RESUMEN
Atherosclerosis (AS) is a major cause of cardiovascular diseases that may lead to mortality. This study aimed to evaluate the therapeutic potential of tetrandrine in high cholesterol diet (HCD)-induced atherosclerosis, in rats, via modulation of miR-34a, as well as, Wnt5a/Ror2/ABCA1/NF-κB pathway and to compare its efficacy with atorvastatin. Induction of AS, in male rats, was done via IP administration of vitamin D3 (70 U/Kg for 3 days) together with HCD. At the end of the 9th week, rats were treated with atorvastatin at a dose of 20 mg/kg, and tetrandrine at different doses of (18.75, and 31.25 mg/kg) for 22 days. Serum inflammatory cytokines and lipid profile, liver oxidative stress parameters, and aortic tissue Wnt5a, Ror2, ABCA1, NF-κB, miR-34a levels were assessed in all experimental groups. Histopathological and Immunohistochemical assessments of aortic tissue sections were done. Results showed that tetrandrine treatment reverted the inflammatory and oxidative stress state together with reducing the serum lipids via modulating miR-34a, and Wnt5a/Ror2/ABCA1/NF-κB pathway. Moreover, it reverted the histopathological abnormalities observed in AS rats. Tetrandrine beneficial effects, in both doses, were comparable to that of atorvastatin, in most of the discussed parameters. These findings praise tetrandrine as a promising agent for management of atherosclerosis.
Asunto(s)
Transportador 1 de Casete de Unión a ATP , Aterosclerosis , Bencilisoquinolinas , MicroARNs , FN-kappa B , Proteína Wnt-5a , Animales , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/metabolismo , Aterosclerosis/patología , Proteína Wnt-5a/metabolismo , Ratas , FN-kappa B/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Masculino , Bencilisoquinolinas/farmacología , Bencilisoquinolinas/uso terapéutico , Transportador 1 de Casete de Unión a ATP/metabolismo , Transportador 1 de Casete de Unión a ATP/genética , Estrés Oxidativo/efectos de los fármacos , Colecalciferol/farmacología , Transducción de Señal/efectos de los fármacos , Ratas Wistar , Dieta Alta en Grasa/efectos adversos , Colesterol en la Dieta/efectos adversosRESUMEN
Dysfunction or loss of pancreatic ß cells can cause insulin deficiency and impaired glucose regulation, resulting in conditions like type 2 diabetes. The ATP-binding cassette transporter A1 (ABCA1) plays a key role in the reverse cholesterol transport system, and its decreased expression is associated with pancreatic ß cell lipotoxicity, resulting in abnormal insulin synthesis and secretion. Increased glutamate release can cause glucotoxicity in ß cells, though the detailed mechanisms remain unclear. This study investigated the effect of N-methyl-D-aspartic acid (NMDA) on ABCA1 expression in INS-1 cells and primary pancreatic islets to elucidate the signaling mechanisms that suppress insulin secretion. Using Western blotting, microscopy, and biochemical analyses, we found that NMDA activated the mitogen-activated protein kinase (MEK)-dependent pathway, suppressing ABCA1 protein and mRNA expression. The MEK-specific inhibitor PD98059 restored ABCA1 promoter activity, indicating the involvement of the extracellular signal-regulated kinase (MEK/ERK) pathway. Furthermore, we identified the liver X receptor (LXR) as an effector transcription factor in NMDA regulation of ABCA1 transcription. NMDA treatment increased cholesterol and triglyceride levels while decreasing insulin secretion, even under high-glucose conditions. These effects were abrogated by treatment with PD98059. This study reveals that NMDA suppresses ABCA1 expression via the MEK/ERK/LXR pathway, providing new insights into the pathological suppression of insulin secretion in pancreatic ß cells and emphasizing the importance of investigating the role of NMDA in ß cell dysfunction.
Asunto(s)
Transportador 1 de Casete de Unión a ATP , Células Secretoras de Insulina , Receptores X del Hígado , Sistema de Señalización de MAP Quinasas , N-Metilaspartato , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/efectos de los fármacos , Animales , Transportador 1 de Casete de Unión a ATP/metabolismo , Transportador 1 de Casete de Unión a ATP/genética , N-Metilaspartato/farmacología , Ratas , Receptores X del Hígado/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Colesterol/metabolismo , Insulina/metabolismo , Secreción de Insulina/efectos de los fármacos , Masculino , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Línea CelularRESUMEN
Ischemic stroke (IS) is a severe cerebrovascular disease with high disability and mortality rates, where the inflammatory response is crucial to its progression and prognosis. Efferocytosis, the prompt removal of dead cells, can reduce excessive inflammation after IS injury. While electroacupuncture (EA) has been shown to decrease inflammation post-ischemia/reperfusion (I/R), its link to efferocytosis is unclear. Our research identified ATP-binding cassette transporter A1 (Abca1) as a key regulator of the engulfment process of efferocytosis after IS by analyzing public datasets and validating findings in a mouse model, revealing its close ties to IS progression. We demonstrated that EA can reduce neuronal cell death and excessive inflammation caused by I/R. Furthermore, EA treatment increased Abca1 expression, prevented microglia activation, promoted M2 microglia polarization, and enhanced their ability to phagocytose injured neurons in I/R mice. This suggests that EA's modulation of efferocytosis could be a potential mechanism for reducing cerebral I/R injury, making regulators of efferocytosis steps a promising therapeutic target for EA benefits.
