Alzheimer’s disease (AD) is an increasing global healthcare crisis with few effective treatments. The accumulation of amyloid plaques and hyper-phosphorylated tau are thought to underlie the pathogenesis of AD. However, current studies have recognized a prominent role of cerebrovascular dysfunction in AD. We recently reported that SNPs in soluble epoxide hydrolase (sEH) are linked to AD in human genetic studies and that long-term administration of an sEH inhibitor attenuated cerebral vascular and cognitive dysfunction in a rat model of AD. However, the mechanisms linking changes in cerebral vascular function and neuroprotective actions of sEH inhibitors in AD remain to be determined. This study investigated the effects of administration of an sEH inhibitor, 1-(1-Propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU), on neurovascular coupling, blood–brain barrier (BBB) function, neuroinflammation, and cognitive dysfunction in an hAPP/PS1 TgF344-AD rat model of AD. We observed predominant β-amyloid accumulation in the brains of 9–10-month-old AD rats and that TPPU treatment for three months reduced amyloid burden. The functional hyperemic response to whisker stimulation was attenuated in AD rats, and TPPU normalized the response. The sEH inhibitor, TPPU, mitigated capillary rarefaction, BBB leakage, and activation of astrocytes and microglia in AD rats. TPPU increased the expression of pre- and post-synaptic proteins and reduced loss of hippocampal neurons and cognitive impairments in the AD rats, which was confirmed in a transcriptome and GO analysis. These results suggest that sEH inhibitors could be a novel therapeutic strategy for AD.

Juveniles are at increased risk for mild traumatic brain injury (mTBI) due to recreational activities, domestic violence, and vulnerabilities of the developing skull. In industrialized nations, adolescents often consume high-sugar, high-fat diets (HFD), which can impair CNS health and exacerbate mTBI outcomes. Secondary injury following mTBI is characterized by prolonged neuroinflammation, with nuclear factor kappa B (NF-κB) acting as a central regulator of these inflammatory responses. We developed a polypeptide biologic, SynB1-ELP-p50i, consisting of an elastin-like polypeptide delivered NF-κB inhibitor (p50i) and the cell-penetrating peptide SynB1. This study investigates the interaction between diet and NF-κB inhibition in juvenile rats with mTBI by examining SynB1-ELP-p50i biodistribution, pharmacokinetics, therapeutic efficacy, and cell-specific effects. Long Evans rats were assigned to chow or HFD groups at postnatal day 20 (PND20), and mTBI or sham injury was induced at PND30 using the CHIMERA TBI model. Rats received 50 mg/kg SynB1-ELP-p50i or saline post-injury. Behavioral outcomes were assessed with the Morris water maze (MWM), and neuroinflammatory markers were measured using RT-qPCR and single-nucleus RNA sequencing (snRNA-seq). SynB1-ELP-p50i accumulated at injury sites (p < 0.05), and SynB1-ELP-p50i treated chow-fed rats showed improved MWM performance compared to vehicle controls and HFD subjects (p < 0.05). RT-qPCR confirmed increased Aif1 and Gfap expression post-injury (p < 0.05), and snRNA-seq revealed upregulation of markers of microgliosis in activated microglia. These findings indicate that mTBI triggers acute cognitive deficits and neuroinflammation, worsened by HFD. SynB1-ELP-p50i mitigated memory deficits in chow-fed animals, supporting NF-κB inhibition as a promising therapeutic strategy for juvenile mTBI.

Obesity is an established risk factor for breast cancer (BC), and leptin, an adipocyte-derived hormone, may link obesity to tumor progression. However, the role of leptin in the molecular heterogeneity of triple-negative breast cancer (TNBC), particularly across racial groups, remains unclear. Here, we examined circulating leptin levels in Black and White women with and without BC and characterized leptin-induced transcriptional changes in TNBC cell lines of White and Black racial backgrounds using RNA sequencing. Functional enrichment analyses were performed using Gene Ontology and KEGG pathway annotations, and clinical relevance was assessed using publicly available datasets. Circulating leptin levels were significantly elevated in women with BC and were relatively higher in Black than White women and associated with increased odds of luminal A and TNBC diagnoses. Leptin induced distinct transcriptional responses in two TNBC cell lines, with differential enrichment of oncogenic, metabolic, and signaling pathways, including spliceosome, steroid biosynthesis, PI3K-AKT, Notch, and extracellular matrix-receptor interaction. Several leptin-responsive genes showed concordant expression in clinical specimens and exhibited race- and subtype- associated differences and prognostic significance. Collectively, these findings identify distinct, context-dependent leptin-responsive transcriptional programs in TNBC and provide insight into their potential contributions to tumor heterogeneity and breast cancer disparities.