RESUMO
Vascular calcification is a pathological process commonly associated with atherosclerosis, chronic kidney disease, and diabetes. Paraspeckle protein NONO is a multifunctional RNA/DNA binding protein involved in many nuclear biological processes but its role in vascular calcification remains unclear. Here, we observed that NONO expression was decreased in calcified arteries of mice and patients with CKD. We generated smooth muscle-specific NONO-knockout mice and established three different mouse models of vascular calcification by means of 5/6 nephrectomy, adenine diet to induce chronic kidney failure, or vitamin D injection. The knockout mice were more susceptible to the development of vascular calcification relative to control mice, as verified by an increased calcification severity and calcium deposition. Likewise, aortic rings from knockout mice showed more significant vascular calcification than those from control mice ex vivo. In vitro, NONO deficiency aggravated high phosphate-induced vascular smooth muscle cell osteogenic differentiation and apoptosis, whereas NONO overexpression had a protective effect. Mechanistically, we demonstrated that the regulation of vascular calcification by NONO was mediated by bone morphogenetic protein 2 (BMP2). NONO directly bound to the BMP2 promoter using its C-terminal region, exerting an inhibitory effect on the transcription of BMP2. Thus, our study reveals that NONO is a novel negative regulator of vascular calcification, which inhibits osteogenic differentiation of vascular smooth muscle cell and vascular calcification via negatively regulating BMP2 transcription. Hence, NONO may provide a promising target for the prevention and treatment of vascular calcification.
Assuntos
Proteína Morfogenética Óssea 2 , Modelos Animais de Doenças , Camundongos Knockout , Músculo Liso Vascular , Miócitos de Músculo Liso , Osteogênese , Insuficiência Renal Crônica , Transcrição Gênica , Calcificação Vascular , Animais , Humanos , Masculino , Camundongos , Doenças da Aorta/genética , Doenças da Aorta/prevenção & controle , Doenças da Aorta/patologia , Doenças da Aorta/metabolismo , Apoptose/efeitos dos fármacos , Proteína Morfogenética Óssea 2/metabolismo , Proteína Morfogenética Óssea 2/genética , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Regiões Promotoras Genéticas , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/prevenção & controle , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Calcificação Vascular/patologia , Calcificação Vascular/prevenção & controle , Calcificação Vascular/metabolismo , Calcificação Vascular/genética , Calcificação Vascular/etiologiaRESUMO
The inflammation of adipose tissue is one of the most common secondary pathological changes in atherosclerosis, which in turn influences the process of atherosclerosis. Natriuretic peptides have been revealed important effect in regulating adipose metabolism. However, the relationship between natriuretic peptide receptor C and inflammation of adipose tissue in atherosclerosis remains unknown. This study aims to explore the effect natriuretic peptide receptor C exerts on the regulation of the adipose inflammation in atherosclerotic mice induced by western-type diet and its overlying mechanisms. To clarify the importance of NPRC of adipose inflammation in atherosclerotic mice, NPRC expression was measured in mice fed with chow diet and western-type diet for 12 weeks and we found a considerable increase in adipose tissue of atherosclerotic mice. Global NPRC knockout in mice was bred onto ApoE-/- mice to generate NPRC-/- ApoE-/- mice, which displayed remarked increase in browning of white adipose tissue and lipolysis of adipose tissue and decrease in adipose inflammation manifested by decreased macrophage invasion to form less CLS (crown-like structure), reduced oxidative stress and alleviated expression of TNFα, IL-6, IL-1ß and MCP1, but increased expression of adiponectin in adipose tissue. Moreover, our study showed that white adipose tissue browning in NPRC-/- ApoE-/- atherosclerotic mice was associated with decreased inflammatory response through cAMP/PKA signalling activation. These results identify NPRC as a novel regulator for adipose inflammation in atherosclerotic mice by modulating white adipose tissue browning.
