Ursolic acid attenuates lipopolysaccharide-induced cognitive deficits in mouse brain through suppressing p38/NF-κB mediated inflammatory pathways

Evidence indicates that systemic administration of lipopolysaccharide (LPS) induces brain inflammation, ultimately resulting in cognitive deficits. Ursolic acid (UA), a plant-derived pentacyclic triterpenoid, is well known to possess multiple biological functions, including antioxidant, anti-tumor and anti-inflammatory activities. In the present study, we assessed the protective effect of UA against the LPS-induced cognitive deficits in mice. We found that UA significantly improved cognitive deficits of LPS-treated mice in open field, step-through passive avoidance and Morris water maze tasks. One potential mechanism of this action was attributed to the decreased production of pro-inflammatory markers including COX-2, iNOS, TNF-α, IL-1β, IL-2 and IL-6 in LPS-treated mouse brain. Mechanistically, UA markedly inhibited LPS-induced IκBα phosphorylation and degradation, NF-κB p65 nuclear translocation and p38 activation in mouse brain, but did not affect the activation of TLR4, MyD88, ERK, JNK and Akt. Taken together, these results suggest that UA may be useful for mitigating inflammation-associated brain disorders by inhibiting pro-inflammatory factors production, at least in part, through blocking the p38/NF-κB signaling pathways.     

术后镇痛对创伤患者围术期细胞因子和胰岛素抵抗的影响研究

研究术后镇痛对创伤患者围术期细胞因子IL 6、TNFα和胰岛素抵抗（IR）的影响.选取60例患者,随机分为两组,A组患者应用一次性术后镇痛泵,加入舒芬太尼2.5μg/kg＋盐酸托烷司琼4mg,用生理盐水稀释至100ml,2ml/h持续注入.B组患者为术后根据临床需要临时给予杜冷丁每次50mg～100mg肌肉注射,每日不超过3次.发现两组患者术后镇痛效果比较,A组患者舒适程度要优于B组,随访患者无与药物相关的不良反应.术后两组患者血浆IL-6、TNF-α水平均开始升高,术后12h左右达峰值,24h后开始回落,但均明显高于术前.血糖和血胰岛素值也在术后升高,术后24h左右达峰值,之后逐渐回落.ISI在术后开始降低,术后24h降到最低,之后逐渐回升,但均低于术前,说明IL-6、TNF-α水平升高与创伤后胰岛素抵抗有相关性.A组患者术后12h、24h、36h、48h的血糖、血胰岛素、IL-6、TNF-α水平与B组比较明显降低,而且术后48h基本可以恢复术前水平.应用舒芬太尼术后镇痛可以通过抑制血浆中IL-6和TNF-α水平,从而抑制围术期胰岛素抵抗,降低应激反应,从而达到减轻免疫抑制和降低或缩短IR时间的目的.     

盐酸戊乙奎醚对心脏瓣膜置换术患者NF-κB表达的影响

为研究盐酸戊乙奎醚对心脏瓣膜置换术患者心肌NF-κB转录活性的影响,选取择期瓣膜置换术患者60例,随机分为对照组（C）、盐酸戊乙奎醚组1（P1）、盐酸戊乙奎醚组2（P2）,每组20例。结果心肌缺血再灌注后,P1、P2组NF-κB的转录活性明显下降,可见盐酸戊乙奎醚可以抑制心肌NF-κB的激活,在一定程度上具有心肌保护作用。     

Influence of Regularity of Exposure to Chronic Stress on the Pattern of Habituation of Pituitary-Adrenal Hormones, Prolactin and Glucose

