Modern lifestyles have altered diet and metabolic homeostasis, with increased sugar intake, glycemic index, and prediabetes. A strong positive correlation between sugar consumption and diabetic incidence is revealed, but the underlying mechanisms remain obscure. Here we show that oral intake of long-term oscillating glucose (LOsG) (4 times/day) for 38 days, which produces physiological glycemic variability in rats, can lead to β-cells gaining metabolic memory in reactive oxygen species (ROS) stress. This stress leads to suppression of forkhead box O1 (FoxO1) signaling and subsequent upregulation of thioredoxin interacting protein, inhibition of insulin and SOD-2 expression, re-expression of Neurog3, and β-cell dedifferentiation and functional failure. LOsG-treated animals develop prediabetes exhibiting hypoinsulinemia and glucose intolerance. Dynamic and timely administration of antioxidant glutathione prevents LOsG/ROS-induced β-cell failure and prediabetes. We propose that ROS stress is the initial step in LOsG-inducing prediabetes. Manipulating glutathione-related pathways may offer novel options for preventing the occurrence and development of diabetes.
Background Exonuclease 1 (EXO1), a protein involved in mismatch repair and recombination processes, has been identified as a prognostic biomarker in lung adenocarcinoma (LUAD). Nevertheless, its role in LUAD progression remains elusive. This study seeks to elucidate the functional significance of EXO1 in LUAD and evaluate its potential as a therapeutic target. Materials and methods Patient RNA-seq and clinical data were acquired from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Subsequently, a protein-protein interaction (PPI) network was constructed using differentially expressed genes (DEGs) to identify pivotal genes. Validation of the expression of signature genes was carried out through quantitative real-time PCR (qRT-PCR). Additionally, the association between EXO1 expression and clinical data was investigated. Immunohistochemistry was utilized to assess EXO1 expression in 93 cases of invasive pulmonary adenocarcinoma. Finally, cellular functional assays were conducted to investigate the impact of EXO1 on LUAD cells. Results Ten key molecules (PBK, ASPM, NCAPG, EXO1, MKI67, RRM2, AURKA, DLGAP5, UBE2C, and CDC6) exhibited significantly elevated expression levels in LUAD tissues. Moreover, elevated levels of EXO1 gene expression correlated strongly with advanced T, N, and M stages and were significantly associated with immune cell infiltration in LUAD. Furthermore, marked increases in EXO1 protein expression were observed in patients diagnosed with invasive pulmonary adenocarcinoma. Notably, patients diagnosed with invasive pulmonary adenocarcinoma who exhibited elevated EXO1 expression levels exhibited increased lymph node metastasis, pleural invasion, poor tumor differentiation, and advanced clinical stage. Additionally, this study employed wound healing assay and CCK-8 cell proliferation assays to investigate the significant role of EXO1 in promoting the growth and migration of lung adenocarcinoma cells. Conclusions This study identified ten hub genes associated with the initiation and progression of LUAD. Additionally, EXO1 may serve as a prognostic marker for LUAD patients, offering new perspectives for clinical treatments.
To simultaneously determine clinical and immunological responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in young and old females and males, 681 coronavirus disease 2019 (COVID-19) patients and 369 normal controls (NCs) were analyzed based on age and sex classifications using multiple linear regression analysis. Compared to the age-matched NCs, both young and old male and female non-comorbid COVID-19 patients had lower lymphocyte counts and alanine aminotransferase (ALT) concentration, and only young male and female patients had lower neutrophil counts. Compared to young patients, both old males and females had significantly higher plasma ALT and AST concentrations. Compared to young and old females, age-matched males had higher plasma ALT and AST concentrations, but only young males had higher C-reactive protein (CRP) concentration. Compared to females, old males, but not young males, showed higher incidence of critical illness. Compared to young patients, old females had more leukocyte and neutrophil counts above the normal upper limit and B cell count below the normal lower limit (NLL), while old males had more lymphocyte and natural killer (NK) cell counts below the NLL. No sex or age associations with B cell and NK cell counts were observed. However, there were age-dependent decreases in CD8 + T-cell counts in both male and female COVID-19 patients. Age was negatively associated with CD8 + T cell counts but positively associated with neutrophil count, CRP, ALT, and AST concentrations, and sex (females) was negatively associated with neutrophil count, CRP, ALT, and AST concentrations. The present study suggests that SARS-CoV-2 infection mainly induced 1) beneficial sex (female)-related differences regarding reduced COVID-19 disease severity and negative associations with inflammatory responses and liver damage, and 2) harmful age-related differences relating to negative associations with CD8 + T cell count and positive associations with inflammatory responses and liver damage. Thus, sex and age are biological variables that should be considered in the prevention and treatment of COVID-19.
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