Predicting Chinese stock market using XGBoost multi-objective optimization with optimal weighting.

The application of artificial intelligence (AI) technology in various fields has been a recent research hotspot. As a representative technology of AI, the specific application of machine learning models in the field of economics and finance undoubtedly holds significant research value. This article proposes Extreme Gradient Boosting Multi-Objective Optimization Model with Optimal Weights (OW-XGBoost) to comprehensively balance the returns and risks of investment portfolios. The model utilizes fusing label with optimal weights to achieve multi-objective tasks, effectively controlling the impact of various risk and return indicators on the model, thus improving the interpretability and generalization ability of the model. In the experiments, we tested the model using China A-share data from October 2022 to April 2023 and conducted a series of robustness tests. The results indicate that: (1) The OW-XGBoost outperforms the XGBoost Model with Yield as Label (YL-XGBoost), XGBoost Multi-Label Classification Model (MLC-XGBoost) in controlling risk or achieving returns. (2) OW-XGBoost performs better overall compared to baseline models. (3) The robustness tests demonstrate that the model performs well under different market conditions, stock pools, and training set durations. The model performs best in moderately fluctuating stock markets, stock pools comprising high market value stocks, and training set durations measured in months. The methodology and results of this study provide a new perspective and approach for fundamental quantitative investment and also create new possibilities and avenues for the integration of AI, machine learning, and financial quantitative research.

Effect of hemoglobin A1c management levels on coronary physiology evaluated by quantitative flow ratio in patients who underwent percutaneous coronary intervention.

AIMS/INTRODUCTION: The coronary physiology and prognosis of patients with different hemoglobin A1c (HbA1c) levels after percutaneous coronary intervention (PCI) are currently unknown. The aim of this study was to assess the effect of different levels of HbA1c control on coronary physiology in patients who underwent PCI for coronary heart disease combined with type 2 diabetes mellitus by quantitative flow ratio (QFR). MATERIALS AND METHODS: Patients who successfully underwent PCI and completed 1-year coronary angiographic follow up were enrolled, clinical data were collected, and QFR at immediate and 1-year follow up after PCI was retrospectively analyzed. A total of 257 patients (361 vessels) were finally enrolled and divided into the hemoglobin A1c (HbA1c)-compliance group (103 patients, 138 vessels) and non-HbA1c-compliance group (154 patients, 223 vessels) according to the HbA1c cut-off value of 7%. We compared the results of QFR analysis and clinical outcomes between the two groups. RESULTS: At 1-year follow up after PCI, the QFR was significantly higher (0.94 ± 0.07 vs 0.92 ± 0.10, P = 0.019) and declined less (0.014 ± 0.066 vs 0.033 ± 0.095, P = 0.029) in the HbA1c-compliance group. Meanwhile, the incidence of physiological restenosis was lower in the HbA1c-compliance group (2.9% vs 8.5%, P = 0.034). Additionally, the target vessel revascularization rate was lower in the HbA1c-compliance group (6.8% vs 16.9%, P = 0.018). Furthermore, HbA1c ≥7% (OR 2.113, 95% confidence interval 1.081-4.128, P = 0.029) and QFR decline (OR 2.215, 95% confidence interval 1.147-4.277, P = 0.018) were independent risk factors for target vessel revascularization. CONCLUSION: Patients with well-controlled HbA1c levels have better coronary physiological benefits and the incidence of adverse clinical outcome events might be reduced.

Circ-Ddx60 contributes to the antihypertrophic memory of exercise hypertrophic preconditioning.

