Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 11.159
Filtrar
1.
Nan Fang Yi Ke Da Xue Xue Bao ; 44(8): 1518-1528, 2024 Aug 20.
Artigo em Chinês | MEDLINE | ID: mdl-39276047

RESUMO

OBJECTIVE: To elucidate the therapeutic mechanism of Qingxin Jieyu Granule (QXJYG) against atherosclerosis (AS) based on network pharmacology. METHODS: The major targets and pathways of QXJYG against AS were analyzed using network pharmacology. Rat models of AS established by high-fat feeding combined with intraperitoneal vitamin D3 injection were treated daily with normal saline, atorvastatin (13.15 mg/kg), or QXJYG at 0.99, 1.98, and 3.96 g/kg for 8 weeks (n=6). Ultrasound and HE staining were used to assess the function and pathologies of the abdominal aorta. Blood lipids and serum levels of Ang Ⅱ, ET-1, TXA2, PGI2, and ox-LDL of the rats were detected using an automatic biochemical analyzer or ELISA. The expressions of LOX-1, PPARγ, RXRα, p-P65, VCAM-1 and ICAM-1 in the abdominal aorta were detected with immunohistochemistry. RESULTS: The rat models of AS showed obvious abdominal aorta wall thickening, increased pulse wave velocity and pulse index, decreased inner diameter of the abdominal aorta, elevated levels of TC, LDL-C, Ang Ⅱ, ET-1 and TXA2, and lowered levels of HDL-C and PGI2. QXJYG and atorvastatin treatment of the rat models significantly alleviated histopathological changes of the abdominal aorta, decreased serum levels of TC, LDL-C, Ang Ⅱ, ET-1 and TXA2, and increased the levels of HDL-C and PGI2. Network pharmacology study suggested the therapeutic effect of QXJYG against AS was mediated by regulating lipid metabolism, PPAR and NF-κB pathways. Consistently, treatments with QXJYG were found to significantly decrease ox-LDL level and LOX-1, P-P65, VCAM-1 and ICAM-1 protein expressions while increasing PPARγ and RXRα expressions in the aorta of AS rats. CONCLUSION: QXJYG alleviates lipid metabolism disorder and improves histopathological changes of the abdominal aorta of AS rats possibly by lowering ox-LDL level, reducing LOX-1 expression, activating PPARγ and RXRα, and inhibiting P65 phosphorylation to reduce VCAM-1 and ICAM-1 expression in the aorta.


Assuntos
Aterosclerose , Medicamentos de Ervas Chinesas , Metabolismo dos Lipídeos , Animais , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Ratos , Metabolismo dos Lipídeos/efeitos dos fármacos , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Aorta Abdominal/metabolismo , Aorta Abdominal/efeitos dos fármacos , Farmacologia em Rede , Lipoproteínas LDL/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , PPAR gama/metabolismo , Masculino , Atorvastatina/farmacologia , Atorvastatina/uso terapêutico , Molécula 1 de Adesão de Célula Vascular/metabolismo , Ratos Sprague-Dawley , Modelos Animais de Doenças , Lipídeos/sangue , Tromboxano A2/metabolismo , Epoprostenol/análogos & derivados , Receptores Depuradores Classe E
2.
Int J Mol Sci ; 25(17)2024 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-39273324

RESUMO

Several lines of evidence have linked the intestinal bacterium Helicobacter cinaedi with the pathogenesis of atherosclerosis, identifying the Cinaedi Antigen Inflammatory Protein (CAIP) as a key virulence factor. Oxidative stress and inflammation are crucial in sustaining the atherosclerotic process and oxidized LDL (oxLDL) uptake. Primary human macrophages and endothelial cells were pre-incubated with 10 µM diphenyl iodonium salt (DPI) and stimulated with 20 µg/mL CAIP. Lectin-like oxLDL receptor (LOX-1) expression was evaluated by FACS analysis, reactive oxygen species (ROS) production was measured using the fluorescent probe H2DCF-DA, and cytokine release was quantified by ELISA assay. Foam cells formation was assessed by Oil Red-O staining, and phosphorylation of p38 and ERK1/2 MAP kinases and NF-κB pathway activation were determined by Western blot. This study demonstrated that CAIP triggered LOX-1 over-expression and increased ROS production in both macrophages and endothelial cells. Blocking ROS abrogated LOX-1 expression and reduced LDL uptake and foam cells formation. Additionally, CAIP-mediated pro-inflammatory cytokine release was significantly affected by ROS inhibition. The signaling pathway induced by CAIP-induced oxidative stress led to p38 MAP kinase phosphorylation and NF-κB activation. These findings elucidate the mechanism of action of CAIP, which heightens oxidative stress and contributes to the atherosclerotic process in H. cinaedi-infected patients.


