Light Environment Influences Developmental Programming of the Metabolic and Visual Systems in Mice

PurposeLight is a salient cue that can influence neurodevelopment and the immune system. Light exposure out of sync with the endogenous clock causes circadian disruption and chronic disease. Environmental light exposure may contribute to developmental programming of metabolic and neurological systems but has been largely overlooked in Developmental Origins of Health and Disease (DOHaD) research. Here, we investigated whether developmental light exposure altered programming of visual and metabolic systems.MethodsPregnant mice and pups were exposed to control light (12:12 light:dark) or weekly light cycle inversions (circadian disruption [CD]) until weaning, after which male and female offspring were housed in control light and longitudinally measured to evaluate differences in growth (weight), glucose tolerance, visual function (optomotor response), and retinal function (electroretinogram), with and without high fat diet (HFD) challenge. Retinal microglia and macrophages were quantified by positive Iba1 and CD11b immunofluorescence.ResultsCD exposure caused impaired visual function and increased retinal immune cell expression in adult offspring. When challenged with HFD, CD offspring also exhibited altered retinal function and sex-specific impairments in glucose tolerance.ConclusionsOverall, these findings suggest that the light environment contributes to developmental programming of the metabolic and visual systems, potentially promoting a pro-inflammatory milieu in the retina and increasing the risk of visual disease later in life.     

IGFBP-3 Mediates Metabolic Homeostasis During Hyperosmolar Stress in the Corneal Epithelium

PurposeThe insulin-like growth factor binding protein-3 (IGFBP-3) is a multifunctional secretory protein with well-known roles in cell growth and survival. Data in our laboratory suggest that IGFBP-3 may be functioning as a stress response protein in the corneal epithelium. The purpose of this study is to determine the role of IGFBP-3 in mediating the corneal epithelial cell stress response to hyperosmolarity, a well-known pathophysiological event in the development of dry eye disease.MethodsTelomerase-immortalized human corneal epithelial (hTCEpi) cells were used in this study. Cells were cultured in serum-free media with (growth) or without (basal) supplements. Hyperosmolarity was achieved by increasing salt concentrations to 450 and 500 mOsM. Metabolic and mitochondrial changes were assessed using Seahorse metabolic flux analysis and assays for mitochondrial calcium, polarization and mtDNA. Levels of IGFBP-3 and inflammatory mediators were quantified using ELISA. Cytotoxicity was evaluated using a lactate dehydrogenase assay. In select experiments, cells were cotreated with 500 ng/mL recombinant human (rh)IGFBP-3.ResultsHyperosmolar stress altered metabolic activity, shifting cells towards a respiratory phenotype. Hyperosmolar stress further altered mitochondrial calcium levels, depolarized mitochondria, decreased levels of ATP, mtDNA, and expression of IGFBP-3. In contrast, hyperosmolar stress increased production of the proinflammatory cytokines IL-6 and IL-8. Supplementation with rhIGFBP-3 abrogated metabolic and mitochondrial changes with only marginal effects on IL-8.ConclusionsThese findings indicate that IGFBP-3 is a critical protein involved in hyperosmolar stress responses in the corneal epithelium. These data further support a new role for IGFBP-3 in the control of cellular metabolism.     

Differential expression of the TL1A/DcR3 system of TNF/TNFR-like proteins in large vs. small intestinal Crohn's disease

Background

TNF-like cytokine 1A provides co-stimulatory signals to activated lymphocytes through binding to death-domain receptor-3. Decoy receptor-3 inhibits death-domain receptor-3 signalling, rendering immunocytes resistant to apoptosis. These functions may be important for the pathogenesis of Crohn's disease.

Aims

To study the mucosal and systemic expression of Decoy receptor-3 and TNF-like cytokine 1A in Crohn's disease, in relation to disease activity, localization, and response to treatment.

Methods

Soluble Decoy receptor-3 and TNF-like cytokine 1A were measured by ELISA in active or quiescent Crohn's disease. Relative mRNA expression in non-affected and inflamed intestinal mucosa was determined by real-time RT-PCR.

