Cardiac abnormalities after induction of endoplasmic reticulum stress are associated with mitochondrial dysfunction and connexin43 expression

The endoplasmic reticulum (ER) is responsible for protein synthesis and calcium storage. ER stress, reflected by protein unfolding and calcium handling abnormalities, has been studied as a pathogenic factor in cardiovascular diseases. The aim of this study is to examine the effects of ER stress on mechanical and electrophysiological functions in the heart and explore the underlying molecular mechanisms. A total of 30 rats were randomly divided into control, ER stress inducer (tunicamycin[TN]) and ER stress inhibitor (tunicamycin+4-phenylbutyric acid [4-PBA]) groups. ER stress induction led to significantly systolic and diastolic dysfunction as reflected by maximal increasing/decreasing rate of left intraventricular pressure (±dp/dt), left ventricular peaksystolic pressure(LVSP) and LV end-diastolic pressure(LVEDP). Epicardial mapping performed in vivo revealed reduced conduction velocity and increased conduction heterogeneity associated with the development of spontaneous ventricular tachycardia. Masson’s trichrome staining revealed marked fibrosis in the myocardial interstitial and sub-pericardial regions, and thickened epicardium. Western blot analysis revealed increased pro-fibrotic factor transforming growth factor-β1 (TGF-β1), decreased mitochondrial biogenesis protein peroxlsome proliferator-activated receptor-γ coactlvator-1α （PGC-1a）, and decreased mitochondrial fusion protein mitofusin-2 (MFN2). These changes were associated with mitochondria dysfunction and connexin 43(CX43)translocation to mitochondria. These abnormalities can be partially prevented by the ER stress inhibitor 4-PBA. Our study shows that ER stress induction can produce cardiac electrical and mechanism dysfunction as well as structural remodelling. Mitochondrial function alterations are contributed by CX43 transposition to mitochondria. These abnormalities can be partially prevented by the ER stress inhibitor 4-PBA

Identifying Biomarkers from Transcriptomic Signatures in Renal Allograft Biopsies Using Deceased and Living Donors.

The survival of transplant kidneys using deceased donors (DD) is inferior to living donors (LD). In this study, we conducted a whole-transcriptome expression analysis of 24 human kidney biopsies paired at 30 minutes and 3 months post-transplantation using DD and LD. The transcriptome profile was found significantly different between two time points regardless of donor types. There were 446 differentially expressed genes (DEGs) between DD and LD at 30 minutes and 146 DEGs at 3 months, with 25 genes common to both time points. These DEGs reflected donor injury and acute immune responses associated with inflammation and cell death as early as at 30 minutes, which could be a precious window of potential intervention. DEGs at 3 months mainly represented the changes of adaptive immunity, immunosuppressive treatment, remodeling or fibrosis via different networks and signaling pathways. The expression levels of 20 highly DEGs involved in kidney diseases and 10 genes dysregulated at 30 minutes were found correlated with renal function and histology at 12 months, suggesting they could be potential biomarkers. These genes were further validated by quantitative polymerase chain reaction (qPCR) in 24 samples analysed by microarray, as well as in a validation cohort of 33 time point unpaired allograft biopsies. This analysis revealed that SERPINA3, SLPI and CBF were up-regulated at 30 minutes in DD compared to LD, while FTCD and TASPN7 were up-regulated at both time points. At 3 months, SERPINA3 was up-regulated in LD, but down-regulated in DD, with increased VCAN and TIMP1, and decreased FOS, in both donors. Taken together, divergent transcriptomic signatures between DD and LD, and changed by the time post-transplantation, might contribute to different allograft survival of two type kidney donors. Some DEGs including FTCD and TASPN7 could be novel biomarkers not only for timely diagnosis, but also for early precise genetic intervention at donor preservation, implantation and post-transplantation, in particular to effectively improve the quality and survival of DD

