布洛芬辅助治疗下调氟西汀疗效不佳小鼠海马炎症因子表达改善抑郁样行为

目的:探讨布洛芬辅助治疗对氟西汀疗效不佳抑郁小鼠海马炎症因子表达及抑郁样行为的影响。方法:采用慢性不可预见性温和刺激制备抑郁模型,通过糖水偏爱试验、强迫游泳试验以及新奇环境抑制摄食试验等筛查氟西汀疗效不佳抑郁小鼠,将该小鼠随机分为2组,一组继续氟西汀治疗,另一组给予布洛芬辅助治疗,2周后评价2组小鼠抑郁样行为的变化及海马白细胞介素1β(Interleukin 1β,IL-1β)、前列腺素E2(Prostaglandin E2,PGE2)的表达情况。结果:大约20-30%的抑郁小鼠氟西汀治疗效果不佳,其海马IL-1β、PGE2水平明显高于对照组以及氟西汀治疗有效小鼠(P0.05)。布洛芬辅助治疗下调氟西汀疗效不佳抑郁小鼠海马IL-1β、PGE2水平,小鼠的糖水消耗及糖耗比值均较单纯氟西汀治疗组明显提高(P0.05);小鼠强迫游泳的不动时间明显缩短(P0.05)。并且在新奇环境中的摄食行为增强,摄食潜伏期缩短(P0.05)。结论:布洛芬对氟西汀治疗效果不佳(难治性)抑郁小鼠具有辅助抗抑郁治疗作用,能够下调炎症因子表达,改善其抑郁样行为。     

微囊藻毒素与细菌内毒素对草鱼淋巴细胞凋亡的联合毒效应

采用体外暴露方式,以草鱼淋巴细胞为试验对象,研究了水体中微囊藻毒素(MC-LR)与细菌内毒素(LPS)复合作用对鱼免疫系统的影响.结果表明： MC-LR和LPS在单一与复合暴露下都能够诱导草鱼淋巴细胞发生凋亡,呈现细胞凋亡典型的阶梯状DNA电泳特征.但对比复合暴露与单一暴露的凋亡率可以发现,MC-LR与LPS复合暴露会发生协同作用,并呈显著剂量-效应关系,其中复合暴露Ⅳ组凋亡率为单一暴露Ⅰ(MC-LR)和Ⅱ(LPS)组的2-1和3.3倍.MC-LR可协同LPS抑制谷胱甘肽硫转移酶(GST)活性,引发细胞内活性氧(ROS)和丙二醛(MDA)水平上升,导致DNA损伤,致使淋巴细胞阻滞于G0期,增殖受到明显抑制,加速鱼淋巴细胞的凋亡,提高细胞凋亡率.表明MC-LR能够协同LPS加剧其对鱼体免疫细胞毒性,对水产养殖业产生严重不利影响.     

氟西汀对阿尔茨海默病神经细胞模型保护作用分子机制的研究分析

本研究初步探讨氟西汀(fluoxetine)对阿尔茨海默病(Alzheimer's disease,AD)神经细胞模型小鼠神经纤维瘤细胞,野生型N2A/WT细胞和β-淀粉样蛋白(amyloidβ-protein,Aβ)过表达型N2A/APP695swe细胞的保护作用及可能机制。CCK-8法进行氟西汀对APP695细胞抑制率的测定,以半数抑制率(IC50)的氟西汀浓度作为后续实验的药物浓度。后分为WT组、APP695+氟西汀组、APP695组,三组细胞分别培养48 h后,进行细胞原位凋亡染色。最后以Western测定Aβ和BDNF的表达量。实验结果测得半数抑制率(IC50)的氟西汀浓度10-7mol/L。细胞凋亡染色结果显示APP695组凋亡的细胞明显多于其他两组(p0.01),与APP695+氟西汀组相比凋亡细胞增加(p0.05),而WT组与APP695+氟西汀组凋亡细胞无显著性差异(p0.05)。Western结果显示APP695组Aβ表达多于其他两组(p0.05)而BDNF表达明显少于其他两组(p0.01),与APP695+氟西汀组相比Aβ表达增加(p0.05)但BDNF表达减少(p0.05),而WT组与氟西汀组相比Aβ和BDNF的表达量均无显著性差异(p0.05)。本研究结果提示氟西汀可以通过抑制APP695过表达Aβ,从而减少有毒Aβ对BDNF的影响,增加BDNF的表达量,对神经细胞起保护作用,为氟西汀治疗AD提供新的思路。     

