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1.
Sci Rep ; 14(1): 9471, 2024 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-38658568

RESUMO

Most metastases in breast cancer occur via the dissemination of tumor cells through the bloodstream. How tumor cells enter the blood (intravasation) is, however, a poorly understood mechanism at the cellular and molecular levels. Particularly uncharacterized is how intravasation is affected by systemic nutrients. High levels of systemic LDL-cholesterol have been shown to contribute to breast cancer progression and metastasis in various models, but the cellular and molecular mechanisms involved are still undisclosed. Here we show that a high- cholesterol diet promotes intravasation in two mouse models of breast cancer and that this could be reverted by blocking LDL binding to LDLR in tumor cells. Moreover, we show that LDL promotes vascular invasion in vitro and the intercalation of tumor cells with endothelial cells, a phenotypic change resembling vascular mimicry (VM). At the molecular level, LDL increases the expression of SERPINE2, previously shown to be required for both VM and intravasation. Overall, our manuscript unravels novel mechanisms by which systemic hypercholesterolemia may affect the onset of metastatic breast cancer by favouring phenotypic changes in breast cancer cells and increasing intravasation.


Assuntos
Neoplasias da Mama , Receptores de LDL , Animais , Receptores de LDL/metabolismo , Receptores de LDL/genética , Feminino , Camundongos , Humanos , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Invasividade Neoplásica , Colesterol na Dieta/efeitos adversos , LDL-Colesterol/metabolismo , LDL-Colesterol/sangue , Lipoproteínas LDL/metabolismo , Colesterol/metabolismo , Colesterol/sangue
2.
Nat Commun ; 15(1): 3385, 2024 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-38649715

RESUMO

There is a long-standing debate about the magnitude of the contribution of gene-environment interactions to phenotypic variations of complex traits owing to the low statistical power and few reported interactions to date. To address this issue, the Gene-Lifestyle Interactions Working Group within the Cohorts for Heart and Aging Research in Genetic Epidemiology Consortium has been spearheading efforts to investigate G × E in large and diverse samples through meta-analysis. Here, we present a powerful new approach to screen for interactions across the genome, an approach that shares substantial similarity to the Mendelian randomization framework. We identify and confirm 5 loci (6 independent signals) interacted with either cigarette smoking or alcohol consumption for serum lipids, and empirically demonstrate that interaction and mediation are the major contributors to genetic effect size heterogeneity across populations. The estimated lower bound of the interaction and environmentally mediated heritability is significant (P < 0.02) for low-density lipoprotein cholesterol and triglycerides in Cross-Population data. Our study improves the understanding of the genetic architecture and environmental contributions to complex traits.


Assuntos
Interação Gene-Ambiente , Estudo de Associação Genômica Ampla , Herança Multifatorial , Humanos , Herança Multifatorial/genética , Masculino , Triglicerídeos/sangue , Feminino , Consumo de Bebidas Alcoólicas/genética , Polimorfismo de Nucleotídeo Único , Fenótipo , LDL-Colesterol/sangue , LDL-Colesterol/metabolismo , Fumar Cigarros/genética , Locos de Características Quantitativas , Pessoa de Meia-Idade
3.
BMC Cardiovasc Disord ; 24(1): 202, 2024 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-38589776

RESUMO

BACKGROUND: The latest evidence indicates that ATP-binding cassette superfamily G member 2 (ABCG2) is critical in regulating lipid metabolism and mediating statin or cholesterol efflux. This study investigates whether the function variant loss within ABCG2 (rs2231142) impacts lipid levels and statin efficiency. METHODS: PubMed, Cochrane Library, Central, CINAHL, and ClinicalTrials.gov were searched until November 18, 2023. RESULTS: Fifteen studies (34,150 individuals) were included in the analysis. The A allele [Glu141Lys amino acid substitution was formed by a transversion from cytosine (C) to adenine (A)] of rs2231142 was linked to lower levels of high-density lipoprotein cholesterol (HDL-C), and higher levels of low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC). In addition, the A allele of rs2231142 substantially increased the lipid-lowering efficiency of rosuvastatin in Asian individuals with dyslipidemia. Subgroup analysis indicated that the impacts of rs2231142 on lipid levels and statin response were primarily in Asian individuals. CONCLUSIONS: The ABCG2 rs2231142 loss of function variant significantly impacts lipid levels and statin efficiency. Preventive use of rosuvastatin may prevent the onset of coronary artery disease (CAD) in Asian individuals with dyslipidemia.


Assuntos
Dislipidemias , Inibidores de Hidroximetilglutaril-CoA Redutases , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Rosuvastatina Cálcica , Predisposição Genética para Doença , LDL-Colesterol/metabolismo , Dislipidemias/diagnóstico , Dislipidemias/tratamento farmacológico , Dislipidemias/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo
4.
J Ethnopharmacol ; 328: 118076, 2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-38521431