INTRODUCTION: We previously reported a phenomenon called exercise hypertrophic preconditioning (EHP), the underlying mechanisms of which need further clarification. OBJECTIVES: We aimed to investigate whether circular RNAs (circRNAs) are involved in EHP. METHODS: CircRNA sequencing of myocardial tissue was performed in male C57BL/6 mice with EHP and sedentary. Bioinformatics analysis and Sanger sequencing were used to screen hub circRNA expression and to detect full-length circRNAs, respectively. Loss-of-function analyses were conducted to assess the effects of circ-Ddx60 (c-Ddx) on EHP. After 21 days of swimming training or resting, mice underwent transverse aortic constriction (TAC) or sham surgery. Echocardiography, invasive hemodynamic measurement and histological analysis were used to evaluate cardiac remodeling and function. The presence of interaction between c-Ddx and proteins was investigated using comprehensive identification of RNA-binding proteins by mass spectrometry (ChIRP-MS). RESULTS: In this study, we identified a novel circRNA, named c-Ddx that was preferentially expressed in myocardial tissue and significantly up-regulated in EHP mice. Silencing of c-Ddx attenuated the antihypertrophic effect of EHP and worsened heart failure in mice that underwent TAC. ChIRP-MS and molecular docking analysis validated the combination of c-Ddx and eukaryotic elongation factor 2 (eEF2). Mechanistically, c-Ddx silencing inhibited the increase of phosphorylation of eEF2 and its upstream AMP-activated protein kinase (AMPK) induced by EHP. CONCLUSIONS: C-Ddx contributes to the antihypertrophic memory of EHP by binding and activating eEF2, which would provide opportunity to search new therapeutic targets for pathological hypertrophy of heart.

Physiological effects of high-intensity versus low-intensity noninvasive positive pressure ventilation in patients with acute exacerbation of chronic obstructive pulmonary disease: a randomised controlled trial.

BACKGROUND: High-intensity noninvasive positive pressure ventilation (NPPV) is a novel ventilatory approach to maximally decreasing elevated arterial carbon dioxide tension (PaCO2) toward normocapnia with stepwise up-titration of pressure support. We tested whether high-intensity NPPV is more effective than low-intensity NPPV at decreasing PaCO2, reducing inspiratory effort, alleviating dyspnoea, improving consciousness, and improving NPPV tolerance in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). METHODS: In this physiological, randomised controlled trial, we assigned 24 AECOPD patients to undergo either high-intensity NPPV (n = 12) or low-intensity NPPV (n = 12). The primary outcome was PaCO2 24 h after randomisation. Secondary outcomes included gas exchange other than PaCO2 24 h after randomisation, inspiratory effort, dyspnoea, consciousness, NPPV tolerance, patient-ventilator asynchrony, cardiac function, ventilator-induced lung injury (VILI), and NPPV-related adverse events. RESULTS: Inspiratory positive airway pressure 24 h after randomisation was significantly higher (28.0 [26.0-28.0] vs. 15.5 [15.0-17.5] cmH2O; p = 0.000) and NPPV duration within the first 24 h was significantly longer (21.8 ± 2.1 vs. 15.3 ± 4.7 h; p = 0.001) in the high-intensity NPPV group. PaCO2 24 h after randomisation decreased to 54.0 ± 11.6 mmHg in the high-intensity NPPV group but only decreased to 67.4 ± 10.6 mmHg in the low-intensity NPPV group (p = 0.008). Inspiratory oesophageal pressure swing, oesophageal pressure-time product (PTPes)/breath, PTPes/min, and PTPes/L were significantly lower in the high-intensity group. Accessory muscle use and dyspnoea score 24 h after randomisation were also significantly lower in that group. No significant between-groups differences were observed in consciousness, NPPV tolerance, patient-ventilator asynchrony, cardiac function, VILI, or NPPV-related adverse events. CONCLUSIONS: High-intensity NPPV is more effective than low-intensity NPPV at decreasing elevated PaCO2, reducing inspiratory effort, and alleviating dyspnoea in AECOPD patients. TRIAL REGISTRATION: ClinicalTrials.gov (NCT04044625; registered 5 August 2019).

Surface Integrity and Corrosion Resistance of 42CrMo4 High-Strength Steel Strengthened by Hard Turning.

To improve the surface corrosion resistance of 42CrMo4 high-strength steel used in a marine environment, this article studied the effects of hard turning on the surface integrity and corrosion resistance of 42CrMo4 high-strength steel through the single factor experimental method, namely hard turning, polarization corrosion, electrochemical impedance spectroscopy, potentiodynamic polarization curve, and salt spray tests. The results indicated that the surface integrity was modified by the hard turning, with a surface roughness lower than Ra 0.8 µm, decreased surface microhardness, fine and uniform surface microstructure, and dominant surface residual compressive stress. The hard turning process was feasible to strengthen the surface corrosion resistance of 42CrMo4 high-strength steel. The better corrosion resistance of the surface layer than that of the substrate material can be ascribed to the uniform carbides and compact microstructure. The corrosion resistance varied with cutting speeds as a result of the changed surface microhardness and residual compressive stress, varied with feed rates as a result of the changed surface roughness, and varied with cutting depths as a result of the changed surface residual compressive stress, respectively. The surface integrity with smaller surface roughness and microhardness and bigger surface residual compressive stress was beneficial for corrosion resistance.

