Pharmacokinetics of mequindox after intravenous and intramuscular administration to goat

Pharmacokinetics and bioavailability of mequindox were determined after single intravenous (i.v.) or intramuscular (i.m.) administrations of 7 mg/kg body weight (b.w.) to 10 healthy adult goats. Plasma mequindox concentrations were measured by high performance liquid chromatography. Pharmacokinetics were best described by a two-compartment open model and an one-compartment open model for i.v. and i.m. groups, respectively. The elimination half-life and volume of distribution after i.v. and i.m. administrations were statistically different (t1/2β, 1.8 to 1.5 h, P < 0.05 and Vd, 0.35 to 0.45 L·kg-1, P < 0.05, respectively). Mequindox was rapidly (t1/2a, 0.28 h) and almost completely absorbed (F, 99.8%) after i.m. administration. In conclusion, 2~3 times daily i.v. and i.m. administration of mequindox (7 mg/kg b.w.) in goats may be useful in treatment of infectious diseases caused by sensitive pathogens. The plasma disposition kinetics of mequindox in goats is reported for the first time.Key words: Mequindox, pharmacokinetics, high performance liquid chromatography (HPLC), goats

PO-144 Intermittent Exercise Activates NRG1-SERCA2a Pathway to Improve Cardiac Function in Myocardial Infarction Rats

Objective  Intermittent exercise can improve cardiac function in rats with myocardial infarction. The Neuregulin-1(NRG1)/SERCA2a palys a critical role in maintain cardiac function. We want to investigate the effect of Neuregulin-1 (NRG1) on NRG1-SERCA2a signaling pathway activated by intermittent exercise and on improves cardiac function in rats with MI. Methods 32 male sprague-dawley rats were randomly divided into four groups (n=8): Sham-operated group (S), sedentary MI group (MI), MI with interval training group (ME), ME with inhibitor AG1478 group (MA). ME and MA model after the MI model was established by ligation of the left anterior descending coronary artery, and began training 1 week after MI surgery. The S model only by threading without ligation. Rats in ME and MA model taken one week adaptive training, then began 8-week interval training. MA model were injected with inhibitor AG1478, once every two days. The 24h after training, rats were anesthetized, the LVSP, LVEDP, ±dp/dt max were tested by carotid artery intubation which in order to evaluate cardiac function. The protein expression of NRG1, PI3K, Akt, eNOS, PKG, PLN, SERCA2a in myocardium were measured by Westernblotting, themRNA expression of serca2a were tested by RT-qPCR. Results Compared with S, the protein expression of NRG1, PKG, peNOS, pAkt, pPLN, pPI3K and SERCA2a decreased, serca2a mRNA expression decreased, LVSP and ±dp/dt max significantly decreased, LVEDP significantly increased; Compared with MI, the protein expression of NRG1, PKG, peNOS, pAkt, pPLN, pPI3K and SERCA2a increased, serca2a mRNA expression increased, LVSP and ±dp/dt max significantly increased, LVEDP decreased, and the effect of exercise were weaken by inhibitor AG1478. Correlation analysis showed that the myocardial pPLN and SERCA2a protein expression both were positively correlated with LVSP, ±dp/dtmax, and negatively correlated with LVEDP. Conclusions Intermittent exercise can increased myocardial NRG1 protein expression and activates NRG1-SERCA2a signaling pathway, improve myocardial infarction cardiac function

Magnetosome Gene Duplication as an Important Driver in the Evolution of Magnetotaxis in the Alphaproteobacteria

The evolution of microbial magnetoreception (or magnetotaxis) is of great interest in the fields of microbiology, evolutionary biology, biophysics, geomicrobiology, and geochemistry. Current genomic data from magnetotactic bacteria (MTB), the only prokaryotes known to be capable of sensing the Earth’s geomagnetic field, suggests an ancient origin of magnetotaxis in the domain Bacteria. Vertical inheritance, followed by multiple independent magnetosome gene cluster loss, is considered to be one of the major forces that drove the evolution of magnetotaxis at or above the class or phylum level, although the evolutionary trajectories at lower taxonomic ranks (e.g., within the class level) remain largely unstudied. Here we report the isolation, cultivation, and sequencing of a novel magnetotactic spirillum belonging to the genus Terasakiella (Terasakiella sp. strain SH-1) within the class Alphaproteobacteria. The complete genome sequence of Terasakiella sp. strain SH-1 revealed an unexpected duplication event of magnetosome genes within the mamAB operon, a group of genes essential for magnetosome biomineralization and magnetotaxis. Intriguingly, further comparative genomic analysis suggests that the duplication of mamAB genes is a common feature in the genomes of alphaproteobacterial MTB. Taken together, with the additional finding that gene duplication appears to have also occurred in some magnetotactic members of the Deltaproteobacteria, our results indicate that gene duplication plays an important role in the evolution of magnetotaxis in the Alphaproteobacteria and perhaps the domain Bacteria

An adaptive finite element method based on Superconvergent Cluster Recovery for the Cahn-Hilliard equation

In this study, we construct an error estimate for a fully discrete finite element scheme that satisfies the criteria of unconditional energy stability, as suggested in [1]. Our theoretical findings, in more detail, demonstrate that this system has second-order accuracy in both space and time. Additionally, we offer a powerful space and time adaptable approach for solving the Cahn-Hilliard problem numerically based on the posterior error estimation. The major goal of this technique is to successfully lower the calculated cost by controlling the mesh size using a Superconvergent Cluster Recovery (SCR) approach in accordance with the error estimation. To demonstrate the effectiveness and stability of the suggested SCR-based algorithm, numerical results are provided

