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1.
Journal of Southern Medical University ; (12): 232-241, 2023.
Article in Chinese | WPRIM | ID: wpr-971520

ABSTRACT

OBJECTIVE@#To study the role of apolipoprotein E (APOE) in regulating endometrial cancer metastasis and explore the signaling pathway in the regulatory mechanism.@*METHODS@#Human endometrial cancer cell line HEC-1B was transfected with a control siRNA (siCtrl) or a specific siRNA targeting APOE (siAPOE) or with either pEGFP-N1 plasmid or an APOEoverexpressing plasmid. The changes in migration, proliferation, apoptosis and cell cycle of the transfected cells were examined using wound healing assay, Transwell migration assay, MTT assay, flow cytometry, and Hoechst staining. The activity of the ERK/MMP9 signaling pathway in the transfected cells was assessed using RT-qPCR and Western blotting. The expression level of APOE in clinical specimens of endometrial cancer tissues were detected using immunohistochemistry and its correlation with differentiation of endometrial cancer tissues was analyzed.@*RESULTS@#Wound healing assay and Transwell migration assay showed that compared with those in siCtrl group, HEC-1B cells transfected with siAPOE showed significantly reduced migration ability (P < 0.05), whereas APOE overexpression significantly promoted the migration of the cells (P < 0.05). Neither APOE knockdown nor overexpression produced significant effects on HEC-1B cell proliferation as shown by MTT assay and flow cytometry. Hoechst staining revealed that transfection with siAPOE did not significantly affect apoptosis of HEC-1B cells. APOE knockdown obviously reduced and APOE overexpression enhanced ERK phosphorylation and MMP9 expression in HEC-1B cells (P < 0.05). Treatment with U0126 partially reversed the effects of APOE overexpression on ERK phosphorylation, migration and MMP9 expression in HEC-1B cells (P < 0.05). APOE is highly expressed in clinical samples of endometrial cancer tissues as compared with the adjacent tissues.@*CONCLUSION@#APOE is highly expressed in endometrial cancer tissues to promote cancer cell migration by enhancing ERK phosphorylation and MMP9 expression.


Subject(s)
Female , Humans , Matrix Metalloproteinase 9/metabolism , Cell Line, Tumor , Signal Transduction , Endometrial Neoplasms/genetics , Cell Proliferation , Apoptosis , Cell Movement , RNA, Small Interfering , Apolipoproteins E , Apolipoproteins/pharmacology
2.
China Journal of Chinese Materia Medica ; (24): 202-210, 2023.
Article in Chinese | WPRIM | ID: wpr-970515

ABSTRACT

This study aims to explore the effect of Buyang Huanwu Decoction glycosides on the inflammatory response of apolipoprotein E~(-/-)(ApoE~(-/-)) mice and RAW264.7 cells through nuclear factor kappa-B(NF-κB) signaling pathway. In the in vivo experiment, ApoE~(-/-) mice were fed with high-fat diets for 12 weeks to induce the animal model of atherosclerosis, and 75 μg·mL~(-1) oxidized low-density lipoprotein(Ox-LDL) incubated RAW264.7 cells for 24 h to establish the atherosclerosis cell model. Automatic biochemical analyzer, hematoxylin-eosin(HE) staining, enzyme-linked immunosorbent assay(ELISA), Western blot, and droplet digital polymerase chain reaction(PCR) were used to determine the blood lipid levels, aortic intimal thickness, inflammatory factor content, NF-κB pathway-related proteins, and mRNA expression levels, and evaluate arterial atherosclerotic lesions and anti-atherosclerotic mechanisms of the drug. The model of atherosclerosis was successfully established in ApoE~(-/-) mice after 12 weeks of feeding with high-fat diets. In the model group, the plasma levels of total cholesterol(TC), triglyceride(TG), and low-density lipoprotein cholesterol(LDL-C) were increased(P<0.01), the intima of the blood vessels was thickened, the levels of inflammatory factors tumor necrosis factor-α(TNF-α) and interleukin-6(IL-6) were increased, and the protein and mRNA expressions of NF-κB and inhibitor of NF-κB(IκBα) were significantly increased as compared with the control group. Compared with the model group, the high-dose Buyang Huanwu Decoction glycoside group decreased the plasma levels of TC, TG, and LDL-C, reduced the plaque area and thickness and the content of inflammatory factor TNF-α, and inhibited the protein and mRNA expressions of NF-κB and IκBα, with the effect same as Buyang Huanwu Decoction. In the in vivo experiment, 75 μg·mL~(-1) Ox-LDL stimulated RAW264.7 cells for 24 h to successfully establish a foam cell model. As compared with the control group, the nuclear amount of NF-κB and the protein and mRNA expressions of IκBα in the model group increased. Compared with the model group, the middle-dose and high-dose Buyang Huanwu Decoction glycoside groups decreased the nuclear amount of NF-κB and the protein and mRNA expressions of IκBα. The above results show that the glycosides are the main effective substances of Buyang Huanwu Decoction against atherosclerosis, which inhibit the NF-κB pathway and reduce the inflammatory response, thus playing the role against atherosclerotic inflammation same as Buyang Huanwu Decoction.


