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Nature Communications Jun 2024People with lower extremity peripheral artery disease (PAD) have increased oxidative stress, impaired mitochondrial activity, and poor walking performance. NAD+ reduces... (Randomized Controlled Trial)
Randomized Controlled Trial
People with lower extremity peripheral artery disease (PAD) have increased oxidative stress, impaired mitochondrial activity, and poor walking performance. NAD+ reduces oxidative stress and is an essential cofactor for mitochondrial respiration. Oral nicotinamide riboside (NR) increases bioavailability of NAD+ in humans. Among 90 people with PAD, this randomized double-blind clinical trial assessed whether 6-months of NR, with and without resveratrol, improves 6-min walk distance, compared to placebo, at 6-month follow-up. At 6-month follow-up, compared to placebo, NR significantly improved 6-min walk (+7.0 vs. -10.6 meters, between group difference: +17.6 (90% CI: + 1.8,+∞). Among participants who took at least 75% of study pills, compared to placebo, NR improved 6-min walk by 31.0 meters and NR + resveratrol improved 6-min walk by 26.9 meters. In this work, NR meaningfully improved 6-min walk, and resveratrol did not add benefit to NR alone in PAD. A larger clinical trial to confirm these findings is needed.
Topics: Humans; Peripheral Arterial Disease; Niacinamide; Male; Female; Aged; Pyridinium Compounds; Double-Blind Method; Resveratrol; Middle Aged; Walking; Treatment Outcome; Oxidative Stress
PubMed: 38871717
DOI: 10.1038/s41467-024-49092-5 -
Redox Biology Aug 2024Nuclear erythroid 2-related factor 2 (Nrf2), a transcription factor, is critically involved in the regulation of oxidative stress and inflammation. However, the role of...
BACKGROUND
Nuclear erythroid 2-related factor 2 (Nrf2), a transcription factor, is critically involved in the regulation of oxidative stress and inflammation. However, the role of endothelial Nrf2 in atherogenesis has yet to be defined. In addition, how endothelial Nrf2 is activated and whether Nrf2 can be targeted for the prevention and treatment of atherosclerosis is not explored.
METHODS
RNA-sequencing and single-cell RNA sequencing analysis of mouse atherosclerotic aortas were used to identify the differentially expressed genes. In vivo endothelial cell (EC)-specific activation of Nrf2 was achieved by injecting adeno-associated viruses into ApoE mice, while EC-specific knockdown of Nrf2 was generated in Cdh5Cas9ApoE mice.
RESULTS
Endothelial inflammation appeared as early as on day 3 after feeding of a high cholesterol diet (HCD) in ApoE mice, as reflected by mRNA levels, immunostaining and global mRNA profiling, while the immunosignal of the end-product of lipid peroxidation (LPO), 4-hydroxynonenal (4-HNE), started to increase on day 10. TNF-α, 4-HNE, and erastin (LPO inducer), activated Nrf2 signaling in human ECs by increasing the mRNA and protein expression of Nrf2 target genes. Knockdown of endothelial Nrf2 resulted in augmented endothelial inflammation and LPO, and accelerated atherosclerosis in Cdh5Cas9ApoE mice. By contrast, both EC-specific and pharmacological activation of Nrf2 inhibited endothelial inflammation, LPO, and atherogenesis.
CONCLUSIONS
Upon HCD feeding in ApoE mice, endothelial inflammation is an earliest event, followed by the appearance of LPO. EC-specific activation of Nrf2 inhibits atherosclerosis while EC-specific knockdown of Nrf2 results in the opposite effect. Pharmacological activators of endothelial Nrf2 may represent a novel therapeutic strategy for the treatment of atherosclerosis.
Topics: Animals; NF-E2-Related Factor 2; Atherosclerosis; Mice; Apolipoproteins E; Endothelial Cells; Inflammation; Lipid Peroxidation; Humans; Oxidative Stress; Mice, Knockout; Disease Models, Animal; Male
PubMed: 38870781
DOI: 10.1016/j.redox.2024.103229 -
PloS One 2024Previous research demonstrates the joint association of self-reported physical activity and genotype with coronary artery disease. However, an existing research gap is...