Assuntos
Aterosclerose , Infecções por Helicobacter , Helicobacter , Lipoproteínas LDL , Macrófagos , Espécies Reativas de Oxigênio , Receptores Depuradores Classe E , Humanos , Espécies Reativas de Oxigênio/metabolismo , Aterosclerose/metabolismo , Aterosclerose/microbiologia , Aterosclerose/patologia , Macrófagos/metabolismo , Macrófagos/microbiologia , Infecções por Helicobacter/metabolismo , Infecções por Helicobacter/microbiologia , Receptores Depuradores Classe E/metabolismo , Lipoproteínas LDL/metabolismo , Helicobacter/patogenicidade , Células Endoteliais/metabolismo , Células Endoteliais/microbiologia , NF-kappa B/metabolismo , Células Espumosas/metabolismo , Citocinas/metabolismo , Estresse Oxidativo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Proteínas de Bactérias/metabolismo , Sistema de Sinalização das MAP Quinases , Células Cultivadas , Transdução de Sinais
3.
Int J Mol Sci ; 25(17)2024 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-39273434

RESUMO

Recent findings from the World Heart Federation (WHF) reported a significant increase in cardiovascular disease (CVD)-related deaths, highlighting the urgent need for effective prevention strategies. Atherosclerosis, a key precursor to CVD, involves the accumulation of low-density lipoprotein (LDL) and its oxidation within the endothelium, leading to inflammation and foam cell formation. Ginger extracts, known for their antioxidative and anti-inflammatory properties, show promise in preventing CVD initiation by inhibiting LDL oxidation and reducing foam cell formation. Our results revealed that the active fractions in ginger extracts had antioxidative effects, particularly fractions D and E. Further research is needed to identify the active compounds in these fractions and understand their mechanisms of action. In this context, microfluidic models could offer insights into the effects of ginger on monocyte recruitment in a more physiologically relevant context. Overall, ginger extracts represent a potential novel treatment for preventing CVD initiation, but additional studies are necessary to identify the active molecules in these fractions.


Assuntos
Células Espumosas , Extratos Vegetais , Zingiber officinale , Zingiber officinale/química , Humanos , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Células Espumosas/efeitos dos fármacos , Células Espumosas/metabolismo , Doenças Cardiovasculares/prevenção & controle , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Lipoproteínas LDL/metabolismo , Antioxidantes/farmacologia , Aterosclerose/metabolismo , Aterosclerose/prevenção & controle , Aterosclerose/tratamento farmacológico , Moléculas de Adesão Celular/metabolismo
4.
Int J Mol Sci ; 25(17)2024 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-39273525

RESUMO

In recent years, extensive research has focused on cannabidiol (CBD), a well-studied non-psychoactive component of the plant-derived cannabinoids. CBD has shown significant therapeutic potential for treating various diseases and disorders, including antioxidants and anti-inflammatory effects. Due to the promising therapeutic effect of CBD in a wide variety of diseases, synthetic derivatization of this compound has attracted the attention of drug discovery in both industry and academia. In the current research, we focused on the derivatization of CBD by introducing Schiff base moieties, particularly (thio)-semicarbazide and aminoguanidine motifs, at the 3-position of the olivetolic ring. We have designed, synthesized, and characterized new derivatives based on CBD's framework, specifically aminoguanylhydrazone- and (thio)-semicarbazones-CBD-aldehyde compounds. Their antioxidant potential was assessed using FRAP and DPPH assays, alongside an evaluation of their effect on LDL oxidation induced by Cu2+ and AAPH. Our findings suggest that incorporating the thiosemicarbazide motif into the CBD framework produces a potent antioxidant, warranting further investigation.


Assuntos
Antioxidantes , Canabidiol , Desenho de Fármacos , Canabidiol/química , Canabidiol/farmacologia , Canabidiol/síntese química , Antioxidantes/síntese química , Antioxidantes/farmacologia , Antioxidantes/química , Oxirredução , Semicarbazidas/química , Semicarbazidas/síntese química , Semicarbazidas/farmacologia , Lipoproteínas LDL/metabolismo , Bases de Schiff/química , Bases de Schiff/farmacologia , Bases de Schiff/síntese química
5.
FASEB J ; 38(15): e23857, 2024 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-39114953

RESUMO

Atherosclerotic plaque formation is largely attributed to the impaired efferocytosis, which is known to be associated with the pathologic upregulation of cluster of differentiation 47 (CD47), a key antiphagocytic molecule. By gene expression omnibus (GEO) datasets analysis, we identified that four miRNAs are aberrantly downregulated in atherosclerosis, coronary artery disease, and obesity. Of them, hsa-miR-299-3p (miR-299-3p) was predicted to target the 3'UTR of human CD47 mRNA by bioinformatics analysis. Further, we demonstrated that miR-299-3p negatively regulates CD47 expression by binding to the target sequence "CCCACAU" in the 3'UTR of CD47 mRNA through luciferase reporter assay and site-directed mutagenesis. Additionally, we found that miR-299-3p was downregulated by ~32% in foam cells in response to oxidized low-density lipoprotein (ox-LDL) stimulation, thus upregulating CD47 and contributing to the impaired efferocytosis. Whereas, restoration of miR-299-3p reversed the ox-LDL-induced upregulation of CD47, thereby facilitating efferocytosis. In high-fat diet (HFD) fed ApoE-/- mice, we discovered that miR-299-3p was downregulated thus leading to upregulation of CD47 in abdominal aorta. Conversely, miR-299-3p restoration potently suppressed HFD-induced upregulation of CD47 and promoted phagocytosis of foam cells by macrophages in atherosclerotic plaques, thereby reducing necrotic core, increasing plaque stability, and mitigating atherosclerosis. Conclusively, we identify miR-299-3p as a negative regulator of CD47, and reveal a molecular mechanism whereby the ox-LDL-induced downregulation of miR-299-3p leads to the upregulation of CD47 in foam cells thus contributing to the impaired efferocytosis in atherosclerosis, and propose miR-299-3p can potentially serve as an inhibitor of CD47 to promote efferocytosis and ameliorate atherosclerosis.


