BACKGROUND: Mitochondria, which harbor their own genome (mtDNA), have attracted attention due to the potential of mtDNA copy number (mtDNA-CN) as an indicator of mitochondrial dysfunction. Although mtDNA-CN has been proposed as a simple and accessible biomarker for metabolic disorders such as metabolic dysfunction-associated steatotic liver disease, the underlying mechanisms and the causal relationship remain insufficiently elucidated. In this investigation, we combined longitudinal epidemiological data, animal studies, and in vitro assays to elucidate the potential causal relationship between reduced mtDNA-CN and the development of steatotic liver disease (SLD). METHODS: We conducted a longitudinal study using data from a health examination cohort initiated in 1981 in Yakumo, Hokkaido, Japan. Data from examinations performed in 2015 and 2022 were analyzed, focusing on 76 subjects without SLD at baseline (2015) to assess the association between baseline mtDNA-CN and subsequent risk of SLD development. In addition, 28-day-old SD rats were fed ad libitum on a 45% high-fat diet and dissected at 2 and 8 weeks of age. Blood and liver mtDNA-CN were measured and compared at each feeding period. Additionally, in vitro experiments were performed using HepG2 cells treated with mitochondrial function inhibitors to induce mtDNA-CN depletion and to examine its impact on intracellular lipid accumulation. RESULTS: Epidemiological analysis showed that the subjects with low mtDNA-CN had a significantly higher odds ratio for developing SLD compared to high (odds ratio [95% confidence interval]: 4.93 [1.08-22.50]). Analysis of the animal model showed that 8 weeks of high-fat diet led to the development of fatty liver and a significant decrease in mtDNA-CN. A further 2 weeks of high-fat diet consumption resulted in a significant decrease in hepatic mtDNA-CN, despite the absence of fatty liver development, and a similar trend was observed for blood. Complementary in vitro experiments revealed that pharmacologically induced mitochondrial dysfunction led to a significant reduction in mtDNA-CN and was associated with increases in intracellular lipid accumulation in HepG2 cells. CONCLUSIONS Our findings suggest that reduced mtDNA-CN may contribute causally to SLD development and could serve as a convenient, noninvasive biomarker for early detection and risk assessment.
Animals ; DNA, Mitochondrial/genetics* ; Humans ; Male ; DNA Copy Number Variations ; Female ; Fatty Liver/blood* ; Rats ; Middle Aged ; Longitudinal Studies ; Rats, Sprague-Dawley ; Adult ; Japan/epidemiology* ; Aged ; Biomarkers/blood* ; Hep G2 Cells ; Diet, High-Fat/adverse effects*

Purpose: The purpose of this study was to clarify the panoramic image differences of cleft alveolus patients with or without a cleft palate, with emphases on the visibility of the line formed by the junction between the nasal septum and nasal floor (the upper line) and the appearances of the maxillary lateral incisor. Materials and Methods: Panoramic radiographs of 238 patients with cleft alveolus were analyzed for the visibility of the upper line, including clear, obscure or invisible, and the appearances of the maxillary lateral incisor, regarding congenital absence, incomplete growth, delayed eruption and medial inclination. Differences in the distribution ratio of these visibility and appearances were verified between the patients with and without a cleft palate using the chi-square test. Results: There was a significant difference in the visibility distribution of the upper line between the patients with and without a cleft palate (p<0.05). In most of the patients with a cleft palate, the upper line was not observed. In the unilateral cleft alveolus patients, the medial inclination of the maxillary lateral incisor was more frequently observed in patients with a cleft palate than in patients without a cleft palate. Conclusion Two differences were identified in panoramic appearances. The first was the disappearance (invisible appearance) of the upper line in patients with a cleft palate, and the second was a change in the medial inclination on the affected side maxillary lateral incisor in unilateral cleft alveolus patients with a cleft palate.

BACKGROUNDEstrogen receptor alpha (ER alpha) is the most important endocrine therapy responsiveness predictor for women with breast cancer. The accuracy of the prediction of the response to endocrine therapy was thought to be affected by involving the estrogen receptor coregulatory proteins and cross-talk between ER and other growth factor-signaling networks. Nuclear corepressor 1 (NCOR1) is one of the ER a transcription repressor. The objective of the study is to investigate the expression of NCOR1 at the protein level and pursue its predictive value for breast cancer endocrine therapy.

METHODSIn the present study, the level of expression of NCOR1 protein has been assessed by immunohistochemistry in 104 cases of invasive carcinoma of the breast. Associations between NCOR1 protein expression and different clinicopathological factors and survival were sought.

RESULTSIt was found that NCOR1 was expressed at significantly higher levels in responsive patients treated with endocrine therapy as first-line treatment on relapse. Responsive patients also had a significantly longer post-relapse survival and overall survival. No NCOR1 expression difference was found between patient by age, tumor size, lymph node status, different histological grade groups and human epidermal growth factor receptor 2 (HER2) status. Multivariate analysis showed that NCOR1 is an independent prognostic factor for over-all survival.

CONCLUSIONSIn breast cancer, NCOR1 protein expression level predicts response to endocrine therapy as first-line treatment for breast cancer patients on relapse and NCOR1 protein level assay may increase the accuracy in the endocrine treatment determination and, therefore, improving the patients survival.

Antineoplastic Agents, Hormonal ; therapeutic use ; Breast Neoplasms ; drug therapy ; metabolism ; Estrogen Receptor alpha ; metabolism ; Female ; Gene Expression Regulation ; Humans ; Immunohistochemistry ; Middle Aged ; Nuclear Receptor Co-Repressor 1 ; metabolism ; Receptor, ErbB-2 ; metabolism ; Receptors, Progesterone ; metabolism ; Tamoxifen ; therapeutic use