三氯生单独暴露对斑马鱼幼鱼眼部的毒性研究

三氯生(2,4,4’-三氯均二苯脲, triclosan, TCS)是环境中应用最为广泛的新兴外源性污染物之一,可强烈地吸附在土壤、沉积物、胶体中。TCS具有生物蓄积作用,在生物体内的富集浓度远超过在水、土壤等环境中的浓度,并且可通过生物富集作用进入食物链。本实验以斑马鱼(Danio rerio)胚胎为模型,探讨不同浓度的TCS暴露对斑马鱼胚胎、幼鱼发育的影响。结果发现, TCS暴露对斑马鱼胚胎和幼鱼具有较强的致畸、致死效应。为了进一步了解TCS对斑马鱼眼部超微结构的影响,将其眼部电镜切片放在透射电镜下观察。结果显示, TCS暴露后斑马鱼幼鱼眼部感光细胞外节盘数量明显减少,外网状层及内网状层较对照组明显变薄且空泡化严重,外核层细胞核固缩现象严重甚至部分细胞核出现溶解的现象。实验结果表明TCS暴露对斑马鱼幼鱼眼部发育有潜在的毒性作用,这可为进一步探讨TCS对人体潜在的毒性作用提供科学、可靠的依据。     

氟西汀对CUS大鼠抑郁样行为及海马内源性大麻素相关基因表达的调节作用

目的:探讨内源性大麻素1型受体(Cannabinoid receptor1,CB1R)、二酰基甘油脂肪酶(Diacylglycerol lipase alpha,DAGLα)和单酰甘油脂肪酶(Monoacylglycerol,MAGL)在氟西汀(Fluoxetine)改善慢性不可预见应激(Chronic unpredictable stress,CUS)大鼠抑郁样行为中的作用。方法:在本研究中,给予暴露于慢性不可预测应激(CUS)的大鼠腹腔注射氟西汀(10 mg/kg)或生理盐水治疗14天,最后一次腹腔注射结束24小时后评估抑郁样行为以及海马中CB1R,DAGLα和MAGL的表达。此外,通过注射慢病毒下调大鼠海马中CB1R和DAGLα的表达。病毒注射两周后,所有大鼠接受CUS刺激,然后腹腔注射10 mg/kg氟西汀或生理盐水14天。给药结束24小时后进行行为学及分子生物学检测。结果:(1)CUS组大鼠具有明显的抑郁样行为,包括旷场中心活动时间减少(P0.05),糖水摄取量下降(P0.05),强迫游泳不动时间增加(P0.01);氟西汀治疗可以缓解CUS大鼠的抑郁行为,与CUS组相比较,CUS+Flx组大鼠的糖水偏好和旷场中心活动时间增加(P0.05,P0.05),强迫游泳不动时间减少(P0.05);(2)CUS组大鼠海马的CB1R、DAGLα的表达下调(P0.05),MAGL的表达上调(P0.05);氟西汀上调CUS大鼠海马的CB1R和DAGLα表达(P 0.05),下调了MAGL表达(P0.05);(3)病毒干预下调海马区的CB1R或DAGLα后,抑制了氟西汀的抗抑郁作用。结论:氟西汀可以通过调节CUS大鼠海马的内源性大麻素相关基因表达改善CUS大鼠的抑郁行为,发挥抗抑郁作用。     

