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Atherosclerosis is a chronic inflammatory disease of the arterial wall caused by an imbalance of lipid metabolism and a maladaptive inflammatory response. A variety of harmful cellular changes associated with atherosclerosis include endothelial dysfunction, the migration of circulating inflammatory cells to the arterial wall, the production of proinflammatory cytokines, lipid buildup in the intima, local inflammatory responses in blood vessels, atherosclerosis-associated apoptosis, and autophagy. PTEN inhibits the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/AKT)/mammalian target of rapamycin (mTOR) pathway through its lipid phosphatase activity. Previous studies have shown that PTEN is closely related to atherosclerosis. This article reviews the role of PTEN in atherosclerosis from the perspectives of autophagy, apoptosis, inflammation, proliferation, and angiogenesis.
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OBJECTIVES: To study the clinical characteristics of children with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: A retrospective analysis was conducted on the clinical data of 25 children diagnosed with AAV at the Second Xiangya Hospital of Central South University from January 2010 to June 2022. RESULTS: Among the AAV children, there were 5 males and 20 females, with a median age of onset of 11.0 years. Involvement of the urinary system was seen in 18 cases (72%); respiratory system involvement in 10 cases (40%); skin involvement in 6 cases (24%); eye, ear, and nose involvement in 5 cases (20%); joint involvement in 4 cases (16%); digestive system involvement in 2 cases (8%). Eleven cases underwent kidney biopsy, with 5 cases (46%) showing focal type, 2 cases (18%) showing crescentic type, 2 cases (18%) showing mixed type, and 2 cases (18%) showing sclerotic type. Immune complex deposits were present in 5 cases (45%). Seven cases reached chronic kidney disease (CKD) stage V, with 2 cases resulting in death. Two cases underwent kidney transplantation. At the end of the follow-up period, 2 cases were at CKD stage II, and 1 case was at CKD stage III. Of the 16 cases of microscopic polyangiitis (MPA) group, 13 (81%) involved the urinary system. Of the 9 cases of granulomatosis with polyangiitis (GPA), 6 cases (66%) had sinusitis. Serum creatinine and uric acid levels were higher in the MPA group than in the GPA group (P<0.05), while red blood cell count and glomerular filtration rate were lower in the MPA group (P<0.05). CONCLUSIONS: AAV is more common in school-age female children, with MPA being the most common clinical subtype. The onset of AAV in children is mainly characterized by renal involvement, followed by respiratory system involvement. The renal pathology often presents as focal type with possible immune complex deposits. Children with MPA often have renal involvement, while those with GPA commonly have sinusitis. The prognosis of children with AAV is poor, often accompanied by renal insufficiency.
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Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Humanos , Feminino , Masculino , Criança , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/complicações , Estudos Retrospectivos , Adolescente , Pré-Escolar , Insuficiência Renal Crônica/etiologiaRESUMO
OBJECTIVES: To study the correlation of anti-C1q antibodies with active systemic lupus erythematosus (SLE) and lupus nephritis (LN) in children, as well as their diagnostic value for active SLE and LN. METHODS: A retrospective selection of 90 hospitalized children with SLE at the Children's Medical Center of Second Xiangya Hospital, Central South University from January 2016 to March 2019 as the SLE group, all of whom were tested for anti-C1q antibodies. A control group was formed by collecting 70 hospitalized children with other autoimmune diseases (OAD) during the same period. The differences in anti-C1q antibody levels were compared between two groups.The correlation of anti-C1q antibodies with various indicators of SLE and LN was analyzed, and the diagnostic value of anti-C1q in SLE and LN was evaluated. RESULTS: The serum levels of anti-C1q antibodies in the SLE group were higher than those in the OAD group (P<0.05). The SLE disease activity index score was positively correlated with anti-C1q antibodies (rs=0.371, P<0.001) and positively correlated with anti-double-stranded DNA antibodies (rs=0.370, P<0.001). The sensitivity and specificity of anti-C1q antibodies for diagnosing active SLE were 89.90% and 53.90%, respectively, with an area under the curve of 0.720 (P<0.05) and a critical value of 5.45 U/mL. The sensitivity and specificity of anti-C1q antibody levels for diagnosing active LN were 58.50% and 85.00%, respectively, with an area under the curve of 0.675 (P<0.05) and a critical value of 22.05 U/mL. CONCLUSIONS: Anti-C1q antibodies can serve as non-invasive biomarkers for evaluating the activity of SLE or predicting the activity of LN in children.