Previous research demonstrates the joint association of self-reported physical activity and genotype with coronary artery disease. However, an existing research gap is whether accelerometer-measured overall physical activity or physical activity intensity can offset genetic predisposition to coronary artery disease. This study explores the independent and joint associations of accelerometer-measured physical activity and genetic predisposition with incident coronary artery disease. Incident coronary artery disease based on hospital inpatient records and death register data serves as the outcome of this study. Polygenic risk score and overall physical activity, measured as Euclidean Norm Minus One, and intensity, measured as minutes per day of moderate-to-vigorous intensity physical activity (MVPA), are examined both linearly and by decile. The UK Biobank population-based cohort recruited over 500,000 individuals aged 40 to 69 between 2006 and 2010, with 103,712 volunteers participating in a weeklong wrist-worn accelerometer study from 2013 to 2015. Individuals of White British ancestry (n = 65,079) meeting the genotyping and accelerometer-based inclusion criteria and with no missing covariates were included in the analytic sample. In the sample of 65,079 individuals, the mean (SD) age was 62.51 (7.76) and 61% were female. During a median follow-up of 6.8 years, 1,382 cases of coronary artery disease developed. At the same genetic risk, physical activity intensity had a hazard ratio (HR) of 0.41 (95% CI: 0.29-0.60) at the 90th compared to 10th percentile, equivalent to 31.68 and 120.96 minutes of moderate-to-vigorous physical activity per day, respectively, versus an HR of 0.61 (95% CI: 0.52-0.72) for overall physical activity. The combination of high genetic risk and low physical activity intensity showed the greatest risk, with an individual at the 10th percentile of genetic risk and 90th percentile of intensity facing an HR of 0.14 (95% CI: 0.09-0.21) compared to an individual at the 90th percentile of genetic risk and 10th percentile of intensity. Physical activity, especially physical activity intensity, is associated with an attenuation of some of the risk of coronary artery disease but this pattern does not vary by genetic risk. This accelerometer-based study provides the clearest evidence to date regarding the joint influence of genetics, overall physical activity, and physical activity intensity on coronary artery disease.
Topics: Humans; Coronary Artery Disease; Female; Male; Middle Aged; United Kingdom; Accelerometry; Exercise; Aged; Genetic Predisposition to Disease; Biological Specimen Banks; Adult; Cohort Studies; Risk Factors; Incidence; UK Biobank
PubMed: 38870224
DOI: 10.1371/journal.pone.0304653 -
International Journal of... 2024Corilagin possesses a diverse range of pharmacologic bioactivities. However, the specific protective effects and mechanisms of action of corilagin in the context of...
INTRODUCTION
Corilagin possesses a diverse range of pharmacologic bioactivities. However, the specific protective effects and mechanisms of action of corilagin in the context of atherosclerosis remain unclear. In this study, we investigated the impact of corilagin on the toll-like receptor (TLR)4 signaling pathway in a mouse vascular smooth muscle cell line (MOVAS) stimulated by oxidized low-density lipoprotein (ox-LDL). Additionally, we examined the effects of corilagin in Sprague-Dawley rats experiencing atherosclerosis.
METHODS
The cytotoxicity of corilagin was assessed using the CCK8 assay. MOVAS cells, pre-incubated with ox-LDL, underwent treatment with varying concentrations of corilagin. TLR4 expression was modulated by either downregulation through small interfering (si)RNA or upregulation via lentivirus transfection. Molecular expression within the TLR4 signaling pathway was analyzed using real-time polymerase chain reaction (PCR) and Western blotting. The proliferation capacity of MOVAS cells was determined through cell counting. In a rat model, atherosclerosis was induced in femoral arteries using an improved guidewire injury method, and TLR4 expression in plaque areas was assessed using immunofluorescence. Pathological changes were examined through hematoxylin and eosin staining, as well as Oil-Red-O staining.