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: QiXian Granule (QXG) is an integrated traditional Chinese medicine formula used to treat postmenopausal atherosclerotic (AS) cardiovascular diseases. The previous studies have found that QXG inhibited isoproterenol (ISO)-induced myocardial remodeling. And its active ingredient, Icraiin, can inhibit ferroptosis by promoting oxidized low-density lipoprotein (xo-LDL)-induced vascular endothelial cell injury and autophagy in atherosclerotic mice. Another active ingredient, Salvianolic Acid B, can suppress ferroptosis and apoptosis during myocardial ischemia/reperfusion injury by reducing ubiquitin-proteasome degradation of Glutathione Peroxidase 4 (GPX4) and down-regulating the reactive oxygen species (ROS)- c-Jun N-terminal kinases (JNK)/mitogen-activated protein kinase (MAPK) pathway. AIM OF THE STUDY: The objective of this research was to assess the possible impact of QXG on atherosclerosis in postmenopausal individuals and investigate its underlying mechanisms. MATERIALS AND METHODS: Female ApoE-/- mice underwent ovariectomy and were subjected to a high-fat diet (HFD) to establish a postmenopausal atherosclerosis model. The therapeutic effects of QXG were observed in vivo and in vitro through intraperitoneal injection of erastin, G-protein Coupled Estrogen Receptor (GPER) inhibitor (G15), and silent Mucolipin Transient Receptor Potential Channel 1 (TRPML1) adenovirus injection via tail vein. UPLC-MS and molecular docking techniques identified and evaluated major QXG components, contributing to the investigation of QXG's anti-postmenopausal atherosclerotic effects. RESULTS: QXG increased serum Estradiol levels, decreased follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels, which indicated QXG had estrogen-like effects in Ovx/ApoE-/- mice. Furthermore, QXG demonstrated the potential to impede the progression of AS in Ovx/ApoE-/- mice, as evidenced by reductions in serum triglycerides (TG), total cholesterol (TC), and low-density lipoprotein-cholesterol (LDL-C) levels. Additionally, QXG inhibited ferroptosis in Ovx/ApoE-/- mice. Notably, UPLC-MS analysis identified a total of 106 active components in QXG. The results of molecular docking analysis demonstrated that Epmedin B, Astragaloside II, and Orientin exhibit strong binding affinity towards TRPML1. QXG alleviates the progression of atherosclerosis by activating TRPML1 through the GPER pathway or directly activating TRPML1, thereby inhibiting GPX4 and ferritin heavy chain (FTH1)-mediated iron pendant disease. In vitro, QXG-treated serum suppressed proliferation, migration, and ox-LDL-induced MMP and ROS elevation in HAECs. CONCLUSION: QXG inhibited GPX4 and FTH1-mediated ferroptosis in vascular endothelial cells through up-regulating GPER/TRPML1 signaling, providing a potential therapeutic option for postmenopausal females seeking a safe and effective medication to prevent atherosclerosis. The study highlights QXG's estrogenic properties and its promising role in combating postmenopausal atherosclerosis.


Assuntos
Aterosclerose , Medicamentos de Ervas Chinesas , Ferroptose , Feminino , Animais , Camundongos , Células Endoteliais , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Pós-Menopausa , Cromatografia Líquida , Simulação de Acoplamento Molecular , Espectrometria de Massas em Tandem , Aterosclerose/tratamento farmacológico , Aterosclerose/prevenção & controle , Aterosclerose/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , LDL-Colesterol/metabolismo , Estrogênios/metabolismo , Apolipoproteínas E , Lisossomos/metabolismo
5.
Food Funct ; 15(7): 3479-3495, 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38456359

RESUMO

Objective: The optimal probiotic supplementation in pregnant women has not been thoroughly evaluated. By employing a network meta-analysis (NMA) approach, we compared the effectiveness of different probiotic supplementation strategies for pregnant women. Methods: A comprehensive search across multiple databases was performed to identify studies comparing the efficacy of probiotic supplements with each other or the control (placebo) among pregnant women. Results: This NMA, including 32 studies, systematically evaluated 6 probiotic supplement strategies: Lactobacillus, Lacticaseibacillus rhamnosus and Bifidobacterium (LRB), Lactobacillus acidophilus and Bifidobacterium (LABB), Lactobacillus acidophilus, Lacticaseibacillus casei, and Bifidobacterium bifidum (LLB), multi-combination of four probiotics (MP1), and multi-combination of six or more probiotics (MP2). Among these strategies, LLB, MP1, and MP2 all contain LABB. The NMA findings showed that MP1 was the most effective in reducing fasting blood sugar (FBS) (surface under the cumulative ranking curve [SUCRA]: 80.5%). In addition, MP2 was the most efficacious in lowering the homeostasis model assessment of insulin resistance (HOMA-IR) (SUCRA: 89.1%). LABB was ranked as the most effective in decreasing low-density lipoprotein cholesterol (LDLC) (SUCRA: 95.5%), total cholesterol (TC) (SUCRA: 95.5%), and high-sensitivity C-reactive protein (hs-CRP) (SUCRA: 94.8%). Moreover, LLB was ranked as the most effective in raising total antioxidant capacity (TAC) (SUCRA: 98.5%). Conclusion: Multi-combination of probiotic strains, especially those strategies containing LABB, may be more effective than a single probiotic strain in glycolipid metabolism, inflammation, and oxidative stress of pregnant women.


