DW14006 as a direct AMPKα1 activator improves pathology of AD model mice by regulating microglial phagocytosis and neuroinflammation

Alzheimer’s disease (AD) is a progressively neurodegenerative disease with typical hallmarks of amyloid β (Aβ) plaque accumulation, neurofibrillary tangle (NFT) formation and neuronal death extension. In AD brain, activated microglia phagocytose Aβ and neuronal debris, but also aggravate inflammation stress by releasing inflammatory factors and cytotoxins. Improving microglia on Aβ catabolism and neuroinflammatory intervention is thus believed to be a promising therapeutic strategy for AD. AMP-activated protein kinase (AMPK) is highly expressed in microglia with AMPKα1 being tightly implicated in neuroinflammatory events. Since indirect AMPKα1 activators may cause side effects with undesired intracellular AMP/ATP ratio, we focused on direct AMPKα1 activator study by exploring its potential function in ameliorating AD-like pathology of AD model mice. Here, we reported that direct AMPKα1 activator DW14006 (2-(3-(7-chloro-6-(2′-hydroxy-[1,1′-biphenyl]-4-yl)-2-oxo-1,2-dihydroquinolin-3-yl)phenyl)acetic acid) effectively improved learning and memory impairments of APP/PS1 mice, and the underlying mechanisms have been intensively investigated. DW14006 reduced amyloid plaque deposition by promoting microglial o-Aβ₄₂ phagocytosis and ameliorated innate immune response by polarizing microglia to an anti-inflammatory phenotype. It selectively enhanced microglial phagocytosis of o-Aβ₄₂ by upgrading scavenger receptor CD36 through AMPKα1/PPARγ/CD36 signaling and suppressed inflammation by AMPKα1/IκB/NFκB signaling. Together, our work has detailed the crosstalk between AMPKα1 and microglia in AD model mice, and highlighted the potential of DW14006 in the treatment of AD.     

Cyclooxygenase-2 inhibition prevents stress induced amygdala activation and anxiety-like behavior

Stress is a major risk factor for the development and exacerbation of mood and anxiety disorders, and recent studies have suggested inflammatory contributions to the pathogenesis of depression. Interestingly, pharmacological inhibition of cyclooxygenase-2 (COX-2) has shown promise in the treatment of affective disorders in small scale clinical studies; however, the mechanisms by which COX-2 inhibition affects behavioral domains relevant to affective disorders are not well understood. Here, we examined the effects of pharmacological inhibition of COX-2 with the highly selective inhibitor Lumiracoxib (LMX) on anxiety-like behavior and in vivo basolateral amygdala (BLA) neural activity in response to acute restraint stress exposure. In male mice, pretreatment with LMX prevented the increase in BLA calcium transients induced by restraint stress and prevented anxiogenic behavior seen after restraint stress exposure. Specifically, acute injection of LMX 5 mg kg⁻¹ reduced anxiety-like behavior in the light–dark box (LD) and elevated-zero maze (EZM). In addition, in vivo fiber photometry studies showed that acute stress increased calcium transients and the predicted action potential frequency of BLA neurons, which was also normalized by acute LMX pretreatment. These findings indicate pharmacological inhibition of COX-2 can prevent acute stress-induced increase in BLA cellular activity and anxiety-like behavior and provides insights into the neural mechanisms by which COX-2 inhibition could affect anxiety domain symptoms in patients with affective disorders.     

Early childhood adversity in adult patients with metastatic lung cancer: Cross-sectional analysis of symptom burden and inflammation