Results

We found significant upregulation of Decoy receptor-3 and its ligands TNF-like cytokine 1A and FasL in inflamed intestinal mucosa of Crohn's disease patients. During active disease, Decoy receptor-3 and TNF-like cytokine 1A were detected in the serum in the majority of patients. Intestinal inflammation was strongly associated with these elevations as they were absent during remission and significantly reduced with anti-inflammatory treatment. Regional diversity was observed as Decoy receptor-3 was upregulated in colonic and ileal sites, whereas TNF-like cytokine 1A was preferentially induced in the large bowel mucosa and systemic circulation of patients with colonic involvement.

Conclusions

TNF-like cytokine 1A and Decoy receptor-3 are upregulated during active Crohn's disease and may participate in disease pathogenesis and offer novel therapeutic opportunities.     

维生素D缺乏与干眼关系的研究进展

干眼是泪液和眼球表面的多因素疾病,能引起不适、视觉障碍和泪膜不稳定,可能损害眼表,伴有泪液渗透压升高和眼表炎症。维生素D是一种脂溶性维生素,在皮肤中产生或随食物摄取,具有多种功能,对骨骼、肠道、肾脏,特别是免疫系统等有重要的调节作用。近年研究发现,维生素D缺乏与干眼存在密切联系。本文就维生素D缺乏与干眼之间的关系进行综述。     

肾素血管紧张素系统与微炎症

高血压、糖尿病、脂质代谢紊乱和肥胖常常簇集出现而形成代谢综合征,严重影响公众的健康水平。近年来,代谢性疾病的微炎症背景备受学者关注,微炎症状态与代谢性疾病的发生发展密切关联。肾素一血管紧张素系统（RAS）,除了血流动力学调节作用外,在微炎症反应中也发挥重要的作用。阻断RAS,对代谢性疾病具有一定的保护作用。目前已证实,RAS主要通过血管紧张素转换酶一血管紧张素1I-ATl受体（ACE-AnglI-ATlR）轴和ACE2-Ang（1-7）-Mas轴发挥作用,这两条途径具有相反的生物学活性,后者对前者有拈抗作用。血管紧张素Ⅱ（AngII）由血管紧张素Ⅱ受体介导通过多种机制发挥致炎作用,而Ang（1-7）可以拮抗AngII,抑制炎症反应。本文就RAS参与微炎症反应的相关机制做一综述。     

小梁网细胞氧化应激在青光眼发病中的研究进展

青光眼是一种常见的不可逆性致盲眼病,病理性眼压升高为主要临床特征。眼压的形成与房水循环密切相关,房水动力学异常,会引起病理性眼压升高。小梁网是房水外流通道的主要组成部分,对维持正常眼压起到非常关键的作用。氧化应激是导致青光眼眼压升高的直接危险因素,表现为氧化与抗氧化作用的失衡。小梁网细胞氧化应激可能导致细胞外基质的沉积与退行性变,使细胞发生自噬和衰老,造成小梁网细胞功能障碍,最终导致房水外流阻力增大,引起病理性眼压升高。本文将针对小梁网细胞氧化应激与青光眼关系的研究进展进行综述,以期为进一步的临床研究提供依据,为探讨青光眼的发病机制、预防及治疗青光眼提供参考。     

