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Transforming growth factor-ß (TGF-ß) and Hippo signaling are two critical pathways engaged in cancer progression by regulating both oncogenes and tumor suppressors, yet how the two pathways coordinately exert their functions in the development of hepatocellular carcinoma (HCC) remains elusive. In this study, we firstly conducted an integrated analysis of public liver cancer databases and our experimental TGF-ß target genes, identifying CYR61 as a pivotal candidate gene relating to HCC development. The expression of CYR61 is downregulated in clinical HCC tissues and cell lines than that in the normal counterparts. Evidence revealed that CYR61 is a direct target gene of TGF-ß in liver cancer cells. In addition, TGF-ß-stimulated Smad2/3 and the Hippo pathway downstream effectors YAP and TEAD4 can form a protein complex on the promoter of CYR61, thereby activating the promoter activity and stimulating CYR61 gene transcription in a collaborative manner. Functionally, depletion of CYR61 enhanced TGF-ß- or YAP-mediated growth and migration of liver cancer cells. Consistently, ectopic expression of CYR61 was capable of impeding TGF-ß- or YAP-induced malignant transformation of HCC cells in vitro and attenuating HCC xenograft growth in nude mice. Finally, transcriptomic analysis indicates that CYR61 can elicit an antitumor program in liver cancer cells. Together, these results add new evidence for the crosstalk between TGF-ß and Hippo signaling and unveil an important tumor suppressor function of CYR61 in liver cancer.
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Carcinoma Hepatocelular , Proteína Rica em Cisteína 61 , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas , Fator de Crescimento Transformador beta , Proteínas de Sinalização YAP , Animais , Humanos , Camundongos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Movimento Celular , Proteína Rica em Cisteína 61/metabolismo , Proteína Rica em Cisteína 61/genética , Mineração de Dados , Regulação Neoplásica da Expressão Gênica/genética , Via de Sinalização Hippo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/genética , Camundongos Nus , Regiões Promotoras Genéticas , Transdução de Sinais/genética , Proteína Smad2/metabolismo , Proteína Smad2/genética , Proteína Smad3/metabolismo , Proteína Smad3/genética , Fatores de Transcrição de Domínio TEA/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta/genética , Regulação para Cima , Proteínas de Sinalização YAP/metabolismo , Proteínas de Sinalização YAP/genéticaRESUMO
Vascular calcification is an actively regulated biological process resembling bone formation, and osteogenic differentiation of vascular smooth muscle cells (VSMCs) plays a crucial role in this process. 1-Palmitoyl-2-(5'-oxo-valeroyl)-sn-glycero-3-phosphocholine (POVPC), an oxidized phospholipid, is found in atherosclerotic plaques and has been shown to induce oxidative stress. However, the effects of POVPC on osteogenic differentiation and calcification of VSMCs have yet to be studied. In the present study, we investigated the role of POVPC in vascular calcification using in vitro and ex vivo models. POVPC increased mineralization of VSMCs and arterial rings, as shown by alizarin red staining. In addition, POVPC treatment increased expression of osteogenic markers Runx2 and BMP2, indicating that POVPC promotes osteogenic transition of VSMCs. Moreover, POVPC increased oxidative stress and impaired mitochondria function of VSMCs, as shown by increased ROS levels, impairment of mitochondrial membrane potential, and decreased ATP levels. Notably, ferroptosis triggered by POVPC was confirmed by increased levels of intracellular ROS, lipid ROS, and MDA, which were decreased by ferrostatin-1, a ferroptosis inhibitor. Furthermore, ferrostatin-1 attenuated POVPC-induced calcification of VSMCs. Taken together, our study for the first time demonstrates that POVPC promotes vascular calcification via activation of VSMC ferroptosis. Reducing the levels of POVPC or inhibiting ferroptosis might provide a novel strategy to treat vascular calcification.