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Complemento C1q , Lúpus Eritematoso Sistêmico , Nefrite Lúpica , Humanos , Complemento C1q/imunologia , Nefrite Lúpica/imunologia , Nefrite Lúpica/sangue , Feminino , Criança , Masculino , Lúpus Eritematoso Sistêmico/imunologia , Estudos Retrospectivos , Adolescente , Autoanticorpos/sangue , Pré-Escolar , Anticorpos Antinucleares/sangue , Anticorpos Antinucleares/imunologiaRESUMO
Systemic lupus erythematosus (SLE) is an autoimmune disease that affects multiple organ systems, presenting a complex and diverse clinical manifestation. The heterogeneous treatment response and prognosis of SLE pose significant challenges to its diagnosis, classification, and homogeneous treatment. The emergence of new technologies and fields, such as synthetic biology, genomics, and proteomics, has contributed to a deeper exploration of the pathogenesis and biomarkers of SLE, facilitating precision diagnosis and treatment. This review summarizes the latest research data and achievements in SLE for the years 2021-2022, providing an overview and summary of relevant studies conducted in the past two years.
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Lúpus Eritematoso Sistêmico , Humanos , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/terapia , ProteômicaRESUMO
The global leading cause of death is cardiovascular disease (CVD). Although advances in prevention and treatment have been made, the role of RNA epigenetics in CVD is not fully understood. Studies have found that RNA modifications regulate gene expression in mammalian cells, and m5C (5-methylcytosine) is a recently discovered RNA modification that plays a role in gene regulation. As a result of these developments, there has been renewed interest in elucidating the nature and function of RNA "epitranscriptomic" modifications. Recent studies on m5C RNA methylomes, their functions, and the proteins that initiate, translate and manipulate this modification are discussed in this review. This review improves the understanding of m5C modifications and their properties, functions, and implications in cardiac pathologies, including cardiomyopathy, heart failure, and atherosclerosis.
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BACKGROUND: Macrophages participate in all stages of the inflammatory response, and the excessive release of inflammatory mediators and other cytokines synthesized and secreted by macrophages is fundamentally linked to an uncontrolled inflammatory response. The zinc finger 667 (ZNF667) protein, a novel DNAbinding protein, has been shown to play a vital role in oxidative stress. However, none of the target genes in macrophages or the potential roles of ZNF667 have been elucidated to date. > Objectives: The present study was designed to investigate the effects of ZNF667 on LPS-induced inflammation in macrophages. > Methods: The RAW264.7 macrophage cell line was selected as a model system. Inflammatory response-related gene expression levels and phosphorylation levels of PI3K, AKT, and mTOR were detected in LPS-treated macrophages via RT-PCR and western blotting, respectively. > Results: We found that LPS resulted in the up-regulation of ZNF667 in macrophages and a peak response in ZNF667 protein expression levels when used at a concentration of 100 ng/mL. ZNF667 overexpression significantly inhibited the LPS-induced up-regulation of iNOS, and IL-1ß mRNA and protein expression levels, together with the secretion of IL-1ß, IL-6, and TNF-α. ZNF667 overexpression also inhibited PI3K, AKT, and mTOR hyperphosphorylation and had no effect on the phosphorylation of NF-κB p65, ERK1/2, MAPK p38, and the transcriptional activity of NF-κB in macrophages. The up-regulation of ZNF667 inhibited the levels of expression of HK2 and PFKFB3, glucose consumption, and lactate production in LPS-stimulated macrophages. The up-regulation of mRNA levels of LPS-induced glycolytic genes HK2 and PFKFB3 and the increased mRNA expression of pro-inflammatory cytokines (IL-1ß and iNOS) were abolished by hexokinase inhibitor 2-DG in ZNF667-deficient macrophages. Meanwhile, glucose consumption and lactate production were abrogated in macrophages when cells were treated with the specific mTOR inhibitor RPM. > Conclusion: Our results demonstrate that ZNF667 suppressed LPS-stimulated RAW264.7 macrophage inflammation by regulating mTOR-dependent aerobic glycolysis.>.
