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Mood stabilizers that are approved for treating bipolar disorder (BD), when given chronically to rats, decrease expression of markers of the brain arachidonic metabolic cascade, and reduce excitotoxicity and neuroinflammation-induced upregulation of these markers. These observations, plus evidence for neuroinflammation and excitotoxicity in BD, suggest that arachidonic acid (AA) cascade markers are upregulated in the BD brain. To test this hypothesis, these markers were measured in postmortem frontal cortex from 10 BD patients and 10 age-matched controls. Mean protein and mRNA levels of AA-selective cytosolic phospholipase A 2 (cPLA 2 ) IVA, secretory sPLA 2 IIA, cyclooxygenase (COX)-2 and membrane prostaglandin E synthase (mPGES) were significantly elevated in the BD cortex. Levels of COX-1 and cytosolic PGES (cPGES) were significantly reduced relative to controls, whereas Ca 2+ -independent iPLA 2 VIA, 5-, 12-, and 15-lipoxygenase, thromboxane synthase and cytochrome p450 epoxygenase protein and mRNA levels were not significantly different. These results confirm that the brain AA cascade is disturbed in BD, and that certain enzymes associated with AA release from membrane phospholipid and with its downstream metabolism are upregulated. As mood stabilizers downregulate many of these brain enzymes in animal models, their clinical efficacy may depend on suppressing a pathologically upregulated cascade in BD. An upregulated cascade should be considered as a target for drug development and for neuroimaging in BD.

Abstract Background/Aims: Radiotherapy is applied to patients with inoperable cancer types including advanced stage non-small cell lung cancer (NSCLC) and radioresistance functions as a critical obstacle in radiotherapy. This study was aimed to investigate the mechanism of radioresistance regulated by surfactant protein B (SP-B). Methods: To investigate the role of SP-B in radioresistance, ΔSFTPB A549 cell line was established and SP-B expression was analyzed. In response to ionizing radiation (IR), the change of SP-B expression was analyzed in A549 and NCI-H441 cell lines. Conditioned media (CM) from NSCLC cells were utilized to evaluate the downstream signaling pathway. The in vivo effects of SP-B were assessed through mouse xenograft model with intratumoral injection of CM. Results: In response to IR, NSCLC cell lines showed decreased SP-B regulated by the TGF-β signaling and decreased SP-B stimulated cell survival and epithelial-mesenchymal transition. Treatment with CM from irradiated cells activated sPLA2, enhanced protein kinase Cδ-MAPKs signaling pathway, and increased arachidonic acid production. We confirmed the in vivo roles of SP-B through mouse xenograft model. Conclusion: Our results revealed that down-regulation of SP-B was involved in the radiation-induced metastatic conversion of NSCLC and provided evidence that SP-B acted as a suppressor of NSCLC progression.

Among the phospholipase A (PLA ) family, the secreted PLA (sPLA ) family in mammals contains 11 members that exhibit unique tissue or cellular distributions and enzymatic properties. Current studies using knockout and/or transgenic mice for a nearly full set of sPLA s, in combination with comprehensive lipidomics, have revealed the diverse pathophysiological roles of sPLA s in various biological events. Individual sPLA s exert specific functions within tissue microenvironments, likely through the hydrolysis of extracellular phospholipids. Lipids are an essential biological component for skin homeostasis, and disturbance of lipid metabolism by deletion or overexpression of lipid-metabolizing enzymes or lipid-sensing receptors often leads to skin abnormalities that are easily visible on the outside. Over the past decades, our studies using knockout and transgenic mice for various sPLA s have uncovered several new aspects of these enzymes as modulators of skin homeostasis and disease. This article summarizes the roles of several sPLA s in skin pathophysiology, providing additional insight into the research fields of sPLA s, lipids, and skin biology.

Phospholipase A 2 (PLA 2 ) catalyses the release of arachidonic acid for generation of lipid mediators of inflammation and is crucial in diverse inflammatory processes. The functions of the secretory PLA 2 enzymes (sPLA 2 ), numbering nine members in humans, are poorly understood, though they have been shown to participate in lipid mediator generation and the associated inflammation. To further understand the roles of sPLA 2 in disease, we quantified the expression of these enzymes in the synovial fluid in rheumatoid arthritis and used gene‐deleted mice to examine their contribution in a mouse model of autoimmune erosive inflammatory arthritis. Contrary to expectation, we find that the group V sPLA 2 isoform plays a novel anti‐inflammatory role that opposes the pro‐inflammatory activity of group IIA sPLA 2 . Mechanistically, group V sPLA 2 counter‐regulation includes promotion of immune complex clearance by regulating cysteinyl leukotriene synthesis. These observations identify a novel anti‐inflammatory function for a PLA 2 and identify group V sPLA 2 as a potential biotherapeutic for treatment of immune‐complex‐mediated inflammation.

