Glycemic Variability and CNS Inflammation: Reviewing the Connection

Glucose is the primary energy source for the brain, and exposure to both high and low levels of glucose has been associated with numerous adverse central nervous system (CNS) outcomes. While a large body of work has highlighted the impact of hyperglycemia on peripheral and central measures of oxidative stress, cognitive deficits, and vascular complications in Type 1 and Type 2 diabetes, there is growing evidence that glycemic variability significantly drives increased oxidative stress, leading to neuroinflammation and cognitive dysfunction. In this review, the latest data on the impact of glycemic variability on brain function and neuroinflammation will be presented. Because high levels of oxidative stress have been linked to dysfunction of the blood–brain barrier (BBB), special emphasis will be placed on studies investigating the impact of glycemic variability on endothelial and vascular inflammation. The latest clinical and preclinical/in vitro data will be reviewed, and clinical/therapeutic implications will be discussed.     

Dexamethasone potentiates in vitro blood-brain barrier recovery after primary blast injury by glucocorticoid receptor-mediated upregulation of ZO-1 tight junction protein

Owing to the frequent incidence of blast-induced traumatic brain injury (bTBI) in recent military conflicts, there is an urgent need to develop effective therapies for bTBI-related pathologies. Blood-brain barrier (BBB) breakdown has been reported to occur after primary blast exposure, making restoration of BBB function and integrity a promising therapeutic target. We tested the hypothesis that treatment with dexamethasone (DEX) after primary blast injury potentiates recovery of an in vitro BBB model consisting of mouse brain endothelial cells (bEnd.3). DEX treatment resulted in complete recovery of transendothelial electrical resistance and hydraulic conductivity 1 day after injury, compared with 3 days for vehicle-treated injured cultures. Administration of RU486 (mifepristone) inhibited effects of DEX, confirming that barrier restoration was mediated by glucocorticoid receptor signaling. Potentiated recovery with DEX treatment was accompanied by stronger zonula occludens (ZO)-1 tight junction immunostaining and expression, suggesting that increased ZO-1 expression was a structural correlate to BBB recovery after blast. Interestingly, augmented ZO-1 protein expression was associated with specific upregulation of the α⁺ isoform but not the α⁻ isoform. This is the first study to provide a mechanistic basis for potentiated functional recovery of an in vitro BBB model because of glucocorticoid treatment after primary blast injury.     

Resveratrol attenuates high-fat diet-induced non-alcoholic steatohepatitis by maintaining gut barrier integrity and inhibiting gut inflammation through regulation of the endocannabinoid system

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腹腔镜胆囊切除术对胆道结石合并糖尿病患者肠屏障功能的影响

目的观察胆道结石合并糖尿病患者腹腔镜胆囊切除术(LC)后肠屏障功能的变化。方法将择期行LC的126例患者分为糖尿病组41例和非糖尿病组85例。术前及术后第1、3天,采用高效液相色谱法检测尿乳果糖与甘露醇比值(L/M),并采用酶联免疫吸附法(ELISA)检测尿脂肪酸结合蛋白(IFABP)及血清D-乳酸水平。结果2组患者均成功完成手术,无中转开放手术者。糖尿病组术后肛门排气时间长于非糖尿病组,差异有统计学意义(P<0.05)。糖尿病组术后第1、3天尿L/M、血清D-乳酸、尿IFABP均高于术前及非糖尿病组,差异均有统计学意义(P<0.05)。结论合并糖尿病的胆道结石患者行LC后会加重肠屏障功能障碍程度,术前控制好血糖水平或可降低肠道功能损伤的严重程度。     

健脾化湿解毒方对急性肝损伤小鼠肠屏障功能的影响

目的:探讨健脾解毒凉血方治疗肝损伤肠屏障功能障碍的作用靶点。方法:选取C57BL/6雄性小鼠32只,随机分为正常组、模型组、中药组、培菲康组,腹腔注射硫代乙酰胺100 mg/kg造模;中药组予以健脾解毒凉血方灌胃,培菲康组给予培菲康溶液灌胃;16 h后采集小鼠血清、肝组织、小肠组织,观察小鼠肝功能、肠道组织HE染色变化,免疫组织化学染色方法观察小肠闭锁小带蛋白-1表达。结果:模型组、中药组、培菲康组小鼠的ALT、AST均显著高于正常组,模型组、中药组、培菲康组比较差异无统计学意义(P0.05)。小肠组织在光镜和电镜下均可观察到中药组病变轻于模型组和培菲康组,免疫组织化学染色在小肠上皮细胞上可见闭锁小带蛋白-1棕黄色阳性标记,模型组、中药组、培菲康组阳性标记均显著少于正常组,中药组阳性标记显著多于模型组(P0.05)。结论:健脾解毒凉血方治疗硫代乙酰胺诱导急性肝损伤小鼠,可维护肠上皮细胞紧密连接部闭锁小带蛋白-1表达,修复肠屏障功能。     