Assuntos
Apolipoproteínas E/deficiência , Hipercolesterolemia/complicações , Paniculite/etiologia , Paniculite/metabolismo , Receptores do Fator Natriurético Atrial/deficiência , Animais , Biomarcadores , AMP Cíclico , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças , Regulação da Expressão Gênica , Hipercolesterolemia/genética , Hipercolesterolemia/metabolismo , Imuno-Histoquímica , Inflamassomos/metabolismo , Camundongos , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Estresse Oxidativo , Paniculite/patologia , Transdução de SinaisRESUMO
We evaluated the performance of arterial spin-labeled perfusion imaging and diffusion-weighted imaging in diagnosing full-term neonatal hypoxic-ischemic encephalopathy. Arterial spin-labeled, diffusion-weighted imaging and conventional magnetic resonance imaging (T1-weighted imaging, T2-weighted imaging and T2 fluid-attenuated inversion recovery) were performed in 23 full-term neonates with hypoxic-ischemic encephalopathy group 10 normal neonates (Control group). The cerebral blood flow and the apparent diffusion coefficient were measured in the bilateral basal ganglia, thalamus and frontal white matter. The effect of neonatal age on the CBF and apparent diffusion coefficient values were further investigated after dividing the 23 ischemic encephalopathy cases into three subgroups (1-3 days, 4-7 days, and 8-15 days). The cerebral blood flow values in the thalamus and lenticular nucleus were significantly higher. The apparent diffusion coefficient values in the thalamus, frontal white matter and lenticular nucleus head were significantly lower in the hypoxic-ischemic encephalopathy group than those in the Control group (p < 0.05). There were no significant differences between the ischemic encephalopathy and Control groups in the cerebral blood flow values in the caudate nucleus head and frontal lobe white matter (p > 0.05). The cerebral blood flow and apparent diffusion coefficient values in the thalamus and lenticular nucleus were negatively correlated. Comparison among different age subgroups of hypoxic-ischemic encephalopathyneonates showed that the cerebral blood flow value was higher. In comparison, the apparent diffusion coefficient value was lower in the 1-3 days old neonates than those in the older neonates (p < 0.05). Arterial spin-labeled and diffusion-weighted imaging could reflect the ischemic encephalopathy pathological processes more comprehensively. The cerebral blood flow measurement and apparent diffusion coefficient values in the thalamus and the lenticular nucleus may represent a novel way to diagnose ischemic encephalopathy early.
Assuntos
Circulação Cerebrovascular , Hipóxia-Isquemia Encefálica/diagnóstico por imagem , Imageamento por Ressonância Magnética/normas , Neuroimagem/normas , Fatores Etários , Circulação Cerebrovascular/fisiologia , Imagem de Difusão por Ressonância Magnética/métodos , Imagem de Difusão por Ressonância Magnética/normas , Feminino , Substância Cinzenta/diagnóstico por imagem , Humanos , Recém-Nascido , Imageamento por Ressonância Magnética/métodos , Masculino , Neuroimagem/métodos , Imagem de Perfusão/métodos , Imagem de Perfusão/normas , Marcadores de Spin , Substância Branca/diagnóstico por imagemRESUMO
Catalytic conversion of CO2 including hydrogenation has attracted great attention as a method for chemical fixation of CO2 in combination with other techniques such as CO2 capture and storage. Potassium is a well-known promotor for many industrial catalytic processes such as in Fischer-Tropsch synthesis. In this work, we performed density functional theory (DFT) calculations to investigate the effect of potassium on the adsorption, activation, and dissociation of CO2 over Fe(100), Fe5C2(510) and Fe3O4(111) surfaces. The function of K was analyzed in terms of electronic interactions between co-adsorbed CO2 and K-surfaces which showed conspicuous promotion in the presence of K of the adsorption and activation of CO2. The adsorption strength of CO2 on these surfaces ranks as oct2-Fe3O4(111) > Fe(100) > Fe5C2(510). Generally, we observed a direct proportional correlation between the adsorption strength and the charges on the adsorbates. Adding K on the catalyst surface also reduces the kinetic barrier for CO2 dissociation. CO2 dissociation is more facile to occur on Fe(100) and Fe5C2(510) in the presence of K whereas the Fe3O4(111) surfaces impede CO2 dissociation regardless of the existence of K. Instead, a stable CO3- species is formed upon CO2 adsorption on Fe3O4(111) which will be directly hydrogenated when sufficient H* are available on the surface. Our results highlight the origin of the promotion effect of potassium and provide insight for the future design of K-promoted Fe-based catalysts for CO2 hydrogenation.
