RNF149 Destabilizes IFNGR1 in Macrophages to Favor Post-Infarction Cardiac Repair.

BACKGROUND: Macrophage-driven inflammation critically involves in cardiac injury and repair following myocardial infarction (MI). However, the intrinsic mechanisms that halt the immune response of macrophages, which is critical to preserve homeostasis and effective infarct repair, remain to be fully defined. Here, we aimed to determine the ubiquitination-mediated regulatory effects on averting exaggerated inflammatory responses in cardiac macrophages. METHODS: We used transcriptome analysis of mouse cardiac macrophages and bone marrow-derived macrophages to identify the E3 ubiquitin ligase RNF149 (RING finger protein 149) as a modulator of macrophage response to MI. Employing loss-of-function methodologies, bone marrow transplantation approaches, and adenovirus-mediated RNF149 overexpression in macrophages, we elucidated the functional role of RNF149 in MI. We explored the underlying mechanisms through flow cytometry, transcriptome analysis, immunoprecipitation/mass spectrometry analysis, and functional experiments. RNF149 expression was measured in the cardiac tissues of patients with acute MI and healthy controls. RESULTS: RNF149 was highly expressed in murine and human cardiac macrophages at the early phase of MI. Knockout of RNF149, transplantation of Rnf149-/- bone marrow, and bone marrow macrophage-specific RNF149-knockdown markedly exacerbated cardiac dysfunction in murine MI models. Conversely, overexpression of RNF149 in macrophages attenuated the ischemia-induced decline in cardiac contractile function. RNF149 deletion increased infiltration of proinflammatory monocytes/macrophages, accompanied by a hastened decline in reparative subsets, leading to aggravation of myocardial apoptosis and impairment of infarct healing. Our data revealed that RNF149 in infiltrated macrophages restricted inflammation by promoting ubiquitylation-dependent proteasomal degradation of IFNGR1 (interferon gamma receptor 1). Loss of IFNGR1 rescued deleterious effects of RNF149 deficiency on MI. We further demonstrated that STAT1 activation induced Rnf149 transcription, which, in turn, destabilized the IFNGR1 protein to counteract type-II IFN (interferon) signaling, creating a feedback control mechanism to fine-tune macrophage-driven inflammation. CONCLUSIONS: These findings highlight the significance of RNF149 as a molecular brake on macrophage response to MI and uncover a macrophage-intrinsic posttranslational mechanism essential for maintaining immune homeostasis and facilitating cardiac repair following MI.

Factors influencing the association between depressive symptoms and cardiovascular disease in US population.

Cardiovascular disease (CVD) and depression are common diseases that lead to adverse health outcomes. Depressive Symptoms may be a risk factor for CVD. But few studies focused on the impact of socioeconomic factors, common medical history and dietary intake about this association. This study analyzed National Health and Nutrition Examination Survey (NHANES) 2007-2016. Complex sampling-weighted logistic regression models were used to compare the odds ratios (ORs) of CVD in participants with different depressive symptoms. 11,516 NHANES participants aged ≥ 40 years were included in the final analysis, of whom 1842 had CVD. Compared with participants with no/minimal depression, participants with mild, moderate, and moderately severe/severe depression had OR values of 1.25 (95%  CI 1.01-1.54), 1.98 (95% CI 1.32-2.96), and 2.41 (95% CI 1.63-3.57). The association of depressive symptoms with CVD follow a dose-dependent pattern. The interactions of depressive symptoms with gender (Interaction P = 0.009), diabetes (Interaction P = 0.010), household income level (Interaction P = 0.002), dietary cholesterol intake (Interaction P = 0.017) on CVD were observed. More severe depressive symptoms are associated with increased risk of CVD in US population. The association may be more pronounced in the female population, population with diabetes, low family income level, or high dietary cholesterol intake.

High serum lactate dehydrogenase as a predictor of cardiac insufficiency at follow-up in elderly patients with acute myocardial infarction.