Subject(s)
Mice , Animals , NF-kappa B/metabolism , NF-KappaB Inhibitor alpha/metabolism , Tumor Necrosis Factor-alpha/metabolism , Glycosides/pharmacology , Cholesterol, LDL , Atherosclerosis/genetics , Signal Transduction , Inflammation/drug therapy , Interleukin-6 , Apolipoproteins E/pharmacology , RNA, Messenger/metabolism
3.
China Journal of Chinese Materia Medica ; (24): 465-471, 2023.
Article in Chinese | WPRIM | ID: wpr-970483

ABSTRACT

The present study observed the regulatory effect of total flavonoids of Ziziphora clinopodioides on autophagy and the phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt)/mammalian target of rapamycin(mTOR) signaling pathways in ApoE~(-/-) mice and explored the mechanism of total flavonoids of Z. clinopodioides against atherosclerosis(AS). ApoE~(-/-) mice were fed on a high-fat diet for eight weeks to induce an AS model. The model mice were randomly divided into a model group, a positive control group, and low-, medium-and high-dose groups of total flavonoids of Z. clinopodioides, while C57BL/6J mice fed on a common diet were assigned to the blank group. The serum and aorta samples were collected after intragastric administration for 12 weeks, and the serum levels of total cholesterol(TC), triglyceride(TG), low density lipoprotein-cholesterol(LDL-C), and high density lipoprotein-cholesterol(HDL-C) were detected by an automatic biochemical analyzer. The serum expression levels of intercellular adhesion molecule-1(ICAM-1), vascular cell adhesion molecule-1(VCAM-1), matrix metalloproteinase-2(MMP-2), and matrix metalloprotei-nase-9(MMP-9) were detected by enzyme-linked immunosorbent assay(ELISA). Oil red O staining was used to observe the aortic plaque area in mice. Hematoxylin-eosin(HE) staining was used to observe the aortic plaque and pathological changes in mice. The expression of P62 and LC3 in the aorta was detected by the immunofluorescence method. The protein expression of LC3Ⅱ/Ⅰ, Beclin-1, P62, p-PI3K, p-Akt, and p-mTOR in the aorta of mice was detected by Western blot. The results showed that compared with the blank group, the serum levels of TC, TG, LDL-C, ICAM-1, VCAM-1, MMP-2 and MMP-9 in the model group were significantly increased(P<0.01 or P<0.05), the content of HDL-C was decreased(P<0.05), intra-aortic plaque area was enlarged(P<0.01), the expression of LC3 in the aorta was significantly down-regulated, P62 expression was up-regulated(P<0.01 or P<0.05), the expressions of LC3Ⅱ/Ⅰ and Beclin-1 in the aortic lysate were significantly down-regulated, and the expressions of p-PI3K, p-Akt, p-mTOR and P62 were significantly increased(P<0.01). The medium-and high-dose groups of total flavonoids of Z. clinopodioides could reduce the serum levels of TC, TG, LDL-C, ICAM-1, VCAM-1, MMP-2, and MMP-9 in AS model mice(P<0.01 or P<0.05), and increase the content of HDL-C(P<0.01 or P<0.05). The aortic plaque area of mice after middle and high doses of total flavonoids of Z. clinopodioides was significantly reduced(P<0.01), the content of foam cells decrease, and the narrowing of the lumen decreased. The total flavonoids of Z. clinopodioides significantly increased the expression of LC3 in the aorta and the expression of LC3Ⅱ/Ⅰ and Beclin-1 in the lysate, and decreased the expression of P62 in the aorta and the expression of p-PI3K, p-Akt, p-mTOR and P62 in the lysate(P<0.01 or P<0.05). The results showed that the total flavonoids of Z. clinopodioides could improve the content of blood lipids and inflammatory factors, and reduce the generation of foam cells and plaques in aortic tissue, and the mechanism may be related to the regulation of PI3K/Akt/mTOR signaling pathway.


Subject(s)
Animals , Mice , Apolipoproteins E , Atherosclerosis/genetics , Beclin-1 , Cholesterol, LDL , Intercellular Adhesion Molecule-1 , Matrix Metalloproteinase 2/genetics , Matrix Metalloproteinase 9/genetics , Mice, Inbred C57BL , Phosphatidylinositol 3-Kinases/metabolism , Plaque, Atherosclerotic , Proto-Oncogene Proteins c-akt/metabolism , TOR Serine-Threonine Kinases/genetics , Vascular Cell Adhesion Molecule-1/genetics
4.
Chinese journal of integrative medicine ; (12): 1121-1132, 2023.
Article in English | WPRIM | ID: wpr-1010316

ABSTRACT

OBJECTIVE@#To interpret the pharmacology of quercetin in treatment of atherosclerosis (AS).@*METHODS@#Fourteen apolipoprotein E-deficient (ApoE-/-) mice were divided into 2 groups by a random number table: an AS model (ApoE-/-) group and a quercetin treatment group (7 in each). Seven age-matched C57 mice were used as controls (n=7). Quercetin [20 mg/(kg·d)] was administered to the quercetin group intragastrically for 8 weeks for pharmacodynamic evaluation. Besides morphological observation, the distribution of CD11b, F4/80, sirtuin 1 (Sirt1) and P21 was assayed by immunohistochemistry and immunofluorescence to evaluate macrophage infiltration and tissue senescence. Ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MSC/MS) was performed to study the pharmacology of quercetin against AS. Then, simultaneous administration of an apelin receptor antagonist (ML221) with quercetin was conducted to verify the possible targets of quercetin. Key proteins in apelin signaling pathway, such as angiotensin domain type 1 receptor-associated proteins (APJ), AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), tissue plasminogen activator (TPA), uncoupling protein 1 (UCP1) and angiotensin II receptor 1 (AT1R), were assayed by Western blot.@*RESULTS@#Quercetin administration decreased lipid deposition in arterial lumen and improved the morphology of ApoE-/- aortas in vivo. Quercetin decreased the densities of CD11b, F4/80 and P21 in the aorta and increased the level of serum apelin and the densities of APJ and Sirt1 in the aorta in ApoE-/- mice (all P<0.05). Plasma metabolite profiling identified 118 differential metabolites and showed that quercetin affected mainly glycerophospholipids and fatty acyls. Bioinformatics analysis suggested that the apelin signaling pathway was one of the main pathways. Quercetin treatment increased the protein expressions of APJ, AMPK, PGC-1α, TPA and UCP1, while decreased the AT1R level (all P<0.05). After the apelin pathway was blocked by ML221, the effect of quercetin was abated significantly, confirming that quercetin attenuated AS by modulating the apelin signaling pathway (all P<0.05).@*CONCLUSION@#Quercetin alleviated AS lesions by up-regulation the apelin signaling pathway.