Discovery of nitazoxanide-based derivatives as autophagy activators for the treatment of Alzheimer's disease

Drug repurposing is an efficient strategy for new drug discovery. Our latest study found that nitazoxanide (NTZ), an approved anti-parasite drug, was an autophagy activator and could alleviate the symptom of Alzheimer's disease (AD). In order to further improve the efficacy and discover new chemical entities, a series of NTZ-based derivatives were designed, synthesized, and evaluated as autophagy activator against AD. All compounds were screened by the inhibition of phosphorylation of p70S6K, which was the direct substrate of mammalian target of rapamycin (mTOR) and its phosphorylation level could reflect the mTOR-dependent autophagy level. Among these analogs, compound 22 exhibited excellent potency in promoting β-amyloid (Aβ) clearance, inhibiting tau phosphorylation, as well as stimulating autophagy both in vitro and in vivo. What's more, 22 could effectively improve the memory and cognitive impairments in APP/PS1 transgenic AD model mice. These results demonstrated that 22 was a potential candidate for the treatment of AD.     

Chronic sleep loss disrupts blood–testis and blood–epididymis barriers,and reduces male fertility

Sleep loss increases blood–brain barrier permeability. As the blood–brain barrier and the blood–tissue barriers in the reproductive tract (blood–testis and blood–epididymis barriers) share common characteristics, we hypothesized that sleep restriction may also modify their barrier function. Previous reports showed that sleep loss decreased sperm viability and progressive fast mobility, which may be a consequence of altered blood–testis and blood–epididymis barrier. Therefore, we quantified changes in blood–testis and blood–epididymis barrier after sleep loss and related them to male fertility. Adult male Wistar rats were sleep restricted using the multiple‐platform technique in a protocol of 20 hr daily sleep deprivation plus 4 hr of sleep recovery in the home‐cage. At the 10th day, barrier permeability assays were performed with Na‐fluorescein, 10 kDa Cascade blue‐dextrans and Evans blue, and the expression of tight junction proteins, actin and androgen receptor was quantified. At the 10th day of sleep restriction and after sleep recovery days 1–7, males were placed with sexually receptive females, sexual behaviour was tested, and the percentage of pregnancies was calculated. Sleep restriction increased the barrier permeability to low‐ and high‐molecular‐weight tracers, and decreased the expression of tight junction proteins, actin and androgen receptor. Concomitantly, sleep restriction reduced the percentage of ejaculating males and the number of pregnancies. Sleep recovery for 2–3 days progressively re‐established fertility, as indicated by a higher percentage of ejaculating males and impregnated females. In conclusion, chronic sleep loss alters fertility concomitantly with the disruption of the blood–tissue barriers at the reproductive tract, the mechanism involves androgen signalling.     

血脑屏障通透性与接受溶栓的急性脑梗死患者预后的相关性

目的 探讨血脑屏障通透性与接受溶栓治疗的急性脑梗死患者预后的相关性。方法 纳入绵阳市盐亭县人民医院在2018年5月-2019年5月收治的急性脑梗死且接受溶栓治疗的患者共76例,随访3个月,根据预后情况分为预后良好组和预后不佳组,比较2组患者临床资料、实验室检查指标水平、血脑屏障通透性等。结果 所有研究对象随访3个月后共有8例患者失访,其中mRs评分为良好(0～1分)共32例,为预后良好组,余为预后不佳组(2～6分)共36例; 2组患者性别、BMI、梗死部位、冠心病史、高血压病史、糖尿病史、高脂血症史、脑卒中史、发病时间、吸烟史、饮酒史、家族史、应用药物、基线NIHSS评分、Cr,BUN,HDLc,LDLc,PLT,HGB,APTT,DD、空腹血糖、糖化血红蛋白水平均无明显差异(P>0.05); 预后良好组患者年龄、房颤史的比例、UA水平与预后不佳组比较均有明显差异(P<0.05); 2组患者AUC无明显差异(P>0.05); 预后良好组患者K_trans及V_P与预后不佳组比较均有明显差异(P<0.05); 进行logistics回归分析显示年龄(OR=1.190,P=0.026)、K_trans(OR=1.104,P=0.005)为预后不佳的危险因素,V_P(OR=0.556,P=0.022)为保护因素。结论 血脑屏障通透性为影响接受溶栓治疗的急性脑梗死患者预后的相关因素。