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As one of the best-known commercial goat breeds in the world, Boer goat has undergone long-term artificial selection for nearly 100 years, and its excellent growth rate and meat production performance have attracted considerable worldwide attention. Herein, we used single nucleotide polymorphisms (SNPs) called from the whole-genome sequencing data of 46 Australian Boer goats to detect polymorphisms and identify genomic regions related to muscle development in comparison with those of 81 non-specialized meat goat individuals from Europe, Africa, and Asia. A total of 13 795 202 SNPs were identified, and the whole-genome selective signal screen with a π ratio of nucleotide diversity (πcase /πcontrol ) and pairwise fixation index (FST ) was analyzed. Finally, we identified 1741 candidate selective windows based on the top 5% threshold of both parameters; here, 449 candidate genes were only found in 727 of these regions. A total of 433 genes out of the 449 genes obtained were annotated to 2729 gene ontology terms, of which 51 were directly linked to muscle development (e.g., muscle organ development, muscle cell differentiation) by 30 candidate genes (e.g., JAK2, KCNQ1, PDE5A, PDLIM5, TBX5). In addition, 246 signaling pathways were annotated by 178 genes, and two pathways related to muscle contraction, including vascular smooth muscle contraction (ADCY7, PRKCB, PLA2G4E, ROCK2) and cardiac muscle contraction (CACNA2D3, CASQ2, COX6B1), were identified. The results could improve the current understanding of the genetic effects of artificial selection on the muscle development of goat. More importantly, this study provides valuable candidate genes for future breeding of goats.

Background Thromboxane A2 (TXA2 ) participates in many pathophysiological processes of coronary artery disease. However, its mechanism of TXA2 -induced contraction in the coronary artery remains to be clarified. Methods Multi Myograph System was used to measure the isometric tension of the mouse coronary arteries and identify the effect and pathway of TXA2 analogues U46619. Confocal laser scanning microscopy was used to measure the intracellular calcium concentration ([Ca2+ ]i ) in mouse coronary artery smooth muscle cells. Results Results from the experiment had shown that contraction in coronary artery was generated by U46619 in a concentration- dependent manner, which was completely abolished by a specific TXA2 receptor blocker, GR32191. PI-PLC inhibitors U73122 and D609 and Rho-Kinase inhibitor Y-27632 can block the U46619 elicited coronary artery contraction in a dose-dependent manner. Then, the vasoconstriction response to U46619 was obviously inhibited by two pan-PKC inhibitors chelerythrine or Gӧ6983, and a selective PKCδ inhibitor rottlerin, but wasn't blocked by a selective PKCζ inhibitor PKC-PS or a selective PKCβ inhibitor hispidin. Meanwhile, the PKC activator PDBu-induced vasoconstriction was significantly inhibited by 1 μM nifedipine,then mostly inhibited by 100 μM 2-APB and 10 μM Y27632. We further found that the response to U46619 was inhibited respectively by three calcium channel blockers nifedipine, SKF96356 or 2-APB in a concentration-dependent manner. Although Store-operated Ca2+ (SOC) channels generated the increase of [Ca2+ ]i in mouse coronary artery smooth muscle cells, SOC channels didn't contribute to the vasoconstriction in mouse coronary arteries. Caffeine-induced sarcoplasmic reticulum (SR) Ca2+ release could obviously induce coronal vasoconstriction. In addition, NPPB, a cell membrane Ca2+ activated C1- channel blocker, could obviously inhibit the U46619-induced vasoconstriction. Conclusions The U46619-induced mouse coronary artery contraction was involved in the increase in [Ca2+ ]i mediated by Cav1.2, TRPC channels and SR release through the activation of G-protein-coupled TP receptors and the kinases signaling pathway in TP downstream proteins, while SOC channels didn't participate in the vasoconstriction.

The intrinsic vascular smooth muscle contraction and vasoconstriction show time-of-day variations, contributing to the blood pressure circadian rhythm, which is essential for cardiovascular health. This brief review provides an overview of our current understanding of the mechanisms underlying the time-of-day variations of vascular smooth muscle contraction. We discuss the potential contribution of the time-of-day variations of vasoconstriction to the physiological blood pressure circadian rhythm. Finally, we survey the data obtained in the type 2 diabetic db/db mouse model that demonstrate the alterations of the time-of-day variations of vasoconstriction and the non-dipping blood pressure in diabetes.

Introduction: Endothelial dysfunction is an imbalance in bioavailability of endothelium-derived relaxing (Nitric Oxide) and contracting factors (Endothelin). Studies have shown that NO has antiatherogenic property as it inhibits vascular smooth muscle contraction and proliferation, platelet aggregation and leukocyte adhesion. On the other hand, Endothelin-1 causes proliferation and vasoconstriction of myocytes resulting in elevated vascular tone thereby contributing to endothelial dysfunction. This dysfunction is a well-established response to cardiovascular risk factors and precedes the development of atherosclerosis. As a result, status of an endothelial dysfunction may reflect the propensity to develop atherosclerotic disease and may serve as a marker of an unfavourable cardiovascular prognosis. Materials and Methods: 50 cases of angiographically proven ischemic heart disease and 50 age and sex matched patients with no evidence of ischaemic heart disease on angiography were selected from G.B Pant Hospital, New Delhi, India. Serum levels of Endothelin were estimated by sandwich ELISA and nitric oxide levels by modified Griess reaction. Results: Serum levels of Endothelin were raised while nitric oxide levels were significantly reduced (p=0.049) in the cases as compared to controls. The mean plasma nitric oxide level in the study group (cases) was 23.51±13.48 µM and in the control group was 29.35±15.73 µM. The difference between the two was significant (p=0.049*). The mean plasma endothelin level in the study group was 3.04±1.37fmol/ml and in the control group was 2.95±1.70 fmol/ml. The difference between the two was not significant (p = 0.764). Conclusion: Higher Endothelin-1 and lower NO levels in cases suggest their role in causing endothelial dysfunction in ischemic heart disease patients. However, larger sample size is required to assess the role of Endothelin as a biomarker of endothelial dysfunction in patients of ischemic heart disease.

Sperm carries a reservoir of proteins regulating the molecular functions to attain functional competence. Semen samples collected from buffalo bulls were assessed for sperm functional attributes (n = 11) and proteome profiling (n = 6). Sperm proteins were extracted and profiled by employing LC–MS/MS. Overall, the buffalo sperm contained 1365 proteins, of which 458 were common between the groups. The unique proteins were 477 and 430 in good and poor quality semen, respectively. In the whole proteome of buffalo sperm, sexual reproduction with phosphatidylethanolamine-binding protein1 (PEBP1), fetuin-B (FETUB) and acrosin (ACR) was the most enriched (p = 8.44E−19) biological process, also with thermogenesis (p = 0.003), oocyte meiosis (p = 0.007) and vascular smooth muscle contraction (p = 0.009) apart from metabolic pathways. In good quality semen, mesenchyme migration (p = 1.24E−07) and morphogenesis (p = 0.001) were abundant biological processes. In good quality semen, the fluid shear stress (p = 0.01) and, in poor quality semen, valine, leucine and isoleucine degradation (p = 3.8E−05) pathways were enriched. In good quality semen, 7 proteins were significantly (p

Psoriatic arthritis (PsA) is inflammatory arthritis associated with psoriasis, which involves the axial joint and the distal interphalangeal joints. Its clinical features are varied, often resulting in delayed diagnosis and treatment. Improved knowledge about disease mechanisms will catalyze the rapid development of effective targeted therapies for this disease. The perturbations in the gene co-expression network may not be detected by the differential expression analysis of the microarray. This study aims to identify key modules and hub genes in psoriatic arthritis-applied WGCNA (weighted gene co-expression network analysis) on a microarray.This study downloaded the array data of GSE61281 from the gene expression overview (GEO) database, which includes 20 psoriatic arthritis samples and 12 healthy controls. The analysis was performed with the WGCNA package. Gene ontology (GO) annotation and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on these key modules. Candidate hub genes were identified using GS and MM measures, Cytoscape, and the online database STRING.A total of 10 co-expression modules were constructed. The lightcyan module was identified as the key module. GO and KEGG pathway analyses were mainly enriched in dephosphorylation, regulation of small GTPase-mediated signal transduction, Ras signaling pathway, MAPK signaling pathway, and vascular smooth muscle contraction. Two hub genes, RHOH/TRAF1, were selected.This finding may indicate that RHOH/TRAF1 play a critical role in the pathogenesis of PsA. This is one of the first studies in PsA using WGCNA, which may provide a new research direction for further understanding of the molecular mechanism and clinical application of PsA. Key points • The WGCNA method was applied to the expression profile microarray of psoriatic arthritis and the co-expression module was constructed. • Identify the key modules by combining the onset time of psoriasis in patients with psoriatic arthritis. • Three screening methods are used to identify and verify hub genes of key modules.