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Lipopolissacarídeos , NF-kappa B , Humanos , NF-kappa B/metabolismo , Lipopolissacarídeos/farmacologia , Transdução de Sinais , Anti-Inflamatórios/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Inflamação/metabolismo , Macrófagos , Serina-Treonina Quinases TOR/metabolismo , Citocinas/metabolismo , RNA Mensageiro/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Dedos de ZincoRESUMO
Atherosclerosis, a silent chronic vascular pathology, is the cause of the majority of cardiovascular ischaemic events. Atherosclerosis is characterized by a series of deleterious changes in cellularity, including endothelial dysfunction, transmigration of circulating inflammatory cells into the arterial wall, pro-inflammatory cytokines production, lipid accumulation in the intima, vascular local inflammatory response, atherosclerosis-related cells apoptosis and autophagy. Proteins of Annexin A (AnxA) family, the well-known Ca2+ phospholipid-binding protein, have many functions in regulating inflammation-related enzymes and cell signaling transduction, thus influencing cell adhesion, migration, differentiation, proliferation and apoptosis. There is now accumulating evidence that some members of the AnxA family, such as AnxA1, AnxA2, AnxA5 and AnxA7, play major roles in the development of atherosclerosis. This article discusses the major roles of AnxA1, AnxA2, AnxA5 and AnxA7, and the multifaceted mechanisms of the main biological process in which they are involved in atherosclerosis. Considering these evidences, it has been proposed that AnxA are drivers- and not merely participator- on the road to atherosclerosis, thus the progression of atherosclerosis may be prevented by targeting the expression or function of the AnxA family proteins.
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Anexina A1 , Aterosclerose , Anexinas , Apoptose , Aterosclerose/patologia , Autofagia , Humanos , InflamaçãoRESUMO
Cardiovascular and related metabolic diseases are significant global health challenges. Glucagon-like peptide 1 (GLP-1) is a brain-gut peptide secreted by the ileal endocrine system and is now an established drug target in type 2 diabetes (T2DM). GLP-1 targeting agents have been shown not only to treat T2DM, but also to exert cardiovascular protective effects by regulating multiple signaling pathways. The mitogen-activated protein kinase (MAPK) pathway, a common signal transduction pathway for transmitting extracellular signals to downstream effector molecules, is involved in regulating diverse cellular physiological processes, including cell proliferation, differentiation, stress, inflammation, functional synchronization, transformation, and apoptosis. The purpose of this review is to highlight the relationship between GLP-1 and cardiovascular disease (CVD) and discuss how GLP-1 exerts cardiovascular protective effects through the MAPK signaling pathway. This review also discusses the future challenges in fully characterizing and evaluating the CVD protective effects of GLP-1 receptor agonists (GLP-1RA) at the cellular and molecular levels. A better understanding of the MAPK signaling pathway that is dysregulated in CVD may aid in the design and development of promising GLP-1RA.
