BACKGROUND & AIMS: :Increased ammonia accumulation in the brain due to liver dysfunction is a major contributor to the pathogenesis of hepatic encephalopathy (HE). Fatal outcome of rapidly progressing (acute) HE is mainly related to cytotoxic brain edema associated with astrocytic swelling. An increase of brain ammonia in experimental animals or treatment of cultured astrocytes with ammonia generates reactive oxygen and nitrogen species in the target tissues, leading to oxidative/nitrosative stress (ONS). In cultured astrocytes, ammonia-induced ONS is invariably associated with the increase of the astrocytic cell volume. Interrelated mechanisms underlying this response include increased nitric oxide (NO) synthesis which is partly coupled to the activation of NMDA receptors and increased generation of reactive oxygen species by NADPH oxidase. ONS and astrocytic swelling are further augmented by excessive synthesis of glutamine (Gln) which impairs mitochondrial function following its accumulation in there and degradation back to ammonia ("the Trojan horse" hypothesis). Ammonia also induces ONS in other cell types of the CNS: neurons, microglia and the brain capillary endothelial cells (BCEC). ONS in microglia contributes to the central inflammatory response, while its metabolic and pathophysiological consequences in the BCEC evolve to the vasogenic brain edema associated with HE. Ammonia-induced ONS results in the oxidation of mRNA and nitration/nitrosylation of proteins which impact intracellular metabolism and potentiate the neurotoxic effects. Simultaneously, ammonia facilitates the antioxidant response of the brain, by activating astrocytic transport and export of glutathione, in this way increasing the availability of precursors of neuronal glutathione synthesis.

背景与目标： : 由于肝功能障碍，大脑中氨积累的增加是肝性脑病 (HE) 发病机理的主要原因。快速进展 (急性) HE的致命结果主要与星形细胞肿胀相关的细胞毒性脑水肿有关。实验动物中脑氨的增加或用氨处理培养的星形胶质细胞会在目标组织中产生活性氧和氮，从而导致氧化/亚硝化应激 (ONS)。在培养的星形胶质细胞中，氨诱导的ONS总是与星形细胞体积的增加有关。此响应的相关机制包括增加的一氧化氮 (NO) 合成，这部分与NMDA受体的激活以及NADPH氧化酶增加的活性氧生成有关。谷氨酰胺 (Gln) 的过度合成进一步加剧了ONS和星形细胞的肿胀，谷氨酰胺 (Gln) 在其中积累并降解回氨后会损害线粒体功能 (“特洛伊木马” 假说)。氨还在中枢神经系统的其他细胞类型中诱导ONS: 神经元，小胶质细胞和脑毛细血管内皮细胞 (BCEC)。小胶质细胞中的ONS有助于中枢炎症反应，而其在BCEC中的代谢和病理生理后果则演变为与HE相关的血管源性脑水肿。氨诱导的ONS导致mRNA的氧化和蛋白质的硝化/亚硝基化，从而影响细胞内代谢并增强神经毒性作用。同时，氨通过激活星形细胞的运输和谷胱甘肽的出口来促进大脑的抗氧化反应，从而增加了神经元谷胱甘肽合成前体的可用性。

