Identification of circRNA and mRNA expression profiles and functional networks of vascular tissue in lipopolysaccharide‐induced sepsis

Sepsis is the most common cause of death in intensive care units. This study investigated the circular RNA (circRNA) and mRNA expression profiles and functional networks of the aortic tissue in sepsis. We established a lipopolysaccharide (LPS)‐induced rat sepsis model. High‐throughput sequencing was performed on the aorta tissue to identify differentially expressed (DE) circRNAs and mRNAs, which were validated by real‐time quantitative polymerase chain reaction (RT‐qPCR). Bioinformatic analysis was carried out and coding and non‐coding co‐expression (CNC) and competing endogenous RNA (ceRNA) regulatory networks were constructed to investigate the mechanisms. In total, 373 up‐regulated and 428 down‐regulated circRNAs and 2063 up‐regulated and 2903 down‐regulated mRNAs were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of mRNAs showed that the down‐regulated genes were mainly enriched in the process of energy generation. CNC and ceRNA regulatory networks were constructed with seven DE circRNAs. The results of functional enrichment analysis of CNC target genes revealed the important role of circRNAs in inflammatory response. The ceRNA network also highlighted the significant enrichment in calcium signalling pathway. Significant alterations in circRNAs and mRNAs were observed in the aortic tissue of septic rats. In addition, CNC and ceRNA networks were established.     

Inhibition of the Notch1 pathway induces peripartum cardiomyopathy

Increased expression and activity of cardiac and circulating cathepsin D and soluble fms‐like tyrosine kinase‐1 (sFlt‐1) have been demonstrated to induce and promote peripartum cardiomyopathy (PPCM) via promoting cleavage of 23‐kD prolactin (PRL) to 16‐kD PRL and neutralizing vascular endothelial growth factor (VEGF), respectively. We hypothesized that activation of Hes1 is proposed to suppress cathepsin D via activating Stat3, leading to alleviated development of PPCM. In the present study, we aimed to investigate the role of Notch1/Hes1 pathway in PPCM. Pregnant mice between prenatal 3 days and postpartum 3 weeks were fed with LY‐411575 (a notch inhibitor, 10 mg/kg/d). Ventricular function and pathology were evaluated by echocardiography and histological analysis. Western blotting analysis was used to examine the expression at the protein level. The results found that inhibition of Notch1 significantly promoted postpartum ventricular dilatation, myocardial hypertrophy and myocardial interstitial fibrosis and suppressed myocardial angiogenesis. Western blotting analysis showed that inhibition of Notch1 markedly increased cathepsin D and sFlt‐1, reduced Hes1, phosphorylated Stat3 (p‐Stat3), VEGFA and PDGFB, and promoted cleavage of 23k‐D PRL to 16‐kD PRL. Collectively, inhibition of Notch1/Hes1 pathway induced and promoted PPCM via increasing the expressions of cathepsin D and sFlt‐1. Notch1/Hes1 was a promising target for prevention and therapeutic regimen of PPCM.     

Tumour‐associated macrophages as a novel target of VEGI‐251 in cancer therapy

Tumour‐associated macrophages (TAMs), which possess M2‐like characters and are derived from immature monocytes in the circulatory system, represent a predominant population of inflammatory cells in solid tumours. TAM infiltration in tumour microenvironment can be used as an important prognostic marker in many cancer types and is a potential target for cancer prevention or treatment. VEGI‐251 not only is involved in the inhibition of tumour angiogenesis, but also participates in the regulation of host immunity. This work aimed to investigate the involvement of VEGI‐251 in the regulation of specific antitumour immunity. We found that recombinant human VEGI‐251(rhVEGI‐251) efficiently mediated the elimination of TAMs in tumour tissue in mice, and induced apoptosis of purified TAMs in vitro. During this process, caspase‐8 and caspase‐3 were activated, leading to PARP cleavage and apoptosis. Most importantly, we further elucidated the mechanism underlying VEGI‐251‐triggered TAM apoptosis, which suggests that ASK1, an intermediate component of the VEGI‐251, activates the JNK pathway via TRAF2 in a potentially DR3‐dependent manner in the process of TAM apoptosis. Collectively, our findings provide new insights into the basic mechanisms underlying the actions of VEGI‐251 that might lead to future development of antitumour therapeutic strategies using VEGI‐251 to target TAMs.     

