Obesity-related glomerulopathy (ORG) is a significant renal complication associated with obesity, characterized by glomerular fibrosis and lipid accumulation. The underlying molecular mechanisms remain poorly understood, necessitating the exploration of potential therapeutic targets. This study aimed to investigate the effects of indole-3-propionic acid (IPA) on the modulation of key proteins involved in ORG. Utilizing virtual screening, we identified fatty acid-binding protein 4 (FABP4) as a target protein for IPA. Our findings revealed that IPA did not alter the expression of FABP4, but it significantly increased protein abundance of peroxisome proliferator-activated receptor γ (PPARγ). Mechanistically, IPA competitively binds to FABP4, thereby disrupting the FABP4-PPARγ interaction. This reduction in binding led to decreased degradation of PPARγ, ultimately resulting in attenuated renal fibrosis and reduced lipid deposition in a PPARγ-dependent manner. These results suggest that IPA may serve as a potential therapeutic agent for the treatment of ORG by modulating the FABP4-PPARγ axis.

BACKGROUND:Atherosclerosis, driven by macrophage foam cell formation and lipid accumulation, remains inadequately addressed by current pharmacotherapies, necessitating novel natural therapeutic strategies. Nimbolide (NIM), a limonoid derived from Azadirachta indica, possesses established anti-inflammatory properties, yet its efficacy against atherosclerosis and underlying mechanisms remain elusive. PURPOSE:The study was designed to assess the impact of NIM on treating atherosclerosis, focusing on cholesterol efflux and lipophagy. STUDY DESIGN:The study combined both in vivo atherosclerotic mouse modeling and in vitro macrophage foam cell studies. METHODS:Apolipoprotein E-deficient (ApoE-/-) mice fed a high-fat diet received NIM to assess therapeutic effect. Oxidized low-density lipoprotein was used to induce macrophage foam cell formation, and effects of NIM on cholesterol efflux and lipophagy were assessed by western blot, immunofluorescence and electron microscopy. Cellular thermal shift assay (CETSA), surface plasmon resonance (SPR), and co-immunoprecipitation (Co-IP) were employed to investigate molecular interactions. A TFEB-knockdown mouse model was used to evaluate the mediating role of transcription factor EB (TFEB). RESULTS:NIM administration dose-dependently attenuated aortic plaque burden, improved serum lipid profiles, and reduced vascular inflammation in ApoE-/- mice. In macrophages, NIM enhanced cholesterol efflux via upregulation of ATP-binding cassette transporter A1/G1 and activated lipophagy through TFEB nuclear translocation. Mechanistically, NIM directly bound 14-3-3 epsilon and competitively displaced TFEB, thereby promoting TFEB dephosphorylation and autophagy-lysosomal activation. TFEB knockdown abolished NIM-mediated lipophagy and atheroprotection both in vitro and in vivo. CONCLUSION:NIM exerts anti-atherosclerotic effects by disrupting the 14-3-3 epsilon/TFEB interaction to enhance macrophage cholesterol clearance and lipophagy, identifying this axis as a promising therapeutic target for atherosclerosis.

Acute myocardial infarction(MI)claims millionsof lives worldwide annually and remains the primary driver of chronic heart failure(HF).A hallmark of MI-induced cardiac damage is the extensive death of cardiomyocytes(CMs).Cardiac injury triggers massive mitochondria-derived reactive oxygen species(ROS),which directly or indirectly induce CM death,thereby contributing to cardiac damage during the acute phase of ischemia-reperfusion(I/R)injury and the chronic myocardial remodeling process after MI[1].

Background:: Coronary Heart Disease (CHD) is one of the most common types of cardiovascular disease, and Heart Failure (HF) is an important factor in its progression. We aimed to evaluate the diagnostic value and predictors of multiparametric Cardiac Magnetic Resonance (CMR) in CHD patients with HF. Methods:: The study retrospectively included 145 CHD patients who were classified into CHD (HF+) (n = 91) and CHD (HF–) (n = 54) groups according to whether HF occurred. CMR assessed LV function, myocardial strain and T1 mapping. Multivariate linear regression analyses were performed to identify predictors of LV dysfunction, myocardial fibrosis, and LV remodeling Results:: CHD (HF+) group had impaired strain, with increased native T1, ECV, and LVM index. The impaired strain was associated with LVM index (p < 0.05), where native T1 and ECV were affected by log-transformed amino-terminal pro-B-type natriuretic peptide (NT-proBNP) levels. ROC analysis showed the combination of global circumferential strain (GCS), native T1, and LVM had a higher diagnostic value for the occurrence of HF in CHD patients. Meanwhile, log-transformed NT-proBNP was an independent determinant of impaired strain, increased LVM index, native T1 and ECV. Conclusion:: HF has harmful effects on LV systolic function in patients with CHD. In CHD (HF+) group, LV dysfunction is strongly correlated with the degree of LV remodeling and myocardial fibrosis. The combination of the three is more valuable in diagnosing HF than conventional indicators.