The aim of the present study was to establish an integrated network of DNA methylation and RNA expression in an ovalbumin (OVA)‑induced asthma model, and to investigate the epigenetically‑regulated genes involved in asthma development. Genome‑wide CpG‑DNA methylation profiling was conducted through the use of a methylated DNA immunoprecipitation microarray and RNA sequencing was performed using three lung samples from mice with OVA‑induced asthma. A total of 35,401 differentially methylated regions (DMRs) were identified between mice with OVA‑induced asthma and control mice. Of these, 3,060 were located in promoter regions and 370 of the genes containing these DMRs demonstrated an inverse correlation between methylation and gene expression. Kyoto Encyclopedia of Genes and Genomes pathway analysis identified that 368 genes were upregulated or downregulated in OVA‑induced asthma samples, including genes involved in 'chemokine signalling pathway', 'focal adhesion', 'leukocyte transendothelial migration' and 'vascular smooth muscle contraction signaling' pathways. Integrated network analysis identified four hub genes, consisting of three upregulated genes [forkhead box O1 (FOXO1), SP1 transcription factor (SP1) and amyloid β precursor protein (APP)], and one downregulated gene [RUNX family transcription factor 1 (RUNX1)], all of which demonstrated an association between DNA methylation and gene expression. These genes were highly interconnected nodes in the Ingenuity Pathway Analysis module and were functionally significant. A total of four interconnected hub genes, FOXO1, RUNX1, SP1 and APP, were identified from the integrated DNA methylation and gene expression networks involved in asthma development. These results suggested that modulating these four genes could effectively control the development of asthma.

Oculopharyngodistal myopathy (OPDM) is an adult-onset inherited neuromuscular disorder characterized by progressive ptosis, external ophthalmoplegia, and weakness of the masseter, facial, pharyngeal, and distal limb muscles. The myopathological features are presence of rimmed vacuoles (RVs) in the muscle fibers and myopathic changes of differing severity. Inheritance is variable, with either putative autosomal-dominant or autosomal-recessive pattern. Here, using a comprehensive strategy combining whole-genome sequencing (WGS), long-read whole-genome sequencing (LRS), linkage analysis, repeat-primed polymerase chain reaction (RP-PCR), and fluorescence amplicon length analysis polymerase chain reaction (AL-PCR), we identified an abnormal GGC repeat expansion in the 5′ UTR of GIPC1 in one out of four families and three sporadic case subjects from a Chinese OPDM cohort. Expanded GGC repeats were further confirmed as the cause of OPDM in an additional 2 out of 4 families and 6 out of 13 sporadic Chinese individuals with OPDM, as well as 7 out of 194 unrelated Japanese individuals with OPDM. Methylation, qRT-PCR, and western blot analysis indicated that GIPC1 mRNA levels were increased while protein levels were unaltered in OPDM-affected individuals. RNA sequencing indicated p53 signaling, vascular smooth muscle contraction, ubiquitin-mediated proteolysis, and ribosome pathways were involved in the pathogenic mechanisms of OPDM-affected individuals with GGC repeat expansion in GIPC1. This study provides further evidence that OPDM is associated with GGC repeat expansions in distinct genes and highly suggests that expanded GGC repeat units are essential in the pathogenesis of OPDM, regardless of the genes in which the expanded repeats are located.

The new coronavirus species, SARS-CoV-2, caused an unprecedented global pandemic of COVID-19 disease since late December 2019. A comprehensive characterization of protein-protein interactions (PPIs) between SARS-CoV-2 and human cells is a key to understanding the infection and preventing the disease. Here we present a novel approach to predict virus-host PPIs by multi-label machine learning classifiers of random forests and XGBoost using amino acid composition profiles of virus and human proteins. Our models harness a large-scale database of Viruses.STRING with >80,000 virus-host PPIs along with evidence scores for multi-level evidence prediction, which is distinct from predicting binary interactions in previous studies. Our multi-label classifiers are based on 5 evidence levels binned from evidence scores. Our best model of XGBoost achieves 74% AUC and 68% accuracy on average in 10-fold cross validation. The most important amino acids are cysteine and histidine. In addition, our model predicts experimental PPIs with higher accuracy than text mining-based PPIs by 4% despite their smaller data size by more than 6-fold. We then predict evidence levels of ∼2,000 SARS-CoV-2 virus-human PPIs from public experimental proteomics data. Interactions with SARS-CoV-2 Nsp7b show high evidence. We also predict evidence levels of all pairwise PPIs of ∼550,000 between the SARS-CoV-2 and human proteomes to provide a draft virus-host interactome landscape for SARS-CoV-2 infection in humans in a comprehensive and unbiased way in silico. Most human proteins from 140 highest evidence predictions interact with SARS-CoV-2 Nsp7, Nsp1, and ORF14, with significant enrichment in the top 2 pathways of vascular smooth muscle contraction (CALD1, NPR2, CALML3) and Myc targets (CBX3, PES1). Our prediction also suggests that histone H2A components are targeted by multiple SARS-CoV-2 proteins.

Hypertension is a major cause of cardiovascular morbidity and mortality, despite the availability of antihypertensive drugs with different targets and mechanisms of action. Here, we provide evidence that pharmacological inhibition of TMEM16A (ANO1), a calcium-activated chloride channel expressed in vascular smooth muscle cells, blocks calcium-activated chloride currents and contraction in vascular smooth muscle invitro and decreases blood pressure in spontaneously hypertensive rats. The acylaminocycloalkylthiophene TMinh-23 fully inhibited calcium-activated TMEM16A chloride current with nanomolar potency in Fischer rat thyroid cells expressing TMEM16A, and in primary cultures of rat vascular smooth muscle cells. TMinh-23 reduced vasoconstriction caused by the thromboxane mimetic U46619 in mesenteric resistance arteries of wild-type and spontaneously hypertensive rats, with a greater inhibition in spontaneously hypertensive rats. Blood pressure measurements by tail-cuff and telemetry showed up to a 45-mmHg reduction in systolic blood pressure lasting for four-six hours in spontaneously hypertensive rats after a single dose of TMinh-23. A minimal effect on blood pressure was seen in wild-type rats or mice treated with TMinh-23. Five-day twice daily treatment of spontaneously hypertensive rats with TMinh-23 produced sustained reductions of 20-25 mmHg in daily mean systolic and diastolic blood pressure. TMinh-23 action was reversible, with blood pressure returning to baseline in spontaneously hypertensive rats by three days after treatment discontinuation. Thus, our studies provide validation for TMEM16A as a target for antihypertensive therapy and demonstrate the efficacy of TMinh-23 as an antihypertensive with a novel mechanism of action.

To identify candidate key genes and pathways associated with lymph node tuberculosis (LNTB) and reveal the potential molecular mechanisms of LNTB development. Gene expression profile of GSE63548 was downloaded from the Gene Expression Omnibus (GEO) database. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichments of differentially expressed genes (DEGs) were analyzed by DAVID, and the protein-protein interaction (PPI) network was performed from STRING database. Furthermore, Cytoscape was used to integrate the network of transcription factor (TF) target and miRNA target. A total of 239 DEGs were screened out. Based on the DEGs, a miRNA of hsa-miR-4536 and 28 TFs, such as GATA1, JUND, NR2F1, POU1F1, and RELB, were obtained. Pathway enrichment analyses revealed that DEGs were mainly enriched in the pathways of regulation of lipolysis in adipocytes, vascular smooth muscle contraction, fat digestion and absorption, NOD-like receptor, and TNF signaling pathway. Furthermore, 53 nodes and 241 interactions were identified in the PPI network. In addition, the integrated regulatory network showed that CXCL9, CD36, LEP, ACACB, ALDH1A3, GPX3, STAT1, and LPL were the target genes of hsa-miR-4536. This study revealed the candidate key genes and pathways that are involved in the pathogenesis of LNTB, which will provide potential therapeutic targets for the treatment of LNTB.

Magang geese exhibit a unique characteristic of follicular development, with eight largest orderly arranged pre-ovulatory follicles in the abdominal cavity. However, little is known about the mechanisms underlying this follicular development. This study aimed to compare gene expression profiles of granulosa cells (GCs) at different stages of follicular development and provide comprehensive insights into follicle selection and the mechanisms underlying the well-defined follicle hierarchy in Magang geese. GCs of large white follicles (LWFs), small yellow follicles (SYFs), F8, F4, and F1 were used for RNA-seq analysis; 374, 1117, 791, and 593 genes were differentially expressed in stages LWFs to SYFs, SYFs to F8, F8 to F4, and F4 to F1, respectively, suggesting that these genes contribute to follicle selection and development. Reliability of sequencing data was verified through qPCR analysis of 24 genes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways revealed a complex mechanism that remodels the extracellular matrix and turnover of extracellular matrix components in follicular development and ovulation and involves multiple pathway, such as focal adhesion, adherens junction, and extracellular matrix-receptor interaction. Some unique characteristics were observed during the different follicular development stages. For instance, some differentially expressed genes were enriched in progesterone-mediated oocyte maturation and steroid biosynthesis from stage SYFs to F8, whereas others were enriched in actin cytoskeleton regulation and vascular smooth muscle contraction from stage F4 to F1. These findings enhance our current understanding of GC function and ovarian follicles during the key stages of follicular development.

