Therapeutic Effect of Targeting Branched-Chain Amino Acid Catabolic Flux in Pressure-Overload Induced Heart Failure.

Background Branched-chain amino acid (BCAA) catabolic defect is an emerging metabolic hallmark in failing hearts in human and animal models. The therapeutic impact of targeting BCAA catabolic flux under pathological conditions remains understudied. Methods and Results BT2 (3,6-dichlorobenzo[b]thiophene-2-carboxylic acid), a small-molecule inhibitor of branched-chain ketoacid dehydrogenase kinase, was used to enhance BCAA catabolism. After 2 weeks of transaortic constriction, mice with significant cardiac dysfunctions were treated with vehicle or BT2. Serial echocardiograms showed continuing pathological deterioration in left ventricle of the vehicle-treated mice, whereas the BT2-treated mice showed significantly preserved cardiac function and structure. Moreover, BT2 treatment improved systolic contractility and diastolic mechanics. These therapeutic benefits appeared to be independent of impacts on left ventricle hypertrophy but associated with increased gene expression involved in fatty acid utilization. The BT2 administration showed no signs of apparent toxicity. Conclusions Our data provide the first proof-of-concept evidence for the therapeutic efficacy of restoring BCAA catabolic flux in hearts with preexisting dysfunctions. The BCAA catabolic pathway represents a novel and potentially efficacious target for treatment of heart failure

Co-Loading of Inorganic Nanoparticles and Natural Oil in the Electrospun Janus Nanofibers for a Synergetic Antibacterial Effect

Side-by-side electrospinning is a powerful but challenging technology that can be used to prepare Janus nanofibers for various applications. In this work, cellulose acetate (CA) and polycaprolactone (PCL) were used as polymer carriers for silver nanoparticles (Ag NPs) and lavender oil (LO), respectively, processing these into two-compartment Janus fibers. A bespoke spinneret was used to facilitate the process and prevent the separation of the working fluids. The process of side-by-side electrospinning was recorded with a digital camera, and the morphology and internal structure of the products were characterized by electron microscopy. Clear two-compartment fibers are seen. X-ray diffraction patterns demonstrate silver nanoparticles have been successfully loaded on the CA side, and infrared spectroscopy indicates LO is dispersed on the PCL side. Wetting ability and antibacterial properties of the fibers suggested that PCL-LO//CA-Ag NPs formulation had strong antibacterial activity, performing better than fibers containing only one active component. The PCL-LO//CA-Ag NPs had a 20.08 ± 0.63 mm inhibition zone for E. coli and 19.75 ± 0.96 mm for S. aureus. All the fibers had water contact angels all around 120°, and hence, have suitable hydrophobicity to prevent water ingress into a wound site. Overall, the materials prepared in this work have considerable promise for wound healing applications

Inhibition of TRPA1 Attenuates Doxorubicin-Induced Acute Cardiotoxicity by Suppressing Oxidative Stress, the Inflammatory Response, and Endoplasmic Reticulum Stress

The transient receptor potential ankyrin 1 (TRPA1) channel is expressed in cardiomyocytes and involved in many cardiovascular diseases. However, the expression and function of TRPA1 in doxorubicin- (Dox-) induced acute cardiotoxicity have not been elucidated. This study aimed at investigating whether blocking the TRPA1 channel with the specific inhibitor HC-030031 (HC) attenuates Dox-induced cardiac injury. The animals were randomly divided into four groups: control, HC, Dox, and Dox + HC. Echocardiography was used to evaluate cardiac function, and the heart was removed for molecular experiments. The results showed that the expression of TRPA1 was increased in the heart after Dox treatment. Cardiac dysfunction and increased serum CK-MB and LDH levels were induced by Dox, but these effects were attenuated by HC treatment. In addition, HC mitigated Dox-induced oxidative stress, as evidenced by the decreased MDA level and increased GSH level and SOD activity in the Dox + HC group. Meanwhile, HC treatment lowered the levels of the proinflammatory cytokines IL-1β, IL-6, IL-17, and TNF-α induced by Dox. Furthermore, HC treatment mitigated endoplasmic reticulum (ER) stress and cardiomyocyte apoptosis induced by Dox. These results indicated that inhibition of TRPA1 could prevent Dox-induced cardiomyocyte apoptosis in mice by inhibiting oxidative stress, inflammation, and ER stress

In silico method for systematic analysis of feature importance in microRNA-mRNA interactions

