Identification of KU-55933 as an anti-atherosclerosis compound by using a hemodynamic-based high-throughput drug screening platform.

Several compounds have been used for atherosclerosis treatment, including clinical trials; however, no anti-atherosclerotic drugs based on hemodynamic force-mediated atherogenesis have been discovered. Our previous studies demonstrated that "small mothers against decapentaplegic homolog 1/5" (Smad1/5) is a convergent signaling molecule for chemical [e.g., bone morphogenetic proteins (BMPs)] and mechanical (e.g., disturbed flow) stimulations and hence may serve as a promising hemodynamic-based target for anti-atherosclerosis drug development. The goal of this study was to develop a high-throughput screening (HTS) platform to identify potential compounds that can inhibit disturbed flow- and BMP-induced Smad1/5 activation and atherosclerosis. Through HTS using a Smad1/5 downstream target inhibitor of DNA binding 1 (Id-1) as a luciferase reporter, we demonstrated that KU-55933 and Apicidin suppressed Id-1 expression in AD-293 cells. KU-55933 (10 µM), Apicidin (10 µM), and the combination of half doses of each [1/2(K + A)] inhibited disturbed flow- and BMP4-induced Smad1/5 activation in human vascular endothelial cells (ECs). KU-55933, Apicidin, and 1/2(K + A) treatments caused 50.6%, 47.4%, and 73.3% inhibitions of EC proliferation induced by disturbed flow, respectively, whereas EC inflammation was only suppressed by KU-55933 and 1/2(K + A), but not Apicidin alone. Administrations of KU-55933 and 1/2(K + A) to apolipoprotein E-deficient mice inhibited Smad1/5 activation in ECs in athero-susceptible regions, thereby suppressing endothelial proliferation and inflammation, with the attenuation of atherosclerotic lesions in these mice. A unique drug screening platform has been developed to demonstrate that KU-55933 and its combination with Apicidin are promising therapeutic compounds for atherosclerosis based on hemodynamic considerations.

Endothelial Yin Yang 1 Phosphorylation at S118 Induces Atherosclerosis Under Flow.

RATIONALE: Disturbed flow occurring in arterial branches and curvatures induces vascular endothelial cell (EC) dysfunction and atherosclerosis. We postulated that disturbed flow plays important role in modulating phosphoprotein expression profiles to regulate endothelial functions and atherogenesis. OBJECTIVE: The goal of this study is to discover novel site-specific phosphorylation alterations induced by disturbed flow in ECs to contribute to atherosclerosis. METHODS AND RESULTS: Quantitative phosphoproteomics analysis of ECs exposed to disturbed flow with low and oscillatory shear stress (0.5±4 dynes/cm2) versus pulsatile shear stress (12±4 dynes/cm2) revealed that oscillatory shear stress induces phospho-YY1S118 (serine [S]118 phosphorylation of Yin Yang 1) in ECs. Elevated phospho-YY1S118 level in ECs was further confirmed to be present in the disturbed flow regions in experimental animals and human atherosclerotic arteries. This disturbed flow-induced EC phospho-YY1S118 is mediated by CK2α (casein kinase 2α) through its direct interaction with YY1. Yeast 2-hybrid library screening and in situ proximity ligation assays demonstrate that phospho-YY1S118 directly binds ZKSCAN4 (zinc finger with KRAB [krüppel-associated box] and SCAN [SRE-ZBP, CTfin51, AW-1 and Number 18 cDNA] domains 4) to induce promoter activity and gene expression of HDM2 (human double minute 2), which consequently induces EC proliferation through downregulation of p53 and p21CIP1. Administration of apoE-deficient (ApoE-/-) mice with CK2-specific inhibitor tetrabromocinnamic acid or atorvastatin inhibits atherosclerosis formation through downregulations of EC phospho-YY1S118 and HDM2. Generation of novel transgenic mice bearing EC-specific overexpression of S118-nonphosphorylatable mutant of YY1 in ApoE-/- mice confirms the critical role of phospho-YY1S118 in promoting atherosclerosis through EC HDM2. CONCLUSIONS: Our findings provide new insights into the mechanisms by which disturbed flow induces endothelial phospho-YY1S118 to promote atherosclerosis, thus indicating phospho-YY1S118 as a potential molecular target for atherosclerosis treatment.