氟西汀对卒中后抑郁的预防效果及神经功能康复的促进作用观察

为了探讨氟西汀对卒中后抑郁的预防效果及神经功能康复的促进作用,本研究选取2015年9月至2017年12月期间本院收治的脑卒中患者200例,根据不同的治疗方式将患者分为氟西汀组(n=100)和对照组(n=100),两组患者均给予神经内科常规和康复治疗,氟西汀组在此基础上口服氟西汀(20 mg/d)。通过比较两组患者的疗效、抑郁程度、神经功能缺损程度、日常活动能力及不良反应,本研究发现治疗8周后,氟西汀组的有效率(86.00%)显著高于对照组(74.00%)(p=0.034);通过采用汉密尔顿抑郁量表(HAMD)评价患者的抑郁程度,治疗8周后氟西汀组患者的HAMD评分(7.25±2.53)显著低于对照组(16.32±3.30)(p=0.032);通过采用中国脑卒中患者临床神经功能缺损程度评分量表(CSS)评价患者的神经功能缺损程度,治疗8周后氟西汀组的CSS评分(8.30±3.37)显著低于对照组(15.16±4.14)(p=0.010);通过采用简式Fugl-Meyer运动功能评分量表(FMA)来评价脑卒中患者的日常活动能力,治疗8周后氟西汀组的FMA评分(71.22±16.34)显著高于对照组(61.26±14.33)(p=0.035)。本研究表明采用氟西汀治疗脑卒中患者可有效预防卒中后抑郁症状的发生,显著改善患者的神经功能和日常活动能力,具有较好的疗效和较低的不良反应。     

三氯生残留及其对甲状腺激素的影响机制

随着环境内分泌干扰物（Endocrine Disrupting Chemicals,EDCs）的检出率和残留量逐渐增加，EDCs对自然环境和人类健康的威胁也日益受到全球各界人士的关注。三氯生（Triclosan,TCS）是一类广泛应用于国内外的高效广谱性抗菌剂，常作为添加剂被广泛用于个人护理品和日用品的制作中，目前科学家已经证实其能产生内分泌干扰效应，是一种典型EDCs。甲状腺激素（TH）是调节能量与物质代谢的主要激素，对机体的生长发育和神经系统的发育有重要意义。文章梳理了TCS环境与体内残留量及TCS暴露对不同动物甲状腺激素影响相关研究进展，为评估TCS的环境安全与健康风险提供了理论基础，为加强TCS相关化学品的风险管理提供了科学依据，对保障人体健康有重要的科学意义和社会意义。     

氟西汀抑制PTSD大鼠海马神经元PSD-95和突触素Ⅰ水平的下调与学习记忆力的损害

目的探讨氟西汀(fluoxetine,FLXT)对创伤后应激障碍(post-traumatic-stress-disorder,PTSD)大鼠记忆及大鼠海马神经元突触后致密物蛋白95(postsynaptic density 95,PSD-95)和突触素Ⅰ(synapsinⅠ)表达的影响。方法采用国际认定的SPS方法刺激大鼠建立PTSD大鼠模型,应用水迷宫实验观察氟西汀对PTSD大鼠学习记忆的影响,采用免疫荧光染色和免疫印迹法检测海马神经元PSD-95和突触素Ⅰ水平。结果 Morris水迷宫前5天的定位航行实验结果显示,SPS刺激后大鼠(PTSD大鼠)找到水下平台的游泳距离和潜伏期比正常组大鼠长,给予氟西汀的PTSD大鼠找到水下平台的距离和潜伏期较未用氟西汀处理的PTSD大鼠缩短。Morris水迷宫第6天空间探索实验结果显示,PTSD大鼠穿越平台的次数和在靶象限花费时间的百分比明显低于正常对照大鼠,而氟西汀可显著增加PTSD大鼠在水迷宫实验中的穿台次数和在靶象限停留的时间百分比。免疫荧光染色和Western Blot检测显示,PTSD大鼠PSD-95和突触素Ⅰ的水平降低,氟西汀干预可抑制PTSD大鼠PSD-95和突触素Ⅰ水平的降低。结论氟西汀可通过抑制PTSD大鼠海马神经元细胞PSD-95和SynapsinⅠ水平的下调,减轻PTSD大鼠空间记忆和学习能力的损伤。     