RESUMO
Protein tyrosine phosphatase 1B (PTP1B) is implicated as a negative regulator of insulin receptor (IR) signaling and a potential drug target for the treatment of type II diabetes and other associated metabolic syndromes. Thus, small molecule inhibitors of PTP1B can be considered as an attractive approach for the design of new therapeutic agents of type II diabetes and cancer diseases. In a continuing search for new PTP1B inhibitors, a new tetramic acid possessing a rare pyrrolidinedione skeleton named fumosorinone A (1), together with five known ones 2-6 were isolated from the entomogenous fungus Isaria fumosorosea. The structures of 2-6 were elucidated by extensive spectroscopic analysis. Fumosorinone A (1) and beauvericin (6) showed significant PTP1B inhibitory activity with IC50 value of 3.24 µM and 0.59 µM.
Assuntos
Depsipeptídeos/química , Hypocreales/química , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Succinimidas/química , Depsipeptídeos/isolamento & purificação , Humanos , Transdução de Sinais , Succinimidas/isolamento & purificaçãoRESUMO
AIMS/INTRODUCTION: Regulatory T cells (Tregs) have protected against many cardiovascular diseases. This study was intended to explore the effect of Tregs on diabetic cardiomyopathy (DCM) using a db/db mouse model. MATERIALS AND METHODS: Eight-week-old male db/db mice were randomly divided into four groups: the control group, administered 200 µL phosphate-buffered saline; the small-dose Treg group, administered 105 Tregs; the large-dose Treg group, administered 106 Tregs; and the PC group, administered 100 µg anti-CD25 specific antibody (PC61) and 106 Tregs. After 12 weeks, mice were euthanized. Transthoracic echocardiography was carried out at the beginning and end of the experiment. Relevant basic experiments to evaluate the effects of Tregs on DCM were carried out. RESULTS: Echocardiography showed that the impaired diastolic and systolic functions were significantly improved in mice administered large-dose Tregs. Large-dose Tregs significantly ameliorated myocardial hypertrophy and fibrosis, and decreased hypertrophic gene expression and collagen deposition. The protective effects of Tregs on diabetic hearts were associated with decreased oxidative stress, inflammatory response and apoptosis. In addition, Tregs promoted the activation of the phosphatidylinositol 3-kinase-protein kinase B signaling pathway, whereas they inhibited extracellular signal-regulated kinase 1/2 and Jun N-terminal kinase phosphorylation, which might be responsible for the cardioprotective role of Tregs against DCM. CONCLUSIONS: Tregs ameliorated myocardial hypertrophy and fibrosis, improved cardiac dysfunction, and protected against DCM progression in db/db mice. The mechanisms involved a decrease of inflammatory response, oxidative stress and apoptosis, which might be mediated by phosphatidylinositol 3-kinase-protein kinase B and mitogen-activated protein kinase pathways. Hence, Tregs might serve as a promising therapeutic approach for DCM treatment.