Assuntos
Gestantes , Probióticos , Humanos , Feminino , Gravidez , Glicemia/metabolismo , Lactobacillus acidophilus/metabolismo , Estresse Oxidativo , Inflamação , LDL-Colesterol/metabolismo
6.
Cells ; 13(6)2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38534331

RESUMO

High blood levels of low-density lipoprotein (LDL)-cholesterol (LDL-C) are associated with atherosclerosis, mainly by promoting foam cell accumulation in vessels. As cholesterol is an essential component of cell plasma membranes and a regulator of several signaling pathways, LDL-C excess may have wider cardiovascular toxicity. We examined, in untreated hypercholesterolemia (HC) patients, selected regardless of the cause of LDL-C accumulation, and in healthy participants (HP), the expression of the adenosine A2A receptor (A2AR), an anti-inflammatory and vasodilatory protein with cholesterol-dependent modulation, and Flotillin-1, protein marker of cholesterol-enriched plasma membrane domains. Blood cardiovascular risk and inflammatory biomarkers were measured. A2AR and Flotillin-1 expression in peripheral blood mononuclear cells (PBMC) was lower in patients compared to HP and negatively correlated to LDL-C blood levels. No other differences were observed between the two groups apart from transferrin and ferritin concentrations. A2AR and Flotillin-1 proteins levels were positively correlated in the whole study population. Incubation of HP PBMCs with LDL-C caused a similar reduction in A2AR and Flotillin-1 expression. We suggest that LDL-C affects A2AR expression by impacting cholesterol-enriched membrane microdomains. Our results provide new insights into the molecular mechanisms underlying cholesterol toxicity, and may have important clinical implication for assessment and treatment of cardiovascular risk in HC.


Assuntos
Doenças Cardiovasculares , Hipercolesterolemia , Proteínas de Membrana , Humanos , LDL-Colesterol/metabolismo , Receptor A2A de Adenosina/metabolismo , Leucócitos Mononucleares/metabolismo , Adenosina , Fatores de Risco , Colesterol , Proteínas de Transporte , Fatores de Risco de Doenças Cardíacas , Microdomínios da Membrana/metabolismo
7.
J Ethnopharmacol ; 328: 118066, 2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-38499259

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Gynostemma pentaphyllum (Thunb.) Makino has traditional applications in Chinese medicine to treat lipid abnormalities. Gypenosides (GPs), the main bioactive components of Gynostemma pentaphyllum, have been reported to exert hypolipidemic effects through multiple mechanisms. The lipid-lowering effects of GPs may be attributed to the aglycone portion resulting from hydrolysis of GPs by the gut microbiota. However, to date, there have been no reports on whether gypenoside aglycones (Agl), the primary bioactive constituents, can ameliorate hyperlipidemia by modulating the gut microbiota. AIM OF THE STUDY: This study explored the potential therapeutic effects of gypenoside aglycone (Agl) in a rat model of high-fat diet (HFD)-induced hyperlipidemia. METHODS: A hyperlipidemic rat model was established by feeding rats with a high-fat diet. Agl was administered orally, and serum lipid levels were analyzed. Molecular techniques, including RT-polymerase chain reaction (PCR) and fecal microbiota sequencing, were used to investigate the effects of Agl on lipid metabolism and gut microbiota composition. RESULTS: Agl administration significantly reduced serum levels of total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) and mitigated hepatic damage induced by HFD. Molecular investigations have revealed the modulation of key lipid metabolism genes and proteins by Agl. Notably, Agl treatment enriched the gut microbiota with beneficial genera, including Lactobacillus, Akkermansia, and Blautia and promoted specific shifts in Lactobacillus murinus, Firmicutes bacterium CAG:424, and Allobaculum stercoricanis. CONCLUSION: This comprehensive study established Agl as a promising candidate for the treatment of hyperlipidemia. It also exhibits remarkable hypolipidemic and hepatoprotective properties. The modulation of lipid metabolism-related genes, along with the restoration of gut microbiota balance, provides mechanistic insights. Thus, Agl has great potential for clinical applications in hyperlipidemia management.


Assuntos
Microbioma Gastrointestinal , Hiperlipidemias , Ratos , Animais , Dieta Hiperlipídica/efeitos adversos , Gynostemma , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/metabolismo , Triglicerídeos/metabolismo , Metabolismo dos Lipídeos , LDL-Colesterol/metabolismo , Extratos Vegetais
8.
Discov Med ; 36(182): 538-545, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38531794

RESUMO

BACKGROUND: Atherosclerosis (AS) is a chronic vascular inflammatory disease resulting from vascular endothelial injury and lipid deposition, closely linked to abnormal lipid metabolism within the body. The critical processes involved in atherosclerosis encompass lipid deposition, oxidation, metabolic disruptions, and inflammatory stimulation within the inner vessel wall. Lipid deposition emerges as a pivotal factor triggering these pathological changes, with vascular smooth muscle cells (VSMCs) playing a significant role in the development of AS. Therefore, the goal was to employ lipids, specifically palmitic acid (PA) and oleic acid (OA) solutions, to stimulate VSMCs and create an in vitro atherosclerosis model. This approach allows for the establishment of a rapid and efficient cell model for simulating atherosclerosis in vitro. METHODS: Primary vascular smooth muscle cells (VSMCs) were isolated and cultured from the thoracic aorta of healthy rats using the tissue-block method. VSMCs were identified through cell climbing slices and immunofluorescence. The growth of VSMCs was observed using light microscopy. The logarithmic growth phase of VSMCs was induced and stimulated by various concentrations of palmitic acid (PA) and oleic acid (OA) ranging from 0 to 650 µmol/L, with a gradient dilution of 50 µmol/L. VSMC activity was assessed using the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Intracellular lipid deposition was visualized through Oil Red O staining. The levels of total cholesterol (TC), triglyceride (TG), high-density lipoprotein-cholesterol (HDL-C), and low-density lipoprotein-cholesterol (LDL-C) within VSMCs were quantified using commercially available kits. RESULTS: The optimal conditions for VSMC proliferation were determined to be an OA concentration of 500 µmol/L, a PA concentration of 300 µmol/L, and a culture duration of 48 hours. In comparison to the control group, the presence of lipid droplets within VSMCs became significantly evident following treatment with OA or PA. Furthermore, the levels of TC, TG, and LDL-C increased, while the HDL-C content decreased after treatment with OA or PA. CONCLUSIONS: A research model for atherosclerosis (AS) and the early stages of cardiovascular events, specifically lipid deposition, was successfully established through the use of OA and PA solutions. This model has the potential to open up new research avenues for gaining a deeper understanding of the pathogenesis and progression of AS.


