The FASEB Journal最新文献

Pathological fatigue has emerged as a significant contributor to cardiac dysfunction. Unfortunately, suitable animal models to study cardiac dysfunction caused by fatigue are lacking, and the underlying mechanisms remain unclear. This study aimed to establish a pathological fatigue model induced by 5-week combined stress and explore the mechanisms of cardiac dysfunction triggered by fatigue. Five-week combined stress induced fatigue-like phenotypes, which included reluctance to move, reduced exercise endurance, and muscle strength. Moreover, the 5-week combined stress resulted in a significant reduction in both EF and FS, along with a marked upregulation of several myocardial injury biomarkers, thereby confirming the presence of abnormal cardiac function. Targeted metabolomics analysis indicated that 80% of the differential metabolites were downregulated, suggesting a hypometabolic profile in the heart. Interestingly, among the downregulated fatty acid metabolites, we identified two bacterial metabolites, namely acetate and butyrate. More importantly, we observed an inverse correlation between the levels of acetate and butyrate and the concentrations of certain cardiac injury markers. We then observed disturbances in gut bacteria, and group differences at the genus level revealed that all six differential bacteria, which ranked in the top 10 in terms of relative abundance, may directly or indirectly influence the production of acetic acid and butyric acid. Among them, the abundance of Akkermansia bacteria was positively correlated with reduced acetic acid levels. In summary, the present study provides a novel animal model of pathological fatigue-induced cardiac dysfunction and suggests that hypometabolic features and gut microbiota dysbiosis may be an important mechanism.

USP20 is a deubiquitinase enzyme in the ubiquitin–proteasome system that plays a role in the development and progression of tumors. However, the relationships between USP20 expression and clinical prognosis and tumor immunity remain unclear. In this study, the USP20 expression and its relationships with potential prognostic value, the tumor microenvironment (TME), immune-related genes, the tumor mutational burden (TMB), microsatellite instability (MSI), homologous recombination deficiency, cancer stemness, and correlated signaling pathways were investigated via The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Cancer Cell Line Encyclopedia (CCLE), STRING, Gene Expression Profiling Interactive Analysis (GEPIA2), and the Human Protein Atlas (HPA). Moreover, we explored the oncogenic capability of USP20 in breast cancer. Data analysis was performed via GraphPad Prism and the R package. The results indicated that the expression of USP20 was upregulated in most cancers and was associated with survival in 17 tumor types. Furthermore, USP20 expression was strongly correlated with immune infiltration and the expression of immunomodulatory genes. We also verified the correlations between USP20 expression and tumor heterogeneity, cancer stemness, and the corresponding signaling pathways. Moreover, our work revealed that USP20 was highly expressed and predicted a poor outcome in patients with breast cancer. Basic experiments verified that USP20 overexpression promoted both the proliferation and migration of breast cancer cells. This study comprehensively investigated the expression of USP20 and its correlation with clinical prognostic assessment and tumor immune modulation across cancers, indicating that USP20 might have utility as a biomarker associated with prognosis and cancer immunotherapy.

Cancer cells are capable of surviving, proliferating, and invading or migrating within hypoxic environments by regulating various adaptive mechanisms. Due to the activation of oncogenes and the inactivation of tumor suppressor genes, and relative deficiencies in oxygen and nutrients, cancer cells demonstrate elevated production of reactive oxygen species (ROS), primarily sourced from NADPH oxidases (NOX family). A key aspect of the reorientation of tumor cell metabolism is the combating of cellular oxidative stress through the promotion of antioxidant molecule synthesis to counteract ROS production. Given that most cancers experience hypoxia and that NOX is closely linked to numerous redox-dependent signaling pathways, the expression and function of NOX are altered in various malignancies. Therefore, this review summarizes the characteristics of NOX family members, their influence on tumor proliferation, invasion, and migration, the role of NOX in promoting tumor angiogenesis, the impact of NOX on the function of immune cells within the tumor microenvironment, and the potential of targeting NOX in tumor therapy. This aims to offer a fresh viewpoint on a comprehensive understanding of the functions of NOX family members.