Assuntos
Cardiomiopatias Diabéticas , Linfócitos T Reguladores , Animais , Linfócitos T Reguladores/imunologia , Cardiomiopatias Diabéticas/prevenção & controle , Cardiomiopatias Diabéticas/imunologia , Masculino , Camundongos , Estresse Oxidativo , Apoptose , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/imunologia , Modelos Animais de Doenças , Transdução de SinaisRESUMO
Acute respiratory distress syndrome (ARDS) is a devastating respiratory disorder, characterized by overwhelming inflammation in the alveoli without effective pharmacological treatment. We aimed to investigate the effect and mechanism of angiotensin II type 2 receptor (AT2R) agonist, Compound 21 (C21), on the lipopolysaccharide (LPS)-induced acute lung injury (ALI) model. The protective effect of C21 was evaluated via enzyme-linked immunosorbent assay (ELISA), Western blot (WB), real-time PCR, and fluorescence microscopy in LPS-challenged THP1-derived macrophages. Besides, the in vivo efficacy of C21 was assessed using cell counting, ELISA, protein quantification, hematoxylin-eosin (H&E) staining, and WB in an LPS-induced ALI mouse model. The results showed that C21 significantly inhibited the secretion of pro-inflammatory cytokines (CCL-2, IL-6), overproduction of intracellular ROS, and activation of inflammatory pathways (NF-κB/NLRP3, p38/MAPK) in THP-1 cell-derived macrophages stimulated by LPS. In in vivo study, intraperitoneal injection of C21 could reduce airway leukocytes accumulation and chemokine/cytokine (keratinocyte chemoattractant (KC), IL-6) generation, as well as alleviate diffuse alveolar damage induced by LPS. Conclusively, the AT2R agonist C21 significantly inhibited LPS-stimulated excess inflammatory responses and oxidative stress in macrophages. Meanwhile, C21 could effectively alleviate acute inflammation and tissue damage in the lungs of ALI mice challenged by LPS. The results of this study bring new hope for the early treatment of ALI/ARDS.
Assuntos
Lesão Pulmonar Aguda , Síndrome do Desconforto Respiratório , Camundongos , Animais , Lipopolissacarídeos/toxicidade , Receptor Tipo 2 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/uso terapêutico , Interleucina-6/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/metabolismo , Citocinas/metabolismo , Pulmão/metabolismo , Macrófagos , NF-kappa B/metabolismo , Inflamação/tratamento farmacológico , Síndrome do Desconforto Respiratório/induzido quimicamente , Síndrome do Desconforto Respiratório/tratamento farmacológicoRESUMO
BACKGROUND: Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a common acute respiratory failure due to diffuse pulmonary inflammation and oedema. Elaborate regulation of macrophage activation is essential for managing this inflammatory process and maintaining tissue homeostasis. In the past decades, metabolic reprogramming of macrophages has emerged as a predominant role in modulating their biology and function. Here, we observed reduced expression of carnitine palmitoyltransferase 1A (CPT1A), a key rate-limiting enzyme of fatty acid oxidation (FAO), in macrophages of lipopolysaccharide (LPS)-induced ALI mouse model. We assume that CPT1A and its regulated FAO is involved in the regulation of macrophage polarization, which could be positive regulated by interleukin-10 (IL-10). METHODS: After nasal inhalation rIL-10 and/or LPS, wild type (WT), IL-10-/-, Cre-CPT1Afl/fl and Cre+CPT1Afl/fl mice were sacrificed to harvest bronchoalveolar lavage fluid, blood serum and lungs to examine cell infiltration, cytokine production, lung injury severity and IHC. Bone marrow-derived macrophages (BMDMs) were extracted from mice and stimulated by exogenous rIL-10 and/or LPS. The qRT-PCR, Seahorse XFe96 and FAO metabolite related kits were used to test the glycolysis and FAO level in BMDMs. Immunoblotting assay, confocal microscopy and fluorescence microplate were used to test macrophage polarization as well as mitochondrial structure and function damage. RESULTS: In in vivo experiments, we found that mice lacking CPT1A or IL-10 produced an aggravate inflammatory response to LPS stimulation. However, the addition of rIL-10 could alleviate the pulmonary inflammation in mice effectively. IHC results showed that IL-10 expression in lung macrophage decreased dramatically in Cre+CPT1Afl/fl mice. The in vitro experiments showed Cre+CPT1Afl/fl and IL-10-/- BMDMs became more "glycolytic", but less "FAO" when subjected to external attacks. However, the supplementation of rIL-10 into macrophages showed reverse effect. CPT1A and IL-10 can drive the polarization of BMDM from M1 phenotype to M2 phenotype, and CPT1A-IL-10 axis is also involved in the process of maintaining mitochondrial homeostasis. CONCLUSIONS: CPT1A modulated metabolic reprogramming and polarisation of macrophage under LPS stimulation. The protective effects of CPT1A may be partly attributed to the induction of IL-10/IL-10 receptor expression.