恩诺沙星和铜复合污染对蚯蚓消化酶活性的影响

从农田土壤畜禽粪源污染的实际出发,以典型兽药抗生素恩诺沙星(ENR)和饲料添加剂铜(Cu)为污染物,研究了两污染物单一/复合暴露对蚯蚓的毒性效应.结果表明: 单一污染暴露下,恩诺沙星(0.1～4 mg·kg^-1,28 d)对蚯蚓蛋白酶未产生显著影响,对纤维素酶和碱性磷酸酶产生了抑制作用,而对酸性磷酸酶产生了诱导效应;铜(20～200 mg·kg^-1,28 d)对蚯蚓的蛋白酶、纤维素酶和磷酸酶活性总体均表现为抑制效应.复合污染暴露下,两污染物对蚯蚓消化酶的影响以抑制效应为主,且对纤维素酶和酸性磷酸酶的抑制表现出毒性增加的协同效应.消化酶随暴露时间的响应动态规律为: 调整性反应(3 d)-激烈反应(7 d)-反应平复(14 d)-慢性暴露(28 d).慢性暴露结果显示,含高剂量(200 mg·kg^-1 Cu或4 mg·kg^-1 ENR)污染物的复合组更具生态风险性.     

氟西汀对APP/PS1双转基因阿尔茨海默病模型小鼠记忆能力的改善作用及其机制

本研究初步探讨氟西汀(Fluoxetine)改善淀粉样蛋白前体蛋白(β-amyloid precursor protein,APP)/早老素1(presenilin 1,PS1)双转基因阿尔茨海默病(Alzheimer's disease,AD)模型小鼠的学习记忆能力及可能机制。采用APP/PS1双转基因AD模型雄性小鼠,随机分成氟西汀处理组(FLU)和生理盐水组(NS),分别给予氟西汀10 mg·kg-1·d-1和等量生理盐水腹腔注射60 d。药物处理后行水迷宫检测小鼠学习记忆能力,采用尼氏染色观察海马神经元数量的变化,用免疫组化检测海马的Ach E的变化。水迷宫定位航行实验结果显示氟西汀组较生理盐水组的逃避潜伏期、总路程明显缩短(p0.05),游泳速度无明显差异;空间探索实验氟西汀组穿台次数较生理盐水组明显增加(p0.05)。尼氏染色结果显示氟西汀组在CA1区神经元数量和生理盐水组无显著性差异(p0.05),氟西汀组在DG区神经元数量比生理盐水组明显增多(p0.05)。乙酰胆碱酯酶(Ach E)免疫组化染色结果显示氟西汀组在海马CA1、DG区乙酰胆碱酯酶表达量较生理盐水组明显减少(p0.05)。穿台次数与CA1和DG区Ach E的表达量之间的有显著性的相关性(CA1区r=-0.791,p=0.002,DG区r=-0.839,p=0.001)。本研究结果提示氟西汀可通过减少AD小鼠海马DG区神经元的数量丢失和下调AD小鼠海马区Ach E表达量而改善AD模型小鼠的空间学习记忆能力。     