目的:研究心内科临床见习教学中微信平台的应用效果.方法:观察对象为2020年于我院心内科实习的60例临床见习学生,参考随机数字表法分为研究组(30例)与对照组(30例),对照组选取传统教学模式,研究组基于传统教学行微信公众平台教学模式,比较两组专业技能(仪器、用具、诊治、沟通)评分与理论知识评分、临床技能评分、批判性思维能力评分、综合能力评分、满意度.结果:研究组专业技能评分与理论知识评分、临床技能评分、批判性思维能力评分、综合能力评分、满意度较对照组更高,差异有显著性(P ＜ 0.05).结论:心内科临

Hypertrophic cardiomyopathy (HC) is characterized by the enlargement of individual cardiomyocytes, which is a typical pathophysiological process that occurs in various cardiovascular diseases. Ionizing radiation (IR) is an important independent risk factor for hypertrophic cardiomyopathy, but the underlying molecular mechanism is still unclear. In the present study, we aimed to clarify the role of IR in promoting cardiac hypertrophy and investigate the mechanism by which the SUMO2-mediated SUMOylation of SH3GLB1 affects mitophagy in IR-induced cardiac hypertrophy. In vivo, IR promoted cardiac hypertrophy by activating mitophagy. In vitro, IR upregulated PINK1 and Parkin protein expression and damaged mitochondrial morphological structure. We further demonstrated that SH3GLB1 deficiency inhibited mitophagy activation and restored mitochondrial cristae, revealing a regulatory role of SH3GLB1 in cardiac hypertrophy. IR promoted interactions between SH3GLB1 and mitochondrial membrane proteins, such as MFN1/2, TOM20 and Drp1, further indicating that the mechanism by which SH3GLB1 functions in cardiac hypertrophy might involve mitophagy. A bioinformatics prediction found that SUMO2 could SUMOylate SH3GLB1 at position K82. Consistent with this finding, both co-IP assays and laser confocal microscopy showed that IR promoted the interaction and colocalization of SUMO2 and SH3GLB1. In summary, our study identifies IR as an important factor that promotes hypertrophic cardiomyopathy by accelerating the activation of mitophagy through the SUMO2-mediated SUMOylation of SH3GLB1; thus, IR exerts dual therapeutic effects in the treatment of thoracic tumours with long-term radiotherapy. Additionally, this study provides novel treatment strategies and targets for preventing the hypertrophic cardiomyopathy caused by thoracic tumour radiotherapy. Furthermore, SH3GLB1 may be a promising experimental target for the development of strategies for treating cardiovascular diseases caused by IR.

1 基本情况 患者,男,17岁.1年前体检时发现血压升高,当时血压为 170/120 mm Hg(1 mm Hg=0.133 kPa),偶有头晕、胸闷,无头痛,无气促.夜间无打鼾及呼吸暂停,无阵发性颜面潮红,无心悸,无夜尿增多,无四肢麻木,无恶心、呕吐,未服药,未规律监测血压.为查明高血压病因入住我科.既往史:既往体健.否认特殊个人史.反复仔细询问患者家族史,但均否认家庭成员中有类似疾病患者.