复方牛胎肝提取物联合阿德福韦酯治疗慢性乙型肝炎疗效观察

目的观察复方牛胎肝提取物片联合阿德福韦酯片治疗慢性乙型肝炎患者对肝纤维化的临床疗效。方法将42例慢性乙型肝炎患者随机分为治疗组21例,给予口服复方牛胎肝提取物片及阿德福韦酯片和对照组21例,给予口服阿德福韦酯片,疗程均为48周。观察两组患者在治疗前及治疗48周后两次肝穿刺活检病理学变化和血清透明质酸（HA）的变化。结果治疗后治疗组肝组织炎症活动度2例加重,10例无明显变化,9例减轻,对照组肝组织炎症活动度6例加重,12例无明显变化,3例减轻。治疗组肝脏炎症活动度改善优于对照组,差异有显著性（P=0.029）;治疗组纤维化程度2例加重,10例无明显变化,9例减轻,对照组纤维化程度9例加重,9例无明显变化,3例减轻。治疗组纤维化程度改善明显优于对照组,差异有显著性（P=0.006）;治疗组治疗后HA下降明显（P〈0.001）,对照组未见降低,两组间差异有显著性（P〈0.001）。结论复方牛胎肝提取物片联合阿德福韦酯片能显著地改善肝脏炎症活动度和纤维化程度,优于单用阿德福韦酯治疗。     

系统性炎症与慢性阻塞性肺疾病大动脉弹性的相关性研究

目的 探讨慢性阻塞性肺疾病( COPD)患者系统性炎症与大动脉弹性之间的关系.方法 采用病例对照研究的方法,研究对象分为两组:病例组:102例COPD稳定期患者;对照组:83例同期健康体检者.两组研究对象用同样的方法应用脉搏波速度自动测定仪测定颈-股动脉搏波传导速度(C-FPWV)和颈-足背动脉搏波传导速度(C-DPWV)作为大动脉弹性的参数,应用免疫比浊法测定血清超敏C反应蛋白(hs-CRP)浓度,放射免疫分析法测定血清白介素1(IL-1)、白介素6(IL-6)、肿瘤坏死因子α(TNF-α)浓度,这些炎性因子的测定作为系统性炎症的参数,与正常对照组作比较.结果 ①病例组C-FPWV、C-DPWV、IL-1、IL-6、TNF-α、hs-CRP均高于正常对照组,差异有统计学意义,P＜0.05.②病例组C-FPWV与年龄、吸烟指数、收缩压、IL-1、IL-6、TNF-α、hs-CRP呈正相关,P＜0.05.C-DPWV与年龄、吸烟指数、IL-1、IL-6、TNF-α、hs-CRP呈正相关,P＜0.05.③IL-6、吸烟指数、TNF-α是影响C-FPWV的独立因素;IL-6是影响GDPWV的独立因素.结论 系统性炎症与COPD患者大动脉弹性间存在相关性.系统性炎症可能参与了COPD患者大动脉弹性下降的发病过程,它是COPD患者发生心血管疾病的高危因素.     

白血病抑制因子与支气管哮喘

在支气管哮喘(简称哮喘)的发病过程中,机体神经、免疫与内分泌系统均参与其中,它是一个多步骤的过程,涉及到大量的细胞因子、炎症介质和神经递质.白血病抑制因子(leukemia inhibitory factor,LIF)是连接神经-免疫-内分泌系统网络的桥梁,LIF通过调节多种炎症细胞,如嗜酸粒细胞、淋巴细胞和肥大细胞等,促进炎性介质的释放;促进气道感觉神经末梢释放P物质等神经肽,上调气道上皮细胞神经激肽-1受体(neurokinin-1 receptor,NK-1R)的表达,诱发气道神经源性炎症;此外,LIF还可下调糖皮质激素受体的表达,导致糖皮质激素抵抗.因此LIF水平在哮喘患者血清、痰液、支气管肺泡灌洗液、支气管黏膜中均可有所升高.本文就LIF的生物学特征以及与哮喘发病的关系作一综述,旨在为探讨哮喘的发病机制和临床治疗提供理论依据.     

小胶质细胞在病毒性中枢神经系统感染中的作用

小胶质细胞是中枢神经系统中的免疫细胞,是中枢神经系统抵抗病原体入侵的第一道防线。当病原微生物进入脑组织后,小胶质细胞迅速做出反应,识别、吞噬病原微生物,呈递抗原和分泌多种生物活性物质。但是,小胶质细胞的过度活化又可诱发中枢神经系统免疫病理损伤或神经退行性病变。因而,具有生理和病理双重作用。本文就小胶质细胞在病毒感染性中枢神经系统疾病中的作用及其机制进行综述。