The effect of regularity of exposure to two different chronic stressors (noise or immobilization (IMO)) on the pattern of habituation of pituitary-adrenal (PA) hormones, prolactin and glucose was evaluated in adult male rats. Animals were chronically subjected to either regular or irregular time schedule of noise (30 min/day) or IMO (2 h/day) for two weeks. The day after the last stress session the rats were killed without stress or after having been subjected to 30 min of the homotypic stressor. Whereas regular noise did not affect food intake, body weight gain or adrenal weight, irregular noise decreased body weight gain and induced a moderate adrenal hypertrophy. In addition, previous daily exposure to regular but not to irregular noise reduced both prolactin and corticosterone responses to acute noise. In contrast, glucose response to acute noise was reduced after both regular and irregular exposure to chronic noise. Either regular or irregular exposure to chronic IMO decreased food intake and body weight and increased adrenal weight to the same extent. Likewise, no influence of regularity of exposure to chronic IMO on corticosterone and prolactin responses to acute IMO was observed. However, habituation of the ACTH response to acute IMO was observed in rats subjected to chronic regular IMO, but not in rats subjected to chronic irregular IMO. Finally, acute IMO-induced hyperglycemia diminished to the same extent after regular and irregular IMO. From these results we can conclude that: first, the process of habituation of the PA axis to chronic stress is greatly dependent upon factors such as regularity of exposure to the stressor and stressor intensity, and second, the influence of regularity on the pattern of habituation to a repeated stressor is dependent on the physiological variable we are dealing with.     

Maternal separation in early life impairs tumor immunity in adulthood in the F344 rat

Neonatal stress alters the hypothalamic-pituitary-adrenal (HPA) axis in rodents, such that, when these animals are exposed to stress as adults they hypersecrete corticosterone. Given that glucocorticoids are immunosuppressive, we examined the impact of maternal separation on HPA axis reactivity, natural killer (NK) cytotoxicity, and tumor growth in Fischer 344 rats following chronic restraint stress in adulthood. Pups underwent a chronic stress protocol whereby they were separated from their dams for 3 h on postnatal days 1-21. In adulthood, corticosterone responses were assessed following exposure to chronic (6 days for 10 h) restraint stress. Rats allocated to the chronic stress condition were inoculated with MADB106 tumor cells on day 4 of the restraint protocol. Blood was assessed for NK cytotoxicity on the final day of the chronic restraint protocol, and tumor colonization was assessed 3 weeks thereafter. Maternal separation impaired developmental weight gain (P < 0.05), depressed NK cytotoxicity (P < 0.05), and increased tumor colonization in the presence of chronic restraint stress in adulthood (P < 0.00 l). These findings occurred independently of circulating plasma corticosterone as only adult stress exposure potentiated corticosterone responses (P < 0.05). Our findings indicate that maternal separation and chronic stress can impair NK cytotoxicity and hence tumor immunity, but these effects are not directly mediated by perturbations in HPA axis function.     

The Effect of Selective Serotonin Releasing Agents in the Chronic Mild Stress Model of Depression in Rats

Chronic exposure to mild unpredictable stress has been found to depress the consumption of, and preference for, highly palatable sucrose solution in rats. Stress-induced behavioral deficits may be maintained for a long time, however chronic administration of clinically effective antidepressants can restore normal behavior. This is the first report showing that Sprague-Dawley rats can be used in this model. A preference deficit in this strain of rats took at least 7 weeks to develop; about twice the time required when hooded Lister or Wistar rats are used in this model. Water consumption was not effected by chronic exposure to the mild stress regime and/or by chronic administration of the selective serotonin (5-HT) releasing agent MMAI (5-methoxy-6-methyl-2-aminoindan). The stress-induced deficit in sucrose intake was completely reversed by chronic treatment with MMAI (5 mg/kg, 2 x day) over 3 weeks in the two-bottle tests. In single-bottle tests, chronic treatment with the selective 5-HT releasers, MMAI (5 mg/kg, 2 x day) or MTA (p-methylthioamphetamine; 5 mg/kg, 2 x day), reversed the deficit in rewarded behavior (anhedonia) measured as a decrease in the consumption of 1% sucrose solution in the chronic mild stress model of depression in rats. With the experimental procedure employed, and at a dose of 10 mg/kg/day of 5-HT releasers, the magnitude and onset of this effect were greater than observed following similar administration of the selective 5-HT reuptake inhibitor (SSRI) sertraline (10 mg/kg/day), used as a standard anti-depressant drug.     