Impairment of the bacterial biofilm stability by triclosan

The accumulation of the widely-used antibacterial and antifungal compound triclosan (TCS) in freshwaters raises concerns about the impact of this harmful chemical on the biofilms that are the dominant life style of microorganisms in aquatic systems. However, investigations to-date rarely go beyond effects at the cellular, physiological or morphological level. The present paper focuses on bacterial biofilms addressing the possible chemical impairment of their functionality, while also examining their substratum stabilization potential as one example of an important ecosystem service. The development of a bacterial assemblage of natural composition--isolated from sediments of the Eden Estuary (Scotland, UK)--on non-cohesive glass beads (<63 μm) and exposed to a range of triclosan concentrations (control, 2-100 μg L(-1)) was monitored over time by Magnetic Particle Induction (MagPI). In parallel, bacterial cell numbers, division rate, community composition (DGGE) and EPS (extracellular polymeric substances: carbohydrates and proteins) secretion were determined. While the triclosan exposure did not prevent bacterial settlement, biofilm development was increasingly inhibited by increasing TCS levels. The surface binding capacity (MagPI) of the assemblages was positively correlated to the microbial secreted EPS matrix. The EPS concentrations and composition (quantity and quality) were closely linked to bacterial growth, which was affected by enhanced TCS exposure. Furthermore, TCS induced significant changes in bacterial community composition as well as a significant decrease in bacterial diversity. The impairment of the stabilization potential of bacterial biofilm under even low, environmentally relevant TCS levels is of concern since the resistance of sediments to erosive forces has large implications for the dynamics of sediments and associated pollutant dispersal. In addition, the surface adhesive capacity of the biofilm acts as a sensitive measure of ecosystem effects.     

Physiological effects and bioconcentration of triclosan on amphibian larvae

We examined the acute effects of triclosan (TCS) exposure, a common antimicrobial found as a contaminant in the field, on survival and physiology of amphibian larvae. LC50 values were determined after 96 h for North American larval species: Acris crepitans blanchardii, Bufo woodhousii woodhousii, Rana sphenocephala, and for a developmental model: Xenopus laevis. Amphibian larvae were most sensitive to TCS exposure during early development based upon 96-h LC50 values. Heart rates for X. laevis and North American larvae exposed to TCS were variable throughout development. Metabolic rates of X. laevis and R. sphenocephala larvae exposed to TCS were significantly affected in larvae exposed to [50% LC50] and [LC50]. Tissue uptake and tissue bioconcentration factor (BCF) of TCS were investigated in X. laevis, B. woodhousii woodhousii, and R. sphenocephala. In general, a significant increase was observed as exposure concentration increased. Tissue BCF values were dependent upon stage and species. While TCS concentrations used here are higher than environmental concentrations, exposure to TCS was dependent upon species and developmental stage, with early developmental stages being most sensitive to TCS exposure.     

Long‐term consequences of neonatal fluoxetine exposure in adult rats

Serotonin (5‐HT) plays important roles during neural development. Administration of selective serotonin reuptake inhibitor (SSRI)‐type medication during gestation may influence the maturation of the fetal brain and subsequent brain functions. To mimic the condition of late‐gestation SSRI exposure, we administered fluoxetine (FLX) in neonatal rats during the first postnatal week, which roughly corresponds to the third trimester period of human gestation. FLX‐exposed adult male rats exhibited reduced locomotor activity and depression‐like behaviors. Furthermore, sensorimotor gating capacity was also impaired. Interestingly, increased social interaction was noticed in FLX‐exposed rats. When the levels of 5‐HT and tryptophan hydroxylase were examined, no significant changes were found in FLX rats compared to control (CON) rats. The behavioral phenotypes of FLX rats suggested malfunction of the limbic system. Dendritic architectures of neurons in the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) were examined. Layer II/III mPFC pyramidal neurons in FLX rats had exuberant dendritic branches with elongated terminal segments compared to those in CON rats. In BLA pyramidal neurons, the dendritic profiles were comparable between the two groups. However, in FLX rats, the density of dendritic spines was reduced in both mPFC and BLA. Together, our results demonstrated the long‐lasting effects of early FLX treatment on emotional and social behaviors in adult rats in which impaired neuronal structure in the limbic system was also noticed. The risk of taking SSRI‐type antidepressants during pregnancy should be considered. © 2014 Wiley Periodicals, Inc. Develop Neurobiol 74: 1038–1051, 2014     

