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Wei Wei,1,2,* Yongli Pan,2,3,* Xinyu Yang,4 Zhonglun Chen,1 Yue Heng,1 Bufan Yang,1 Mingjun Pu,1 Jiacai Zuo,1 Zhuhong Lai,5 Yufeng Tang,1 Wenqiang Xin2,4 1Department of Neurology, Mianyang Central Hospital, Mianyang, Sichuan, People’s Republic of China; 2Department of Neurology, University Medical Center of Göttingen, Georg-August-University of Göttingen, Göttingen, Lower Saxony, Germany; 3Department of Neurology, Weifang Medical University, Weifang, Shandong, People’s Republic of China; 4Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China; 5Department of Cardiology, Mianyang Central Hospital, Mianyang, Sichuan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wenqiang Xin, Department of Neurosurgery, Tianjin Medical University General Hospital, Anshan Road No. 154, Tianjin, 300052, People’s Republic of China, Tel +86– 18526201182, Fax +86– 2260362062, Email xinwenqiangdr@126.com Wei Wei, Department of Neurology, Mianyang Central Hospital, Changjia Lane No. 12, Mianyang, 621000, People’s Republic of China, Tel +86– 15983634286, Fax +86-8162222566, Email weiwei1990sci@163.comAbstract: Eukaryotic cells release different types of extracellular vesicles (EVs), including exosomes, apoptotic bodies and microvesicles. EVs carry proteins, lipids and nucleic acids specific to cells and cell states. Autophagy is an intracellular degradation process, which, along with EVs, can significantly affect the development and progression of neurological diseases and, therefore, has been the hotspot. Generally, EVs and autophagy are closely associated. EVs and autophagy can interact with each other. On the one hand, the level of autophagy in target cells is closely related to the secretion and transport of EVs. In another, the application of EVs provides a great opportunity for adjuvant treatment of neurological disorders, for which autophagy is an excellent target. EVs can release their cargos into target cells, which, in turn, regulate the autophagic level of target cells through autophagy-related proteins directly and the non-coding RNA, signal transducer and activator of transcription 3 (STAT3), phosphodiesterase enzyme (PDE) 1-B, etc. signaling pathways indirectly, thus regulating the development of related neurological disorders.Keywords: extracellular vesicle, autophagy, neurological disorders, non-coding RNA, STAT3, PDE1-B

Hypoxia is a central pathophysiological component in cancer, myocardial infarction and ischemic stroke, which represent the most common medical conditions resulting in long-term disability and death. Recent evidence suggests common signaling pathways in these diverse settings mediated by non-coding RNAs (ncRNAs), which are packaged in extracellular vesicles (EVs) protecting ncRNAs from degradation. EVs are a heterogeneous group of lipid bilayer-covered vesicles released from virtually all cells, which have important roles in intercellular communication. Recent studies pointed out that ncRNAs including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) are selectively sorted into EVs, modulating specific aspects of cancer development, namely cell proliferation, migration, invasion, angiogenesis, immune tolerance or drug resistance, under conditions of hypoxia in recipient cells. In myocardial infarction and stroke, ncRNAs shuttled via EVs have been shown to control tissue survival and remodeling post-hypoxia by regulating cell injury, inflammatory responses, angiogenesis, neurogenesis or neuronal plasticity. This review discusses recent evidence on EV-associated ncRNAs in hypoxic cancer, myocardial infarction and stroke, discussing their cellular origin, biological function and disease significance. The emerging concept of lncRNA-circular RNA/ miRNA/ mRNA networks is outlined, upon which ncRNAs synergistically respond to hypoxia in order to modify disease responses. Particular notion is given to ncRNAs participating in at least two of the three conditions, which revealed a large degree of overlaps across pathophysiological conditions. Possible roles of EV-ncRNAs as therapeutic products or theranostic markers are defined.