Evaluation of anti-fatigue property of Porphyridium cruentum in mice

Purpose: To evaluate the potential effects of Porphyridium cruentum (PC) on fatigue induced by forced swimming test in mice. Methods: Mice were randomly divided into normal control group (NC, i.e., untreated non-swimming); model control group (MC, untreated swimming); Spirulina treated group (SP, 800 mg/kg); PC-treated groups (50, 100, and 200 mg/kg), respectively. After intragastric administration for 14 consecutive days, a weight-bearing swimming experiment was conducted for the mice, and the biochemical indicators related to fatigue were examined, including exhaustive swimming time, glucose levels (Glu), hepatic glycogen contents (HG), muscle glycogen contents (MG), glutathione peroxidase activities (GSH-Px), creatine kinase (CK), malondialdehyde (MDA), urea nitrogen levels (SUN), lactate dehydrogenase activities (LDH), lactic acid (LA) as well as superoxide dismutase (SOD). Results: PC significantly prolonged the swimming endurance time compared to MC. After PC treatment, Glu, HG and MG were effectively increased dose-dependently, SUN, LA, LDH and CK levels in serum were significantly reduced. Moreover, PC treatment elevated the bioactivities of two antioxidant enzymes, namely, GSH-Px and SOD, while MDA content decreased when compared to MC group. Conclusion: These results indicate that PC exhibits strong anti-fatigue effect. Thus, PC may be suitable for incorporation in functional food to counter fatigue

PGK1 is a Potential Survival Biomarker and Invasion Promoter by Regulating the HIF-1α–Mediated Epithelial-Mesenchymal Transition Process in Breast Cancer

Background/Aims: Glycolysis, a multi-step enzymatic reaction, is considered to be the root of cancer development and progression. The aim of this study is to figure out which glycolysis enzyme participates in the progression of breast cancer and its possible mechanisms. Materials: We firstly screened out PGK1 by performing an RT-PCR array of glycolysis-related genes in three paired breast cancer samples, and further investigated PGK1 using TCGA and our own database. The effect and mechanism of PGK1 on cell invasion was further explored both in vitro and using patient samples. Results: PGK1 was most upregulated in T3N0 with distant metastases compared to those with no metastases. In the TCGA database, high PGK1 expression predicted poor overall survival (OS) in breast cancer and some other cancers (P< 0.001). In the validation cohort, high PGK1 expression was significantly correlated with larger tumor size (P=0.011) and advanced TNM stage (P=0.033), and PGK1 expression was an independent prognostic factor for OS and disease free survival (DFS) in both univariate and multivariate regression analyses (P< 0.05). Functional studies indicated that knockdown of PGK1 expression significantly inhibited invasion and reversed the epithelial-mesenchymal transition process in breast cancer cells (P< 0.05). Mechanistically, PGK1 increased HRE luciferase activity in a dose-dependent manner, while silencing PGK1 expression decreased HRE activity. Conclusion: High PGK1 expression was associated with poor prognosis in breast cancer, because PGK1 and HIF-1α formed a positive feed-forward loop and thus stimulated breast cancer progression and metastases. Based on these results, PGK1 may serve as a promising biomarker and target therapy for breast cancer

Doxorubicin In Vivo Rapidly Alters Expression and Translation of Myocardial Electron Transport Chain Genes, Leads to ATP Loss and Caspase 3 Activation

BackgroundDoxorubicin is one of the most effective anti-cancer drugs but its use is limited by cumulative cardiotoxicity that restricts lifetime dose. Redox damage is one of the most accepted mechanisms of toxicity, but not fully substantiated. Moreover doxorubicin is not an efficient redox cycling compound due to its low redox potential. Here we used genomic and chemical systems approaches in vivo to investigate the mechanisms of doxorubicin cardiotoxicity, and specifically test the hypothesis of redox cycling mediated cardiotoxicity.Methodology/principal findingsMice were treated with an acute dose of either doxorubicin (DOX) (15 mg/kg) or 2,3-dimethoxy-1,4-naphthoquinone (DMNQ) (25 mg/kg). DMNQ is a more efficient redox cycling agent than DOX but unlike DOX has limited ability to inhibit gene transcription and DNA replication. This allowed specific testing of the redox hypothesis for cardiotoxicity. An acute dose was used to avoid pathophysiological effects in the genomic analysis. However similar data were obtained with a chronic model, but are not specifically presented. All data are deposited in the Gene Expression Omnibus (GEO). Pathway and biochemical analysis of cardiac global gene transcription and mRNA translation data derived at time points from 5 min after an acute exposure in vivo showed a pronounced effect on electron transport chain activity. This led to loss of ATP, increased AMPK expression, mitochondrial genome amplification and activation of caspase 3. No data gathered with either compound indicated general redox damage, though site specific redox damage in mitochondria cannot be entirely discounted.Conclusions/significanceThese data indicate the major mechanism of doxorubicin cardiotoxicity is via damage or inhibition of the electron transport chain and not general redox stress. There is a rapid response at transcriptional and translational level of many of the genes coding for proteins of the electron transport chain complexes. Still though ATP loss occurs with activation caspase 3 and these events probably account for the heart damage