Cytisine attenuates bone loss of ovariectomy mouse by preventing RANKL‐induced osteoclastogenesis

Postmenopausal Osteoporosis (PMOP) is oestrogen withdrawal characterized of much production and activation by osteoclast in the elderly female. Cytisine is a quinolizidine alkaloid that comes from seeds or other plants of the Leguminosae (Fabaceae) family. Cytisine has been shown several potential pharmacological functions. However, its effects on PMOP remain unknown. This study designed to explore whether Cytisine is able to suppress RANKL‐induced osteoclastogenesis and prevent the bone loss induced by oestrogen deficiency in ovariectomized (OVX) mice. In this study, we investigated the effect of Cytisine on RAW 264.7 cells and bone marrow monocytes (BMMs) derived osteoclast culture system in vitro and observed the effect of Cytisine on ovariectomized (OVX) mice model to imitate postmenopausal osteoporosis in vivo. We found that Cytisine inhibited F‐actin ring formation and tartrate‐resistant acid phosphatase (TRAP) staining in dose‐dependent ways, as well as bone resorption by pit formation assays. For molecular mechanism, Cytisine suppressed RANK‐related trigger RANKL by phosphorylation JNK/ERK/p38‐MAPK, IκBα/p65‐NF‐κB, and PI3K/AKT axis and significantly inhibited these signalling pathways. However, the suppression of PI3K‐AKT‐NFATc1 axis was rescued by AKT activator SC79. Meanwhile, Cytisine inhibited RANKL‐induced RANK‐TRAF6 association and RANKL‐related gene and protein markers such as NFATc1, Cathepsin K, MMP‐9 and TRAP. Our study indicated that Cytisine could suppress bone loss in OVX mouse through inhibited osteoclastogenesis. All data provide the evidence that Cytisine may be a promising agent in the treatment of osteoclast‐related diseases such as osteoporosis.     

Bmp2 regulates Serpinb6b expression via cAMP/PKA/Wnt4 pathway during uterine decidualization

Serpinb6b is a novel member of Serpinb family and found in germ and somatic cells of mouse gonads, but its physiological function in uterine decidualization remains unclear. The present study revealed that abundant Serpinb6b was noted in decidual cells, and advanced the proliferation and differentiation of stromal cells, indicating a creative role of Serpinb6b in uterine decidualization. Further analysis found that Serpinb6b modulated the expression of Mmp2 and Mmp9. Meanwhile, Serpinb6b was identified as a target of Bmp2 regulation in stromal differentiation. Treatment with rBmp2 resulted in an accumulation of intracellular cAMP level whose function in this differentiation program was mediated by Serpinb6b. Addition of PKA inhibitor H89 impeded the Bmp2 induction of Serpinb6b, whereas 8‐Br‐cAMP rescued the defect of Serpinb6b expression elicited by Bmp2 knock‐down. Attenuation of Serpinb6b greatly reduced the induction of constitutive Wnt4 activation on stromal cell differentiation. By contrast, overexpression of Serpinb6b prevented this inhibition of differentiation process by Wnt4 siRNA. Moreover, blockage of Wnt4 abrogated the up‐regulation of cAMP on Serpinb6b. Collectively, Serpinb6b mediates uterine decidualization via Mmp2/9 in response to Bmp2/cAMP/PKA/Wnt4 pathway.     

IL‐17A‐producing T cells exacerbate fine particulate matter‐induced lung inflammation and fibrosis by inhibiting PI3K/Akt/mTOR‐mediated autophagy