Asunto(s)
Transportador 1 de Casete de Unión a ATP , Electroacupuntura , Inflamación , Ratones Endogámicos C57BL , Microglía , Fagocitosis , Daño por Reperfusión , Animales , Microglía/metabolismo , Microglía/patología , Electroacupuntura/métodos , Transportador 1 de Casete de Unión a ATP/metabolismo , Daño por Reperfusión/patología , Daño por Reperfusión/terapia , Daño por Reperfusión/metabolismo , Inflamación/patología , Masculino , Isquemia Encefálica/patología , Isquemia Encefálica/metabolismo , Isquemia Encefálica/terapia , Ratones , Neuronas/metabolismo , Neuronas/patología , Modelos Animales de Enfermedad , EferocitosisRESUMEN
BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) remains a significant challenge in cancer therapy, especially due to its resistance to established treatments like Gemcitabine, necessitating novel therapeutic approaches. METHODS: This study utilized Gemcitabine-resistant cell lines, patient-derived organotypic tumor spheroids (PDOTs), and patient-derived xenografts (PDX) to evaluate the effects of Saikosaponin-a (SSA) on ICC cellular proliferation, migration, apoptosis, and its potential synergistic interaction with Gemcitabine. Techniques such as transcriptome sequencing, Luciferase reporter assays, and molecular docking were employed to unravel the molecular mechanisms. RESULTS: SSA exhibited antitumor effects in both in vitro and PDX models, indicating its considerable potential for ICC treatment. SSA markedly inhibited ICC progression by reducing cellular proliferation, enhancing apoptosis, and decreasing migration and invasion. Crucially, it augmented Gemcitabine's efficacy by targeting the p-AKT/BCL6/ABCA1 signaling pathway. This modulation led to the downregulation of p-AKT and suppression of BCL6 transcriptional activity, ultimately reducing ABCA1 expression and enhancing chemosensitivity to Gemcitabine. Additionally, ABCA1 was validated as a predictive biomarker for drug resistance, with a direct correlation between ABCA1 expression levels and the IC50 values of various small molecule drugs in ICC gene profiles. CONCLUSION: This study highlights the synergistic potential of SSA combined with Gemcitabine in enhancing therapeutic efficacy against ICC and identifies ABCA1 as a key biomarker for drug responsiveness. Furthermore, the introduction of the novel PDOTs microfluidic model provides enhanced insights into ICC research. This combination strategy may provide a novel approach to overcoming treatment challenges in ICC.
Asunto(s)
Transportador 1 de Casete de Unión a ATP , Neoplasias de los Conductos Biliares , Colangiocarcinoma , Desoxicitidina , Resistencia a Antineoplásicos , Gemcitabina , Ácido Oleanólico , Proteínas Proto-Oncogénicas c-akt , Saponinas , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Ácido Oleanólico/farmacología , Ácido Oleanólico/análogos & derivados , Saponinas/farmacología , Colangiocarcinoma/tratamiento farmacológico , Humanos , Línea Celular Tumoral , Animales , Proteínas Proto-Oncogénicas c-akt/metabolismo , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Resistencia a Antineoplásicos/efectos de los fármacos , Transportador 1 de Casete de Unión a ATP/metabolismo , Ratones , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Sinergismo Farmacológico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Purpose: Dysregulated cholesterol metabolism is critical in the pathogenesis of AMD. Cellular senescence contributes to the development of numerous age-associated diseases. In this study, we investigated the link between cholesterol burden and the cellular senescence of photoreceptors. Methods: Retinas from rod-specific ATP binding cassette subfamily A member 1 (Abca1) and G member 1 (Abcg1) (Abca1/g1-rod/-rod) knockout mice fed with a high-fat diet were analyzed for the signs of cellular senescence. Real-time quantitative PCR and immunofluorescence were used to characterize the senescence profile of the retina and cholesterol-treated photoreceptor cell line (661W). Inducible elimination of p16(Ink4a)-positive senescent cells (INK-ATTAC) mice or the administration of senolytic drugs (dasatinib and quercetin: D&Q) were used to examine the impact of senolytics on AMD-like phenotypes in Abca1/g1-rod/-rod retina. Results: Increased accumulation of senescent cells as measured by markers of cellular senescence was found in Abca1/g1-rod/-rod retina. Exogenous cholesterol also induced cellular senescence in 661W cells. Selective elimination of senescent cells in Abca1/g1-rod/-rod;INK-ATTAC mice or by administration of D&Q improved visual function, lipid accumulation in retinal pigment epithelium, and Bruch's membrane thickening. Conclusions: Cholesterol accumulation promotes cellular senescence in photoreceptors. Eliminating senescent photoreceptors improves visual function in a model of retinal neurodegeneration, and senotherapy offers a novel therapeutic avenue for further investigation.
