Treadmill Exercise Modulates the Leptin/LepR/GSK-3β Signalling Pathway to Improve Leptin Sensitivity and Alleviate Neuroinflammation in High-Fat Diet-Fed APP/PS1 MiceWang, Liao, Tong
et alMol Neurobiol (2025)
Abstract: Neuroinflammation plays a critical role in the development of Alzheimer's disease (AD) and is closely associated with obesity. In AD, the fat cell-secreted protein leptin crosses the blood-brain barrier and protects against nerve damage. However, obesity may induce leptin resistance, reduce leptin sensitivity, stimulate excessive glial cell activation, promote inflammatory factor production and exacerbate brain inflammation. Unfortunately, the mechanism of interaction among high-fat diets, obesity, neuroinflammation and neurodegenerative diseases remains unclear. We investigated the changes in neuroinflammation and leptin sensitivity in the brains of wild-type and high-fat-diet-fed APP/PS1 transgenic mice. We explored the effects of treadmill exercise for 12 weeks on the leptin/LepR/GSK-3β signalling pathway and memory. The body weights of the high-fat-diet-fed mice increased, and elevated levels of markers for leptin resistance, including suppressor of signalling 3 (SOCS3), protein tyrosine phosphatase 1B (PTP1B) and proinflammatory factors such as tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6), were observed. After 12 weeks of aerobic exercise, the leptin mRNA and protein levels increased, GSK-3β protein expression decreased and the mean fluorescence intensities of brain microglial (IBA-1) and neuron markers (NeuN) decreased, indicating that exercise may activate the leptin/LepR/GSK-3β signalling pathway, reducing glial cell activation and inflammation. Our study revealed that obesity induces and exacerbates the AD-related neuroinflammatory response. Aerobic exercise activates the leptin/LepR/GSK-3β pathway to relieve neuroinflammation and protect nerve cells, alleviating AD-associated memory loss. These promising outcomes could inform the development of nondrug-based aerobic exercise interventions for the treatment of AD and associated cognitive disorders.© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Effect and Mechanism of Vitamin D on Inflammatory Factors and Neutrophil Activity in Preterm Placenta of Rats Induced by LPSYang, Chen, Lv
Cell Biochem Biophys (2025)
Abstract: To investigate the impact mechanisms of vitamin D on inflammatory factors and neutrophil activity in preterm pregnant rats. 24 pregnant rats were selected as the research objects and randomly divided into control group, LPS group and LPS + VD group, with 8 rats in each group. On the second day of pregnancy, the LPS + VD group was injected intraperitoneally with 50 mg/L vitamin D30.2 mL, and the LPS group and the control group were injected with the same amount of 0.9% NaCl twice a day. On the seventh day of pregnancy, the LPS group and the LPS + VD group were injected with 0.2 mL LPS into the tail vein to establish a preterm labor model induced by infection. The control group was injected with the same amount of physiological saline into the tail vein. Placental tissues from rats in the LPS + VD group and the LPS group were collected, and the expression levels of inflammatory factors TGF-β1, TNF-α, and VDBP were detected by immunohistochemistry. At the same time, serum IL-2 concentration was measured by ELISA and radioimmunoassay, the activity of neutrophils was evaluated by flow cytometry, and the expression of Hippo-YAP signaling pathway protein was detected by Western blot. Compared with the control group, the content of TNF-α, VDBP, and TGF-β1 in placenta in LPS group were higher than that in the control group (P < 5); Compared with the LPS group, the contents of TNF-α, BP and TGF-β1 in the LPS+VD group were significantly reduced,(P < 0.05); Compared with the control group, the serum IL-2 concentration in the LPS group was significantly higher than that in the control group (P < 0.05); Compared with the LPS group, the serum IL-2 concentration in the LPS + VD group decreased significantly (P < 0.05); Compared with the control group, the neutrophil ratio and absolute neutrophil value in the LPS group were higher than those in the control group (P < 0.05); Compared with the LPS group, the neutrophil ratio and absolute value of neutrophils decreased (P < 0.05); compared with the control group, the expression levels of YAP and P-YAP protein in the LPS group increased (P < 0.05); compared with the LPS group, the expression levels of YAP and P-YAP protein in the LPS + VD group decreased (P < 0.05). Vitamin D can improve the immune status of preterm pregnant mice by inhibiting the expression of placental inflammatory factors.© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Distinct Cytokine Responses in Central and Systemic Compartments after Subarachnoid HaemorrhageBandyopadhyay, Gaastra, Zolnourian
