We demonstrate here that functional NMDAR1 receptors and NMDAR2 receptors are expressed by Mcf-7 and SKBR3 breast cancer cell lines, and possibly by most or all high-grade breast tumors, and that these receptors are important for the growth of human breast cancer xenografts in mice. RT-PCR demonstrated mRNA for both NMDAR1 and NMDAR2 receptors are expressed in both Mcf-7 and SKBR3 cell lines, and these messages likely have sequences identical to those reported for human mRNAs. Proteins of the expected respective sizes 120 and 170 KD are generated from these mRNAs by the tumor cells. Cell growth was found to be significantly (p<0.0001) impaired down to 10% of normal growth by the irreversible NMDAR1 antagonists MK-801 and memantine with IC 50s ranging from 600–>800 μM and from 200–300 μM for the two lines. Paradoxically, memantine with a lower binding affinity had the greater influence of the two inhibitors on cell viability. Immunohistochemical examination of high-grade invasive ductal and lobular breast cancer with our polyclonal antibodies against a peptide (-Met-Ser-Ile-Tyr-Ser-Asp-Lys-Ser-Ile-His-) in the extracellular domain of the NMDAR1 receptor gave specific positive staining for the receptor in all 10 cases examined. Positive staining was chiefly concentrated at the membranes of these tumor tissues. No staining with these antibodies was found for normal breast and kidney tissues. When Mcf-7 cells were grown as tumor xenografts in nu/nu mice, the growth of these tumors was completely arrested by daily treatments with MK-801 over five days. All of these data point to active NMDAR receptors being expressed by most breast cancers, and having an important influence on their survival.

Currently published studies have implicated that microRNAs (miRNAs) including exosomes-encapsulated miRNAs play a critical role in rheumatoid arthritis (RA). Previously, we have found that exosomes-encapsulated miR-548a-3p was significantly decreased in serum samples from RA patients by miRNAs microarray analysis. However, little is known of the role of miR-548a-3p in the development and progression of RA. In this study, we aim to investigate the underlying molecular mechanisms of miR-548a-3p in RA, which will provide new insight into understanding the pathogenesis of RA and identifying novel therapeutics targets for this disease. As validated by quantitative real-time polymerase chain reaction (qRT-PCR), the expression of miR-548a-3p in serum exosomes and peripheral blood mononuclear cells (PBMCs) of RA patients (n = 76) was obviously down-regulated compared with healthy controls (n = 20). Serum exosomal miR-548a-3p was negatively associated with levels of CRP, RF, and ESR in serum of patients with RA. MiR-548a-3p could inhibit the proliferation and activation of pTHP-1 cells by regulating the TLR4/NF-κB signaling pathway. Accordingly, exosomes-delivered miR-548a-3p may be a critical factor predicting the disease activity of RA. MiR-548a-3p/TLR4/NF-κB axis can serve as promising targets for RA diagnosis and treatment.

We performed a systematic review of genome-wide gene expression datasets to identify key genes and functional modules involved in the pathogenesis of systemic lupus erythematosus (SLE) at a systems level. Genome-wide gene expression datasets involving SLE patients were searched in Gene Expression Omnibus and ArrayExpress databases. Robust rank aggregation (RRA) analysis was used to integrate those public datasets and identify key genes associated with SLE. The weighted gene coexpression network analysis (WGCNA) was adapted to identify functional modules involved in SLE pathogenesis, and the gene ontology enrichment analysis was utilized to explore their functions. The aberrant expressions of several randomly selected key genes were further validated in SLE patients through quantitative real-time polymerase chain reaction. Fifteen genome-wide gene expression datasets were finally included, which involved a total of 1,778 SLE patients and 408 healthy controls. A large number of significantly upregulated or downregulated genes were identified through RRA analysis, and some of those genes were novel SLE gene signatures and their molecular roles in etiology of SLE remained vague. WGCNA further successfully identified six main functional modules involved in the pathogenesis of SLE. The most important functional module involved in SLE included 182 genes and mainly enriched in biological processes, including defense response to virus, interferon signaling pathway, and cytokine-mediated signaling pathway. This study identifies a number of key genes and functional coexpression modules involved in SLE, which provides deepening insights into the molecular mechanism of SLE at a systems level and also provides some promising therapeutic targets.