The hypersensitive response (HR), characterized by a rapid and localized cell death at the inoculation site, is one of the most efficient resistance reactions to pathogen attack in plants. The transcription factor AtMYB30 was identified as a positive regulator of the HR and resistance responses during interactions between Arabidopsis and bacteria. Here, we show that AtMYB30 and the secreted phospholipase AtsPLA₂-α physically interact in vivo, following the AtMYB30-mediated specific relocalization of AtsPLA₂-α from cytoplasmic vesicles to the plant cell nucleus. This protein interaction leads to repression of AtMYB30 transcriptional activity and negative regulation of plant HR. Moreover, Atspla₂-α mutant plants are more resistant to bacterial inoculation, whereas AtsPLA₂-α overexpression leads to decreased resistance, confirming that AtsPLA₂-α is a negative regulator of AtMYB30-mediated defense. These data underline the importance of cellular dynamics and, particularly, protein translocation to the nucleus, for defense-associated gene regulation in plants.

Resistance to conventional chemotherapies remains a significant clinical challenge in treatment of cancer. The cancer stem cells (CSCs) have properties necessary for tumor initiation, resistance to therapy, and progression. HER/ERBB-elicited signaling supports CSC properties. Our previous studies revealed that secretory phospholipase A2 group IIa (sPLA2-IIa) is overexpressed in both prostate and lung cancer cells, leading to an aberrant high level in the interstitial fluid, i.e., tumor microenvironment and blood. HER/ERBB-PI3K-Akt-NF-κB signaling stimulates sPLA2-IIa overexpression, and in turn, sPLA2-IIa activates EGFR family receptors and HER/ERBB-elicited signaling and stimulates sPLA2-IIa overexpression in a positive feedback manner. The present study determined the molecular mechanisms of sPLA2-IIa in stimulating HER/ERBB-elicited signaling and supporting CSC properties. We found that sPLA2-IIa binds both EGFR and HER3 demonstrated by co-immunoprecipitation experiments and also indirectly interacts with HER2, suggesting that sPLA2-IIa functions as a ligand for both EGFR and HER3. Furthermore, both side population CSCs from non-small cell lung cancer (NSCLC) A549 and H1975 cells and ALDH1-high CSCs from castration-resistant prostate cancer (CRPC) 22Rv1 cells overexpress sPLA2-IIa and produce tumors when inoculated into subcutis of nude mice. Given an aberrant high level of sPLA2-IIa in the tumor microenvironment that should be much higher than that in the blood, our findings support the notion that sPLA2-IIa functions as a ligand for EGFR family receptors and supports CSC properties via HER/ERBB-elicited signaling, which may contribute to resistance to therapy and cancer progression.

Long non-coding RNA (lncRNA) SRA-like non-coding RNA (SLNCR1; also known as linc00673) is a recently identified oncogenic lncRNA. The role of SLNCR1 in non-small cell lung cancer (NSCLC), a common malignancy, remains poorly understood. The present study aimed to investigate the involvement of long non-coding RNA SLNCR1 in the pathogenesis of NSCLC. Reverse transcription-quantitative PCR (RT-qPCR) and ELISA were performed to measure the levels of lncRNA SLNCR1 and secretory phospholipase A2 (sPLA2) in lung biopsies, respectively. Correlations between expression levels of lncRNA SLNCR1 and sPLA2 were analyzed by Pearson's correlation analysis. Diagnostic value of lncRNA SLNCR1 for NSCLC was evaluated by receiver operating characteristic curve analysis. lncRNA SLNCR1 small interfering (si)RNA and sPLA2 overexpression vector were transfected into NSCLC cells. Cell migration, invasion and stemness were examined by Transwell migration assay, Matrigel invasion assay and flow cytometric assay, respectively. Following transfection, expression of lncRNA SLNCR1 and sPLA2 was detected by RT-qPCR and western blotting, respectively. The results demonstrated that lncRNA SLNCR1 expression levels were upregulated in tumor tissues compared with adjacent healthy tissues of patients with NSCLC. Plasma lncRNA SLNCR1 and sPLA2 expression levels were upregulated in patients with NSCLC compared with healthy controls. Plasma lncRNA SLNCR1 and sPLA2 were positively correlated in patients with NSCLC, but not in healthy controls. lncRNA SLNCR1 siRNA silencing inhibited, whereas sPLA2 overexpression promoted cell migratory and invasive abilities and stemness. lncRNA SLNCR1 siRNA silencing led to downregulated sPLA2 expression, whereas sPLA2 overexpression did not significantly affect lncRNA SLNCR1 expression. sPLA2 overexpression attenuated the inhibitory effects of lncRNA SLNCR1 siRNA silencing on cell migration, invasion and stemness. In conclusion, lncRNA SLNCR1 may regulate cancer cell migration, invasion and stemness in NSCLC through interactions with sPLA2.