BACKGROUND & AIMS: BACKGROUND:Diabetes mellitus (DM) is associated with hyperglycemia, inflammatory disorders and abnormal lipid profiles, currently the extracts from leaves of cynara scolymus has been discovered to treat metabolic disorders and has been stated by multitudinous scientists according to a good source of polyphenols compounds. The present study aimed to evaluate the protective effect of the ethanol leaves extract of C. scolymus in alloxan induced stress oxidant, hepatic-kidney dysfunction and histological changes in liver, kidney and pancreas of different experimental groups of rats. METHODS:We determinate the antioxidant activity by ABTS .+ and antioxidant total capacity (TAC) of all extracts of C. scolymus leaves, the inhibition of α-amylase activity in vitro was also investigated. Forty male Wistar rats were induced to diabetes with a single dose intraperitoneal injection (i.p.) of alloxan (150 mg/kg body weight (b.w.)). Diabetic rats were orally and daily administrated of ethanol extract from C. scolymus at two doses (200-400 mg/kg, b.w) or (12 mg/kg, b.w) with anti-diabetic reference drug, Acarbose for one month. Ethanol extract of C. scolymus effect was confirmed by biochemical analysis, antioxidant activity and histological study. RESULTS:The results indicated that the ethanol extract from leaves of C. scolymus showed the highest antioxidant activity by ABTS .+ (499.43g± 39.72 Trolox/g dry extract) and (128.75 ± 8.45 mg VC /g dry extract) for TAC and endowed the powerful inhibition in vitro of α-amylase activity with IC50=72,22 ug/uL. In vivo, the results showed that ethanol extract from the leaves of C. scolymus (200-400 mg/kg) decreased significantly (p < 0.001) the α-amylase levels in serum of diabetic rats, respectively associated with significant reduction (p < 0.001) in blood glucose rate of 42,84% and 37,91% compared to diabetic groups after 28 days of treatment, a significant lowered of plasma total cholesterol (T-Ch) by 18,11% and triglyceride (TG) by 60,47%, significantly and low-density lipoproteins (LDL-C) by 37,77%, compared to diabetic rats, moreover, the administration of ethanol extract appears to exert anti-oxidative activity demonstrated by the increase of CAT, SOD and GSH activities in liver, kidney and pancreas of diabetic rats. This positive effect of the ethanol extract from C. scolymus was confirmed by histological study. CONCLUSION:These observed strongly suggest that ethanol extract from the leaves of C. scolymus has anti-hyperglycemic properties, at least partly mediated by antioxidant and hypolipidemic effects.

背景与目标：

BACKGROUND & AIMS: :Rooibos leaves and fine stems (Aspalathus linearis; Fabaceae) are increasingly enjoyed as herbal tea, largely in fermented (oxidised) red-brown form, but also in unfermented (unoxidised) green form. Rooibos is rich in antioxidant polyphenols, with the dihydrochalcone, aspalathin, as a major active ingredient. We used Caenorhabditis elegans as model organism to investigate the effect of rooibos extracts against oxidative stress in vivo. In a high glucose environment, C. elegans treated with rooibos extract exhibited an extended lifespan. Furthermore, green rooibos was a more potent antioxidant than red rooibos, probably due to its substantially higher aspalathin content. In addition, rooibos decreased acute oxidative damage caused by the superoxide anion radical generator, juglone, with aspalathin playing a major role in improving the survival rate of C. elegans. Quantitative real-time PCR results demonstrated that aspalathin targets stress and ageing related genes, reducing the endogenous intracellular level of ROS. These findings suggest that rooibos increases stress resistance and promotes longevity under stress, probably mediated via a regulation of the DAF-16/FOXO insulin-like signalling pathway, supporting some of the health claims put forward for rooibos tea.

背景与目标： : Rooibos的叶子和细茎 (Aspalathus linearis; Fabaceae) 作为凉茶越来越受到欢迎，主要以发酵 (氧化) 的红棕色形式，但也以未发酵 (未氧化) 的绿色形式。Rooibos富含抗氧化剂多酚，其中二氢查耳酮，aspalathin是主要的活性成分。我们使用秀丽隐杆线虫作为模型生物，研究了rooibos提取物对体内氧化应激的影响。在高葡萄糖环境中，用rooibos提取物处理的秀丽隐杆线虫的寿命延长。此外，绿色rooibos是比红色rooibos更有效的抗氧化剂，这可能是由于其aspalathin含量高得多。此外，rooibos降低了由超氧阴离子自由基发生器juglone引起的急性氧化损伤，而aspalathin在提高秀丽隐杆线虫的存活率中起着重要作用。实时定量PCR结果表明，aspalathin靶向应激和衰老相关基因，降低了细胞内ROS的内源性水平。这些发现表明，rooibos可能通过调节DAF-16/FOXO胰岛素样信号通路介导，可以提高应激抵抗力并促进应激状态下的寿命，从而支持rooibos茶提出的一些健康要求。

BACKGROUND & AIMS: :Mitochondrial dysfunction is the most prominent source of oxidative stress in acute and chronic kidney disease. NLRX1 is a receptor of the innate immune system that is ubiquitously expressed and localized in mitochondria. We investigated whether NLRX1 may act at the interface of metabolism and innate immunity in a model of oxidative stress. Using a chimeric mouse model for renal ischemia-reperfusion injury, we found that NLRX1 protects against mortality, mitochondrial damage, and epithelial cell apoptosis in an oxidative stress-dependent fashion. We found that NLRX1 regulates oxidative phosphorylation and cell integrity, whereas loss of NLRX1 results in increased oxygen consumption, oxidative stress, and subsequently apoptosis in epithelial cells during ischemia-reperfusion injury. In line, we found that NLRX1 expression in human kidneys decreased during acute renal ischemic injury and acute cellular rejection. Although first implicated in immune regulation, we propose that NLRX1 function extends to the control of mitochondrial activity and prevention of oxidative stress and apoptosis in tissue injury.