Abstract Background Asprosin, a newly discovered adipokine, is a C-terminal cleavage product of profibrillin. Asprosin has been reported to participate in lipid metabolism and cardiovascular disease, but its role in atherogenesis remains elusive. Methods Asprosin was overexpressed in THP-1 macrophage-derived foam cells and apoE−/− mice using the lentiviral vector. The expression of relevant molecules was determined by qRT-PCR and/or western blot. The intracellular lipid accumulation was evaluated by high-performance liquid chromatography and Oil red O staining. HE and Oil red O staining was employed to assess plaque burden in vivo. Reverse cholesterol transport (RCT) efficiency was measured using [3H]-labeled cholesterol. Results Exposure of THP-1 macrophages to oxidized low-density lipoprotein down-regulated asprosin expression. Lentivirus-mediated overexpression of asprosin promoted cholesterol efflux and inhibited lipid accumulation in THP-1 macrophage-derived foam cells. Mechanistic analysis revealed that asprosin overexpression activated p38 and stimulated the phosphorylation of ETS-like transcription factor (Elk-1) at Ser383, leading to Elk-1 nuclear translocation and the transcriptional activation of ATP binding cassette transporters A1 (ABCA1) and ABCG1. Injection of lentiviral vector expressing asprosin diminished atherosclerotic lesion area, increased plaque stability, improved plasma lipid profiles and facilitated RCT in apoE−/− mice. Asprosin overexpression also increased the phosphorylation of p38 and Elk-1 as well as up-regulated the expression of ABCA1 and ABCG1 in the aortas. Conclusion Asprosin inhibits lipid accumulation in macrophages and decreases atherosclerotic burden in apoE−/− mice by up-regulating ABCA1 and ABCG1 expression via activation of the p38/Elk-1 signaling pathway.

Zinc finger E-box binding homeobox 1 (ZEB1), an important transcription factor belonging to the ZEB family, plays a crucial role in regulating gene expression required for both normal physiological and pathological processes. Accumulating evidence has shown that ZEB1 participates in the initiation and progression of atherosclerotic cardiovascular disease. Recent studies suggest that ZEB1 protects against atherosclerosis by regulation of endothelial cell angiogenesis, endothelial dysfunction, monocyte-endothelial cell interaction, macrophage lipid accumulation, macrophage polarization, monocyte-vascular smooth muscle cell (VSMC) interaction, VSMC proliferation and migration, and T cell proliferation. In this review, we summarize the recent progress of ZEB1 in the pathogenesis of atherosclerosis and provide insights into the prevention and treatment of atherosclerotic cardiovascular disease.

Lipid metabolism disorder and inflammatory response are considered to be the major causes of atherosclerogenesis. Astragalin, the most important functional component of flavonoid obtained from persimmon leaves, has the hypolipidemic effects. However, it is unknown, how astragalin protects against atherosclerosis. The aim of this study was to observe the effects of astragalin on cholesterol efflux and inflammatory response and to explore the underlying mechanisms. Our results showed that astragalin upregulated the expression of ATP-binding cassette transporters A1 and G1 (ABCA1 and ABCG1), promoted cholesterol efflux, and suppressed foam cell formation. Inhibition of the PPAR gamma/LXR alpha pathway abrogated the promotive effects of astragalin on both transporter expression and cholesterol efflux. In addition, treatment of astragalin markedly decreased the secretion of inflammatory factors, including interleukin 6, monocyte chemotactic protein 1, tumor necrosis factor alpha, and interleukin 1 beta. Mechanistically, astragalin upregulated ABCA1 and ABCG1 expression, which in turn reduced TLR4 surface levels and inhibited NF-kappa B nuclear translocation. Consistently, astragalin reduced atherosclerotic plaque area in apoE(-/-) mice. Taken together, these findings suggest that astragalin protects against atherosclerosis by promoting ABCA1- and ABCG1-mediated cholesterol efflux and inhibiting proinflammatory mediator release.

Objective: The purpose of this study was to explore the role of long noncoding RNA (lncRNA) prostate cancer antigen 3 (PCA3) in atherosclerosis and the underlying mechanism. Methods: The Gene Expression Omnibus (GEO) datasets were used to divide differentially expressed lncRNAs, microRNAs (miRNAs), and mRNAs. The expression of PCA3, miR-140-5p, RFX7 and ABCA1 were determined by qPCR or Western blot in ox-LDL-treated macrophages. Macrophage lipid accumulation s was evaluated using the Oil Red O staining and high-performance liquid chromatography. Target relationships among PCA3, miR-140-5p, RFX7, and ABCA1 promoter area were validated via dual-luciferase reporter gene assay or chromatin immunoprecipitation assay. The apoE(-/-) mouse model in vivo was designed to evaluate the effect of PCA3 on the reverse cholesterol transport (RCT) and atherosclerosis. Results: PCA3 was down-regulated in foam cells, whereas miR-140-5p was highly expressed. Overexpression of PCA3 promoted ABCA1-mediated cholesterol efflux and reduced lipid accumulation in macrophages. Besides, RFX7 bound to the ABCA1 promoter and increased ABCA1 expression. Targeted relationships and interactions on the expression between miR-140-5p and PCA3 or RFX7 were elucidated. PCA3 up-regulated ABCA1 expression by binding to miR-140-5p to up-regulate RFX7 and ABCA1 expression in macrophages. PCA3 promoted RCT and impeded the progression of atherosclerosis by sponging miR-140-5p in apoE(-/-) mice. Meanwhile, miR-140-5p also inhibit ABCA1 expression via downregulation of RFX7 to impede RCT and aggravate atherosclerosis. Conclusions: lncRNA PCA3 promotes ABCA1-mediated cholesterol efflux to inhibit atherosclerosis through sponging miR-140-5p and up-regulating RFX7.