Subject(s)
Mice , Animals , Apelin , Tissue Plasminogen Activator/metabolism , Quercetin/therapeutic use , AMP-Activated Protein Kinases/metabolism , Sirtuin 1/metabolism , Signal Transduction/physiology , Atherosclerosis/metabolism , Apolipoproteins E
5.
Chinese Medical Journal ; (24): 1291-1299, 2023.
Article in English | WPRIM | ID: wpr-980925

ABSTRACT

Triggering receptor expressed on myeloid cells 2 (TREM2) is a membrane receptor on myeloid cells and plays an important role in the body's immune defense. Recently, TREM2 has received extensive attention from researchers, and its activity has been found in Alzheimer's disease, neuroinflammation, and traumatic brain injury. The appearance of TREM2 is usually accompanied by changes in apolipoprotein E (ApoE), and there has been a lot of research into their structure, as well as the interaction mode and signal pathways involved in them. As two molecules with broad and important roles in the human body, understanding their correlation may provide therapeutic targets for certain diseases. In this article, we reviewed several diseases in which TREM2 and ApoE are synergistically involved in the development. We further discussed the positive or negative effects of the TREM2-ApoE pathway on nervous system immunity and inflammation.


Subject(s)
Humans , Alzheimer Disease/metabolism , Apolipoproteins E/genetics , Microglia/metabolism , Myeloid Cells/metabolism , Signal Transduction , Neuroinflammatory Diseases
6.
China Journal of Chinese Materia Medica ; (24): 4164-4172, 2023.
Article in Chinese | WPRIM | ID: wpr-1008613

ABSTRACT

The study aims to observe the effects and explore the mechanisms of Buyang Huanwu Decoction and Astragali Radix-Angelicae Sinensis Radix combination in the treatment of the inflammatory response of mice with atherosclerosis(AS) via the Toll-like receptor 4(TLR4)/myeloid differentiation primary response protein 88(MyD88)/nuclear factor-κB(NF-κB) signaling pathway. Male ApoE~(-/-) mice were randomly assigned into a model group, a Buyang Huanwu Decoction group, an Astragali Radix-Angelicae Sinensis Radix combination group, and an atorvastatin group, and male C57BL/6J mice of the same weeks old were used as the control group. Other groups except the control group were given high-fat diets for 12 weeks to establish the AS model, and drugs were administrated by gavage. Aortic intimal hyperplasia thickness, blood lipid level, plasma inflammatory cytokine levels, M1/M2 macrophage markers, and expression levels of proteins in TLR4/MyD88/NF-κB pathway in the vessel wall were measured to evaluate the effects of drugs on AS lesions and inflammatory responses. The results showed that the AS model was successfully established with the ApoE~(-/-) mice fed with high-fat diets. Compared with the control group, the model group showed elevated plasma total cholesterol(TC), triglyceride(TG), and low-density lipoprotein cholesterol(LDL-c) levels(P<0.05), thickened intima(P<0.01), and increased plasma tumor necrosis factor-α(TNF-α) and interleukin-6(IL-6) levels(P<0.01). Moreover, the model group showed increased expression of vascular cell adhesion molecule-1(VCAM-1) and inducible nitric oxide synthase(iNOS)(P<0.01), inhibited expression of endothelial nitric oxide synthase(eNOS) and cluster of differentiation 206(CD206)(P<0.01), and up-regulated mRNA and protein levels of TLR4, MyD88, NF-κB inhibitor alpha(IκBα), and NF-κB in the vessel wall(P<0.05). Compared with the model group, Buyang Huanwu Decoction and Astragali Radix-Angelicae Sinensis Radix combination lowered the plasma TC and LDL-c levels(P<0.01), alleviated the intimal hyperplasia(P<0.01), and reduced the plasma TNF-α and IL-6 levels(P<0.05). Moreover, the two interventions promoted the expression of eNOS and CD206(P<0.05), inhibited the expression of VCAM-1 and iNOS(P<0.01), and down-regulated the mRNA and protein levels of TLR4, MyD88, IκBα, and NF-κB(P<0.05) in the vessel wall. This study indicated that Buyang Huanwu Decoction and Astragali Radix-Angelicae Sinensis Radix combination could delay the progression of AS, inhibit the polarization of vascular wall macrophages toward M1 type, and attenuate vascular inflammatory response by inhibiting the activation of TLR4/MyD88/NF-κB signaling pathway in the vascular wall. Astragali Radix and Angelicae Sinensis Radix were the main pharmacological substances in Buyang Huanwu Decoction for alleviating the AS vascular inflammatory response.


Subject(s)
Mice , Male , Animals , NF-kappa B/metabolism , Toll-Like Receptor 4/metabolism , NF-KappaB Inhibitor alpha/metabolism , Tumor Necrosis Factor-alpha/metabolism , Interleukin-6/metabolism , Myeloid Differentiation Factor 88/metabolism , Vascular Cell Adhesion Molecule-1/metabolism , Cholesterol, LDL , Hyperplasia , Mice, Inbred C57BL , Atherosclerosis/genetics , Apolipoproteins E/therapeutic use , RNA, Messenger
7.
Chinese Journal of Preventive Medicine ; (12): 280-286, 2022.
Article in Chinese | WPRIM | ID: wpr-935282