Effect of Foot Reflexology Intervention on Depression, Anxiety, and Sleep Quality in Adults: A Meta-Analysis and Metaregression of Randomized Controlled Trials.

OBJECTIVES: The aim of this study was to conduct a systematic review, meta-analysis, and metaregression to determine the current best available evidence of the efficacy and safety of foot reflexology for adult depression, anxiety, and sleep quality. METHODS: Electronic databases (PubMed, ClinicalKey, ScienceDirect, EMBASE, PsycINFO, and the Cochrane Library) were searched till August, 10, 2020, and the validity of the eligible studies was critically appraised. Randomized controlled trials comparing foot reflexology groups with control groups for adult depression, anxiety, and sleep quality were included. Twenty-six eligible studies were included to assess the effect of foot reflexology intervention on the reducing symptoms of depression and anxiety and improving quality of sleep, respectively, as the primary outcome. RESULTS: Twenty-six randomized controlled trials involving 2,366 participants met the inclusion criteria. The meta-analyses showed that foot reflexology intervention significantly improved adult depression (Hedges' g = -0.921; 95% CI: -1.246 to -0.595; P < 0.001), anxiety (Hedges' g = -1.237; 95% CI -1.682 to -0.791; P < 0.001), and sleep quality (Hedges' g = -1.665; 95% CI -2.361 to -0.970; P < 0.001). Metaregression reveals that an increase in total foot reflexology time (P = 0.002) and duration (P = 0.01) can significantly improve sleep quality. CONCLUSIONS: Foot reflexology may provide additional nonpharmacotherapy intervention for adults suffering from depression, anxiety, or sleep disturbance. However, high quality and rigorous design RCTs in specific population, along with an increase in participants, and a long-term follow-up are recommended in the future.

The effect of yoga on sleep quality and insomnia in women with sleep problems: a systematic review and meta-analysis.

BACKGROUND: To examine the effectiveness and safety of yoga of women with sleep problems by performing a systematic review and meta-analysis. METHODS: Medline/PubMed, ClinicalKey, ScienceDirect, Embase, PsycINFO, and the Cochrane Library were searched throughout the month of June, 2019. Randomized controlled trials comparing yoga groups with control groups in women with sleep problems were included. Two reviewers independently evaluated risk of bias by using the risk of bias tool suggested by the Cochrane Collaboration for programming and conducting systematic reviews and meta-analyses. The main outcome measure was sleep quality or the severity of insomnia, which was measured using subjective instruments, such as the Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI), or objective instruments such as polysomnography, actigraphy, and safety of the intervention. For each outcome, a standardized mean difference (SMD) and confidence intervals (CIs) of 95% were determined. RESULTS: Nineteen studies in this systematic review included 1832 participants. The meta-analysis of the combined data conducted according to Comprehensive Meta-Analysis showed a significant improvement in sleep (SMD = - 0.327, 95% CI = - 0.506 to - 0.148, P < 0.001). Meta-analyses revealed positive effects of yoga using PSQI scores in 16 randomized control trials (RCTs), compared with the control group in improving sleep quality among women using PSQI (SMD = - 0.54; 95% CI = - 0.89 to - 0.19; P = 0.003). However, three RCTs revealed no effects of yoga compared to the control group in reducing insomnia among women using ISI (SMD = - 0.13; 95% CI = - 0.74 to 0.48; P = 0.69). Seven RCTs revealed no evidence for effects of yoga compared with the control group in improving sleep quality for women with breast cancer using PSQI (SMD = - 0.15; 95% CI = - 0.31 to 0.01; P = 0.5). Four RCTs revealed no evidence for the effects of yoga compared with the control group in improving the sleep quality for peri/postmenopausal women using PSQI (SMD = - 0.31; 95% CI = - 0.95 to 0.33; P = 0.34). Yoga was not associated with any serious adverse events. DISCUSSION: This systematic review and meta-analysis demonstrated that yoga intervention in women can be beneficial when compared to non-active control conditions in term of managing sleep problems. The moderator analyses suggest that participants in the non-breast cancer subgroup and participants in the non-peri/postmenopausal subgroup were associated with greater benefits, with a direct correlation of total class time with quality of sleep among other related benefits.