丙戊酸增强人罗同巢癌耐药细胞株COC1／DDP对顺铂敏感性的研究

探讨丙戊酸是否增强COC1/DDP对顺铂的敏感性并初步探讨其机制。采用WST-1、流式细胞术、免疫细胞化学法。结果丙戊酸与顺铂联合对细胞生长抑制和凋亡诱导明显强于顺铂组;NF-κB P65的表达量顺铂组高于对照组,联合组明显低于顺铂组。因此,丙戊酸增强COC1/DDP对顺铂的敏感性,且与NF-κB有关。     

Hypothalamic circuit regulating colonic transit following chronic stress in rats

Although acute stress accelerates colonic transit, the effect of chronic stress on colonic transit remains unclear. In this study, rats received repeated restraint stress (chronic homotypic stress) or various types of stress (chronic heterotypic stress) for 5 and 7 days, respectively. Vehicle saline, oxytocin (OXT), OXT receptor antagonist or corticotropin-releasing factor (CRF) receptor antagonists were administered by intracerebroventricular (ICV) injection prior to restraint stress for 90 min. Immediately after the stress exposure, the entire colon was removed and the geometric center (GC) of Na51CrO4 (a nonabsorbable radioactive marker; 0.5 μCi) distribution was calculated to measure the transit. Gene expression of OXT and CRF in the paraventricular nucleus (PVN) was evaluated by in situ hybridization. Accelerated colonic transit with the acute stressor was no longer observed following chronic homotypic stress. This restored colonic transit was reversed by ICV injection of an OXT antagonist. In contrast, chronic heterotypic stress significantly accelerated colonic transit, which was attenuated by ICV injection of OXT and by a CRF receptor 1 antagonist. OXT mRNA expression in the PVN was significantly increased following chronic homotypic stress, but not chronic heterotypic stress. However, CRF mRNA expression in the PVN was significantly increased following acute and chronic heterotypic stress, but not chronic homotypic stress. These results indicate that central OXT and CRF play a pivotal role in mediating the colonic dysmotility following chronic stress in rats.     

Long-lasting effects of inescapable-predator stress on brain tryptophan metabolism and the behavior of juvenile mice

The kynurenine (KYN) pathway, which is initiated by indoleamine 2,3-dioxygenase, is the main tryptophan (TRP) metabolic pathway. It shares TRP with the serotonin (5-HT) pathway. We investigated the influence of inescapable-predator (rat) stress on behavior and brain TRP metabolism in mice. Male ICR mice (4W) were exposed to 20-min inescapable-predator stress. Behavior on an elevated plus-maze, and TRP, KYN, and 5-HT levels in the prefrontal cortex, hippocampus, amygdala, and dorsal raphe nuclei were measured 1 and 4 weeks after stress exposure. Predator stress increased the number of open-arm entries (NOA) 4 weeks after stress exposure without altering the number of closed-arm entries (NCA). Thus, the open/closed-arm entry ratio (NOA/NCA) increased after stress exposure. Predator stress increased KYN levels in the prefrontal cortex (until 4 weeks after stress exposure) and dorsal raphe nuclei (for 1 week after stress exposure), decreased 5-HT levels in all brain regions (until 4 weeks after stress exposure). Thus, predator stress increased the KYN/5-HT ratio in all regions, in particular in the prefrontal cortex and hippocampus until 4 weeks after stress exposure. Predator stress shifted the balance between the KYN and 5-HT pathways to the KYN pathway, and induced behavioral disinhibition.     

Chronic stress and carbohydrate metabolism: persistent changes and slow return to normalcy in male albino rats

