NOSH‐aspirin (NBS‐1120), a novel nitric oxide and hydrogen sulfide releasing hybrid,attenuates neuroinflammation induced by microglial and astrocytic activation: A new candidate for treatment of neurodegenerative disorders

Hydrogen sulfide (H₂S) and nitric oxide (NO) have been described as gasotransmitters. Anti‐inflammatory activity in the central and peripheral nervous systems may be one of their functions. Previously we demonstrated that several SH^‐ donors including H₂S‐releasing aspirin (S‐ASA) exhibited anti‐inflammatory and neuroprotective activity in vitro against toxins released by activated microglia and astrocytes. Here we report that NOSH‐ASA, an NO‐ and H₂S‐releasing hybrid of aspirin, has a significantly greater anti‐inflammatory and neuroprotective effect than S‐ASA or NO‐ASA. When activated by LPS/IFNγ, human microglia and THP‐1 cells release materials that are toxic to differentiated SH‐SY5Y cells. These phenomena also occur with IFNγ‐stimulated human astroglia and U373 cells. When the cells were treated with the S‐ASA or NO‐ASA, there was a significant enhancement of neuroprotection. However, NOSH‐ASA had significantly more potent protection properties than NO‐ASA or S‐ASA. The effect was concentration‐dependent, as well as incubation time‐dependent. Such treatment not only reduced the release of the TNFα and IL‐6, but also attenuated activation of P38 MAPK and NFκB proteins. All the compounds tested were not harmful when applied directly to SH‐SY5Y cells. These data suggest that NOSH‐ASA has significant anti‐inflammatory properties and may be a new candidate for treating neurodegenerative disorders that have a prominent neuroinflammatory component such as Alzheimer disease and Parkinson disease. GLIA 2013;61:1724–1734     

评价VSX1突变与圆锥角膜合并角膜颗粒状营养不良在伊朗家族中的关联

目的:为了评估视觉系统同源框1(VSX1)基因的突变和圆锥角膜(KCN)以及颗粒状角膜营养不良(GCD)之间的关联.方法:对一个同时患有KCN和GCD的四代伊朗人家系进行了直接测序,鉴别出一个包含四代人同时患有GCD的伊朗KCN家系.从全血样品中提取基因组DNA.然后,为了研究KCN和GCD之间可能的连锁关系,通过PCR在每个样品中扩增VSX1基因的整个编码区和内含子-外显子边界.随后,对PCR产物进行直接测序,并在患者和对照组中进行突变分析.结果:VSX1基因突变分析未发现KCN和GCD疾病与VSX1基因相关的证据.我们的数据排除了VSX1作为该特定家系中KCN / GCD致病基因的可能性.结论:尽管患有GCD的KCN患者与VSX1基因变异无关联,但是仍需要对其它可能与KCN合并GCD发病机制相关的基因进行研究.     

圆锥角膜基质环植入手术前后人工晶状体度数的比较

目的:评估圆锥角膜基质环(keraring 355°)(ICRS)植入术前术后3mo人工晶状体(IOL)度数的计算和生物学特征.方法:队列研究.收集18例(19眼)圆锥角膜接受角膜基质环植入术患者术前及术后3mo数据.分析裸眼视力(UCVA), 最佳矫正视力(BCVA),屈光度,人工晶体度数计算公式,眼轴长度(AL)和角膜曲率.结果:患者平均年龄为29.58±0.6y.裸眼视力由0.84(0.35) LogMAR 显著提高到0.43 (0.31) LogMAR (P<0.001).3mo后,最佳矫正视力和眼轴长度无明显变化.球镜度数,柱镜度数和等效球镜(SE)均显著提高 (P<0.001).另一方面,角膜曲率1(K1)和角膜曲率2(K2)显著下降.3mo后, SRK/II (P<0.001), Hoffer Q (P<0.001) and Holladay I (P<0.001)发生显著变化.结论:角膜基质环植入术后,视力,屈光率和角膜曲率均有所提高,此外,人工晶状体计算公式度数明显改变.然而,角膜基质环植入术过程没有过度干预眼轴长,但降低角膜曲率值使得人工晶状体度数计算更加精确,所有公式得出同一晶状体度数.     

Pediatric reference intervals for lymphocyte vitamin C (ascorbic acid)

ObjectiveTo establish pediatric reference intervals for lymphocyte vitamin C.Design and methodsThis was a prospective study of 194 well children aged 0–7 years old of mixed ethnicity who had blood drawn for the purpose of this study. Blood was collected during elective surgery under general anesthesia and lymphocytes isolated and stored as frozen ascorbic acid lymphocyte lysates for later HPLC analysis by previously described methodology. Reference intervals were established according to the Clinical and Laboratory Standards Institute (CLSI) and the International Federation of Clinical Chemistry (IFCC) guidelines (C28-A3). Horn–Pesce robust method was used to estimate the 95% confidence interval and 95% reference interval.ResultsReference intervals were independent of age or gender and shown to be 12.9–52.8 μg/10⁸ cells (lymphocytes).ConclusionWe have defined pediatric reference ranges for lymphocyte vitamin C in healthy, fasted children at a relevant age group (0–7 years). The new reference interval can now be used to more reliably explore possible implications of variation of vitamin C levels on bleeding and other clinical signs.     