Assuntos
Aterosclerose , Ácido Palmítico , Ratos , Animais , Ácido Palmítico/metabolismo , Ácido Palmítico/farmacologia , Ácido Oleico/metabolismo , Ácido Oleico/farmacologia , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , LDL-Colesterol/metabolismo , Aterosclerose/metabolismo , Proliferação de Células , Células Cultivadas
9.
Biochem Biophys Res Commun ; 708: 149815, 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38531220

RESUMO

Sesamin, a special compound present in sesame and sesame oil, has been reported a role in regulating lipid metabolism, while the underlying mechanisms remain unclear. Autophagy has been reported associated with lipid metabolism and regarded as a key modulator in liver steatosis. The present work aimed to investigate whether sesamin could exert its protective effects against lipid accumulation via modulating autophagy in HepG2 cells stimulated with oleic acid (OA). Cell viability was evaluated using the CCK-8 method, and triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein, cholesterol (LDL-C), alanine aminotransferase (ALT), along with aspartate aminotransferase (AST) were assessed by oil red O staining, transmission electron microscopy (TEM), and biochemical kits to investigate the lipid-lowering effects of sesamin. Differentially expressed genes were screened by RNA sequencing and validated using real-time quantitative PCR and Western blot. Autophagy and mitophagy related molecules were analyzed employing TEM, Western blot, and immunofluorescence. The data shows that in HepG2 cells stimulated by OA, sesamin reduces levels of TG, TC, LDL-C, ALT, and AST while elevating HDL-C, alleviates the lipid accumulation and improves fatty acid metabolism through modulating the levels of fat metabolism related genes including PCSK9, FABP1, CD36, and SOX4. Sesamin restores the suppressed autophagy in HepG2 cells caused by OA, which could be blocked by autophagy inhibitors. This indicates that sesamin improves fatty acid metabolism by enhancing autophagy levels, thereby mitigating the intracellular lipid accumulation. Furthermore, sesamin significantly enhances the mitophagy and improves mitochondrial homeostasis via activating the PINK/Parkin pathway. These data suggest that sesamin alleviates the excessive lipid accumulation in HepG2 caused by OA by restoring the impaired mitophagy via the PINK1/Parkin pathway, probably playing a preventive or therapeutic role in hepatic steatosis.


Assuntos
Dioxóis , Fígado Gorduroso , Lignanas , Pró-Proteína Convertase 9 , Fatores de Transcrição SOXC , Humanos , Células Hep G2 , Pró-Proteína Convertase 9/metabolismo , Mitofagia , Ácido Oleico/metabolismo , LDL-Colesterol/metabolismo , LDL-Colesterol/farmacologia , Fígado Gorduroso/metabolismo , Metabolismo dos Lipídeos , Colesterol/metabolismo , Triglicerídeos/metabolismo , Proteínas Quinases/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Fígado/metabolismo
10.
Zhongguo Zhen Jiu ; 44(2): 169-174, 2024 Feb 12.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-38373762

RESUMO

OBJECTIVES: To observe the effects of Lizhong Tongmai acupuncture (acupuncture for regulating middle jiao and promoting meridians) on trimethylamine-N-oxide (TMAO), CD36 expression, and cholesterol deposition in atherosclerotic (AS) mice, exploring potential mechanism of electroacupuncture (EA) in treating AS. METHODS: A total of 31 male SPF-grade C57BL/6J ApoE-/- mice were fed with high-fat diet for 8 weeks to establish AS model. After successful modeling, the remaining 30 mice were randomly divided into a model group, a medication group, and an EA group, with 10 mice in each group. An additional 10 normal mice of the same strain were selected as a blank group. The mice in the blank group and the model group received no intervention. The mice in the medication group were treated with intragastric administration of atorvastatin calcium. The mice in the EA group were treated with EA at "Neiguan" (PC 6), "Tianshu" (ST 25) and "Zusanli" (ST 36). The same-side "Neiguan" (PC 6) and "Zusanli" (ST 36), "Tianshu" (ST 25) and the tail of the mice were connected to the EA apparatus, with disperse-dense wave, a frequency of 2 Hz/15 Hz, and a current intensity of 0.3 mA for 10 min per session. Acupuncture was performed unilaterally per session, alternating between the left and right sides, with a frequency of once every other day. After intervention, HE staining was used to observe the pathological morphology of the aorta. Microplate assays were conducted to measure triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) levels in serum. Ultra high performance liquid chromatography-mass spectrometry technique (UPLC-MS) was employed to detect TMAO level in plasma. Western blot was performed to assess CD36 protein expression level in the aorta. Microanalysis was used to measure cholesterol ester (CE) level in the aorta and the CE/TC ratio was calculated. RESULTS: Compared with the blank group, the mice in the model group exhibited significant pathological changes of atherosclerosis, serum TG, TC, LDL-C levels were increased (P<0.01), and HDL-C level was decreased (P<0.01); the plasma TMAO level, aortic CE level, and the CE/TC ratio were increased (P<0.01), along with elevated CD36 protein expression level in the aorta (P<0.01). Compared with the model group, the mice in the medication group and the EA group showed improvements in aortic pathology, serum TG, TC, LDL-C levels were reduced, HDL-C levels were increased (P<0.05); plasma TMAO levels, aortic CE levels, and the CE/TC ratio were decreased (P<0.01), and CD36 protein expression levels were lowered (P<0.05). The serum TG and TC levels in the EA group were higher than those in the medication group (P<0.05). CONCLUSIONS: The Lizhong Tongmai acupuncture can ameliorate aortic pathological changes, regulate blood lipid levels, reduce plasma TMAO level, inhibit CD36 protein expression in the aorta, and decrease cholesterol deposition. These effects may contribute to the therapeutic mechanism of EA in treating AS.


