RESUMO
BACKGROUND: Hyperlipidemia damages vascular wall and serves as a foundation for diseases such as atherosclerosis, hypertension and stiffness. The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is implicated in vascular dysfunction associated with hyperlipidemia-induced vascular injury. Sodium tanshinone IIA sulfonate (STS), a well-established cardiovascular protective drug with recognized anti-inflammatory, antioxidant, and vasodilatory properties, is yet to be thoroughly investigated for its impact on vascular relaxant imbalance induced by hyperlipidemia. METHODS: In this study, we treated ApoE-knockout (ApoE-/-) mouse with STS and assessed the activation of the NLRP3 inflammasome, expression of MMP2/9, integrity of elastic fibers, and vascular constriction and relaxation. RESULTS: Our findings reveal that STS intervention effectively preserves elastic fibers, significantly restores aortic relaxation function in ApoE-/- mice, and reduces their excessive constriction. Furthermore, STS inhibits the phosphorylation of spleen tyrosine kinase (SYK), suppresses NLRP3 inflammasome activation, and reduces MMP2/9 expression. CONCLUSIONS: These results demonstrate that STS protects vascular relaxation against hyperlipidemia-induced damage through modulation of the SYK-NLRP3 inflammasome-MMP2/9 pathway. This research provides novel insights into the mechanisms underlying vascular relaxation impairment in a hyperlipidemic environment and uncovers a unique mechanism by which STS preserves vascular relaxation, offering valuable foundational research evidence for its clinical application in promoting vascular health.
Assuntos
Modelos Animais de Doenças , Inflamassomos , Metaloproteinase 2 da Matriz , Metaloproteinase 9 da Matriz , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Proteína 3 que Contém Domínio de Pirina da Família NLR , Fenantrenos , Transdução de Sinais , Quinase Syk , Vasodilatação , Animais , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Inflamassomos/metabolismo , Quinase Syk/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Fenantrenos/farmacologia , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Vasodilatação/efeitos dos fármacos , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/fisiopatologia , Vasodilatadores/farmacologia , Fosforilação , Camundongos , Aorta/efeitos dos fármacos , Aorta/fisiopatologia , Aorta/metabolismo , Aorta/enzimologia , Apolipoproteínas ERESUMO
Diabetes accelerates vascular senescence, which is the basis for atherosclerosis and stiffness. The activation of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and oxidative stress are closely associated with the deteriorative senescence in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs). For decades, Sodium Tanshinone IIA Sulfonate (STS) has been utilized as a cardiovascular medicine with acknowledged anti-inflammatory and anti-oxidative properties. Nevertheless, the impact of STS on vascular senescence remains unexplored in diabetes. Diabetic mice, primary ECs and VSMCs were transfected with the NLRP3 overexpression/knockout plasmid, the tumor necrosis factor alpha-induced protein 3 (TNFAIP3/A20) overexpression/knockout plasmid, and treated with STS to detect senescence-associated markers. In diabetic mice, STS treatment maintained catalase (CAT) level and vascular relaxation, reduced hydrogen peroxide probe (ROSgreen) fluorescence, p21 immunofluorescence, Senescence ß-Galactosidase Staining (SA-ß-gal) staining area, and collagen deposition in aortas. Mechanistically, STS inhibited NLRP3 phosphorylation (serine 194), NLRP3 dimer formation, NLRP3 expression, and NLRP3-PYCARD (ASC) colocalization. It also suppressed the phosphorylation of IkappaB alpha (IκBα) and NFκB, preserved A20 and CAT levels, reduced ROSgreen density, and decreased the expression of p21 and SA-ß-gal staining in ECs and VSMCs under HG culture. Our findings indicate that STS mitigates vascular senescence by modulating the A20-NFκB-NLRP3 inflammasome-CAT pathway in hyperglycemia conditions, offering novel insights into NLRP3 inflammasome activation and ECs and VSMCs senescence under HG culture. This study highlights the potential mechanism of STS in alleviating senescence in diabetic blood vessels, and provides essential evidence for its future clinical application.
