Deciphering the environmental chemical basis of muscle quality decline by interpretable machine learning models.

BACKGROUND: Sarcopenia is known as a decline in skeletal muscle quality and function that is associated with age. Sarcopenia is linked to diverse health problems, including endocrine-related diseases. Environmental chemicals (ECs), a broad class of chemicals released from industry, may influence muscle quality decline. OBJECTIVE: In our work, we aim to simultaneously elucidate the associations between muscle quality decline and diverse EC exposures based on the data from the 2011-2012 and 2013-2014 survey cycles in the National Health and Nutrition Examination Survey (NHANES) project using machine learning models. METHODS: Six machine learning models were trained based on the EC and non-EC exposures from NHANES to distinguish low from normal muscle quality index status. Different machine learning metrics were evaluated for these models. The SHAP (SHapley Additive exPlanations) approach was used to provide explainability for machine learning models. RESULTS: Random Forest (RF) performed best on the independent testing dataset. Based on the testing dataset, ECs can independently predict the binary muscle quality status with good performance by RF (Area Under the Receiver Operating Characteristic Curve (AUROC) = 0.793, Area Under the Precision-Recall Curve (AUPRC) = 0.808). The SHAP ranked the importance of ECs for the RF model. As a result, several metals and chemicals in urine, including 3-phenoxybenzoic acid and cobalt, were more associated with the muscle quality decline. CONCLUSIONS: Altogether, our analyses suggest that ECs can independently predict muscle quality decline with a good performance by RF, and the SHAP-identified ECs can be closely related to muscle quality decline and sarcopenia. Our analyses may provide valuable insights into environmental chemicals that may be the important basis of sarcopenia and endocrine-related diseases in U.S.

EPRIM: An approach of identifying cancer immune-related epigenetic regulators.

Epigenetic regulation contributes to the dysregulation of gene expression involved in cancer biology. Nevertheless, the roles of epigenetic regulators (ERs) in tumor immunity and immune response remain basically unclear. Here, we developed the epigenetic regulator in immunology (EPRIM) approach to identify immune-related ERs and comprehensively dissected the ER regulation in tumor immune response across 33 cancers. The identified immune-related ERs were related to immune infiltration and could stratify cancer patients into two risk groups in multiple independent datasets. These patient groups were characterized by distinct immune functions, immune infiltrates, driver gene mutations, and prognoses. Furthermore, we constructed an immune ER-based signature and highlighted its potential utility in predicting clinical benefit from immunotherapy and selecting therapeutic agents. Taken together, our identification and evaluation of immune-related ERs highlight the usefulness of EPRIM for the understanding of ERs in immune regulation and the clinical relevance in evaluation of cancer patient prognosis and response to immune checkpoint blockade therapy.

SIRT1 Inhibits High Glucose-Induced TXNIP/NLRP3 Inflammasome Activation and Cataract Formation.

Purpose: To determine whether SIRT1 regulates high glucose (HG)-induced inflammation and cataract formation through modulating TXNIP/NLRP3 inflammasome activation in human lens epithelial cells (HLECs) and rat lenses. Methods: HG stress from 25 to 150 mM was imposed on HLECs, with treatments using small interfering RNAs (siRNAs) targeting NLRP3, TXNIP, and SIRT1, as well as a lentiviral vector (LV) for SIRT1. Rat lenses were cultivated with HG media, with or without the addition of NLRP3 inhibitor MCC950 or SIRT1 agonist SRT1720. High mannitol groups were applied as the osmotic controls. Real-time PCR, Western blots, and immunofluorescent staining evaluated the mRNA and protein levels of SIRT1, TXNIP, NLRP3, ASC, and IL-1ß. Reactive oxygen species (ROS) generation, cell viability, and death were also assessed. Results: HG stress induced a decline in SIRT1 expression and caused TXNIP/NLRP3 inflammasome activation in a concentration-dependent manner in HLECs, which was not observed in the high mannitol-treated groups. Knocking down NLRP3 or TXNIP inhibited NLRP3 inflammasome-induced IL-1ß p17 secretion under HG stress. Transfections of si-SIRT1 and LV-SIRT1 exerted inverse effects on NLRP3 inflammasome activation, suggesting that SIRT1 acts as an upstream regulator of TXNIP/NLRP3 activity. HG stress induced lens opacity and cataract formation in cultivated rat lenses, which was prevented by MCC950 or SRT1720 treatment, with concomitant reductions in ROS production and TXNIP/NLRP3/IL-1ß expression levels. Conclusions: The TXNIP/NLRP3 inflammasome pathway promotes HG-induced inflammation and HLEC pyroptosis, which is negatively regulated by SIRT1. This suggests viable strategies for treating diabetic cataract.

DAPL1 deficiency in mice impairs antioxidant defenses in the RPE and leads to retinal degeneration with AMD-like features.

The decreased antioxidant capacity in the retinal pigment epithelium (RPE) is the hallmark of retinal degenerative diseases including age-related macular degeneration (AMD). Nevertheless, the exact regulatory mechanisms underlying the pathogenesis of retinal degenerations remain largely unknown. Here we show in mice that deficiencies in Dapl1, a susceptibility gene for human AMD, impair the antioxidant capacity of the RPE and lead to age-related retinal degeneration in the 18-month-old mice homozygous for a partial deletion of Dapl1. Dapl1-deficiency is associated with a reduction of the RPE's antioxidant capacity, and experimental re-expression of Dapl1 reverses this reduction and protects the retina from oxidative damage. Mechanistically, DAPL1 directly binds the transcription factor E2F4 and inhibits the expression of MYC, leading to upregulation of the transcription factor MITF and its targets NRF2 and PGC1α, both of which regulate the RPE's antioxidant function. When MITF is experimentally overexpressed in the RPE of DAPL1 deficient mice, antioxidation is restored and retinas are protected from degeneration. These findings suggest that the DAPL1-MITF axis functions as a novel regulator of the antioxidant defense system of the RPE and may play a critical role in the pathogenesis of age-related retinal degenerative diseases.

DAPL1 prevents epithelial-mesenchymal transition in the retinal pigment epithelium and experimental proliferative vitreoretinopathy.

Epithelial-mesenchymal transition (EMT) of the retinal pigment epithelium (RPE) is a hallmark of the pathogenesis of proliferative vitreoretinopathy (PVR) that can lead to severe vision loss. Nevertheless, the precise regulatory mechanisms underlying the pathogenesis of PVR remain largely unknown. Here, we show that the expression of death-associated protein-like 1 (DAPL1) is downregulated in PVR membranes and that DAPL1 deficiency promotes EMT in RPE cells in mice. In fact, adeno-associated virus (AAV)-mediated DAPL1 overexpression in RPE cells of Dapl1-deficient mice inhibited EMT in physiological and retinal-detachment states. In a rabbit model of PVR, ARPE-19 cells overexpressing DAPL1 showed reduced ability to induce experimental PVR, and AAV-mediated DAPL1 delivery attenuated the severity of experimental PVR. Furthermore, a mechanistic study revealed that DAPL1 promotes P21 phosphorylation and its stabilization partially through NFκB (RelA) in RPE cells, whereas the knockdown of P21 led to neutralizing effects on DAPL1-dependent EMT inhibition and enhanced the severity of experimental PVR. These results suggest that DAPL1 acts as a novel suppressor of RPE-EMT and has an important role in antagonizing the pathogenesis of experimental PVR. Hence, this finding has implications for understanding the mechanism of and potential therapeutic applications for PVR.