Yongli Pan,1,2,* Ting Wang,3,* Zhiqiang Zhao,4,* Wei Wei,2,5,* Xinyu Yang,6 Xianbin Wang,7 Wenqiang Xin2,6 1Department of Neurology, Weifang Medical University, Weifang, Shandong, People’s Republic of China; 2Georg-August-University of Göttingen, Göttingen, Lower Saxony, Germany; 3Department of Radiology, The Second Affiliated Hospital of Baotou Medical College, Baotou, 014030, People’s Republic of China; 4Department of Neurosurgery, Heji Hospital affiliated Changzhi Medical College, Shanxi, People’s Republic of China; 5Department of Neurology, Mianyang Central Hospital, Mianyang, Sichuan, People’s Republic of China; 6Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China; 7Department of Emergency Medicine, The Second Affiliated Hospital of Baotou Medical College, Baotou, 014030, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wenqiang XinDepartment of Neurosurgery, Tianjin Medical University General Hospital, Anshan Road No. 154, Tianjin, 300052, People’s Republic of ChinaTel +86– 18526201182, Fax +86– 2260362062, Email xinwenqiangdr@126.com Xianbin WangDepartment of Emergency Medicine, The Second Affiliated Hospital of Baotou Medical College, Baotou, 014030, People’s Republic of ChinaEmail wangxianbin198006@163.comAbstract: Nuclear paraspeckle assembly transcript 1 (Neat1) located at chromosome 11 is a long non-coding RNA that is widely expressed in mammalian cell types, and which is overexpressed in several inflammation-related disorders. Inflammation implies a plethora of mutual interactions between both soluble factors and cells due to various stimuli including tissue injury. Although there is no doubt that inflammation is critically involved in multiple biological and pathological processes alike, the precise mechanisms being involved are still open for debate. In this context, the role of Neat1 as a regulator of inflammation, microglial activation, and lipid accumulation under various inflammatory conditions remains elusive. Herein, we review the regulation of Neat1 and how it modulates the expression of its target genes. Thereafter, we will review the impact of Neat1 on inflammation by activating or inhibiting various signaling pathways, such as microRNAs, AKT, TLR4, TRAF6, and NF-κB.Keywords: Neat1, inflammation, microglia, lipids, microRNA, NF-κB

Yongli Pan,1,* Qingzheng Jiao,2,* Wei Wei,3,* Tianyang Zheng,4,* Xinyu Yang,5 Wenqiang Xin5 1Department of Neurology, Weifang Medical University, Weifang, Shandong, People’s Republic of China; 2Second Department of Internal Medicine, Gucheng County Hospital, Gucheng, Hebei, People’s Republic of China; 3Department of Neurology, Mianyang Central Hospital, Mianyang, Sichuan, People’s Republic of China; 4Department of Neurosurgery, The First Hospital of Jilin University, Changchun, Jilin, People’s Republic of China; 5Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wenqiang XinDepartment of Neurosurgery, Tianjin Medical University General Hospital, Anshan Road No. 154, Tianjin, 300052, People’s Republic of ChinaTel +86– 185 26201182Fax +86– 22 60362062Email xinwenqiangdr@126.comAbstract: As a crucial kind of pervasive gene, long noncoding RNAs (lncRNAs) are abundant and key players in brain function as well as numerous neurological disorders, especially ischemic stroke. The mechanisms underlying ischemic stroke include angiogenesis, autophagy, apoptosis, cell death, and neuroinflammation. Inflammation plays a vital role in the pathological process of ischemic stroke, and systemic inflammation affects the patient’s prognosis. Although a great deal of research has illustrated that various lncRNAs are closely relevant to regulate neuroinflammation and microglial activation in ischemic stroke, the specific interactional relationships and mechanisms between lncRNAs and neuroinflammation have not been described clearly. This review aimed to summarize the therapeutic effects and action mechanisms of lncRNAs on ischemia by regulating inflammation and microglial activation. In addition, we emphasize that lncRNAs have the potential to modulate inflammation by inhibiting and activating various signaling pathways, such as microRNAs, NF‐κB and ERK.Keywords: ischemic stroke, long noncoding RNA, microglia, neuroinflammation