comparison between two volume-matched squat exercises with and without momentary failure for changes in hormones, maximal voluntary isometric contraction strength and perceived muscle soreness. J Strength Cond Res 35(11): 3063-3068, 2021-The present study compared 2 squat exercises with and without momentary failure (MF) for changes in blood hormones, maximal voluntary isometric contraction (MVC) strength, and perceived muscle soreness (SOR). Ten physically active male students performed squat exercises at 75% of their 1 repetition maximum in 2 conditions. First, they performed each set to MF for 3 sets, and 2 weeks later, performed the same number of repetitions in 6 sets without MF (NMF). The rate of perceived exertion was assessed at 30 minutes after exercise. Blood lactate, serum concentrations of growth hormone (GH), testosterone, insulin-like growth factor 1 (IGF-1) and cortisol, MVC strength, and SOR were measured before and after each exercise. Rate of perceived exertion was higher (p < 0.01) in MF (8.3 ± 1.2) than in NMF (4.1 ± 1.4). Blood lactate was greater (p < 0.01) at 5 minutes after MF (7.2 ± 0.7 mM·L-1) than NMF (3.6 ± 0.7 mM·L-1). At 30 minutes after exercise, GH (MF: 12.3 ± 8.3 ng·ml-1, NMF: 4.4 ± 5.2 ng·ml-1) and cortisol (MF: 19.0 ± 4.3 µg·dl-1, NMF: 14.2 ± 4.6 µg·dl-1) were greater (p < 0.01) for MF than NMF, but no significant differences were observed between conditions for testosterone and IGF-1. Maximal voluntary isometric contraction strength decrease (6.1 ± 8.8%) at 24 hours after exercise was evident only for MF, but SOR at 24 hours after exercise was similar between MF (4.8 ± 3.3 cm) and NMF (2.5 ± 2.4 cm) conditions. These results suggest that mechanical and metabolic stimulus to the muscles were greater for MF than NMF condition.

Warm-Up Intensity and Time Course Effects on Jump Performance.

Jump performance is affected by warm-up intensity and body temperature, but the time course effects have not been thoroughly investigated. The purpose of this study was to investigate time course effects on jump performance after warm-up at different intensities. Nine male athletes (age: 20.9 ± 1.0 years; height: 1.75 ± 0.03 m; weight: 66.4 ± 6.3 kg; mean ± SD) volunteered for this study. The participants performed three warm-ups at different intensities: 15 min at 80% VO2 max, 15 min at 60% VO2 max, and no warm-up (control). After each warm-up, counter movement jump (CMJ) height, vastus lateralis temperature, heart rate and subjective fatigue level were measured at three intervals: immediately after warm-up, 10 min after, and 20 min after, respectively. Significant main effects and interactions were found for muscle temperature (intensity: p < 0.01, η2p = 0.909; time: p < 0.01, η2p = 0.898; interaction: p < 0.01, η2p = 0.917). There was a significant increase of muscle temperature from the baseline after warm-up, which lasted for 20 min after warm-up with 80% VO2 max and 60% VO2 max (p < 0.01). Muscle temperature was significantly higher with warm-up at 80% VO2 max than other conditions (P < 0.01). Significant main effects and interactions for CMJ height were found (intensity: p < 0.01, η2p = 0.762; time: p < 0.01, η2p = 0.810; interaction: p < 0.01, η2p = 0.696). Compared with the control conditions, CMJ height after 80% VO2 max and 60% VO2 max warm-ups were significantly higher (p < 0.01 and p < 0.05, respectively). CMJ height at 20 min after warm-up was significantly higher for 80% VO2 max warm-up than for 60% VO2 max warm-up (p < 0.01). However, CMJ height at 10 min after 60% VO2 max warm-up was not significantly different from the baseline (p < 0.05). These results showed that both high and moderate intensity warm-up can maintain an increase in muscle temperature for 20 min. Jump performance after high-intensity warm-up was increased for 20 min compared to a moderate intensity warm-up.

Effect of General Warm-Up Plus Dynamic Stretching on Endurance Running Performance in Well-Trained Male Runners.