Assuntos
Aterosclerose , Antígeno CD47 , Eferocitose , MicroRNAs , Animais , Humanos , Camundongos , Regiões 3' não Traduzidas , Aterosclerose/metabolismo , Aterosclerose/genética , Aterosclerose/patologia , Antígeno CD47/metabolismo , Antígeno CD47/genética , Dieta Hiperlipídica/efeitos adversos , Células Espumosas/metabolismo , Células Espumosas/patologia , Lipoproteínas LDL/metabolismo , Camundongos Endogâmicos C57BL , MicroRNAs/genética , MicroRNAs/metabolismo
6.
Pediatr Rheumatol Online J ; 22(1): 73, 2024 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-39118148

RESUMO

BACKGROUND: Juvenile dermatomyositis (JDM) is a systemic vasculopathy associated with metabolic derangements and possible increased risk for premature atherosclerosis. Oxidation of low-density lipoprotein (LDL) in the endothelium is an early step in atherosclerotic plaque formation. It is not known if oxidized LDL is altered in children with untreated JDM. The deposition of oxidized LDL in the vasculature of muscle biopsies (MBx) from patients with untreated JDM and pediatric controls was assessed. FINDINGS: Frozen tissue sections of MRI-directed MBx from 20 female children with untreated JDM and 5 female controls were stained with DAPI and fluorescently labeled antibodies against von Willebrand factor (vWF) and LDL oxidized by copper (oxLDL). Blood vessels were identified by positive vWF staining, and total fluorescence of oxLDL within the vessel walls was measured. Children with untreated JDM had increased deposition of oxLDL in the walls of muscle vasculature compared to healthy children (difference in means ± SEM = 19.86 ± 8.195, p = 0.03). Within the JDM cohort, there was a trend towards increased oxLDL deposition with longer duration of untreated disease (r = 0.43, p = 0.06). There was no significant correlation found between oxLDL deposition and markers of acute JDM disease activity including disease activity scores or muscle enzymes. CONCLUSIONS: This study found increased deposition of oxLDL within blood vessels of children with untreated JDM supporting the concern that these children are at increased risk for premature atherosclerosis from chronic exposure to vascular oxLDL. This study highlights the importance of early diagnosis and treatment initiation to ameliorate cardiovascular damage.


Assuntos
Dermatomiosite , Lipoproteínas LDL , Humanos , Feminino , Lipoproteínas LDL/metabolismo , Dermatomiosite/metabolismo , Dermatomiosite/patologia , Criança , Adolescente , Músculo Esquelético/metabolismo , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/patologia , Pré-Escolar , Estudos de Casos e Controles , Imageamento por Ressonância Magnética/métodos , Biópsia
7.
Mol Med ; 30(1): 117, 2024 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-39123116

RESUMO

BACKGROUND: Lipid metabolism disorders are associated with degeneration of multiple tissues and organs, but the mechanism of crosstalk between lipid metabolism disorder and intervertebral disc degeneration (IDD) has not been fully elucidated. In this study we aim to investigate the regulatory mechanism of abnormal signal of lipid metabolism disorder on intervertebral disc endplate chondrocyte (EPC) senescence and calcification. METHODS: Human intervertebral disc cartilage endplate tissue, cell model and rat hyperlipemia model were performed in this study. Histology and immunohistochemistry were used to human EPC tissue detection. TMT-labelled quantitative proteomics was used to detect differential proteins, and MRI, micro-CT, safranin green staining and immunofluorescence were performed to observe the morphology and degeneration of rat tail intervertebral discs. Flow cytometry, senescence-associated ß-galactosidase staining, alizarin red staining, alkaline phosphatase staining, DCFH-DA fluorescent probe, and western blot were performed to detect the expression of EPC cell senescence, senescence-associated secretory phenotype, calcification-related proteins and the activation of cell senescence-related signaling pathways. RESULTS: Our study found that the highly expressed oxidized low-density lipoprotein (ox-LDL) and Lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1) in human degenerative EPC was associated with hyperlipidemia (HLP). TMT-labelled quantitative proteomics revealed enriched pathways such as cell cycle regulation, endochondral bone morphogenesis and inflammation. The rat model revealed that HLP could induce ox-LDL, LOX-1, senescence and calcification markers high expression in EPC. Moreover, we demonstrated that ox-LDL-induced EPCs senescence and calcification were dependent on the LOX-1 receptor, and the ROS/P38-MAPK/NF-κB signaling pathway was implicated in the regulation of senescence induced by ox-LDL/LOX-1 in cell model. CONCLUSIONS: So our study revealed that ox-LDL/LOX-1-induced EPCs senescence and calcification through ROS/P38-MAPK/NF-κB signaling pathway, providing information on understanding the link between lipid metabolism disorders and IDD.


