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Pulmonary arterial hypertension (PAH) is a progressive disease with a complex aetiology and high mortality. Functional and structural changes in the small pulmonary arteries lead to elevated pulmonary arterial pressure, resulting in right heart failure. The pathobiology of PAH is not fully understood, and novel treatment targets in PAH are desperately needed. The renin-angiotensin system is critical for maintaining homeostasis of the cardiovascular system. The system consists of the angiotensin converting enzyme (ACE)-angiotensin (Ang) II-angiotensin type 1 receptor (AT1R) axis and the ACE2-Ang-(1–7)-Mas receptor axis. The former, the ACE-Ang II-AT1R axis, is involved in vasoconstrictive and hypertensive actions along with cardiac and vascular remodelling. The latter, the ACE2-Ang-(1–7)-Mas axis, generally mediates counterbalancing effects against those mediated by the ACE-Ang II-AT1R axis. Based on established functions, the ACE2-Ang-(1–7)-Mas axis may represent a novel target for the treatment of PAH. This review focuses on recent advances in pulmonary circulation science and the role of the ACE2-Ang-(1–7)-Mas axis in PAH.

Activation of transient receptor potential vanilloid 4 (TRPV4) induces neuronal injury. TRPV4 activation enhances inflammatory response and promotes the proinflammatory cytokine release in various types of tissue and cells. Hyperneuroinflammation contributes to neuronal damage in epilepsy. Herein, we examined the contribution of neuroinflammation to TRPV4-induced neurotoxicity and its involvement in the inflammation and neuronal damage in pilocarpine model of temporal lobe epilepsy in mice. Icv. injection of TRPV4 agonist GSK1016790A (GSK1016790A-injected mice) increased ionized calcium binding adapter molecule-1 (Iba-1) and glial fibrillary acidic protein (GFAP) protein levels and Iba-1-positive (Iba-1+) and GFAP-positive (GFAP+) cells in hippocampi, which indicated TRPV4-induced microglial cell and astrocyte activation. The protein levels of nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3) inflammasome components NLRP3, apoptosis-related spotted protein (ASC) and cysteinyl aspartate-specific protease-1 (caspase-1) were increased in GSK1016790A-injected mice, which indicated NLRP3 inflammasome activation. GSK1016790A also increased proinflammatory cytokine IL-1β, TNF-α and IL-6 protein levels, which were blocked by caspase-1 inhibitor Ac-YVAD-cmk. GSK1016790A-induced neuronal death was attenuated by Ac-YVAD-cmk. Icv. injection of TRPV4-specific antagonist HC-067047 markedly increased the number of surviving cells 3 d post status epilepticus in pilocarpine model of temporal lobe epilepsy in mice (pilocarpine-induced status epilepticus, PISE). HC-067047 also markedly blocked the increase in Iba-1 and GFAP protein levels, as well as Iba-1+ and GFAP+ cells 3 d post-PISE. Finally, the increased protein levels of NLRP3, ASC and caspase-1 as well as IL-1β, TNF-α and IL-6 were markedly blocked by HC-067047. We conclude that TRPV4-induced neuronal death is mediated at least partially by enhancing the neuroinflammatory response, and this action is involved in neuronal injury following status epilepticus.

Background. Although accumulating evidence suggested that a molecular signature panel may be more effective for the prognosis prediction than routine clinical characteristics, current studies mainly focused on colorectal or colon cancers. No reports specifically focused on the signature panel for rectal cancers (RC). Our present study was aimed at developing a novel prognostic signature panel for RC. Methods. Sequencing (or microarray) data and clinicopathological details of patients with RC were retrieved from The Cancer Genome Atlas (TCGA-READ) or the Gene Expression Omnibus (GSE123390, GSE56699) database. A weighted gene coexpression network was used to identify RC-related modules. The least absolute shrinkage and selection operator analysis was performed to screen the prognostic signature panel. The prognostic performance of the risk score was evaluated by survival curve analyses. Functions of prognostic genes were predicted based on the interaction proteins and the correlation with tumor-infiltrating immune cells. The Human Protein Atlas (HPA) tool was utilized to validate the protein expression levels. Results. A total of 247 differentially expressed genes (DEGs) were commonly identified using TCGA and GSE123390 datasets. Brown and yellow modules (including 77 DEGs) were identified to be preserved for RC. Five DEGs (ASB2, GPR15, PRPH, RNASE7, and TCL1A) in these two modules constituted the optimal prognosis signature panel. Kaplan-Meier curve analysis showed that patients in the high-risk group had a poorer prognosis than those in the low-risk group. Receiver operating characteristic (ROC) curve analysis demonstrated that this risk score had high predictive accuracy for unfavorable prognosis, with the area under the ROC curve of 0.915 and 0.827 for TCGA and GSE56699 datasets, respectively. This five-mRNA classifier was an independent prognostic factor. Its predictive accuracy was also higher than all clinical factor models. A prognostic nomogram was developed by integrating the risk score and clinical factors, which showed the highest prognostic power. ASB2, PRPH, and GPR15/TCL1A were predicted to function by interacting with CASQ2/PDK4/EPHA67, PTN, and CXCL12, respectively. TCL1A and GPR15 influenced the infiltration levels of B cells and dendritic cells, while the expression of PRPH was positively associated with the abundance of macrophages. HPA analysis supported the downregulation of PRPH, RNASE7, CASQ2, EPHA6, and PDK4 in RC compared with normal controls. Conclusion. Our immune-related signature panel may be a promising prognostic indicator for RC.

