Conserved mechanisms of self-renewal and pluripotency in mouse and human ESCs regulated by simulated microgravity using a 3D clinostat.

Embryonic stem cells (ESCs) exhibit unique attributes of boundless self-renewal and pluripotency, making them invaluable for fundamental investigations and clinical endeavors. Previous examinations of microgravity effects on ESC self-renewal and differentiation have predominantly maintained a descriptive nature, constrained by limited experimental opportunities and techniques. In this investigation, we present compelling evidence derived from murine and human ESCs, demonstrating that simulated microgravity (SMG)-induced stress significantly impacts self-renewal and pluripotency through a previously unidentified conserved mechanism. Specifically, SMG induces the upregulation of heat shock protein genes, subsequently enhancing the expression of core pluripotency factors and activating the Wnt and/or LIF/STAT3 signaling pathways, thereby fostering ESC self-renewal. Notably, heightened Wnt pathway activity, facilitated by Tbx3 upregulation, prompts mesoendodermal differentiation in both murine and human ESCs under SMG conditions. Recognizing potential disparities between terrestrial SMG simulations and authentic microgravity, forthcoming space flight experiments are imperative to validate the impact of reduced gravity on ESC self-renewal and differentiation mechanisms.

α-Synuclein Negatively Regulates Nurr1 Expression Through NF-κB-Related Mechanism.

The nuclear receptor-related 1 protein (Nurr1) is critical for the development and survival of midbrain dopamine neurons that are predominantly affected and progressively degenerated in Parkinson's disease (PD). The expression level of Nurr1 has been proposed to be modulated by α-synuclein (α-SYN), an important pathological hallmark of PD. However, the underlying molecular mechanisms of α-SYN-Nurr1 interaction are still rarely explored. In this study, we investigated the effect and mechanism of α-SYN on the transcription level of Nurr1. Our results showed that overexpression of α-SYN (WT or A53T) reduced Nurr1 and its downstream gene expressions. α-SYN neither affected the mRNA stability nor bound with the promoter of Nurr1, but modulated the transcription activity of Nurr1 promoter region ranging from -605 bp to -418 bp, which contains the binding site of nuclear factor-kappa B (NF-κB). Moreover, overexpression of α-SYN (WT or A53T) down-regulated NF-κB expression level, thereby inhibiting the transcription factor activity of NF-κB and decreasing the binding quantity of NF-κB with Nurr1 promoter. These findings may give us new insights to better understand the molecular mechanisms underlying the α-SYN-regulated Nurr1 function, which may fascinate the investigation of dopamine neuron degeneration in PD pathogenesis.

Altered Expression Levels of MicroRNA-132 and Nurr1 in Peripheral Blood of Parkinson's Disease: Potential Disease Biomarkers.

MicroRNAs (miRNAs) are small and evolutionary conserved noncoding RNAs that are involved in post-transcriptional gene regulation. Differential expression levels of miRNAs can be used as potential biomarkers of disease. Previous animal studies have indicated that the expression level of miR-132 is negatively correlated with its downstream molecule nuclear receptor related 1 protein (Nurr1), which is one of the key factors for the maintenance of dopaminergic function and is particularly vulnerable in Parkinson's disease (PD). However, this correlation has not been confirmed in human patients with PD. Moreover, the possible involvement of miR-132 during the pathogenesis and progression of PD is not fully investigated. Therefore, in the present study, we determined the peripheral circulation levels of miR-132 and Nurr1 in patients with PD, neurological disease controls (NDC) and healthy controls (HC) by reverse transcription real-time quantitative PCR (RT-qPCR). Our data clearly demonstrated that the plasma miR-132 level in PD was significantly higher than those in HC (178%, p < 0.05) and NDC (188%, p < 0.001). When adjusted for gender and age, higher level of miR-132 expression was associated with the significantly increased risk for PD in males and was closely related with the disease stages and disease severity. Furthermore, peripheral Nurr1 was significantly decreased in PD compared with HC (56%, p < 0.001) and NDC (58%, p < 0.001). Much more interestingly, further analysis revealed a negative correlation between the decreased Nurr1 level and the elevated miR-132 level in PD. All these findings indicated that the combination of a high miR-132 level with the low level of its downstream Nurr1 might be a potential biomarker aiding in the diagnosis of PD and monitoring disease progression.

Impacts of Acute Hypoxia on Alzheimer's Disease-Like Pathologies in APPswe/PS1dE9 Mice and Their Wild Type Littermates.

Alzheimer's disease (AD) is the most common form of dementia and pathologically featured by ß-amyloid (Aß) plaque deposition and hyper-phosphorylated tau aggregation in the brain. Environmental factors are believed to contribute to the pathogenesis and progression of AD. In the present study, we investigated the impacts of acute hypoxia on Aß and tau pathologies, neuroinflammation, mitochondrial function, and autophagy in APPswe/PS1dE9 AD mouse model. Male APPswe/PS1dE9 transgenic (Tg) mice and their age-matched wild type (Wt) littermates were exposed to one single acute hypoxic episode (oxygen 7%) for 24 h. We found that acute hypoxia exposure increased the expressions of amyloid precursor protein (APP), anterior pharynx-defective 1 (APH1) and cyclin-dependent kinase 5 (CDK5), and promoted tau phosphorylation at T181 and T231 residues in both Tg and Wt mice. In addition, acute hypoxia also induced autophagy through the mammalian target of rapamycin (mTOR) signaling, elicited abnormal mitochondrial function and neuroinflammation in both Tg and Wt mice. In summary, all these findings suggest that acute hypoxia could induce the AD-like pathological damages in the brain of APPswe/PS1dE9 mice and Wt mice to some extent.