Objective: Bladder cancer ranks 10th among the most common cancers worldwide, effecting mostly man than women. The aim of this study is to perform a detailed gene expression analysis of bladder urothelial carcinoma to reveal altered molecular mechanisms and to find potential biomarkers for this cancer. Materials and Methods: Bladder urothelial carcinoma RNA-seq data from TCGA and normal bladder samples from GTEx were analyzed by using GEPIA. Differentially expressed genes were annotated to GO-BP and KEGG pathway terms with DAVID and PPI networks were constructed by STRING. The association of upregulated cell cycle pathway proteins and patient survival was further investigated. Results: Upregulated genes mainly annotated to cell cycle, p53 signaling and oocyte meiosis and maturation pathways and cell cycle related GO-BP terms. Downregulated genes mostly annotated to adhesion, ECM-receptor interaction, vascular smooth muscle contraction and cardiomyopathy related KEGG pathways and muscle related GO-BP terms. The protein products of six cell cycle genes, which were upregulated in bladder urothelial carcinoma, showed significant association with patient survival. Conclusion: The results of this study showed altered molecular mechanisms and increased our understanding in bladder urothelial carcinoma, proposed potential prognostic biomarkers.

BACKGROUND: The study explores the differentially expressed genes in the heart tissue of patients with chronic heart failure (CHF) and normal heart tissue, thus providing information for further research on the pathogenesis of CHF. METHODS: The Gene Expression Omnibus (GEO) database was used to download the whole transcriptome sequencing results of CHF patients (GSE2656, n=49). Transcriptome sequencing results of 44 normal left ventricular tissues were randomly screened and downloaded using the Genotype-Tissue Expression (GTEX) database (n=44). We explored the differentially expressed genes between CHF tissue and normal heart tissue. Gene Ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway enrichment analysis were performed for differentially expressed genes. Growth hormone-releasing hormone (GHRH) was used as a representative differential gene for serological sample verification by the enzyme linked immunosorbent assay (ELISA). RESULTS: A total of 902 differentially expressed genes between CHF and normal heart tissues were screened, including 354 up-regulated genes and 548 down-regulated genes. GO enrichment analysis showed that the differentially expressed genes were significantly enriched in the extracellular and sequence-specific DNA binding domains. KEGG enrichment demonstrated that the differential genes were enriched in neuroactive ligand-receptor interaction, the calcium signaling pathway, vascular smooth muscle contraction, and other signaling pathways. ELISA results showed that the expression level of GHRH in patients with heart failure was significantly higher than that in healthy subjects (P

The α1-adrenergic receptors (ARs) are G-protein coupled receptors that bind the endogenous catecholamines, norepinephrine, and epinephrine. They play a key role in the regulation of the sympathetic nervous system along with β and α2-AR family members. While all of the adrenergic receptors bind with similar affinity to the catecholamines, they can regulate different physiologies and pathophysiologies in the body because they couple to different G-proteins and signal transduction pathways, commonly in opposition to one another. While α1-AR subtypes (α1A, α1B, α1C) have long been known to be primary regulators of vascular smooth muscle contraction, blood pressure, and cardiac hypertrophy, their role in neurotransmission, improving cognition, protecting the heart during ischemia and failure, and regulating whole body and organ metabolism are not well known and are more recent developments. These advancements have been made possible through the development of transgenic and knockout mouse models and more selective ligands to advance their research. Here, we will review the recent literature to provide new insights into these physiological functions and possible use as a therapeutic target.

Lubrication disorder is a common health issue that manifests as insufficient sexual arousal at the beginning of sex. It often causes physical and psychological distress. However, there are few studies on lubrication disorder, and the complexity of circular RNA (circRNA) and the related competing endogenous RNA (ceRNA) network in lubrication disorder is still poorly known. Therefore, this study aims to build a regulatory circRNA-micro (mi)RNA-mRNA network and explore potential molecular markers of lubrication disorder. In the study, 12 subjects were recruited, including 6 in the lubrication disorder group and 6 in the normal control group. RNA sequencing was exploited to identify the expression profiles of circRNA, miRNA and mRNA between two groups, and then to construct the circRNA-miRNA-mRNA networks. The enrichment analyses of the differentially expressed (DE)-mRNAs were examined via Gene Set Enrichment Analysis (GSEA). Furthermore, the expression level and interactions among circRNA, miRNA, and mRNA were validated using real-time quantitative polymerase chain reaction (RT-qPCR) and dual-luciferase reporter assays. In the results, 73 circRNAs, 287 miRNAs, and 354 target mRNAs were differentially expressed between two groups when taking | Log2 (fold change)| > 1 and P-value < 0.05 as criteria, and then the results of GSEA revealed that DE-mRNAs were linked with “vascular smooth muscle contraction,” “aldosterone regulated sodium reabsorption,” “calcium signaling pathway,” etc. 19 target relationships among 5 circRNAs, 4 miRNAs, and 7 mRNAs were found and constructed the ceRNA network. Among them, hsa-miR-212-5p and hsa-miR-874-3p were demonstrated to be related to the occurrence of lubrication disorder. Eventually, consistent with sequencing, RT-qPCR showed that hsa_circ_0026782 and ASB2 were upregulated while hsa-miR-874-3p was downregulated, and dual-luciferase reporter assays confirmed the interactions among them. In summary, the findings indicate that the circRNA-miRNA-mRNA regulatory network is presented in lubrication disorder, and ulteriorly provide a deeper understanding of the specific regulatory mechanism of lubrication disorder from the perspective of the circRNA-miRNA-mRNA network.

Long-term natural and artificial selection leads to change in certain regions of the genome, resulting in selection signatures that can reveal genes associated with selected traits, such as horns (i.e., polled/horned), high-quality wool traits, and high-altitude hypoxia adaptability. These are complex traits determined by multiple genes, regulatory pathways, and environmental factors. A list of genes with considerable effects on horn and adaptability traits has not been found, although multiple quantitative trait loci (QTL) have been identified. Selection signatures could be identified using genetic differentiation (FST), polymorphism levels θπ, and Tajima’s D. This study aimed to identify selection signatures in fine-wool sheep and to investigate the genes annotated in these regions, as well as the biological pathways involved in horn and adaptability traits. For this purpose, the whole-genome sequence of 120 individuals from four breeds, which come from different elevations and habitats in China, was used to analyze selection signatures for horn and adaptability traits. Annotation of the consensus regions of FST and θπ ratios revealed a list of identified genes associated with polled/horned and high-altitude hypoxia adaptability traits, such as RXPF2, EERFC4, MSH6, PP1R12A, THBS1, ATP1B2, RYR2, and PLA2G2E. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis identified genes related primarily to mismatch repair, metabolism, vascular smooth muscle contraction, and cardiac muscle contraction. This is the first study to demonstrate that selection signatures play an important role in the polled/horned and high-altitude hypoxia adaptability traits of fine-wool sheep breeds that have undergone high-intensity selection and adapted to different ecological environments in China. Changes observed in the genome of fine-wool sheep may have acted on genomic regions that affect performance traits and provide a reference for genome design and breeding.

XiaoLuoWan (XLW) is a classical formula in traditional Chinese medicine (TCM) that has satisfactory therapeutic effects for uterine fibroids (UFs). However, its underlying mechanisms remain unclear. To elucidate the pharmacological actions of XLW in treating UFs, an ingredient–target–disease framework was proposed based on network pharmacology strategies. The active ingredients in XLW and their putative targets were obtained from the TCM systems pharmacology database and analysis platform (TCMSP) and Bioinformatics Analysis Tool for Molecular mechANism of Traditional Chinese Medicine (BATMAN-TCM) platforms. The known therapeutic targets of UFs were acquired from the DigSee and DrugBank databases. Then, the links between putative XLW targets and therapeutic UF targets were identified to establish interaction networks by Cytoscape. Finally, Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses of overlapping gene targets were performed in the STRING database and visualized in R software. In total, 9 active compounds were obtained from 74 ingredients, with 71 curative targets predicted in XLW. Moreover, 321 known therapeutic targets were closely related to UFs, with 29 targets overlapping with XLW and considered interacting genes. Pathway enrichment revealed that the calcium signaling pathway was significantly enriched and the mitogen-activated protein kinase (MAPK) signaling pathway, cAMP signaling pathway, cancer and vascular smooth muscle contraction pathways, cGMP-PKG signaling pathway, and AGE-RAGE signaling pathway were closely associated with XLW intervention for UFs. In conclusion, the network pharmacology detection identified 9 available chemicals as the active ingredients in XLW that may relieve UFs by regulating 29 target genes involved in the calcium signaling pathway, MAPK pathway and cAMP pathway. Network pharmacology analyses may provide more convincing evidence for the investigation of classical TCM prescriptions, such as XLW.