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Cicloexilaminas , Ferroptose , Fenilenodiaminas , Calcificação Vascular , Humanos , Músculo Liso Vascular/metabolismo , Fosfolipídeos/metabolismo , Fosforilcolina/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Osteogênese , Calcificação Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Células CultivadasRESUMO
This project addresses the urgent need for efficient and cost-effective development of electrocatalysts for the ethanol oxidation reaction (EOR). This reaction offers promising renewable energy solutions but faces challenges due to the slow EOR kinetics, typically requiring costly noble metal catalysts. To overcome these limitations, this study focuses on developing CuZn-based EOR catalysts derived from metal-organic frameworks (MOFs), focusing on understanding the structure-performance relationship between pristine MOF-based electrocatalysts and their pyrolyzed counterparts. Herein, bimetallic MOF materials with varying Cu/Zn ratios were synthesized, followed by pyrolysis to produce carbonized counterparts while preserving the fundamental structure but with altered physicochemical properties. Comparative EOR studies revealed the superior performance of pyrolyzed MOFs, demonstrating that optimized Zn-loading is crucial over Cu-based framework for catalyst performance and durability. Overall, this work highlights the potential of MOF-derived Cu-based catalysts for renewable energy applications and provides insights into optimizing their performance through controlled synthesis and post-treatment strategies.
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Osteoporosis is particularly prevalent among postmenopausal women and the elderly. In the present study, we investigated the effect of the novel small molecule E0924G (N-(4-methoxy-pyridine-2-yl)-5-methylfuran-2-formamide) on osteoporosis. E0924G significantly increased the protein expression levels of osteoprotegerin (OPG) and runt-related transcription factor 2 (RUNX2), and thus significantly promoted osteogenesis in MC3T3-E1 cells. E0924G also significantly decreased osteoclast differentiation and inhibited bone resorption and F-actin ring formation in receptor activator of NF-κB ligand (RANKL)-induced osteoclasts from RAW264.7 macrophages. Importantly, oral administration of E0924G in both ovariectomized (OVX) rats and SAMP6 senile mice significantly increased bone mineral density and decreased bone loss compared to OVX controls or SAMR1 mice. Further mechanistic studies showed that E0924G could bind to and then activate peroxisome proliferator-activated receptor delta (PPARδ), and the pro-osteoblast effect and the inhibition of osteoclast differentiation induced by E0924G were significantly abolished when PPARδ was knocked down or inhibited. In conclusion, these data strongly suggest that E0924G has the potential to prevent OVX-induced and age-related osteoporosis by dual regulation of bone formation and bone resorption through activation of the PPARδ signaling pathway.
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Reabsorção Óssea , Osteogênese , Ovariectomia , PPAR delta , Transdução de Sinais , Animais , Camundongos , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/prevenção & controle , Reabsorção Óssea/metabolismo , Ratos , PPAR delta/metabolismo , Feminino , Osteogênese/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Estrutura Molecular , Células RAW 264.7 , Osteoporose/tratamento farmacológico , Osteoporose/prevenção & controle , Osteoporose/metabolismo , Relação Dose-Resposta a Droga , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/química , Ratos Sprague-Dawley , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Diferenciação Celular/efeitos dos fármacosRESUMO
Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the epidermal growth factor precursor homologous domain A (EGF-A) of low-density lipoprotein receptor (LDLR) in the liver and triggers the degradation of LDLR via the lysosomal pathway, consequently leading to an elevation in plasma LDL-C levels. Inhibiting PCSK9 prolongs the lifespan of LDLR and maintains cholesterol homeostasis in the body. Thus, PCSK9 is an innovative pharmacological target for treating hypercholesterolemia and atherosclerosis. In this study, we discovered that E28362 was a novel small-molecule PCSK9 inhibitor by conducting a virtual screening of a library containing 40,000 compounds. E28362 (5, 10, 20 µM) dose-dependently increased the protein levels of LDLR in both total protein and the membrane fraction in both HepG2 and AML12 cells, and enhanced the uptake of DiI-LDL in AML12 cells. MTT assay showed that E28362 up to 80 µM had no obvious toxicity in HepG2, AML12, and HEK293a cells. The effects of E28362 on hyperlipidemia and atherosclerosis were evaluated in three different animal models. In high-fat diet-fed golden hamsters, administration of E28362 (6.7, 20, 60 mg·kg-1·d-1, i.g.) for 4 weeks significantly reduced plasma total cholesterol (TC), triglyceride (TG), low-density lipoprotein-cholesterol (LDL-C) and PCSK9 levels, and reduced liver TC and TG contents. In Western diet-fed ApoE-/- mice (20, 60 mg·kg-1·d-1, i.g.) and human PCSK9 D374Y overexpression mice (60 mg·kg-1·d-1, i.g.), administration of E28362 for 12 weeks significantly decreased plasma LDL-C levels and the area of atherosclerotic lesions in en face aortas and aortic roots. Moreover, E28362 significantly increased the protein expression level of LDLR in the liver. We revealed that E28362 selectively bound to PCSK9 in HepG2 and AML12 cells, blocked the interaction between LDLR and PCSK9, and induced the degradation of PCSK9 through the ubiquitin-proteasome pathway, which finally resulted in increased LDLR protein levels. In conclusion, E28362 can block the interaction between PCSK9 and LDLR, induce the degradation of PCSK9, increase LDLR protein levels, and alleviate hyperlipidemia and atherosclerosis in three distinct animal models, suggesting that E28362 is a promising lead compound for the treatment of hyperlipidemia and atherosclerosis.
