miRNAs in lung cancer: A link to aging

Lung cancer is a leading cause of cancer deaths worldwide. Development of lung cancer is associated with exposure to carcinogens such as tobacco smoke and some environmental factors. The incidence of lung cancer increases with age, particularly after age 60. It was estimated that less than 2% of all lung cancer cases occurred in patients younger than 45; therefore, this type of tumor can be considered as an aging-related disease. MicroRNAs (miRNAs) are small non-coding RNA molecules capable of regulating expression of over 50% of protein-coding genes. miRNAs were shown to play an extremely important role in cell functioning, affecting all biological processes, as well as development of various diseases. Expression profiles of miRNAs are known to be altered in cancer, including lung cancer, and also exhibit changes during aging. These RNA molecules are stable in tissue sections and blood and reflect tumor origin, histotype, and stage, which make them candidate diagnostic and prognostic biomarkers. miRNA mimetics or inhibitors can be delivered into a cell, with possible therapeutic implications. Here, we review the results obtained during the last several years that demonstrate the aging-related regulation of miRNAs expression, in association with their role in lung cancer initiation, progression, and resistance to anticancer therapy, as well as the possibility to use miRNAs as predictive biomarkers for treatment response.     

肠道微生物在肺癌发生发展及治疗中的研究进展

肺癌是全球恶性肿瘤相关死亡的首位病因,近年来,诸多研究发现肠道菌群在肺癌的发生发展中有着重要作用。 肠道微生物群被认为是一种人体微生物器官,其不仅具有影响人体的消化、抗感染等功能,还可通过参与免疫调节、代谢等途径影响人体对肿瘤治疗的反应。此外,微生物和宿主细胞之间的相互作用对调节局部及全身的生理功能至关重要,可以影响宿主的局部微环境及免疫系统功能,从而影响肿瘤发生发展和抗肿瘤治疗效果。本文对肠道菌群影响肺癌发生发展的机制及其在肺癌治疗中的临床意义进行综述。     

Control of ionic currents and fluid secretion by muscarinic agonists in exocrine glands

Stimulation of muscarinic receptors in exocrine glands leads to a complex set of intracellular events involving activation of a GTP-binding protein, production of inositol trisphosphate, and release of Ca²⁺ from the endoplasmic reticulum. One of the consequences of the ensuing rise in Ca²⁺ is the activation of three classes of Ca²⁺-dependent channels that are involved in the fluid secretion response of the glands. In addition, muscarinic stimulation closes the gap junction channels that link adjacent cells. Application of patch-clamp methods has helped to characterize the channels implicated in these processes. Whole-cell recordings using intracellular solutions containing GTP derivatives or inositol trisphosphate are currently used to study the chain of events that take place during muscarinic stimulation.     

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.