Parental care is common in mammals and allows offspring to obtain milk, a substance rich in a range of nutritional and non-nutritional factors crucial to the survival of newborns. The discus fish Symphysodon spp., an Amazonian cichlid, shows an unusual behaviour: Free-swimming fry bite on their parents' skin mucus for growth and development during the first month after hatching. This is similar to the breastfeeding behaviour of mammals, but little is known about the regulatory mechanism by which discus secrete 'milk' and the related genes involved in parental care. Here, transcriptome sequencing was performed by using the brain tissues of female discus fish in parental and non-parental care. The results showed that a total of 86 differentially expressed genes (71 up-regulated genes and 15 down-regulated genes) were obtained by comparing parental with non-parental discus fish, including up-regulated LAPTM, FOXB, SOX1S, OTX2 and NR1F2, and down-regulated EDNRB, PRKCD, H1-5 and HBE. Through functional enrichment analysis, a total of 20 pathways were identified, e.g., estrogen signaling pathway, inflammatory mediator regulation of TRP channels, vascular smooth muscle contraction, GnRH signaling pathway, neurotrophin signaling pathway, NOD-like receptor signaling pathway, Jak-STAT signaling pathway, Fc gamma R-mediated phagocytosis, serotonergic synapse, autophagy-animal and cytokine-cytokine receptor interaction. These pathways and related genes might play important roles in the regulation of discus 'milk' secretion.

Hypertension is a major cause of cardiovascular morbidity and mortality, despite the availability of antihypertensive drugs with different targets and mechanisms of action. There is an unmet need for antihypertensive drugs with novel mechanisms of action to better control hypertension and reduce cardiovascular morbidity and mortality. Here, we provide evidence that pharmacological inhibition of TMEM16A (transmembrane member 16A or anoctamin-1), a Ca 2+ -activated Cl - channel expressed in vascular smooth muscle cells, reduces in vitro vascular smooth muscle contraction and decreases blood pressure in spontaneously hypertensive rats (SHR). We recently identified by high-throughput screening and subsequent medicinal chemistry, small molecule TMEM16A inhibitor TM inh -23 (2-bromodifluoroacetylamino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxylic acid o-tolylamide) that inhibits TMEM16A current fully, with IC 50 ~ 30 nM. TM inh -23 pretreatment blocked maximum in vitro vascular smooth muscle contractions induced by a thromboxane mimetic (U46619) in rat mesenteric arteries by 90%. Intraperitoneal (ip) administration of TM inh -23 to rodents at 10 mg/kg produced sustained serum concentrations of >10 μM for >4 hours. BP measurements by tail-cuff and telemetry showed a maximum ~45 mmHg reduction in SBP in spontaneously hypertensive rats (SHR) after a single dose (10 mg/kg, ip) TM inh -23 administration compared to vehicle treatment, with BP gradually returning to baseline values within 6-8 hours after TM inh -23 treatment. Minimal effect on BP (less than 10 mmHg decrease in SBP) was seen in wild-type rats and mice with TM inh -23 treatment (10 mg/kg, ip). Chronic 5-day treatment of SHR with TM inh -23 (10 mg/kg, ip, twice daily) caused sustained decreases (~20-25 mmHg) in daily average SBP, DBP and MAP during the treatment period. TM inh -23 action was reversible, with BP returning to baseline (~170/115 mmHg) by 3 days after discontinuation of treatment. These studies provide validation for TMEM16A as a target for antihypertensive therapy, and demonstrate the proof-of-concept for efficacy of TM inh -23 as an antihypertensive with a novel mechanism of action.

The selection of raw milk with high levels of functional components that have health-promoting activities is very important for the exploitation and production of functional milk, but the differences in the functional components of whey from buffalo raised at different altitudes have not been thoroughly investigated. Here, we detected the effects of altitudes on the functional components in whey from dairy buffalo farms situated at low altitude (LA), medium altitude (MA), and high altitude (HA) sites with data-independent acquisition proteomic approaches. In 33 samples, 9331 peptides corresponding to 1008 high-confidence proteins were detected. HA-whey had a lower level of angiotensinogen than that of the LA- and MA-whey, and conversely contained higher levels of immune-enhancing components than for the latter two groups. Differential proteins were involved in vascular smooth muscle contraction, complement and coagulation cascades, and the secretion, production and regulation pathways in immune components. LA-whey showed higher levels of lymphocyte antigen and selenoprotein F than that of the HA-whey. Owing to the biological functions of their most abundant components, HA- and LA-whey are suitable for the processing of functional milk for lowering blood pressure, and the production of immune milk, respectively.

Development of ovarian follicles requires interactions between granulosa cells, theca cells, and oocytes. Multiple transcription levels are involved but information about the role of noncoding RNAs, especially circular RNAs (circRNAs), is lacking. Here, we used RNA sequencing to profile circRNAs and mRNAs in theca cells from three types of follicle: small yellow follicles (SYF), the smallest hierarchical follicles (F6), and the largest hierarchical follicles (F1). Using bioinformatics analysis, we identified a total of 14,502 circRNAs in all theca cells, with 5622 widely distributed in all stages of development. Differential expression analysis suggested that some genes display differential isoforms during follicular development. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed enrichment of both differentially expressed circRNAs and mRNAs in pathways associated with reproduction, including the TGF-β signaling pathway, oocyte meiosis, and vascular smooth muscle contraction. Our study provides the first visual information about circRNAs and mRNAs in theca cells during follicle development in chickens and adds to the growing body of knowledge about theca cells.

Background Bronchopulmonary dysplasia (BPD) is a severe chronic lung disease in preterm infants. Circular RNAs (circRNAs) are key regulators of various biological processes. The present study aimed to explore the biological roles of circRNAs in BPD pathogenesis. Methods A newborn BPD rat model was developed to construct a circRNA library; Illumina deep sequencing (Illumina, San Diego, CA, USA) was used to reveal differential expression of circRNAs in the hyperoxia-induced BPD rat models. Sanger sequencing and a reverse transcription-polymerase chain reaction were performed to confirm circRNAs that may be related to BPD. After miRNA binding-site prediction, we constructed a network diagram of circRNA-competing endogenous RNAs (ceRNAs) related to transforming growth factor (TGF)-β and p53 pathways using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Results In total, 256 differentially expressed circRNAs were detected between the hyperoxia group and the normoxia group. Of these circRNAs, 195 were up-regulated and 61 were down-regulated. The differences of circRNA distribution between the two groups were analyzed and six circRNAs were validated in the tissue samples. GO analysis indicated that 6519 target genes were enriched in cell location and biological processes. KEGG pathway enrichment analysis showed that circRNAs involved in 242 KEGG pathways. A network diagram of circRNA-ceRNA related to TGF-β and p53 pathways was constructed. Conclusions CircRNAs are differentially expressed between the BPD model and control group. Many target genes of circRNAs are involved in the developmental process, which suggests that BPD may be associated with pathways including extracellular matrix-receptor interaction, vascular endothelial growth factor signaling and vascular smooth muscle contraction.

The plateau pika, a typical hypoxia-tolerant mammal lives 3000–5000 m above sea level on the Qinghai-Tibet Plateau, has acquired many physiological and morphological characteristics and strategies in its adaptation to sustained, high-altitude hypoxia. Blunted hypoxic pulmonary vasoconstriction is one such strategy, but the genes involved in this strategy have not been elucidated. Here, we investigated the genes involved and their expression profiles in the lung transcriptome of plateau pikas subjected to different hypoxic conditions (using low-pressure oxygen cabins). A slight, right ventricular hypertrophy was observed in pikas of the control group (altitude: 3200 m) vs. those exposed to 5000 m altitude conditions for one week. Our assembly identified 67,774 genes; compared with their expression in the control animals, 866 and 8364 genes were co-upregulated and co-downregulated, respectively, in pikas subjected to 5000 m altitude conditions for 1 and 4 w. We elucidated pathways that were associated with pulmonary vascular arterial pressure, including vascular smooth muscle contraction, HIF-1 signalling, calcium signalling, cGMP-PKG signalling, and PI3K-Akt signalling based on the differentially expressed genes; the top-100 pathway enrichments were found between the control group and the group exposed to 5000 m altitude conditions for 4 w. The mRNA levels of 18 candidate gene showed that more than 83% of genes were expressed and the number of transcriptome The up-regulated genes were EPAS1, Hbα, iNOS, CX40, CD31, PPM1B, HIF-1α, MYLK, Pcdh12, Surfactant protein B, the down-regulated genes were RYR2, vWF, RASA1, CLASRP, HIF-3α. Our transcriptome data are a valuable resource for future genomic studies on plateau pika.