With inhibition or absence of the bradykinin B 2 receptor (B2R), B1R is upregulated and assumes some of the hemodynamic properties of B 2R, indicating that both participate in the maintenance of normal vasoregulation or to development of hypertension. Herein we further evaluate the role of bradykinin in normal blood pressure (BP) regulation and its relationship with other vasoactive factors by selectively blocking its receptors. Six groups of Wistar rats were treated for 3 wk: one control group with vehicle alone, one with concurrent administration of B 1R antagonist R-954 (70 g ⅐ kg Ϫ1 ⅐ day Ϫ1 ) and B2R antagonist HOE-140 (500 g ⅐ kg Ϫ1 ⅐ day Ϫ1 ), one with R-954 alone, one with HOE 140 alone, one with concurrent administration of both R-954 and HOE-140 plus the angiotensin antagonist losartan (5 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ), and one with only losartan. BP was measured continuously by radiotelemetry. Only combined administration of B 1R and B2R antagonists produced a significant BP increase from a baseline of 107-119 mmHg at end point, which could be partly prevented by losartan and was not associated with change in catecholamines, suggesting no involvement of the sympathoadrenal system. The impact of blockade of bradykinin on other vasoregulating systems was assessed by evaluating gene expression of different vasoactive factors. There was upregulation of the eNOS, AT1 receptor, PGE2 receptor, and tissue kallikrein genes in cardiac and renal tissues, more pronounced when both bradykinin receptors were blocked; significant downregulation of AT 2 receptor gene in renal tissues only; and no consistent changes in B 1R and B2R genes in either tissue. The results indicate that both B 1R and B2R contribute to the maintenance of normal BP, but one can compensate for inhibition of the other, and the chronic inhibition of both leads to significant upregulation in the genes of related vasoactive systems. bradykinin inhibition; angiotensin II; vasoactive factors; gene expression DESPITE A LARGE BODY OF LITERATURE on kinins, the role of bradykinin in normal blood pressure (BP) regulation and the specific functions mediated by its B 1 and B 2 type receptors are still insufficiently understood.It has long been accepted that under normal conditions the cardiovascular and renal effects of bradykinin are exerted via the B 2 receptors, which are constitutively abundant in cardiac, renal, and vascular tissues and act by activating the vasoactive components of the prostaglandin-NO cascade (34), whereas the B 1 receptors are inducible by stimuli such as tissue damage, bacterial lipopolysaccharides, etc., and are mostly involved in inflammatory and nociceptive reactions (35,28).Pharmacological experiments using selective antagonists of the B 2 receptor in normotensive rats have given contradictory results: whereas some demonstrated an acute or chronic increase in BP (7, 24), others failed to show change in normal BP (3, 23), although they did show exacerbation of salt-induced (25) or angiotensin-induced hypertension (26) during B 2 recepto...

Congenital and hereditary diseases constituted the major causes of low vision in the study population. Strategies that make good-quality rehabilitation services available, affordable and accessible, especially in developing countries, will have the greatest impact on visual impairment. In China, both urban and rural, the coverage of low vision services should be strengthened.