Hahn-PCNN-CNN: an end-to-end multi-modal brain medical image fusion framework useful for clinical diagnosis.

BACKGROUND: In medical diagnosis of brain, the role of multi-modal medical image fusion is becoming more prominent. Among them, there is no lack of filtering layered fusion and newly emerging deep learning algorithms. The former has a fast fusion speed but the fusion image texture is blurred; the latter has a better fusion effect but requires higher machine computing capabilities. Therefore, how to find a balanced algorithm in terms of image quality, speed and computing power is still the focus of all scholars. METHODS: We built an end-to-end Hahn-PCNN-CNN. The network is composed of feature extraction module, feature fusion module and image reconstruction module. We selected 8000 multi-modal brain medical images downloaded from the Harvard Medical School website to train the feature extraction layer and image reconstruction layer to enhance the network's ability to reconstruct brain medical images. In the feature fusion module, we use the moments of the feature map combined with the pulse-coupled neural network to reduce the information loss caused by convolution in the previous fusion module and save time. RESULTS: We choose eight sets of registered multi-modal brain medical images in four diease to verify our model. The anatomical structure images are from MRI and the functional metabolism images are SPECT and 18F-FDG. At the same time, we also selected eight representative fusion models as comparative experiments. In terms of objective quality evaluation, we select six evaluation metrics in five categories to evaluate our model. CONCLUSIONS: The fusion image obtained by our model can retain the effective information in source images to the greatest extent. In terms of image fusion evaluation metrics, our model is superior to other comparison algorithms. In terms of time computational efficiency, our model also performs well. In terms of robustness, our model is very stable and can be generalized to multi-modal image fusion of other organs.

Reduced SULT2B1b expression alleviates ox-LDL-induced inflammation by upregulating miR-148-3P via inhibiting the IKKß/NF-κB pathway in macrophages.

Atherosclerosis is a lipid-driven chronic inflammatory disease in which lipid-laden macrophage foam cells lead to inflamed lesions in arteries. Previous studies have proven that sulfotransferase 2B1b (SULT2B1b) has several roles in the regulation of lipid metabolism and the inflammatory response. However, little is known about the functions of SULT2B1b in ox-LDL-induced inflammation in macrophages. In this study, after treatment with either ox-LDL alone or combined with transfection of siRNAs targeting SULT2B1b, IL-6, TNF-α, NF-κB, IKKß and IκB mRNA and protein expression were determined in Raw264.7 cells by real-time PCR and Western blot, respectively. The proliferative capacity was determined by EdU staining and Cell Counting Kit-8. Our data demonstrated that SULT2B1b knockdown could reduce phosphorylated NF-κB levels and downregulate IKKß protein levels. Additionally, IκB levels were increased and the proliferation of ox-LDL stimulated cells was inhibited after SULT2B1b silencing. Downregulation of SULT2B1b expression was found to upregulate miR-148a-3p expression by microarray assay, while IKKß was a miR-148a-3p target gene. Our study suggests that SULT2B1b knockdown could promote miR148a-3p expression and inhibit activation of the IKKß/NF-κB signalling pathway, which suppressed the inflammatory response in macrophages. Therefore, targeting the SULT2B1b gene might be potentially beneficial for atherosclerosis prevention by decreasing the inflammatory response.

Bibliometric Study of Sodium Glucose Cotransporter 2 Inhibitors in Cardiovascular Research.