RESULTS
Corilagin demonstrated inhibitory effects on the TLR4 signaling pathway in MOVAS cells pre-stimulated with ox-LDL, consequently impeding the proliferative impact of ox-LDL. The modulation of TLR4 expression, either through downregulation or upregulation, similarly influenced the expression of downstream molecules. In an in vivo context, corilagin exhibited the ability to suppress TLR4 and MyD88 expression in the plaque lesion areas of rat femoral arteries, thereby alleviating the formation of atherosclerotic plaques.
CONCLUSION
Corilagin can inhibit the TLR4 signaling pathway in VSMCs, possibly by downregulating TLR4 expression and, consequently, relieving atherosclerosis.
Topics: Animals; Toll-Like Receptor 4; Hydrolyzable Tannins; Rats, Sprague-Dawley; Signal Transduction; Atherosclerosis; Muscle, Smooth, Vascular; Lipoproteins, LDL; Male; Glucosides; Mice; Cell Line; Rats; Cell Proliferation; Myocytes, Smooth Muscle; Disease Models, Animal; Myeloid Differentiation Factor 88
PubMed: 38869980
DOI: 10.1177/03946320241254083 -
Immunity, Inflammation and Disease Jun 2024Numerous studies have demonstrated that Absent in Melanoma 2 (AIM2) is upregulated in aortic plaques, especially in Vascular Smooth Muscle Cells in Coronary Artery...
BACKGROUND
Numerous studies have demonstrated that Absent in Melanoma 2 (AIM2) is upregulated in aortic plaques, especially in Vascular Smooth Muscle Cells in Coronary Artery Disease (CAD), and is related to inflammasome-induced inflammation. However, the underlying mechanism of this phenomenon and the role of AIM2 in atherosclerosis remained unclear.
METHODS
This study enrolled 133 CAD patients and 123 controls. We isolated Peripheral Blood Leukocytes (PBLs) and the mRNA expression of AIM2 inflammasome and its downstream genes (ASC, Caspase-1, IL-1β, and IL-18) were detected by real-time quantitative PCR (qPCR). We assessed correlations between AIM2 expressions and clinical characteristics by multiple linear regression and spearman's correlation. The THP-1 cells cultured in poly(dA:dT), A151, interferon-gamma (IFN-γ), AG490, or JC2-11. And then the mRNA and protein levels of AIM2, ASC, Caspase-1, IL-1β, IL-18, GSDMD, and STAT1 were analyzed by qPCR and Western blot analysis, respectively. The migration and adhesive capacity of THP-1 cells was assessed using an inverted microscope and an inverted fluorescence microscope, respectively.
RESULTS
In this study, we found that expressions of components of AIM2 inflammasome and its downstream genes (ASC, Caspase-1, IL-1β, and IL-18), were all increased in PBLs of CAD patients, which indicated the inflammasome activation. AIM2 inflammasome activation further induced pyroptosis, and stimulated migration and adhesion in monocyte cell lines, which was regulated by IFN-γ probably through JAK2/STAT1 pathway. In addition, AIM2 expressions were positively correlated with systemic inflammatory indicators as an independent risk factor for CAD.
CONCLUSIONS
In conclusion, increased AIM2 expression, induced by the IFN-γ/JAK2/STAT1 signal, orientates monocytes to inflammatory status or even pyroptosis through AIM2 inflammasome activation, which is involved in the development of CAD.
Topics: Aged; Female; Humans; Male; Middle Aged; Coronary Artery Disease; DNA-Binding Proteins; Inflammasomes; Interferon-gamma; Janus Kinase 2; Monocytes; Pyroptosis; Signal Transduction; STAT1 Transcription Factor; THP-1 Cells
PubMed: 38869352
DOI: 10.1002/iid3.1317 -
Lipids in Health and Disease Jun 2024Previous studies have shown a correlation between depression and obesity, as well as between depression and the Atherogenic Index of Plasma (AIP). However, there is...