ABSTRACT

Objective: To explore the correlation of serum lipids levels of Alzheimer's disease (AD) patients with sex, age and apolipoprotein E (Apo E) gene polymorphism. Methods: The retrospective study method was used, and 407 AD patients (142 males and 265 females, aged 52-91 years) were selected from Beijing Tiantan Hospital from January 2015 to August 2021 as the research target, and 894 healthy persons (339 males and 555 females, aged 52-94 years) who did body examination were selected as the control group. The AD patients were divided into four age groups according to the age interval of 10 years, including 85 aged 50-59 years, 163 aged 60-69 years, 119 aged 70-79 years, and 40 aged more than 80 years. The serum lipids levels were detected by biochemical analyzer, including triglycerides (TG), cholesterol (CHO), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), apolipoproteinA1(Apo A1) and apolipoprotein B (Apo B). ApoE gene polymorphism were detected by PCR fluorescent probe method. Mann-Whitney U test and Kruskal-Wallis H test were used to compare the serum lipids levels in each group. Results: The levels of serum CHO and LDL-C were 3.30(1.41,4.82) mmol/L and 1.76(1.39,2.78) mmol/L in AD patients, and 4.84(4.24, 5.56) mmol/L and 2.91(2.36, 3.57) mmol/L in control group, and the levels of serum CHO and LDL-C of AD patients were significantly lower than control group (Z=-15.172,Z=-14.583 , P<0.001, P<0.001). The levels of serum HDL-C and Apo B were 1.84(1.30, 3.88) mmol/L and 1.17(0.85, 1.57) g/L in AD patients, and 1.39(1.18, 1.64) mmol/L and 0.93(0.81, 1.09) g/L in control group, and the levels of serum HDL-C and Apo-B of AD patients were significantly higher than control group (Z=-12.249 , Z=-9.706 , P<0.001, P<0.001). There was no significant difference in TG and Apo A1 between 2 groups (Z=-1.577 , Z=-0.408 , P=0.115, P=0.683). The levels of TG, CHO, LDL-C in female AD patients were significantly higher than male patients (Z=-2.737 , Z=-3.963 , Z=-4.417, P=0.006, P<0.001, P<0.001). There were significant differences in TG, CHO, HDL-C, LDL-C, Apo A1 and Apo B among AD patients of all age groups (Z=11.263 , Z=10.060 , Z=40.246 , Z=10.451 , Z=24.315 , Z=19.922 , P=0.010 , P=0.018 , P<0.001 , P=0.015 , P<0.001 , P<0.001). The serum CHO and LDL-C levels were positively correlated with age (rs=0.160, rs=0.174, P=0.001, P<0.001), and HDL-C, Apo A1 and Apo B levels were negatively correlated with age (rs=-0.312, rs=-0.272, rs=-0.146, P<0.001, P<0.001, P=0.003), and there was no correlation between TG level and age in AD patients (rs=0.086, P=0.082). There were 3 cases (3.33%) of E2, 43 cases of E3 (47.78%) and 44 cases of E4 (48.89%) in AD patients, and 22 cases (12.72%) of E2, 117 cases of E3 (67.63%) and 34 cases of E4 (19.65%) in control group. There was significant difference in Apo E genotype distribution between AD patients and control group (χ²=26.381 , P<0.001). Apo E4 was the most common genotype in AD patients, and the proportion was 48.89%. Except for Apo A1(Z=7.821 , P=0.020), there was no significant difference in TG, CHO, HDL-C, LDL-C and Apo B levels among all patients with different genotypes (Z=3.732 , Z=1.677 , Z=1.455 , Z=1.619 , Z=2.202 , P=0.155, P=0.432, P=0.483, P=0.445, P=0.333). Conclusion: The levels of CHO and LDL-C decreased while the levels of HDL-C and Apo B increased in AD patients. The dyslipidemia in AD patients might be correlated with age, but not sex and Apo E genotypes.


Subject(s)
Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Alzheimer Disease/genetics , Apolipoproteins E/genetics , Cholesterol, HDL/blood , Polymorphism, Genetic , Retrospective Studies , Triglycerides/blood
8.
Journal of Southern Medical University ; (12): 330-337, 2022.
Article in Chinese | WPRIM | ID: wpr-936320

ABSTRACT

OBJECTIVE@#To investigate the effects of Bax inhibitor 1 (BI- 1) and optic atrophy protein 1 (OPA1) on vascular calcification (VC).@*METHODS@#Mouse models of VC were established in ApoE-deficient (ApoE-/-) diabetic mice by high-fat diet feeding for 12 weeks followed by intraperitoneal injections with Nε-carboxymethyl-lysine for 16 weeks. ApoE-/- mice (control group), ApoE-/- diabetic mice (VC group), ApoE-/- diabetic mice with BI-1 overexpression (VC + BI-1TG group), and ApoE-/- diabetic mice with BI-1 overexpression and OPA1 knockout (VC+BI-1TG+OPA1-/- group) were obtained for examination of the degree of aortic calcification using von Kossa staining. The changes in calcium content in the aorta were analyzed using ELISA. The expressions of Runt-related transcription factor 2 (RUNX2) and bone morphogenetic protein 2 (BMP-2) were detected using immunohistochemistry, and the expression of cleaved caspase-3 was determined using Western blotting. Cultured mouse aortic smooth muscle cells were treated with 10 mmol/L β-glycerophosphate for 14 days to induce calcification, and the changes in BI-1 and OPA1 protein expressions were examined using Western blotting and cell apoptosis was detected using TUNEL staining.@*RESULTS@#ApoE-/- mice with VC showed significantly decreased expressions of BI-1 and OPA1 proteins in the aorta (P=0.0044) with obviously increased calcium deposition and expressions of RUNX2, BMP-2 and cleaved caspase-3 (P= 0.0041). Overexpression of BI-1 significantly promoted OPA1 protein expression and reduced calcium deposition and expressions of RUNX2, BMP-2 and cleaved caspase-3 (P=0.0006). OPA1 knockdown significantly increased calcium deposition and expressions of RUNX2, BMP-2 and cleaved caspase-3 in the aorta (P=0.0007).@*CONCLUSION@#BI-1 inhibits VC possibly by promoting the expression of OPA1, reducing calcium deposition and inhibiting osteogenic differentiation and apoptosis of the vascular smooth muscle cells.