BACKGROUND: An increasing number of studies have shown that sodium glucose cotransporter 2 (SGLT2) inhibitors, initially used as antidiabetic agents, have cardiovascular (CV) benefits. However, few bibliometric analyses have examined this field systematically. Our study aimed to visualize the publications to determine the trends and hotspots in CV research on SGLT2 inhibitors. METHODS: Publications on SGLT2 inhibitors in cardiovascular research were retrieved from the Web of Science Core Collection. Microsoft Excel 2019, VOSviewer, and CiteSpace V were used to analyze and plot the references. RESULTS: On July 3, 2020, 1509 records of CV research on SGLT2 inhibitors published from 2013 to 2020 were retrieved. Nearly half were authored by American scholars, and most were published in Diabetes Obesity Metabolism, Cardiovascular Diabetology, and Diabetes Therapy. The USA was the leading driving force, with a strong academic reputation in this area. Inzucchi SE published the most related articles, while Neal B was cited the most frequently. All the top 10 co-cited references were in the leading co-cited journal, The New England Journal of Medicine. "Atherosclerotic cardiovascular event" was the leading research hotspot. The keywords "cardiac metabolism," "heart failure hospitalization," and "heart failure with preserved ejection fraction" appeared most recently as research frontiers. CONCLUSION: Most studies focused on clinical trial outcomes, such as cardiovascular death and heart failure (HF) hospitalization. The mechanisms of SGLT2 inhibitors, especially those related to cardiac metabolism, may soon become hotspots and should be closely monitored.

SULT2B1b inhibits reverse cholesterol transport and promotes cholesterol accumulation and inflammation in lymphocytes from AMI patients with low LDL-C levels.

The current main treatment for coronary artery disease (CAD) is to reduce low-density lipoprotein cholesterol (LDL-C) by statins, which could decrease the incidence of major adverse cardiovascular events (MACEs) by 30%. However, many residual risks still remain. To clarify the mechanism involved, we studied patients with acute myocardial infarction (AMI) with low LDL-C levels. Lymphocytes were isolated, and it was found that despite no difference in plasma LDL-C level, the lymphocyte cholesterol content was higher in AMI patient than those in non-CAD patients; thus, the decrease in intracellular cholesterol content was inconsistent with that in the plasma. Additionally, [3H]-cholesterol efflux rates were lower and mRNA levels of the inflammatory factors tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) higher in AMI lymphocytes. It was found that sulphotransferase 2B1b (SULT2B1b) expression was higher in AMI lymphocytes. Further research using Jurkat T lymphocytes confirmed that SULT2B1b knockdown increased cholesterol efflux capacity and decreased mRNA levels of TNF-α and IFN-γ by increasing liver X receptor (LXR)-ß levels. Furthermore, the degree of CpG island methylation in the SULT2B1b promoter was reduced in cells from AMI patients. In conclusion, SULT2B1b up-regulation due to hypomethylation of its promoter promotes cholesterol accumulation and inflammation by inhibiting LXR-ß in lymphocytes of AMI patients with low LDL-C levels. Therefore, reducing intracellular cholesterol is also important as plasma cholesterol levels. Therapeutic approaches to decrease SULT2B1b expression might be potentially beneficial for CAD prevention by decreasing intracellular cholesterol.

LCK inhibitor attenuates atherosclerosis in ApoE-/- mice via regulating T cell differentiation and reverse cholesterol transport.

Lots of studies demonstrated that CD4+ T cells regulate the development of atherosclerosis (AS). Previously, we reported that LCK, a key molecule in activation of T cell receptor (TCR) signalling and T cells, adversely affects reverse cholesterol transport (RCT), which ameliorates AS in vitro. To investigate the effect of LCK on AS in vivo, we injected the LCK inhibitor, PP2, into ApoE-/- mice fed a chow diet or a high-fat diet (HFD). Although, AS plaques were not affected by PP2 in chow diet-fed mice, PP2 significantly reduced the lesion percentage and necrotic core areas in HFD-fed mice. We further analysed the plaque contents and found that the accumulation of lipids and macrophages were decreased, while the contents of collagen and smooth muscle cells were increased by the LCK inhibitor. Thus, inhibiting LCK enhanced the plaque stability. We also found the LCK inhibitor improved cholesterol efflux capacity of HDL and up-regulated RCT regulatory proteins in the spleen. Moreover, inhibiting LCK regulated differentiation of T cells by increasing regulatory T (Treg) cells and decreasing the number of T helper 1 (Th1) cells in the aorta, thymus and spleen. Consistent with these results, infiltration of CD4+ T cells in plaques, secretion of pro-atherosclerotic cytokines, INF-γ and TNF-α synthesized mostly by Th1 cells, and the activation of PI3K/AKT/mTOR signalling were inhibited by the LCK inhibitor. Moreover, the effect of LCK inhibitor on the ratio of Th1 to Treg cells were compromised by activation of mTOR. Together, these data indicate that inhibiting LCK in TCR signalling attenuated the development of AS and promoted plaque stability. Improving RCT by upregulating RCT regulatory proteins and decreasing the Th1/Treg ratio by inhibiting PI3K/AKT/mTOR signalling may contribute to the anti-atherosclerotic effects of LCK inhibition.