Assuntos
Aterosclerose , Eletroacupuntura , Metilaminas , Masculino , Camundongos , Animais , Antígenos CD36/genética , LDL-Colesterol/metabolismo , Cromatografia Líquida , Camundongos Endogâmicos C57BL , Pontos de Acupuntura , Camundongos Knockout para ApoE , Espectrometria de Massas em Tandem , Aterosclerose/genética , Aterosclerose/terapia , Aterosclerose/metabolismo
11.
PLoS One ; 19(2): e0298629, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38416767

RESUMO

BACKGROUND: Past studies have demonstrated that patients diagnosed with rheumatoid arthritis (RA) often exhibit abnormal levels of lipids. Furthermore, certain lipid-modifying medications have shown effectiveness in alleviating clinical symptoms associated with RA. However, the current understanding of the causal relationship between lipids, lipid-modifying medications, and the risk of developing RA remains inconclusive. This study employed Mendelian randomization (MR) to investigate the causal connection between lipids, lipid-modifying drugs, and the occurrence of RA. METHODS: We obtained genetic variation for lipid traits and drug targets related to lipid modification from three sources: the Global Lipids Genetics Consortium (GLGC), UK Biobank, and Nightingale Health 2020. The genetic data for RA were acquired from two comprehensive meta-analyses and the R8 of FINNGEN, respectively. These variants were employed in drug-target MR analyses to establish a causal relationship between genetically predicted lipid-modifying drug targets and the risk of RA. For suggestive lipid-modified drug targets, we conducted Summary-data-based Mendelian Randomization (SMR) analyses and using expression quantitative trait loci (eQTL) data in relevant tissues. In addition, we performed co-localization analyses to assess genetic confounders. RESULTS: Our analysis revealed no significant causal relationship between lipid and RA. We observed that the genetically predicted 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) -mediated low density lipoprotein cholesterol (LDL-C) (OR 0.704; 95% CI 0.56, 0.89; P = 3.43×10-3), Apolipoprotein C-III (APOC3) -mediated triglyceride (TG) (OR 0.844; 95% CI 0.77, 0.92; P = 1.50×10-4) and low density lipoprotein receptor (LDLR) -mediated LDL-C (OR 0.835; 95% CI 0.73, 0.95; P = 8.81×10-3) were significantly associated with a lowered risk of RA. while Apolipoprotein B-100 (APOB) -mediated LDL-C (OR 1.212; 95%CI 1.05,1.40; P = 9.66×10-3) was significantly associated with an increased risk of RA. CONCLUSIONS: Our study did not find any supporting evidence to suggest that lipids are a risk factor for RA. However, we observed significant associations between HMGCR, APOC3, LDLR, and APOB with the risk of RA.


Assuntos
Artrite Reumatoide , Análise da Randomização Mendeliana , Humanos , LDL-Colesterol/metabolismo , HDL-Colesterol/metabolismo , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Polimorfismo de Nucleotídeo Único
12.
J Atheroscler Thromb ; 31(6): 979-1003, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38325860

RESUMO

AIMS: Although fat mass (FM) and fat-free mass (FFM) have an impact on lipid metabolism, the relationship between different body composition phenotypes and lipid profiles is still unclear. By dividing the FM and FFM by the square of the height, respectively, the fat mass index (FMI) and fat-free mass index (FFMI) can be used to determine the variations in body composition. This study aimed to investigate the relationship of combined FMI and FFMI with low-density lipoprotein cholesterol (LDL-C) levels. METHODS: This cross-sectional study comprised 5,116 men and 13,630 women without cardiovascular disease and without treatment for hypertension, and diabetes. Following sex-specific quartile classification, FMI and FFMI were combined into 16 groups. Elevated LDL-C levels were defined as LDL-C ≥ 140 mg/dL and/or dyslipidemia treatment. Multivariable logistic regression models were used to examine the relationships between combined FMI and FFMI and elevated LDL-C levels. RESULTS: Overall, elevated LDL-C levels were found in 1,538 (30.1%) men and 5,434 (39.9%) women. In all FFMI subgroups, a higher FMI was associated with elevated LDL-C levels. Conversely, FFMI was inversely associated with elevated LDL-C levels in most FMI subgroups. Furthermore, the groups with the highest FMI and lowest FFMI had higher odds ratios for elevated LDL-C levels than those with the lowest FMI and highest FFMI. CONCLUSIONS: Regardless of FFMI, FMI was positively associated with elevated LDL-C levels. Conversely, in the majority of FMI subgroups, FFMI was inversely associated with elevated LDL-C levels.