The present study tested the hypothesis that long-term repeated exposure to stressors results in irreversible changes in carbohydrate metabolism. Groups of adult male rats (five per group) were restrained for 1?h and 4?h later were forced to swim for 15?min everyday for 2, 4, or 24 weeks; five rats were autopsied after each interval. Groups of five rats exposed to stress for 2 or 4 weeks were maintained without further treatment (recovery groups) for up to 24 weeks. The fasting blood glucose concentration, measured at weekly intervals, was significantly higher in the stressed rats than in controls throughout the experiment, except in the 24th week, whereas that of the recovery groups was significantly higher than controls only up to the 8th week after the end of stress exposure and then reached normalcy. The blood concentrations of glucose, lactate, and pyruvate were significantly higher in the 2 and 4 weeks stress groups than in controls, whereas, except for lactate, in rats stressed for 24 weeks these values did not significantly differ from those in controls. These changes were accompanied by increased gluconeogenesis and glycogenolysis as shown by alterations in activities of hepatic carbohydrate metabolizing enzymes and unaltered blood insulin concentrations in rats stressed for 2, 4, and 24 weeks. Furthermore, the blood insulin levels did not significantly vary among controls and the 2, 4, and 24 weeks stress groups. The results reveal that though hyperglycemia induced by long-term stress exposure is reversible, it persists for a prolonged period, even after the termination of stress exposure, before reaching normalcy. Prevalence of hyperglycemia for a prolonged period through increased activities of hepatic enzymes in stressed rats exemplifies allostasis.     

Differentiating the impact of episodic and chronic stressors on hypothalamic-pituitary-adrenocortical axis regulation in young women.

OBJECTIVE: The goal of this study was to examine the impact of episodic stress and chronic interpersonal stress on indices of HPA regulation. To explore the potential downstream consequences of altered HPA dynamics, the authors also assessed indicators of metabolic control and systemic inflammation. DESIGN: One hundred four medically healthy women between the ages of 15 and 19 participated. Following an in-depth interview of life stress, a sample of blood was drawn through antecubital venipuncture. Over the course of the next 2 days, participants gathered salivary cortisol samples. MAIN OUTCOME MEASURES: Cortisol morning response, cortisol daily output, glucocorticoid receptor (GR) mRNA, C-reactive protein (CRP), insulin, and glucose. RESULTS: The simple presence of episodic stress or chronic interpersonal stress was not reliably associated with cortisol output, GR mRNA, insulin, or glucose. When women were exposed to an episodic stressor in the midst of chronic stress they showed increased cortisol output and reduced expression of GR mRNA. By contrast, when women had low levels of chronic stress, episodic events were associated with decreased cortisol output and increased GR mRNA. Episodic and chronic stress also interacted to predict CRP, but not insulin or glucose. CONCLUSIONS: The impact of episodic stress is accentuated in the midst of chronic interpersonal stress and diminished in its absence. Simultaneous exposure to episodic and chronic stress may create wear and tear on the body, whereas exposure to episodic stress in the context of a supportive environment may toughen the body, protecting it against subsequent stressors.     

A prospective study of appraisals in childhood posttraumatic stress disorder

This study investigated the predictors of posttraumatic stress disorder (PTSD) in children following a diagnosis of traumatic injury. Children (N=76) aged between 7 and 13 who were admitted to hospital following injury were assessed within a month of trauma for acute stress disorder (ASD), negative appraisals, as well as parental stress reactions. Children (N=62) were re-assessed 6-months later for PTSD and negative appraisals. The majority of the variance of chronic posttraumatic stress was accounted for by negative appraisals about future harm. This study supports cognitive models of PTSD, and suggests that younger children who exaggerate their vulnerability after trauma exposure are high risk for PTSD after trauma.     

Psychological stress reactivates dextran sulfate sodium-induced chronic colitis in mice

Inflammatory bowel disease (IBD) is a chronic condition with alternating active and quiescent phases of inflammation. Stress has been suggested as a factor triggering a relapse of IBD. We investigated the role of repetitive psychological stress [water avoidance stress (WAS)] in reactivating colonic inflammation in a murine model of dextran sulfate sodium (DSS)-induced chronic colitis. Colitis was induced in C57BL/6 female mice by exposure to 3% DSS (5 days). During chronic inflammation(day 34), mice underwent repetitive WAS (1 h/day/7 days) and were given a sub-threshold concentration of DSS (1%, 5 days)or normal water to drink. At euthanasia (day 40), inflammatory parameters were assessed (colon inflammatory score, levels of inflammatory markers and histology). Mice with chronic colitis exposed to WAS had higher macroscopic and microscopic colonic inflammatory scores and levels of inflammatory markers (mainly IL-1beta, IL12p40 and CCL5) than non-stressed mice. Inflammatory responses were further enhanced by the presence of a sub-threshold concentration of DSS (1%). In mice without chronic inflammation, neither WAS nor 1% DSS, individually or in combination, elicited any inflammation. Hence stress, per se, reactivates a quiescent chronic inflammation, but does not initiate inflammation in healthy mice. Stress should be regarded as an environmental factor triggering IBD relapses in humans.     

