Paroxetine suppresses reactive microglia-mediated but not lipopolysaccharide-induced inflammatory responses in primary astrocytes.

BACKGROUND: Astrocytes are the most abundant glial cells in a brain that mediate inflammatory responses and provide trophic support for neurons. We have previously disclosed that paroxetine, a common selective serotonin reuptake inhibitor, ameliorates LPS-induced microglia activation. However, it remains elusive for the role of paroxetine in astrocytic responses. METHODS: Isolated primary astrocytes were pretreated with paroxetine and stimulated with different stimuli, lipopolysaccharide (LPS) or microglia conditioned medium pre-activated with LPS (M/Lps). Inflammatory and neurotrophic responses, underlying mechanisms and the impact on neuronal survival were assessed. RESULTS: Paroxetine had no impact on LPS-stimulated iNOS, TNF-α, and IL-1ß expression, but inhibited M/Lps-induced TNF-α and IL-1ß expression in primary astrocytes. Paroxetine suppressed M/Lps- but not LPS-induced activation of NF-κB and had no impact on the activation of MAPKs and STAT3. Incubation with the resulted astrocyte conditioned media caused no change in the viability of SH-SY5Y cells. BDNF and MANF mRNA expressions were upregulated by M/Lps and paroxetine, respectively. However, M/Lps- or LPS-induced extracellular releases of NO, TNF-α, and/or BDNF in astrocytes were in minor amount compared to those by microglia. CONCLUSIONS: Paroxetine ameliorates the reactive microglia-mediated inflammatory responses in astrocytes partially via inhibition of the NF-κB pathway but has no impact on LPS-stimulated astrocyte activation. While the effects of paroxetine on secondary astrocytic responses are not robust compared to its effect on the innate immune responses of microglia, the results together may implicate a therapeutic potential of paroxetine against neuroinflammation-associated neurological disorders such as Parkinson's disease.

NLRC5 deficiency ameliorates diabetic nephropathy through alleviating inflammation.

NOD-like receptor family caspase recruitment domain family domain containing 5 (NLRC5) has important roles in inflammation and innate immunity. NLRC5 was highly expressed in kidney from streptozotocin-induced diabetic mice, db/ db mice and patients with diabetes. Based on that evidence, the present study was designed to explore the roles of NLRC5 in the progression of diabetic nephropathy (DN). We examined kidney injury, including inflammation and fibrosis in Nlrc5 gene knockout ( Nlrc5-/-) and wild-type (WT) diabetic mice. We found that Nlrc5-/- mice developed less-severe diabetic kidney injury compared with WT mice, exhibiting lower albuminuria, less fibronectin and collagen IV expression, and reduced macrophage infiltration but greater levels of podocin and nephrin in the diabetic kidney. The underlying mechanisms were further investigated in vitro with peritoneal macrophages and mesangial cells treated with high glucose. Reduced proinflammatory effect was observed in peritoneal macrophages from Nlrc5-/- mice, associated with NF-κB pathway suppression. Knocking down of NLRC5 in mesangial cells in high-glucose conditions was also associated with reduced NF-κB and TGF-ß/Smad signaling. Taken together, NLRC5 promotes inflammation and fibrosis during DN progression partly through the effects on NF-κB and TGF-ß/Smad pathways. NLRC5 may, therefore, be a promising therapeutic target for DN treatment.-Luan, P., Zhuang, J., Zou, J., Li, H., Shuai, P., Xu, X., Zhao, Y., Kou, W., Ji, S., Peng, A., Xu, Y., Su, Q., Jian, W., Peng, W. NLRC5 deficiency ameliorates diabetic nephropathy through alleviating inflammation.

The inhibition of the effect and mechanism of vascular intimal hyperplasia in Tiam1 knockout mice.

T-Cell Lymphoma Invasion and Metastasis 1 (Tiam1) is a specific nucleotide exchange factor (GEF) that can activate Rho-like GTPase and Rac1 and regulate various cellular processes, including cell cycle progression and cell migration. The roles of Tiam1 in vascular intimal hyperplasia, especially in vascular smooth muscle cell proliferation and migration, are not fully understood. In this study, we investigated the effect of Tiam1 on vascular intimal hyperplasia in a carotid artery ligation model and human aortic smooth muscle cells (HASMCs). We found that the expression of Tiam1 was up-regulated in the neointima of carotid artery ligation mice and that Tiam1-/- mice following carotid artery ligation had less neointimal formation compared with wild type mice. Knockdown of Tiam1 by siRNA markedly attenuated PDGF-induced migration and proliferation in HASMCs by inhibiting the activation of Rac1. Therefore, these results suggest that Tiam1 is an important regulator of intima hyperplasia. It may regulate vascular intimal hyperplasia through the activation of Rac1.