A meta-analysis was performed to evaluate the efficacy of methylprednisolone pulse therapy for Graves' ophthalmopathy. Eight studies involving 376 patients were included. A higher effective rate was found for patients treated with intravenous glucocorticoids (IVGC) over oral glucocorticoids (OGC) (risk ratio [RR] = 1.48; 95% confidence interval [CI] = 1.18− 1.86). The combined IVGC and orbital radiotherapy (OR) was markedly more effective than OGC+OR (RR = 1.40; 95% CI = 1.11−1.77). IVGC resulted in an obvious reduction of clinical activity score (CAS) compared with OGC, with a weighted mean difference (WMD) of 0.86 (95% CI = 0.53−1.18). The WMD for the reduction of the CAS between IVGC+OR and OGC+OR was 0.66 (95% CI = 0.30−1.02). IVGC is an effective treatment and cause fewer adverse events. Limiting the total cumulative dose of methylprednisolone, careful patient selection and monitoring the condition of patients during treatment are necessary.

We previously showed that functional N-methyl-D-aspartate (NMDA) receptors are expressed by human neuroblastoma cells. In this study we demonstrate functional NMDAR1 and NMDAR2 receptors are expressed by small-cell lung cancer (SCLC) classical cell lines NCI H146, NCI H345, and DMS 53, by variant cell line NCI H82, and by most SCLC tumors, and that these receptors are important for the growth of human SCLC tumor xenografts in mice. Reverse transcription-polymerase chain reaction demonstrated mRNA for both receptors, with sequences identical to those for human mRNAs, are expressed in all four cell lines, and these generated proteins of the expected sizes 120 and 170 kDa. Cell viability tests showed cell growth was significantly (P < 0.0001) impaired by NMDAR1 antagonists MK-801 and memantine. Ifenprodil and Ro25-6981, NMDAR2B antagonists at the polyamine site, also significantly (P < 0.001) inhibited the growth/survival of these cells. Alternatively, the glycine-binding antagonist, L701, 324, increased viability to 140% and 120% in NCI H345 and NCI H82 cells after 48 hours of incubation. Immunohistochemistry of SCLC tumors with our polyclonal antibodies gave specific positive staining for the NMDAR1 receptor in 8 of 10 tissues examined. Small amounts of these same antibodies significantly reduced the growth of NCI-H345 cells up to 25% (P < 0.001). When NCI H345 cells were grown as tumor xenografts in mice, the growth of these tumors was reduced by 60% (P < 0.001) by treatments with MK-801 over five days. All of these data point to active NMDAR receptors possibly having an important influence on SCLC growth and survival.

BackgroundLow vision, along with cataract, trachoma, onchocerciasis, childhood blindness and refractive error, is one of the priorities in the global initiative, VISION 2020-The Right to Sight. The purpose of this study was to characterize the traits of patients presenting at a low vision clinic in China.MethodsA retrospective study was conducted of the records of 299 patients who visited the Low Vision Clinic of Eye and ENT Hospital Affiliated to Fudan University from January 2009 to May 2014. Reviewed parameters included age, gender, education, occupation, cause of visual impairment and types of low vision aids (LVAs) dispensed.ResultsOf all the patients (193 male; aged from 3 to 96 years, with a mean of 29.74 ± 25.23 years), 43.48% experienced moderate visual impairment, 25.42% had severe visual impairment and 21.07% were blind. The four major causes of visual impairment were congenital cataract (14.38%), degenerative myopia (13.71%), juvenile macular degeneration (9.36%) and retinitis pigmentosa (9.36%). The most common causes of visual impairment were congenital cataract (22.67%) in 0-19-year-olds, retinitis pigmentosa (20.62%) in 20-59-year-olds, and age-related macular degeneration (36.54%) in the 60+ group. With the help of LVAs, a significant improvement of distance and/or near vision or visual field was observed in 243 patients, of whom 185 accepted LVAs and 58 patients refused due to high price, inconvenience, young age (≤6 y), clumsy appearance and ignorance. The most commonly dispensed LVAs were stand magnifiers (21.57%) followed by spectacle-type LVAs (19.21%).ConclusionsThe majority of the patients in our low vision clinic were young, the main causes of visual impairment were congenital and hereditary diseases. Stand magnifiers were the most commonly dispensed LVAs. High price was the major reason for refusing LVAs.