<p>Abstract</p> <p>Background</p> <p>MicroRNA (miRNA), which is short non-coding RNA, plays a pivotal role in the regulation of many biological processes and affects the stability and/or translation of mRNA. Recently, machine learning algorithms were developed to predict potential miRNA targets. Most of these methods are robust but are not sensitive to redundant or irrelevant features. Despite their good performance, the relative importance of each feature is still unclear. With increasing experimental data becoming available, research interest has shifted from higher prediction performance to uncovering the mechanism of microRNA-mRNA interactions.</p> <p>Results</p> <p>Systematic analysis of sequence, structural and positional features was carried out for two different data sets. The dominant functional features were distinguished from uninformative features in single and hybrid feature sets. Models were developed using only statistically significant sequence, structural and positional features, resulting in area under the receiver operating curves (AUC) values of 0.919, 0.927 and 0.969 for one data set and of 0.926, 0.874 and 0.954 for another data set, respectively. Hybrid models were developed by combining various features and achieved AUC of 0.978 and 0.970 for two different data sets. Functional miRNA information is well reflected in these features, which are expected to be valuable in understanding the mechanism of microRNA-mRNA interactions and in designing experiments.</p> <p>Conclusions</p> <p>Differing from previous approaches, this study focused on systematic analysis of all types of features. Statistically significant features were identified and used to construct models that yield similar accuracy to previous studies in a shorter computation time.</p

Exploring wettability difference-driven wetting by utilizing electrospun chimeric Janus microfiber comprising cellulose acetate and polyvinylpyrrolidone

In exploring the difference in the wettability of fibers with various structures, three inner constructions of fibers, namely, uniaxial, Janus and chimeric Janus, have been fabricated by electrospinning. In electrospun fibers, polyvinyl pyrrolidone and cellulose acetate were used as a polymer matrix and ketoprofen was used as a model drug. Morphologies and inner structures were respectively investigated by scanning electron microscopy (SEM) and Transmission electron microscopy (TEM). Physical states and compatibilities of materials were detected by X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR). Water contact angle (WCA) tests were conducted to determine the difference between wettability and wetting time among assorted fiber membranes. Results showed that the wettability gradient could drive water movement and wetting, which resulted in the rapid decrease of the WCA, to prepare Janus and chimeric Janus fiber membranes compared with uniaxial fiber membranes. Otherwise, in vitro drug release experiments were carried out and four fitting models were applied in matching release profiles. The results showed that electrospun fiber membranes belonged to sustained-release systems and such membranes were influenced by drug diffusion and backbone corrosion effects. In this study, whether electrospun multilayer Janus fibers could affect wettability and drug release was investigated

The association between outdoor air pollution and body mass index, central obesity, and visceral adiposity index among middle-aged and elderly adults: a nationwide study in China

BackgroundPrevious animal studies have suggested that air pollution (AP) exposure may be a potential risk factor for obesity; however, there is limited epidemiological evidence available to describe the association of obesity with AP exposure.MethodsA retrospective cross-sectional study was conducted on 11,766 participants across mainland China in 2015. Obesity was assessed using body mass index (BMI), waist circumference (WC), and visceral adiposity index (VAI). The space-time extremely randomized tree (STET) model was used to estimate the concentration of air pollutants, including SO2, NO2, O3, PM1, PM2.5, and PM10, matched to participants’ residential addresses. Logistic regression models were employed to estimate the associations of obesity with outdoor AP exposure. Further stratified analysis was conducted to evaluate whether sociodemographics or lifestyles modified the effects.ResultsIncreased AP exposure was statistically associated with increased odds of obesity. The odds ratio (ORs) and 95% confidence interval (CI) of BMI-defined obesity were 1.21 (1.17, 1.26) for SO2, 1.33 (1.26, 1.40) for NO2, 1.15 (1.10, 1.21) for O3, 1.38 (1.29, 1.48) for PM1, 1.19 (1.15, 1.22) for PM2.5, and 1.11 (1.09, 1.13) for PM10 per 10 μg/m3 increase in concentration. Similar results were found for central obesity. Stratified analyses suggested that elderly participants experienced more adverse effects from all 6 air pollutants than middle-aged participants. Furthermore, notable multiplicative interactions were found between O3 exposure and females as well as second-hand smokers in BMI-defined obesity.ConclusionsThis study suggested that outdoor AP exposure had a significant association with the risk of obesity in the middle-aged and elderly Chinese population. Elderly individuals and women may be more vulnerable to AP exposure