Therapeutic contribution of melatonin to the treatment of septic cardiomyopathy: A novel mechanism linking Ripk3-modified mitochondrial performance and endoplasmic reticulum function.

The basic pathophysiological mechanisms underlying septic cardiomyopathy have not yet been completely clarified. Disease-specific treatments are lacking, and care is still based on supportive modalities. The aim of our study was to assess the protective effects of melatonin on septic cardiomyopathy, with a focus on the interactions between receptor-interacting protein kinase 3 (Ripk3), the mitochondria, endoplasmic reticulum (ER) and cytoskeletal degradation in cardiomyocytes. Ripk3 expression was increased in heart samples challenged with LPS, followed by myocardial inflammation, cardiac dysfunction, myocardial breakdown and cardiomyocyte death. The melatonin treatment attenuated septic myocardial injury in a comparable manner to the genetic depletion of Ripk3. Molecular investigations revealed that Ripk3 intimately regulated mitochondrial function, ER stress, cytoskeletal homeostasis and cardioprotective signaling pathways. Melatonin-mediated inhibition of Ripk3 improved mitochondrial bioenergetics, reduced mitochondria-initiated oxidative damage, sustained mitochondrial dynamics, ameliorated ER stress, normalized calcium recycling, and activated cardioprotective signaling pathways (including AKT, ERK and AMPK) in cardiomyocytes. Interestingly, Ripk3 overexpression mediated resistance to melatonin therapy following the infection of LPS-treated hearts with an adenovirus expressing Ripk3. Altogether, our findings identify Ripk3 upregulation as a novel risk factor for the development of sepsis-related myocardial injury, and melatonin restores the physiological functions of the mitochondria, ER, contractile cytoskeleton and cardioprotective signaling pathways. Additionally, our data also reveal a new, potentially therapeutic mechanism by which melatonin protects the heart from sepsis-mediated dysfunction, possibly by targeting Ripk3.

[Correlation of lipoprotein(a) with clinical stability and severity of coronary artery lesions in patients with coronary artery disease].

OBJECTIVE: To analyze the correlation of lipoprotein(a) [Lp(a)] with the clinical stability and severity of coronary artery stenosis in patients with coronary artery disease (CAD). METHODS: A total of 531 patients undergoing coronary angiography in Nanfang Hospital between January, 2013 and December, 2016 were enrolled in this study. At the cutoff Lp(a) concentration of 300 mg/L, the patients were divided into high Lp(a) group (n=191) and low Lp(a) group (n=340). In each group, the patients with an established diagnosis of CAD based on coronary angiography findings were further divided into stable angina pectoris (SAP) group and acute coronary syndrome (ACS) group. The correlation between the severity of coronary artery stenosis and Lp(a) was evaluated. RESULTS: The patients in high and low Lp(a) groups showed no significant differences in age, gender, body mass index, smoking status, hypertension, or diabetes (P>0.05). Multivariate logistic regression analysis revealed that age, gender, and serum levels of low-density lipoprotein cholesterol (LDL-C) and Lp(a) were independent risk factors for CAD in these patients. A high Lp(a) level was associated with an increased risk of CAD (OR=2.443, 95%CI: 1.205-4.951, P=0.013). The patients with a high Lp(a) level were at a significantly higher risk of CAD than those with a low Lp(a) level irrespective of a low or high level of LDL-C (P=0.006 and 0.020). In the patients with CAD, the ACS group had a significantly higher Lp(a) level than the SAP group (P < 0.001); the proportion of the patients with high Gensini scores was significantly greater in high Lp(a) group than in low Lp(a) group (17.3% vs 5.6%, P=0.026), and a linear relationship was found between Lp(a) level and Gensini score (R=0.130, P=0.006). CONCLUSIONS: Serum level of Lp(a) is an independent risk factor for CAD, and an increased Lp(a) is the residual risk for CAD. In patients with CAD, a high Lp(a) level is associated with the clinical instability and severity of coronary artery stenosis.

