Kim JG, et al. Clin Nutr Res. 2025 Jan;14(1):65-77. https://doi.org/10.7762/cnr.2025.14.1.65

Background: Sex differences are evident in anxiety and depression, and women more frequently present with comorbid anxiety and depression alongside gastrointestinal disturbances. This pattern suggests contributions from sex-specific biological mechanisms and gut–brain communication. Negr1 , a molecule regulating neuronal growth and connectivity, has been linked to depression-relevant behaviors in animal models. However, its mechanisms and potential sex-specific effects remain unclear. Methods: Behavioral tests were used to assess phenotypes related to depression, anxiety, and learning in male and female wild-type (WT) and Negr1 ^–/– mice, and molecular assays were performed to evaluate endoplasmic reticulum (ER) stress and apoptosis in the brain, liver, and colon. Behavioral test data were analyzed using a three-way mixed repeated-measures analysis of variance (RM-ANOVA), and molecular data were analyzed using two-way or three-way ANOVA. Result: Negr1 ^–/– mice exhibited sex-dependent phenotypes in both central and peripheral systems. Baseline analyses revealed increased intestinal permeability in Negr1 ^–/– mice and sex-specific patterns of brain-derived neurotrophic factor ( Bdnf ) mRNA expression across multiple time points. Behaviorally, Negr1 ^–/– mice showed increased anxiety-like behavior, decreased social interaction, and impaired spatial learning in the Morris water maze, regardless of sex. Female Negr1 ^–/– mice displayed impaired fear learning and increased depression-like behavior, while male Negr1 ^–/– mice exhibited heightened anxiety-like responses. At the molecular level, ER stress marker spliced X-box binding protein 1 ( Xbp1s) mRNA was upregulated in peripheral tissues of males but downregulated in females. Apoptosis analysis revealed enhanced caspase-3 activation in peripheral tissues of female Negr1 ^–/– mice, while males showed no significant changes. Brain tissue showed no significant apoptotic alterations in either sex. Conclusions: This study demonstrates that, in Negr1 ^–/– mice, both sexes show general behavioral alterations. However, female Negr1 ^–/– mice exhibit greater vulnerability to fear learning impairments and depression-like behavior, whereas males Negr1 ^–/– mice show heightened anxiety responses. These behavioral differences were associated with opposing ER stress responses and differential apoptotic signaling between the sexes in peripheral tissues. Our findings highlight the importance of considering sex as a biological variable in depression research and suggest that Negr1 plays a crucial role in the sex-specific pathophysiology of psychiatric disorders through complex mechanisms spanning central and peripheral systems.

Chestnut inner shells, generated as waste during chestnut processing, were extracted either raw (RC) or after boiling (BC) using four different extraction methods to determine the effects of those on physiological activities. The hot-water extract of RC showed the highest radical scavenging activities among all the extracts, the autoclave extract of RC showed the highest SOD-like activity and the hot-water extract of BC showed the highest lipase and α-glucosidase inhibitory activities. The lowest NO production in the macrophages treated with the stirring extract of BC and hot water extract of RC most significantly reduced the mRNA expression of inducible NO synthase and pro-inflammatory cytokines, IL-6 and TNF-α. These results implied that the application of boiling and a certain extraction method enhances specific target activities and confirmed the potential of chestnut inner shell as a useful material with health benefits and economic value.

This study comprehensively evaluated how the inclusion of the inner shell and the choice of extraction method influence the antioxidant activity of Quercus Fructus (QF). Eight QF extracts were prepared with or without the inner shell using stirring (S) and ultrasonication (U) with 80% ethanol, boiled water (B) and autoclave (A) with distilled water. Among them, the ultrasonication extract with inner shell (IU) exhibited the highest antioxidant capacity, showing strong DPPH radical scavenging (228.8 mg TEAC/g), ABTS activity (162.9 mg TEAC/g), reducing power (380.9 mg TERP/g), and SOD-like activity (38.1%). HPLC-UV profiling identified quercetin-7-glucoside (Q7G) as a major detectable compound, although several polar phenolics remained unidentified. In LPS-stimulated Raw 264.7 cells, IU significantly suppressed nitric oxide production and iNOS expression without cytotoxicity. Additionally, IU treatment markedly reduced ROS accumulation in H₂O₂-exposed zebrafish embryos. These findings suggest that including the inner shell with ultrasonication extraction synergistically enhances QF’s antioxidant efficacy, suggesting a practical strategy for maximizing the functional potential of QF in natural antioxidant development.

Background: Sucralose is widely used as a non-nutritive sweetener, yet its systemic consequences of long-term exposure remain incompletely understood. This study investigated the effects of long-term sucralose consumption on metabolic homeostasis and neurobehavioral outcomes. Methods: Male C57BL/6J mice were treated with 5 mg/kg body weight sucralose under non-stressed and unpredictable chronic mild stress conditions for 14 weeks. Results: Sucralose altered hepatic cholesterol regulation without significantly increasing serum triglyceride or total cholesterol relative to water controls. Significant treatment–stress interactions were detected for hepatic Srb1 (F = 6.511, p = 0.004) and intestinal Npc1l1 (F = 3.763, p = 0.032), indicating stress-dependent modulation of cholesterol absorption. Hepatic inflammation also showed significant interactions for Il6 (p < 0.001) and Tnfa (p = 0.003). In addition, the sucralose group exhibited heightened neuroinflammation, cerebral endoplasmic reticulum stress, and increased depressive-like behaviors. 16S rRNA sequencing demonstrated reduced α-diversity and a shift in microbial composition and predicted carbohydrate processing and transport functions. Spearman correlation analysis linked microbial, intestinal, hepatic, neuroinflammatory, and behavioral variables within sucralose-treated mice. Conclusions: Long-term sucralose consumption altered gut microbial composition, hepatic cholesterol regulation, and neuroinflammatory and behavioral outcomes.