背景与目标： : 线粒体功能障碍是急性和慢性肾脏疾病中氧化应激的最突出来源。NLRX1是先天免疫系统的受体，广泛表达并定位在线粒体中。我们研究了NLRX1是否可能在氧化应激模型中作用于代谢和先天免疫的界面。使用嵌合小鼠肾缺血再灌注损伤模型，我们发现NLRX1以氧化应激依赖性方式保护死亡率，线粒体损伤和上皮细胞凋亡。我们发现NLRX1调节氧化磷酸化和细胞完整性，而NLRX1的丢失会导致缺血再灌注损伤期间的耗氧量增加，氧化应激以及上皮细胞的凋亡。我们发现，在急性肾缺血损伤和急性细胞排斥反应期间，人肾脏中NLRX1的表达降低。尽管首先涉及免疫调节，但我们建议NLRX1功能扩展到控制线粒体活性以及预防组织损伤中的氧化应激和凋亡。

BACKGROUND & AIMS: :The present study utilized longitudinal data from a high-risk community sample (N = 377; 166 trauma-exposed; 202 males; 175 females; 73% non-Hispanic Caucasian) to test pretrauma measures of adolescent internalizing and externalizing symptoms as unique prospective predictors of type of trauma exposure and PTSD over and above the influence of correlated family adversity (a composite of family conflict, stress, and parental psychopathology). Data were analyzed with logistic and multinomial logistic regressions. Results indicated that females, but not males, with higher levels of internalizing (OR = 2.91) and externalizing (OR = 2.37) symptoms during adolescence were significantly more likely to be exposed to assaultive violence (over and above family adversity). In fact, males with higher levels of internalizing symptoms were significantly less likely to be exposed to assaultive violence (OR = 0.54). Neither internalizing nor externalizing symptoms uniquely predicted exposure to traumatic events that did not involve assaultive violence. Among trauma-exposed participants, the unique association between internalizing symptoms and later PTSD yielded an odds ratio of 1.79 (p = .07) over and above the influences of family adversity, type of trauma exposure, and gender. Assaultive violence exposure fully mediated the association between females' externalizing symptoms and future PTSD. Findings may help inform the prevention of both assaultive violence exposure and PTSD.

背景与目标： : 本研究利用了来自高风险社区样本的纵向数据 (N = 377; 166创伤暴露; 202男性; 175女性; 73% 非西班牙裔高加索人) 测试青少年内在化和外在化症状的创伤前措施，作为创伤暴露类型和创伤后应激障碍的独特前瞻性预测因子，超越相关家庭逆境 (家庭冲突、压力和父母心理病理学的组合) 的影响。数据采用logistic和多项logistic回归分析。结果表明，女性而不是男性，在青春期具有较高水平的内在化 (或 = 2.91) 和外在化 (或 = 2.37) 症状的女性更容易遭受攻击性暴力 (超过家庭逆境)。事实上，具有较高水平内化症状的男性暴露于攻击性暴力的可能性显著降低 (OR = 0.54)。内部化或外部化症状都不能唯一地预测暴露于不涉及攻击性暴力的创伤事件。在创伤暴露的参与者中，内在化症状与后来的PTSD之间的独特关联产生了1.79的优势比 (p = .07)，超出了家庭逆境，创伤暴露类型和性别的影响。攻击性暴力暴露充分介导了女性外在症状与未来创伤后应激障碍之间的关联。研究结果可能有助于预防攻击性暴力暴露和PTSD。

BACKGROUND & AIMS: :Evidence for the stress-buffering effects of social support in intimate relationships raises important questions about whether partner support promotes recovery in physiological systems implicated in physical health. The present study examined (a) whether observed dyadic coping enhances cortisol stress recovery and (b) whether a stressed partner's self-reported attachment anxiety and avoidance moderate these effects. Stress was experimentally induced by asking either the man or woman in 123 heterosexual couples to participate in a standardized public speaking task. Stressed individuals recovered faster from stress the more positive dyadic coping they received from the partner, with women high in attachment anxiety benefiting less from these behaviors. Attachment avoidance did not moderate these associations. This study highlights the value of examining the interplay between partners' behaviors and attachment orientations in order to understand the impact of stress on close relationships and partners' health.

