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Liver aging is associated with age-related histopathological and functional changes that significantly enhance the risk of numerous diseases or disorders developing in elderly populations. 6-Bromoindirubin-3′-oxime (6BIO), a potent inhibitor of glycogen synthase kinase-3 (GSK-3), has been implicated in various age-related diseases and processes, such as tumorigenesis, neurodegeneration, and diabetes. Recent studies have also revealed that 6BIO increases autophagy in yeast, mammalian cell lines, and dopaminergic neurons, which is one of the classical mechanisms strongly associated with liver aging. However, the impact or the mechanism of action of 6BIO in liver remains entirely unknown. Here, we find that 6BIO reduces oxidative stress, improves lipid metabolism, enhances autophagy, and significantly retards liver aging via modulating the GSK-3β pathway and mTOR pathway. Our findings suggest that 6BIO could be a potential agent to protect the liver in the field of anti-aging pharmacology.

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Background Diabetic encephalopathy (DE) is a complication of type 2 diabetes mellitus (T2DM) that features Alzheimer's disease (AD)-like pathology, which can be degraded by the autophagy-lysosome pathway (ALP). Since transcription factor EB (TFEB) is a master regulator of ALP, TFEB-mediated ALP activation might have a therapeutic effect on DE, but this has yet to be investigated. Methods We established T2DM mouse models and cultured HT22 cells under high-glucose (HG) conditions to confirm the role of ALP in DE. To further investigate this, both mice and HT22 cells were treated with 3-methyladenine (3-MA). We also analyzed the content of TFEB in the nucleus and cytoplasm to evaluate its role in ALP. To confirm the effect of TFEB activation at the post-translational level in DE, we used rapamycin to inhibit the mechanistic target of rapamycin (mTOR). We transduced both mice and cells with TFEB vector to evaluate the therapeutic effect of TFEB overexpression on DE. Conversely, we conducted TFEB knockdown to verify its role in DE in another direction. Results We found that T2DM mice experienced compromised cognitive function, while HG-cultured HT22 cells exhibited increased cell apoptosis. Additionally, both T2DM mice and HG-cultured HT22 cells showed impaired ALP and heavier AD-like pathology. This pathology worsened after treatment with 3-MA. We also observed decreased TFEB nuclear translocation in both T2DM mice and HG-cultured HT22 cells. However, inhibiting mTOR with rapamycin or overexpressing TFEB increased TFEB nuclear translocation, enhancing the clearance of ALP-targeted AD-like pathology. This contributed to protection against neuronal apoptosis and alleviation of cognitive impairment. Conversely, TFEB knockdown lessened ALP-targeted AD-like pathology clearance and had a negative impact on DE. Conclusion Our findings suggest that impaired ALP is responsible for the aggravation of AD-like pathology in T2DM. We propose that mTOR-dependent TFEB activation and TFEB overexpression are promising therapeutic strategies for DE, as they enhance the clearance of ALP-targeted AD-like pathology and alleviate neuronal apoptosis. Our study provides insight into the underlying mechanisms of DE and offers potential avenues for the development of new treatments for this debilitating complication of T2DM. Graphic Abstract

Background Appropriate levels of blood oxygen are crucial for critically ill patients. However, the optimal oxygen saturation has not been confirmed for AECOPD patients during their ICU stays. The purpose of this study was to determine the optimal oxygen saturation range target to reduce mortality for those individuals. Methods Data of 533 critically ill AECOPD patients with hypercapnic respiratory failure from the MIMIC-IV database were extracted. The association between median SpO2 value during ICU stay and 30days mortality was analyzed by LOWESS curve, and an optimal range of SpO2(92–96%) platform was observed. Comparisons between subgroups and linear analyses of the percentage of SpO2 in 92–96% and 30days or 180 days mortality were performed to support our view further. Methods Although patients with 92–96% SpO2 had a higher rate of invasive ventilator than those with 88–92%, there was no significant increase in the adjusted ICU stay duration, non-invasive ventilator duration, or invasive ventilator duration while leading to lower 30days and 180days mortality in the subgroup with 92–96%. In addition, the percentage of SpO2 in 92–96% was associated with decreased hospital mortality. Conclusion In conclusion, SpO2 within 92–96% could lead to lower mortality than 88–92% and > 96% for AECOPD patients during their ICU stay.

Background In neuroblastoma, hyperactivation of the PI3K signaling pathway has been correlated with aggressive neuroblastomas, suggesting PI3Ks as promising targets for the treatment of neuroblastoma. However, the oncogenic roles of individual PI3K isoforms in neuroblastoma remain elusive. Results We found that PI3K isoform p110α was expressed at higher levels in neuroblastoma tissues compared with normal tissues, and its high expression was correlated with an unfavorable prognosis of neuroblastoma. Accordingly, PI3K activation in neuroblastoma cells was predominantly mediated by p110α but not by p110β or p110δ. Suppression of p110α inhibited the growth of neuroblastoma cells both in vitro and in vivo, suggesting a crucial role of p110α in the tumorigenesis of neuroblastoma. Mechanistically, inhibition of p110α decreased anaplastic lymphoma kinase (ALK) in neuroblastoma cells by decreasing its protein stability. Conclusions In this study, we investigated the oncogenic roles of PI3K isoforms in neuroblastoma. Our data shed light on PI3K isoform p110α in the tumorigenesis of neuroblastoma, and strongly suggest the p110α inhibitors as potential drugs in treating neuroblastoma.