Nucling is an Apaf1‐binding proapoptotic protein involved in apoptosome‐mediated apoptosis. Luciferase assays have revealed that the activation of nuclear factor‐κB induced by tumor necrosis factor‐α, interleukin‐1β and lipopolysaccharide is downregulated by the overexpression of Nucling in HEK293 cells. Moreover, the expression of endogenous cyclooxygenase 2, tumor necrosis factor‐α and galectin‐3, the end‐point molecules in the pathway for the activation of nuclear factor‐κB, as well as nuclear factor‐κB (p65) itself, is upregulated in Nucling gene‐deficient mouse embryonic fibroblasts, suggesting that nuclear factor‐κB is a target of Nucling. Subsequent study has revealed that Nucling physically interacts with nuclear factor‐κB (p65 and p50) and that the binding domain of Nucling is its amino‐terminal region (amino acids 1–466) containing ankyrin repeats. Overexpression of Nucling prevents the translocation of nuclear factor‐κB into the nucleus. In addition, the cytoplasmic retention of endogenous nuclear factor‐κB in resting cells is not observed in Nucling gene‐deficient mouse embryonic fibroblasts. These results reveal a novel function of Nucling as a suppressor of nuclear factor‐κB, mediated by its cytoplasmic retention through physical interaction.

Nucling is a stress‐inducible protein associated with apoptosomes. The cytochrome c‐triggered formation of apoptosomes represents a key‐initiating event in apoptosis. We have recently reported that Nucling regulates the apoptotic pathway by controlling the activation of NF‐κB as well. Here we show that hepatocellular carcinoma (HCC) arising spontaneously against a background of hepatitis occurred more frequently in Nucling‐knockout (KO) mice than wild‐type (WT) mice. Biochemical serum testing revealed potential liver dysfunction with hypercholesterolemia in Nucling‐KO males. In the background of Nucling‐KO mice, we observed the up‐regulation of TNFα, spontaneous NF‐κB‐activation and the induction of galectin‐3 expression in liver. In addition, we observed a decrease in the number of Kupffer cells (KCs) in the KO mice. KCs are important for the hepatic immune system, acting as phagocytes or antigen‐presenting cells (APCs). We found that KCs in Nucling‐KO mice were apoptotic possibly through the up‐regulation of TNFα. These observations indicate that Nucling is important for the regulation of NF‐κB signals in liver. We propose that Nucling deficiency could be a powerful tool to reveal the NF‐κB‐related molecular networks leading to hepatitis and HCC development.

Nucling is a proapoptotic protein that regulates the apoptosome and nuclear factor-kappa B (NF-κB) signalling pathways. Strong stimuli, such as Gram-negative bacterial lipopolysaccharide (LPS), induce the simultaneous secretion of cytokines following the activation of NF-κB. Proinflammatory cytokines can induce liver damage through several mechanisms such as increases in oxidative stress and apoptotic reactions leading to tissue necrosis. Herein, we show that Nucling-knockout (KO) mice are resistant to LPS that consistently caused mortality in wild-type (WT) counterparts. Although serum levels of cytokines such as tumour necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 did not differ significantly between WT and Nucling-KO mice after the LPS challenge, hepatocytes of Nucling-KO mice were refractory to LPS- or TNF-α-induced cell death. These results were consistent with the decreased expression of proapoptotic proteins including apoptosis-inducing factor and cleaved form of poly (ADP-ribose) polymerase and terminal deoxynucleotidyl transferase dUTP nick end-labelling positive cells in the liver of Nucling-KO mice after the administration of a lethal dose of LPS. Moreover, the upregulation of NF-κB-regulated anti-apoptotic molecules including cellular inhibitor of apoptosis (cIAP) 1 and cIAP2 was observed in the liver of Nucling-KO mice after LPS treatment. These findings indicate that the Nucling deficiency leads to resistance to apoptosis in liver. We propose that Nucling is important for the induction of apoptosis in cells damaged by cytotoxic stressors through the NF-κB signalling pathway.

Menstruation-related symptoms in young women are associated with lifestyle factors such as stress. This study aimed to examine menstrual conditions, menstruation-related symptoms, and types of stress in Japanese female students from their first to second years of university and the association between menstruation-related symptoms and stress levels. This prospective longitudinal cohort study utilized a self-reported web survey with the Menstrual Distress Questionnaire (MDQ) at three timepoints (2, 8, and 14 months) following admission and continuing into the second year. Data from 33 out of 102 students, who were followed throughout the study period, were used for analysis. Results indicated a trend towards changes in menstrual regularity, with the lowest (48.5%) at timepoint 1 and the highest (72.7%) at timepoint 3, and significant changes in perceived bleeding amount. Stress related to study and academic performance was consistently highest, with significant differences across timepoints. Intra-menstrual MDQ scores were highest at timepoint 1, with significant variations in impaired concentration severity across timepoints. Significant correlations were found between the MDQ scores and stress related to health and personality at all timepoints, and to future prospects, friendships, study, and academic performance at different timepoints. In short, stress related to academic performance, along with a strong correlation between MDQ scores and specific stress types, such as health and personality, was observed across all timepoints. This implies the need to provide new students with health education regarding menstruation and stress management before specific timepoints.

University education is still being impacted two years after the COVID-19 outbreak. We performed a rapid survey in February 2022 at two public universities in Vietnam to examine the effects of the pandemic on well-being and the factors that may associate with online class preference among university students as well as to investigate the need for support to improve resilience. A web-based survey included 1589 undergraduate students in total. Both quantitative and qualitative data analysis was carried out. Overall, approximately a quarter of respondents said that they perceived an influence on their health, 42.9% expressed stress, and more than 70% reported worrying about the future. In total, 61.9% of the respondents reported having satisfaction with online classes, while over half of them preferred a program of 50% online classes. Students who live in an urban area, are female, have had pre-COVID-19 campus life experience, have decreased income, and/or experience low online satisfaction and over-information may be in need of more support. The results show implications for universities to consider policies addressing well-being and post-pandemic online education. Providing support to university students to improve their resilience against the impact on their studying, campus life, health, and well-being should be prioritized during and post-pandemic.

Mothers and family members of young female students play important roles for guiding their self-care strategies for menstruation-related symptoms; which often affect their daily life and academic life. The aim of this study is to clarify the differences in menstruation-related symptoms before and during menstruation in university students living alone and university students living with their family in Japan. We conducted a cross-sectional online survey to assess menstruation-related symptoms before and during menstruation using the menstrual distress questionnaire (MDQ). Among 135 students; the proportion of students living alone was 60.7% and the proportion of students living with their family was 39.3%. Before menstruation; the MDQ total score and the scores for negative affect and behavior change were significantly higher in students living alone than in students living with their family. During menstruation; scores for negative affect and impaired concentration were also significantly higher in students living alone. In addition; before menstruation; scores for an increase in appetite and craving for sweets were significantly higher in students living alone. Thus; living alone affected the psychological aspects of menstruation-related symptoms in young women. The results suggest that university students who live alone should be aware of the importance of talking about their menstruation problems with family members and seeking their advice