EBioMedicine最新文献

Background: Both low-grade systemic inflammation and acute inflammatory events may contribute to Alzheimer Disease (AD) progression. However, studies examining the prognostic utility of systemic inflammatory biomarkers in AD, and how systemic inflammatory events may contribute to clinical trajectories in AD, have yielded conflicting results.

Methods: We quantified plasma cytokines/chemokines in 333 individuals with mild-moderate AD at baseline, 12 and 18 months alongside baseline neurodegenerative biomarkers. AD severity was assessed using the Alzheimer Disease Assessment Scale (ADAS-Cog), Clinical Dementia Rating Scale (CDR-Sb) and Disability Assessment for Dementia (DAD).

Findings: Systemic inflammatory biomarkers were primarily associated with age/socio-demographic characteristics, remained strikingly stable over time, and were not associated with AD progression. Rather, higher baseline plasma p-tau217 was associated with greater yearly progression on both the ADAS-Cog (β: 2.82; 95% CI: 1.12, 4.52; nominal p = 0.001) and DAD (β: -2.34; 95% CI: -3.86, -0.82; nominal p = 0.003). Higher baseline GFAP was also associated with subsequent decline on both the CDR-Sb (β: 1.02; 95% CI: 0.38, 1.67; nominal p = 0.002) and DAD (β: 1.91; 95% CI: -3.45, -0.37; nominal p = 0.02). Experiencing one or more episodes of delirium was associated with accelerated decline on the CDR-Sb at 18-months (β: 2.63; 95% CI: 1.55, 3.71; adjusted p < 0.001).

Interpretation: Biomarkers of neuroinflammation (GFAP), neurodegeneration (p-tau217) and incident delirium, rather than systemic inflammatory biomarkers, were associated with clinically-significant decline in mild-moderate AD.

Funding: European Commission (FP7 grant; 279093); Meath Foundation (MFRG 121/2021); Wellcome Trust (227946/Z/23/Z & 203930/B/16/Z); Health Research Board (203930/B/16/Z; ECSA-2024-003).

Background: Physical activity helps maintain a healthy stable body weight. One mechanism underlying this beneficial effect could be the improved coupling between energy intake and expenditure, since hunger and satiety are better regulated in active individuals. Whether this enhancement of appetite control by exercise is reflected in overall adaptations in the gut and gut-brain communication remains poorly defined.

Methods: We investigated how increased physical activity alters gut morphology, intestinal endocrine function, and central appetite signalling in C57BL/6NRJ male mice fed ad-libitum chow diet. We assessed intestinal growth, L-cell density, and glucose-stimulated endocrine secretion, as well as circulating levels and gene expression of gut derived peptide hormones. Additionally, we quantified neuronal activity in the brainstem dorsal vagal complex following a fasting-refeeding intervention and examined the effects of PYY, CCK, ghrelin, and GLP-1 administration on food intake in sedentary and physically active mice. Depending on the dataset, unpaired or paired Student's t-tests, two-way ANOVA followed by Bonferroni's post hoc test, simple linear regression or a linear mixed-effects model were applied. Statistical significance was set at P < 0.05.

Findings: Physical activity induced a slight growth of the small intestine, increased L-cell density, and enhanced glucose-stimulated GLP-1 secretion. It altered the circulating levels of PYY and ghrelin and increased the dynamic regulation of neuronal activity in the area postrema and nucleus tractus solitarius. Active mice displayed greater sensitivity to gut-derived hormones PYY, CCK, and ghrelin exerting amplified and prolonged effects on food intake, whereas native GLP-1 showed no effect, likely due to its short half-life. Physical activity prevented post-fasting hyperphagia, thereby promoting sustained maintenance of fasting-induced weight loss.

Interpretation: The findings demonstrate that physical activity promotes adaptations in the gut and gut-to-brain communication possibly enhancing the responsiveness to appetite-regulating signals. Such adaptations may strengthen the alignment between energy intake and expenditure to support body weight maintenance.

Funding: This study was supported by Novo Nordisk Foundation (0059436) and Trygfonden Centre for Physical Activity Research (101390, 20045, 125132, and 177225). P.S. is supported by Lundbeck Foundation (R380-2021-1300).