Assuntos
LDL-Colesterol , Humanos , Masculino , Feminino , Estudos Transversais , LDL-Colesterol/sangue , LDL-Colesterol/metabolismo , Pessoa de Meia-Idade , Composição Corporal , Índice de Massa Corporal , Idoso , Adulto , Estudos de Coortes , Tecido Adiposo/metabolismo , Dislipidemias/sangue , Dislipidemias/metabolismo , Dislipidemias/epidemiologia , Prognóstico , Seguimentos , Fatores de Risco
13.
Lipids Health Dis ; 23(1): 28, 2024 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-38273354

RESUMO

BACKGROUND: As independent and correctable risk factors, disturbances in lipid metabolism are significantly associated with type 2 diabetes mellitus (T2DM). This research investigated the mechanism underlying the lipid-regulating effects of Yam Gruel in diabetic rats. METHODS: First, rats in the control group were given a normal diet, and a diabetic rat model was established via the consumption of a diet that was rich in both fat and sugar for six weeks followed by the intraperitoneal injection of streptozotocin (STZ). After the model was established, the rats were divided into five distinct groups: the control group, model group, Yam Gruel (SYZ) group, metformin (MET) group, and combined group; each treatment was administered for six weeks. The fasting blood glucose (FBG), body and liver weights as well as liver index of the rats were determined. Total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), aspartic acid transaminase (AST), alanine aminotransferase (ALT), and nonesterified fatty acid (NEFA) levels were measured. Oil Red O staining was used to assess hepatic steatosis. In addition, the levels of Phospho-acetyl-CoA carboxylase (p-ACC), acetyl coenzyme A carboxylase (ACC), AMP-activated protein kinase (AMPK), Phospho-AMPK (p-AMPK), carnitine palmitoyl transferase I (CPT-1), and Malonyl-CoA decarboxylase (MLYCD) in liver tissues were measured by real-time PCR (q-PCR) and western blotting. RESULTS: After 6 weeks of treatment, Yam Gruel alone or in combination with metformin significantly reduced FBG level, liver weight and index. The concentrations of lipid indices (TG, TC, NEFA, and LDL-C), the levels of liver function indices (ALT and AST) and the degree of hepatic steatosis was improved in diabetic rats that were treated with Yam Gruel with or without metformin. Furthermore, Yam Gruel increased the protein levels of p-ACC/ACC, p-AMPK/AMPK, MLYCD, and CPT-1, which was consistent with the observed changes in gene expression. Additionally, the combination of these two agents was significantly more effective in upregulating the expression of AMPK pathway-related genes and proteins. CONCLUSIONS: These results demonstrated that Yam Gruel may be a potential diet therapy for improving lipid metabolism in T2DM patients and that it may exert its effects via AMPK/ACC/CPT-1 pathway activation. In some respects, the combination of Yam Gruel and metformin exerted more benefits effects than Yam Gruel alone.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Dioscorea , Fígado Gorduroso , Transtornos do Metabolismo dos Lipídeos , Metformina , Humanos , Ratos , Animais , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Dioscorea/metabolismo , Metabolismo dos Lipídeos , Metformina/farmacologia , Metformina/uso terapêutico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Ácidos Graxos não Esterificados/metabolismo , LDL-Colesterol/metabolismo , Fígado/metabolismo , Fígado Gorduroso/metabolismo , Transtornos do Metabolismo dos Lipídeos/metabolismo , Triglicerídeos/metabolismo , Dieta Hiperlipídica/efeitos adversos
14.
Discov Med ; 36(180): 121-128, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38273752

RESUMO

BACKGROUND: Curcumin is a kind of natural hydrophobic polyphenol isolated from the stem of the Curcuma plant. To investigate regulatory curcumin effect on atherosclerotic endothelial cell injury. METHODS: 30 male ApoE-/- mice were selected and divided into the control group, model group, and curcumin group (n = 10). The curcumin group was treated with curcumin by gavage. Body weight, atherosclerotic plaque area, plaque cap thickness, blood lipid levels, total cholesterol (TC), triacylglycerol (TG), low-density lipoprotein cholesterol (LDL-C) content, nitric oxide (NO) content, interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α) content and circulating endothelial cell number of mice in each group were detected. Western blot detected NACHT, LRR, and receptor family pyrin domain-containing 3 (NLRP3) and Asc-type amino acid transporter protein 1 (ASC) protein level in mice. Human aortic endothelial cells (HAEC) were cultured to establish an atherosclerotic endothelial cell injury model in vivo. Cell counting kit-8 (CCK-8) detected the cell viability of each group. RESULTS: Body weight, atherosclerotic plaque area, plaque cap thickness, TC, TG, and LDL-C content of blood lipid levels of the curcumin group were obviously reduced as compared with the model group (p < 0.05), the content of NO and the number of circulating endothelial cells in curcumin group were obviously decreased (p < 0.05). The cell viability of the curcumin group was obviously higher than that of the model group (p < 0.05). The NO content of the curcumin group was lower than the model group (p < 0.05). The content of IL-1ß and TNF-α in the curcumin group was obviously lower than in the model group (p < 0.05). Compared with the model group, the expression of receptor family pyrin domain-containing 3 (NLRP3) and ASC protein in the curcumin group was decreased obviously (p < 0.05). CONCLUSION: Curcumin improves endothelial cell injury in atherosclerosis by inhibiting the expression of NLRP3 inflammatory bodies.