Asunto(s)
Transportador 1 de Casete de Unión a ATP , Senescencia Celular , Colesterol , Modelos Animales de Enfermedad , Ratones Noqueados , Degeneración Retiniana , Animales , Ratones , Senescencia Celular/fisiología , Colesterol/metabolismo , Transportador 1 de Casete de Unión a ATP/metabolismo , Degeneración Retiniana/metabolismo , Degeneración Retiniana/patología , Reacción en Cadena en Tiempo Real de la Polimerasa , Ratones Endogámicos C57BL , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1/genética , Células Fotorreceptoras Retinianas Bastones/metabolismo , Células Fotorreceptoras Retinianas Bastones/patología , Células Fotorreceptoras Retinianas Bastones/fisiologíaRESUMEN
ABCA1 plays an essential role in the formation of high-density lipoprotein (HDL), and its mutations cause Tangier disease (TD), a familial HDL deficiency. In addition to the disappearance of HDL, TD patients exhibit cholesterol deposition in peripheral tissues through a mechanism poorly understood, which may contribute to the development of premature atherosclerosis. We and others previously showed that ABCA1 deficiency causes hyperactivation of the SREBP2 pathway in vitro. Here, we show using Abca1 knockout mice that ABCA1 deficiency leads to tissue-specific dysregulation of SREBP2 activity in a nutritional status-dependent manner, which may underlie the pathophysiology of TD.
Asunto(s)
Transportador 1 de Casete de Unión a ATP , Transducción de Señal , Enfermedad de Tangier , Animales , Humanos , Ratones , Transportador 1 de Casete de Unión a ATP/genética , Transportador 1 de Casete de Unión a ATP/metabolismo , Transportador 1 de Casete de Unión a ATP/deficiencia , Colesterol/metabolismo , Lipoproteínas HDL/metabolismo , Lipoproteínas HDL/genética , Ratones Endogámicos C57BL , Ratones Noqueados , Especificidad de Órganos , Proteína 2 de Unión a Elementos Reguladores de Esteroles/metabolismo , Proteína 2 de Unión a Elementos Reguladores de Esteroles/genética , Enfermedad de Tangier/genética , Enfermedad de Tangier/metabolismo , Enfermedad de Tangier/patologíaRESUMEN
Therapeutics enhancing apolipoprotein (APOE) positive function are a priority, because APOE4 is the major genetic risk factor for Alzheimer's disease (AD). The function of APOE, the key constituent of lipoprotein particles that transport cholesterol and lipids in the brain, is dependent on lipidation by ABCA1, a cell-membrane cholesterol transporter. ABCA1 transcription is regulated by liver X receptors (LXR): agonists have been shown to increase ABCA1, often accompanied by unwanted lipogenesis and elevated triglycerides (TG). Therefore, nonlipogenic ABCA1-inducers (NLAI) are needed. Two rounds of optimization of an HTS hit, derived from a phenotypic screen, gave lead compound 39 that was validated and tested in E3/4FAD mice that express human APOE3/4 and five mutant APP and PSEN1 human transgenes. Treatment with 39 increased ABCA1 expression, enhanced APOE lipidation, and reversed multiple AD phenotypes, without increasing TG. This NLAI/LXR-agonist study is the first in a human APOE-expressing model with hallmark amyloid-ß pathology.
Asunto(s)
Transportador 1 de Casete de Unión a ATP , Enfermedad de Alzheimer , Apolipoproteína E3 , Apolipoproteína E4 , Modelos Animales de Enfermedad , Ratones Transgénicos , Animales , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Transportador 1 de Casete de Unión a ATP/metabolismo , Transportador 1 de Casete de Unión a ATP/genética , Humanos , Ratones , Apolipoproteína E4/metabolismo , Apolipoproteína E4/genética , Apolipoproteína E3/genética , Apolipoproteína E3/metabolismo , Receptores X del Hígado/agonistas , Receptores X del Hígado/metabolismo , Presenilina-1/genética , Presenilina-1/metabolismoRESUMEN
Progressive Rod-Cone Degeneration (PRCD) is an integral membrane protein found in photoreceptor outer segment (OS) disc membranes and its function remains unknown. Mutations in Prcd are implicated in Retinitis pigmentosa (RP) in humans and multiple dog breeds. PRCD-deficient models exhibit decreased levels of cholesterol in the plasma. However, potential changes in the retinal cholesterol remain unexplored. In addition, impaired phagocytosis observed in these animal models points to potential deficits in the retinal pigment epithelium (RPE). Here, using a Prcd-/- murine model we investigated the alterations in the retinal cholesterol levels and impairments in the structural and functional integrity of the RPE. Lipidomic and immunohistochemical analyses show a 5-fold increase in the levels of cholesteryl esters (C.Es) and lipid deposits in the PRCD-deficient retina, respectively, indicating alterations in total retinal cholesterol. Furthermore, the RPE of Prcd-/- mice exhibit a 1.7-fold increase in the expression of lipid transporter gene ATP-binding cassette transporter A1 (Abca1). Longitudinal fundus and spectral domain optical coherence tomography (SD-OCT) examinations showed focal lesions and RPE hyperreflectivity. Strikingly, the RPE of Prcd-/- mice exhibited age-related pathological features such as lipofuscin accumulation, Bruch's membrane (BrM) deposits and drusenoid focal deposits, mirroring an Age-related Macular Degeneration (AMD)-like phenotype. We propose that the extensive lipofuscin accumulation likely impairs lysosomal function, leading to the defective phagocytosis observed in Prcd-/- mice. Our findings support the dysregulation of retinal cholesterol homeostasis in the absence of PRCD. Further, we demonstrate that progressive photoreceptor degeneration in Prcd-/- mice is accompanied by progressive structural and functional deficits in the RPE, which likely exacerbates vision loss over time.