Subject(s)
Animals , Mice , Apolipoproteins E/metabolism , Calcium/metabolism , Caspase 3/metabolism , Cells, Cultured , Core Binding Factor Alpha 1 Subunit/metabolism , Diabetes Mellitus, Experimental/pathology , GTP Phosphohydrolases/metabolism , Membrane Proteins/metabolism , Mice, Knockout , Muscle, Smooth, Vascular/pathology , Myocytes, Smooth Muscle/pathology , Optic Atrophy, Autosomal Dominant/pathology , Osteogenesis , Vascular Calcification/pathology , bcl-2-Associated X Protein/metabolism
9.
Chinese Journal of Medical Genetics ; (6): 94-98, 2022.
Article in Chinese | WPRIM | ID: wpr-928370

ABSTRACT

OBJECTIVE@#To assess the influence of apolipoprotein E (ApoE) gene polymorphisms on the therapeutic effect of lipid-lowering statins in patients with ischemic cerebral infarction.@*METHODS@#One hundred and six patients with ischemic cerebral infarction who orally took lipid-lowering statins for 3 months were enrolled. Changes in serum triacylglycerol (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) before and after the drug administration were analyzed. ApoE gene polymorphisms were detected by real-time fluorescent quantitative PCR, and genotypes of ApoE gene in patients with different effects were compared.@*RESULTS@#The detection rates for E2/E2, E2/E3, E3/E3, E2/E4 and E3/E4 genotypes were 0.94%, 11.32%, 63.21%, 1.89% and 22.64%, respectively. And the detection rates for E2, E3 and E4 alleles were 7.55%, 80.19% and 12.26%, respectively. Biochemical phenotypes included E2 type (13 cases, 12.26%), E3 type (69 cases, 65.09%) and E4 type (24 cases, 22.65%). Before administration, TG and TC of E2 type were the highest (P<0.05), but no significant difference was detected in HDL-C and LDL-C among the three phenotypes (P>0.05).Following the drug administration, TG, TC and LDL-C were decreased, while HDL-C was increased. HDL-C of E2 type was the highest, TC and LDL-C of E4 type were the highest (P<0.05). The E3/E3 ratio in low-efficiency group at admission was lower than that in the high-efficiency group, while the E3/E4 ratio was higher than that in the high-efficiency group (P<0.05). The proportion of E3 allele in low-efficiency group was lower than that in high-efficiency group, while the proportion of E4 allele was higher than that in high-efficiency group (P<0.05).@*CONCLUSION@#ApoE gene polymorphisms are closely correlated with the therapeutic effect of lipid-lowering statins in patients with ischemic cerebral infarction. The lipid-lowering effects are more significant in patients with E2 and E3 genotypes, but were poor in those with the E4 genotype. Personalized regimens should be applied.


Subject(s)
Humans , Apolipoproteins E/genetics , Cerebral Infarction/genetics , Genotype , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Lipids , Polymorphism, Genetic , Triglycerides
10.
Neuroscience Bulletin ; (6): 809-819, 2022.
Article in English | WPRIM | ID: wpr-939834

ABSTRACT

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease featuring progressive cognitive impairment. Although the etiology of late-onset AD remains unclear, the close association of AD with apolipoprotein E (APOE), a gene that mainly regulates lipid metabolism, has been firmly established and may shed light on the exploration of AD pathogenesis and therapy. However, various confounding factors interfere with the APOE-related AD risk, raising questions about our comprehension of the clinical findings concerning APOE. In this review, we summarize the most debated factors interacting with the APOE genotype and AD pathogenesis, depict the extent to which these factors relate to APOE-dependent AD risk, and discuss the possible underlying mechanisms.


Subject(s)
Humans , Alzheimer Disease/pathology , Apolipoprotein E4/genetics , Apolipoproteins E/genetics , Genotype , Lipid Metabolism , Neurodegenerative Diseases , Risk Factors
11.
Chinese journal of integrative medicine ; (12): 509-517, 2022.
Article in English | WPRIM | ID: wpr-939770

ABSTRACT

OBJECTIVE@#To detect whether Danlou Tablet (DLT) regulates the hypoxia-induced factor (HIF)-1α-angiopoietin-like 4 (Angptl4) mRNA signaling pathway and explore the role of DLT in treating chronic intermittent hypoxia (CIH)-induced dyslipidemia and arteriosclerosis.@*METHODS@#The mature adipocytes were obtained from 3T3-L1 cell culturation and allocated into 8 groups including control groups (Groups 1 and 5, 0.1 mL of cell culture grade water); DLT groups (Groups 2 and 6, 0.1 mL of 1,000 µg/mL DLT submicron powder solution); dimethyloxalylglycine (DMOG) groups (Groups 3 and 7, DMOG and 0.1 mL of cell culture grade water); DMOG plus DLT groups (Groups 4 and 8, DMOG and 0.1 mL of 1,000 µg/mL DLT submicron powder solution). Groups 1-4 used mature adipocytes and groups 5-8 used HIF-1 α-siRNA lentivirus-transfected mature adipocytes. After 24-h treatment, real-time polymerase chain reaction and Western blot were employed to determine the mRNA and protein expression levels of HIF-1 α and Angptl4. In animal experiments, the CIH model in ApoE-/- mice was established. Sixteen mice were complete randomly divided into 4 groups including sham group, CIH model group [intermittent hypoxia and normal saline (2 mL/time) gavage once a day]; Angptl4 Ab group [intermittent hypoxia and Angptl4 antibody (30 mg/kg) intraperitoneally injected every week]; DLT group [intermittent hypoxia and DLT (250 mg/kg) once a day], 4 mice in each group. After 4-week treatment, enzyme linked immunosorbent assay was used to detect the expression levels of serum total cholesterol (TC) and triglyceride (TG). Hematoxylin-eosin and CD68 staining were used to observe the morphological properties of arterial plaques.@*RESULTS@#Angptl4 expression was dependent on HIF-1 α, with a reduction in mRNA expression and no response in protein level to DMOG or DLT treatment in relation to siHIF-1 α -transfected cells. DLT inhibited HIF-1 α and Angptl4 mRNA expression (P<0.05 or P<0.01) and reduced HIF-1 α and Angptl4 protein expressions with DMOG in mature adipocytes (all P<0.01), as the effect on HIF-1 α protein also existed in the presence of siHIF-1 α (P<0.01). ApoE-/- mice treated with CIH had increased TG and TC levels (all P<0.01) and atherosclerotic plaque. Angptl4 antibody and DLT both reduce TG and TC levels (all P<0.01), as well as reducing atherosclerotic plaque areas, narrowing arterial wall thickness and alleviating atherosclerotic lesion symptoms to some extent.@*CONCLUSION@#DLT had positive effects in improving dyslipidemia and arteriosclerosis by inhibiting Angptl4 protein level through HIF-1 α-Angptl4 mRNA signaling pathway.


