Perivascular mechanical environment: A narrative review of the role of externally applied mechanical force in the pathogenesis of atherosclerosis

Atherosclerosis is promoted by systemic factors, such as dyslipidemia, hypertension, diabetes, and smoking, which cause atherosclerosis in blood vessels throughout the body. However, atherosclerotic lesions are characterized by their frequent occurrence in specific vessels and sites. Blood vessels are exposed to various mechanical forces related to blood pressure and flow. Although shear stress promotes the initiation and progression of atherosclerotic lesions, the pathogenesis of site specificity of atherosclerosis is not sufficiently explained by shear stress. We propose the concept of a perivascular mechanical environment (PVME). Compelling evidence suggests that site specificity in atherosclerotic lesions depends on a distinct local PVME. Atheroprone arteries, such as the coronary artery, are markedly affected by externally applied mechanical force (EMF), whereas atheroprotective arteries, such as the internal thoracic artery, are less affected. Recent studies have shown that the coronary artery is affected by cardiac muscle contraction, the carotid artery by the hyoid bone and the thyroid cartilage, and the abdominal aorta and lower extremity arteries by musculoskeletal motion. We speculate that the thoracic cage protects the internal thoracic artery from EMF owing to a favorable PVME. Furthermore, evidence suggests that plaque eccentricity is provided by EMF; plaques are frequently observed on an external force-applied side. In each vascular tree, site-specific characteristics of the PVME differ substantially, inducing individual atherogenicity. From the perspective of the mechanical environment, hemodynamic stress occurs in an inside-out manner, whereas EMF occurs in an outside-in manner. These inward and outward forces apply mechanical load individually, but interact synergistically. The concept of a PVME is a novel pathogenesis of atherosclerosis and also might be a pathogenesis of other arterial diseases

Role of O-linked N-acetylglucosamine in the homeostasis of metabolic organs, and its potential links with diabetes and its complications.

Recent studies using genetically manipulated mouse models have shown the pivotal role of O-linked N-acetylglucosamine modification (O-GlcNAcylation) in the metabolism of multiple organs. The molecular mechanism involves the sensing of glucose flux by the hexosamine biosynthesis pathway, which leads to the adjustment of cellular metabolism to protect against changes in the environment of each organ through O-GlcNAcylation. More recently, not only glucose, but also fluxes of amino acids and fatty acids have been reported to induce O-GlcNAcylation, affecting multiple cellular processes. In this review, we discuss how O-GlcNAcylation maintains homeostasis in organs that are affected by diabetes mellitus: skeletal muscle, adipose tissue, liver and pancreatic β-cells. Furthermore, we discuss the importance of O-GlcNAcylation in the pathogenesis of diabetic complications. By elucidating the molecular mechanisms whereby cellular homeostasis is maintained, despite changes in metabolic flux, these studies might provide new targets for the treatment and prevention of diabetes and its complications

Original Article Fish Oil Regulates Adiponectin Secretion by a Peroxisome Proliferator-Activated Receptor-␥-Dependent Mechanism in Mice

Adiponectin has insulin-sensitizing, antiatherogenic, and anti-inflammatory properties, but little is known about factors that regulate its secretion. To examine the effect of fish oil on adiponectin secretion, mice were fed either a control diet or isocaloric diets containing 27% safflower oil or 27, 13.5, and 8% menhaden fish oil. Within 15 days, fish oil feeding raised plasma adiponectin concentrations twoto threefold in a dose-dependent manner, and the concentrations remained approximately twofold higher for 7 days when the fish oil diet was replaced by the safflower oil diet. Within 24 h, fish oil markedly induced transcription of the adiponectin gene in epididymal adipose tissue but not in subcutaneous fat. The increase of plasma adiponectin by fish oil was completely blocked by administration of the peroxisome proliferator-activated receptor (PPAR)␥ inhibitor bisphenol-A-diglycidyl ether. In contrast, there was no effect of fish oil feeding on adiponectin secretion in PPAR␣-null mice. These data suggest that fish oil is a naturally occurring potent regulator of adiponectin secretion in vivo and that it does so through a PPAR␥-dependent and PPAR␣-independent manner in epididymal fat. Diabetes 55: 924 -928, 200

Real-world evidence of the impact of obesity on residual teeth in the Japanese population : A cross-sectional study

