Targeting purinergic receptors to attenuate inflammation of dry eye.

Inflammation is one of the potential factors to cause the damage of ocular surface in dry eye disease (DED). Increasing evidence indicated that purinergic A1, A2A, A3, P2X4, P2X7, P2Y1, P2Y2, and P2Y4 receptors play an important role in the regulation of inflammation in DED: A1 adenosine receptor (A1R) is a systemic pro-inflammatory factor; A2AR is involved in the activation of the MAPK/NF-kB pathway; A3R combined with inhibition of adenylate cyclase and regulation of the mitogen-activated protein kinase (MAPK) pathway leads to regulation of transcription; P2X4 promotes receptor-associated activation of pro-inflammatory cytokines and inflammatory vesicles; P2X7 promotes inflammasome activation and release of pro-inflammatory cytokines IL-1ß and IL-18; P2Y receptors affect the phospholipase C(PLC)/IP3/Ca2+ signaling pathway and mucin secretion. These suggested that purinergic receptors would be promising targets to control the inflammation of DED in the future.

Potential mechanisms of macular degeneration protection by fatty fish consumption.

Age-related macular degeneration (AMD) is a progressive retinal disease that is a leading cause of visual impairment and severe vision loss. The number of people affected by AMD is increasing and constitutes a huge worldwide health problem. The beneficial effects of fish consumption on AMD have been revealed over the past decades, and in this review, we summarizes the beneficial effects of fatty fish on AMD and its mechanism of action. Fatty fish affects the development of AMD by inhibiting neovascularization, interacting with retinal pigment epithelial (RPE) cells, displacing Omega-6, and inducing cellular responses. It is recommended that people at high risk or with moderate or more severe AMD should consider eating more fatty fish in addition to maintaining a healthy lifestyle of weight control and smoking cessation and the need to promote new models of personalized AMD prevention and treatment.

ATP and Adenosine in the Retina and Retinal Diseases.

Extracellular ATP and its ultimate degradation product adenosine are potent extracellular signaling molecules that elicit a variety of pathophysiological pathways in retina through the activation of P2 and P1 purinoceptors, respectively. Excessive build-up of extracellular ATP accelerates pathologic responses in retinal diseases, whereas accumulation of adenosine protects retinal cells against degeneration or inflammation. This mini-review focuses on the roles of ATP and adenosine in three types of blinding diseases including age-related macular degeneration (AMD), glaucoma, and diabetic retinopathy (DR). Several agonists and antagonists of ATP receptors and adenosine receptors (ARs) have been developed for the potential treatment of glaucoma, DR and AMD: antagonists of P2X7 receptor (P2X7R) (BBG, MRS2540) prevent ATP-induced neuronal apoptosis in glaucoma, DR, and AMD; A1 receptor (A1R) agonists (INO-8875) lower intraocular pressure in glaucoma; A2A receptor (A2AR) agonists (CGS21680) or antagonists (SCH58261, ZM241385) reduce neuroinflammation in glaucoma, DR, and AMD; A3 receptor (A3R) agonists (2-Cl-lB-MECA, MRS3558) protect retinal ganglion cells (RGCs) from apoptosis in glaucoma.

Sodium Ferulate Protects against Angiotensin II-Induced Cardiac Hypertrophy in Mice by Regulating the MAPK/ERK and JNK Pathways.

Background and Objective. It has been reported that sodium ferulate (SF) has hematopoietic function against anemia and immune regulation, inflammatory reaction inhibition, inhibition of tumor cell proliferation, cardiovascular and cerebrovascular protection, and other functions. Thus, this study aimed to investigate the effects of SF on angiotensin II- (AngII-) induced cardiac hypertrophy in mice through the MAPK/ERK and JNK signaling pathways. Methods. Seventy-two male C57BL/6J mice were selected and divided into 6 groups: control group, PBS group, model group (AngII), model + low-dose SF group (AngII + 10 mg/kg SF), model + high-dose SF group (AngII + 40 mg/kg SF), and model + high-dose SF + agonist group (AngII + 40 mg/kg SCU + 10 mg/kg TBHQ). After 7 d/14 d/28 days of treatments, the changes of blood pressure and heart rates of mice were compared. The morphology of myocardial tissue and the apoptosis rate of myocardial cells were observed. The mRNA and protein expressions of atrial natriuretic peptide (ANP), transforming growth factor-ß (TGF-ß), collagen III (Col III), and MAPK/ERK and JNK pathway-related proteins were detected after 28 days of treatments. Results. SF improved the mice's cardiac abnormality and decreased the apoptosis rate of myocardial cells in a time- and dose-dependent manner (all P < 0.05). MAPK/ERK pathway activator inhibited the protective effect of SF in myocardial tissue of mice (P < 0.05). SF could inhibit the expression of p-ERK, p-p38MAPK, and p-JNK and regulate the expressions of ANP, TGF-ß, and Col III (all P < 0.05). Conclusion. Our findings provide evidence that SF could protect against AngII-induced cardiac hypertrophy in mice by downregulating the MAPK/ERK and JNK pathways.