BACKGROUND
Previous studies have shown a correlation between depression and obesity, as well as between depression and the Atherogenic Index of Plasma (AIP). However, there is limited research on the association between visceral obesity and depression, as well as the potential mediating role of AIP in this relationship.
METHODS
This study included 13,123 participants from the 2005-2018 National Health and Nutrition Examination Survey. Visceral obesity was measured with the Body Roundness Index (BRI), while depression was evaluated with the Patient Health Questionnaire-9. The AIP served as a marker for lipid disorders. To investigate the association between the BRI and depression, multivariate logistic regressions, restricted cubic spline models, subgroup analyses, and interaction tests were used. Additionally, a mediation analysis was conducted to explore the role of AIP in mediating the effect of BRI on depression.
RESULTS
There was a positive linear correlation between the BRI and depression. After controlling for all covariates, individuals in the highest BRI (Q4) group had an OR of 1.42 for depression (95% CI: 1.12-1.82) in comparison with individuals in the lowest BRI (Q1) group. Moreover, the AIP partially mediated the association between the BRI and depression, accounting for approximately 8.64% (95% CI: 2.04-16.00%) of the total effect.
CONCLUSION
The BRI was positively associated with depression, with the AIP playing a mediating role. This study provides a novel perspective on the mechanism that connects visceral obesity to depression. Managing visceral fat and monitoring AIP levels may contribute to alleviating depression.
Topics: Humans; Depression; Female; Male; Middle Aged; Nutrition Surveys; Adult; Atherosclerosis; Obesity, Abdominal; Body Mass Index; Logistic Models; Aged; Biomarkers
PubMed: 38867232
DOI: 10.1186/s12944-024-02177-y -
Lipids in Health and Disease Jun 2024The atherogenic index of plasma (AIP) is a simple and reliable marker of insulin resistance and is closely associated with various cardiovascular diseases (CVDs)....
BACKGROUND
The atherogenic index of plasma (AIP) is a simple and reliable marker of insulin resistance and is closely associated with various cardiovascular diseases (CVDs). However, the relationships between AIP and left ventricular (LV) geometric indicators have not been adequately assessed. This study was carried out to investigate the association between AIP and LV geometric abnormalities in obstructive sleep apnea (OSA) patients.
METHODS
This retrospective cross-sectional study included a total of 618 OSA patients (57.3 ± 12.4 years, 73.1% males, BMI 28.1 ± 4.2 kg/m) who underwent echocardiography. Patients with OSA were diagnosed with clinical symptoms and an apnea-hypopnea index ≥ 5.0. LV hypertrophy (LVH) was defined as left ventricular mass index (LVMI) ≥ 50.0 g/m for men and 47.0 g/m for women. AIP was calculated as log (TG/HDL-C).
RESULTS
Compared with the non-LVH group, AIP was significantly higher in the LVH group (0.19 ± 0.29 vs 0.24 ± 0.28, P = 0.024) and the concentric LVH group (0.18 ± 0.29, 0.19 ± 0.30, 0.20 ± 0.26 and 0.29 ± 0.29 in the control, concentric remodeling, eccentric hypertrophy and concentric hypertrophy groups, respectively, P = 0.021). Meanwhile, in the group of patients with the highest AIP tertile, the levels of LVMI (42.8 ± 10.5, 43.2 ± 9.3 and 46.1 ± 12.1 in the T1, T2 and T3 groups, respectively, P = 0.003), and the prevalence of LVH (25.2%, 24.0% and 34.6% in the T1, T2 and T3 groups, respectively, P = 0.032) and concentric LVH (10.7%, 9.8% and 20.2% in the T1, T2 and T3 groups, respectively, P = 0.053) were higher compared with those in the other groups. Positive correlations between AIP and LV geometric indicators including the LVMI, LVMI, LV mass (LVM), diastolic left ventricular inner diameter (LVIDd), diastolic left ventricular posterior wall thickness (PWTd) and diastolic interventricular septal thickness (IVSTd), were revealed according to correlation analysis (P < 0.05). Furthermore, AIP was independently associated with LVMI according to multivariate linear regression model (β = 0.125, P = 0.001). Notably, AIP remained independently associated with an elevated risk of LVH [odds ratio (OR) = 1.317 per 1 standard deviation (SD) increment, 95% confidence interval (CI): 1.058 - 1.639, P = 0.014) and concentric LVH (OR = 1.545 per 1 SD increment, 95% CI: 1.173 - 2.035, P = 0.002) after fully adjusting for all confounding risk factors by multivariate logistic regression analyses.
