We have previously shown that neural precursor cell-expressed developmentally downregulated gene 4-2 (Nedd4-2) isoforms with a C2 domain are closely related to ubiquitination of epithelial sodium channel (ENaC), resulting in salt-sensitive hypertension by Nedd4-2 C2 targeting in mice. The sodium voltage-gated channel alpha subunit 5 (SCN5A) gene encodes the α subunit of the human cardiac voltage-gated sodium channel (I Na), and the potassium voltage-gated channel subfamily H member 2 (KCNH2) gene encodes rapidly activating delayed rectifier K channels (I Kr). Both ion channels have also been shown to bind to Nedd4-2 via a conserved Proline-Tyrosine (PY) motif in C-terminal with subsequent ubiquitination and degradation by proteasome. Therefore, loss of Nedd4-2 C2 isoform might be involved in electrophysiological impairment under various conditions. We demonstrate here that Nedd4-2 C2 isoform causes cardiac conduction change in resting condition as well as proarrhythmic change after acute myocardial infarction (MI). The Nedd4-2 C2 knockout (KO) mice showed bradycardia, prolonged QRS, QT intervals, and suppressed PR interval in resting condition. In addition, enhancement of T peak/T end interval was found in mice with surgical ligation of the distal left coronary artery. Morphological analyses based on both ultrasonography of the living heart, as well as histopathological findings revealed that Nedd4-2 C2 KO mice show no significant structural changes from wild-type littermates under resting conditions. These results suggested that Nedd4-2 with C2 domain might play an important role in cardio-renal syndrome through post-transcriptional modification of both ENaC and cardiac ion channels, which are critical for kidney and heart functions.

The newly established mouse cortical-bone-derived stem cells (mCBSCs) are unique stem cells compared to mouse mesenchymal stem cells (mMSCs). The mCBSC-treated hearts after myocardial infarction have been reported to have greater improvement in myocardial structure and functions. In this study, we examined the stemness features, cell surface glycan profiles, and paracrine functions of mCBSCs compared with mMSCs. The stemness analysis revealed that the self-renewing capacity of mCBSCs was greater than mMSCs; however, the differentiation capacity of mCBSCs was limited to the chondrogenic lineage among three types of cells (adipocyte, osteoblast, chondrocyte). The cell surface glycan profiles by lectin array analysis revealed that α2-6sialic acid is expressed at very low levels on the cell surface of mCBSCs compared with that on mMSCs. In contrast, the lactosamine (Galβ1-4GlcNAc) structure, poly lactosamine- or poly N-acetylglucosamine structure, and α2-3sialic acid on both N- and O-glycans were more highly expressed in mCBSCs. Moreover, we found that mCBSCs secrete a greater amount of TGF-β1 compared to mMSCs, and that the TGF-β1 contributed to the self-migration of mCBSCs and activation of fibroblasts. Together, these results suggest that unique characteristics in mCBSCs compared to mMSCs may lead to advanced utility of mCBSCs for cardiac and noncardiac repair.

Background: Oral frailty (OF), defined as a multidimensional decline in oral function, is an early marker of functional vulnerability in older adults. Although frailty is linked to cardiovascular disease incidence and prognosis, the relationship between OF, heart disease (HD), and multimorbidity (MM) remains unclear.Methods and Results: We conducted a cross-sectional analysis of 16,294 community-dwelling adults aged ≥65 years in the 2022 Japan Gerontological Evaluation Study. OF was assessed using the Oral Frailty 5-item Checklist. Among 1,575 participants with HD, we compared those with HD alone and those with HD plus comorbidities (HD+MM). We also compared OF and its components across the 4 groups based on HD and MM status. The overall prevalence of OF was 33.9%, increasing to 42.9% in individuals with HD. OF was significantly more prevalent in the HD+MM group than in the HD-only group (44.3% vs. 36.2%). Respiratory, digestive, immune, and ear diseases were strongly associated with OF. Furthermore, OF, lower Tokyo Metropolitan Institute of Gerontology Index of Competence scores, and higher body mass index were independently associated with a greater comorbidity burden in older adults.Conclusions: OF is common in older adults with HD, particularly in those with MM. Incorporating oral function assessment into cardiovascular risk evaluation may help identify high-risk individuals and support comprehensive management strategies for the aging population.

Background: The newly established mouse cortical bone–derived stem cells (mCBSCs) are unique stem cells compared with mouse mesenchymal stem cells (mMSCs), and can improve cardiac function after myocardial infarction. However, the mCBSCs’ characterizations including their stem cell features, non-cardiac therapeutic potential, and cell surface features have not been fully understood. In this study, we examined stem cell features, cell surface glycan profiles, and cell functional features in mCBSCs compared to the bone marrow-derived mMSCs. Methods: The stem cell features were compared between mCBSCs and mMSCs by immunoblotting of stem cell markers, self-renewal assay, and multilineage differentiation. The cell surface glycan profiles were examined by lectin array analysis and fluorescence-activated cell sorting analysis using lectins. The production of transforming growth factor (TGF)-β1 from mCBSCs were examined by ELISA. The effects of TGF-β1 released from mCBSCs on self-migration and on activation of fibroblast were examined by migration assay and immunocytostaining, respectively. Results: The stem cell feature, including the self-renewing ability in mCBSCs was higher than that in mMSCs. In contrast, the differentiation ability of mCBSCs was limited to the chondrogenic lineage among three types of cells (adipocyte, osteoblast, chondrocyte). The cell surface glycan profiles revealed that α2-6sialic acid is expressed at very low levels on the cell surface of mCBSCs compared with that on mMSCs. Additionally, the lactosamine (Galβ1-4GlcNAc)-structure, poly lactosamine- or poly N-acetylglucosamine-structure, and α2-3sialic acid on both N- and O-glycans are more highly expressed in mCBSCs compared with mMSCs. Furthermore, these highly expressed glycans were increased with cellular aging of mCBSCs. We found that TGF-β1 was released from mCBSCs and the released TGF-β1 contributed to the self-migration of mCBSCs and activation of fibroblasts. Conclusions: These results reveal the differences between mCBSCs and mMSCs, and it is proposed that there is the potential use of mCBSCs for infarct healing and wound healing.

Factors influencing oral problems, such as malocclusion and oral motor dysfunction, in patients with prolonged disorders of consciousness (DOC) remain unclear. This study aimed to clarify the relationship between oral problems and physical function, communication, respiration, and oral intake status, as well as related factors in patients with DOC receiving long-term care at home. A cross-sectional study was conducted in October 2018; 127 patients who developed DOC > 5 years ago were analyzed. The differences between patients with and without oral problems were examined, and a binomial logistic regression analysis was performed to examine factors associated with oral problems, with the presence of oral problems as the dependent variable, and age, the number of years since onset, drooling, oral intake status, and the presence of a family dentist as explanatory variables. A post hoc power analysis of the binomial logistic regression analysis for oral problems (odds ratio: 2.05, alpha value: 0.05, incidence of oral problems: 0.80, and total sample size: 127) demonstrated an observed power of 93.09%. Oral intake status (p = 0.010) and the number of years since onset (p = 0.046) were significantly related to oral problems. Preventive oral management and rehabilitation from the early stage after onset may be effective for oral problems in patients with DOC.