Assuntos
Lesão Pulmonar Aguda , Carnitina O-Palmitoiltransferase , Interleucina-10 , Macrófagos , Animais , Masculino , Camundongos , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/tratamento farmacológico , Carnitina O-Palmitoiltransferase/metabolismo , Carnitina O-Palmitoiltransferase/genética , Modelos Animais de Doenças , Interleucina-10/metabolismo , Lipopolissacarídeos , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Fenótipo , Camundongos KnockoutRESUMO
Acute lung injury (ALI) or its severe form, acute respiratory distress syndrome (ARDS) is a life-threatening illness without effective therapeutic interventions currently. Multiple lines of evidence indicated that overwhelming inflammatory responses and impaired epithelial barrier contributed to the pathogenesis of ALI/ARDS. Recently, dopamine (DA) system was identified to participate in various pulmonary diseases. Here, we discovered that dopamine D1-like receptors mainly expressed in macrophages and airway epithelial cells (AECs), which were downregulated by lipopolysaccharide (LPS) challenge in ALI mouse lung. SKF38393 (SKF) is a selective agonist for D1-like receptors and was demonstrated to inhibit excessive inflammatory responses and oxidative stress in THP-1 cell-derived macrophages and Beas-2B cells, as well as improve airway epithelial barrier dysfunction induced by LPS stimulation. Moreover, SKF administration could effectively decrease pulmonary inflammation, ameliorate tissue damage in the LPS-triggered ALI mice. The broad protective actions of SKF might be attributed to the activation of Nrf2 antioxidative system by use of the specific inhibitor, ML385. This study offers evidence of potent immunoregulatory activity of SKF in macrophages, AECs as well as ALI mouse model, which opens novel therapeutic avenues for the intervention of ALI/ARDS.
Assuntos
Lesão Pulmonar Aguda , Síndrome do Desconforto Respiratório , Animais , Camundongos , Lipopolissacarídeos/toxicidade , Agonistas de Dopamina/efeitos adversos , Dopamina , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/patologia , Macrófagos , Células Epiteliais/patologia , Síndrome do Desconforto Respiratório/patologia , Receptores de Dopamina D1 , PulmãoRESUMO
Cardiac fibrosis plays a key role in the progression of diabetic cardiomyopathy (DCM). Previous studies demonstrated the cardioprotective effects of natriuretic peptides. However, the effects of natriuretic peptide receptor C (NPRC) on cardiac fibrosis in DCM remains unknown. Here, we observed that myocardial NPRC expression was increased in mice and patients with DCM. NPRC-/- diabetic mice showed alleviated cardiac fibrosis, as well as improved cardiac function and remodeling. NPRC knockdown in both cardiac fibroblasts and cardiomyocytes decreased collagen synthesis and proliferation of cardiac fibroblasts. RNA sequencing identified that NPRC deletion up-regulated the expression of TGF-ß-induced factor homeobox 1 (TGIF1), which inhibited the phosphorylation of Smad2/3. Furthermore, TGIF1 up-regulation was mediated by the activation of cAMP/PKA and cGMP/PKG signaling induced by NPRC deletion. These findings suggest that NPRC deletion attenuated cardiac fibrosis and improved cardiac remodeling and function in diabetic mice, providing a promising approach to the treatment of diabetic cardiac fibrosis.