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Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/uso terapêutico , Humanos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Transdução de SinaisRESUMO
Background: Over the past two decades, both transport modes as well as overweight/obesity have changed dramatically among students in China, but their relationships are not clear. This study aimed to investigate modes of transport to school and their associations with the weight status of Chinese students. Methods: A cross-sectional study was conducted with non-resident students aged 6 to 17 years from all 16 districts across Shanghai, China in October and November 2019. Information about sociodemographic characteristics and the models of travel to school among students was investigated using an online, self-administered, structured questionnaire (or those assisted by their parents). Weight and height were measured by school health workers, and the Chinese standard age adjusted BMI (weight/height2) was used to classify students' weight status. Cumulative logistic regression modelling was used to examine the relationships. Results: The main mode of transport to school was an active mode (46.5%, defined as walking, bicycling, or public transport), followed by an inactive mode of transport (30.5%, defined as a car or bicycle as a passenger), and a combination of both modes (23%). About one-third of the students were overweight or obese and 5% were underweight. No statistically significant association between transport modes and weight status was found in this study. Conclusions: In Shanghai, close to one-third of children travel to school by an inactive mode of transport. The findings of this study did not support the notion that an active mode to school could be beneficial for preventing overweight/obesity in students in China.
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Instituições Acadêmicas , Estudantes , Adolescente , Peso Corporal , Criança , China/epidemiologia , Estudos Transversais , Humanos , Sobrepeso/epidemiologiaRESUMO
AIMS: To explore the biological function and mechanism of Syntaxin2 (STX2) in Colorectal cancer (CRC) proliferation. MAIN METHODS: A series of gain- and loss-of-function analysis were conducted the to explore the biological function of STX2 in CRC proliferation in vivo and in vitro. Western blot, Co-immunoprecipitation (Co-IP) and the functional analyses were taken to analyze the regulative role of STX2 on Exosome Complex 4 (EXOSC4) in CRC proliferation; Immunohistochemistry (IHC) and Real-time quantitative polymerase chain reaction (qPCR) were used to further verify the relationship between the expression of STX2 and EXOSC4 in human CRC samples. KEY FINDINGS: Our study revealed that the over-expression of STX2 promoted CRC proliferation, while knockdown of STX2 repressed CRC proliferation; STX2 promoted CRC proliferation via increasing EXOSC4 protein; There was a positive correlation between STX2 and EXOSC4 expression. SIGNIFICANCE: The current data verify that STX2 drives the proliferation of CRC via increasing the expression of EXOSC4.
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Proliferação de Células/genética , Neoplasias Colorretais/patologia , Complexo Multienzimático de Ribonucleases do Exossomo/genética , Proteínas de Ligação a RNA/genética , Sintaxina 1/genética , Animais , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Feminino , Técnicas de Silenciamento de Genes , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Regulação para CimaRESUMO
Background: Paclitaxel plays a pivotal role in the chemotherapy of breast cancer, but resistance to this drug is an important obstacle in the treatment. It is reported that microRNA-152-3p (miR-152-3p) is involved in tamoxifen resistance in breast cancer, but whether it is involved in paclitaxel resistance in breast cancer remains unknown. Materials and methods: We examined the expression of miR-152-3p in breast cancer tissues and cells by qRT-PCR. After transfecting paclitaxel-resistant MCF-7/TAX cells with miR-152-3p mimics, we analyzed the function of miR-152-3p in these cells by MTT assay and flow cytometry. We screened the target gene, endothelial PAS domain-containing protein 1 (EPAS1), using bioinformatics analysis and verified it with the dual luciferase reporter gene experiment. The relationship between EPAS1 and miR-152-3p and their roles in paclitaxel resistance of breast cancer were further investigated using RNA interference and transfection techniques. Results: The expression of miR-152-3p in normal breast tissues and cells was markedly higher than that in breast cancer. Overexpression of miR-152-3p decreased the survival rate and increased the apoptosis rate and sensitivity of MCF-7/TAX cells to paclitaxel. We confirmed that EPAS1 is the target of miR-152-3p and is negatively regulated by this miRNA. Moreover, transfection with EPAS1 siRNA enhanced the susceptibility and apoptosis rate of MCF-7/TAX cells to paclitaxel. Co-transfection of miR-152-3p mimics and EPAS1 increased paclitaxel sensitivity and apoptosis induced by the drug. Conclusion: miR-152-3p inhibits the survival of MCF-7/TAX cells and promotes their apoptosis by targeting the expression of EPAS1, thereby, enhancing the sensitivity of these breast cancer cells to paclitaxel.