Introduction Prostate adenocarcinoma is one of the most prevalent causes of cancer-related deaths in males worldwide. However, the underlying mechanisms remain poorly understood. Hence, it is important to identify specific and effective therapeutic targets, to be able to determine appropriate therapy and management. So, this study aimed to predict that miR-93-5p is an important oncogene in prostate cancer by bioinformatics analysis. Methods In this study, initially we identified differentially expressed genes (DEGs) and differently expressed miRNAs (DEMs) in the The Cancer Genome Atlas (TCGA) database, performed Gene Ontology (GO) and pathway enrichment analysis, then investigated the relationship between DEGs and DEMs, and finally through consulting the literature and retrieving the database, we found that miR-93-5p may play a major role in prostate cancer, so we predicted the expression and survival of miR-93-5p and its isomers by bioinformatics analysis, meanwhile, evaluated the function of miR-93-5p in vitro. Results In total, 104 DEMs were differently expressed between prostate cancer and normal samples, including 56 downregulated ones and 48 upregulated ones; miR-93-5p (upregulated) was identified as a good biomarker. And 1904 DEGs were retrieved, including 794 downregulated ones and 1110 upregulated ones. We also obtained 1254 DEGs of the DEMs. In GO and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, the significantly enriched pathways involved pathway in focal adhesion, vascular smooth muscle contraction, and regulation of actin cytoskeleton. By the KEGG pathway, we got 16 target genes and 92 pathways of the miR-93-5p in prostate cancer. We also found that the miR-93-5p and its isomers can express in prostate cancer, and which with a high expression had a poor overall survival and a significant difference recurrence rate within 5 years. Further in vitro verification results demonstrated that the low expression of miR-93-5p can inhibit cell proliferation, migration, invasion, change cell cycle, and promote early apoptosis of PC-3 cells. Conclusion The miR-93-5p and its target genes were used to define important molecular targets that could serve as a prognostic and predictive marker in the treatment of prostate cancer. Further research on the function of the miR-93-5p and its target genes in the KEGG pathway could provide references for the treatment of prostate cancer.

Background: Erectile dysfunction (ED) affects 30 million men in the US with a decrease in quality of life. Thirty percent of hypertensive men suffer from ED. Objective: This review will debate the interplay between hypertension and ED, discovering novel insights concerning hypertension-linked ED, as well as the influence of antihypertensive medications on patients with ED. Method: Total number of records screened from PubMed yielded by the search which performed from January 2000 - June 2018. Results: Hypertension can cause ED as a consequence of high blood pressure or antihypertensive treatment. Both hypertension and ED have endothelial dysfunction as a common base mechanism, which can lead to an increase in vascular smooth muscle contraction. Also, some phosphodiesterase (PDE)-5 inhibitors used to treat ED can recover blood pressure. Conclusion: Understanding of common mechanisms involved in ED accompanied with hypertension and the research on antihypertensive drugs that impact ED will bring important approaches for identifying novel therapeutic strategies that will improve quality of life in patients with these conditions.

Background: A large percentage of maternal mortality is related to hypertensive disorders of pregnancy. The etiology of preeclampsia is uncertain with imbalance between vasoconstrictor and vasodilators leading to vasospasm and endothelial dysfunction. Magnesium and Calcium plays a role in vascular smooth muscle contraction and thus regulating blood pressure. Aim: We compared the serum level of Calcium and Magnesium of preeclamptic women with normotensive women at SRMS-IMS, Bareilly. Method: 30 preeclamptic patient between 18-35 years with BP>140/90mmHg and gestation age >30 weeks were selected. Blood sample were taken for serum calcium and magnesium level and the results were compared with 20 normotensives pregnant. Result: Mean serum Calcium and Magnesium level in preeclamptic woman was 9.00± 0.47 and 1.90±0.31 mg/dl, respectively. Mean serum Calcium and Magnesium in normal pregnant woman was 9.12±0.37 and 1.92±0.23mg/dl, respectively. There was statistically no significant difference with p value of 0.34 and 1.00, respectively. Conclusion: Serum Calcium and Magnesiumlevelwere observed to be same in preeclamptic and normotensive pregnant women.

Cephalosporins are beta-lactam antibiotics that are widely used in clinics in China. However, information on their toxicity to zebrafish is limited. This study reports that the toxicity effects of cephalosporins containing an N-methyltetrazolthio ring at the C-3 position (CNMTs) exposure on zebrafish were comparable to those predicted by in silico analysis. The effects of CNMTs on the mortality and malformation rate of zebrafish were concentration-dependent. The transcriptional levels of the has1 and cnnm2a genes, which are related to embryo development and absorption of Mg2+ in vivo, significantly changed. Several pathways that were enriched by differentially expressed genes (DEGs) were identified, and the most significantly co-enriched pathways were related to neuroactive ligand-receptor interactions, cardiac muscle contraction, and vascular smooth muscle contraction. In sum, the C-3 substituent in the nucleus 7-aminocephalosporanic acid (7-ACA) of CNMTs is responsible for the observed toxicity at higher concentrations, and the C-7 substituent plays an important role in toxicity at lower concentrations. Our results show that zebrafish embryos and transcriptomics may be useful for determining target organ toxicity, assessing the structure and toxicity relationship of chemicals, and improving drug safety assessments.

The role of melatonin in promoting the yield of Cashmere goat wool has been demonstrated for decades though there remains a lack of knowledge regarding melatonin mediated hair follicle growth. Recent studies have demonstrated that long non-coding RNAs (lncRNAs) are widely transcribed in the genome and play ubiquitous roles in regulating biological processes. However, the role of lncRNAs in regulating melatonin mediated hair follicle growth remains unclear. In this study, we established an in vitro Cashmere goat secondary hair follicle culture system, and demonstrated that 500 ng/L melatonin exposure promoted hair follicle fiber growth. Based on long intergenic RNA sequencing, we demonstrated that melatonin promoted hair follicle elongation via regulating genes involved in focal adhesion and extracellular matrix receptor pathways and further cis predicting of lncRNAs targeted genes indicated that melatonin mediated lncRNAs mainly targeted vascular smooth muscle contraction and signaling pathways regulating the pluripotency of stem cells. We proposed that melatonin exposure not only perturbed key signals secreted from hair follicle stem cells to regulate hair follicle development, but also mediated lncRNAs mainly targeted to pathways involved in the microvascular system and extracellular matrix, which constitute the highly orchestrated microenvironment for hair follicle stem cell. Taken together, our findings here provide a profound view of lncRNAs in regulating Cashmere goat hair follicle circadian rhythms and broaden our knowledge on melatonin mediated hair follicle morphological changes.

To investigate the effects of Zhizi Chuanxiong Capsule (ZCC, 栀子川芎胶囊) on abnormal DNA methylation in a rabbit model of atherosclerosis (AS). After 1 week of adaptive feeding, 48 New Zealand white rabbits were randomly divided into 4 groups: a control group (n=12) fed with normal diet for 22 weeks; a model group (n=12) fed with high fat diet for 14 weeks followed by 8 weeks of normal diet feeding; a low-dose ZCC group (n=12) fed with high fat diet and low-dose ZCC for 14 weeks, followed by 8 weeks of normal diet and low-dose drug; a high-dose ZCC group (n=12) fed with high fat diet and high-dose drug for 14 weeks, followed by 8 weeks of normal diet and high-dose drug. After 22 weeks of feeding, blood samples were taken from the rabbit ear vein, and the genomic DNA was extracted for methylation immunoprecipitation sequencing (Medip-seq). The aorta tissues were collected for hematoxylin-eosin (HE) staining. Eight rabbits died during the feeding process. HE staining showed that the size of the lipid deposition on vessel wall and atherosclerotic plaque formation were reduced in both low- and high-dose group. The Medip-seq results showed that there were 146 abnormally methylated genes (including both hypermethylated gene and hypomethylated genes) in the model group, compared with the control group. Gene Ontology (GO) and Pathway analysis showed that these abnormally methylated genes were found to be involved in multiple AS-related functions and pathways, such as protein kinase C activity, cholesterol transport, mitogen-activated protein kinase (MAPK) signaling pathway, peroxisome proliferater-activated receptor signaling pathway, vascular smooth muscle contraction, inflammation and so on. The abnormal methylated genes in AS model group were altered in both low- and high-dose groups: low-dose ZCC could change 72 of the 146 abnormally methylated genes, high-dose ZCC could change 71. Through GO and Pathway analysis, these altered methylated genes were involved in protein kinase C activity, inflammatory pathway, MAPK signaling pathway, vascular endothelial growth factor signaling pathway, etc. ZCC could treat AS through regulating the abnormal hypermethylated and hypomethylated genes in AS rabbit model.

Systems toxicology approaches have been used as important tools in the drug discovery and medicine quality control processes. The aim of this study was to assess the pharmacokinetic and toxicity properties of cephalosporins with an aminothiazoyl ring at the C-7 position (CATRs). Cardiac toxicity of the compounds was assessed in zebrafish embryos, and it was determined that CATRs disturbed the formation and development of the heart in a dose-dependent manner. Differentially expressed genes (DEGs) related to the heart were also identified by transcriptome analysis, and co-DEGs were obtained in the protein-protein interaction (PPI) network. Several Gene Ontology (GO) terms and pathways that were enriched by DEGs were identified, and the most significantly enriched pathways were adrenergic signaling in cardiomyocytes, cardiac muscle contraction, and vascular smooth muscle contraction. Combined molecular docking results elucidated that cardiac toxicity mainly depends on the mother nucleus structure 7-aminocephalosporanic acid (7-ACA). The predicted absorption, distribution, metabolism and excretion (ADME) profile suggests that there is a modification at the C-3 side chain of 7-ACA that could change the compound distribution in vivo. The 7-ACA mother nucleus is responsible for the CATRs induced cardiac toxicity, and the three DEGs (nppa, adra2c, and tnni1c) may potentially be utilized as novel biomarkers for CATRs. Our results show that zebrafish embryos may be used to reveal the pathways of cardiac toxicity and they play a vital role in drug safety assessments.