Assuntos
Aterosclerose , Curcumina , Placa Aterosclerótica , Camundongos , Humanos , Animais , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Curcumina/farmacologia , Curcumina/uso terapêutico , Curcumina/metabolismo , Placa Aterosclerótica/metabolismo , Células Endoteliais , Fator de Necrose Tumoral alfa , LDL-Colesterol/metabolismo , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Lipídeos , Peso Corporal , Inflamassomos/metabolismo
15.
J Am Assoc Nurse Pract ; 36(2): 136-142, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-37624754

RESUMO

ABSTRACT: Familial hypercholesterolemia (FH) is one of the most common genetic conditions. Affected individuals are unable to metabolize cholesterol due to inherited changes in the low-density lipoprotein (LDL) receptor, which impairs the ability to metabolize cholesterol, resulting in extremely high levels of cholesterol that leads to premature coronary artery disease. Autosomal dominant FH is caused by variants in several genes, which may present as heterozygous FH (less severe) or homozygous FH (more severe). Clinical diagnosis may be more likely when there is a family history of two or more first-degree relatives with total and LDL-cholesterol (LDL-C) level elevations, a child is identified, or the affected individual or close relatives have tendon xanthomas and/or progressive atherosclerosis. This article provides an overview of autosomal dominant FH, including disease prevalence, clinical diagnostic criteria, genetic variants, diagnostic testing, pathognomonic findings, and treatment options. It also shares a brief case, which highlights challenges associated with genetic test interpretation and the importance of including experienced providers in the diagnosis and treatment of this underdiagnosed and often untreated or undertreated genetic condition.


Assuntos
Hiperlipoproteinemia Tipo II , Criança , Humanos , LDL-Colesterol/genética , LDL-Colesterol/metabolismo , LDL-Colesterol/uso terapêutico , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Colesterol/uso terapêutico , Testes Genéticos
16.
Annu Rev Pharmacol Toxicol ; 64: 135-157, 2024 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-37506332

RESUMO

Lipoprotein(a) [Lp(a)] is a molecule bound to apolipoprotein(a) with some similarity to low-density lipoprotein cholesterol (LDL-C), which has been found to be a risk factor for cardiovascular disease (CVD). Lp(a) appears to induce inflammation, atherogenesis, and thrombosis. Approximately 20% of the world's population has increased Lp(a) levels, determined predominantly by genetics. Current clinical practices for the management of dyslipidemia are ineffective in lowering Lp(a) levels. Evolving RNA-based therapeutics, such as the antisense oligonucleotide pelacarsen and small interfering RNA olpasiran, have shown promising results in reducing Lp(a) levels. Phase III pivotal cardiovascular outcome trials [Lp(a)HORIZON and OCEAN(a)] are ongoing to evaluate their efficacy in secondary prevention of major cardiovascular events in patients with elevated Lp(a). The future of cardiovascular residual risk reduction may transition to a personalized approach where further lowering of either LDL-C, triglycerides, or Lp(a) is selected after high-intensity statin therapy based on the individual risk profile and preferences of each patient.


Assuntos
Doenças Cardiovasculares , Humanos , LDL-Colesterol/metabolismo , LDL-Colesterol/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/genética , Fatores de Risco , Lipoproteína(a)/genética , Lipoproteína(a)/metabolismo , Lipoproteína(a)/uso terapêutico , Fatores de Risco de Doenças Cardíacas
17.
J Biochem Mol Toxicol ; 38(1): e23566, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37888945

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is an abnormal lipid accumulation disease in hepatocytes. The existing drugs for NAFLD have some side effects, so new therapeutic agents are required to be explored. In this study, the effect and mechanism of icariin (ICA) on high-fat diet-induced NAFLD were investigated. Firstly, a high-fat diet was used to construct a NAFLD rat model and HepG2 cells were treated with 1 mM free fatty acid (FFA). After ICA treatment, the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBil), triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were measured; liver injury and lipid deposition were observed by H&E and Oil Red O staining; interleukin-1ß (IL-1ß), IL-12, and IL-6 were measured by enzyme-linked immunosorbent assay. Additionally, qRT-PCR and western blot were performed to detect miR-206 expression and NF-κB/MAPK pathway-related protein expression in liver tissues and cells. After a variety of trials, we discovered that compared with the NAFLD group, ICA significantly reduced ALT, AST, TBil, TG, TC, and LDL-C levels and increased HDL-C levels, and improved liver tissue injury and lipid deposition. Moreover, ICA reduced IL-1ß, IL-12, and IL-6 levels in liver tissues and cells as well as inhibited MAPK and NF-κB-related protein expression in the liver tissues. Notably, ICA could significantly increase miR-206 expression in liver tissues and cells. Further experiments confirmed that inhibition of miR-206 was able to reverse the effect of ICA on NAFLD. In conclusion, ICA can alleviate NAFLD by upregulating miR-206 to mediate NF-κB and MAPK pathways.


