👤 Shutaro Sumiyoshi

Aging-related cognitive decline is a major concern in aging societies. Theobromine (TB), a cacao-derived methylxanthine, exerts neuroprotective effects through anti-inflammatory, antioxidant, and neurotrophic mechanisms; however, its efficacy in aging models remains unclear. This study investigated the mechanisms underlying neuroprotective effects of chronic TB administration in senescence-accelerated mouse prone 8 (SAMP8), a model of age-related memory impairment. SAMP8 and SAMR1 mice were fed either a control diet or a diet supplemented with 0.05% TB for 50 d. Cognitive performance was evaluated by the novel object recognition (NOR) test. Neurotrophic factors (BDNF and NT-3), synaptic proteins (PSD95 and synaptophysin), and plasticity-related signaling molecules (phosphorylated CREB and TrkB) were analyzed in the prefrontal cortex and hippocampus. Inflammatory cytokines, lipid peroxides, and antioxidant enzymes were quantified. Molecular docking was used to assess TB's interaction with phosphodiesterase (PDE) enzymes. TB improved short-term memory in SAMP8, increasing discrimination index in the NOR test. This was accompanied by increased BDNF, NT-3, PSD95, and synaptophysin levels and enhanced CREB and TrkB phosphorylation. Furthermore, TB lowered the levels of pro-inflammatory cytokines (IL-1β, TNF-α) and phosphorylated NF-κB, reduced lipid peroxidation, and increased the levels of antioxidant markers (HO-1, GSH). These effects were minimal in SAMR1. No adverse effects on body weight or blood parameters were observed. Molecular docking indicated that TB binds to PDE enzymes with weaker inhibitory activity than selective inhibitors. TB enhances short-term memory and synaptic function in aged mice via neurotrophic, antioxidant, and anti-inflammatory mechanisms, supporting its potential as a safe dietary intervention for age-related cognitive decline. Show less

Background Idiopathic multicentric Castleman disease (iMCD) is a chronic inflammatory condition for which Janus kinase (JAK) inhibition has been hypothesized to be a potential treatment. However, filgotinib, a JAK1 preferential inhibitor, did not show apparent efficacy for iMCD in a clinical trial at eight weeks. This study aimed to compare the serum cytokine and chemokine profiles of patients treated with filgotinib with those of patients treated with tocilizumab to speculate why filgotinib was not effective at eight weeks. Methods This study included five patients treated with filgotinib who participated in a phase Ib single-arm clinical trial of filgotinib for iMCD and five tocilizumab-treated patients whose data were collected retrospectively. Serum levels of 41 cytokines/chemokines before and after treatment were measured. Results The tocilizumab group showed improvement in C-reactive protein, hemoglobin, and albumin levels after treatment while the filgotinib group showed no changes in these markers. The tocilizumab group showed significant changes in 12 cytokines/chemokines from baseline to after treatment, whereas the filgotinib group showed only a decrease in IL-18 and IL-27 levels. After treatment, significant differences were observed between the two groups for 10 cytokines/chemokines. Five cytokines (FGF-2, IL-4, IL-6, TNF-β, and VEGF-A) showed significant changes after tocilizumab treatment and differences between the tocilizumab and filgotinib groups after treatment. Conclusion This study identified FGF-2, IL-4, IL-6, TNF-β, and VEGF-A as potential factors that could explain the lack of apparent efficacy of filgotinib in iMCD treatment at eight weeks. These findings may contribute to future drug development for iMCD. Show less

Na Knockdown of ATP1A1 expression was performed in human CC cell lines HT29 and Caco2 using small interfering RNA. The roles of ATP1A1 in various biological processes of cells (i.e., proliferation, cell cycle, apoptosis, migration, and invasion) were assessed. Microarray analysis was utilized for gene expression profiling. Samples obtained from 200 patients with CC who underwent curative colectomy were analyzed through immunohistochemistry. ATP1A1 knockdown suppressed cell proliferation, migration, and invasion and induced apoptosis. The results of the microarray analysis revealed that the upregulated or downregulated gene expression in ATP1A1-depleted cells was related to the extracellular signal-regulated kinase 5 (ERK5) signaling pathway [epidermal growth factor receptor (EGFR), mitogen-activated protein kinase kinase 5 (MAP2K5), mitogen-activated protein kinase 7 (MAPK7), FOS, MYC, and BCL2 associated agonist of cell death (BAD)]. Immunohistochemical analysis demonstrated a correlation between ATP1A1 expression and pathological T stage (p = 0.0054), and multivariate analysis identified high ATP1A1 expression as an independent predictor of poor recurrence-free survival in patients with CC (p = 0.0040, hazard ratio: 2.807, 95% confidence interval 1.376-6.196). ATP1A1 regulates tumor progression through the ERK5 signaling pathway. High ATP1A1 expression is associated with poor long-term outcomes in patients with CC. Show less

Zinc finger protein ZPR1 (ZPR1) binds to eukaryotic translation elongation factor 1alpha (eEF1alpha) in response to growth stimuli, and is also involved in transcription and cell cycle regulation. In this study, we characterized the interaction of ZPR1 and eEF1alpha and generated a ZPR1 mutant that constitutively interacted with eEF1alpha. ZPR1-DeltaA (Delta193-246) bound to eEF1alpha independently of Zn(2+) in vivo. This study indicates that ZPR1-DeltaA (Delta193-246) is a useful tool to provide structural insights into ZPR1 and to investigate the biological significance of the interaction between ZPR1 and eEF1alpha. Show less

A differential display was performed to analyze differential gene expression in the brain of mice in association with dietary high beef tallow. Consumption of a high beef tallow diet up-regulated the expression of zinc finger protein ZPR1 mRNA in the brain. Expression of ZPR1 mRNA in the cerebellum and hippocampus was elevated in response to the high beef tallow diet. The increased ZPR1 expression in the neuronal, Neuro-2A cells, caused a significant increase in H(2)O(2)-induced cell death. These results suggest that a high beef tallow diet up-regulates ZPR1 mRNA expression in the brain and might increase the vulnerability to oxidative stress. Show less