Cassava genome from a wild ancestor to cultivated varieties

Cassava is a major tropical food crop in the Euphorbiaceae family that has high carbohydrate production potential and adaptability to diverse environments. Here we present the draft genome sequences of a wild ancestor and a domesticated variety of cassava and comparative analyses with a partial inbred line. We identify 1,584 and 1,678 gene models specific to the wild and domesticated varieties, respectively, and discover high heterozygosity and millions of single-nucleotide variations. Our analyses reveal that genes involved in photosynthesis, starch accumulation and abiotic stresses have been positively selected, whereas those involved in cell wall biosynthesis and secondary metabolism, including cyanogenic glucoside formation, have been negatively selected in the cultivated varieties, reflecting the result of natural selection and domestication. Differences in microRNA genes and retrotransposon regulation could partly explain an increased carbon flux towards starch accumulation and reduced cyanogenic glucoside accumulation in domesticated cassava. These results may contribute to genetic improvement of cassava through better understanding of its biology

Influence of Bearing Stiffness on the Nonlinear Dynamics of a Shaft-Final Drive System

The bearing stiffness has a considerable influence on the nonlinear coupling vibration characteristics of the shaft-final drive system. A 14-DOF nonlinear coupled vibration model was established by employing the lumped mass method so as to identify the coupling effects of the bearing stiffness to the vibration response of the shaft-final drive system. The engine’s torque ripple, the alternating load from the universal joint (U-joint), and the time-varying mesh parameters of hypoid gear of the shaft-final drive system were also considered for accurate quantitative analysis. The numerical analysis of the vibration response of the coupled system was performed and the experimental measurements were carried out for the validation test. Results show that, at the given driving speed, improving the bearing stiffness can reduce the vibration response of the given coupled system; however, when the bearing stiffness increases to a critical value, the effects of bearing stiffness on the vibration reduction become insignificant; when the driving speed changes, the resonance regions of the coupled system vary with the bearing stiffness. The results are helpful to determine the proper bearing stiffness and the optimum control strategy for the shaft-final drive system. It is hoped that the optimal shaft-final drive system can provide good vibration characteristics to achieve the energy saving and noise reduction for the vehicle application

Effects of Coordination Ability of Nitrogen-Containing Carboxylic Acid Ligands on Nieuwland Catalyst

This article investigated the effect of three nitrogen-containing carboxylic acid ligands for the Nieuwland catalyst system. The catalyst system containing 4.5% N-(2-acetamido) iminodiacetic acid exhibited improved catalytic activity with excellent performance. The yield of monovinylacetylene (MVA) was maintained at 36.7% after 24 h, which was increased by 17.1% relative to the Nieuwland catalyst system. Based on a variety of analyses on the crystals precipitated from the catalyst solutions, it can be inferred that the outstanding performance and lifetime of the catalysts were related to the abilities of these ligands to form strong coordination with Cu+ ions and stabilize them

Dimerization of Acetylene to Monovinylacetylene (MVA) by Bimetallic Zr/Cu Catalyst in Nieuwland Catalytic System

Nieuwland catalyst is a key step in the dimerization of acetylene. Various zirconium metal additives incorporating Nieuwland catalysts were prepared, and their catalytic performances were assessed in acetylene dimerization. Different characterization techniques (i.e., thermogravimetric analysis, temperature-programmed reduction, X-ray diffraction, X-ray photoelectron spectroscopy, hydrogen ion concentration measurement and transmission electron microscopy) were employed in this study. The best catalytic performance was obtained over zirconium-acetylacetonate-incorporated Nieuwland catalysts, with an acetylene conversion of 53.3% and a monovinylacetylene selectivity of 87.4%. Based on these results, the zirconium acetylacetonate additive could reduce the types of transition state complexes, and it could also change the morphology of the catalyst. In addition, the additives could significantly inhibit the occurrence of trimerization products and polymers. Hence, the conversion of acetylene, monovinylacetylene selectivity, and stability of the Nieuwland catalysts were enhanced