慢性应激诱导的抑郁大鼠纹状体par-4基因的表达

为研究慢性温和应激诱导的抑郁大鼠纹状体内前列腺凋亡反应蛋白(prostate apoptosis response-4, par-4)的表达, 及甲基化是否参与par-4基因表达的调控, 将10周龄大鼠随机分为实验组和对照组, 实验组接受慢性温和应激, 对照组不接受实验性处理。于大鼠13周龄时, 采用强迫游泳、糖水偏爱测验测定大鼠的抑郁水平, 以实时定量PCR检测纹状体par-4及多巴胺D2受体(Dopamine receptor D2, DRD2) mRNA表达水平, 免疫印迹法检测纹状体par-4蛋白质表达水平, 用亚硫酸盐测序法检测par-4基因启动子区甲基化水平。结果发现, 与对照组大鼠相比, 实验组大鼠漂浮时间延长, 糖水偏爱率降低, 脑纹状体par-4、DRD2 mRNA及par-4蛋白质表达水平均降低, par-4基因启动子区甲基化水平两组差异不显著。提示慢性温和应激诱导大鼠产生了抑郁样行为, 并能抑制纹状体par-4基因的表达, 而基因甲基化可能并不参与其调控机制。     

Chronic effects of high salt intake and conflict stress on blood pressure in primates. A progress report.

The effects of combined behavioral stress and high dietary salt on blood pressure were examined in baboons (N = 4) over the course of 1 year. Either high salt diet (240 mEq Na+/day) or conflict stress were administered for 8 to 16 weeks, followed by high salt intake and stress combined. Mean arterial pressure (MAP) increased by 8 mmHg during high dietary salt alone, by 4 mmHg during stress alone, and increased further to 14 mmHg above baseline during combined salt and stress. Control baboons (N = 2) had no change in MAP across 47 weeks. The data indicate additive effects of chronic high dietary salt intake and behavioral stress on blood pressure in non-human primates.     

Chronic effects of high salt intake and conflict stress on blood pressure in primates

The effects of combined behavioral stress and high dietary salt on blood pressure were examined in baboons (N=4) over the course of 1 year. Either high salt diet (240 mEq Na⁺/day) or conflict stress were administered for 8 to 16 weeks, followed by high salt intake and stress combined. Mean arterial pressure (MAP) increased by 8 mmHg during high dietary salt alone, by 4 mmHg during stress alone, and increased further to 14 mmHg above baseline during combined salt and stress. Control baboons (N=2) had no change in MAP across 47 weeks. The data indicate additive effects of chronic high dietary salt intake and behavioral stress on blood pressure in non-human primates.     

Lactation deficit in OFA hr/hr rats may be caused by differential sensitivity to stress compared with Wistar and Sprague Dawley rats

OFA hr/hr (OFA) rats present a major lactation deficit that impairs offspring survival. To explore whether abnormal stress responsiveness causes this deficit, we compared their hormonal (prolactin, progesterone, and corticosterone) responses to stress (room change and 2-min ether exposure) with those of Wistar and Sprague Dawley (SD) rats. We tested responses during the estrous cycle, pregnancy, lactation, after ovariectomy, and ovarian steroid hormone priming, and responses to suckling. We evaluated hypothalamic expression of receptors for prolactin (PRLRlong) and the isoforms of receptors for progesterone (PRA and B) and estrogen (ERα and β) in late pregnancy. We tested whether administration of an anxiolytic (diazepam) improved lactation. Ether exposure increased circulating levels of the three hormones in the three strains of rats, cycling and ovariectomized, but was less effective in pregnancy and lactation. Elevated estrogen level (estrus and estradiol-treated ovariectomized rats) potentiated the prolactin response more in SD and OFA rats than in Wistar rats. Elevated progesterone level (late pregnancy, lactation, progesterone-treated ovariectomized rats) inhibited the prolactin response less in OFA than in SD or Wistar rats. Ether exposure inhibited the prolactin and oxytocin responses to suckling only in OFA rats. Diazepam treatment increased pup survival rate and the prolactin response to suckling. Hypothalamic total PR mRNA content, assayed by RT-PCR, was higher in pregnant OFA rats compared with SD and Wistar rats, but the PRB/PRA protein ratio determined by Western blot was lowest in Wistar rats, intermediate in OFA rats, and highest in SD rats. The heightened sensitivity to stress of lactating OFA rats may contribute to their lactational deficit and be caused by a combination of hypoprolactinemia and reduced inhibitory capacity of progesterone.     