CONCLUSIONS
AIP was independently associated with an increased risk of LVH and concentric LVH in OSA patients. Therefore, AIP, as a practical and cost-effective test, might be useful in monitoring hypertrophic remodeling of the heart and improving CVDs risk stratification in clinical management of OSA.
Topics: Humans; Male; Sleep Apnea, Obstructive; Female; Middle Aged; Hypertrophy, Left Ventricular; Cross-Sectional Studies; Retrospective Studies; Aged; Echocardiography; Atherosclerosis; Triglycerides; Adult; Cholesterol, HDL; Insulin Resistance; Risk Factors
PubMed: 38867215
DOI: 10.1186/s12944-024-02170-5 -
Lipids in Health and Disease Jun 2024Although there has been abundant evidence of the association between dyslipidemia as a single factor and osteoporosis, the non-linear relationship between osteoporosis...
INTRODUCTION
Although there has been abundant evidence of the association between dyslipidemia as a single factor and osteoporosis, the non-linear relationship between osteoporosis and the Atherogenic Index of Plasma (AIP) has not yet been thoroughly investigated. This study aimed to investigate the complex relationship between AIP and bone mineral density (BMD) to elucidate their interrelationship.
METHODS
An analysis of 2007-2018 National Health and Nutrition Survey (NHANES) data was conducted for this study. The study enrolled 5,019 participants. Logarithmically multiplying triglycerides and high-density lipoprotein cholesterol yields the AIP (base 10). The measured variables consisted of BMD in the total femur (TF), femoral neck (FN), and lumbar spine (LS). The association between AIP and BMD was examined using a range of statistical models, such as weighted multivariable logistic regression, generalized additive model, etc. RESULTS: It was found that AIP was positively associated with BMD after adjusting for age, gender, race, socioeconomic status, degree of education, income, Consuming alcoholic beverages, osteoporosis status (Yes or No), ALT, AST, serum creatinine, and total calcium levels. Further studies supported the association link between elevated BMD and AIP. Furthermore, compared to men, females had a higher positive connection between AIP and BMD. In general, there was a curve in the reverse L-shape seen, with a point of change around 0.877, indicating a relationship between AIP and TF BMD. Moreover, a curve exhibiting an L-formed pattern, with a point of inflection at around 0.702, was seen between AIP and FN BMD. In addition, a J-shaped curve was seen, with a point of inflection at 0.092, which demonstrates the association between AIP and LS BMD.
CONCLUSION
The AIP and TF BMD curves resemble inverted L shapes, as do the AIP and FN BMD curves. The relationship between AIP and LS BMD was further demonstrated by a J-shaped curve. The results indicate a possible association between AIP and bone mineral density, which should be explored in more detail.
Topics: Humans; Bone Density; Male; Female; Middle Aged; Cross-Sectional Studies; Atherosclerosis; Osteoporosis; Adult; Cholesterol, HDL; Triglycerides; Lumbar Vertebrae; Femur Neck; Aged; Nutrition Surveys; Femur
PubMed: 38867213
DOI: 10.1186/s12944-024-02180-3 -
BMC Cardiovascular Disorders Jun 2024Diabetes is a common chronic metabolic disease. The progression of the disease promotes vascular inflammation and the formation of atherosclerosis, leading to...