Inhibited fatty acid ß-oxidation impairs stress resistance ability in Nile tilapia (Oreochromis niloticus).

Energy metabolism plays important roles in stress resistance and immunity in mammals, however, such functions have not been established in fish. In the present study, Nile tilapia (Oreochromis niloticus) was fed with mildronate, an inhibitor of mitochondrial fatty acid (FA) ß-oxidation, for six weeks subsequently challenged with Aeromonas hydrophila and ammonia nitrogen exposure. Mildronate treatment reduced significantly l-carnitine concentration and mitochondrial FA ß-oxidation efficiency, while it increased lipid accumulation in liver. The fish with inhibited hepatic FA catabolism had lower survival rate when exposed to Aeromonas hydrophila and ammonia nitrogen. Moreover, fish fed mildronate supplemented diet had lower immune enzymes activities and anti-inflammatory cytokine genes expressions, but had higher pro-inflammatory cytokine genes expressions. However, the oxidative stress-related biochemical indexes were not significantly affected by mildronate treatment. Taken together, inhibited mitochondrial FA ß-oxidation impaired stress resistance ability in Nile tilapia mainly through inhibiting immune functions and triggering inflammation. This is the first study showing the regulatory effects of lipid catabolism on stress resistance and immune functions in fish.

Isolation of active compounds from methanol extracts of Toddalia asiatica against Ichthyophthirius multifiliis in goldfish (Carassius auratus).

The parasitic ciliate Ichthyophthirius multifiliis infests all species of freshwater fish and can cause severe economic losses in fish breeding. The present study aims to evaluate the antiparasitic activity of the active components from Toddalia asiatica against I. multifiliis. Bioassay-guided fractionation and isolation of compounds with antiparasitic activity were performed on the methanol extract of T. asiatica yielding two bioactive compounds: chelerythrine and chloroxylonine identified by comparing spectral data (NMR and ESI-MS) with literature values. Results from in vitro antiparasitic assays revealed that chelerythrine and chloroxylonine could be 100% effective against I. multifiliis at the concentration of 1.2 mg L(-1) and 3.5 mg L(-1), with the median effective concentration (EC50) values of 0.55 mg L(-1) and 1.90 mg L(-1) respectively. In vivo experiments demonstrated that fish treated with chelerythrine and chloroxylonine at the concentrations of 1.8 and 8.0 mg L(-1) carried significantly fewer parasites than the control (P<0.05). The acute toxicity (LC50) of chelerythrine for goldfish was 3.3 mg L(-1).

[Effect of N, P, K on yield and quality of Rabdosia rubescens].

OBJECTIVE: To research the three fertilizer of N, P, K impacting Rabdosia rubescens on the yield and quality. METHODS: The optimum design of three factors with D-saturation design plan of N, P, K was adopted in the pot experiment. RESULTS: The fertilizers of N, P, K made an obvious improvement in the growth, yield and quality of Rabdosia rubescens. CONCLUSIONS: The N fertilizer plays an important role in the growth of plants. The K fertilizer makes a great impact on the accumulating of oridonin. The N, P, K fertilizers applied reasonably can make the Rabdosia rubescens high yields and improve its quality.

[The extraction, purification and assaying of Gynostemma pentaphyllum polysaccharides].

By orthogonal design, and considering extracting efficiency and cost, optimizing the extract method of Gynostemma pentaphyllum polysaccharides. We purified the crude Gynostemma pentaphyllum polysaccharides initially, and assayed the polysaccharides content of Gynostemma pentaphyllum polysccharides. The content of Gynostemma pentaphyllum polysaccharides was sigificantly higher than the predecessor. It would provide conditions for the deep exploitation of Gynostemma pentaphyllum.