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BACKGROUND: It is not completely clear whether a very high pre-therapy viral load (≥ 500 000 copies/ml) can impair the virological response. The aim of this study was to examine the influence of very high baseline HIV-RNA levels on long-term virological responses under one type of regimen. METHODS: A retrospective study was performed based on data from two multicenter cohorts in China from January to November 2009, and from May 2013 to December 2015. Untreated HIV infected adults between 18 and 65 years old were recruited before receiving non-nucleoside reverse transcriptase inhibitor-based regimen. All patients had baseline HIV-RNA levels over 500 copies/ml, good adherence, and were followed for at least 24 weeks. Virological suppression was defined as the first HIV-RNA < 50 copies/ml. Virological failure was defined as any of incomplete viral suppression (HIV-RNA ≥ 200 copies/ml without virological suppression within 24 weeks of treatment) and viral rebound (confirmed HIV-RNA level ≥ 50 copies/ml after virological suppression). Chi-square test, Kaplan-Meier analysis, Cox proportional hazards model and Logistic regression were used to compare virological response between each pretreated viral load stratum. RESULTS: A total of 758 treatment-naïve HIV patients in China were enlisted. Median follow-up time (IQR) was 144 (108-276) weeks. By week 48, rates of virological suppression in three groups (< 100 000, 100 000-500 000 and ≥ 500 000 copies/ml) were 94.1, 85.0, and 63.8%, respectively (P < 0.001). Very high baseline HIV viremia over 500 000 copies/ml were found to be associated with delayed virological suppression (≥ 500 000 vs < 100 000, adjusted relative hazard = 0.455, 95% CI: 0.32-0.65; P < 0.001) as well as incomplete viral suppression (≥ 500 000 vs < 100 000, adjusted odds ratio [aOR] = 6.084, 95% CI: 2.761-13.407; P < 0.001) and viral rebound (≥ 50 000 vs < 100 000, aOR = 3.671, 95% CI: 1.009-13.355, P = 0.048). CONCLUSIONS: Very high levels of pre-treatment HIV-RNA were related with delayed efficacy of NNRTI-based ART and increased risk of treatment failure. More potent initial regimens should be considered for those with this clinical character.
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Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Viremia/tratamento farmacológico , Adulto , Idoso , China , Estudos de Coortes , Feminino , Infecções por HIV/sangue , Infecções por HIV/virologia , Humanos , Masculino , Pessoa de Meia-Idade , DNA Polimerase Dirigida por RNA/uso terapêutico , Estudos Retrospectivos , Carga Viral , Viremia/sangue , Viremia/virologiaRESUMO
Atherosclerosis is the pathological basis of most cardiovascular diseases. Reverse cholesterol transport (RCT) is a main mechanism of cholesterol homeostasis and involves the direct transport of high-density lipoprotein (HDL) cholesteryl ester by selective cholesterol uptake. Hepatic scavenger receptor class B member 1 (SR-BI) overexpression can effectively promote RCT and reduce atherosclerosis. SR-BI may be an important target for prevention or treatment of atherosclerotic disease. In our study, we inserted human SR-BI mRNA 3' untranslated region (3'UTR) downstream of the luciferase reporter gene, to establish a high-throughput screening model based on stably transfected HepG2 cells and to screen small-molecule compounds that can significantly enhance the mRNA stability of the SR-BI gene. Through multiple screenings of 25 755 compounds, the top five active compounds that have similar structures were obtained, with a positive rate of 0.19%. The five positive compounds could enhance the SR-BI expression and uptake of DiI-HDL in the hepatocyte HepG2. E238B-63 could also effectively extend the half-life of SR-BI mRNA and enhance the SR-BI mRNA and protein level and the uptake of DiI-HDL in hepatocytes in a time-dependent and dose-dependent manner. The structure-activity relationship analysis showed that the structure N-(3-hydroxy-2-pyridyl) carboxamide is possibly the key pharmacophore of the active compound, providing reference for acquiring candidate compounds with better activity. The positive small molecular compounds obtained in this study might become new drug candidates or lead compounds for the treatment of cardiovascular diseases and contribute to the further study of the posttranscriptional regulation mechanism of the SR-BI gene.