Impact of subchronic exposure to triclosan and/or fluoride on estrogenic activity in immature female rats: The expression pattern of calbindin‐D9k and estrogen receptor α genes

This study explored the influence of triclosan (TCS) in the absence and presence of sodium fluoride (NaF) on estrogenic activity and thyroid function of adolescent female rats. The results indicated that the individual exposure to TCS evoked a significant decline in T₃ and T₄ but the levels of estradiol, FSH, and LH were significantly elevated beside marked up regulation of calbindin‐D9k and estrogen α mRNA expression. On the other hand, the single exposure to NaF causes insignificant changes in thyroid hormones, but evoked a trend toward an increase in both estradiol and LH levels. No significant differences in the TSH level were recorded among the experimental groups. The joint exposure to TCS and NaF induced a significant improvement in thyroid and reproductive hormone levels. Overall, these findings revealed that exposure to TCS resulted in significant endocrine and reproductive alterations in immature female rats, while TCS + NaF coexposure resulted in lessening most effects.     

Chronic administration of fluoxetine alters locomotor behavior, but does not potentiate the locomotor stimulating effects of CRH in juvenile Chinook salmon (Oncorhynchus tshawytscha)

The present study investigated: 1) the behavioral effects of chronic administration of a serotonin uptake inhibitor (fluoxetine) in juvenile Chinook salmon, Oncorhynchus tshawytscha and, 2) whether chronic administration of fluoxetine alters the behavioral effects of corticotropin-releasing hormone (CRH). Chronic (20 day) treatment with fluoxetine decreased locomotor activity when compared to fish given long-term injections of saline. An intracerebroventricular (i.c.v.) injection of CRH had no effect on locomotor activity following a 20 day intraperitoneal treatment with either saline or fluoxetine. Chronic treatment with fluoxetine also increased the amount of time fish spent near the center of the tank. A similar increase was seen in fish given a chronic intraperitoneal (i.p.) series of saline followed by an acute i.c.v. injection of CRH. However, the effect was not additive when fish were given chronic i.p. injections of fluoxetine followed by an acute i.c.v. injection of CRH. These results provide evidence to support the hypothesis that the serotonergic system is involved in mediating locomotor activity and habitat choice in teleosts.     

Effects of long-term heat exposure on the auditory nerve-brainstem evoked responses

1. 1.|The purpose of this study was to determine whether chronic latency changes were induced in the auditory nerve-brainstem potentials (ABR) during long-term heat exposure (acclimation).

2. 2.|Latency prolongations of the ABR were observed during acute (5 days) heat exposure. This was followed by a shortening of latencies and amplitude elevation after long-term (2 months) heat exposure (acclimation).

3. 3.|It was concluded that long-term exposure to heat induces chronic changes in nervous activity.

Effects of acute and chronic introduction of fluoxetine on anxiety-depressive condition of male and female mice

The effects of acute and chronic fluoxetine treatment in intact and anxiety-depressive male and female inbred mice of the C57BL/6J strain were studied. The gender differences in the behaviour of mice in the tests estimating anxiety, locomotion and exploration activity, communication, and depressive-like state after fluoxetine injection were established. The dependence of fluoxetine treatment on normal or pathological state in mice was discovered. It was concluded that use of the animals in pathological condition and chronic (but nor acute) fluoxetine treatment are represented as the most correct estimative means of antidepressant efficiency.     

Effects of chronic cold exposure on the activities of cytochrome c oxidase, glutathione peroxidase and glutathione reductase in rat tissues (Rattus norvegicus)

The effects of cold acclimation on the activity levels of cytochrome c oxidase, glutathione peroxidase and glutathione reductase in various tissues of the rat (Rattus norvegicus) were investigated. One group was individually housed at 4 +/- 1 degrees C and the other at 24 +/- 1 degrees C for 6 months. Chronic cold acclimation resulted in significantly (P < 0.05) increased cytochrome c oxidase activity levels in liver, kidney, heart, interscapular brown adipose tissue and gastrocnemius muscle. The activity of glutathione peroxidase was significantly (P < 0.05) elevated in liver, interscapular brown adipose tissue, lung and muscle, whereas glutathione reductase was only significantly (P < 0.05) elevated in interscapular brown adipose tissue as a result of chronic cold exposure. The results obtained are possibly indicative of a positive compensatory response against the increased production of oxygen derived radicals as a result of chronic cold exposure.     

