👤 Kentaro Ikuta

Olfactory dysfunction often emerges before cognitive symptoms and may signal early vulnerability to neurodegenerative processes. This study examined whether genetic risk, specifically the presence of the epsilon 4 allele in apolipoprotein E, is associated with altered functional connectivity between the hippocampus and olfactory regions. Resting-state functional imaging data from 126 participants (mean age = 71.8 years, SD = 6.9; 67 females) across a range of clinical stages were analyzed. Functional connectivity was computed between the hippocampus and four olfactory-related regions: anterior piriform cortex, posterior piriform cortex, olfactory bulb, and olfactory tract. Multiple regression models assessed whether genetic risk, age, sex, and clinical diagnosis predicted connectivity strength. Genetic risk was significantly associated with increased connectivity between the hippocampus and the olfactory tract (model R² = 0.12). A nominal APOE ε4 effect was also observed in the olfactory bulb, although the overall model did not reach significance, while no significant effects were observed in the piriform cortex regions. Clinical diagnosis was not a significant predictor of connectivity in any region. These results suggest that genetic risk is linked to early functional reorganization in specific olfactory-hippocampal pathways, particularly the olfactory tract, independent of clinical progression. The olfactory-hippocampal network may serve as a sensitive target for detecting early brain changes associated with neurodegenerative risk. Show less

Multi-organ regulation underlies metabolic health, especially in the context of adipose-liver dysfunction during obesity. Previous findings identified Melinjo seed extract (MSE) as a promising modulator of metabolic disorders, although its active component remained unknown. Gnetin C, a trans-resveratrol dimer from MSE, likely serves as the key factor, yet its direct metabolic role remains unclear. Here, Gnetin C was administered to high-fat diet (HFD)-fed mice, which significantly improved body weight and fasting glucose, attributed to enhanced adiponectin (APN) multimerization. In adipose tissue, Gnetin C directly promotes APN multimerization and suppresses fat accumulation by up-regulating the PPARγ-DsbA-L axis, while concurrently modulating hepatic Sirt1, which may contribute to increased FGF21 production. This paracrine FGF21 signaling, suggested by elevated Fgfr1 in hepatocytes and βKlotho in adipocytes, further augments APN multimerization. These findings underscore the importance of a multi-tissue approach to obesity management and position Gnetin C as an integrative therapeutic candidate, restoring metabolic balance via dual adipose and hepatic effects in HFD mice. Show less

Angiopoietin-like protein 3 (ANGPTL3) is expressed predominantly in the liver and plays a major role in regulating the circulating triglyceride and lipoprotein fraction concentrations by inhibiting lipoprotein lipase (LPL) activity. Given these physiological roles, ANGPTL3 may play an important role in metabolic changes related to fat accumulation during the fattening period in Japanese Black. This study aimed to reveal the physiological roles of hepatic ANGPTL3 in Japanese Black steers (Bos taurus) during the fattening period and investigate the regulatory effects of hepatic ANGPTL3. To investigate the gene expression and protein localization of ANGPTL3, 18 tissue samples were collected from tree male Holstein bull calves aged 7 wk. Biopsied liver tissues and blood samples were collected from 21 Japanese Black steers during the early (T1; 13 mo of age), middle (T2; 20 mo), and late fattening phases (T3; 28 mo). Relative mRNA expression, blood metabolite concentrations, hormone concentrations, growth, and carcass traits were analyzed. To identify the regulatory factors of hepatic ANGPTL3, primary bovine hepatocytes collected by two Holstein calves aged 7 wk were incubated with insulin, palmitate, oleate, propionate, acetate, or beta-hydroxybutyric acid (BHBA). The ANGPTL3 gene was most highly expressed in the liver, with minor expression in the renal cortex, lungs, reticulum, and jejunum in Holstein bull calves. In Japanese Black steers, relative ANGPTL3 mRNA expressions were less as fattening progressed, and blood triglyceride, total cholesterol, and nonesterified fatty acid (NEFA) concentrations increased. Relative ANGPTL8 and Liver X receptor alpha (LXRα) mRNA expressions decreased in late and middle fattening phases, respectively. Furthermore, relative ANGTPL3 mRNA expression was positively correlated with ANGPTL8 (r = 0.650; P < 0.01) and ANGPTL4 (r = 0.540; P < 0.05) in T3 and T1, respectively, and LXRα showed no correlation with ANGPTL3. Relative ANGTPL3 mRNA expression was negatively correlated with total cholesterol (r = -0.434; P < 0.05) and triglyceride (r = -0.645; P < 0.01) concentrations in T3 and T1, respectively; There was no significant correlation between ANGTPL3 and carcass traits. Relative ANGTPL3 mRNA expression in cultured bovine hepatocytes was downregulated in oleate treatment. Together, these findings suggest that ANGPTL3 downregulation in late fattening phases is associated with the changes in lipid metabolism. Show less

We investigated the physiological changes during the fattening period and production characteristics in Japanese Black steers bred and raised using the typical feeding system in Japan. Here, 21 Japanese Black steers aged 12 months were used, with experimental period divided into early (12-14 months of age), middle (15-22 months), and late fattening phases (23-30 months). The liver transcriptome, blood metabolites, hormones, and rumen fermentation characteristics were analyzed. Blood triglyceride and non-esterified fatty acid concentrations increased, whereas blood ketone levels decreased, with fattening phases. Blood insulin increased with fattening phases and was positively correlated with carcass weight and marbling in late fattening phases. Rumen fermentation characteristics showed high propionate levels and low butyrate levels in late fattening phases, likely due to increased energy intake. Genes related to glucose metabolism, such as SESN3, INSR, LEPR, and FOXO3, were down-regulated in late fattening phases. Genes related to lipid metabolism, such as FABP4, were up-regulated, whereas FADS1 and FADS2 were down-regulated. These findings suggest that the physiological changes resulted from changes in the energy content and composition of diets. Liver metabolism changed with changes in fat metabolism. Insulin was strongly associated with physiological changes and productivity in Japanese Black cattle. Show less

Axin1, a regulator of Wnt signaling, was previously identified as playing a negative role in the late phase of human immunodeficiency virus type 1 (HIV-1) replication in HeLa-derived J111 cells. In this report, we studied the molecular mechanism of how Axin1 regulates HIV-1 replication. HIV-1 transactivator, Tat-dependent viral reporter gene expression was enhanced in J111 cells transfected with small interfering RNA (siRNA) against Axin1. In addition, viral transcription was upregulated in J111 cells transfected with siRNA against Axin1. In contrast, HIV-1 gene expression was not enhanced by transfecting HeLa cells with siRNA against Axin1. The expression levels of T cell factor-4 (TCF4) and beta-catenin were higher in J111 than HeLa cells. In addition, siRNAs against TCF4 and beta-catenin inhibited the Axin1 siRNA-dependent enhancement of HIV-1 gene expression in J111 cells. These results suggest that Axin1 plays a negative role in HIV-1 transcription through the Wnt signaling pathway in J111 cells under normal cell culture conditions. Show less