Assuntos
Senescência Celular , Diabetes Mellitus Experimental , Inflamassomos , NF-kappa B , Proteína 3 que Contém Domínio de Pirina da Família NLR , Fenantrenos , Transdução de Sinais , Animais , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Inflamassomos/metabolismo , Camundongos , NF-kappa B/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Fenantrenos/farmacologia , Senescência Celular/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Catalase/metabolismo , Masculino , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacosRESUMO
We evaluated the combination treatment of ethaselen (BBSKE) as a thioredoxin reductase (TrxR) inhibitor plus cisplatin (CDDP) on the human colon adenocarcinoma cell line LoVo. Therapeutic effects ranging from nearly additive to clearly synergistic demonstrated an effective combination, i.e., the cytostatic dose of CDDP could be reduced without a loss in efficacy. To further investigate the cellular response mechanisms of these favorable outcomes, we analyzed the cell-cycle profiles, mRNA expression patterns, and protein levels of several key genes after incubation with BBSKE or CDDP separately and in combination. In appropriate conditions, CDDP induced arrest at the G2/M phase accompanied by the enhanced inhibitory phosphorylation of Cdk1 and the elevated protein expression of cyclin B1. BBSKE downregulated expression of cyclin D1 by increasing mRNA and protein levels of p21, and thus induced G1 phase arrest. BBSKE returned Cdk1 to an activated state, and reduced the protein level of cyclin B1 after incubation in combination with CDDP, which was consistent with the reduction in the percentage of cells in G2/M identified by flow cytometry. By regulating the G1 phase and reversing CDDP-induced G2/M phase arrest, BBSKE increases drug sensitivity of LoVo cells toward CDDP, and probably provides a meaningful anticancer strategy for further clinical studies.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Divisão Celular/efeitos dos fármacos , Cisplatino/farmacologia , Neoplasias do Colo/enzimologia , Neoplasias do Colo/patologia , Fase G1/efeitos dos fármacos , Compostos Organosselênicos/farmacologia , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Divisão Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/genética , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Citometria de Fluxo , Fase G1/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Modelos Biológicos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Tiorredoxina Dissulfeto Redutase/metabolismoRESUMO
It has been proposed that thioredoxin reductase (TR) is a mediator that allows non-small cell lung cancer (NSCLC) to develop resistance to irradiation; however, little is known regarding the detailed mechanisms of action. Thus, ethaselen {1, 2-[bis (1,2-benzisoselenazolone-3 (2H)-ketone)] ethane, BBSKE}, a novel organoselenium TR inhibitor, is currently being investigated in a phase I clinical trial in China. However, its radiosensitizing effect remains unexplored. In this study, we found that the activity of TR increased dramatically in both A549 and H1299 cells after radiation, and moreover, could be inhibited by pretreatment with BBSKE (5 µmol/l). As a TR inhibitor, BBSKE enhanced the efficacy of radiation therapy both in vivo and in vitro without observable toxicity. BBSKE was found to suppress irradiation-induced NF-κB activation dramatically when using A549 cells stably transfected with NF-κB luciferase reporter. These results show the critical role of TR in the radioresistance of NSCLC and suggest that BBSKE is a potentially promising agent for the treatment of patients with NSCLC clinically.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Compostos Organosselênicos/farmacologia , Radiossensibilizantes/farmacologia , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/toxicidade , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Linhagem Celular Tumoral , Genes Reporter , Humanos , Luciferases/genética , Neoplasias Pulmonares/radioterapia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/efeitos dos fármacos , NF-kappa B/metabolismo , NF-kappa B/efeitos da radiação , Compostos Organosselênicos/toxicidade , Tolerância a Radiação , Radiossensibilizantes/toxicidade , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , TransfecçãoRESUMO
The increasing incidence of morbidly adherent placenta (MAP) is placing women at a higher risk of life-threatening massive hemorrhage. The involvement of interventional radiology to manage this complex condition by performing prophylactic iliac artery balloon occlusion has been reported recently. However, the effectiveness and safety of this technique have not been fully determined. Here we report the case of a 25-year-old woman with placenta increta with preemptive bilateral internal iliac artery balloons who had external iliac artery thrombosis detected by computed tomography angiography (CTA) 72 h post cesarean section. A digital subtraction angiogram (DSA) and intra-arterial thrombolysis were instantly performed followed by supplementary conservative treatments, leading to a desirable resolution of thrombus without sequela. This is the first report of vascular complications with successful interventional thrombolysis in this setting. Our experience suggests that prophylactic iliac artery balloon occlusion should be used cautiously in cases of MAP and consideration given to minimizing vascular complications given the hypercoagulable state of pregnancy.
Assuntos
Oclusão com Balão/efeitos adversos , Artéria Ilíaca/cirurgia , Placenta Acreta/cirurgia , Terapia Trombolítica/métodos , Adulto , Angiografia Digital , Coagulação Sanguínea , Perda Sanguínea Cirúrgica/prevenção & controle , Cateterismo , Cesárea , Feminino , Humanos , Imageamento Tridimensional , Imageamento por Ressonância Magnética , Tomografia Computadorizada Multidetectores , Placenta/cirurgia , Gravidez , Doenças VascularesRESUMO
This brief article focuses on two aims: i) To investigate the in vitro pharmaco-dynamic interactions of combining synthetic potent microtubule targeting anticancer agent, Fludelone (FD) with cyto-protective agent, Panaxytriol (PXT) derived from Panax ginseng, and ii) To illustrate step-by-step operation for conducting two-drug combination in vitro using the combination index method, in terms of experimental design, data acquisition, computerized simulation and data interpretation. The Chou-Talalay method for drug combination is based on the median-effect equation, which provides the theoretical basis for the combination index (CI)-isobologram equation that allows quantitative determination of drug interactions, where CI<1, =1, and >1 indicates synergism, additive effect and antagonism, respectively. Based on these algorithms, computer software, CompySyn, is used for determining synergism and antagonism at all doses or effect levels simulated automatically. The use of Chou-Talalay's CI method in quantifying synergism or antagonism is increasing steadily during the past two decades, however, confusing questions and pitfalls were still frequently raised by insufficient understanding of the theory, especially reflected when researchers trying to use the computerized software to design and conduct experiments. In order to specifically address the confusions and to illustrate the practical features of this method, in this paper, a selected example is given based on our unpublished data regarding the combinational pharmacologic interactions of FD and PXT against the growth of breast cancer cell line MX-1. The step-by-step operation from experimental design to the real data analysis is illustrated. The results indicated that FD and PXT combination in vitro exerted synergistic effect when cell growth inhibition was greater than 45%, with CI ranged 0.836-0.609 for the fractional inhibition of Fa=0.50~0.90, as shown by the Fa-CI plot and by the isobologram. Thus, quantitative conclusion of synergism is obtained using the Chou-Talalay CI method, under the well-defined simple conditions for the FD and PXT combinations in vitro.