Subject(s)
Animals , Mice , Angiopoietin-Like Protein 4/genetics , Apolipoproteins E , Atherosclerosis/metabolism , Drugs, Chinese Herbal , Dyslipidemias/genetics , Hypoxia/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Plaque, Atherosclerotic , Powders , RNA, Messenger/genetics , Signal Transduction , Triglycerides , Water
12.
Acta cir. bras ; 36(1): e360105, 2021. graf
Article in English | LILACS | ID: biblio-1152695

ABSTRACT

ABSTRACT Purpose To investigate the relationship between atherosclerotic abdominal aortic aneurysm (AAA) and CXC chemokine receptor type 2 (CXCR2). Methods Mouse AAA model was established by embedding angiotensin-II pump (1000 ng/kg/min) in ApoE-/- mice. Mice were received SB225002, a selective CXCR2 antagonist, for treatment. Blood pressure was recorded, and CXCR2+ macrophages were examined by flow cytometry analysis. Terminal-deoxynucleotidyl transferase mediated nick end labeling (TUNEL) staining was performed to detect cell apoptosis of abdominal aortic aneurysms. Macrophages were isolated from ApoE-/- mice and treated with Ang II and/or SB225002. Dihydroethidium staining was carried out to determine reactive oxygen species (ROS) activity. Enzyme-linked immunosorbent assay (ELISA) was performed to determine the production of IL-1β and TNF-α. The corresponding gene expressions were measured using real-time polymerase chain reaction (PCR), western blot, and immunohistochemistry staining. Results We found that Ang II activated the expression of CXCR2 in monocytes during the formation of AAA. Inhibition of CXCR2 significantly reduced the size of AAA, attenuated inflammation and phenotypic changes in blood vessels. Ang II-induced macrophages exhibited elevated ROS activity, and elevated levels of 1β and TNF-α, which were then partly abolished by SB225002. Conclusions CXCR2 plays an important role in AAA, suggesting that inhibiting CXCR2 may be a new treatment for AAA.


Subject(s)
Animals , Mice , Aortic Aneurysm, Abdominal/prevention & control , Aortic Aneurysm, Abdominal/drug therapy , Apolipoproteins E/genetics , Angiotensin II , Receptors, Interleukin-8B , Disease Models, Animal , Macrophages , Mice, Inbred C57BL
13.
Repert. med. cir ; 30(2): 134-141, 2021. tab.
Article in English, Spanish | LILACS, COLNAL | ID: biblio-1362701

ABSTRACT

Introducción: la apolipoproteína E (APOE) es una glicoproteína implicada en el transporte de moléculas lipídicas. Se han descrito tres alelos del gen APOE: Ɛ2, Ɛ3 y Ɛ4. Varios estudios demuestran asociación de la isoforma APOE4 con Alzheimer de inicio tardío. Objetivos: determinar las frecuencias genotípicas y alélicas del gen APOE en una muestra de adultos en Bogotá. Materiales y métodos: estudio observacional descriptivo de corte transversal. A partir de una muestra de sangre periférica se extrajo ADN genómico y se realizó PCR-Tetraprimer para la determinación de los alelos de APOE. Resultados: se incluyeron 1.254 sujetos, 942 mujeres (75%) y 312 hombres (25%) con edades entre 40 y 100 años. El alelo más frecuente fue el Ɛ3 (85%), seguido por Ɛ4 (11%) y Ɛ2 (2%). De la población que manifestó tener ascendencia cundiboyacense, 567 sujetos (74.6%) presentaban el genotipo Ɛ3/Ɛ3, mientras que 156 (20.4%) el Ɛ3/Ɛ4, 23 (3%) el Ɛ2/Ɛ3, 11 (1.5%) el Ɛ4/Ɛ4y 4 (0.5%) el Ɛ2/Ɛ4. Los individuos con genotipoƐ2/Ɛ2 manifestaron no conocer el dato de ascendencia. Conclusiones: las frecuencias alélicas y genotípicas de APOE varían según el origen étnico, sin embargo es posible la identificación de sujetos con el genotipo menos frecuente (Ɛ2/Ɛ2) al analizar muestras de mayor tamaño. En los reportes previos en el país no se ha descrito el genotipo Ɛ2/Ɛ2, el cual fue identificado en la presente muestra como el de menor proporción.