Glioblastoma, the most aggressive type of primary brain tumour, shows worse prognosis linked to diabetes or obesity persistence. These pathologies are chronic inflammatory conditions characterized by altered profiles of inflammatory mediators, including leptin and secreted phospholipase A2-IIA (sPLA2-IIA). Both proteins, in turn, display diverse pro-cancer properties in different cell types, including astrocytes. Herein, to understand the underlying relationship between obesity and brain tumors, we investigated the effect of leptin, alone or in combination with sPLA2-IIA on astrocytoma cell functions. sPLA2-IIA induced up-regulation of leptin receptors in 1321N1 human astrocytoma cells. Leptin, as well as sPLA2-IIA, increased growth and migration in these cells, through activation/phosphorylation of key proteins of survival cascades. Leptin, at concentrations with minimal or no activating effects on astrocytoma cells, enhanced growth and migration promoted by low doses of sPLA2-IIA. sPLA2-IIA alone induced a transient phosphorylation pattern in the Src/ERK/Akt/mTOR/p70S6K/rS6 pathway through EGFR transactivation, and co-addition of leptin resulted in a sustained phosphorylation of these signaling regulators. Mechanistically, EGFR transactivation and tyrosine- and serine/threonine-protein phosphatases revealed a key role in this leptin-sPLA2-IIA cross-talk. This cooperative partnership between both proteins was also found in primary astrocytes. These findings thus indicate that the adipokine leptin, by increasing the susceptibility of cells to inflammatory mediators, could contribute to worsen the prognosis of tumoral and neurodegenerative processes, being a potential mediator of some obesity-related medical complications.

Phospholipases A2 (PLA2) hydrolyzes phospholipids, initiating the production of inflammatory lipid mediators. We have previously shown that in rats, sPLA2 and cPLA2 play opposing roles in the pathophysiology of ovalbumin (OVA)-induced experimental allergic bronchitis (OVA-EAB), an asthma model: Upon disease induction sPLA2 expression and production of the broncho-constricting CysLTs are elevated, whereas cPLA2 expression and the broncho-dilating PGE2 production are suppressed. These were reversed upon disease amelioration by treatment with an sPLA2 inhibitor. However, studies in mice reported the involvement of both sPLA2 and cPLA2 in EAB induction. To examine the relevance of mouse and rat models to understanding asthma pathophysiology. OVA-EAB was induced in mice using the same methodology applied in rats. Disease and biochemical markers in mice were compared with those in rats. As in rats, EAB in mice was associated with increased mRNA of sPLA2, specifically sPLA2gX, in the lungs, and production of the broncho-constricting eicosanoids CysLTs, PGD2 and TBX2 in bronchoalveolar lavage (BAL). In contrast, EAB in mice was associated also with elevated cPLA2 mRNA and PGE2 production. Yet, treatment with an sPLA2 inhibitor ameliorated the EAB concomitantly with reverting the expression of both cPLA2 and sPLA2, and eicosanoid production. In both mice and rats sPLA2 is pivotal in OVA-induced EAB. Yet, amelioration of asthma markers in mouse models, and human tissues, was observed also upon cPLA2 inhibition. It is plausible that airway conditions, involving multiple cell types and organs, require the combined action of more than one, essential, PLA2s.

The mechanism for maternal recognition of pregnancy (MRP) in horses is unknown. To maintain a pregnancy, a mobile conceptus must be recognized by the uterus before d 14 postovulation (PO). This recognition prevents endometrial secretion of PGF2α on d14 through 16, which would otherwise initiate luteolysis. The objective of this study was to evaluate gene expression in the endometrium of pregnant and nonpregnant mares during and after MRP to identify possible genes involved during this time. Twelve normally cycling mares were used in a crossover design and randomly assigned to a specific collection day. Endometrial samples were collected from a pregnant and nonpregnant (nonmated) mare on cycle d 12, 14, 16, and 18 (n = 3/d) PO. Microarray analysis comparing the endometrial gene expression in pregnant and nonpregnant mares revealed no differences at d 12. Ten genes were identified to have consistently higher or lower expression levels in the endometrium from pregnant versus nonpregnant mares on d 14, 16, and 18 (P < 0.001). The expression of these 10 genes was further analyzed with real-time PCR. d 14, 16, and 18 gene expression patterns were consistent with the microarray analysis, but on d 12, 4 of the 10 were identified as differentially expressed. Endometrial samples were then collected on d 13 PO (n = 3) and processed for western blot and immunohistochemical analysis of 2 proteins due to their reproductive significance. SPLA2 and DKK1 antibody specificity were confirmed via western blot analysis but were not different in samples from pregnant and nonpregnant mares (P = 0.114 and P = 0.514, respectively) and cellular localization was examined by immunohistochemical analysis. This is the first study to describe gene expression and cellular localization in the endometrium at the time of MRP for these genes and suggests that the uterus does not prepare to support a pregnancy until d 14. The function of these genes may be critical in the process of MRP.