BackgroundThe white-backed planthopper (WBPH),Sogatella furcifera(Horváth) (Hemiptera, Delphacidae), is a migratory pest of rice in Asia. Shandong Province, in northern China, is located on the migration pathway of WBPH between southern and northeast China. The potential sources of WBPH in northern China are poorly understood. We studied the sources of WBPH in Shandong Province by determining the population genetic structure of WBPH in 18 sites distributed in Shandong and in six regions of the Greater Mekong Subregion (GMS). We used mitochondrial gene and single-nucleotide polymorphism (SNP) markers for analysis.ResultsAll of the WBPH populations studied in the seven regions had low genetic diversity. Pairwise FSTvalues based on mtDNA ranged from − 0.061 to 0.285, while FSTbased on SNP data ranged from − 0.007 to 0.009. These two molecular markers revealed that 4.40% (mtDNA) and 0.19% (SNP) genetic variation could be explained by the interpopulation variation, while the rest came from intrapopulation variation. The populations in the seven geographic regions comprised four hypothetical genetic clusters (K = 4) not associated with geographic location. Eighty-four of 129 individuals distributed across the given area were designated as recent migrants or of admixed ancestry. Although the substantial migration presented, a weak but significant correlation between genetic and geographic distances was found (r = 0.083, P = 0.004).ConclusionThe Greater Mekong Subregion was the main genetic source of WBPH in Shandong, while other source populations may also exist. The genetic structure of WBPH is shaped by both migration and geographic barriers.These results help clarify the migration route and the source of WBPH in northern China.

PurposeSalusin-β, a multifunctional vasoactive peptide, has a potentially important function in the pathological development of hypertension. However, the exact functional role of salusin-β and the underlying mechanism in this process are still not fully understood. The current study aimed to investigate the effects of silencing salusin-β on vascular function and vascular remodeling, as well as its signaling pathways in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY).MethodsSilencing salusin-β was performed by caudal vein injection of adenovirus expressing salusin-β short hairpin RNA (shRNA). Acetylcholine (ACh)-induced endothelium-dependent relaxation was used to evaluate vasodilator function, and high K+ solution-induced constriction was used to evaluate vasoconstriction function.ResultsSalusin-β levels in plasma and its protein expression in mesenteric artery (MA), coronary artery (CA), and pulmonary artery (PA) of SHR were higher than those in WKY. The salusin-β level and expression were decreased effectively by salusin-β shRNA. Knockdown of salusin-β decreased arterial blood pressure (ABP) and high K+ solution-induced vascular constrictions, and improved the endothelium-dependent relaxation and vascular remodeling in SHR. The improved effect of silencing salusin-β on ACh-induced relaxation in SHR was almost blocked by the nitric oxide synthase (NOS) inhibitor L-NAME. Compared to WKY, the endothelial NOS (eNOS) activity and level, and nitric oxide (NO) level were decreased, while NAD(P)H oxidase activity and reactive oxygen species (ROS) levels in MA, CA, and PA of SHR were increased, which were all redressed by salusin-β knockdown.ConclusionThese results indicate that knockdown of salusin-β improves endothelium-dependent vascular relaxation and vascular remodeling and decreases ABP and vasoconstriction in SHR, which might be accomplished by increasing eNOS activation and NO release while inhibiting NAD(P)H oxidase derived-ROS generation. Scavenging salusin-β improves vascular function and then prevents the development and progression of vasculopathy of hypertension.

Attenuated vasodilatation of small arteries is a hallmark feature of hypertension. Salusin-β, which is a TOR2A gene product and an important vasoactive peptide, has a close relationship with cardiovascular disease. This study aimed to determinate the roles of salusin-β in vasodilatation, and its signal pathways in Wistar–Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Isometric tension experiments were performed. Vasodilatation was induced by acetylcholine (ACh) or sodium nitroprusside (SNP). Plasma salusin-β levels and their protein expressions in coronary artery (CA), mesenteric artery (MA), and pulmonary artery (PA) of SHR were much higher than that of WKY. Intravenous injection of salusin-β increased arterial blood pressure in SHR, while anti-salusin-β IgG decreased it. Salusin-β further deteriorated, while anti-salusin-β IgG improved, the attenuated ACh-induced relaxation, the decreased nitric oxide (NO) level, and endothelial nitric oxide synthase (eNOS) activity in arteries of SHR, and salusin-β had no significant effect on SNP-induced relaxation. The NAD(P)H oxidase activity and reactive oxygen species (ROS) level in arteries of SHR were much higher than that of WKY, which was further increased by salusin-β but reduced by anti-salusin-β IgG. ROS scavenger NAC or antioxidant apocynin significantly inhibited, while SOD inhibitor DETC aggravated, the effects of salusin-β, and the eNOS inhibitor L-NAME inhibited the effects of anti-salusin-β IgG. These results indicated that enhanced salusin-β activity is involved in attenuated endothelium-dependent vasodilatation pathogenesis in SHR by activating NAD(P)H oxidase derived ROS generation and inhibiting eNOS activation and NO release.