Introduction:apolipoprotein E (APOE) is a glycoprotein involved in the transport of lipid molecules. Three alleles of the APOE gene have been described: Ɛ2, Ɛ3 and Ɛ4. Several studies show an association of the APOE isoform with late-onset Alzheimer ́s disease. Objectives: to determine the genotypic and allelic frequencies of the APOE gene in an adult sample in Bogotá. Materials and Methods: a cross-sectionalobservational descriptive study. Genomic DNA was extracted from a peripheral blood sample and APOE alleles and genotypes were determined using the PCR tetra-primer method. Results:we included 1254 subjects, 942 women (75%) and 312 men (25%) aged between 40 and 100 years. The most frequent allele was Ɛ3 (85%), followed by Ɛ4 (11%) and Ɛ2 (2%). Of the population that declared to have Cundinamarca and Boyacá sub-regions ancestry, 567 subjects (74.6%) had genotype Ɛ3/Ɛ3, while 156 (20.4%) hadƐ3/Ɛ4, 23 (3%) Ɛ2/Ɛ3, 11 (1.5%) Ɛ4/Ɛ4and 4 (0.5%) had genotype Ɛ2/Ɛ4.The individuals with genotype Ɛ2/Ɛ2 declared not to know the data on their ancestry. Conclusions: the allelic and genotypic frequencies of APOE vary according to ethnic origin. However identifying subjects with the less frequent genotype (Ɛ2/Ɛ2) is possible when analyzing larger samples. In previous reports in the country, genotype Ɛ2/Ɛ2, has not been described and was identified in the present sample as the one with the lowest proportion.


Subject(s)
Humans , Male , Female , Middle Aged , Apolipoproteins E , Polymerase Chain Reaction , Alzheimer Disease , Protein Isoforms
14.
Braz. j. med. biol. res ; 54(2): e10098, 2021. tab, graf
Article in English | LILACS, ColecionaSUS | ID: biblio-1142576

ABSTRACT

We aimed to present an overview of the literature regarding the interaction between physical exercise and APOE gene polymorphism on cognitive function, particularly in patients with Alzheimer's disease (AD). Firstly, this review focused on the effect of the physical exercise on cognitive function, regardless of APOE gene polymorphism. Some studies have shown that a high level of cardiorespiratory fitness is associated with less neuronal damage with an improvement in memory score tests whereas other studies failed to detect any association between physical exercise and cognitive improvement either in healthy individuals or patients with AD. Taken together, standardized protocols and more longitudinal studies are required to provide a better insight into the effects of physical exercise on cognitive function. Although there is no agreement in the literature regarding the effects of physical exercise on cognitive function, it is well established that it improves social interaction and the feeling of well-being, thereby positively contributing to the quality of life of the elderly. Regarding the influence of physical exercise on cognitive function in APOE ε4 allele carriers, the data trend shows that the carriers of allele ε4 for APOE gene were more responsive to the beneficial effects of physical exercise on cognitive function compared with non-carriers. Nevertheless, studies with larger sample sizes will provide more accuracy about this relationship.


Subject(s)
Humans , Aged , Aged, 80 and over , Apolipoproteins E/genetics , Exercise , Cognition , Polymorphism, Genetic , Quality of Life , Alleles , Alzheimer Disease/genetics , Genotype
15.
China Journal of Chinese Materia Medica ; (24): 5320-5329, 2021.
Article in Chinese | WPRIM | ID: wpr-921679

ABSTRACT

In this study, ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry(UPLC-Q-TOF-MS)-based liver metabolomics approach was used to explore the mechanism of "Trichosanthis Fructus-Allii Macrostemonis Bulbus" in improving atherosclerosis(AS) of mice with apolipoprotein E gene knockout(ApoE~(-/-)). AS mouse model was induced by high-fat diet. The pathological and biochemical indexes such as the histopathological changes, body weight, liver weight, blood lipid level and inflammatory factors in the liver of mice were determined. The metabolic profiling of mice liver samples was performed with UPLC-Q-TOF-MS. Multiple statistical analysis methods including partial least squares discriminant analysis(PLS-DA) and orthogonal partial least squares discriminant analysis(OPLS-DA) were employed to screen and identify biomarkers. The levels of related enzymes including LCAT, sPLA2, EPT1 and ACER1 were detected. The results showed that "Trichosanthis Fructus-Allii Macrostemonis Bulbus" significantly reduced the areas of aortic plaque and fat vacuoles of liver in AS mice and decreased the accumulation of lipid droplets and liver coefficient. "Trichosanthis Fructus-Allii Macrostemonis Bulbus" also regulated the levels of blood lipid and inflammatory injury in the liver. The metabolites of the control group, the model group and the "Trichosanthis Fructus-Allii Macrostemonis Bulbus" group could be distinguished significantly. Fifteen potential biomarkers related to AS were discovered and preliminarily identified, seven of which could be regulated by "Trichosanthis Fructus-Allii Macrostemonis Bulbus" in a trend of returning to normal. Metabolic pathway analysis screened out two major metabolic pathways. "Trichosanthis Fructus-Allii Macrostemonis Bulbus" obviously regulated the levels of LCAT, sPLA2, EPT1 and ACER1. It was inferred that "Trichosanthis Fructus-Allii Macrostemonis Bulbus" could play a major role in AS treatment by regulating glycerophospholipid and sphingolipid metabolism disorders in the liver, with the mechanism probably relating to the intervention of the expression of LCAT, sPLA2, EPT1 and ACER1.


Subject(s)
Animals , Mice , Apolipoproteins E/genetics , Atherosclerosis/genetics , Chromatography, High Pressure Liquid , Drugs, Chinese Herbal , Liver , Metabolomics
16.
Annals of the Academy of Medicine, Singapore ; : 474-480, 2021.
Article in English | WPRIM | ID: wpr-887515

ABSTRACT

INTRODUCTION@#The apolipoprotein E (@*METHODS@#We classified the @*RESULTS@#The baseline serum levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were significantly lower in carriers of @*CONCLUSION@#Polymorphism in the


Subject(s)
Humans , Apolipoproteins E/genetics , Atherosclerosis/genetics , Cardiovascular Diseases , Genotype , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Lipids
17.
Acta Physiologica Sinica ; (6): 42-50, 2021.
Article in Chinese | WPRIM | ID: wpr-878234

ABSTRACT

This study was designed to evaluate the role of short-chain fatty acid butyrate acid on intestinal morphology and function, and atherosclerotic plaque formation in apolipoprotein E-knockout (ApoE