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Molybdenum (Mo) is a rare and important element extensively utilised in aerospace, radar communications, optoelectronic devices, and the military. This study proposes an environmentally friendly physical method based on photon-phonon resonance absorption for the separation of Mo from sodium molybdate (Na2MoO4). We examined the vibrational spectrum of Na2MoO4 using the CASTEP code, employing first-principles density functional theory. Through dynamic process analysis, we analysed the vibrational modes and assigned peaks corresponding to experimental infrared (IR) and Raman data. We focused on the vibrational modes associated with Mo and identified that the highest-intensity IR-active peak at 858 cm-1 corresponded to Mo-O bond asymmetric stretching. Therefore, we propose the use of a high-power terahertz laser at ~25 THz to facilitate the separation of Mo from Na2MoO4. Experimental investigations are expected in the future.
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OBJECTIVE: To investigate the association of leisure-time physical activity and serum cotinine levels with the risk of periodontitis in the general population and to further analyze the interaction between leisure-time physical activity and serum cotinine levels on the risk of periodontitis. METHODS: This was a cross-sectional study, extracting data from 9605 (56.19%) participants in the National Health and Nutrition Examination Survey (NHANES) database from 2009 to 2014, and analyzing the relationship and interaction effects of serum cotinine level, leisure time physical activity, and risk of periodontitis by weighted univariate logistic modeling; Effect sizes were determined using ratio of ratios (OR), 95% confidence intervals (95% CI). RESULTS: 5,397 (56.19%) of 9,605 participants had periodontitis; an increased risk of periodontitis was found in those in the leisure time physical activity intensity < 750 MET × min/week group (OR = 1.44, 95% CI: 1.17-1.78). Serum cotinine levels ≥ 0.05 ng/ml were associated with an increased risk of periodontitis (OR = 1.99, 95% CI: 1.69-2.33). The group with low leisure physical activity and serum cotinine levels ≥ 0.05 ng/ml had an increased risk of periodontitis compared to the group with high leisure physical activity and serum cotinine levels < 0.05 ng/ml (OR = 2.48, 95% CI: 1.88-3.27). Interaction metrics RERI = 0.90 (95% CI: 0.44-1.36) and API = 0.36 (95% CI: 0.18-0.55); CI for SI = 2.55 (95% CI: 1.03-6.28). for API 0.36. CONCLUSION: Leisure time physical activity intensity interacted with smoking exposure on periodontitis risk and may provide the general population with the opportunity to Increasing leisure-time physical activity and smoking cessation may provide recommendations for the general population.
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Periodontite , Poluição por Fumaça de Tabaco , Humanos , Cotinina/análise , Fumar/efeitos adversos , Poluição por Fumaça de Tabaco/efeitos adversos , Inquéritos Nutricionais , Estudos Transversais , Periodontite/epidemiologia , Exercício Físico , Atividades de LazerRESUMO
Li-excess oxide cathodes have received increasing attention due to their high capacity derived from accumulated cation and anion redox activity. However, Li-excess layered oxides suffer from capacity and voltage decay due to the irreversible phase transition, while cation-disordered cathodes also have the problems of poor cycling stability and rate capability. The rocksalt oxides with a layered-disordered coexistence nanostructure can combine the advantages of both phases such as the inherent high capacity of Li-excess oxides, good rate capability of the layered phase, and structural stability resulting from the intergrown disordered phase. Herein, for rational design, we developed a descriptor by correlating the ionic radius and electronic configuration to predict layered, cation-disordered, and coexistent structures of Li-excess cathode materials. Accordingly, we experimentally synthesized Li1.2Ni0.4Mn0.2Nb0.2O2 oxide with a coexistent structure in which the layered and disordered phases are well combined in the nanoscale region, achieving a high capacity (312 mAh g-1) with good cycling stability and rate capability. The design principle with composition predicting structure provides a valuable strategy in controllably designing and preparing Li-excess cathode materials.