Potential upstream lncRNA-miRNA-mRNA regulatory network of the ferroptosis-related gene SLC7A11 in renal cell carcinoma.

Background: SLC7A11 is a key regulator of ferroptosis, which mediates cysteine uptake for glutathione biosynthesis and maintains redox homeostasis. Emerging evidence has shown that SLC7A11 is upregulated in many human tumors. Nevertheless, the prognosis and posttranslational regulatory mechanism of SLC7A11 in renal cell carcinoma (RCC) remains obscure. Methods: The Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), and The Cancer Genome Atlas (TCGA) databases were used to analyze the difference in SLC7A11 expression between malignant and normal tissues. Furthermore, the GEPIA, the University of ALabama at Birmingham CANcer data analysis Portal (UALCAN), and starBase databases were used to conduct the survival analyses. For correlation analysis, the UALCAN and starBase databases were employed. The Tumor Immune Estimation Resource (TIMER) database was used to approximate the abundance of immune infiltration. Results: We confirmed that SLC7A11 was upregulated in most human cancers, including 3 types of RCC. SLC7A11 overexpression was linked to poor prognosis of individuals with kidney renal clear cell carcinoma (KIRC), kidney chromophobe cell carcinoma (KICH), and kidney renal papillary cell carcinoma (KIRP). SLC7A11 expression was also linked to immune cell infiltration levels. After performing a comprehensive analysis of the regulatory mechanisms of SLC7A11 expression, the results depicted a potential noncoding (ncRNA)-messenger RNA (mRNA) axis, incorporating SNHG6-miR-26a-5p-SLC7A11 networks in KICH, CASC19/CYTOR/LINC00997-miR-27b-3pSLC7A11 networks in KIRC, and CASC19/CYTOR/PVT1-miR27b-3p-SLC7A11 networks in KIRP as partially responsible for the functions of SLC7A11 in RCC. SLC7A11 expression was positively linked to infiltrated immune cells and their matching marker sets in 3 types of RCC, including CD8+ and myeloid dendritic cells. Conclusions: Our research elucidated the crucial functions and the upstream long noncoding RNA (lncRNA)-microRNA (miRNA) regulatory network of SLC7A11 in RCC. Importantly, SLC7A11 can be used as a potential prognostic biomarker for 3 types of RCC and to determine the infiltration of immune cells in malignant tissues.

miR-145-5p Inhibits Neuroendocrine Differentiation and Tumor Growth by Regulating the SOX11/MYCN Axis in Prostate cancer.

Recent studies have shown that the downregulation of miR-145-5p in prostate cancer (PCa) is significantly associated with poor differentiation and prognosis. We aimed to investigate the biological role of miR-145-5p in the neuroendocrine differentiation (NED) of PCa. In this study, TheCancer Genome Atlas was used to identify the association of miR-145-5p with PCa. The functions of miR-145-5p were evaluated using the Cell Counting Kit-8 (CCK-8) assay and cell cycle analysis. We validated changes in cell cycle control by testing the expression of cyclin-related genes by western blot. The luciferase reporter assay was performed to test miR-145-5p-targeting genes and direct transcriptional targets of SOX11. The expression of miR-145-5p was found to be significantly downregulated in castration-resistant PCa, and this was correlated with higher Gleason score and prostate-specific antigen. We confirmed these results using PC3 and LNCaP cell lines depicted a gradual decline of miR-145-5p while the cells were cultured under androgen depletion conditions. Moreover, the knockdown of miR-145-5p significantly promoted NED and proliferation of LNCaP cells, whereas overexpression of miR-145-5p significantly inhibited NED and proliferation of LNCaP cells. Mechanistically, we found that SOX11 was a direct target of miR-145-5p, which regulates MYCN might mediate induction of NED and proliferation of LNCaP cells. Furthermore, knockdown of miR-145-5p promoted tumor growth in vivo. Our findings suggest that miR-145-5p can inhibit NED and tumor growth by targeting SOX11, which regulates the expression of MYCN, and that this could be a novel therapeutic strategy for preventing the progression of PCa.

Prognostic value of plasma adipokine chemerin in patients with coronary artery disease.