Asunto(s)
Modelos Animales de Enfermedad , Epitelio Pigmentado de la Retina , Tomografía de Coherencia Óptica , Animales , Epitelio Pigmentado de la Retina/metabolismo , Epitelio Pigmentado de la Retina/patología , Ratones , Metabolismo de los Lípidos , Ratones Noqueados , Ratones Endogámicos C57BL , Transportador 1 de Casete de Unión a ATP/genética , Transportador 1 de Casete de Unión a ATP/metabolismo , Colesterol/metabolismo , Ésteres del Colesterol/metabolismo , Distrofias de Conos y Bastones/metabolismo , Distrofias de Conos y Bastones/genética , Electrorretinografía , Lámina Basal de la Coroides/metabolismo , Lámina Basal de la Coroides/patología , Inmunohistoquímica , Degeneración Macular/congénitoRESUMEN
In humans, α-tocopherol (α-TOC) is mainly stored in adipose tissue, where it participates in preventing damages induced by inflammation and reactive oxygen species. Factors, including genetic ones, that explain adipose tissue α-TOC concentration remain poorly understood. This study, therefore, aimed to characterize the interindividual variability of adipose tissue α-TOC concentration in healthy individuals and to identify single nucleotide polymorphisms (SNPs) associated with it. The study used a randomized cross-over design with 42 healthy adult males. α-TOC concentration was measured in fasting plasma and periumbilical adipose tissue samples, both at fast and 8 h after consumption of three standard meals. Partial least squares (PLS) regression was performed to identify SNPs associated with the interindividual variability of adipose tissue α-TOC concentration. Adipose tissue α-TOC concentration was not associated with fasting plasma concentration (Pearson's r = 0.24, 95% CI: [-0.08, 0.51]). There was a high interindividual variability of adipose tissue α-TOC concentration (CV = 61%). A PLS regression model comprising 10 SNPs in five genes (PPARG, ABCA1, BUD13, CD36, and MGLL) explained 60% (adjusted R2) of the variability of this concentration. The interindividual variability of adipose tissue α-TOC concentration in humans is due, at least partly, to SNPs in genes involved in α-TOC and triglyceride metabolism.
Asunto(s)
Estudios Cruzados , Polimorfismo de Nucleótido Simple , Grasa Subcutánea , alfa-Tocoferol , Humanos , Masculino , alfa-Tocoferol/sangre , alfa-Tocoferol/metabolismo , Adulto , Grasa Subcutánea/metabolismo , Adulto Joven , Ayuno , Transportador 1 de Casete de Unión a ATP/genética , Transportador 1 de Casete de Unión a ATP/metabolismo , Antígenos CD36/genética , Antígenos CD36/metabolismo , Voluntarios SanosRESUMEN
Despite recent findings indicating a paradoxical association between high-density lipoprotein cholesterol (HDL-C) levels and cardiovascular disease (CVD) mortality, the impact of HDL-C on subsequent outcomes after ischemic stroke remains unclear. The study aims to investigate the relationships between HDL-C levels and post-stroke functional outcomes while examining the potential modifying influence of HDL-C-related single nucleotide polymorphisms identified through genome-wide association studies. This cohort study included 1,310 patients diagnosed with acute ischemic stroke (AIS), all of whom had their admission serum lipid profile and genotyping information. Participants were categorized into four groups based on gender and HDL-C level. Prognostic outcomes were assessed using a modified Rankin Scale (mRS) at 1, 3, and 12 months post-admission. Multivariate logistic regression and restricted cubic spline regression analysis were used to assess the associations between HDL-C levels and outcomes. The mean age of patients was 61.17 ± 12.08 years, and 69.31% were men. After adjusting confounders, patients with the highest HDL-C level group had a significantly higher risk of poor functional outcomes at 1, 3, and 12 months following stroke compared to the reference group. Restricted cubic splines depicted a nonlinear association between HDL-C levels and poor prognosis in both men and women. The ABCA1 gene rs2575876 AA genotype combined with abnormal HDL-C levels exhibited a significantly heightened risk of post-stroke adverse outcomes at 1 and 3 months compared to patients with normal HDL-C levels and GG + GA genotype. These findings suggest that the combined effects of ABCA1 genetic variants with either low or high HDL-C levels could further heighten this risk.