背景与目标： : 亲密关系中社会支持的压力缓冲作用的证据提出了有关伴侣支持是否促进生理系统恢复与身体健康有关的重要问题。本研究检查了 (a) 观察到的二元应对是否会增强皮质醇压力恢复，以及 (b) 压力伴侣的自我报告的依恋焦虑和回避是否会减轻这些影响。通过要求123异性恋夫妇中的男人或女人参加标准化的公开演讲任务，实验性地引发了压力。压力大的人从伴侣那里得到的积极的二元应对能力会更快地从压力中恢复过来，而依恋焦虑的女性从这些行为中受益较少。避免依恋并没有缓和这些关联。这项研究强调了检查伴侣行为与依恋取向之间相互作用的价值，以了解压力对亲密关系和伴侣健康的影响。

BACKGROUND & AIMS: :This corrects the article DOI: 10.1038/ncomms15111.

背景与目标： : 这更正了文章DOI: 10.1038/ncomms15111。

BACKGROUND & AIMS: BACKGROUND:In the first population-based study of psychopathology conducted in Haiti, we documented earthquake-related experiences associated with risk for posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) 2-4 months following the 2010 Haiti earthquake. METHODS:A population-based survey was conducted of 1,323 survivors randomly selected from the general nondisplaced community, internally displaced persons camps, and a community clinic. Respondents were from the Nazon area of Port-au-Prince, ∼20 miles from the epicenter. RESULTS:Respondents (90.5%) reported at least one relative/close friend injured/killed, 93% saw dead bodies, and 20.9% lost their job post-earthquake. The prevalence of PTSD (24.6%) and MDD (28.3%) was high. History of violent trauma was associated with risk of PTSD and MDD (adjusted odds ratio [AOR] 1.4, 95% confidence interval [CI], 1.0-1.9; AOR, 1.7, 95% CI 1.3, 2.2, respectively). Low social support (AOR, 1.7, 95% CI 1.2, 2.3; AOR 1.4, 95% CI 1.0, 1.9, respectively) increased risk of PTSD and MDD among women. Suffering damage to the home increased risk of MDD in males (AOR 2.8, 95% CI 1.5, 5.5). Associations between being trapped in rubble, major damage to house, job loss, and PTSD; and participation in rescue/recovery, friends/family injured/killed, and MDD varied based on prior history of violent trauma. CONCLUSIONS:Addressing mental health in a post-earthquake setting such as Haiti will require focusing resources on screening and treatment of identified vulnerable groups while targeting improvement of post-earthquake living conditions. Investment in sources of social support for women may make help mitigate the vulnerability of women to PTSD and MDD.

背景与目标：

BACKGROUND & AIMS: :Sequestosome 1 (SQSTM1) also known as ubiquitin-binding protein p62 (p62) is a cargo protein involved in the degradation of misfolded proteins via selective autophagy. Disruption of autophagy and resulting accumulation of misfolded proteins in the endoplasmic reticulum (ER) leads to ER stress. ER stress is implicated in several neurodegenerative diseases and obesity. As knockout of p62 (p62KO) reportedly induces obesity in mice, we examined how p62 contributes to ER stress and the ensuing unfolded protein response (UPR) in hypothalamus using mouse organotypic cultures in the present study. Cultures from p62KO mice showed significantly reduced formation of LC3-GFP puncta, an index of autophagosome formation, in response to the chemical ER stressor thapsigargin compared to wild-type (WT) cultures. Hypothalamic cultures from p62KO mice exhibited higher basal expression of the UPR/ER stress markers CHOP mRNA and ATF4 mRNA than WT cultures. Thapsigargin enhanced CHOP, ATF4, and BiP mRNA as well as p-eIF2α protein expression in both WT and p62KO cultures, but all peak values were greater in p62KO cultures. A proteasome inhibitor increased p62 expression in WT cultures and upregulated the UPR/ER stress markers CHOP mRNA and ATF4 mRNA in both genotypes, but to a greater extent in p62KO cultures. Therefore, p62 deficiency disturbed autophagosome formation and enhanced both basal and chemically induced ER stress, suggesting that p62 serves to prevent ER stress in mouse hypothalamus by maintaining protein folding capacity.