Assuntos
Senescência Celular , Condrócitos , Degeneração do Disco Intervertebral , Metabolismo dos Lipídeos , Lipoproteínas LDL , Receptores Depuradores Classe E , Degeneração do Disco Intervertebral/metabolismo , Degeneração do Disco Intervertebral/patologia , Lipoproteínas LDL/metabolismo , Animais , Humanos , Receptores Depuradores Classe E/metabolismo , Condrócitos/metabolismo , Condrócitos/patologia , Ratos , Masculino , Calcinose/metabolismo , Calcinose/patologia , Disco Intervertebral/metabolismo , Disco Intervertebral/patologia , Modelos Animais de Doenças , Feminino , Pessoa de Meia-Idade , Transdução de Sinais , Adulto , Proteômica/métodos , Ratos Sprague-Dawley
8.
Bull Math Biol ; 86(9): 112, 2024 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-39093509

RESUMO

Macrophages in atherosclerotic lesions exhibit a spectrum of behaviours or phenotypes. The phenotypic distribution of monocyte-derived macrophages (MDMs), its correlation with MDM lipid content, and relation to blood lipoprotein densities are not well understood. Of particular interest is the balance between low density lipoproteins (LDL) and high density lipoproteins (HDL), which carry bad and good cholesterol respectively. To address these issues, we have developed a mathematical model for early atherosclerosis in which the MDM population is structured by phenotype and lipid content. The model admits a simpler, closed subsystem whose analysis shows how lesion composition becomes more pathological as the blood density of LDL increases relative to the HDL capacity. We use asymptotic analysis to derive a power-law relationship between MDM phenotype and lipid content at steady-state. This relationship enables us to understand why, for example, lipid-laden MDMs have a more inflammatory phenotype than lipid-poor MDMs when blood LDL lipid density greatly exceeds HDL capacity. We show further that the MDM phenotype distribution always attains a local maximum, while the lipid content distribution may be unimodal, adopt a quasi-uniform profile or decrease monotonically. Pathological lesions exhibit a local maximum in both the phenotype and lipid content MDM distributions, with the maximum at an inflammatory phenotype and near the lipid content capacity respectively. These results illustrate how macrophage heterogeneity arises in early atherosclerosis and provide a framework for future model validation through comparison with single-cell RNA sequencing data.


Assuntos
Aterosclerose , Lipoproteínas HDL , Lipoproteínas LDL , Macrófagos , Conceitos Matemáticos , Fenótipo , Humanos , Macrófagos/metabolismo , Macrófagos/patologia , Aterosclerose/patologia , Aterosclerose/metabolismo , Aterosclerose/sangue , Lipoproteínas LDL/metabolismo , Lipoproteínas LDL/sangue , Lipoproteínas HDL/sangue , Lipoproteínas HDL/metabolismo , Modelos Cardiovasculares , Metabolismo dos Lipídeos , Lipoproteínas/metabolismo , Lipoproteínas/sangue , Simulação por Computador
9.
Discov Med ; 36(187): 1678-1691, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39190383

RESUMO

BACKGROUND: Remodeling of vascular smooth muscle cells (VSMCs), as a pathological hallmark of cardiovascular diseases, is related to the molecular rewiring of Calcium signaling, which induces upregulation of stromal interaction molecule (STIM) proteins. This study analyzed the influence of STIM1 proteins on the remodeling of VSMCs in atherosclerosis (AS). METHODS: After oxidized low-density lipoprotein (ox-LDL) treatment and transfection, VSMC viability, migration, and invasion were separately measured using Cell Counting Kit-8, Scratch assay, and Transwell assay. An animal AS model was constructed, and histological analysis via hematoxylin-eosin staining was conducted on the aorta. RESULTS: Ox-LDL promoted expression of STIM1 and Orai calcium release-activated calcium modulator 1 (Orai1). STIM1 or Orai1 downregulation suppressed viability, migration, invasion, and phenotypic switching of ox-LDL-treated VSMCs, whereas STIM1 or Orai1 upregulation had opposite effects. Orai1 level was upregulated by STIM1 overexpression. Orai1 silencing reversed the effects of STIM1 overexpression in VSMCs. STIM1 deficiency alleviated AS and regulated expression of Orai1 and phenotypic switch-related factors in vivo. CONCLUSION: STIM1 deficiency suppresses viability, migration, invasion, and phenotypic switching of ox-LDL-induced VSMCs and alleviates AS by inhibiting Orai1.


Assuntos
Aterosclerose , Movimento Celular , Lipoproteínas LDL , Músculo Liso Vascular , Miócitos de Músculo Liso , Proteína ORAI1 , Molécula 1 de Interação Estromal , Animais , Humanos , Masculino , Camundongos , Aterosclerose/patologia , Aterosclerose/metabolismo , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Lipoproteínas LDL/metabolismo , Músculo Liso Vascular/patologia , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/genética , Proteína ORAI1/metabolismo , Proteína ORAI1/genética , Proteína ORAI1/antagonistas & inibidores , Molécula 1 de Interação Estromal/metabolismo , Molécula 1 de Interação Estromal/genética , Remodelação Vascular/efeitos dos fármacos
10.
PeerJ ; 12: e17915, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39184397