Subject(s)
Animals , Humans , Mice , Apolipoproteins E/genetics , Atherosclerosis/prevention & control , Butyrates/pharmacology , Caco-2 Cells , Diet, High-Fat/adverse effects , Fatty Acids, Volatile , Mice, Inbred C57BL , Mice, Knockout , Plaque, Atherosclerotic
18.
Braz. j. med. biol. res ; 54(4): e9764, 2021. tab, graf
Article in English | LILACS | ID: biblio-1153532

ABSTRACT

Naringenin (NAR) is a major flavanone in citrus fruits that has multiple pharmacological attributes such as anticancer and antiatherogenic. This study aims to investigate the mechanism of NAR in high-fat-diet (HFD)-induced atherosclerosis (AS) in apolipoprotein E-knockout (ApoE-/-) mice. A HFD-induced AS ApoE-/- mouse model was established. The mice were treated with HFD, different doses of NAR and simvastatin (Simv). After drug treatment, the levels of total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), glutathione peroxidase (GSH-Px), malondialdehyde (MDA), superoxide dismutase (SOD), and alanine aminotransferase (ALT) were determined. The expression of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) was detected using qRT-PCR and enzyme-linked immunosorbent assay. The plaque area of the aorta of AS mice was determined using oil red O staining. Western blot analysis was applied to measure the levels of autophagy-related proteins [protein 1 light chain 3B (LC3B), beclin 1, and p62]. The TC, TG, LDL-C, TNF-α, ALT, and MDA levels were significantly increased while the HDL-C, SOD, and GSH-Px levels were decreased in the HFD-induced AS ApoE-/- mice. NAR treatment reversed the expression of the above indicators in mice. After they were treated with different doses of NAR, the LC3B and beclin 1 levels were improved while the p62 protein level was decreased. This study suggested that NAR could promote cell autophagy to improve HFD-induced AS in ApoE-/- mice.


Subject(s)
Animals , Rabbits , Flavanones/pharmacology , Atherosclerosis/drug therapy , Apolipoproteins E/genetics , Autophagy
19.
20.
Arq. bras. cardiol ; 115(5): 873-881, nov. 2020. tab, graf
Article in Portuguese | SES-SP, LILACS | ID: biblio-1142278

ABSTRACT

Resumo Fundamento: O conhecimento dos fatores ambientais e genéticos para um envelhecimento bem-sucedido em idosos longevos é controverso. Acrescenta-se a esta evidência, o fato de serem poucos os estudos delineados com essa população. Objetivo: Investigar a relação entre os genótipos mais frequentes da apolipoproteína E (APOE) e a mortalidade em idosos longevos que vivem em comunidade e sua sobrevida de acordo com os fatores de risco cardiovascular. Métodos: Uma amostra de 74 idosos com 80 anos ou mais da coorte do Projeto Veranópolis foi selecionada para genotipagem da APOE. Na linha de base, foram coletadas variáveis antropométricas, dosagens sanguíneas de glicose e lipídeos, pressão arterial e variáveis de estilo de vida (tabagismo, consumo de álcool e atividade física). A escala Bayer de Atividades da Vida Diária foi aplicada aos cuidadores dos idosos. O tempo de seguimento total do estudo foi 21 anos. Um p<0,05 bicaudal foi considerado estatisticamente significativo. Resultados: Não encontramos associação entre os genótipos da APOE e mortalidade. Entretanto, o risco de morte em idosos fumantes foi 2,30 vezes (hazard ratio [HR]; intervalo de confiança de 95% [IC 95%] 1,01 a 5,24); em diabéticos, 3,95 vezes (HR; IC 95% 1,27 a 12,30) do risco dos não diabéticos. Indivíduos que praticavam atividade física vigorosa tiveram uma redução no risco de óbito em 51% (HR = 0,49; IC 95% 0,27 a 0,88). Para o aumento de 1 mmHg na pressão arterial sistólica houve uma redução de 2% (HR = 0,98; IC 95% 0,97 a 0,99) no risco de morte. Conclusão: Nesta amostra de longevos, não houve associação entre os genótipos da APOE e mortalidade. Entretanto, os fatores de risco cardiovasculares clássicos podem ser importantes para a mortalidade geral em pessoas muito idosas.


Abstract Background: Knowledge of environmental and genetic factors for healthy aging in elderly people is controversial. In addition to this evidence, few studies have been designed for this population. Objectives: To investigate the relationship between the most frequent apolipoprotein E (APOE) genotypes and mortality in very elderly individuals living in a community and to evaluate survival according to cardiovascular risk factors. Methods: A sample of 74 elderly individuals aged ≥ 80 years, from the Veranópolis Project cohort, was selected for APOE genotyping. At baseline, anthropometric variables, glucose and lipid levels, blood pressure, and lifestyle variables (smoking, alcohol consumption, and physical activity) were collected. The Bayer Activities of Daily Living Scale was applied to their caregivers. Total study follow-up was 21 years. Two-sided p < 0.05 was considered statistically significant. Results: There was no association between APOE genotypes and mortality. However, the risk of death in elderly smokers was 2.30 times higher (hazard ratio [HR], 95% CI 1.01 to 5.24); in individuals with diabetes, it was 3.95 times higher (HR, 95% CI 1.27 to 12.30) than in individuals without diabetes. Subjects who practiced vigorous physical activity had a 51% reduction in risk of death (HR = 0.49, 95% CI 0.27 to 0.88). For an increase of 1 mmHg in systolic blood pressure, there was a 2% reduction (HR = 0.98, 95% CI 0.97 to 0.99) in risk of death. Conclusion: In this sample population, APOE genotypes were not associated with mortality. However, classic cardiovascular risk factors may be important for overall mortality in the very elderly.


Subject(s)
Humans , Aged , Aged, 80 and over , Cardiovascular Diseases/genetics , Apolipoproteins E , Activities of Daily Living , Risk Factors , Cohort Studies
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