Asunto(s)
Transportador 1 de Casete de Unión a ATP , HDL-Colesterol , Accidente Cerebrovascular Isquémico , Polimorfismo de Nucleótido Simple , Humanos , Masculino , Femenino , Persona de Mediana Edad , Accidente Cerebrovascular Isquémico/genética , Accidente Cerebrovascular Isquémico/sangre , Anciano , HDL-Colesterol/sangre , Transportador 1 de Casete de Unión a ATP/genética , Taiwán , Pronóstico , Lipoproteínas HDL/sangre , Lipoproteínas HDL/genética , Factores de Riesgo , GenotipoRESUMEN
MicroRNAs (miRs) are small non-coding RNAs that regulate gene expression post-transcriptionally and are crucial in lipid metabolism. ATP-binding cassette transporter A1 (ABCA1) is essential for cholesterol efflux from cells to high-density lipoprotein (HDL). Dysregulation of miRs targeting ABCA1 can affect cholesterol homeostasis and contribute to coronary artery disease (CAD). This study aimed to investigate the expression of miRs targeting ABCA1 in human monocytes, their role in cholesterol efflux, and their relationship with CAD. We included 50 control and 50 CAD patients. RT-qPCR examined the expression of miR-33a-5p, miR-26a-5p, and miR-144-3p in monocytes. Logistic regression analysis explored the association between these miRs and CAD. HDL's cholesterol acceptance was analyzed using the J774A.1 cell line. Results showed that miR-26a-5p (p = 0.027) and ABCA1 (p = 0.003) expression levels were higher in CAD patients, while miR-33a-5p (p < 0.001) levels were lower. Downregulation of miR-33a-5p and upregulation of ABCA1 were linked to a lower CAD risk. Atorvastatin upregulated ABCA1 mRNA, and metformin downregulated miR-26a-5p in CAD patients. Decreased cholesterol efflux correlated with higher CAD risk and inversely with miRs in controls. Reduced miR-33a-5p expression and increased ABCA1 expression are associated with decreased CAD risk. miR deregulation in monocytes may influence atherosclerotic plaque formation by regulating cholesterol efflux. Atorvastatin and metformin could offer protective effects by modulating miR-33a-5p, miR-26a-5p, and ABCA1, suggesting potential therapeutic strategies for CAD prognosis and treatment.
Asunto(s)
Transportador 1 de Casete de Unión a ATP , Enfermedad de la Arteria Coronaria , MicroARNs , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Transportador 1 de Casete de Unión a ATP/genética , Transportador 1 de Casete de Unión a ATP/metabolismo , Enfermedad de la Arteria Coronaria/genética , Enfermedad de la Arteria Coronaria/metabolismo , Enfermedad de la Arteria Coronaria/sangre , Masculino , Femenino , Persona de Mediana Edad , Leucocitos Mononucleares/metabolismo , Regulación de la Expresión Génica , Anciano , Línea Celular , Colesterol/metabolismo , Colesterol/sangre , Monocitos/metabolismoRESUMEN
Eriodictyol, a flavonoid distributed in citrus fruits, has been known to exhibit anti-inflammatory activity. In this study, destabilized medial meniscus (DMM)-induced OA model was used to investigate the protective role of eriodictyol on OA. Meanwhile, we used an IL-1ß-stimulated human osteoarthritis chondrocytes model to investigate the anti-inflammatory mechanism of eriodictyol on OA. The production of nitric oxide was detected by Griess reaction. The productions of MMP1, MMP3, and PGE2 were detected by ELISA. The expression of LXRα, ABCA1, PI3K, AKT, and NF-κB were measured by western blot analysis. The results demonstrated that eriodictyol could alleviate DMM-induced OA in mice. In vitro, eriodictyol inhibited IL-1ß-induced NO, PGE2, MMP1, and MMP3 production in human osteoarthritis chondrocytes. Eriodictyol also suppressed the phosphorylation of PI3K, AKT, NF-κB p65, and IκBα induced by IL-1ß. Meanwhile, eriodictyol significantly increased the expression of LXRα and ABCA1. Furthermore, eriodictyol disrupted lipid rafts formation through reducing the cholesterol content. And cholesterol replenishment experiment showed that adding water-soluble cholesterol could reverse the anti-inflammatory effect of eriodictyol. In conclusion, the results indicated eriodictyol inhibited IL-1ß-induced inflammation in human osteoarthritis chondrocytes through suppressing lipid rafts formation, which subsequently inhibiting PI3K/AKT/NF-κB signaling pathway.