et alTransl Stroke Res (2025)
Abstract: Neuroinflammation may contribute to outcomes following subarachnoid haemorrhage (SAH). Human cerebrospinal fluid (CSF) cytokine data is limited and its relationship with systemic inflammation is unknown. This study compares the inflammatory responses in CSF and plasma compartments, and their associations with outcome.Ten cytokines were measured in CSF and plasma from 98 SAH patients and 18 control patients. Outcome was assessed with the modified Rankin scale (mRS) and Subarachnoid Haemorrhage Outcome Tool (SAHOT) at days 7, 28, 90 and 180. Regression analyses and principal component analysis (PCA) were performed.Median levels of all CSF cytokines and plasma IL-6 were higher in SAH patients than controls (p < 0.001). Plasma IL-6 peaked earlier (3 days after SAH) than CSF cytokines (7-9 days after SAH). On day 7, CSF levels were greater than plasma levels for all cytokines (p < 0.001). There was no correlation between individual cytokines in the plasma and CSF. Only plasma IL-6 levels correlated with long-term outcome (mRS (p = 0.009) and SAHOT (p = 0.007) at day 180), accounting for WFNS and blood volume. Seven principal components of cytokines had an eigenvalue greater than 1. Only the first plasma principal component (dominated by IL-6, IL-8, IL-12, IL-13, and TNF-α) was associated with outcomes (p < 0.05). Mediation analysis suggested the effects of WFNS and blood volume on outcome were not mediated by IL-6 or this principal component.SAH provokes an inflammatory response in CSF and plasma. The response pattern is different and distinct in each compartment. Each compartment's relationship with outcomes differ, suggesting separate roles in SAH pathophysiology. Plasma IL-6 is independently associated with outcomes.© 2025. Crown.
Pharmacologically activating BDNF/TrkB signaling exerted rapid-acting antidepressant-like effects through improving synaptic plasticity and neuroinflammationSun, Zhao, Bi
et alMetab Brain Dis (2025) 40 (4), 158
Abstract: BDNF (Brain-derived neurotrophic factor)/TrkB (tropomyosin receptor kinase B) signaling has great therapeutic potential for depression, but the underlying mechanism remains unclear. This study aims to investigate the molecular mechanism underlying the BDNF/TrkB signaling-mediated antidepressant effects. Chronic Cort drinking for 4 weeks and a single injection of LPS for 24 h were used to induce depression-like behaviors; this study used 7,8-dihydroxyflavone (7,8-DHF, 10 mg/kg, i.p.), a selective TrkB receptor agonist, to activate the BDNF/TrkB signaling and examined its rapid-acting antidepressant-like effects; levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) in BV2 microglial cells and synapse-related factors (BDNF, GluA1, Synapsin-1, and PSD95) in HT22 cells were examined by ELISA. Our behavioral results suggested that 7,8-DHF (10 mg/kg, i.p.) exerted rapid-acting antidepressant-like effects in Cort/LPS-treated mice; our immunofluorescence staining results suggested that Cort/LPS reduced the number of NeuN + HT22 cells and increased the number of Iba1 + BV2 microglial cells, which were completely reversed by 7,8-DHF pre-treatment. Our ELISA results suggested that 7,8-DHF significantly normalized the release of synapse-related factors (BDNF, GluA1, and PSD95) in HT22 cells and suppressed the production of inflammatory cytokines (IL-1β, IL-6, and TNF-α) in BV2 microglial cells. Taken together, this study suggested that pharmacologically activating the BDNF/TrkB signaling pathway exerted rapid-acting antidepressant-like effects through improving synaptic plasticity and inhibiting neuroinflammation, which provided new insights for developing next-generation rapid-acting antidepressants.© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
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