ZAP70 deficiency promotes reverse cholesterol transport through MAPK/ERK pathway in Jurkat cell.

BACKGROUND: Lots of studies have demonstrated that immune cells could regulate reverse cholesterol transport (RCT). However, neither T cell receptor (TCR) signalling nor Zeta-chain associated protein 70 (ZAP70) have been demonstrated to be associated with RCT. To investigate this association, we used a ZAP70-deficient Jurkat-derived mutant, P116 cell line, to detect the effect of ZAP70 on RCT and inflammatory response. ZAP70 deficiency improved cholesterol efflux capacity by 14%. Meanwhile, mRNA and proteins expression of RCT regulatory proteins such as ABCA1, ABCG1 and SR-BI were increased in P116 cells. ZAP70-deficiency had no influence on LXR-α and PPAR-γ. Regarding the inflammatory response, the mRNA expression and secretion of pro-atherosclerotic cytokines, TNF-α, IFN-γ, IL-2 and IL-6, were significantly decreased in the ZAP70-deficient cell line. Activation of MAP kinases cascades, as determined by of ERK, JNK and p38 MAPK phosphorylation, were found to be inhibited in the absence of ZAP70. Specific inhibition of ERK, JNK and p38 MAPK activity was also found to decreased TNF-α, IFN-γ, and IL-6 secretion. However, only the ERK inhibition was observed to reduce IL-2 secretion, improve cholesterol efflux capacity and increase expression of ABCA1, ABCG1 and SR-BI without increasing LXR-α and PPAR-γ. Using ChIP assay to detect the binding of LXR-α to LXRE, which promotes the expression of ABCG1, we found that inhibiting ERK improved binding without increasing LXR-α levels. Thus, we speculate that ZAP70-deficiency may improve RCT and decrease the inflammatory response of T cells. Furthermore, these effects are probably achieved via ERK signalling pathway.

Association between homocysteine levels and calcific aortic valve disease: a systematic review and meta-analysis.

Previous studies have reported inconsistent results regarding the association between homocysteine (Hcy) levels and calcific aortic valve disease (CAVD). We investigate the association between Hcy levels in patients with CAVD and controls by conducting a systematic review and meta-analysis. We conducted a systematic search of studies published prior to the end of March 2017 in the PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials and the Chinese Biomedical Literature databases. Eligible studies evaluating plasma Hcy levels in CAVD patients and controls were identified by two independent investigators. Standardized mean difference (SMD) and the corresponding 95% confidence intervals (95% CIs) were estimated using the random-effects model. Ten studies involving 6349 participants were included. Pooled analysis demonstrated that Hcy levels were significantly elevated in patients with CAVD compared with controls (pooled SMD: 0.57, 95% CI: 0.36-0.79). This elevation was more obvious in American and Asian populations than in Turkish populations. Furthermore, Hcy levels were significantly elevated in patients with mild-to-moderate CAVD and severe CAVD. Our results demonstrate that CAVD is associated with elevated Hcy levels.

PSRC1 overexpression attenuates atherosclerosis progression in apoE-/- mice by modulating cholesterol transportation and inflammation.