NO-releasing NSAIDs suppress NF-κB signaling in vitro and in vivo through S-nitrosylation

NO-NSAIDs are promising anticancer drugs, comprising an NSAID, an NO-releasing moiety, and a spacer linking them. Although the effect of NO-NSAIDs on a wide variety of signaling and other cellular mechanisms has been deciphered, a key question remains unanswered, that being the role of NO to the overall biological effect of these agents. It has been shown that NO can directly modify sulfhydryl residues of proteins through S-nitrosylation and induce apoptosis. We studied 3 NO-NSAIDs having a different NSAID, spacer, and NO-releasing moiety. In vitro: aspirin, NO-ASA, naproxen, and NO-naproxen inhibited HT-29 human colon cancer cell growth, the IC₅₀s being >5000, 192 ± 6, 2800 ± 210 and 95 ± 5 μM at 24 h, respectively. NO-Aspirin and NO-naproxen reduced NF-κB protein levels, and activated caspase-3 enzyme in a dose- and time-dependent manner. Based on the biotin switch assay, NO-ASA and NO-naproxen S-nitrosylated NF-κB p65 in a time-dependent manner. Pretreatment of the cells with carboxy-PTIO, abrogated the S-nitrosylation of NF-κB p65. In vivo: rats treated with NO-ASA, NONO-ASA, and NO-naproxen showed S-nitrosylation of NF-κB p65 in the stomach tissue, increases in plasma TNF-α, and reductions in mucosal PGE₂ levels. These data provide a mechanistic role for NO and a rational for the chemopreventive effects of NO-NSAIDs.     

Muscarinic cholinergic receptor subtypes in cerebral cortex of Fisher 344 rats: a light microscope autoradiography study of age-related changes

The density and localization of muscarinic cholinergic M1-M5 receptor subtypes was investigated in frontal and occipital cortex of male Fisher 344 rats aged 6 months (young-adult), 15 months (mature) and 22 months (senescent) by combined kinetic and equilibrium binding and light microscope autoradiography. In 6-month-old rats, the rank order density of muscarinic cholinergic receptor subtypes was M1>M2>M4>M3>M5 both in frontal and occipital cortex. A not homogeneous distribution of different receptor subtypes throughout cerebrocortical layers of frontal or occipital cortex was found. In frontal cortex silver grains corresponding to the M1 and M2 receptor subtypes were decreased in 15- and 22-month-old groups. The M3 receptor density was remarkably and moderately decreased in layers II/III and V, respectively, of rats aged 15 and 22 months. A reduced M4 receptor density was observed in layer I and to a lesser extent in layer V of mature and senescent rats, whereas no age-related changes of M5 receptor were found. In occipital cortex a diminution of M1 receptor was observed in layers II/III and V of mature and senescent rats. The M2 receptor expression decreased in layer I of 15- and 22-month-old senescent rats, whereas M3-M5 receptors were unchanged with exception of a slight decrease of the M4 receptor in layer IV and of M5 receptor in layers II/III. These findings indicate a different sensitivity to aging of muscarinic receptor subtypes located in various cerebrocortical layers. This may account for the difficulty in obtaining relevant results in manipulating cholinoceptors to counter age-related impairment of cholinergic system.     

Gap analysis of pediatric reference intervals for risk biomarkers of cardiovascular disease and the metabolic syndrome

The childhood obesity epidemic has begun to compromise the health of the pediatric population by promoting premature development of atherosclerosis and the metabolic syndrome (MS), both of which significantly increase the risk of cardiovascular disease (CVD) early in life. As a result, recently, there has been increased recognition of the need to assess and closely monitor children and adolescents for risk factors of CVD and components of the MS. Serum/Plasma biomarkers including total cholesterol, triglycerides, HDL-C, LDL-C, insulin and C-peptide have been used for this purpose for many years. Recently, emerging biomarkers such as apolipoprotein AI, apolipoprotein B, leptin, adiponectin, free fatty acids, and ghrelin have been proposed as tools that provide valuable complementary information to that obtained from traditional biomarkers, if not more powerful predictions of risk. In order for biomarkers to be clinically useful in accurately diagnosing and treating disorders, age-specific reference intervals that account for differences in gender, pubertal stage, and ethnic origin are a necessity. Unfortunately, to date, many critical gaps exist in the reference interval database of most of the biomarkers that have been identified. This review contains a comprehensive gap analysis of the reference intervals for emerging and traditional risk biomarkers of CVD and the MS and discusses the clinical significance and analytical considerations of each biomarker.