BACKGROUND: Impairment of cardiac function progresses after acute myocardial infarction (AMI). Lactate dehydrogenase (LDH), a marker of cardiac injury and an enzyme in anaerobic glycolysis, is suggested as a risk factor for patient mortality in inflammatory diseases. METHODS: In this study, 448 older and 445 younger AMI patients were recruited and followed up. The effect of baseline serum LDH on post-infarction cardiac function was assessed at follow-up. RESULTS: Elderly patients in the high baseline LDH group had a high risk of being diagnosed with cardiac insufficiency during follow-up (adjusted hazard ratio: 3.643, P = 0.007), and the follow-up left ventricular ejection fraction of the quartile subgroup tended to decrease with increasing in baseline serum LDH (adjusted odds ratio: 1.301, P = 0.001) for each 100 U/L increase. The LVDd and LVVd of elderly patients in the high LDH group were not significantly different from those of patients in the normal LDH group at baseline but were further increased in the high LDH group at follow-up. In younger patients, the effect of LDH on post-infarction cardiac structure and function was similar to that in older patients, but unlike older patients, Cox regression analysis showed that LDH was not the predominant influence. CONCLUSION: Longitudinal changes in cardiac function were independently associated with high baseline serum LDH levels in patients with AMI. Baseline LDH levels are superior to other myocardial injury markers and may be a useful parameter in predicting future cardiac dysfunction after AMI, especially in the elderly.

Spinosin inhibits activated hepatic stellate cell to attenuate liver fibrosis by targeting Nur77/ASK1/p38 MAPK signaling pathway.

AIM: Liver fibrosis remains a great challenge in the world. Spinosin (SPI), a natural flavonoid-C-glycoside, possesses various pharmacological activities including anti-inflammatory and anti-myocardial fibrosis effects. In this study, we investigate whether SPI can be a potential lead for the treatment of liver fibrosis and explore whether the orphan nuclear receptor Nur77, a negative regulator of liver fibrosis development, plays a critical role in SPI's action. METHODS: A dual luciferase reporter system of α-SMA was established to evaluate the effect of SPI on hepatic stellate cell (HSC) activation in LX2 and HSC-T6 cells. A mouse model of CCl4-induced liver fibrosis was used to test the efficacy of SPI against liver fibrosis. The expression levels of Nur77, inflammatory cytokines and collagen were determined by Western blotting and qPCR. Potential kinase pathways involved were also analyzed. The affinity of Nur77 with SPI was documented by fluorescence titration. RESULTS: SPI can strongly suppress TGF-ß1-mediated activation of both LX2 and HSC-T6 cells in a dose-dependent manner. SPI increases the expression of Nur77 and reduces TGF-ß1-mediated phosphorylation levels of ASK1 and p38 MAPK, which can be reversed by knocking out of Nur77. SPI strongly inhibits collagen deposition (COLA1) and reduces inflammatory cytokines (IL-6 and IL-1ß), which is followed by improved liver function in the CCl4-induced mouse model. SPI can directly bind to R515 and R563 in the Nur77-LBD pocket with a Kd of 2.14 µM. CONCLUSION: Spinosin is the major pharmacological active component of Ziziphus jujuba Mill. var. spinosa which has been frequently prescribed in traditional Chinese medicine. We demonstrate here for the first time that spinosin is a new therapeutic lead for treatment of liver fibrosis by targeting Nur77 and blocking the ASK1/p38 MAPK signaling pathway.

Association between missing teeth number and all-cause and cardiovascular mortality: NHANES 1999-2004 and 2009-2014.

BACKGROUND: The association between tooth loss and all-cause and cardiovascular mortality requires further investigation. METHODS: This study included 17993 participants from the National Health and Nutrition Examination Surveys (NHANES) 1999-2004 and 2009-2014. Weighted multivariable Cox proportional hazard models were used to assess the association between tooth loss and all-cause and cardiovascular mortality. Restricted cubic splines (RCS) were incorporated in the models to explore potential nonlinear relationships. RESULTS: Over a median follow-up of 116 months, 2152 participants died, including 625 cardiovascular deaths. Compared to participants without missing teeth, participants with 11-19 missing teeth had the highest risk of all-cause mortality (hazard ratio [HR] 1.89, 95% confidence interval [CI] 1.43-2.51), while participants with 6-10 missing teeth had the highest risk of cardiovascular mortality (HR 2.51, 95% CI 1.68-3.76). RCS analyses revealed nonlinear associations between number of missing teeth and all-cause (p < 0.001) and cardiovascular (p = 0.001) mortality. With < 10 missing teeth, each additional missing tooth increased all-cause and cardiovascular mortality by 6% (HR 1.06, 95% CI 1.03-1.09) and 9% (HR 1.09, 95% CI 1.03-1.15), respectively. However, when the number of missing teeth was ≥10, the risk of mortality did not continue to increase with more missing teeth. A significant interaction was found between tooth loss and age (p < 0.001 for both outcomes). CONCLUSION: We observed an inverted L-shaped association between tooth loss and mortality, wherein risks increased with more missing teeth until 10, but did not continue increasing thereafter. The association was stronger in adults < 65 years old.