AIMS: Human genome-wide association studies (GWAS) have found that proline/serine-rich coiled-coil 1 (PSRC1) encodes a protein that is associated with serum lipid levels and coronary artery disease. In addition, our previous study showed that the cholesterol efflux capacity is decreased in macrophages following a treatment silencing Psrc1, indicating that PSRC1 has anti-atherosclerotic effects. However, the role of PSRC1 in the development of atherosclerosis is unknown. This study aims to explore the effect of PSRC1 on atherosclerosis and its underlying mechanisms. METHOD AND RESULTS: A recombinant adenovirus expressing Psrc1 (Ad-PSRC1) was constructed and transfected in RAW264.7 cells as well as injected intravenously into apoE-/- mice. The in vitro study showed that PSRC1 overexpression reduced the cellular cholesterol content, increased the cholesterol efflux capacity and inhibited foam cell formation by upregulating the expression of peroxisome proliferator-activated receptor γ (PPAR-γ) and liver X receptor α (LXR-α), which are key cholesterol transportation-related proteins. Infecting apoE-/- mice with Ad-PSRC1 inhibited the development of atherosclerotic lesions and enhanced atherosclerotic plaque stability. Consistent with these results, PSRC1 overexpression in apoE-/- mice decreased the plasma levels of TC, TG, LDL-C, TNF-α, IL-1ß and IL-6, increased the plasma HDL-C levels and improved HDL function. Similarly, the PPAR-γ and LXR-α expression levels were upregulated in the liver and in peritoneal macrophages of PSRC1-overexpressing apoE-/- mice. Finally, the liver and peritoneal macrophages of apoE-/- mice displayed elevated expression of ß-catenin, which is a direct downstream gene of PSRC1 and an upstream gene of PPAR-γ and LXR-α, but decreased activity of nuclear transcription factor (NF-κB), which acts as a key gene in the regulation of inflammation. CONCLUSIONS: PSRC1 protects against the development of atherosclerosis and enhances the stability of plaques by modulating cholesterol transportation and inflammation in macrophages and the liver of apoE-/- mice.

Lck Inhibits Heat Shock Protein 65-Mediated Reverse Cholesterol Transport in T Cells.

Previously, we reported that heat shock protein (HSP)65 impairs the effects of high-density lipoprotein on macrophages. We also showed that immune response activation adversely affects reverse cholesterol transport (RCT). In this study, we investigated the effects of the Src family kinase lymphocyte-specific protein tyrosine kinase (Lck) and elucidated the mechanism underlying HSP65-regulated cholesterol efflux in T cells. We evaluated cell proliferation, Lck expression, and inflammatory cytokine production in Jurkat cells and CD4+ T cells. HSP65-mediated inhibition of RCT was assessed by evaluating ABCA1, ABCG1, SR-BI, PPAR-γ, and liver X receptor-α expression. A dose-dependent relationship was found between the levels of these proteins and the suppression of cholesterol efflux. Stimulation of Lck-silenced T cells with ionomycin resulted in a decrease in intracellular calcium levels. Treatment of Jurkat cells with PP2, an inhibitor of Src family kinase, inhibited calcium-induced, but not PMA-induced, ERK phosphorylation. NF-κB activation in response to PMA was minimally inhibited in cells stimulated with PP2. HSP65 failed to trigger downstream ERK or JNK phosphorylation or to activate NF-κB or protein kinase C-γ in Lck-silenced cells. Additionally, elevation of intracellular calcium was also impaired. However, HSP65 significantly enhanced cholesterol efflux and decreased cellular cholesterol content by inducing the expression of cholesterol transport proteins in Lck-silenced cells. The treatment of Jurkat cells with PP2 also inhibited cell proliferation and promoted RCT. In conclusion, Lck is a key molecule in the TCR signaling cascade that inhibits cholesterol efflux and upregulates intracellular cholesterol ester content in T cells. Our results demonstrate that the immune response plays a previously unrecognized role in RCT.

High-density Lipoprotein and Inflammation and Its Significance to Atherosclerosis.

Great advances are being made in the understanding of the structural and functional diversity of high-density lipoprotein at the mechanistic level. High-density lipoprotein possesses numerous physiological activities, the most studied of which is the ability to promote excess cholesterol efflux from peripheral tissues to the liver for excretion via a mechanism believed to confer protection against atherosclerosis. Accumulating evidence has demonstrated that atherosclerosis is a chronic inflammatory response. Recent studies have suggested that high-density lipoprotein possesses anti-inflammatory properties and regulates both innate and adaptive immune responses. However, further complicating this very complex system is the finding that inflammation, via alteration of the proteomic and lipidomic composition of high-density lipoprotein species, can modulate at least some of their functional activities. Modified high-density lipoprotein exhibits a reduced ability to mediate cholesterol efflux from peripheral tissues and to inhibit cytokine-induced adhesion molecule expression and even promotes the occurrence of inflammation. This review focuses on the underlying mechanism of the interaction between high-density lipoprotein and inflammation to clarify the pathologic process of atherosclerosis.