BACKGROUND
Diabetes is a common chronic metabolic disease. The progression of the disease promotes vascular inflammation and the formation of atherosclerosis, leading to cardiovascular disease. The coronary artery perivascular adipose tissue attenuation index based on CCTA is a new noninvasive imaging biomarker that reflects the spatial changes in perivascular adipose tissue attenuation in CCTA images and the inflammation around the coronary arteries. In this study, a radiomics approach is proposed to extract a large number of image features from CCTA in a high-throughput manner and combined with clinical diagnostic data to explore the predictive ability of vascular perivascular adipose imaging data based on CCTA for coronary heart disease in diabetic patients.
METHODS
R language was used for statistical analysis to screen the variables with significant differences. A presegmentation model was used for CCTA vessel segmentation, and the pericoronary adipose region was screened out. PyRadiomics was used to calculate the radiomics features of pericoronary adipose tissue, and SVM, DT and RF were used to model and analyze the clinical data and radiomics data. Model performance was evaluated using indicators such as PPV, FPR, AAC, and ROC.
RESULTS
The results indicate that there are significant differences in age, blood pressure, and some biochemical indicators between diabetes patients with and without coronary heart disease. Among 1037 calculated radiomic parameters, 18.3% showed significant differences in imaging omics features. Three modeling methods were used to analyze different combinations of clinical information, internal vascular radiomics information and pericoronary vascular fat radiomics information. The results showed that the dataset of full data had the highest ACC values under different machine learning models. The support vector machine method showed the best specificity, sensitivity, and accuracy for this dataset.
CONCLUSIONS
In this study, the clinical data and pericoronary radiomics data of CCTA were fused to predict the occurrence of coronary heart disease in diabetic patients. This provides information for the early detection of coronary heart disease in patients with diabetes and allows for timely intervention and treatment.
Topics: Humans; Predictive Value of Tests; Diabetes Mellitus, Type 2; Middle Aged; Adipose Tissue; Male; Female; Coronary Angiography; Computed Tomography Angiography; Coronary Artery Disease; Aged; Coronary Vessels; Radiographic Image Interpretation, Computer-Assisted; Support Vector Machine; Adiposity; Prognosis; Epicardial Adipose Tissue; Radiomics
PubMed: 38867152
DOI: 10.1186/s12872-024-03970-4 -
Scientific Reports Jun 2024Images obtained from single-photon emission computed tomography for myocardial perfusion imaging (MPI SPECT) contain noises and artifacts, making cardiovascular disease...
Images obtained from single-photon emission computed tomography for myocardial perfusion imaging (MPI SPECT) contain noises and artifacts, making cardiovascular disease diagnosis difficult. We developed a deep learning-based diagnosis support system using MPI SPECT images. Single-center datasets of MPI SPECT images (n = 5443) were obtained and labeled as healthy or coronary artery disease based on diagnosis reports. Three axes of four-dimensional datasets, resting, and stress conditions of three-dimensional reconstruction data, were reconstructed, and an AI model was trained to classify them. The trained convolutional neural network showed high performance [area under the curve (AUC) of the ROC curve: approximately 0.91; area under the recall precision curve: 0.87]. Additionally, using unsupervised learning and the Grad-CAM method, diseased lesions were successfully visualized. The AI-based automated diagnosis system had the highest performance (88%), followed by cardiologists with AI-guided diagnosis (80%) and cardiologists alone (65%). Furthermore, diagnosis time was shorter for AI-guided diagnosis (12 min) than for cardiologists alone (31 min). Our high-quality deep learning-based diagnosis support system may benefit cardiologists by improving diagnostic accuracy and reducing working hours.
Topics: Humans; Deep Learning; Myocardial Perfusion Imaging; Tomography, Emission-Computed, Single-Photon; Coronary Artery Disease; Male; Female; Middle Aged; Aged; Neural Networks, Computer; Image Processing, Computer-Assisted; ROC Curve
PubMed: 38866884
DOI: 10.1038/s41598-024-64445-2