背景与目标： : Sequestosome 1 (SQSTM1) 也称为泛素结合蛋白p62 (p62) 是一种通过选择性自噬参与错误折叠蛋白降解的货物蛋白。自噬的破坏和内质网 (ER) 中错误折叠的蛋白质的积累导致ER应激。ER应激与几种神经退行性疾病和肥胖症有关。据报道，由于p62 (p62KO) 的敲除会导致小鼠肥胖，因此我们在本研究中使用小鼠器官型培养物检查了p62如何促进下丘脑的内质网应激和随后的未折叠蛋白反应 (UPR)。与野生型 (WT) 培养物相比，来自p62KO小鼠的培养物显示出响应于化学ER应激源thapsigargin的LC3-GFP点形成显着减少，这是自噬体形成的指标。p62KO小鼠的下丘脑培养物显示出UPR/ER应激标记物CHOP mRNA和ATF4 mRNA的基础表达高于WT培养物。Thapsigargin在WT和p62KO培养物中均增强了CHOP，ATF4和BiP mRNA以及p-eIF2α 蛋白的表达，但在p62KO培养物中所有峰值均较大。蛋白酶体抑制剂在两种基因型中均增加了WT培养物中的p62表达，并上调了UPR/ER应激标记物CHOP mRNA和ATF4 mRNA，但在p62KO培养物中更大程度。因此，p62缺乏干扰了自噬体的形成，并增强了基础和化学诱导的ER应激，表明p62通过维持蛋白质折叠能力来预防小鼠下丘脑的ER应激。

BACKGROUND & AIMS: BACKGROUND:Epidemiological studies have shown significant ethnic differences in coronary heart disease death rates with South Asians showing significantly greater coronary heart disease mortality than other groups. PURPOSE:This research examined ethnic differences in cardiovascular reactivity (CVR) among Chinese, Malays and Indians in Singapore as well as a sample of Indians living in India. METHODS:Experiment 1 examined differences across 303 Chinese, Malay and Indian undergraduates in Singapore, while Experiment 2 looked at differences in CVR between Indian participants from Singapore, and 145 Indians living in India. Systolic and diastolic blood pressure (SBP, DBP), heart rate (HR), cardiac index (CI) and total peripheral resistance index (TPRI) were measured during baselines and five laboratory tasks. RESULTS:Ethnicity main effects for SBP and CI reactivity were obtained in Experiment 1, with Indians showing significantly lower BP and CI reactivity than the Chinese and Malays. Significant main effects for sex were found with females showing lower reactivity than males for TPRI, and greater reactivity than males for HR and CI. Experiment 2 found that participants from India showed higher reactivity for SBP, HR and CI, while Indian participants from Singapore showed higher TPRI reactivity. These differences, however, often varied by task. CONCLUSIONS:These results point to differences in CVR among ethnic groups in Singapore as well as between Indians living in India and those living in Singapore. These differences may reflect cultural differences and need to be explored further with respect to their relationship to different rates of coronary heart disease among these groups.

背景与目标：

BACKGROUND & AIMS: :Psychiatrists and psychotherapists in the US (1970s to 1985) and Switzerland (1988-1993) used MDMA legally as a prescription drug, to enhance the effectiveness of psychotherapy. Early reports suggest that it is useful in treating trauma-related disorders. Recently, the first completed pilot study of MDMA-assisted psychotherapy for PTSD yielded encouraging results. Designed to test the safety and efficacy of MDMA-assisted psychotherapy in patients with treatment-resistant PTSD; our randomized, double-blind, active-placebo controlled trial enrolled 12 patients for treatment with either low-dose (25 mg, plus 12.5 mg supplemental dose) or full-dose MDMA (125 mg, plus 62.5 mg supplemental dose). MDMA was administered during three experimental sessions, interspersed with weekly non-drug-based psychotherapy sessions. Outcome measures used were the Clinician-Administered PTSD Scale (CAPS) and the Posttraumatic Diagnostic Scale (PDS). Patients were assessed at baseline, three weeks after the second and third MDMA session (end of treatment), and at the 2-month and 1-year follow-ups. We found that MDMA-assisted psychotherapy can be safely administered in a clinical setting. No drug-related serious adverse events occurred. We did not see statistically significant reductions in CAPS scores (p = 0.066), although there was clinically and statistically significant self-reported (PDS) improvement (p = 0.014). CAPS scores improved further at the 1-year follow-up. In addition, three MDMA sessions were more effective than two (p = 0.016).