Prognostic significance of TBX2 expression in non-small cell lung cancer.

T-box2 (TBX2) expression has been reported to be related to aggressive tumor features. However, the role of TBX2 in non-small-cell lung cancer (NSCLC) tumorigenesis has never been elucidated. So we aimed at investigating the potential role of TBX2 in NSCLC. TBX2 expression was evaluated by qRT-PCR and Western blotting in 50 paired fresh lung cancer tissues as well as immunohistochemistry on 212 paraffin-embedded sections. We showed that the expression level of TBX2 was significantly increased in NSCLC as compared with the adjacent noncancerous tissue. Positive expression level of TBX2 was associated with histological type, lymph node metastasis and distant metastasis. Kaplan-Meier survival curves showed that positive expression level of TBX2 was associated with poor overall survival (OS) and progression-free survival of NSCLC patients. Results showed that TBX2 positivity was an independent prognostic factor for OS (HR 1.87, 95% CI 1.004-3.153, p = 0.012). On the basis of these results, we suggested that TBX2 protein expression may be an unfavorable independent prognostic parameter for NSCLC.

Mechanical stretch modulates microRNA 21 expression, participating in proliferation and apoptosis in cultured human aortic smooth muscle cells.

OBJECTIVES: Stretch affects vascular smooth muscle cell proliferation and apoptosis, and several responsible genes have been proposed. We tested whether the expression of microRNA 21 (miR-21) is modulated by stretch and is involved in stretch-induced proliferation and apoptosis of human aortic smooth muscle cells (HASMCs). METHODS AND RESULTS: RT-PCR revealed that elevated stretch (16% elongation, 1 Hz) increased miR-21 expression in cultured HASMCs, and moderate stretch (10% elongation, 1 Hz) decreased the expression. BrdU incorporation assay and cell counting showed miR-21 involved in the proliferation of HASMCs mediated by stretch, likely by regulating the expression of p27 and phosphorylated retinoblastoma protein (p-Rb). FACS analysis revealed that the complex of miR-21 and programmed cell death protein 4 (PDCD4) participated in regulating apoptosis with stretch. Stretch increased the expression of primary miR-21 and pre-miR-21 in HASMCs. Electrophoretic mobility shift assay (EMSA) demonstrated that stretch increased NF-κB and AP-1 activities in HASMCs, and blockade of AP-1 activity by c-jun siRNA significantly suppressed stretch-induced miR-21 expression. CONCLUSIONS: Cyclic stretch modulates miR-21 expression in cultured HASMCs, and miR-21 plays important roles in regulating proliferation and apoptosis mediated by stretch. Stretch upregulates miR-21 expression at least in part at the transcription level and AP-1 is essential for stretch-induced miR-21 expression.

Intravascular ultrasound area strain imaging used to characterize tissue components and assess vulnerability of atherosclerotic plaques in a rabbit model.

The purpose of this study was to investigate the association of area strain and tissue components and vulnerability of atherosclerotic plaques in a rabbit model. Forty purebred New Zealand rabbits underwent balloon-induced abdominal aorta endothelium injury, then a high-cholesterol diet for 24 weeks. Intravascular ultrasound (IVUS) images of abdominal aortas were acquired in situ and two consecutive frames near the end-diastole were used to construct an IVUS elastogram. Histologic slices matched with corresponding IVUS images were stained for fatty and collagen components, smooth muscle cells (SMCs) and macrophages. Regions-of-interest (ROIs) in plaques were classified as fibrous, fibro-fatty or fatty according to histologic study. Vulnerability indexes of ROIs were calculated as (fat + macrophage)/(collagen + SMCs). The area strain of these ROIs was calculated by use of an in-house-designed software system with a block-matching-based algorithm. Area strain was significantly higher in fatty ROIs (0.056 ± 0.003) than in fibrous (0.019 ± 0.002, p < 0.001) or fibro-fatty ROIs (0.033 ± 0.003, p < 0.001). The sensitivity and specificity of area strain for fatty ROIs characterization was 75.0% and 80.2% (area under the curve [AUC] 0.858, 95% confidence interval [CI] = 0.800-0.916, p < 0.001) and 75.0% and 75.3% (AUC 0.859, 95% CI = 0.801-0.917, p < 0.001) for fibrous ROIs, as demonstrated by receiver operating characteristic curve analysis. Area strain was positively correlated with vulnerability index (r(2) = 0.495, p < 0.001), fatty components (r(2) = 0.332, p < 0.001) and macrophage infiltration (r(2) = 0.406, p < 0.001); and negatively correlated with collagen and SMC composition (r(2) = 0.115 and r(2) = 0.169, p < 0.001, respectively). Area strain calculation with IVUS elastography based on digital B-mode analysis is feasible and can be useful for tissue characterization and plaque vulnerability assessment.