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Aterosclerose/tratamento farmacológico , Ensaios de Triagem em Larga Escala , Receptores Depuradores Classe B/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Aterosclerose/genética , Aterosclerose/metabolismo , Ésteres do Colesterol/genética , Ésteres do Colesterol/metabolismo , HDL-Colesterol/genética , Células Hep G2 , Hepatócitos/metabolismo , Humanos , Lipoproteínas HDL/genética , Lipoproteínas HDL/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Estabilidade Proteica/efeitos dos fármacos , Receptores Depuradores Classe B/genéticaRESUMO
OBJECTIVE: To examine the transfection of Homeobox A13 (HOXA13) on epithelial-mesenchymal transition (EMT) and the expression of bone morphogenetic protein-7 (BMP-7) induced by albumin-overload in human kidney tubular epithelial cells (HKCs). METHODS: The cultured HKCs were treated with 20 mg/mL human serum albumin (HSA) for 48 hours. Protein expression of cytokeratin (CK), vimentin and HOXA13 in the HKCs was assessed by Western blot. Protein expression of CK, vimentin, and BMP-7 was also detected in HKCs transfected with lipofectamine contained HOXA13 DNA. RESULTS: HSA induced EMT in HKCs, presented by decreased CK expression (P<0.01) and increased vimentin expression (P<0.01). The up-regulated expression of HOXA13 transfected by lipofectamine inhibited the level of EMT induced by HSA in HKCs (P<0.05). The decreased rate of BMP-7 protein expression induced by HSA was inhibited by over-expressed HOXA13 in HKCs (P<0.05). CONCLUSIONS: Transfection of HOXA13 in HKCs could inhibit the degree of EMT induced by albumin-overload, possibly by increasing BMP-7 expression.
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Proteína Morfogenética Óssea 7/genética , Transição Epitelial-Mesenquimal , Proteínas de Homeodomínio/fisiologia , Túbulos Renais/metabolismo , Células Cultivadas , Células Epiteliais/metabolismo , Humanos , Queratinas/genética , Transfecção , Vimentina/genéticaRESUMO
In the previous study, a high-throughput screening method was established to find the antagonists of CD36. In the present study, a new compound named IMB-1680 was found using this method. The anti-atherosclerotic activities of IMB-1680 were then evaluated. Dose-dependent activities of IMB-1680 were detected by using Sf9 [hCD36] and CHO [hCD36] models. Fluorescence microscopic photography and flow cytometry were used to analyze uptake of mLDL. Foam cell test with RAW264.7 macrophages was used to examine lipid accumulation. The results showed that IMB-1680 inhibited CD36 activity with IC50 of 2.80 and 8.79 micromol x L(-1) in Sf9[hCD36] and CHO [hCD36] cells, respectively. Fluorescence microscopic photography and flow cytometry revealed that IMB-1680 could significantly reduce DiI-AcLDL uptake. Meanwhile, IMB-1680 also could reduce lipids accumulation in RAW264.7 macrophages. In all, the data indicated that IMB-1680 might be a potent effective anti-atherosclerotic leading compound.