RESUMO

Oxidized light-density lipoprotein (ox-LDL) causes endothelial dysfunction, which is an important determinant of atherogenesis, and subsequently leads to apoptosis. Atherosclerosis is one of the most significant cardiovascular diseases (CVDs) threatening human health and causes death worldwide. Recently, long noncoding RNAs (lncRNAs) have been suggested to involved in vascular biology. Ox-LDL activates nuclear factor kappa-B (NF-κB), and NF-κB interacting lncRNA (NKILA) inhibits NF-κB signaling. In this study, the hypothesis is that NKILA may regulate endothelial cell (EC) apoptosis and, therefore, play a role in the pathogenesis of atherosclerosis. This hypothesis is based on the knowledge that EC apoptosis contributes to atherosclerosis development and that NKILA has become a prominent lncRNA in CVDs. The expression of Bcl-2-associated X protein (BAX), caspase 9 (CASP9), cytochrome c (Cyt c, CYCS), apoptotic protease activating factor 1 (APAF1), and B-cell lymphoma 2 (BCL-2) genes in human umbilical vein endothelial cells (HUVEC) treated with ox-LDL and transfected with NKILA siRNA was analyzed using quantitative reverse transcription polymerase chain reaction (RT-qPCR). BAX, CASP9, CYCS, APAF1, and BCL-2 gene expression was downregulated in ox-LDL and NKILA siRNA-treated HUVEC. In addition, when threshold/quantification cycle (Cq) values of NKILA gene expression increased, Cq values of BAX, CASP9, APAF1, and BCL-2 gene expression increased statistics significantly. The expression detection of all these genes, resulting from NKILA gene silencing, may provide guidance for epigenetic studies on EC apoptosis in atherosclerosis.


Assuntos
Apoptose , Fator Apoptótico 1 Ativador de Proteases , Aterosclerose , Células Endoteliais da Veia Umbilical Humana , RNA Longo não Codificante , Humanos , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Apoptose/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Fator Apoptótico 1 Ativador de Proteases/genética , Fator Apoptótico 1 Ativador de Proteases/metabolismo , Lipoproteínas LDL/metabolismo , Caspase 9/genética , Caspase 9/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo , Citocromos c/metabolismo , Citocromos c/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Regulação da Expressão Gênica
11.
Discov Med ; 36(187): 1721-1731, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39190387

RESUMO

BACKGROUND: Hyperlipidemia is one of the main causes of aggravated hepatic ischemia-reperfusion injury (IRI). Simvastatin (SIM), a lipid-lowering drug, has been shown to effectively alleviate IRI caused by hyperlipidemia. However, the regulatory mechanism by which SIM alleviates hyperlipidemia-induced hepatic IRI is still not clear. This study aims to explore the potential mechanisms of SIM in inhibiting hyperlipidemia-induced hepatic IRI, providing new therapeutic strategies for the alleviation of hepatic IRI. METHODS: An animal model of hyperlipidemia was induced by feeding mice a high-fat diet for 8 weeks. Subsequently, a hepatic IRI animal model of hyperlipidemia was established by occluding the hepatic artery and portal vein for one hour, followed by reperfusion for 6 or 12 h. Enzyme linked immunosorbent assay, Western blotting, hematoxylin-eosin (H&E) staining, immunohistochemistry, immunofluorescence, and Terminal-deoxynucleoitidyl Transferase Mediated Nick End Labeling assay, were used to evaluate liver injury, neutrophil extracellular traps (NETs) formation, and related molecular mechanisms. RESULTS: Hepatic IRI was accelerated by hyperlipidemia, which enhanced the expression of oxidized low-density lipoprotein (oxLDL) and Macrophage-1antigen (Mac-1), leading to the promotion of NETs formation and apoptosis of liver cells. The administration of simvastatin reduced the levels of oxLDL and Mac-1, decreased the formation of NETs, and alleviated hepatic IRI induced by hyperlipidemia. CONCLUSIONS: Simvastatin reduced hyperlipidemia-induced hepatic IRI by inhibiting the formation of NETs through the regulation of the oxLDL/Mac-1 pathway.


Assuntos
Dieta Hiperlipídica , Armadilhas Extracelulares , Hiperlipidemias , Fígado , Traumatismo por Reperfusão , Sinvastatina , Animais , Sinvastatina/farmacologia , Sinvastatina/uso terapêutico , Traumatismo por Reperfusão/prevenção & controle , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Camundongos , Armadilhas Extracelulares/efeitos dos fármacos , Armadilhas Extracelulares/metabolismo , Masculino , Dieta Hiperlipídica/efeitos adversos , Fígado/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/metabolismo , Hiperlipidemias/patologia , Hiperlipidemias/complicações , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Lipoproteínas LDL/metabolismo , Transdução de Sinais/efeitos dos fármacos , Apoptose/efeitos dos fármacos
12.
Int Immunopharmacol ; 140: 112834, 2024 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-39116495