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The construction of heterostructure materials has been demonstrated as the promising approach to design high-performance anode materials for sodium ion batteries (SIBs). Herein, micro-mesoporous cobalt phosphosulfide nanowires (Co3S4/CoP/NC) with Co3S4/CoP hetero-nanocrystals encapsulating into N-doped carbon frameworks were successfully synthesized via hydrothermal reaction and subsequent phosphosulfidation process. The obtained micro-mesoporous nanowires greatly improve the charge transport kinetics from the facilitation of the charge transport into the inner part of nanowire. When evaluated as SIBs anode material, the Co3S4/CoP/NC presents outstanding electrochemical performance and battery properties owing to the synergistic effect between Co3S4 and CoP nanocrystals and the conductive carbon frameworks. The electrode material delivers outstanding reversible rate capacity (722.33 mAh/g at 0.1 A/g) and excellent cycle stability with 522.22 mAh/g after 570 cycles at 5.0 A/g. Besides, the Ex-situ characterizations including XRD, XPS, and EIS further revealed and demonstrated the outstanding sodium ion storage mechanism of Co3S4/CoP/NC electrode. These findings pave a promising way for the development of novel metal phosphosulfide anodes with unexpected performance for SIBs and other alkali ion batteries.
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Tungsten (W) is an extremely rare and vital metal extensively used in metallurgy, the chemical industry, optoelectronic devices, and machinery manufacturing. In this work, an environmentally friendly and efficient physical method based on photon-phonon resonance absorption (PPRA) is proposed for separating W from scheelite. We calculated the vibrational spectrum of calcium tungstate (CaWO4) and assigned the infrared (IR) absorption and Raman scattering peaks through a dynamic analysis of the normal modes. We focused on the strong IR absorption peaks related to W and identified three high-intensity IR-active modes at around 830 cm-1, corresponding to the stretching of the W-O bonds. Therefore, we propose the use of high-power terahertz (â¼25 THz) laser radiation to facilitate W extraction from compounds, leveraging the high efficiency of PPRA. Experimental testing is required to determine the precise absorption frequency under industrial production conditions.
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Familial acute myeloid leukemia (AML) pedigrees with germline CCAAT/enhancer-binding protein-α (CEBPA) mutation have been rarely reported due to insufficient knowledge of their clinical features. Here, we report two Chinese families with multiple AML cases carrying germline CEBPA mutations, one of which had 11 cases spanning four consecutive generations. Additionally, we collected clinical data of 57 AML patients from 22 families with germline CEBPA mutations, with 58.3% of them harboring double CEBPA mutations. The first mutation frequently occurred at the N-terminal of CEBP/α (78.6%), resulting in an exclusive expression of p30 of CEBPA (CEBPAp30). The second mutation was mostly found at the C-terminal of CEBP/α (CEBPAothers). Germline CEBPAp30 carriers had higher incidences of AML (80.36% vs. 42.86%) and earlier onset of AML (18 vs. 38.5 years old) compared to germline CEBPAothers carriers. Despite the high rates of relapse, most familial AML cases exhibited favorable overall survival (OS), with germline CEBPAp30 carriers having better survival outcomes (>25 years vs. 11 years for CEBPAothers carriers). Among the 27 healthy germline CEBPA-mutated carriers, we detected a pre-leukemia clone harboring a pathogenic IDH2 variant (R140Q)in one individual. These findings should aid in the genetic counseling and management of AML patients and healthy carriers with germline CEBPA mutations.