Asunto(s)
Condrocitos , Flavanonas , FN-kappa B , Osteoartritis , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Flavanonas/farmacología , Animales , Humanos , Transducción de Señal/efectos de los fármacos , FN-kappa B/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Condrocitos/efectos de los fármacos , Condrocitos/metabolismo , Ratones , Osteoartritis/tratamiento farmacológico , Osteoartritis/metabolismo , Osteoartritis/patología , Interleucina-1beta/metabolismo , Receptores X del Hígado/metabolismo , Masculino , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/patología , Transportador 1 de Casete de Unión a ATP/metabolismo , Transportador 1 de Casete de Unión a ATP/genética , Progresión de la Enfermedad , Modelos Animales de Enfermedad , Antiinflamatorios/farmacología , Óxido Nítrico/metabolismo , Ratones Endogámicos C57BLRESUMEN
Underexpression, overexpression, and point mutations in peripheral myelin protein 22 (PMP22) cause most cases of Charcot-Marie-Tooth disease (CMTD). While its exact functions remain unclear, PMP22 is clearly essential for formation and maintenance of healthy myelin in the peripheral nervous system. This review explores emerging evidence for roles of PMP22 in cholesterol homeostasis. First, we highlight dysregulation of lipid metabolism in PMP22-based forms of CMTD and recently-discovered interactions between PMP22 and cholesterol biosynthesis machinery. We then examine data that demonstrates PMP22 and cholesterol co-traffic in cells and co-localize in lipid rafts, including how disease-causing PMP22 mutations result in aberrations in cholesterol localization. Finally, we examine roles for interactions between PMP22 and ABCA1 in cholesterol efflux. Together, this emerging body of evidence suggests that PMP22 plays a role in facilitating enhanced cholesterol synthesis and trafficking necessary for production and maintenance of healthy myelin.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth , Colesterol , Homeostasis , Proteínas de la Mielina , Células de Schwann , Colesterol/metabolismo , Humanos , Células de Schwann/metabolismo , Proteínas de la Mielina/metabolismo , Proteínas de la Mielina/genética , Enfermedad de Charcot-Marie-Tooth/metabolismo , Enfermedad de Charcot-Marie-Tooth/genética , Animales , Vaina de Mielina/metabolismo , Metabolismo de los Lípidos , Transportador 1 de Casete de Unión a ATP/metabolismo , Transportador 1 de Casete de Unión a ATP/genética , MutaciónRESUMEN
While the cardiovascular system is a primary target of organophosphorus flame retardants (OPFRs), particularly aryl-OPFRs, it is still exclusive whether the diisodecyl phenyl phosphate (DIDPP), widely used and broadly present in the environment at high concentrations, elicits atherosclerosis effects. Liver X receptors (LXRs) play a direct role in regulating the formation of atherosclerotic lesions. This study was the first to demonstrate that DIDPP acts as an LXRα ligand and functions as an LXRα antagonist with a half-maximal inhibitory concentration of 16.2 µM. We showed that treatment of an in vitro macrophage model with 1 to 10 µM of DIDPP resulted in the downregulation of direct targets of LXRα, namely ABCA1, ABCG1 and SR-B1, thereby leading to a 7.9-13.2 % reduction in cholesterol efflux. This caused dose-dependent, 24.1-43.1 % increases in the staining intensity of foam cells in the macrophage model. This atherosclerotic effect of DIDPP was proposed to be due to its antagonism of LXRα activity, as DIDPP treatment did not alter cholesterol influx. In conclusion, the findings of this study demonstrate that exposure to DIDPP may be a risk factor for atherosclerosis due to the LXRα-antagonistic activity of DIDPP and its ubiquity in the environment.
Asunto(s)
Células Espumosas , Receptores X del Hígado , Receptores X del Hígado/metabolismo , Células Espumosas/efectos de los fármacos , Células Espumosas/metabolismo , Animales , Transportador 1 de Casete de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1/metabolismo , Colesterol/metabolismo , Organofosfatos/farmacología , Organofosfatos/toxicidad , Ratones , Humanos , Retardadores de Llama/toxicidad , Retardadores de Llama/farmacología , Células RAW 264.7 , Receptores Depuradores de Clase B/metabolismoRESUMEN
Euphorbia lathyris L. (EL) is a traditional poisonous herbal medicine used to treat dropsy, ascites, amenorrhea, anuria and constipation. Processing to reduce toxicity of EL is essential for its safe and effective application. However, there is little known regarding the molecular mechanism of reducing toxicity after EL processing. This research aimed to screen the differential markers for EL and PEL, explore the differential mechanisms of inflammatory injury induced by EL and processed EL (PEL) to expound the mechanism of alleviating toxicity after EL processing. The results showed that 15 potential biomarkers, mainly belonging to diterpenoids, were screened to distinguish EL from PEL. EL promoted the expressions of TLR4, NLRP3, NF-κB p65, IL-1ß and TNF-α, increased lipid rafts abundance and promoted TLR4 positioning to lipid rafts. Meanwhile, EL decreased LXRα and ABCA1 expression, and reduced cholesterol efflux. In contrast to EL, the effects of PEL on these indicators were markedly weakened. In addition, Euphorbia factors L1, L2, and L3 affected LXRα, ABCA1, TLR4, NLRP3, NF-κB p65, TNF-α and IL-1ß expression, influenced cholesterol efflux and lipid rafts abundance, and interfered with the colocalization of TLR4 and lipid rafts. The inflammatory injury caused by processed EL was significantly weaker than that caused by crude EL, and reduction of Euphorbia factors L1, L2, and L3 as well as attenuation of inflammatory injury participated in processing-based detoxification of EL. Our results provide valuable insights into the attenuated mechanism of EL processing and will guide future research on the processing mechanism of toxic traditional Chinese medicine.