RESUMO

BACKGROUND: Atherosclerotic (AS) plaques require a dense necrotic core and a robust fibrous cap to maintain stability. While previous studies have indicated that the traditional Chinese medicine Huang Lian Jie Du Decoction (HLJDD) possesses the capability to stabilize AS plaques, the underlying mechanisms remain obscure. This study aims to delve deeper into the potential mechanisms by which HLJDD improves AS through an integrated research strategy. METHODS: Leveraging an AS model in ApoE-/- mice exposed to a high-fat diet (HFD), we scrutinized the therapeutic effects of HLJDD using microscopic observations, oil red O staining, HE staining and Masson staining. Employing comprehensive techniques of network pharmacology, bioinformatics, and molecular docking, we elucidated the mechanism by which HLJDD stabilizes AS plaques. In vitro experiments, utilizing ox-LDL-induced macrophages and apoptotic vascular smooth muscle cells (VSMCs), assessed the impact of HLJDD on efferocytosis and the role of SLC2A1. RESULTS: In vivo experiments showcased the efficacy of HLJDD in reducing the quantity of aortic plaques, diminishing lipid deposition, and enhancing plaque stability in AS mice. Employing network pharmacology and machine learning, we pinpointed SLC2A1 as a crucial regulatory target. Molecular docking further validated the binding of HLJDD components with SLC2A1. The experiments demonstrated a dose-dependent upregulation in SLC2A1 expression by HLJDD, amplifying efferocytosis. Importantly, this effect was reversed by the SLC2A1 inhibitor STF-31, highlighting the pivotal role of SLC2A1 as a target. CONCLUSION: The HLJDD can modulate macrophage efferocytosis by enhancing the expression levels of SLC2A1, thereby improving the stability of atherosclerotic plaques.


Assuntos
Medicamentos de Ervas Chinesas , Transportador de Glucose Tipo 1 , Macrófagos , Placa Aterosclerótica , Animais , Placa Aterosclerótica/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Camundongos , Masculino , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Transportador de Glucose Tipo 1/genética , Dieta Hiperlipídica , Camundongos Endogâmicos C57BL , Fagocitose/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Modelos Animais de Doenças , Apoptose/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Lipoproteínas LDL/metabolismo , Células RAW 264.7 , Camundongos Knockout para ApoE , Eferocitose
13.
Comput Biol Med ; 180: 108994, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39121680

RESUMO

Oxidized low-density lipoprotein (oxLDL) induces the formation of atherosclerotic plaques. Apolipoprotein B100 (apoB100) is a crucial protein component in low-density lipoprotein (LDL), which includes oxLDL. The oxidation of amino acids and subsequent alterations in their structure generate oxLDL, which is a significant biomarker for the initial phases of coronary artery disease. This study employed molecular docking and molecular dynamics utilizing the MM/GBSA method to identify aptamers with a strong affinity for oxidized apoB100. Molecular docking and molecular dynamics were performed on two sequences of the aptamer candidates (aptamer no.11 (AP11: 5'-CTTCGATGTAGTTTTTGTATGGGGTGCCCTGGTTCCTGCA-3') and aptamer no.26 (AP26: 5'-GCGAACTCGCGAATCCAGAACGGGCTCGGTCCCGGGTCGA-3')), yielding respective binding free energies of -149.08 kcal/mol and -139.86 kcal/mol. Interaction modeling of the simulation revealed a strong hydrogen bond between the AP11-oxidized apoB100 complexes. In an aptamer-based gold nanoparticle (AuNP) aggregation assay, AP11 exhibits a color shift from red to purple with the highest absorbance ratio, and shows strong binding affinity to oxLDL, correlating with the simulation model results. AP11 demonstrated the potential for application as a novel recognition element in diagnostic methodologies and may also contribute to future advancements in preventive therapies for coronary artery disease.


Assuntos
Apolipoproteína B-100 , Aptâmeros de Nucleotídeos , Lipoproteínas LDL , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Lipoproteínas LDL/química , Lipoproteínas LDL/metabolismo , Aptâmeros de Nucleotídeos/química , Aptâmeros de Nucleotídeos/metabolismo , Apolipoproteína B-100/química , Apolipoproteína B-100/metabolismo , Humanos , Ouro/química , Nanopartículas Metálicas/química
14.
Innate Immun ; 30(5): 82-89, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39090856

RESUMO

Cardiovascular diseases (CVDs) linked to atherosclerosis remains the leading cause of death worldwide. Atherosclerosis is primarily caused by the accumulation of oxidized forms of low density lipoprotein (LDL) in macrophages (MΦs) in the subendothelial layer of arteries leading to foam cell and fatty streak formation. Many studies suggest that LDL that is modified by myeloperoxidase (MPO) is a key player in the development of atherosclerosis. MΦs can adopt a variety of functional phenotypes that include mainly the proinflammatory M1 and the anti-inflammatory M2 MΦ phenotypes which are both implicated in the process of atherogenesis. In fact, MΦs that reside in atherosclerostic lesions were shown to express a variety of phenotypes ranging between the M1- and M2 MΦ types. Recently, we pointed out the involvement of MPO oxidized-LDL (Mox-LDL) in increasing inflammation in MΦs by reducing their secretion of IL-10. Since little is known about Mox-LDL-mediated pro-atherosclerostic responses in MΦs, our study aimed at analyzing the in vitro effects of Mox-LDL at this level through making use of the well-established model of human THP-1-derived Mφs. Our results demonstrate that Mox-LDL has no effect on apoptosis, reactive oxygen species (ROS) generation and cell death in our cell model; yet, interestingly, our results show that Mox-LDL is significantly engulfed at a higher rate in the different MΦ subtypes supporting its key role in foam cell formation during the progression of the disease as well as previous data that were generated using another primary MΦ cell model of atherosclerosis.