Background: Upper tract urothelial carcinoma (UTUC) is an uncommon but aggressive malignancy. Muscle invasion is strongly associated with poor prognosis and limited treatment options. Revealing the molecular basis of muscle invasiveness in UTUC is crucial.

Methods: We characterised somatic structural variants (SSVs) from 162 patients with UTUC and integrated these data with bulk RNA-seq, single cell RNA-seq and spatial transcriptomics, with selected SSVs validated by single-molecule sequencing. Furthermore, functional validation experiments, including dual-luciferase reporter assays, wound healing, and invasion/migration assays, were conducted on both the SSV region upstream of TPX2 and the TPX2 gene itself in the 5637 cell line.

Findings: We found that SSVs were enriched in muscle-invasive (MI) -UTUC compared with non-muscle-invasive (NMI)-UTUC, and were associated with gene expression changes independent of copy-number variation. TPX2 emerged as a representative target, with TPX2-associated SSVs linked to TPX2 over expression and patient poorer progression-free and overall survival. Functional study indicated that a TPX2-upstream SSV region enhances TPX2 expression through promoter regulation, leading to increased invasiveness of 5637 cells. Single cell analyses revealed that TPX2-positive cycling epithelial cells exhibited heightened proliferative signalling and distinct ligand-receptor interactions, particularly involving EGFR- and EPHA2-related pathways. Spatial transcriptomics further localised TPX2-positive spots to epithelial mesenchymal transition (EMT) -enriched neighbourhoods with elevated EGFR/EPHA2 associated ligands, and showed markedly higher abundance in MI-UTUC.

Interpretation: SSVs drive transcriptional reprogramming, disease aggressiveness and microenvironmental remodelling in UTUC. The signatures of SSVs could classify UTUC into classes with different prognosis. Furthermore, SSVs of TPX2 might be a potential biomarker and candidate therapeutic vulnerability.

Funding: Stated in acknowledgements section of manuscript.

Background: Fluctuations in oestrogen (E2) and progesterone (P4) shape brain morphology across menstrual cycles. Yet, it remains unclear how these hormonal dynamics translate into region-specific changes in grey matter structure.

Methods: Using structural magnetic resonance imaging (MRI), we assessed grey matter volume (GMV) and cortical thickness (CT) in 32 healthy women during the periovulatory phase (peak E2) and menstruation (low E2 and P4). Region-of-interest (ROI) and exploratory whole-brain analyses were performed, complemented by multiple regression models to assess associations between E2, P4, and brain morphology. Further, spatial colocalisation analyses were applied to link observed macrostructural changes with receptor density maps.

Findings: Predefined ROI analyses targeting the amygdala and the hippocampus yielded no significant effects after correction for multiple comparisons. While E2 correlated positively with parietal regions in the periovulatory phase, P4 exhibited robust phase-dependent associations with the cerebellar and fusiform volumes in the periovulatory phase, and with the frontal volumes and widespread CT during menstruation. Spatial colocalisation with hormone receptor distributions indicated stronger structural changes in regions with higher P4 receptor density.

Interpretation: These results identify P4 as a key modulator of brain morphology, with its effects varying according to the menstrual phase. Understanding the hormone-driven brain dynamics is essential for a more accurate model of female brain function and mental health.

Funding: German Research Foundation.

Sleep disorders, cardiovascular diseases (CVDs), and hormonal imbalances, particularly with respect to testosterone levels, are closely interconnected and significantly impact public health. This review examines the complex interactions between these 3 factors. Poor sleep quality and conditions like obstructive sleep apnea (OSA) are prevalent among individuals with CVDs and contribute to cardiovascular pathology through several mechanisms, including sympathetic activation, oxidative stress, and systemic inflammation. Testosterone plays a critical role in metabolic regulation, muscle and bone health, and mood. Low testosterone levels are associated with increased CVD risk factors like insulin resistance and arterial stiffness. Substantial evidence suggests that sleep disorders may impair testosterone levels, partially improved after specific treatments (for instance: positive airway pressure for OSA). On the other hand, appropriate indications for testosterone replacement therapy (TRT) can alleviate hypogonadism symptoms and cardiometabolic dysfunction, but may increase the risk of OSA, requiring careful management. This narrative review highlights the importance of a holistic approach in managing sleep disorders, CVDs, and hormonal imbalances and emphasises the need for further research to improve patient outcomes.