Association of blood cadmium with all-cause and cause-specific mortality in patients with hypertension.

Background: Cadmium is a commonly found heavy metal with a prolonged biological half-life, which results in long-term health burden for the population. Prior studies have demonstrated an association between blood cadmium and hypertension. However, few studies examined the relationship between blood cadmium and long-term health outcomes in patients with hypertension. This study aimed to investigate the association of blood cadmium with mortality in patients with hypertension. Methods: This study analyzed data from the National Health and Nutrition Examination Survey 1999-2012. Complex sampling-weighted multivariate Cox proportional hazards models were used to evaluate the hazard ratios (HRs) of all-cause, cardiovascular, and Alzheimer's disease mortality in patients with hypertension classified by blood cadmium concentrations' quantiles. Results: The study included 12,208 patients with hypertension with a median follow-up duration of 10.8 years. During this period, there were 4,485 all-cause deaths, including 1,520 cardiovascular deaths and 180 Alzheimer's disease deaths. Compared with the lowest quintile of blood cadmium (≤0.25 µg/L) group, the highest quintile of blood cadmium (≥0.80 µg/L) group's adjusted HRs were 1.85 (95% CI, 1.59-2.14) for all-cause mortality, 1.76 (95% CI, 1.33-2.34) for cardiovascular mortality, and 3.41 (95% CI, 1.54-7.51) for Alzheimer's disease mortality. Additionally, the adjusted HR for cardiovascular mortality was 2.12 (95% CI, 1.36-3.30) in never-smoking patients with hypertension. Conclusion: Higher blood cadmium is associated with increased risks of all-cause, cardiovascular, and Alzheimer's disease mortality in patients with hypertension. The effect of blood cadmium on cardiovascular mortality may be more pronounced in never-smoking hypertensive patients.

Association of urinary bisphenol A with cardiovascular and all-cause mortality: National Health and Nutrition Examination Survey (NHANES) 2003-2016.

Bisphenol A (BPA), one of the most widely consumed endocrine disrupting chemicals, has been found to be associated with a variety of diseases, especially cardiovascular diseases. However, few studies have investigated the association of BPA with long-term health outcomes. This study analyzed data from the National Health and Nutrition Examination Survey (NHANES) 2003-2016. The NHANES data were linked to mortality data (with a follow-up point of December 31, 2019). The urinary BPA concentration was estimated by adjusting for urinary creatinine (BPA/Cr, ng/mg). Complex sampling-weighted multivariate Cox proportional hazards models were used to compare the hazard ratios (HRs) of cardiovascular and all-cause mortality among participants with different urinary BPA concentrations. This study included 9243 adult participants. The median follow-up duration was 9.1 years. During this period, 1200 all-cause deaths occurred, of which 374 were cardiovascular deaths. Compared to the lowest BPA/Cr quartile group, the adjusted HRs of the highest BPA/Cr quartile group were 1.76 (95% CI, 1.23-2.52) for cardiovascular mortality and 1.21 (95% CI, 0.98-1.49) for all-cause mortality. In addition, there was a significant interaction between sex and BPA/Cr (P for interaction = 0.044) for the risk of cardiovascular mortality. The adjusted HR for cardiovascular mortality in female participants was 2.80 (95% CI, 1.56-5.02), while that in male participants was only 1.34 (95% CI, 0.79-2.24). Higher urinary BPA is associated with an increased risk of cardiovascular mortality among US adults. The effect of BPA on cardiovascular mortality may be more pronounced in women than in men.

Static Model of Athlete's Upper Limb Posture Rehabilitation Training Indexes.

