RESUMO
Ischemic stroke represents a significant danger to human beings, especially the elderly. Interventions are only available to remove the clot, and the mechanism of neuronal death during ischemic stroke is still in debate. Ferroptosis is increasingly appreciated as a mechanism of cell death after ischemia in various organs. Here we report that the serine protease, thrombin, instigates ferroptotic signaling by promoting arachidonic acid mobilization and subsequent esterification by the ferroptotic gene, acyl-CoA synthetase long-chain family member 4 (ACSL4). An unbiased multi-omics approach identified thrombin and ACSL4 genes/proteins, and their pro-ferroptotic phosphatidylethanolamine lipid products, as prominently altered upon the middle cerebral artery occlusion in rodents. Genetically or pharmacologically inhibiting multiple points in this pathway attenuated outcomes of models of ischemia in vitro and in vivo. Therefore, the thrombin-ACSL4 axis may be a key therapeutic target to ameliorate ferroptotic neuronal injury during ischemic stroke.
Assuntos
Isquemia Encefálica , Coenzima A Ligases , Ferroptose , Trombina , Idoso , Isquemia Encefálica/genética , Coenzima A Ligases/genética , Coenzima A Ligases/metabolismo , Ferroptose/fisiologia , Humanos , Reperfusão , Trombina/genética , Trombina/metabolismoRESUMO
The spreading of misfolded alpha-synuclein (α-syn) protein has been observed in animal models of Parkinson's disease (PD) and other α-synucleinopathies that mimic human PD pathologies. In animal models, the spreading of α-syn has been associated with motor dysfunction and neuronal death. However, variability in both susceptible brain regions and cellular populations limits our understanding of the consequences of α-syn spreading and the development of associated therapies. Here, we have reviewed the physiological and pathological functions of α-syn and summarized the susceptible brain regions and cell types identified from human postmortem studies and exogenous α-syn injection-based animal models. We have reviewed the methods for inducing α-syn aggregation, the specific hosts, the inoculation sites, the routes of propagation, and other experimental settings that may affect the spreading pattern of α-syn, as reported in current studies. Understanding the spread of α-syn to produce a consistent PD animal model is vital for future drug discovery.
Assuntos
Doença de Parkinson , Sinucleinopatias , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Doença de Parkinson/metabolismo , alfa-Sinucleína/metabolismoRESUMO
Regardless of the impressive progress that perovskite solar cells (PSCs) have achieved, especially considering their power conversion efficiency (PCE) over 25%, traditional PSCs still contend with an inherent instability with exposure to humidity, which remains as a critical issue for the realization of commercial production. Herein, we proposed an effective pathway to relieve the instability of PSCs without sacrificing efficiency by introducing a 2D phase at the surface of the 3D perovskite film, based on a novel organic cyclohexylmethylammonium iodide (CMAI). The self-assembled thin 2D capping layer atop the 3D perovskite layer can not only reduce the ionic defects, but also serve as a protective barrier against moisture. Consequently, the champion device incorporating 2D perovskite capping layers delivered an open-circuit voltage (Voc) of 1.19 V, which contributes to an impressive PCE of 22.06% on account of the improved charge extraction and decreased non-radiative recombination. More importantly, an excellent long-term stability along with mitigated hysteresis was observed for the modified devices as a result of the suppressed ion migration and high humidity resistance of the 2D perovskite film. Our finding provides a comprehensive approach for simultaneously enhancing the efficiency and stability of PSCs through dimension engineering utilizing CMA-based 2D perovskite materials.
RESUMO
Vascular cognitive impairment (VCI) refers to the entire spectrum of vascular brain pathologies that contribute to cognitive deficits, ranging from subjective cognitive decline to dementia. The main pathologies in VCI are infarcts and white matter hyperintensities due to ischemia. VCI rodent models can be divided into surgical models (e.g., MCAO, BCAO, BCAS, 2-VO, 4-VO) and genetic models (e.g., SHR/SP, T2DM, CAA, CADASIL) based on construction methods. However, no single model can fully recapitulate the pathogenesis of VCI, and choosing the appropriate model for different research purposes would be of crucial importance. Here, we have summarized the commonly used rodent VCI models and discussed their advantages and limitations to provide a necessary reference for selecting suitable animal models to investigate the molecular pathways involved in VCI and develop therapeutic interventions.
Assuntos
Demência Vascular/patologia , Modelos Animais de Doenças , Animais , Demência Vascular/etiologia , Demência Vascular/genética , RoedoresRESUMO
The molecular mechanisms underlying autism spectrum disorder (ASD) remain elusive, which limits the management options available in the clinic. Accumulating evidence indicates that the pineal gland/melatonin system is associated with the progression of ASD. Here, we review recent advances in our understanding of various mechanisms involving pathological process of ASD, including the abnormal breakdown of melatonin synthesis, the disturbance of intracellular MTNR1A signaling, the effects exerted by melatonin on hippocampal protein serine/threonine kinases, and immune dysregulation/inflammation during ASD. We believe that an in-depth understanding of the interplay between the action of the melatonin system and the onset of autism could promote the development of novel therapeutic strategies against ASD. We anticipate that targeting the neurotransmitters upstream pathway and downstream of melatonin in brain will lead to potential therapeutic treatment for ASD.