背景与目标： : 美国 (20世纪70年代1985年) 和瑞士 (1988-1993) 的精神科医生和心理治疗师合法使用MDMA作为处方药，以提高心理治疗的有效性。早期报告表明，它在治疗创伤相关疾病中很有用。最近，第一个完成的MDMA辅助心理治疗PTSD的初步研究取得了令人鼓舞的结果。旨在测试MDMA辅助心理治疗在治疗耐药的PTSD患者中的安全性和有效性; 我们的随机，双盲，活性安慰剂对照试验招募了12名患者接受低剂量 (25 mg，加12.5 mg补充剂量) 或全剂量MDMA (125 mg，加62.5 mg补充剂量)。MDMA在三个实验课程中进行，并散布在每周的非基于药物的心理治疗课程中。使用的结果指标是临床医生管理的PTSD量表 (CAPS) 和创伤后诊断量表 (PDS)。在基线，第二次和第三次MDMA疗程 (治疗结束) 后三周以及2个月和1年随访时对患者进行评估。我们发现MDMA辅助心理治疗可以在临床环境中安全施用。未发生与药物相关的严重不良事件。尽管有临床和统计学上显着的自我报告 (PDS) 改善 (p = 0.066)，但我们没有看到CAPS评分的统计学显着降低 (p = 0.014)。在1年的随访中，CAPS评分进一步提高。此外，三个MDMA会话比两个更有效 (p = 0.016)。

BACKGROUND & AIMS: :Set2-mediated histone methylation at H3K36 regulates diverse activities, including DNA repair, mRNA splicing, and suppression of inappropriate (cryptic) transcription. Although failure of Set2 to suppress cryptic transcription has been linked to decreased lifespan, the extent to which cryptic transcription influences other cellular functions is poorly understood. Here, we uncover a role for H3K36 methylation in the regulation of the nutrient stress response pathway. We found that the transcriptional response to nutrient stress was dysregulated in SET2-deleted (set2Δ) cells and was correlated with genome-wide bi-directional cryptic transcription that originated from within gene bodies. Antisense transcripts arising from these cryptic events extended into the promoters of the genes from which they arose and were associated with decreased sense transcription under nutrient stress conditions. These results suggest that Set2-enforced transcriptional fidelity is critical to the proper regulation of inducible and highly regulated transcription programs.

背景与目标： : H3K36的Set2-mediated组蛋白甲基化调节多种活动，包括DNA修复，mRNA剪接和抑制不适当的 (隐性) 转录。尽管Set2无法抑制隐性转录与寿命缩短有关，但对隐性转录影响其他细胞功能的程度知之甚少。在这里，我们揭示了H3K36甲基化在营养应激反应途径调节中的作用。我们发现，对营养应激的转录反应在SET2-deleted (set2Δ) 细胞中失调，并且与源自基因体内的全基因组双向隐秘转录相关。这些隐秘事件产生的反义转录本延伸到它们产生的基因的启动子中，并且在营养胁迫条件下与有义转录减少有关。这些结果表明，Set2-enforced的转录保真度对于适当调节可诱导和高度调节的转录程序至关重要。