Asunto(s)
Transportador 1 de Casete de Unión a ATP , Euphorbia , Receptores X del Hígado , Microdominios de Membrana , Receptor Toll-Like 4 , Euphorbia/química , Receptor Toll-Like 4/metabolismo , Receptores X del Hígado/metabolismo , Microdominios de Membrana/efectos de los fármacos , Microdominios de Membrana/metabolismo , Animales , Ratones , Transportador 1 de Casete de Unión a ATP/metabolismo , Inflamación/tratamiento farmacológico , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Células RAW 264.7 , HumanosRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Qinghao-Biejia herb pair (QB) is the core herb pair of "Jieduquyuziyin prescription" and is one of the commonly used herb pairs for the clinical treatment of systemic lupus erythematosus (SLE). Previous studies have shown that QB reduces the expression of inflammatory cytokines like IL-6 and TNF-α in the serum and kidney of MRL/lpr mice. Additionally, it inhibits the expression of TLR4 and MyD88 in the kidney and aorta and reduces the deposition of renal complement C3 and aortic plaque after treatment. These findings suggest that QB has a preventive and therapeutic effect on lupus rats. AIM OF THE STUDY: This study sought to investigate the mechanisms underlying the anti-SLE combined with atherosclerosis activity of the Qinghao-Biejia herb pair. MATERIALS AND METHODS: Drug targets for QB were identified using the HERB database, while targets associated with SLE and atherosclerosis were retrieved from the GeneCards database. The intersection of these drug and disease targets was then analyzed using a protein-protein interaction (PPI) network with GO and KEGG pathway enrichment analysis. In vivo, apolipoprotein E-deficient (ApoE-/-) mice were induced to develop SLE-AS by intraperitoneal injection of pristane and continued feeding of a high-fat diet. The changes in relevant indexes were observed after 12 weeks of gavage treatment with hydroxychloroquine, QB, Q (Qinghao alone), and B (Biejia alone). Bone marrow-derived macrophages from ApoE-/- mice and Raw 264.7 macrophages were used to explore the mechanisms of QB treatment. RESULTS: The levels of inflammatory cytokines in serum and pathological liver changes in mice were improved to varying degrees in the treatment groups. Additionally, there was a reduction in aortic atheromatous plaque formation and some improvement in cholesterol efflux. Furthermore, QB suppressed the expression of inflammatory cytokines in M1 macrophages, suggesting a role in regulating macrophage polarization. CONCLUSION: QB demonstrates clear efficacy for treating SLE-AS, and its therapeutic mechanism may involve the regulation of macrophage phenotypes by promoting cholesterol efflux.
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Transportador 1 de Casete de Unión a ATP , Aterosclerosis , Colesterol , Medicamentos Herbarios Chinos , Lupus Eritematoso Sistémico , Macrófagos , Animales , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Aterosclerosis/tratamiento farmacológico , Ratones , Lupus Eritematoso Sistémico/tratamiento farmacológico , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Transportador 1 de Casete de Unión a ATP/metabolismo , Colesterol/sangre , Colesterol/metabolismo , Células RAW 264.7 , Ratones Endogámicos C57BL , Femenino , Ratones Endogámicos MRL lpr , Ratones Noqueados para ApoERESUMEN
Macrophage lipid accumulation indicates a pathological change in atherosclerosis. Ilexgenin A (IA), a pentacyclic triterpenoid compound, plays a role in preventing inflammation, bacterial infection, and fatty liver and induces a potential anti-atherogenic effect. However, the anti-atherosclerotic mechanism remains unclear. The present study investigated the effects of IA on lipid accumulation in macrophage-derived foam cells and atherogenesis in apoE-/- mice. Our results indicated that the expression of adenosine triphosphate-binding cassette transporter A1 (ABCA1) was up-regulated by IA, promoting cholesterol efflux and reducing lipid accumulation in macrophages, which may be regulated by the protein tyrosine phosphatase non-receptor type 2 (PTPN2)/ERK1/2 signalling pathway. IA attenuated the progression of atherosclerosis in high-fat diet-fed apoE-/- mice. PTPN2 knockdown with siRNA or treatment with an ERK1/2 agonist (Ro 67-7476) impeded the effects of IA on ABCA1 upregulation and cholesterol efflux in macrophages. These results suggest that IA inhibits macrophage lipid accumulation and alleviates atherosclerosis progression via the PTPN2/ERK1/2 signalling pathway.