Background: Adipokine chemerin was proven to be associated with coronary artery disease (CAD), but its prognostic implications in CAD remain unclear. Methods: This study consists of two parts, one is a basic study and the other is a clinical cohort study. First, we investigated the differential expression of six adipokines in the atherosclerotic mice model compared to mice with milder degrees of atherosclerosis and mice without atherosclerosis using microarray data. We then examined the potential of chemerin as a diagnostic and prognostic indicator in a CAD cohort. A total of 152 patients were enrolled in our study, including 77 patients with angiographically proven CAD and 75 control subjects without cardiovascular disease. Plasma adipokine chemerin levels were measured in all patients, and major adverse cardiovascular events (MACEs) were followed up, including ischemic stroke, non-fatal myocardial infarction, revascularization, and cardiovascular death. Results: In the aortas of atherosclerotic mice, chemerin expression was up-regulated compared to control mice. The plasma chemerin levels of CAD patients were higher than those of non-CAD patients (128.93 ± 37.06 vs. 109.85 ± 27.47 mmol/L, respectively, P < 0.001). High chemerin levels were an independent predictor of CAD (ß = 2.702, 95% CI, 1.344-5.431, P = 0.001). We followed up with patients for a median duration of 5.5 years (3.9-5.6). The Kaplan-Meier curves showed that patients in the high chemerin group had a significantly higher risk of MACEs than the low chemerin group in patients with CAD (log-rank P = 0.003), not with non-CAD (Log-rank P = 0.120). Furthermore, Cox multivariate analysis revealed that high chemerin levels were an independent predictor of MACEs (HR 2.267; 95% CI, 1.139-4.515; P = 0.020). Finally, the cellular study showed that chemerin is predominantly expressed in PBMC-derived macrophages. Conclusion: Plasma chemerin levels were increased in the CAD patients, and a high chemerin level increased the risk of MACEs in CAD patients.

Plasma vaspin is an effective biomarker for evaluation of future cardiovascular events in patients with chest pain: a 5-year retrospective observational study.

BACKGROUND: Our previous study showed that visceral adipose tissue-derived serpin (vaspin) was an independent predictor of coronary artery disease (CAD). Further, plasma vaspin levels in patients with unstable angina pectoris were lower than those in patients with stable angina pectoris. In this study, we investigated the prognostic relevance of plasma vaspin levels in patients with CAD and non-CAD. METHODS: It was a retrospective observational study. A total of 197 patients with chest pain were enrolled, of which 88 patients with CAD and 109 patients with non-CAD were confirmed by angiography. Plasma vaspin levels and clinical parameters were measured at baseline. Incidence of major adverse cardiac event (MACE) was determined on follow-up. RESULTS: One hundred eighty-nine patients were successfully followed up for 5 years, of which 63 patients experienced MACEs. Patients with low vaspin levels (<0.385 ng/mL) experienced a higher incidence of MACE as compared to patients with high vaspin levels (>0.385 ng/mL) (42.55% vs. 24.21%, respectively; P=0.007). In both CAD and non-CAD groups, patients with high vaspin levels showed improvement in left ventricular ejection fraction. Kaplan Meier survival curves showed that patients with low vaspin levels had an obviously higher timing of incidence of MACE in the whole population (P=0.006) and in the non-CAD subgroup (P=0.009); however, the trend was not significant in the CAD subgroup. On multivariate analyses, plasma vaspin level was found to be an independent predictor of MACE, particularly in the non-CAD group. CONCLUSIONS: Plasma vaspin may be a useful biomarker for prediction of MACE in patients with chest pain.

Increased plasma microfibrillar-associated protein 4 is associated with atrial fibrillation and more advanced left atrial remodelling.

INTRODUCTION: This study aimed to evaluate the relationship of plasma microfibrillar-associated protein 4 (MFAP4) to atrial fibrillation (AF) and atrial structural remodelling. MATERIAL AND METHODS: Plasma MFAP4 levels were measured in 92 patients with AF (61 paroxysmal AF (PAF) patients and 31 persistent AF (PersAF) patients) and 71 control subjects without AF. Linear and logistic multivariate regression analyses were performed to determine the potential value of MFAP4 for predicting the incidence of AF and left atrial size. Then, plasma and atrial protein levels of MFAP4 and its association with atrial fibrosis ratio were analysed in an atrial-specific fibrosis rat model. RESULTS: There were significant differences in MFAP4 levels based on clinical group, with a gradient from control (1.71 ±0.53 ng/ml) to PAF (1.98 ±0.53 ng/ml) to PersAF (2.09 ±0.76 ng/ml) (p < 0.01). With multivariate analyses, plasma MFAP4 was found to be an independent determinant of left atrial diameter in AF patients. In atrial fibrosis rats, both plasma MFAP4 and atrial MFAP4 protein levels increased in atrial fibrosis rats and positively correlated with atrial fibrosis severity. CONCLUSIONS: Plasma MFAP4 was increased in patients with AF and was highest in those with PersAF; both plasma MFAP4 and atrial MFAP4 protein expression were directly associated with the extent of LA structural remodelling.