[Red blood cell distribution width combined with lipoprotein-associated phospholipase A2 detection for improving diagnostic accuracy of coronary artery stenosis in patients with coronary artery disease].

OBJECTIVE: To study the association of red blood cell distribution width (RDW) and lipoprotein-associated phospholipase A2 (LP-PLA2) with the degree of coronary artery stenosis in patients with coronary artery disease (CAD) and the value of RDW combined with LP-PLA2 detection in accurate evaluation of coronary artery stenosis. METHODS: A total of 224 patients including 119 non-CAD cases and 105 CAD cases admitted in our hospital between June, 2013 and June, 2014 were enrolled in this study. The patients' baseline clinical data were collected and venous blood samples were obtained for detecting WBC, RDW-CV and LP-PLA2. The Gensini score of the CAD patients was calculated based on coronary angiographic findings. RESULTS: Compared with the non-CAD patients, CAD patients had significantly higher RDW-CV (P=0.009) and LP-PLA2 (P=0.004) levels. The CAD patients with high Gensini scores had also significantly higher RDW-CV (P=0.001) and LP-PLA2 (P<0.001) levels than those with low scores; RDW-CV and LP-PLA2 were significantly correlated with the Gensini score, and the area under curve of their combined detection was 0.931. CONCLUSION: Combination of RDW and LP-PLA2 can improve the diagnostic accuracy of the degree of coronary artery stenosis in patients with CAD.

The Impact of Serum Amyloid P-Component on Gene Expression in RAW264.7 Mouse Macrophages.

Serum amyloid P-component (SAP) contributes to host defense and prevents fibrosis. Macrophages are the most abundant inflammatory cell type in atherosclerotic plaques. In the present study, using (3)H-cholesterol-labeled counting radioactivity assay, we demonstrated that the apoAI-mediated cholesterol efflux in RAW264.7 macrophages was increased by SAP treatment in a time- and dose-dependent manner. We analyzed global gene expression changes upon SAP treatment using RNA sequencing. As a result, a total of 175 differentially expressed genes were identified, of which 134 genes were downregulated and 41 genes were upregulated in SAP treated cells compared to control cells. Quantitative RT-PCR analysis confirmed decreased expression of 5 genes and an increase in expression of 1 gene upon SAP treatment. Gene ontology analysis showed that genes involved in response to stimulus were significantly enriched in differentially expressed genes. Beyond protein-coding genes, we also identified 8 differentially expressed long noncoding RNAs. Our study may provide new insights into mechanisms underlying the functional role of SAP in macrophages.

Spirolactone provides protection from renal fibrosis by inhibiting the endothelial-mesenchymal transition in isoprenaline-induced heart failure in rats.

BACKGROUND: Fibrosis results in excessive accumulation of extracellular matrix proteins, collagen component alteration, and abnormalities in structure and is partly derived from a process called the endothelial-mesenchymal transition involving transforming growth factor ß (TGF-ß). We investigated whether spironolactone, an aldosterone receptor blocker, attenuated isoprenaline (Iso)-induced heart failure in rats and also studied the mechanism for the same. METHODS: Sprague-Dawley rats were subcutaneously injected with Iso to induce heart failure, which promoted renal fibrosis; rats with spironolactone treatment were given a gavage of spironolactone (30 or 60 mg/kg/d, for 21 days). Cardiac function and fibrosis indices were measured. Pathological alterations and expression of Type I and III collagen, α-smooth muscle actin, cluster of differentiation-31, and TGF-ß were examined. RESULTS: In Iso-induced heart failure in rats, spironolactone significantly improved cardiac function and decreased myocardial fibrosis, reduced collagen fibrous proliferation in kidney, reduced expression of Type I and III collagen, increased the expression of cluster of differentiation-31, and decreased the expression of α-smooth muscle actin and TGF-ß. CONCLUSION: Spironolactone may prevent renal fibrosis by inhibiting the endothelial-mesenchymal transition.