Glucose metabolism and innate immunity evolved side-by-side. It is unclear if and how the two systems interact with each other during hepatitis B virus (HBV) infections and, if so, which mechanisms are involved. Here, we report that HBV activates glycolysis to impede retinoic acid-inducible gene I (RIG-I)-induced interferon production. We demonstrate that HBV sequesters MAVS from RIG-I by forming a ternary complex including hexokinase (HK). Using a series of pharmacological and genetic approaches, we provide in vitro and in vivo evidence indicating that HBV suppresses RLR signaling via lactate dehydrogenase-A-dependent lactate production. Lactate directly binds MAVS preventing its aggregation and mitochondrial localization during HBV infection. Therefore, we show that HK2 and glycolysis-derived lactate have important functions in the immune escape of HBV and that energy metabolism regulates innate immunity during HBV infection., RIG-I is a cytosolic antiviral nucleic acid sensor that signals via MAVS to produce type 1 interferons. Here the authors show that hepatits B virus can repress this pathway by activating glycolysis and lactate production, enabling accumulated lactate to bind MAVS and prevent its mitochondrial localization.

Activation of transient receptor potential vanilloid 4 (TRPV4) induces neuronal injury. TRPV4 activation enhances inflammatory response and promotes the proinflammatory cytokine release in various types of tissue and cells. Hyperneuroinflammation contributes to neuronal damage in epilepsy. Herein, we examined the contribution of neuroinflammation to TRPV4-induced neurotoxicity and its involvement in the inflammation and neuronal damage in pilocarpine model of temporal lobe epilepsy in mice. Icv. injection of TRPV4 agonist GSK1016790A (GSK1016790A-injected mice) increased ionized calcium binding adapter molecule-1 (Iba-1) and glial fibrillary acidic protein (GFAP) protein levels and Iba-1-positive (Iba-1

Hepatitis B virus X protein (HBx) critically contributes to the development of hepatocellular carcinoma (HCC). However, the mechanisms by which HBx promotes HCC remain unclear. In the present study, using a combination of gene expression profiling and immunohistochemistry, we found higher levels of SH2 domain–containing 5 (SH2D5) in liver tissue from HBV-associated HCC (HBV-HCC) patients than in adjacent nontumor tissues. Moreover, HBV infection elevated SH2D5 levels, and we observed that HBx plays an important role in SH2D5 induction. We also found that HBx triggers SH2D5 expression through the NF-κB and c-Jun kinase pathways. Employing SH2D5 overexpression or knockdown, we further demonstrate that SH2D5 promotes HCC cell proliferation both in vitro and in vivo. While investigating the mechanism of SH2D5-mediated stimulation of HCC cell proliferation, we noted that HBV induces SH2D5 binding to transketolase (TKT), a pentose phosphate pathway enzyme, thereby promoting an interaction between and signal transducer and activator of transcription 3 (STAT3). Furthermore, HBx stimulated STAT3 phosphorylation at Tyr-705 and promoted the activity and downstream signaling pathway of STAT3 via the SH2D5–TKT interaction. Taken together, our results suggest that SH2D5 is an HBV-induced protein capable of binding to TKT, leading to induction of HCC cell proliferation.

Numerous microRNAs (miRNA/miRs) have been reported to be associated with the initiation and progression of non‑small cell lung cancer (NSCLC). The aim of the present study was to examine the expression and biological role of miR‑939 in human NSCLC, in vitro. Reverse transcription‑quantitative polymerase chain reaction analysis was used to evaluate the expression of miR‑939 in NSCLC tissues. Cell Counting Kit‑8, 5‑ethynyl‑29‑deoxyuridine and Transwell assays were also used to determine the effects of miR‑939 on tumor cell proliferation and invasion in two human NSCLC cell lines (H1299 and SPCA1). Furthermore, tissue inhibitor of metalloproteinases 2 (TIMP2) was confirmed to be a target of miR‑939 by luciferase reporter assay, western blotting and bioinformatics analysis. Following downregulation of miR‑939 expression, cell proliferative and invasive abilities were significantly suppressed. Collectively, these findings indicated that the knockdown of miR‑939 may inhibit cell proliferation and invasion by regulating the expression of TIMP2 in NSCLC cells. Thus, miR‑939 may be a potential target in the treatment of NSCLC, although this requires further investigation.

Background As a means of biologically controlling Mikania micrantha H.B.K. in Yunnan, China, the influence of sweet potato [Ipomoea batatas (L.) Lam.] on its reproductive characteristics was studied. The trial utilized a de Wit replacement series incorporating six ratios of sweet potato and M. micrantha plants in 25 m2 plots over 2 years. Results Budding of M. micrantha occurred at the end of September; flowering and fruiting occurred from October to February. Flowering phenology of M. micrantha was delayed (P