Exposure of sink drain microcosms to triclosan: population dynamics and antimicrobial susceptibility

Recent concern that the increased use of triclosan (TCS) in consumer products may contribute to the emergence of antibiotic resistance has led us to examine the effects of TCS dosing on domestic-drain biofilm microcosms. TCS-containing domestic detergent (TCSD) markedly lowered biofouling at 50% (wt/vol) but was poorly effective at use levels. Long-term microcosms were established and stabilized for 6 months before one was subjected to successive 3-month exposures to TCSD at sublethal concentrations (0.2 and 0.4% [wt/vol]). Culturable bacteria were identified by 16S rDNA sequence analysis, and their susceptibilities to four biocides and six antibiotics were determined. Microcosms harbored ca. 10 log(10) CFU/g of biofilm, representing at least 27 species, mainly gamma proteobacteria, and maintained dynamic stability. Viable cell counts were largely unaffected by TCSD exposure, but species diversity was decreased, as corroborated by denaturing gradient gel electrophoresis analysis. TCS susceptibilities ranged widely within bacterial groups, and TCS-tolerant strains (including aeromonads, pseudomonads, stenotrophomonads, and Alcaligenes spp.) were isolated before and after TCSD exposure. Several TCS-tolerant bacteria related to Achromobacter xylosoxidans became clonally expanded during dosing. TCSD addition did not significantly affect the community profiles of susceptibility to the test biocides or antibiotics. Several microcosm isolates, as well as reference bacteria, caused clearing of particulate TCS in solid media. Incubations of consortia and isolates with particulate TCS in liquid led to putative TCS degradation by the consortia and TCS solubilization by the reference strains. Our results support the view that low-level exposure of environmental microcosms to TCS does not affect antimicrobial susceptibility and that TCS is degradable by common domestic biofilms.     

Fluoxetine suppresses AMP-activated protein kinase signaling pathway to promote hepatic lipid accumulation in primary mouse hepatocytes

In the previous study, we demonstrated that fluoxetine (FLX) regulated lipogenic and lipolytic genes to promote hepatic lipid accumulation. On this basis, underlying mechanisms were investigated by focusing on the intracellular signaling transduction in the present study using primary mouse hepatocytes. The expression of lipogenesis- and lipolysis-related genes was evaluated with the application of specific activators and inhibitors. Activation status of respective signaling pathway and the lipid accumulation in hepatocytes were analyzed. We provided evidence that AMP-activated protein kinase (AMPK) activator AICAR (5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside) significantly suppressed the increased expression of representative lipogenesis-related genes, acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) by FLX, while increased the repressed expression of lipolysis-related genes, carboxylesterases. In the meanwhile, FLX regulated the above genes in the same way as AMPK inhibitor Compound C did. Furthermore, AICAR inhibited the proteolytic activation of SREBP1c induced by FLX, resulting in the decreased level of nuclear SREBP1c. Further studies demonstrated that FLX significantly suppressed the phosphorylation of AMPK and subsequent phosphorylation of ACC, following the inhibited phosphorylation and nuclear export of liver kinase B1 (LKB1). As a functional analysis, FLX-induced lipid accumulation in hepatocytes was repeatedly abolished by AICAR. In conclusion, FLX-induced hepatic lipid accumulation is mediated by the suppression of AMPK signaling pathway. The findings not only provide new insight into the understanding of the mechanisms for selective serotonin reuptake inhibitors-mediated dyslipidemia effects, but also suggest a novel therapeutic target to interfere.