Epidermal keratinocytes form the outermost layer of the skin and serve as a pivotal barrier against external insults. This barrier, however, can be compromised in conditions such as atopic dermatitis (AD), where both genetic and environmental factors contribute to its disruption. Recent studies have indicated that macropinocytosis, a non-selective endocytic process, is involved in the internalization of barrier proteins. In this study, we explored the role of macropinocytosis in differentiated keratinocytes and its potential impact on skin barrier integrity in AD. Our results demonstrated that epidermal growth factor (EGF), but not the type 2 cytokines IL-4 and IL-13, significantly promoted macropinocytosis in differentiated HaCaT keratinocytes. EGF stimulation increased the uptake of 70 kDa dextran and induced the internalization of occludin, a component of tight junction proteins. Furthermore, enhanced macropinocytosis was observed in the epidermis of a mouse model of AD, accompanied by elevated EGF expression in the skin, indicating that the AD skin microenvironment may drive this process. NAV1 was identified as a critical regulator of EGF-induced macropinocytosis, as its knockdown significantly impaired this process. Transcriptome analysis of NAV1-knockdown cells further revealed changes in the expression of Rho family GTPases, including CDC42 and MMP14, suggesting that NAV1 modulates macropinocytosis through Rho-dependent pathways. These findings provide new insights into the regulation of macropinocytosis in keratinocytes and its potential contribution to the barrier dysfunction observed in AD.

Leptin and parathyroid hormone (PTH) are key regulators of metabolic and mineral homeostasis. Leptin, primarily secreted by adipose tissue, controls appetite and energy expenditure through its receptors in the central nervous system, while PTH maintains serum calcium and phosphate balance and skeletal integrity by acting on kidneys and bone. The calcium sensing receptor (CaSR) plays a central role in parathyroid function and PTH secretion. While clinical and experimental evidence suggests reciprocal interactions between leptin and PTH, where hyperleptinemia and disrupted leptin signaling in obesity may exacerbate conditions such as secondary hyperparathyroidism, direct effects of leptin on the parathyroid remain poorly defined. We now show that leptin receptor-deficient db/db mice exhibit reduced serum PTH levels at 4 and 7 months of age. Complementary ex vivo experiments in cultured mouse parathyroid glands demonstrate that recombinant leptin increases PTH secretion while downregulating CaSR and c-fos gene expression. Furthermore, CaSR activation using a calcimimetic drug attenuated leptin's stimulatory effect on PTH secretion, indicating that leptin enhances PTH release by down regulating CaSR activity. These findings establish a direct regulatory link between leptin and PTH, highlighting leptin's role in modulating CaSR activity in the parathyroid. By counteracting CaSR-mediated inhibition, leptin may prevent excessive suppression of PTH release by the CaSR. Clinically, these insights may hold implications for conditions such as hyperleptinemia, obesity, and other disorders of PTH dysregulation.

The acute splenic response triggers a surge of immune cells and pro-inflammatory mediators, exacerbating secondary brain injury and worsening the outcome after intracerebral hemorrhage (ICH). Splenectomy confers benefits in experimental ischaemic stroke, but its effects on ICH are not known. We conducted a proof-of-concept study to test the hypothesis that a prior splenectomy would improve behavioral outcomes after ICH. Adult C57BL/6N mice with collagenase-induced ICH that had undergone splenectomy two weeks prior were compared with those with intact spleens. Motor function, haematoma size, cerebral oedema, intracerebral and peripheral blood neutrophil counts were evaluated. Splenectomised mice had lower neutrophil counts in peripheral blood and peri-haematoma regions of the brain. They performed better on the modified Neurological Severity Score during the first week post-ICH and for a shorter duration on rotarod and cylinder tests. Haematomas in non-splenectomised animals showed expansion after the initial hemorrhage and were larger than in splenectomised animals, with more severe surrounding oedema and greater mass effect. This is the first report on the beneficial effects of splenectomy in experimental ICH. Further studies on the optimal timing and mode of splenic response ablation are justified to assess its translational potential.