Background:Tooth loss is associated with nutritional status and significantly affects quality of life, particularly in older individuals. To date, several studies reveal that a high BMI is associated with tooth loss. However, there is a lack of large-scale studies that examined the impact of obesity on residual teeth with respect to age and tooth positions.Objective:We assessed the impact of obesity on the number and position of residual teeth by age groups using large scale of Japanese database.Methods:This was a cross-sectional study of 706150 subjects that were included in the database that combined the data from health insurance claims and health check-up, those lacking information about BMI, HbA1c level, smoking status, and the number of residual teeth were excluded. Thus, a total of 233517 aged 20-74 years were included. Subjects were classified into 4 categories based on BMI, and the number of teeth was compared between age-groups. The percentage of subjects with residual teeth in each position was compared between groups with obesity (BMI ≥25.0 kg/m2) and non-obesity. Logistic regression analysis was performed to clarify whether obesity predicts having <24 teeth.Results:Higher BMI was associated with fewer teeth over 40s (P for trend <0.0001 when <70s). Obesity was associated with the reduction of residual teeth in the maxillary; specifically, the molars were affected over the age 30. Smoking status further affected tooth loss at positions that were not affected by obesity alone. After adjusting for age, sex, smoking status, and HbA1c ≥6.5%, obesity remained an independent predictive factor for having <24 teeth (ORs: 1.35, 95% CIs: 1.30-1.40).Conclusions:We found that an increase in BMI was associated with a decrease in the number of residual teeth from younger ages independently of smoking status and diabetes in the large scale of Japanese database

MicroRNA-494-3p inhibits formation of fast oxidative muscle fibres by targeting E1A-binding protein p300 in human-induced pluripotent stem cells.

MYOD-induced microRNA-494-3p expression inhibits fast oxidative myotube formation by downregulating myosin heavy chain 2 (MYH2) in human induced pluripotent stem cells (hiPSCs) during skeletal myogenesis. However, the molecular mechanisms regulating MYH2 expression via miR-494-3p remain unknown. Here, using bioinformatic analyses, we show that miR-494-3p potentially targets the transcript of the E1A-binding protein p300 at its 3\u27-untranslated region (UTR). Myogenesis in hiPSCs with the Tet/ON-myogenic differentiation 1 (MYOD1) gene (MyoD-hiPSCs) was induced by culturing them in doxycycline-supplemented differentiation medium for 7 days. p300 protein expression decreased after transient induction of miR-494-3p during myogenesis. miR-494-3p mimics decreased the levels of p300 and its downstream targets MYOD and MYH2 and myotube formation efficiency. p300 knockdown decreased myotube formation efficiency, MYH2 expression, and basal oxygen consumption rate. The binding of miR-494-3p to the wild type p300 3\u27-UTR, but not the mutated site, was confirmed using luciferase assay. Overexpression of p300 rescued the miR-494-3p mimic-induced phenotype in MyoD-hiPSCs. Moreover, miR-494-3p mimic reduced the levels of p300, MYOD, and MYH2 in skeletal muscles in mice. Thus, miR-494-3p might modulate MYH2 expression and fast oxidative myotube formation by directly regulating p300 levels during skeletal myogenesis in MyoD-hiPSCs and murine skeletal muscle tissues

Liver fat accumulation assessed by computed tomography is an independent risk factor for diabetes mellitus in a population-based study: SESSA (Shiga Epidemiological Study of Subclinical Atherosclerosis).

AIMS:Ectopic fat accumulation is related to insulin resistance and diabetes mellitus (DM). However, the effect of fatty liver on DM in non-obese individuals has not been clarified. We investigated whether liver fat accumulation assessed by computed tomography (CT) is associated with the incidence of DM.METHODS:In a prospective population-based study, 640 Japanese men were followed up for 5 years. The liver to spleen (L/S) ratio of the CT attenuation value was used as the liver fat accumulation index. We calculated the odds ratio (OR) and 95% confidence interval (CI) for the DM incidence of per 1 standard deviation (SD) lower L/S and those of L/S < 1.0 compared with L/S ≥ 1.0, using logistic regression models.RESULTS:Both per 1 SD lower L/S and L/S < 1.0 were significantly associated with a risk for DM incidence (1 SD lower L/S: OR = 1.57, 95%CI = 1.14-2.16; L/S < 1.0: OR = 2.27, 95%CI = 1.00-5.14). The relationship between L/S and incidence of DM was consistent in the obese and non-obese groups, with thresholds of BMI 25 kg/m2, waist circumference 85 cm, or visceral adipose tissue 100 cm2.CONCLUSIONS:Liver fat accumulation assessed by CT was associated with the incidence of DM

Nakamoto_Figures for reviewer only

Supplemantal materials for Nakamoto Akiko</p

Nakamoto_Figure for reviewer only_20230429_PDF.pdf

Figure for Reviewer only</p

Supplemental Matelials for Nakamoto Akiko

These Figures are supplemental materials for our manuscript entitled “O-GlcNAc modification is essential for physiological adipose expansion induced by high-fat feeding” .</p

Mitochondrial Health in Aging and Age-Related Metabolic Disease

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