With the gradual expansion of the development of sports, the level of sports has been rapidly improved. Athletes have to carry out high-intensity and systemic technical movements in training and competition. Some sports have the greatest burden on the shoulder joint. From the observation and investigation of the injured parts of athletes, it is found that the shoulder joint is the most common sports injury, which is the most typical sports injury. Based on the problem of insufficient strength and endurance reserve after rehabilitation of shoulder external rotator injury, it will cause muscle tension and poor extensibility. To prove the improvement effect of functional training and posture index calibration on the poor posture of the shoulder, considering the measurement of global passive torque, this paper uses a limited set of joint angles and corresponding passive torque data in the upper arm lifting trajectory to train the neural network and uses the trained network to predict the passive torque in other upper arm trajectories. The kinematics model of the shoulder joint is established, and the human-computer interaction experiment is designed on the platform of the gesture index manipulator. The passive and active torque components of the shoulder joint in the human-computer interaction process are calculated by measuring the man-machine interaction force of the subjects in the motion state, which is used as the basis for evaluating the active motion intention of the subjects. Surface electromyography (SEMG) was used to calibrate and verify the attitude index of shoulder active torque. The method proposed in this paper is helpful to achieve more efficient on-demand assisted rehabilitation training exercises, which is of great significance to improve the level of rehabilitation training.

An alternating conduction-insulation "molecular fence" model from fluorinated metallopolymers.

Introducing fluoroalkyl chains into metallopolymers is a prerequisite to studying the self-organization effect of fluoroalkyl chains and their structure-property relationship. In this work, we present a fluorinated metallopolymer to build an alternating conduction-insulation "molecular fence" model synthesized by the coordination of Ru(II) and a bis-terpyridine-end-capped-phenyl (BTP) ligand modified with fluoroalkyl chains. Taking advantage of scanning tunneling microscopy (STM), a well-aligned periodic linear layered structure is observed clearly, which provides the most direct visualization of the self-organization effect of fluoroalkyl chains for the first time. In addition, combining ultraviolet-visible (UV-vis) absorption spectroscopy and theoretical calculations, we find that fluoroalkyl chains demonstrate a septation effect between two adjacent metallopolymer chains and further restrain the occurrence of interchain charge-transfer transition (ICCT) due to their closed packed structure. This "molecular fence" model can provide a novel route for electron conduction in molecular networks and guide potential applications in the materials science field.

Association of caffeine intake with all-cause and cardiovascular mortality in elderly patients with hypertension.

Background: Caffeine is widely consumed not only in coffee but also in soft drinks and tea. However, the long-term health effects of caffeine are still controversial, especially in people with high cardiovascular risk such as elderly patients with hypertension. Methods: This study analyzed data from the National Health and Nutrition Examination Survey 2003-2018. Caffeine intake was calculated by two 24-h dietary recall interviews. Complex sampling-weighted multivariable Cox proportional hazards models were used to compare the hazard ratios (HRs) of all-cause and cardiovascular mortality in elderly hypertensive patients with different caffeine intake (<10, 10 to <100, 100 to <200, 200 to <300, and ≥300 mg/day). Results: This study included 6,076 elderly hypertensive patients. The mean ± standard error follow-up duration was 6.86 ± 0.12 years. During this period, a total of 2,200 all-cause deaths occurred, of which 765 were cardiovascular deaths. Taking patients with caffeine intake < 10 mg/day as a reference, patients with moderate caffeine intake (200 to <300 mg/day) had a lower risk of all-cause (HR, 0.70 [95% CI, 0.56-0.87]) and cardiovascular (HR, 0.55 [95% CI, 0.39-0.77]) mortality. The benefit of reducing all-cause mortality risk was significant in female patients (HR, 0.65 [95% CI, 0.50-0.85]) or patients with well-controlled blood pressure (HR, 0.63 [95% CI, 0.46-0.87]), but not in male patients or patients with poorly controlled blood pressure. In addition, non-linear relationship analysis also showed that moderate caffeine intake had the lowest HRs of all-cause (Non-linear p = 0.022) and cardiovascular mortality (Non-linear p = 0.032) in the present study. Conclusion: Moderate caffeine intake is associated with reduced risk of all-cause and cardiovascular mortality in elderly hypertensive patients.