Assuntos
Aterosclerose , Lipoproteínas LDL , Macrófagos , Peroxidase , Espécies Reativas de Oxigênio , Humanos , Lipoproteínas LDL/metabolismo , Peroxidase/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Aterosclerose/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Apoptose , Células THP-1 , Células Espumosas/metabolismo , Interleucina-10/metabolismo , Inflamação
15.
Int J Biol Macromol ; 278(Pt 4): 134840, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39217040

RESUMO

Hen egg low-density lipoprotein (heLDL), as alternative of serum-derived LDL, was used as drug delivery system of ceftiofur (CEF). The CEF-loaded hen egg low-density lipoprotein (CEF-heLDL) with complete apolipoprotein structure and high drug loading rate was synthesized, possesses suitable particle size. CEF-heLDL undergoes cellular uptake and colocalizes with lysosomes in vitro. An intracellular infection model of the bovine endometrial epithelial cells and a coeliac-induced inflammation model of mice by Staphylococcus aureus (S. aureus) were established, and significantly lower intracellular S. aureus levels of CEF-heLDL group than CEF-free group (P < 0.001) was observed. The antibacterial efficacy was sustained for 24 h. Up to 400 mg/kg of CEF-heLDL, 20 times the clinical practice, were intraperitoneally administrated, and no significant toxicity signs on mice were observed. HeLDLs is an effective, safe, and cheap drug carrier, and could also be used for transmembrane delivering other antibiotics.


Assuntos
Antibacterianos , Cefalosporinas , Galinhas , Lipoproteínas LDL , Staphylococcus aureus , Animais , Staphylococcus aureus/efeitos dos fármacos , Lipoproteínas LDL/metabolismo , Antibacterianos/farmacologia , Antibacterianos/química , Camundongos , Cefalosporinas/farmacologia , Cefalosporinas/farmacocinética , Cefalosporinas/química , Bovinos , Feminino , Portadores de Fármacos/química , Infecções Estafilocócicas/tratamento farmacológico , Ovos
16.
Int J Mol Sci ; 25(16)2024 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-39201490

RESUMO

Atherosclerosis is a chronic inflammatory disease that involves modified low-density lipoproteins (LDL) which play a pivotal role in the initiation and progression of the disease. Myeloperoxidase oxidized LDL (Mox-LDL) is considered to be the most patho-physiologically relevant type of modified LDL and has been reported to be ubiquitously present in atheroma plaques of patients with atherosclerosis. Besides its involvement in the latter disease state, Mox-LDL has also been shown to be implicated in the pathogenesis of various illnesses including sleep disorders, which are in turn associated with heart disease and depression in many intricate ways. Meanwhile, we have recently shown that lox-1-mediated Mox-LDL signaling modulates neuroserpin activity in endothelial cells, which could have major implications that go beyond the pathophysiology of stroke and cerebrovascular disease (CD). Of note is that tissue plasminogen activator (tPA), which is the main target of neuroserpin in the brain, has a crucial function in the processing of brain-derived neurotrophic factor (BDNF) into its mature form. This factor is known to be involved in major depressive disorder (MDD) development and pathogenesis. Since tPA is more conventionally recognized as being involved in fibrinolytic mechanisms, and its effect on the BDNF system in the context of MDD is still not extensively studied, we speculate that any Mox-LDL-driven change in the activity of tPA in patients with atherosclerosis may lead to a decrease in the production of mature BDNF, resulting in impaired neural plasticity and depression. Deciphering the mechanisms of interaction between those factors could help in better understanding the potentially overlapping pathological mechanisms that regulate disease processes in CD and MDD, supporting the possibility of novel and common therapeutic opportunities for millions of patients worldwide.


Assuntos
Aterosclerose , Lipoproteínas LDL , Peroxidase , Humanos , Aterosclerose/metabolismo , Lipoproteínas LDL/metabolismo , Peroxidase/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Depressão/metabolismo , Neuroserpina , Receptores Depuradores Classe E/metabolismo , Transtorno Depressivo Maior/metabolismo
17.
Methods Mol Biol ; 2816: 223-239, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38977602

RESUMO

Lipoproteins in plasma are constituted by the least dense chylomicron, very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) that can be separated using commercially available medium such as iodixanol. Iodixanol constitutes the self-generated density gradient to fractionate lipoproteins by rapid ultracentrifugation method, replacing time-consuming protocols. Filling the centrifuge tubes is technically easier and faster than layering salt gradients and is reproducible. The separated lipoproteins by this method are closest to the native state with 80 to 100% recovery possible. Low-density lipoprotein is the major carrier of cholesterol in systemic circulation. The plasma isolated LDL is purified to be used as native LDL and for the preparation of oxidized LDL (oxLDL). The oxLDL is characterized for its oxidation, by various methods based on assay of the lipid and protein oxidation products such as TBARS, conjugated diene formation, and by other methods such as agarose gel electrophoresis. Rapid isolation of LDL particles from human plasma is useful for lipid peroxidation studies, characterization of subclass for functional studies and clinical correlation especially in cardiovascular diseases apart from lipidomic, and proteomic studies. OxLDL preparations are done in vitro chiefly based on copper-induced oxidation; glucose and other prooxidants. Which are used for various studies using animal model and in vitro cell models especially to understand macrophage-mediated atheroma formation, vascular endothelial cell dysfunction, cell signaling studies has scope for extensive research in metabolic dysfunction of various cells.  This chapter deals with one of the applications in the in vitro cell models using macrophage (THP-1 cell line) and human retinal pigment epithelial cell (ARPE-19 cell line) to study the oxLDL uptake using fluorescently labeled oxidized LDL (DiI-oxLDL).