ObjectivePsychological and physical symptoms commonly occur in patients with metastatic lung cancer and are associated with reduced quality of life and decreased survival. Previous work has associated these symptoms with inflammation. The experience of Early Childhood Adversity (ECA) is linked to chronic inflammation and may identify adult cancer patients who are at-risk for psychological and physical symptoms. We thus hypothesized that ECA in lung cancer patients would be associated with increased psychological symptoms (distress, anxiety, and depression) and physical symptoms and that this relationship would be explained by inflammation.MethodsPatients with metastatic lung cancer (n = 92) were evaluated for ECA using the Risky Families Questionnaire. Concomitant assessments were made of distress (Distress Thermometer and Problem List [DT&PL]), anxiety (Generalized Anxiety Disorder-7), depression (Patient Hospital Questionniare-9), physical symptoms (DT&PL), and inflammation (C-reactive protein [CRP]). Multivariate models were created to explain associations of ECA with depression, anxiety, distress, number of physical problems, and inflammation.ResultsECA was associated with distress (r = 0.24, p = .03), anxiety (r = 0.30, p = .004), depression (r = 0.35, p = .001), greater physical problems (r = 0.25, p = .03), younger age (r = -0.29, p = .006), and elevated CRP (r = 0.22, p = .04). Multivariate analyses of outcomes found that depression severity was independently explained by both ECA and inflammation (β = 0.37, p = .001) but not distress or anxiety, while controlling for age and sex. Number of physical problems were also associated with ECA (β = 0.35, p = .004) but not inflammation. The association between ECA and physical problems was not significant after controlling for depression.ConclusionECA is associated with increased depression and physical symptoms independent of inflammation. Moreover, depression appears to mediate the impact of ECA on physical symptoms. ECA may identify patients at risk for psychological and physical symptoms.     

淫羊藿激活内源性干细胞及其机制研究

干细胞是具有自我更新与增殖分化能力的细胞,通过激活内源性的干细胞而改善再生反应为治疗退行性疾病提供了一个新的思路。笔者在皮质酮大鼠（肾阳虚证模型）观察到淫羊藿总黄酮（EF）能促进肾上腺皮质干细胞的增殖、迁移,采用基因芯片技术发现EF对皮质酮大鼠生长激素（GH）、生长激素释放激素（GHRH）及各类促生长因子如胰岛素样生长因子结合蛋白（IGFBP）、神经生长因子（NGF）等具有显著上调作用。在自然衰老大鼠（肾虚证模型）发现EF能使多个组织的基因表达年轻化,也使老年大鼠下调的GH、GHRH及IGFBP、NGF等的表达上调。采用体外分离的胚鼠神经干细胞进一步证明淫羊藿及其提取物对干细胞具有直接促增殖作用。上述一系列的研究提示淫羊藿及其提取物对干细胞的作用可能是其拮抗糖皮质激素对下丘脑－垂体－肾上腺轴的抑制和延缓衰老的细胞学基础;也表明中医药可通过动员与提高激素、细胞因子水平激活内源性干细胞,发挥机体储备的潜力而治疗疾病。     

免疫检查点抑制剂对耐药结直肠癌的研究现状

错配修复缺陷(dMMR)/微卫星高频不稳定(MSI-H)结直肠癌因其致癌机制引起程序性细胞死亡蛋白1(PD-1)/程序性细胞死亡配体1(PD-L1)上调,对5-氟尿嘧啶(5-FU)等为基础的化疗方案产生肿瘤免疫性抵抗,出现耐药性.本文从以下几方面进行综述:dMMR/MSI-H结直肠癌耐药的特点和PD-1/PD-L1抑制...     

Le kyste hydatique du cœur. Quelle modalité d’imagerie pour un diagnostic précis ?

Cardiac echinococcosis is rare. Its spontaneous course is serious because of the risk of rupture. Its clinical manifestations are variable, often latent and misleading. The diagnosis is sometimes referred to by chest radiography. It is much facilitated by non-invasive imaging techniques in particular transesophageal and transthoracic echocardiography, CT scan and magnetic resonance imaging. The latter through a morphological and topographical analysis accurate diagnosis of hydatid cyst and its relationship to cardiac muscle and surrounding tissue. Through functional analysis in cine cyst movements relative to the heart wall, it confirms its free or fixed character in the heart chambers, determines its insertion area, its deformability, the risk of rupture and its impact on myocardial contraction. Our case illustrates the relative contribution of these different imaging techniques and their respective contributions to the identification of hydatid cyst of its wall, its contents, its relationship with the various tunics and heart chambers and its relations with the lungs and mediastinum.