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Proteína alfa Estimuladora de Ligação a CCAAT , Leucemia Mieloide Aguda , Humanos , Adulto , Proteína alfa Estimuladora de Ligação a CCAAT/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/patologia , Proteínas Estimuladoras de Ligação a CCAAT/genética , Mutação , Células Germinativas/patologia , PrognósticoRESUMO
Synthesis of advanced structure and multiple heteroatom-doped carbon based heterostructure materials are the key to the preparation of high-performance energy storage electrode materials. Herein, the hexapod-shaped Co1-xS@NPSC has been triumphantly prepared using hexapod ZIF-67 as the sacrificial template to prepare Co1-xS inner core and N, P, and S tri-doped carbon (NPSC) as the shell through the carbonization of the organic polymer precursor. When applied as anode for Na+ batteries (SIBs) and K+ batteries (PIBs), Co1-xS@NPSC presents the high reversible specific capability of 747.4 mAh/g at 1.0 A/g after 235 cycles and 387.8 mAh/g at 5.0 A/g after 760 cycles for SIBs, as well as 326.7 mAh/g at 1.0 A/g after 180 cycles for PIBs. The excellent storage capacity and rate capability of Co1-xS@NPSC is ascribed to hexapod structure of ZIF-67 unlike the common dodecahedron, which is constructed with interior porous and exterior framework repository, donating supplemental active sites, and doping of multiple heteroatoms forming organic polymer coating inhibiting the volume expansion and restrains the agglomeration of Co1-xS nanoparticles. This approach has paved a bright avenue to exploit promising anode materials with novel structure and hetero-atom doping for high-performance energy storage devices.
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Tantalum (Ta) is a valuable and rare metal that is extensively used in the production of implant materials and high-performance capacitors. However, a convenient and effective method for the separation of Ta from other compounds has yet to be developed. On the basis of first-principle density functional theory (DFT), we simulated the vibrational spectrum of potassium heptafluorotantalate (K2TaF7). By performing a dynamics analysis of vibrational modes, we assigned peaks in infrared (IR) absorption and Raman scattering spectra to their corresponding vibrations. We focused on the strong IR absorption peaks of Ta-related vibrational modes in K2TaF7 and concluded that three observed IR absorption peaks, at 285, 315, and 530 cm-1, are good candidates. Provided with high power radiation at these three frequencies (at about 8.55, 9.45, and 15.9 THz), the good efficiency of photon-phonon resonance absorption will facilitate Ta separation from a compound.
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BACKGROUND: Hepatocellular cancer (HCC) is one of the most harmful tumors to human health. Currently, there is still a lack of highly sensitive and specific HCC biomarkers in clinical practice. In this study, we aimed to explore the diagnostic performance of prostaglandin A2 (PGA2) for the early detection of HCC. METHODS: Untargeted metabolomic analyses on normal control (NC) and HCC participants in the discovery cohort were performed, and PGA2 was identified to be dysregulated in HCC. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for detecting serum PGA2 was established and applied to validate the dysregulation of PGA2 in another independent validation cohort. Receiver operating characteristic (ROC), decision curve analysis (DCA) and some other statistical analyses were performed to evaluate the diagnostic performance of PGA2 for HCC. RESULTS: At first, PGA2 was found to be dysregulated in HCC in untargeted metabolomic analyses. Then a precise quantitative LC-MS/MS method for PGA2 has been established and has passed rigorous method validation. Targeted PGA2 analyses confirmed that serum PGA2 was decreased in HCC compared to normal-risk NC and high-risk cirrhosis group. Subsequently, PGA2 was identified as a novel biomarker for the diagnosis of HCC, with an area under the ROC curve (AUC) of 0.911 for differentiating HCC from the combined NC + cirrhosis groups. In addition, PGA2 exhibited high performance for differentiating small-size (AUC = 0.924), early-stage (AUC = 0.917) and AFP (-) HCC (AUC = 0.909) from the control groups. The combination of PGA2 and AFP might be useful in the surveillance of risk population for HCC and early diagnosis of HCC. CONCLUSION: This study establishes that PGA2 might be a novel diagnostic biomarker for HCC.
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Biomarcadores Tumorais , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/sangue , Biomarcadores Tumorais/sangue , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/sangue , Masculino , Feminino , Pessoa de Meia-Idade , Espectrometria de Massas em Tandem , Cromatografia Líquida , Curva ROCRESUMO
Antimicrobial resistance (AMR) presents an escalating global challenge as conventional antibiotic treatments become less effective. In response, photodynamic therapy (PDT) and photothermal therapy (PTT) have emerged as promising alternatives. While rooted in ancient practices, these methods have evolved with modern innovations, particularly through the integration of lasers, refining their efficacy. PDT harnesses photosensitizers to generate reactive oxygen species (ROS), which are detrimental to microbial cells, whereas PTT relies on heat to induce cellular damage. The key to their effectiveness lies in the utilization of photosensitizers, especially when integrated into nano- or micron-scale supports, which amplify ROS production and enhance antimicrobial activity. Over the last decade, carbon dots (CDs) have emerged as a highly promising nanomaterial, attracting increasing attention owing to their distinctive properties and versatile applications, including PDT and PTT. They can not only function as photosensitizers, but also synergistically combine with other photosensitizers to enhance overall efficacy. This review explores the recent advancements in CDs, underscoring their significance and potential in reshaping advanced antimicrobial therapeutics.