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Transportador 1 de Casete de Unión a ATP , Aterosclerosis , Metabolismo de los Lípidos , Sistema de Señalización de MAP Quinasas , Macrófagos , Proteína Tirosina Fosfatasa no Receptora Tipo 2 , Animales , Aterosclerosis/metabolismo , Aterosclerosis/patología , Aterosclerosis/genética , Transportador 1 de Casete de Unión a ATP/metabolismo , Transportador 1 de Casete de Unión a ATP/genética , Ratones , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Metabolismo de los Lípidos/efectos de los fármacos , Proteína Tirosina Fosfatasa no Receptora Tipo 2/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 2/genética , Masculino , Triterpenos/farmacología , Colesterol/metabolismo , Células Espumosas/metabolismo , Células Espumosas/efectos de los fármacos , Células Espumosas/patología , Ratones Endogámicos C57BL , Progresión de la Enfermedad , Células RAW 264.7 , Transducción de Señal/efectos de los fármacos , Dieta Alta en Grasa/efectos adversosRESUMEN
BACKGROUND: Atherosclerosis is a long-lasting inflammatory condition affecting the walls of arteries, marked by the buildup of fats, plaque formation, and vascular remodeling. Recent findings highlight the significance of cholesterol removal pathways in influencing atherosclerosis, yet the connection between cholesterol removal and regulation of macrophage inflammation remains poorly understood. RBAP could serve as an anti-inflammatory agent; however, its role in atherosclerosis and the mechanism behind it are still not well understood. PURPOSE: The objective of this research is to explore how RBAP impacts cholesterol efflux, which is a considerable element in the advancement of atherosclerosis. METHODS: An atherosclerosis mouse model was established by using an ApoE KO strain mouse on a high-fat diet (HFD) to assess the effects of RBAP, conducted either orally or through injection. Additionally, in vitro experiments were conducted where the induction of THP-1 cells was conducted for the differentiation towards macrophages, and along with mouse RAW264.7 cells, were challenged with ox-LDL to evaluate the impact of RBAP. RESULTS: In this study, RBAP was found to reduce the production and downregulate TNF-α, IL-1ß, and IL-6 levels and inhibited the activation of the TLR4/MyD88/NF-κB signaling in atherosclerosis model mice, as well as in ox-LDL-challenged THP-1 cells and mouse RAW264.7 macrophages. RBAP's effectiveness also improved the enhancement of reverse cholesterol transport (RCT) and cholesterol removal to HDL and apoA1 by increasing the activity of genes related to cholesterol removal PPARγ/LXRα/ABCA1/ABCG1, both in ApoE-/- mice and in THP-1 cells and mouse RAW264.7 macrophages. Notably, RBAP exerted similar effects on atherosclerosis model mice and macrophages to those of TAK-242, an inhibitor of the TLR4 signaling. When RBAP and TAK-242 were applied simultaneously, the improvement was not enhanced compared with either RBAP or TAK-242 treatment alone. CONCLUSION: These findings suggest that RBAP, as a TLR4 inhibitor, has anti-atherosclerotic effects by improving inflammation and promoting cholesterol effection, indicating its therapeutic potential in intervening atherosclerosis.
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Aterosclerosis , Diferenciación Celular , Colesterol , Células Espumosas , Macrófagos , Oryza , Receptor Toll-Like 4 , Animales , Aterosclerosis/tratamiento farmacológico , Ratones , Colesterol/metabolismo , Células Espumosas/efectos de los fármacos , Células Espumosas/metabolismo , Células RAW 264.7 , Diferenciación Celular/efectos de los fármacos , Humanos , Receptor Toll-Like 4/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Modelos Animales de Enfermedad , Células THP-1 , Masculino , Dieta Alta en Grasa , Transportador 1 de Casete de Unión a ATP/metabolismo , Lipoproteínas LDL/metabolismo , Ratones Endogámicos C57BL , Péptidos/farmacología , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1/metabolismo , Ratones Noqueados para ApoE , FN-kappa B/metabolismo , Apolipoproteínas E , Antiinflamatorios/farmacologíaRESUMEN
Dysregulated host response against infection triggers sepsis that leads to multiple organ dysfunction due to uncontrolled inflammatory responses. Despite marked progress in understanding of sepsis, numerous clinical trials for treatment of sepsis have proven daunting and a new therapeutic approach is highly needed. CE9A215 (inotodiol), a fungal secondary metabolite, has been researched for its pharmacological activities and has shown potent anti-allergic effects. In this study, we evaluated the anti-inflammatory activities of CE9A215 upon lipopolysaccharide (LPS) stimulation in vivo and in vitro for the first time. CE9A215 decreased the production of interleukin (IL)-6, tumor necrosis factor alpha (TNF-α), and IL-1ß in a concentration-dependent manner in LPS-stimulated RAW264.7 cells. Intriguingly, in human mast cell line LUVA, CE9A215 significantly lowered IL-4 and IL-10, and this effect could be beneficial for the clearance of bacterial infection. In addition, administration of CE9A215 improved the survival rate of LPS-stimulated mice and inhibited the pro-inflammatory cytokines, IL-6, TNF-α, and IL-1ß in blood. Moreover, CE9A215 enhanced the expression levels of plasma phospholipid transfer protein (PLTP), apolipoprotein E (ApoE), and ATP-binding cassette transporter (ABCA1) in LPS-stimulated RAW246.7 cells. Liver PLTP level increased significantly in the CE9A215-administered group compared with the control group, which implies that CE9A215 promotes LPS clearance and neutralization by reverse transport of LPS by increasing the expressions of PLTP, ApoE, and ABCA1. Our results highlight CE9A215's potential as a novel therapeutic option for the treatment of sepsis.