Myristica fragrans is a traditional herbal medicine and has been shown to alleviate the development of atherosclerosis. However, the anti-atherogenic mechanisms of M. fragrans are still to be addressed. In this study, we explored the effect of M. fragrans on lipid metabolism and inflammation and its mechanisms in THP-1-derived macrophages. The quantitative polymerase chain reaction and western blot analysis results showed that M. fragrans promotes cholesterol efflux from THP-1-derived macrophages and reduces intracellular total cholesterol, cholesterol ester, and free cholesterol contents in a dose- and a time-dependent manner. Further study found that liver X receptor alpha (LXRα) antagonist GGPP significantly blocked the upregulation of ABCA1 expression with M. fragrans treatment. In addition, chromatin immunoprecipitation assay confirmed that GATA binding protein 3 (GATA3) can bind to the LXRα promoter, and inhibition of GATA3 led to the downregulation of LXRα and ATP-binding cassette subfamily A member 1 expression. Furthermore, M. fragrans reduced lipid accumulation, followed by decreasing tumor necrosis factor-α, interleukin (IL)-6, and IL-1β and increasing IL-10 produced by THP-1-derived macrophages. Therefore, M. fragrans is identified as a valuable therapeutic medicine for atherosclerotic cardiovascular disease.

Background and aims: TP53-induced glycolysis and apoptosis regulator (TIGAR) is now characterized as a fructose-2,6-bisphosphatase to reduce glycolysis and protect against oxidative stress. Recent studies have demonstrated that TIGAR is associated with cardiovascular disease. However, little is known about its role in atherosclerogenesis. In this study, we aimed to investigate the effect of TIGAR on atherosclerosis and explore the underlying molecular mechanism. Methods: The Gene Expression Omnibus (GEO) datasets were used to analyze the differential expression of relative proteins. THP-1-derived macrophages were used as an in vitro model and apolipoprotein E-deficient (Apoe- /- ) mice were used as an in vivo model. [3H] labeled cholesterol was used to assess the capacity of cholesterol efflux and reverse cholesterol transport (RCT). Both qPCR and Western blot were used to evaluate the mRNA and protein expression, respectively. Lentiviral vectors were used to disturb the expression of TIGAR in vitro and in vivo. Oil Red O, hematoxylin-eosin, and Masson staining were performed to evaluate atherosclerotic plaques in Apoe-/- mice fed a Western diet. Conventional assay kits were used to measure the levels of reactive oxygen species (ROS), plasma lipid profiles and 27-hydroxycholesterol (27-HC). Results: Our results showed that TIGAR is increased upon the formation of macrophage foam cells and atherosclerosis. TIGAR knockdown markedly promoted lipid accumulation in macrophages. Silencing of TIGAR impaired cholesterol efflux and down-regulated the expression of ATP-binding cassette transporter A1 (ABCA1) and ABCG1 by interfering with liver X receptor alpha (LXR alpha) expression and activity, but did not influence cholesterol uptake by macrophages. Additionally, this inhibitory effect of TIGAR deficiency on cholesterol metabolism was mediated through the ROS/CYP27A1 pathway. In vivo experiments revealed that TIGAR deficiency decreased the levels of ABCA1 and ABCG1 in plaques and aorta and impaired the capacity of RCT, thereby leading to the progression of atherosclerosis in Apoe-/- mice. Conclusions: TIGAR mitigates the development of atherosclerosis by up-regulating ABCA1 and ABCG1 expression via the ROS/CYP27A1/LXR alpha pathway.