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OBJECTIVE: Type 2 diabetes mellitus (T2DM) is a common chronic metabolic disease. Peroxisome proliferator-activated receptors (PPARs) play crucial roles in regulating glucolipid metabolism. Previous studies showed that E17241 could ameliorate atherosclerosis and lower fasting blood glucose levels in ApoE-/- mice. In this work, we investigated the role of E17241 in glycolipid metabolism in diabetic KKAy mice. APPROACH AND RESULTS: We confirmed that E17241 is a powerful pan-PPAR agonist with a potent agonistic activity on PPARγ, a high activity on PPARα, and a moderate activity on PPARδ. E17241 also significantly increased the protein expression of ATP-binding cassette transporter 1 (ABCA1), a crucial downstream target gene for PPARs. E17241 clearly lowered plasma glucose levels, improved OGTT and ITT, decreased islet cholesterol content, improved ß-cell function, and promoted insulin secretion in KKAy mice. Moreover, E17241 could significantly lower plasma total cholesterol and triglyceride levels, reduce liver lipid deposition, and improve the adipocyte hypertrophy and the inflammatory response in epididymal white adipose tissue. Further mechanistic studies indicated that E17241 boosts cholesterol efflux and insulin secretion in an ABCA1 dependent manner. RNA-seq and qRT-PCR analysis demonstrated that E17241 induced different expression of PPAR target genes in liver and adipose tissue differently from the PPARγ agonist rosiglitazone. In addition, E17241 treatment was also demonstrated to have an exhilarating cardiorenal benefits. CONCLUSIONS: Our results demonstrate that E17241 regulates glucolipid metabolism in KKAy diabetic mice while having cardiorenal benefits without inducing weight gain. It is a promising drug candidate for the treatment of T2DM.
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Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Dislipidemias , Hiperglicemia , Camundongos , Animais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , PPAR gama/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Dislipidemias/tratamento farmacológico , Fígado/metabolismo , Hiperglicemia/tratamento farmacológico , Colesterol/metabolismo , Tecido Adiposo Branco/metabolismoRESUMO
The probability of cardiovascular events has been reported lower in rheumatoid arthritis (RA) patients treated with leflunomide. However, the anti-atherosclerotic and cardiovascular protective effects and metabolism of leflunomide are not explored. In this study, we assessed the potential benefits of leflunomide on atherosclerosis and revealed the underlying mechanism. ApoE-/- mice were fed a western diet (WD) alone or supplemented with leflunomide (20 mg/kg, oral gavage, once per day) for 12 weeks. Samples of the aorta, heart, liver, serum, and macrophages were collected. We found that leflunomide significantly reduced lesion size in both en-face aortas and aortic root in WD-fed ApoE-/- mice. Leflunomide also obviously improved dyslipidemia, reduced hepatic lipid content, and improved disorders of glucose and lipid metabolism in vivo. RNA-Seq results showed that leflunomide effectively regulated the genes' expression involved in the lipid metabolism pathway. Importantly, leflunomide significantly increased the phosphorylation levels of AMPKα and acetyl-CoA carboxylase (ACC) in vivo. Furthermore, leflunomide and its active metabolite teriflunomide suppressed lipid accumulation in free fatty acid (FFA)-induced AML12 cells and improved endothelial dysfunction in palmitic acid (PA)-induced HUVECs through activating AMPK signaling and inhibiting dihydroorotate dehydrogenase (DHODH) signaling pathway. We present evidence that leflunomide and teriflunomide ameliorate atherosclerosis by regulating lipid metabolism and endothelial dysfunction. Our findings suggest a promising use of antirheumatic small-molecule drugs leflunomide and teriflunomide for the treatment of atherosclerosis and related cardiovascular diseases (CVDs).