The novel ZIP4 regulation and its role in ovarian cancer

Our RNAseq analyses revealed that ZIP4 is a top gene up-regulated in more aggressive ovarian cancer cells. ZIP4's role in cancer stem cells has not been reported in any type of cancer. In addition, the role and regulation of ZIP4, a zinc transporter, have been studied in the context of extracellular zinc transporting. Factors other than zinc with ZIP4 regulatory effects are essentially unknown. ZIP4 expression and its regulation in epithelial ovarian cancer cells was assessed by immunoblotting, quantitative PCR, or immunohistochemistry staining in human ovarian tissues. Cancer stem cell-related activities were examined to evaluate the role of ZIP4 in human high-grade serous ovarian cancer cells in vitro and in vivo. RNAi and CRISPR techniques were used to knockdown or knockout ZIP4 and related genes. Ovarian cancer tissues overexpressed ZIP4 when compared with normal and benign tissues. ZIP4 knockout significantly reduced several cancer stem cell-related activities in EOC cells, including proliferation, anoikis-resistance, colony-formation, spheroid-formation, drug-resistance, and side-population in vitro. ZIP4-expressing side-population highly expressed known CSC markers ALDH1 and OCT4. ZIP4 knockout dramatically reduced tumorigenesis and ZIP4 overexpression increased tumorigenesis in vivo. In addition, the ZIP4-expressing side-population had the tumor initiating activity. Moreover, the oncolipid lysophosphatic acid effectively up-regulated ZIP4 expression via the nuclear receptor peroxisome proliferator-activated receptor gamma and lysophosphatic acid 's promoting effects in cancer stem cell-related activities in HGSOC cells was at least partially mediated by ZIP4 in an extracellular zinc-independent manner. Our critical data imply that ZIP4 is a new and important cancer stem cell regulator in ovarian cancer. Our data also provide an innovative interpretation for the apparent disconnection between low levels of zinc and up-regulation of ZIP4 in ovarian cancer tissues

A CRM1 Inhibitor Alleviates Cardiac Hypertrophy and Increases the Nuclear Distribution of NT-PGC-1α in NRVMs

Chromosomal maintenance 1 (CRM1) inhibitors display antihypertrophic effects and control protein trafficking between the nucleus and the cytoplasm. PGC-1α (peroxisome proliferator-activated receptor gamma coactivator-1alpha) is a type of transcriptional coactivator that predominantly resides in the nucleus and is downregulated during heart failure. NT-PGC-1α is an alternative splicing variant of PGC-1α that is primarily distributed in the cytoplasm. We hypothesized that the use of a CRM1 inhibitor could shuttle NT-PGC-1α into the nucleus and activate PGC-1α target genes to potentially improve cardiac function in a mouse model of myocardial infarction (MI). We showed that PGC-1α and NT-PGC-1α were decreased in MI-induced heart failure mice. Phenylephrine and angiotensin II were applied to induce hypertrophy in neonatal rat ventricular myocytes (NRVMs). The antihypertrophic effects of the CRM1-inhibitor Selinexor was verified through profiling the expression of β-MHC and through visualizing the cell cross-sectional area. NRVMs were transfected with adenovirus-NT-PGC-1α or adenovirus-NLS (nucleus localization sequence)-NT-PGC-1α and then exposed to Selinexor. Confocal microscopy was then used to observe the shuttling of NT-PGC-1α. After NT-PGC-1α was shuttled into the nucleus, there was increased expression of its related genes, including PPAR-α, Tfam, ERR-γ, CPT1b, PDK4, and Nrf2. The effects of Selinexor on post-MI C57BL/6j mice were determined by echocardiography and qPCR. We found that Selinexor showed antihypertrophic effects but did not influence the ejection fraction of MI-mice. Interestingly, the antihypertrophic effects of Selinexor might be independent of NT-PGC-1α transportation

Off-label use of Baricitinib improves moderate and severe atopic dermatitis in China through inhibiting MAPK and PI3K/Akt/mTOR pathway via targeting JAK-STAT signaling of CD4+ cells

As an inflammatory disease with a disrupted immune system, cytokine disorders in atopic dermatitis (AD) are closely related to the abnormal activation of JAK-STAT signal pathway. The critical relevance of the JAK-STAT signaling pathway to the pathogenesis of AD provides a strong rationale for JAK inhibitor research. Baricitinib, a small-molecule oral JAK inhibitor, has been proven to inhibit JAK-STAT signaling in a variety of diseases, including AD. It is currently available in China for off-label use. However, its efficacy in China and its mechanism are rarely reported. In our study, we found that the immune status of patients with moderate and severe AD was hyperactive. Among the 49 known immunotherapy targets, JAK1 and JAK2 genes on lymphocytes of AD patients were significantly upregulated, which was closely related to the symptom severity in moderate and severe AD patients. Baricitinib can improve immune hyperresponsiveness and clinical symptoms in moderate and severe AD by inhibiting the activation of Th2 cell subsets and the secretion of Th2-type cytokines through MAPK, mTOR and PI3K-Akt signaling pathways, providing an important theoretical basis for clinical off-label use of Baricitinib to treat moderate and severe AD