Assuntos
Diabetes Mellitus Experimental , Cardiomiopatias Diabéticas , Receptores do Fator Natriurético Atrial , Animais , Camundongos , Diabetes Mellitus Experimental/genética , Cardiomiopatias Diabéticas/genética , Cardiomiopatias Diabéticas/metabolismo , Fibrose , Miócitos Cardíacos/metabolismo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Receptores do Fator Natriurético Atrial/genéticaRESUMO
BACKGROUND: Multiple studies have provided evidence that miR-143 and miR-145 play a crucial role in the pathogenesis and progression of atherosclerosis. In the present study, we aim to investigate the expression of plasma miR-143 and miR-145 in patients with acute coronary syndrome (ACS) and their association with the severity of coronary artery stenosis. METHODS: The study enrolled 279 patients with ACS, including 201 patients with unstable angina (UA) and 78 patients with acute myocardial infarction (AMI), and 65 matched subjects as the control group. The plasma levels of miR-143 and miR-145 were detected by quantitative real-time PCR (qRT-PCR). Gensini score was applied to evaluate the severity of coronary artery stenosis. RESULTS: Plasma levels of miR-143 and miR-145 in patients with ACS were both decreased compared with the control group (p < 0.001). Plasma levels of miR-143 and miR-145 were negatively correlated with Gensini score (miR-143: r = -0.246, p < 0.001; miR-145: r = -0.222, p < 0.001). Logistic regression analysis showed that miR-143 and miR-145 were protective factors for the onset of ACS, UA, or AMI separately. MiR-143 (AUC: 0.786, p < 0.001) and miR-145 (AUC: 0.793, p < 0.001) were able to predict the degree of coronary artery stenosis greater than 50 %. CONCLUSION: The plasma levels of miR-143 and miR-145 were significantly decreased in ACS patients and were negatively correlated with coronary stenosis. In conclusion, plasma miR-143 and miR-145 levels can be used as noninvasive biomarkers for evaluating coronary artery stenosis.
Assuntos
Síndrome Coronariana Aguda , Estenose Coronária , MicroRNAs , Infarto do Miocárdio , Humanos , Síndrome Coronariana Aguda/diagnóstico , Síndrome Coronariana Aguda/genética , Biomarcadores , Estenose Coronária/diagnóstico , Angina Instável , MicroRNAs/genéticaRESUMO
Introduction: The energy imbalance when energy intake exceeds expenditure acts as an essential factor in the development of insulin resistance (IR). The activity of brown adipose tissue, which is involved in the dissipation of energy via heat expenditure decreases under type 2 diabetic mellitus (T2DM) state when the number of pathological aging adipocytes increases. Protein tyrosine phosphatase non-receptor type 2 (PTPN2) regulates several biological processes by dephosphorylating several cellular substrates; however, whether PTPN2 regulates cellular senescence in adipocytes and the underlying mechanism has not been reported. Methods: We constructed a model of type 2 diabetic mice with PTPN2 overexpression to explore the role of PTPN2 in T2DM. Results: We revealed that PTPN2 facilitated adipose tissue browning by alleviating pathological senescence, thus improving glucose tolerance and IR in T2DM. Mechanistically, we are the first to report that PTPN2 could bind with transforming growth factor-activated kinase 1 (TAK1) directly for dephosphorylation to inhibit the downstream MAPK/NF-κB pathway in adipocytes and regulate cellular senescence and the browning process subsequently. Discussion: Our study revealed a critical mechanism of adipocytes browning progression and provided a potential target for the treatment of related diseases.