Objective: Our previous study showed that Coiled-Coil Domain Containing 80 (CCDC80) accelerates the development of atherosclerosis by decreasing lipoprotein lipase (LPL) expression and activity in apoE knockout mice. However, the regulatory mechanism for CCDC80 expression is unclear. This study was designed to evaluate whether noncoding RNAs involved the regulation of CCDC80 expression in vascular smooth muscle cells. Methods and Results: Bioinformatics prediction and luciferase reporter gene results showed that miR-141-3p/200a-3p bound to the 3 ' UTR of CCDC80. Furthermore, miR-141-3p/200a-3p mimics decreased the expression of CCDC80 but increased LPL expression. Opposite results were observed with miR-141-3p/200a-3p inhibitors. We also found that lncRNA metastasis-associated lung adenocarcinoma transcript-1 (MALAT1) interacted with the sequences of miR-141-3p/200a-3p and decreased their expression. RT-qPCR and western blotting results showed that MALAT1 overexpression increased CCDC80 expression and decreased LPL expression, while MALAT1 knockdown displayed an opposite phenotype. The effects of both MALAT1 overexpression and knockdown were blocked by miR-141-3p/200a-3p mimics or inhibitors. Conclusions: Thus, we demonstrated that lncRNA MALAT1 regulates CCDC80 and LPL expression through miR-141-3p/200a-3p.

Atherosclerosis is regarded as a lipid-driven chronic inflammatory disease. A variety of immune cells, including B1 cells, play an important role in the occurrence and development of atherosclerosis. T15/E06 is an IgM Nab secreted by B1 cells. The concentration of T15/E06 is significantly decreased in animal models of atherosclerosis. Accumulating evidence has shown that T15/E06 can protect against atherosclerosis by blocking macrophage lipid uptake, inhibiting vascular inflammation, and promoting apoptotic cell clearance. In this review, we describe the structure, functions and regulation of T15/E06 and summarize the latest advance regarding its atheroprotective effect.

Interleukin-5 (IL-5) is manifested as its involvement in the process of atherosclerosis, but the mechanism is still unknown. In this study, we explored the effect of IL-5 on lipid metabolism and its underlying mechanisms in THP-1-derived macrophages. The quantitative polymerase chain reaction (qPCR) and western blot analysis results showed that IL-5 significantly up-regulated ATP-binding cassette transporter A1 (ABCA1) expression in a dose-dependent and time-dependent manner. [3H]-labeled cholesterol was used to assess the levels of cholesterol efflux, and the results showed that IL-5 increased ABCA1-mediated cholesterol efflux. A high-performance liquid chromatography assay indicated that cellular cholesterol content was decreased by IL-5 treatment in THP-1-derived macrophages. The selective inhibitor and small interfering RNA were used to block the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathway. The results of the qPCR and western blot analysis showed that IL-5 activated JAK2/STAT3 pathway to up-regulate ABCA1 expression. Meanwhile, IL-5 reduced the expression level of miR-211. Furthermore, we found that JAK2 is a target gene of miR-211 and miR-211 mimic inhibited the expression of JAK2 and reduced the levels of p-STAT3 and ABCA1 as revealed by luciferase reporter assay, qPCR and western blot analysis. In summary, these findings indicated that IL-5 promotes ABCA1 expression and cholesterol efflux through the miR-211/JAK2/STAT3 signaling pathway in THP-1-derived macrophages.

Atherosclerosis is the pathological basis of most cardiovascular diseases, the leading cause of morbidity and mortality worldwide. Kallistatin, originally discovered in human serum, is a tissue-kallikrein-binding protein and a unique serine proteinase inhibitor. Upon binding to its receptor integrin β3, lipoprotein receptor-related protein 6, nucleolin, or Krüppel-like factor 4, kallistatin can modulate various signaling pathways and affect multiple biological processes, including angiogenesis, inflammatory response, oxidative stress, and tumor growth. Circulating kallistatin levels are significantly decreased in patients with coronary artery disease and show an inverse correlation with its severity. Importantly, both in vitro and in vivo experiments have demonstrated that kallistatin reduces atherosclerosis by inhibiting vascular inflammation, antagonizing endothelial dysfunction, and improving lipid metabolism. Thus, kallistatin may be a novel biomarker and a promising therapeutic target for atherosclerosis-related diseases. In this review, we focus on the antiatherogenic function of kallistatin and its potential mechanism.