BACKGROUND & AIMS: :Bidirectional communication between neurons and vascular cells is important to the maintenance of the central nervous system (CNS) milieu. Vascular endothelial growth factor (VEGF), through its ability to affect both vascular and neuronal cells, is likely a key protein in this process. Despite considerable literature documenting a neuroprotective function for VEGF, overexpression of this protein has also been shown in a wide variety of CNS diseases, including Alzheimer's disease (AD). Increased oxidative stress and elevated thrombin levels have also been documented in AD, specifically in the microvasculature. The aim of the current study is to examine endothelial cells and neurons in vitro to determine the effects of oxidative stress and thrombin on VEGF release as well as the effects of low and high dose VEGF on neuronal viability. The data show that microvessels isolated from AD patients secrete significantly higher levels of VEGF compared to control-derived vessels. Exposure of brain endothelial cells to oxidative stress (sodium nitroprusside, menadione, or hydrogen peroxide) or thrombin significantly increases VEGF expression. Exposure of cultured neurons to oxidative stress increases expression of thrombin. Treating rat cortical neurons with high dose VEGF (≥500 ng/ml) decreases neuronal survival and expression of the anti-apoptotic protein Bcl-2 while increasing proapoptic proteins caspase 3 and phosphorylated p38 MAPK. High dose VEGF also negates the decrease in amyloid-β evoked by low dose VEGF. These results suggest that despite literature supporting neuroprotective effects of this protein, caution is warranted prior to implementation of VEGF as a therapeutic in the brain.

背景与目标： 神经元和血管细胞之间的双向通信对于维持中枢神经系统 (CNS) 环境很重要。血管内皮生长因子 (VEGF) 通过其同时影响血管和神经元细胞的能力，可能是此过程中的关键蛋白。尽管有大量文献记录了VEGF的神经保护功能，但该蛋白的过表达也已在包括阿尔茨海默氏病 (AD) 在内的多种中枢神经系统疾病中显示。在AD中，特别是在微血管系统中，也记录了氧化应激增加和凝血酶水平升高。当前研究的目的是在体外检查内皮细胞和神经元，以确定氧化应激和凝血酶对VEGF释放的影响以及低剂量和高剂量VEGF对神经元活力的影响。数据显示，与对照来源的血管相比，从AD患者中分离出的微血管分泌的VEGF水平明显更高。脑内皮细胞暴露于氧化应激 (硝普钠，甲萘醌或过氧化氢) 或凝血酶会显着增加VEGF的表达。培养的神经元暴露于氧化应激会增加凝血酶的表达。用高剂量VEGF (≥ 500 ng/ml) 处理大鼠皮质神经元会降低神经元存活和抗凋亡蛋白Bcl-2的表达，同时增加促凋亡蛋白caspase 3和磷酸化p38mapk。高剂量VEGF也抵消了低剂量VEGF引起的淀粉样蛋白 β 的减少。这些结果表明，尽管有文献支持该蛋白的神经保护作用，但在将VEGF用作大脑治疗药物之前还是要谨慎。

BACKGROUND & AIMS: :Manipulation of the corticosteroid milieu by interfering with the mother-newborn relationship has received much attention because of its potential bearing on psychopathology later in life. In the present study, infant rats that were deprived of maternal contact between the 2nd and the 15th postnatal days (MS2-15) for 6 h/day were subjected to a systematic assessment of neurodevelopmental milestones between postnatal days 2 and 21. The analyses included measurements of physical growth and maturation and evaluation of neurological reflexes. Although some somatic milestones (e.g. eye opening) were anticipated, MS2-15 animals showed retardation in the acquisition of postural reflex, air righting and surface righting reflexes, and in the wire suspension test; the latter two abnormalities were only found in males. A gender effect was also observed in negative geotaxis, with retardation being observed in females but not males. To better understand the delay of neurological maturation in MS2-15 rats, we determined the levels of various monoamines in different regions of the brain stem, including the vestibular area, the substantia nigra, ventral tegmental area and dorsal raphe nuclei. In the vestibular region of MS2-15 rats the levels of 5-HT were reduced, while 5-HT turnover was increased. There was also a significant increase of the 5-HT turnover in MS2-15 animals in the raphe nuclei, mainly due to increased 5-hydroxyindoleacetic acid (5-HIAA) levels, and an increase of 3,4-dihydroxyphenylacetic acid (DOPAC) levels in the ventral tegmental area (VTA) of stressed females. No significant differences were found in the immunohistochemical sections for tyrosine and tryptophan hydroxylase in these regions of the brain stem. In conclusion, the present results show that postnatal stress induces signs of neurological pathology that may contribute to the genesis of behavioral abnormalities later in life.