Biobehavioral effects of extended salt loading and conflict stress in intact baboons.

Behavioral stressors may inhibit sodium excretion, potentially increasing plasma volume and elevating blood pressure during chronic exposure. Blood pressure regulation may be especially deranged during manipulations that further challenge the kidney, such as a diet high in salt content. The effects on blood pressure and other variables of combined behavioral stress (food/shock conflict) and dietary salt (12 g NaCl per day; 218 mEq Na+ per day) were examined in adult male baboons over the course of 1 year. Mean arterial pressure was not significantly elevated over baseline after 5 months of high dietary salt alone (6 +/- 5 mmHg) but was maximally elevated by an average of 17 (+/- 3 SEM) mmHg after 5 months of combined salt and conflict stress. Control baboons showed no significant trends in mean arterial pressure across the same time period. Individual subjects whose blood pressure was "salt+stress resistant" or "salt+stress sensitive" were differentiated by their degree of pressure diuresis and natriuresis, urinary free cortisol, and a behavioral index of stress sensitivity. The data indicate additive effects of chronic high dietary salt intake and behavioral stressors on blood pressure in nonhuman primates that are dependent on renal function and pituitary-adrenocortical activity.     

Individual differences in chronically defeated male mice: behavioral, endocrine, immune, and neurotrophic changes as markers of vulnerability to the effects of stress

This study aimed to analyze different behavioral profiles in response to chronic social defeat using the sensorial contact model. We hypothesized that a passive profile, unlike an active one, would be associated with behavioral and physiological characteristics related to depression. Six-week-old OF1 male mice were subjected to defeat for 21 consecutive days. A combination of cluster and discriminant analyses of the behavior exhibited during confrontation on Day 21 established two behavioral profiles: active (n?=?22) and passive (n?=?34). Passive mice, with a high level of immobility and low non-social exploration, had higher plasma corticosterone concentrations than active mice after 21 days of defeat. Three days after the last defeat, passive mice had lower corticosterone levels than manipulated-control mice (n?=?11). Higher levels of interleukin-6 and tumor necrosis factor-α (TNF-α) in the spleen and lower hippocampal brain-derived neurotrophic factor levels were observed in passive mice in comparison with those in active mice and the manipulated controls. The only differences observed in active mice in relation to the manipulated control were higher plasma corticosterone (Day 21) and TNF-α levels. The results show that different behavioral profiles in response to chronic defeat are associated with different physiological profiles, and that the passive profile presents physiological characteristics previously associated with depression.     

阻塞性睡眠呼吸暂停低通气综合征与冠状动脉支架再狭窄关系的研究

探讨冠状动脉内支架再狭窄与阻塞性睡眠呼吸暂停低通气综合征（OSAHS）的关系及其机制.选择冠状动脉支架植入术后患者172例,其中43例确诊患OSAHS者为研究组,129例无OSAHS的患者为对照组.支架术后第3年行冠状动脉造影术,同时检测患者静脉血中TNF-α、IL-6、IL-4、IL-5、IL-10水平.OSAHS患者7例发生支架内再狭窄,比率16.26%,明显高于对照组6例,比率5.67%（P〈0.01）;OSAHS患者血清中TNF-α、IL-6浓度高于对照组（P〈0.01）;IL-4、IL-5、IL-10水平低于对照组（P〈0.01）.合并OSAHS的患者,支架再狭窄的发生率高于非OSAHS患者,而OSAHS引发的炎症介质水平改变及炎症反应失衡可能与支架再狭窄有关.