Assuntos
Flavonoides , MicroRNAs , Hepatopatia Gordurosa não Alcoólica , Ratos , Animais , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/etiologia , NF-kappa B/metabolismo , LDL-Colesterol/metabolismo , LDL-Colesterol/farmacologia , LDL-Colesterol/uso terapêutico , Dieta Hiperlipídica/efeitos adversos , Interleucina-6/metabolismo , Fígado/metabolismo , Triglicerídeos , Bilirrubina/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Interleucina-12/metabolismo , Interleucina-12/farmacologia , Interleucina-12/uso terapêutico
18.
Drug Dev Res ; 85(1): e22131, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37943623

RESUMO

Proprotein convertase subtilisin/kexin type 9 (PCSK9) has attracted lots of attention in preventing the clearance of plasma low-density lipoprotein cholesterol (LDL-C). PCSK9 inhibitors are developed to primarily reduce the cardiovascular risk by lowering LDL-C level. Recently, a number of pleiotropic extrahepatic functions of PCSK9 beyond the regulation of cholesterol metabolism, particularly its effects on central nervous system (CNS) diseases have been increasingly identified. Emerging clinical evidence have revealed that PCSK9 may play a significant role in neurocognition, depression, Alzheimer's disease, and stroke. The focus of this review is to elucidate the functions of PCSK9 and highlight the effects of PCSK9 in CNS diseases, with the aim of identifying the potential risks that may arise from low PCSK9 level (variant or inhibitor) in the clinical practice.


Assuntos
Doenças do Sistema Nervoso Central , Pró-Proteína Convertase 9 , Humanos , Pró-Proteína Convertase 9/metabolismo , LDL-Colesterol/metabolismo , Subtilisinas , Doenças do Sistema Nervoso Central/tratamento farmacológico
19.
Eur J Hum Genet ; 32(2): 215-223, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37903942

RESUMO

Perturbation of lipid homoeostasis is a major risk factor for cardiovascular disease (CVD), the leading cause of death worldwide. We aimed to identify genetic variants affecting lipid levels, and thereby risk of CVD, in Greenlanders. Genome-wide association studies (GWAS) of six blood lipids, triglycerides, LDL-cholesterol, HDL-cholesterol, total cholesterol, as well as apolipoproteins A1 and B, were performed in up to 4473 Greenlanders. For genome-wide significant variants, we also tested for associations with additional traits, including CVD events. We identified 11 genome-wide significant loci associated with lipid traits. Most of these loci were already known in Europeans, however, we found a potential causal variant near PCSK9 (rs12117661), which was independent of the known PCSK9 loss-of-function variant (rs11491147). rs12117661 was associated with lower LDL-cholesterol (ßSD(SE) = -0.22 (0.03), p = 6.5 × 10-12) and total cholesterol (-0.17 (0.03), p = 1.1 × 10-8) in the Greenlandic study population. Similar associations were observed in Europeans from the UK Biobank, where the variant was also associated with a lower risk of CVD outcomes. Moreover, rs12117661 was a top eQTL for PCSK9 across tissues in European data from the GTEx portal, and was located in a predicted regulatory element, supporting a possible causal impact on PCSK9 expression. Combined, the 11 GWAS signals explained up to 16.3% of the variance of the lipid traits. This suggests that the genetic architecture of lipid levels in Greenlanders is different from Europeans, with fewer variants explaining the variance.


Assuntos
Doenças Cardiovasculares , Estudo de Associação Genômica Ampla , Humanos , Pró-Proteína Convertase 9/genética , Groenlândia , Triglicerídeos/genética , Lipídeos/genética , HDL-Colesterol , LDL-Colesterol/genética , LDL-Colesterol/metabolismo , Doenças Cardiovasculares/genética , Polimorfismo de Nucleotídeo Único
20.
Expert Rev Cardiovasc Ther ; 22(1-3): 41-58, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-37996219

RESUMO

INTRODUCTION: Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of global mortality, imposing substantial healthcare economic burdens. Among the modifiable risk factors, hypercholesterolemia, especially elevated low-density lipoprotein cholesterol (LDL-C), plays a pivotal role in ASCVD development. Novel therapies such as PCSK9 (Proprotein Convertase Subtilisin/Kexin type 9) inhibitors are emerging to address this concern. These inhibitors offer the potential to reduce ASCVD risk by directly targeting LDL-C levels. AREAS COVERED: The article reviews the structural and functional aspects of PCSK9, highlighting its role in LDL receptor regulation. The pharmacological strategies for PCSK9 inhibition, including monoclonal antibodies, binding peptides, gene silencing, and active immunization, are explored. Clinical evidence from various trials underscores the safety and efficacy of PCSK9 inhibitors in reducing LDL-C levels and potentially improving cardiovascular outcomes. Despite these promising results, challenges such as cost-effectiveness and long-term safety considerations are addressed. EXPERT OPINION: Among PCSK9 inhibitors, monoclonal antibodies represent a cornerstone. Many trials have showed their efficacy in reducing LDL-C and the risk for major adverse clinical events, revealing long-lasting effects, with special benefits particularly for statin-intolerant and familial hypercholesterolemia patients. However, long-term impacts, high costs, and patient selection necessitate further research.


Assuntos
Anticolesterolemiantes , Aterosclerose , Humanos , Inibidores de PCSK9 , LDL-Colesterol/metabolismo , Anticolesterolemiantes/uso terapêutico , Pró-Proteína Convertase 9/metabolismo , Anticorpos Monoclonais/uso terapêutico , Aterosclerose/tratamento farmacológico
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