Assuntos
Lipoproteínas LDL , Lipoproteínas LDL/metabolismo , Humanos , Oxirredução , Linhagem Celular , Células THP-1 , Ácidos Tri-Iodobenzoicos
18.
Methods Mol Biol ; 2816: 253-263, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38977604

RESUMO

Lipids are compounds involved in many biologic functions including cell structure, metabolism, energy storage and are involved in signaling. A prominent lipid in these functions is cholesterol. Cholesterol also plays a part in the signaling of melanocytes, which contain melanosomes. The maturation of these melanosomes happens during melanocyte growth. The deficit of melanogenesis or melanosome maturation is associated with ocular albinism in the eye. Aberrations of melanosome maturation are also associated with pigment dispersion syndrome. Albinism and pigment dispersion manifestations are systemic. Both melanogenesis and melanocyte maturation are affected by cholesterol metabolism. Cholesterol signaling is a part of many pathways in the body, and evaluating these signals can have implications in systemic disease processes of melanogenesis and melanosome maturation, like ocular albinism and pigment dispersion. Cholesterol is carried by lipoprotein particles. Low-density lipoprotein (LDL) is usually the transport vehicle for cholesterol to reach tissues and organelles. The LDL uptake on cells often sends out a cascade of internal signaling within the cells. We describe here LDL signaling related to lipase activity changes using enzymatic methods with a kit. We describe analyses of cholesterol esters and free cholesterol with liquid chromatography and gas chromatography with or in tandem with mass spectrometry (GC-MS and LC-MS/MS). These analyses will provide insight into melanosome maturation and melanogenesis. The methods described here are applicable to all melanocytes within the body of a model mammalian organism.


Assuntos
Colesterol , Iris , Melanócitos , Transdução de Sinais , Melanócitos/metabolismo , Humanos , Colesterol/metabolismo , Iris/metabolismo , Lipoproteínas/metabolismo , Melanossomas/metabolismo , Lipoproteínas LDL/metabolismo , Espectrometria de Massas em Tandem/métodos , Cromatografia Gasosa-Espectrometria de Massas/métodos , Cromatografia Líquida/métodos , Lipase/metabolismo , Melaninas/metabolismo , Ésteres do Colesterol/metabolismo
19.
Sci Rep ; 14(1): 15331, 2024 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-38961200

RESUMO

Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a promising therapeutic target to reduce lipids. In 2020, we reported a chimeric camelid-human heavy chain antibody VHH-B11-Fc targeting PCSK9. Recently, it was verified that VHH-B11 binds one linear epitope in the PCSK9 hinge region. To enhance its druggability, we have developed a novel biparatopic B11-H2-Fc Ab herein. Thereinto, surface plasmon resonance (SPR) confirmed the epitope differences in binding-PCSK9 among VHH-B11, VHH-H2 and the approved Repatha. Additionally, SPR revealed the B11-H2-Fc exhibits an avidity of approximately 0.036 nM for PCSK9, representing a considerable increase compared to VHH-B11-Fc (~ 0.69 nM). Moreover, we found the Repatha and B11-H2-Fc exhibited > 95% PCSK9 inhibition efficiency compared to approximately 48% for the VHH-Fc at 7.4 nM (P < 0.0005). Further, we verified its biological activity using the human hepatoma cells G2 model, where the B11-H2-Fc exhibited almost 100% efficiency in PCSK9 inhibition at only 0.75 µM. The immunoblotting results of low-density lipoprotein cholesterol (LDL-c) uptake assay also demonstrated the excellent performance of B11-H2-Fc on recovering the LDL-c receptor (LDLR), as strong as the Repatha (P > 0.05). These findings provide the first evidence of the efficacy of a novel Ab targeting PCSK9 in the field of lipid-lowering drugs.


Assuntos
Pró-Proteína Convertase 9 , Humanos , Pró-Proteína Convertase 9/metabolismo , Pró-Proteína Convertase 9/imunologia , Células Hep G2 , Inibidores de PCSK9 , Ressonância de Plasmônio de Superfície , Receptores de LDL/metabolismo , Epitopos/imunologia , Lipoproteínas LDL/metabolismo , Lipoproteínas LDL/imunologia
20.
Immunity ; 57(7): 1448-1451, 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38986438

RESUMO

Autoreactive lymphocytes that infiltrate the pancreatic islet environment and target ß cells are primary drivers of type 1 diabetes. In this issue of Immunity, Srivastava et al.1 examine the role of the islet microenvironment in autoimmunity and find that the scavenging receptor CXCL16 on islet-resident macrophages uptakes oxidized low-density lipoproteins and promotes the differentiation and survival of infiltrating pathogenic CD8+ T cells.


Assuntos
Autoimunidade , Linfócitos T CD8-Positivos , Diabetes Mellitus Tipo 1 , Ilhotas Pancreáticas , Macrófagos , Autoimunidade/imunologia , Diabetes Mellitus Tipo 1/imunologia , Ilhotas Pancreáticas/imunologia , Ilhotas Pancreáticas/metabolismo , Humanos , Animais , Macrófagos/imunologia , Macrófagos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Células Secretoras de Insulina/imunologia , Células Secretoras de Insulina/metabolismo , Lipoproteínas LDL/metabolismo , Lipoproteínas LDL/imunologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...