Purpose The mechanism of action of low level laser irradiation on tissues is unclear. Authors of publications present the positive clinical impact of low and medium power laser irradiation on vascular reactivity. The purpose of this study was to analyze the role of vascular endothelium in laser-induced constricted by endothelin-1 and phenylephrine. Materials and methods Experiments were performed on isolated and perfused rat tail arteries of weighing 250–350 g male Wistar rats. Contractility of arteries as a response to endothelin-1 and phenylephrine was measured after exposure to laser stimulation (10, 30 and 110 mW). Results Laser irradiation inhibits vascular smooth muscle contraction induced by endothelin-1 and an alpha-adrenergic receptor agonist, phenylephrine proportionally to the laser power. Concentration-response curves were shifted to the right with significant reduction in maximal response. Laser irradiation at the power of 10 mW, 30 mW, and 110 mW reduced the maximum response of arteries stimulated with phenylephrine sequentially to 88%, 72%, and 52%. Similar findings were observed during stimulation of endothelin-1. Laser irradiation at the power of 10 mW, 30 mW and 110 mW resulted in maximal response respectively reduced to 94%, 62% and 38%. Conclusion Our results strongly suggest that during low level laser irradiation vascular smooth muscle cells reactivity is reduced, this effect is present in arteries with normal endothelium. The mechanism of action of laser biosimulation on tissues is unclear. Authors of publications present the positive clinical impact of low level laser irradiation on vascular reactivity.

Information processing tools and bioinformatics software have significantly advanced researchers' ability to process and analyze biological data. Molecular data from human and model organism genomes help researchers identify topics for study, which, in turn, improves predictive accuracy, facilitates the identification of relevant genes, and simplifies the validation of laboratory data. The objective of this study was to explore the regulatory network constituted by long noncoding RNA (lncRNA), miRNA, and mRNA in prostate cancer (PCa). Microarray data of PCa were downloaded from The Cancer Genome Atlas database and DESeq package in R language were used to identify the differentially expressed genes (DEGs) between PCa and normal samples. Gene ontology enrichment analysis of DEGs was conducted using the Database for Annotation, Visualization, and Integrated Discovery. TargetScan, microcosm, miRanda, miRDB, and PicTar were used to predict target genes. LncRNA associated with PCa was exploited in the lncRNASNP database, and the LncRNA-miRNA-mRNA regulatory network was visualized using Cytoscape. Our study identified 57 differentially expressed miRNAs and 1252 differentially expressed mRNAs; of these, 691 were downregulated genes primarily involved in focal adhesion, vascular smooth muscle contraction, calcium signaling pathway, and so on. The remaining 561 were upregulated genes principally involved in systemic lupus erythematosus, progesterone-mediated oocyte maturation, oocyte meiosis, and so on. Through the integrated analysis of correlation and target gene prediction, our studies identified 1214 miRNA:mRNA pairs, including 52 miRNAs and 395 mRNAs, and screened out 455 lncRNA-miRNA pairs containing 52 miRNAs. Therefore, owing to the interrelationship of lncRNAs and miRNAs with mRNAs, our study screened out 19,075 regulatory relationships. Our data provide a comprehensive bioinformatics analysis of genes, functions, and pathways that may be involved in the pathogenesis of PCa.

Scutellaria baicalensis Georgi is an extensively used medicinal herb for the treatment of hypertension in traditional Chinese medicine. Baicalin, is an important flavonoid in Scutellaria baicalensis Georgi extracts, which exhibits therapeutic effects on anti-hypertension, but its underlying mechanisms remain to be further explored. Therefore, we investigated the effects and molecular mechanisms of Baicalin on anti-hypertension. In vivo studies revealed that Baicalin treatment significantly attenuated the elevation in blood pressure, the pulse propagation and thickening of the abdominal aortic wall in C57BL/6 mice infused with Angiotensin II (Ang II). Moreover, RNA-sequencing and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses identified 537 differentially expressed transcripts and multiple enriched signaling pathways (including vascular smooth muscle contraction and calcium signaling pathway). Consistently, we found that Baicalin pretreatment significantly alleviated the Ang II induced constriction of abdominal aortic ring, while promoted NE pre-contracted vasodilation of abdominal aortic ring at least partly dependent on L-type calcium channel. In addition, Ang II stimulation significantly increased cell viability and PCNA expression, while were attenuated after Baicalin treatment. Moreover, Baicalin pretreatment attenuated Ang II-induced intracellular Ca2+ release, Angiotensin II type 1 receptor (AT1R) expression and activation of MLCK/p-MLC pathway in vascular smooth muscle cells (VSMCs). The present work further addressed the pharmacological and mechanistic insights on anti-hypertension of Baicalin, which may help better understand the therapeutic effect of Scutellaria baicalensis Georgi on anti-hypertension.

Abdominal aortic aneurysms (AAAs) and intracranial saccular aneurysms (IAs) are the most common types of aneurysms. This study was to investigate the common pathogenesis shared between these two kinds of aneurysms. We collected 12 IAs samples and 12 control arteries from the Beijing Tiantan Hospital and performed microarray analysis. In addition, we utilized the microarray datasets of IAs and AAAs from the Gene Expression Omnibus (GEO), in combination with our microarray results, to generate messenger RNA expression profiles for both AAAs and IAs in our study. Functional exploration and protein-protein interaction (PPI) analysis were performed. A total of 727 common genes were differentially expressed (404 was upregulated; 323 was downregulated) for both AAAs and IAs. The GO and pathway analyses showed that the common dysregulated genes were mainly enriched in vascular smooth muscle contraction, muscle contraction, immune response, defense response, cell activation, IL-6 signaling and chemokine signaling pathways, etc. The further protein-protein analysis identified 35 hub nodes, including TNF, IL6, MAPK13, and CCL5. These hub node genes were enriched in inflammatory response, positive regulation of IL-6 production, chemokine signaling pathway, and T/B cell receptor signaling pathway. Our study will gain new insight into the molecular mechanisms for the pathogenesis of both types of aneurysms and provide new therapeutic targets for the patients harboring AAAs and IAs.

Background Hypertension is one of the primary modifiable risk factors for cardiovascular disease. Adequate vitamin D (vit D) levels have been shown to reduce vascular smooth muscle contraction and to increase arterial compliance, which may be beneficial in hypertension. Further, coenzyme Q10 (COQ10) through its action to lower oxidative stress has been reported to have beneficial effects on hypertension and heart failure. This study examined the possible cardiac and renal protective effects of vit D and COQ10 both separately and in combination with an angiotensin II receptor blocker, valsartan (vals) in l -NAME hypertensive rats. Materials and Methods Hypertension was induced in rats by l -NAME administration. Following induction of hypertension, the rats were assigned into the following 6 subgroups: an l -NAME alone group and treated groups receiving the following drugs intraperitoneally for 6 weeks; vals, vit D, COQ10 and combination of vals with either vit D or COQ10. A group of normotensive rats were used as negative controls. At the end of the treatment period, blood pressure, serum creatinine, blood urea nitrogen, lipids and serum, cardiac and renal parameters of oxidative stress were measured. Results Compared to the l -NAME only group, all treatments lowered systolic, diastolic, mean arterial pressure, total cholesterol, low-density lipoprotein cholesterol, and creatinine levels as well as TNF-α and malondialdehyde. Further, the agents increased serum, cardiac and renal total antioxidant capacity. Interestingly, the combination of agents had further effects on all the parameters compared to treatment with each single agent. Conclusions The study suggests that the additive protective effects of vit D and COQ10 when used alone or concurrent with vals treatment in hypertensive rats may be due to their effects as antioxidants, anticytokines and blood pressure conservers.