Purpose: The purpose of this study was to compare the acute effects of general warm-up (GWU) and GWU plus dynamic stretching (GWU + DS) on endurance running performance in well-trained male runners. Method: The endurance running performances of eight well-trained long-distance male runners were assessed on a treadmill after 2 types of intervention for 5 min after running on the treadmill at a velocity equivalent to 70% maximal oxygen uptake (V̇O2max) in each athlete for 15 min. The interventions were GWU and GWU + DS. In the GWU + DS intervention, dynamic stretching was performed for ten repetitions as quickly as possible for the five muscle groups of the lower extremities. The total duration of the dynamic stretching was 3 min and 45 s. Endurance running performance was assessed at 1 min 15 s after the dynamic stretching. The endurance running performance was evaluated by the time to exhaustion (TTE) during running at a velocity equivalent to 90% [Formula: see text]O2max in each athlete. Results: The TTE (640.6 ± 220.4 s) after GWU + DS intervention was significantly (d = 1.02, p = .03) shorter than that (760.6 ± 249.1 s) after GWU intervention. Conclusions: The results demonstrated that GWU + DS intervention impaired immediate endurance performance of running at a velocity equivalent to 90% [Formula: see text]O2max in well-trained male runners compared with GWU intervention. Thus, we are not able to recommend that well-trained runners and their coaches use the protocol for GWU + DS described in this study during actual warm-ups.

Effects of 3-Week Work-Matched High-Intensity Intermittent Cycling Training with Different Cadences on VO2max in University Athletes.

The aim of this study is to clarify the effects of 3-week work-matched high-intensity intermittent cycling training (HIICT) with different cadences on the VO2max of university athletes. Eighteen university athletes performed HIICT with either 60 rpm (n = 9) or 120 rpm (n = 9). The HIICT consisted of eight sets of 20 s exercise with a 10 s passive rest between each set. The initial training intensity was set at 135% of VO2max and was decreased by 5% every two sets. Athletes in both groups performed nine sessions of HIICT during a 3-week period. The total workload and achievement rate of the workload calculated before experiments in each group were used for analysis. VO2max was measured pre- and post-training. After 3 weeks of training, no significant differences in the total workload and the achievement rate of the workload were found between the two groups. VO2max similarly increased in both groups from pre- to post-training (p = 0.016), with no significant differences between the groups (p = 0.680). These results suggest that cadence during HIICT is not a training variable affecting the effect of VO2max.

Synthesis of Chiral Homoallylic Nitriles by Iridium-Catalyzed Allylation of Cyanoacetates.

A synthesis of chiral homoallylic nitriles by the iridium-catalyzed allylation of cyanoacetates followed by Krapcho demethoxycarbonylation has been developed. A wide range of homoallylic nitriles were obtained with a high enantioselectivity (>95-99% ee). These compounds are useful chiral building blocks because further synthetic elaboration starting from a nitrile or terminal alkene is possible.

Warm-Up Exercises May Not Be So Important for Enhancing Submaximal Running Performance.

Takizawa, K, Yamaguchi, T, and Shibata, K. Warm-up exercises may not be so important for enhancing submaximal running performance. J Strength Cond Res 32(5): 1383-1390, 2018-The purpose of this study was to determine an appropriate warm-up intensity for enhancing performance in submaximal running at 90% vV[Combining Dot Above]O2max (it assumes 3,000-5,000 m in track events). Seven trained male university athletes took part in this study (age: 21.3 ± 2.1 years, height: 169.3 ± 4.7 cm, body mass: 58.4 ± 5.6 kg, V[Combining Dot Above]O2max: 73.33 ± 5.46 ml·kg·min). Each subject ran on a treadmill at 90% vV[Combining Dot Above]O2max until exhaustion after 1 of 4 warm-up treatments. The 4 warm-up treatments were no warm-up, 15 minutes running at 60% vV[Combining Dot Above]O2max, at 70% vV[Combining Dot Above]O2max, and at 80% vV[Combining Dot Above]O2max. The running performance was evaluated by time to exhaustion (TTE). V[Combining Dot Above]O2, and vastus lateralis muscle temperature were also measured. There were no significant differences in TTE among the warm-up exercises (p > 0.05). V[Combining Dot Above]O2 in no warm-up showed slower reaction than the other warm-up exercises. Regarding, the vastus lateralis muscle temperature immediately after warm-up, no warm-up was significantly (p < 0.01) lower compared with the other warm-up exercises. Our results suggested that submaximal running performance was not affected by the presence or absence of a warm-up or by warm-up intensity, although physiological changes occurred.

Evidence for an amphibian sixth digit.