背景与目标： : 通过干扰母婴关系来操纵皮质类固醇环境已受到广泛关注，因为它可能与以后的生活中的精神病理学有关。在本研究中，在出生后第2天和第15天 (MS2-15) 之间被剥夺了6小时/天的母体接触的幼鼠接受了出生后第2天和21天之间神经发育里程碑的系统评估。分析包括身体生长和成熟的测量以及神经反射的评估。尽管预期会有一些躯体里程碑 (例如睁眼)，但MS2-15动物在姿势反射，空气扶正和表面扶正反射的获得以及钢丝悬吊测试中显示出延迟; 后两种异常仅在男性中发现。在负地趋向性中也观察到性别影响，在女性中观察到发育迟缓，但在男性中没有观察到。为了更好地了解MS2-15大鼠神经系统成熟的延迟，我们确定了脑干不同区域 (包括前庭区域，黑质，腹侧被盖区和背缝核) 中各种单胺的水平。在MS2-15大鼠的前庭区域，5-HT的水平降低，而5-HT的周转增加。中缝核中MS2-15动物的5-HT周转率也显着增加，这主要是由于5-羟基吲哚乙酸 (5-HIAA) 水平增加以及3,4-二羟基苯乙酸 (DOPAC) 的增加。压力女性腹侧被盖区 (VTA) 的水平。在脑干这些区域的酪氨酸和色氨酸羟化酶的免疫组织化学切片中未发现显着差异。总之，目前的结果表明，出生后的压力会引起神经病理学的迹象，这可能有助于以后生活中行为异常的发生。

BACKGROUND & AIMS: :Transcriptome analysis was used to investigate the global stress response of the gram-positive bacterium Bacillus subtilis caused by overproduction of the well-secreted AmyQ alpha-amylase from Bacillus amyloliquefaciens. Analyses of the control and overproducing strains were carried out at the end of exponential growth and in stationary phase, when protein secretion from B. subtilis is optimal. Among the genes that showed increased expression were htrA and htrB, which are part of the CssRS regulon, which responds to high-level protein secretion and heat stress. The analysis of the transcriptome profiles of a cssS mutant compared to the wild type, under identical secretion stress conditions, revealed several genes with altered transcription in a CssRS-dependent manner, for example, citM, ylxF, yloA, ykoJ, and several genes of the flgB operon. However, high-affinity CssR binding was observed only for htrA, htrB, and, possibly, citM. In addition, the DNA macroarray approach revealed that several genes of the sporulation pathway are downregulated by AmyQ overexpression and that a group of motility-specific (sigmaD-dependent) transcripts were clearly upregulated. Subsequent flow-cytometric analyses demonstrate that, upon overproduction of AmyQ as well as of a nonsecretable variant of the alpha-amylase, the process of sporulation is severely inhibited. Similar experiments were performed to investigate the expression levels of the hag promoter, a well-established reporter for sigmaD-dependent gene expression. This approach confirmed the observations based on our DNA macroarray analyses and led us to conclude that expression levels of several genes involved in motility are maintained at high levels under all conditions of alpha-amylase overproduction.

背景与目标： : 转录组分析用于研究由解淀粉芽孢杆菌分泌充分的AmyQ α-淀粉酶过量产生引起的革兰氏阳性细菌枯草芽孢杆菌的整体应激反应。当枯草芽孢杆菌的蛋白质分泌最佳时，在指数生长结束时和固定相进行对照和过量生产菌株的分析。表达增加的基因包括htrA和htrB，它们是CssRS调节子的一部分，它们对高水平的蛋白质分泌和热应激做出反应。在相同的分泌胁迫条件下，与野生型相比，对cssS突变体的转录组谱进行分析，揭示了几个以CssRS依赖性方式改变转录的基因，例如citM，ylxF，yloA，ykoJ和flgB操纵子的几个基因。然而，仅在htrA，htrB和可能的citM中观察到高亲和力的CssR结合。此外，DNA macroarray方法揭示了孢子形成途径的几个基因被AmyQ过表达下调，并且一组运动性特异性 (sigmaD依赖性) 转录本被明显上调。随后的流式细胞仪分析表明，在过量生产AmyQ以及不可分泌的 α-淀粉酶变体后，孢子形成过程受到严重抑制。进行了类似的实验以研究hag启动子的表达水平，hag启动子是sigmaD依赖性基因表达的公认报告基因。这种方法证实了基于我们的DNA宏观阵列分析的观察结果，并使我们得出结论，在所有 α-淀粉酶过度生产的条件下，与运动有关的几个基因的表达水平都保持在高水平。