// Meisheng Zou 1,2,* , Chixiong Huang 1,* , Xinzhong Li 1 , Xiang He 1 , Yanmei Chen 1 , Wangjun Liao 3 , Yulin Liao 1 , Jie Sun 1,4 , Ze Liu 2 , Lintao Zhong 1 and Jianping Bin 1 1 Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China 2 Wards of Cadres, Guangzhou General Hospital of Guangzhou Military Region, Guangzhou, China 3 Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China 4 Department of Cardiology, Zhongshan Hospital, Sun Yat-Sen University, Zhongshan, China * These authors have contributed equally to this work Correspondence to: Jianping Bin, email: // Lintao Zhong, email: // Keywords : thoracic aortic dissection, circular RNA, microarray, biomathematics, Pathology Section Received : February 12, 2017 Accepted : June 18, 2017 Published : July 05, 2017 Abstract Objective: To assess the circular RNAs (circRNAs) expression profile and explore the potential functions in human thoracic aortic dissection (TAD). Methods: The differentially expressed circRNAs profiles of the aortic segments between human type A TAD patients ( n =3) and age-matched normal donors (NA; n =3) were analyzed using the Arraystar human circRNAs microarray. Quantitative real-time PCR was used to validate the expression pattern of circRNAs, parental genes, and hsa-miR-320a; Western blotting confirmed MMP9 expression with additional samples. Bioinformatic tools including network analysis, Gene ontology, and KEGG pathway analysis were utilized. Results: Among 8,173 detected circRNA genes, 156 upregulated and 106 downregulated significantly in human TAD as compared to NA (P£0.05). Quantitative real-time PCR showed an elevated expression of the upregulated hsa_circRNA_101238, hsa_circRNA_104634, hsa_circRNA_002271, hsa_circRNA_102771, hsa_circRNA_104349, COL1A1, and COL6A3 and reduced of the downregulated hsa_circRNA_102683, hsa_circRNA_005525, hsa_circRNA_103458, and FLNA. Gene ontology analysis revealed that the parental genes favored several pathological processes, such as negative regulation of cell proliferation and extracellular matrix organization. The circRNA-miRNA co-expression network predicted that 33 circRNAs might interact with at least one target miRNAs altered in TAD. KEGG pathway analysis revealed that 28 altered miRNAs were enriched on focal adhesion and vascular smooth muscle contraction. The hsa_circRNA_101238-miRNA-mRNA network indicated the highest degree of hsa-miR-320a. Quantitative real-time PCR and Western blot manifested the low expression of hsa-miR-320a and high of MMP9 in human TAD tissues, respectively. Conclusions: This study revealed hundreds of differentially expressed circular RNAs in human TAD, suggesting that hsa_circRNA_101238 might inhibit the expression of hsa-miR-320a and increase that of MMP9 in TAD.

Objective To examine the effects of accumulated heat in GI tract (AHGIT) on lung tissue protein expression in pneumonic mice. Methods Nebulized lipopolysaccharides (LPS) were administered to induce a pneumonic mouse model (M1), and a high-calorie/protein diet combined with nebulized LPS was used to induce AHGIT pneumonia (M2). Isobaric tag for relative and absolute quantitation (iTRAQ) proteomics was applied to study lung protein expression, followed by bioinformatics analysis. Results M1 mice developed alveolar damage with prominent septum thickening, vascular dilation, hyperaemia and infiltration of large amounts of inflammatory cells. M2 mice developed more severe pathological responses. A total of 2626 proteins were reliably identified in the lung tissue. Compared with normal mice, the M1 mice had 344 differentially expressed proteins in their lungs, which are involved in the following biological processes: response to organic substance, response to cytokine, response to external stimulus, defense response and immune system process. They are also involved in the following Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways: ECM-receptor interaction, leukocyte transendothelial migration, Fc gamma R-mediated phagocytosis, complement and coagulation cascades, and antigen processing and presentation. Compared with the M1 group, the M2 mice had 164 differentially expressed proteins in their lungs, including 14 upregulated and 150 downregulated proteins. These proteins are involved in the following biological processes: small molecule metabolism, ribose phosphate metabolic process, cell adhesion and biological adhesion. The relevant KEGG pathways included oxidative phosphorylation, Citrate cycle (TCA cycle), complement and coagulation cascades, and vascular smooth muscle contraction. Conclusions AHGIT aggravated the lung inflammatory damage in the mice with LPS-induced pneumonia. It may affect the mouse substance/energy metabolism, and therefore the immune function, to aggravate the LPS-induced inflammatory damage.

During pregnancy, the uterine artery (UA) undergoes extensive remodeling to permit a 20&ndash, 40 fold increase in blood flow with associated changes in the expression of a multitude of genes. This study used next-gen RNA sequencing technology to identify pathways and genes potentially involved in arterial adaptations in pregnant rat UA (gestation day 20) compared with non-pregnant rat UA (diestrus). A total of 2245 genes were differentially expressed, with 1257 up-regulated and 970 down-regulated in pregnant UA. Gene clustering analysis revealed a unique cluster of suppressed genes implicated in calcium signaling pathway and vascular smooth muscle contraction in pregnant UA. Transcription factor binding site motif scanning identified C2H2 ZF, AP-2 and CxxC as likely factors functional on the promoters of down-regulated genes involved in calcium signaling and vascular smooth muscle contraction. In addition, 1686 genes exhibited alternative splicing that were mainly implicated in microtubule organization and smooth muscle contraction. Cross-comparison analysis identified novel genes that were both differentially expressed and alternatively spliced, these were involved in leukocyte and B cell biology and lipid metabolism. In conclusion, this first comprehensive study provides a valuable resource for understanding the molecular mechanism underlying gestational uterine arterial adaptations during pregnancy.

The pathological process and mechanism of myocardial ischemia (MI) is very complicated, and remains unclear. An integrated proteomic-metabolomics analysis was applied to comprehensively understand the pathological changes and mechanism of MI. Male Sprague-Dawley rats were randomly divided into a mock surgery (MS) group and an MI group. The MI model was made by ligating the left anterior descending coronary artery, twenty-four hours after which, echocardiography was employed to assess left ventricular (LV) function variables. Blood samples and left ventricular tissues were collected for ELISA, metabolomics and proteomics analysis. The results showed that LV function, including ejection fraction (EF) and fractional shortening (FS), was significantly reduced and the level of cTnT in the serum increased after MI. iTRAQ proteomics showed that a total of 169 proteins were altered including 52 and 117 proteins with increased and decreased expression, respectively, which were mainly involved in the following activities: complement and coagulation cascades, tight junction, regulation of actin cytoskeleton, MAPK signaling pathway, endocytosis, NOD-like receptor signaling pathway, as well as phagosome coupled with vitamin digestion and absorption. Altered metabolomic profiling of this transition was mostly enriched in pathways including ABC transporters, glycerophospholipid metabolism, protein digestion and absorption and aminoacyl-tRNA biosynthesis. The integrated metabolomics and proteomics analysis indicated that myocardial injury after MI is closely related to several metabolic pathways, especially energy metabolism, amino acid metabolism, vascular smooth muscle contraction, gap junction and neuroactive ligand-receptor interaction. These findings may contribute to understanding the mechanism of MI and have implication for new therapeutic targets.

Mastoparan-7 activates guanine nucleotide-binding proteins (G-proteins) and stimulates both apoptosis and increases in cytoplasmic calcium concentration and may induce smooth muscle contraction. The primary aim of the present study was to evaluate the modulatory effect of laser stimulation on vascular smooth muscle contraction induced by direct stimulation of G-protein with mastoparan-7. Experiments were performed on isolated and perfused tail arteries of Wistar rats. Contraction force in the model was measured by increased levels of perfusion pressure with a constant flow. Irradiation treatment was applied directly to the blood vessels. The laser was applied in increasing doses of 10 mW (E=1.8 J), 30 mW (E=5.5 J) and 110 mW (E=19.8 J). Time of exposure was 3 min for each irradiation. In the laser-stimulated arteries, a significant and dose-dependent decrease was observed. The half maximal effective concentration values were 4.43±2.2x10(-8), 2.4±0.56x10(-7), 3.2±0.72x10(-7) and 7.7±0.3x10(-7) M/l in the control and 10, 30 and 110 mW laser irradiation groups, respectively. Significant (P

Tibetan chicken, a unique plateau breed, has a suite of adaptive features that enable it to tolerate the high-altitude hypoxic environment. HIF-1α (hypoxia inducible factor 1 subunit alpha) is a crucial mediator of the cellular response to hypoxia. HIF-1α maintains oxygen homeostasis by inducing glycolysis, erythropoiesis, and angiogenesis. In this study, using ChIP-seq, we analyzed HIF-1α binding regions in the chorioallantoic membrane (CAM) tissue of embryos, and identified differential HIF-1α target genes (DTGs) by comparing Chahua (CH) and Tibetan chicken (TC) that had distinct genetic performances, associated with hypoxic adaptation. We identified 752 HIF-1α target genes (TGs), of which 112 were DTGs between the two breeds. We found that eight genes (PTK2, GPNMB, CALD1, CBWD1, SLC25A1, SPRY2, NUPL2, and ST8SIA3) play important roles in hypoxic adaptation by regulating blood vessel development, energy metabolism through angiogenesis, vascular smooth muscle contraction, and various hypoxia-related signaling pathways (including VEGF and PI3K-Akt) in Tibetan chickens during embryonic development. This study enhances our understanding of the molecular mechanisms of hypoxic adaptation in Tibetan chickens and provides new insights into adaptation to hypoxia in humans and other species living at high altitude.