Fine particulate matter (PM2.5) is the primary air pollutant that is able to induce airway injury. Compelling evidence has shown the involvement of IL‐17A in lung injury, while its contribution to PM2.5‐induced lung injury remains largely unknown. Here, we probed into the possible role of IL‐17A in mouse models of PM2.5‐induced lung injury. Mice were instilled with PM2.5 to construct a lung injury model. Flow cytometry was carried out to isolate γδT and Th17 cells. ELISA was adopted to detect the expression of inflammatory factors in the supernatant of lavage fluid. Primary bronchial epithelial cells (mBECs) were extracted, and the expression of TGF signalling pathway‐, autophagy‐ and PI3K/Akt/mTOR signalling pathway‐related proteins in mBECs was detected by immunofluorescence assay and Western blot analysis. The mitochondrial function was also evaluated. PM2.5 aggravated the inflammatory response through enhancing the secretion of IL‐17A by γδT/Th17 cells. Meanwhile, PM2.5 activated the TGF signalling pathway and induced EMT progression in bronchial epithelial cells, thereby contributing to pulmonary fibrosis. Besides, PM2.5 suppressed autophagy of bronchial epithelial cells by up‐regulating IL‐17A, which in turn activated the PI3K/Akt/mTOR signalling pathway. Furthermore, IL‐17A impaired the energy metabolism of airway epithelial cells in the PM2.5‐induced models. This study suggested that PM2.5 could inhibit autophagy of bronchial epithelial cells and promote pulmonary inflammation and fibrosis by inducing the secretion of IL‐17A in γδT and Th17 cells and regulating the PI3K/Akt/mTOR signalling pathway.     

Electrically Control Lateral Shift Owning to Guided-Wave Surface Plasmon Resonance with a Lithium Niobate Prism

Electrically controlled lateral shift by an electro-optic crystal prism is studied theoretically. The resonance point of excitation of guided-wave surface plasmon resonance (GWSPR) can be controlled by altering the refractive index of the prism. That is to say, the positions corresponding to the least reflectivity and the largest lateral shift could be conveniently modulated while the lithium niobate prism is operated in an external electric field. The maximal lateral shift is obtained at the excitation of GWSPR when the thickness of the silver film is optimized. The results of numerical simulations confirm theoretical calculation.

     

microRNA‐124 inhibits stem‐like properties and enhances radiosensitivity in nasopharyngeal carcinoma cells via direct repression of expression of JAMA

Cancer stem cells (CSCs) are a source of tumour recurrence in patients with nasopharyngeal carcinoma (NPC); however, the function of microRNA‐124 (miR‐124) in NPC CSCs has not been clearly defined. In this study, we investigated the role of miR‐124 in NPC CSCs. qRT‐PCR was performed to measure miR‐124 expression in NPC tissues and cell lines and the effects of miR‐124 on stem‐like properties and radiosensitivity of NPC cells measured. Luciferase reporter assays and rescue experiments were used to investigate the interaction of miR‐124 with the 3′UTR of junctional adhesion molecule A (JAMA). Finally, we examined the effects of miR‐124 in an animal model and clinical samples. Down‐regulation of miR‐124 was detected in cancer tissues and was inversely associated with tumour stage and lymph node metastasis. Overexpression of miR‐124 inhibited stemness properties and enhanced radiosensitivity of NPC cells in vitro and in vivo via targeting JAMA. Up‐regulation of miR‐124 was correlated with superior overall survival of patients with NPC. Our study demonstrates that miR‐124 can inhibit stem‐like properties and enhance radiosensitivity by directly targeting JAMA in NPC. These findings provide novel insights into the molecular mechanisms underlying therapy failure in NPC.     

Identification of immune-enhanced molecular subtype associated with BRCA1 mutations,immune checkpoints and clinical outcome in ovarian carcinoma

Ovarian carcinoma has the highest mortality among the malignant tumours in gynaecology, and new treatment strategies are urgently needed to improve the clinical status of ovarian carcinoma patients. The Cancer Genome Atlas (TCGA) cohort were performed to explore the immune function of the internal environment of tumours and its clinical correlation with ovarian carcinoma. Finally, four molecular subtypes were obtained based on the global immune-related genes. The correlation analysis and clinical characteristics showed that four subtypes were all significantly related to clinical stage; the immune scoring results indicated that most immune signatures were upregulated in C3 subtype, and the majority of tumour-infiltrating immune cells were upregulated in both C3 and C4 subtypes. Compared with other subtypes, C3 subtype had a higher BRCA1 mutation, higher expression of immune checkpoints, and optimal survival prognosis. These findings of the immunological microenvironment in tumours may provide new ideas for developing immunotherapeutic strategies for ovarian carcinoma.