INTRODUCTION: Despite the great diversity in digit morphology reflecting the adaptation of tetrapods to their lifestyle, the number of digits in extant tetrapod species is conservatively stabilized at five or less, which is known as the pentadactyl constraint. RESULTS: We found that an anuran amphibian species, Xenopus tropicalis (western clawed frog), has a clawed protrusion anteroventral to digit I on the foot. To identify the nature of the anterior-most clawed protrusion, we examined its morphology, tissue composition, development, and gene expression. We demonstrated that the protrusion in the X. tropicalis hindlimb is the sixth digit, as is evident from anatomical features, development, and molecular marker expression. CONCLUSION: Identification of the sixth digit in the X. tropicalis hindlimb strongly suggests that the prehallux in other Xenopus species with similar morphology and at the same position as the sixth digit is also a vestigial digit. We propose here that the prehallux seen in various species of amphibians generally represents a rudimentary sixth digit.

Acute Effect of Dynamic Stretching on Endurance Running Performance in Well-Trained Male Runners.

The purpose of this study was to clarify the acute effect of dynamic stretching (DS) on relative high-intensity endurance running performance. The endurance running performances of 7 well-trained middle- or long-distance male runners were assessed on a treadmill after 2 types of pretreatment. The pretreatments were nonstretching (NS) and DS treatment. In the DS treatment, DS was performed as 1 set of 10 repetitions as quickly as possible for the 5 muscle groups in lower extremities. The endurance running performances were evaluated by time to exhaustion (TTE) and total running distance (TRD) during running at a velocity equivalent to 90% maximal oxygen uptake (VO2max) in each subject. The oxygen uptake (VO2) during running was measured as an index of running economy (RE). The TTE (928.6 ± 215.0 seconds) after DS treatment was significantly (p < 0.01) more prolonged compared with that (785.3 ± 206.2 seconds) after NS. The TRD (4,301.2 ± 893.8 m) after DS treatment was also significantly (p < 0.01) longer than that (3,616.9 ± 783.3 m) after NS. The changes in the VO2 during running, however, did not significantly (p > 0.05) differ between the pretreatments. The results demonstrated that the DS treatment improved the endurance performance of running at a velocity equivalent to 90% VO2max in well-trained male runners, although it did not change the RE. This running velocity is equivalent to that for a 3,000- or 5,000-m race. Our finding suggests that performing DS during warm-up before a race is effective for improving performance.

Postural stabilization by trunk tightening force generated by passive power-assist device.

We are developing a passive power-assist supporter called Smart Suit Lite, which is a compact and lightweight power-assist device that utilizes the restoring force of elastic belts. Smart Suit Lite is designed not only to support muscles but also to stabilize the torso similarly to a corset. However, because a corset is always tight around the waist, negative effects caused by long-term use has been pointed out. In contrast, the tightening force generated by Smart Suit Lite increases only when the wearer adopts a posture corresponding to higher load on the low back. In this research, we performed two basic experiments to evaluate the static balance ability of wearers. As a result, the standard deviation of the lumbar angle decreased by 32.1% on average in wearers with low stability.

A rice diet is associated with less fat synthesis/accumulation than a bread diet before exercise therapy.

For effective exercise therapy after waking up, we focused on the staple food in diet therapy, and compared rice and bread diets. The subjects were 10 healthy college male students. After fasting for 12 h or more from the previous day, the subjects had breakfast consisting of rice (protein, 6.3 g; fat, 0.9 g: CHO, 79.3 g; energy, 368 kcal) or bread (protein, 15.7 g; fat, 5.8 g; CHO, 79.2 g; and energy, 450 kcal) containing the same amount of carbohydrates and the same side dishes (protein, 7.0 g; fat, 9.5 g; CHO, 21.3 g; energy, 199 kcal) in the morning 30 min before the initiation of exercise on a bicycle ergometer at an intensity of about 50% VO2max for 60 min. Measurements of the heart rate and expired gas were initiated 15 min before the start of exercise and continued until 10 min after exercise. Blood was collected before the meal, immediately before and 15, 30, and 45 min after the initiation of exercise, and immediately, 15, and 30 min after its termination. After breakfast containing carbohydrates, decreases were observed in the levels of free fatty acid and noradrenalin. Blood insulin (mealxtime, p<0.05 ANOVA) and triglyceride (meal x time, p<0.01, ANOVA) changed at higher levels in the bread diet than in the rice diet. Blood triglyceride is a resource of fat synthesis/accumulation, and insulin promotes its action. Therefore, the bread diet may promote fat synthesis/accumulation compared with the rice diet.