Background Compromised microvasculature resulting from disrupted bronchial arterial circulation appears to trigger chronic lung allograft dysfunction. Maintaining the microvasculature throughout the transplant process could improve the long-term health of transplanted lungs. We recently developed a bronchial-arterial-circulation-sparing (BACS) lung preservation approach and tested whether this approach would decrease microvascular damage and improve allograft function. Methods The lungs of Lewis rats were procured using either the BACS approach, where the bronchial and pulmonary arteries were synchronously perfused; a conventional approach, where only the pulmonary artery was perfused; or a conventional approach with a prostaglandin flush. After 4 hours of cold ischemia, physiologic function and vascular tone of the grafts were evaluated during ex vivo lung perfusion (EVLP), and microvasculature damage was assessed using 2-photon microscopy analysis. Lung function was compared after transplant among the groups. Results After 4 hours of cold ischemia, the BACS group exhibited significantly higher adenosine triphosphate levels and lower expression of phosphorylated myosin light chain, which is essential for vascular smooth muscle contraction. On EVLP, the BACS and prostaglandin groups showed lower pulmonary vascular resistance and less arterial stiffness. BACS attenuated microvasculature damage in the lung grafts when compared with conventional preservation. After transplantation, the lungs preserved with the BACS approach exhibited significantly better graft function and lower expression of phosphorylated myosin light chain. Conclusions Our data suggest that BACS lung preservation protects the dual circulation inherent to the lungs, facilitating robust microvasculature in lung grafts after transplantation, leading to better posttransplant outcomes.

Aim To compare early-onset pre-eclampsia (EOPE) and late-onset pre-eclampsia (LOPE) and provide insight into the pathophysiology of pre-eclampsia (PE). Methods Our recent work compared the transcriptomics in decidua of EOPE, LOPE and normal pregnancies (NP). Results We found there are a significant number of genes uniquely expressed in the decidua of EOPE and LOPE comparing with NP. Moreover, EOPE and LOPE have their distinct profiles. Unique EOPE-associated genes were mainly involved in apoptosis related pathways such as 'apoptosis' and 'Ras signaling pathway'. PIK3CB and BCL-2 are the core regulatory genes in EOPE decidua, their abnormal expression caused decidual abnormal apoptosis which is relevant to the pathogenesis of EOPE. Whereas, LOPE is a more complicated entity which has more special LOPE-associated genes involved in decidua differentiation, especially in 'gap junction pathway', 'vascular smooth muscle contraction' and 'long-term depression'. PIK3CB, FLT1, CBLC and ITGA7 are the core regulatory genes differentially expressed in EOPE decidua comparing with LOPE. Conclusion In brief, the different decidual transcriptomics of EOPE and LOPE may correlate with their different etiology. These findings highlight the complex pathophysiology of PE and provide potential targets for a new treatment strategy in patients with PE.

Angina pectoris can be used as an early warning for coronary artery disease. Vasodilation is an important mechanism of angina pectoris. Traditional Chinese medicine - Compound Danshen Dripping Pill (CDDP) is widely used to improve the symptoms of cardiovascular diseases (CVDs). To investigate the influence of vasodilation effect and underlying mechanisms of CDDP, we determined the vasodilation effect of thoracic aorta ring on rat induced by norepinephrine (NE). Then targets-fishing method was used to predict the potential mechanism of CDDP on vasodilation, based on the structures of the main components. Then, iTRAQ-based quantitative proteomics analysis was used for verification of the candidate target proteins and pathways to illustrate the underlying mechanisms. Furthermore, the differentially expressed proteins in the enriched pathways were validated by western blotting. In this study, we found that CDDP could significantly inhibit NE induced aortic contraction tension, and the mechanism may be related to platelet activation, cGMP - PKG signaling pathway and vascular smooth muscle contraction. The method provides a new way to uncover the vasodilation mechanism of CDDP, as well as other multi-component herbal medicines.

The Xichuan black-bone chicken, which is a rare local chicken species in China, is an important genetic resource of black-bone chickens. Tyrosine can affect melanin production, but the molecular mechanism underlying tyrosine-induced melanin deposition in Xichuan black-bone chickens is poorly understood. Here, the blackness degree and melanin content of the breast muscle of Xichuan black-bone chickens fed a basic diet with five levels of added tyrosine (i.e., 0.2, 0.4, 0.6, 0.8, and 1.0%; these groups were denoted test groups I-V, respectively) were assessed, and the results showed that 0.8% tyrosine was the optimal level of added tyrosine. Moreover, the effects of tyrosine supplementation on the proliferation and tyrosinase content of melanocytes in Xichuan black-bone chickens were evaluated. The results revealed a dose-dependent relationship between tyrosine supplementation and melanocyte proliferation. In addition, 417 differentially expressed genes (DEGs), including 160 upregulated genes and 257 downregulated genes, were identified in a comparative analysis of the transcriptome profiles constructed using the pooled total RNA from breast muscle tissues of the control group and test group IV, respectively (fold change ≥2.0, P < 0.05). These DEGs were mainly involved in melanogenesis, the calcium signaling pathway, the Wnt signaling pathway, the mTOR signaling pathway, and vascular smooth muscle contraction. The pathway analysis of the DEGs identified some key genes associated with pigmentation, such as DCT and EDNRB2. In summary, the melanin content of breast muscle could be markedly enhanced by adding an appropriate amount of tyrosine to the diet of Xichuan black-bone chickens, and the EDNRB2-mediated molecular regulatory network could play a key role in the biological process of tyrosine-induced melanin deposition. These results have deepened the understanding of the molecular regulatory mechanism of melanin deposition in black-bone chickens and provide a basis for the regulation of nutrition and genetic breeding associated with melanin deposition in Xichuan black-bone chickens.

Thoracic aortic dissection (TAD) is a catastrophic disease worldwide, but the pathogenic genes and pathways are largely unclear. This study aims at integrating two gene expression profile datasets and verifying hub genes and pathways involved in TAD as well as exploring potential molecular mechanisms. We will combine our mRNAs expression profile (6 TAD tissues versus 6 non-TAD tissues) and GSE52093 downloaded from the Gene Expression Omnibus (GEO) database. The two mRNAs expression profiles contained 13 TAD aortic tissues and 11 non-TAD tissues. The two expression profile datasets were integrated and we found out coexpression of differentially expressed genes (DEGs) using bioinformatics methods. The gene ontology and pathway enrichment of DEGs were performed by DAVID and Kyoto Encyclopedia of Genes and Genomes online analyses, respectively. The protein-protein interaction networks of the DEGs were constructed according to the data from the STRING database. Cytohubber calculating result shows the top 10 hub genes with CDC20, AURKA, RFC4, MCM4, TYMS, MCM2, DLGAP5, FANCI, BIRC5, and POLE2. Module analysis revealed that TAD was associated with significant pathways including cell cycle, vascular smooth muscle contraction, and adrenergic signaling in cardiomyocytes. The qRT-PCR result showed that the expression levels of all the hub genes were significantly increased in OA samples (p < 0.05), and these candidate genes could be used as potential diagnostic biomarkers and therapeutic targets of TAD.

Salinity is a major ecological factor in the marine environment, and extremely important for the survival, development, and growth of fish. In this study, gill transcriptomes were examined by high-throughput sequencing at three different salinities (12 ppt as low salinity, 22 ppt as control salinity, and 32 ppt as high salinity) in an importantly economical fish silvery pomfret. A total of 187 genes were differentially expressed, including 111 up-regulated and 76 down-regulated transcripts in low-salinity treatment group and 107 genes differentially expressed, including 74 up-regulated and 33 down-regulated transcripts in high-salinity treatment group compared with the control group, respectively. Some pathways including NOD-like receptor signaling pathway, cytokine-cytokine receptor interaction, Toll-like receptor pathway, cardiac muscle contraction, and vascular smooth muscle contraction were significantly enriched. qPCR analysis further confirmed that mRNA expression levels of immune (HSP90A, IL-1β, TNFα, TLR2, IP-10, MIG, CCL19, and IL-11) and ion transport–related genes (WNK2, NPY2R, CFTR, and SLC4A2) significantly changed under salinity stress. Low salinity stress caused more intensive expression changes of immune-related genes than high salinity. These results imply that salinity stress may affect immune function in addition to regulating osmotic pressure in silvery pomfret.

Tibetan chicken, an indigenous breed, is highly adapted to the extreme environment of the Qinghai-Tibet Plateau. It serves as a model organism to identify genetic differences between hypoxia-adapted and lowland breeds. However, the mechanisms underlying hypoxia adaptation are yet unclear. This study aimed to identify differently abundant proteins (DAPs) and elucidate the mechanisms involved in hypoxic adaptation in the Tibetan chicken. In this study, we obtained proteome data for the embryonic heart tissues of Tibetan and Chahua chickens incubated under hypoxia (TCH and CHH) and normoxia (TCN and CHN) using isobaric tags for relative and absolute quantitation (iTRAQ) technology. We identified 4210 proteins from 53,352 unique peptides in the heart tissue of chicken embryos. Pairwise TCH vs. CHH, TCH vs. TCN, CHH vs. CHN, and TCN vs. CHN comparisons revealed 118, 176, 103, and 162 differently abundant proteins, respectively. Several key proteins (EGLN1, MAP2K2, MYLK, QARS, NOTCH2, and MYH7) and pathways (glutathione metabolism, PPAR signaling pathway, and vascular smooth muscle contraction) were identified and considered important candidates for high-altitude adaptation in Tibetan chicken. This study provides novel insights into the chicken embryonic heart tissue and furthers the current understanding of the mechanisms of survival among animals in high-altitude environments.