RESUMO
Acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) is a critical respiratory syndrome with limited effective interventions. Lung macrophages play a critical role in the pathogenesis of abnormal inflammatory response in the syndrome. Recently, impaired fatty acid oxidation (FAO), one of the key lipid metabolic signalings, was found to participate in the onset and development of various lung diseases, including ALI/ARDS. Lipid/fatty acid contents within mouse lungs were quantified using the Oil Red O staining. The protective effect of FAO activator L-carnitine (Lca, 50, 500, or 5 mg/mL) was evaluated by cell counting kit 8 (CCK-8) assay, real-time quantitative PCR (qPCR), ELISA, immunoblotting, fluorescence imaging, and fluorescence plate reader detection in lipopolysaccharide (LPS) (100 ng/mL)-stimulated THP-1-derived macrophages. The in vivo efficacy of Lca (300 mg/kg) was determined in a 10 mg/kg LPS-induced ALI mouse model. We found for the first time that lipid accumulation in pulmonary macrophages was significantly increased in a classical ALI murine model, which indicated disrupted FAO induced by LPS. Lca showed potent anti-inflammatory and antioxidative effects on THP-1 derived macrophages upon LPS stimulation. Mechanistically, Lca was able to maintain FAO, mitochondrial activity, and ameliorate mitochondrial dynamics. In the LPS-induced ALI mouse model, we further discovered that Lca inhibited neutrophilic inflammation and decreased diffuse damage, which might be due to the preservation of mitochondrial homeostasis. These results broadened our understanding of ALI/ARDS pathogenesis and provided a promising drug candidate for this syndrome.
Assuntos
Lesão Pulmonar Aguda , Síndrome do Desconforto Respiratório , Camundongos , Animais , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patologia , Lipopolissacarídeos , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/induzido quimicamente , Inflamação/metabolismo , Síndrome do Desconforto Respiratório/metabolismo , Síndrome do Desconforto Respiratório/patologia , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Ácidos Graxos , Pulmão/patologiaRESUMO
Previous studies suggested a beneficial effect of natriuretic peptides in animal models of cardiovascular disease, but the role of natriuretic peptide receptor C (NPRC) in the pathogenesis of atherosclerosis (AS) remains unknown. This study was designed to test the hypothesis that NPRC may promote AS lesion formation and instability by enhancing oxidative stress, inflammation, and apoptosis via protein kinase A (PKA) signaling. ApoE-/- mice were fed chow or Western diet for 12 weeks and NPRC expression was significantly increased in the aortic tissues of Western diet-fed mice. Systemic NPRC knockout mice were crossed with ApoE-/- mice to generate ApoE-/-NPRC-/- mice, and NPRC deletion resulted in a significant decrease in the size and instability of aortic atherosclerotic lesions in ApoE-/-NPRC-/- versus ApoE-/- mice. In addition, endothelial cell-specific NPRC knockout attenuated atherosclerotic lesions in mice. In contrast, endothelial cell overexpression of NPRC aggravated the size and instability of atherosclerotic aortic lesions in mice. Experiments in vitro showed that NPRC knockdown in human aortic endothelial cells (HAECs) inhibited ROS production, pro-inflammatory cytokine expression and endothelial cell apoptosis, and increased eNOS expression. Furthermore, NPRC knockdown in HAECs suppressed macrophage migration, cytokine expression, and phagocytosis via its effects on endothelial cells. On the contrary, NPRC overexpression in endothelial cells resulted in opposite effects. Mechanistically, the anti-inflammation and anti-atherosclerosis effects of NPRC deletion involved activation of cAMP/PKA pathway, leading to downstream upregulated AKT1 pathway and downregulated NF-κB pathway. In conclusion, NPRC deletion reduced the size and instability of atherosclerotic lesions in ApoE-/- mice via attenuating inflammation and endothelial cell apoptosis and increasing eNOS expression by modulating cAMP/PKA-AKT1 and NF-κB pathways. Thus, targeting NPRC may provide a promising approach to the prevention and treatment of atherosclerosis.
Assuntos
Aterosclerose , NF-kappa B , Receptores do Fator Natriurético Atrial , Animais , Humanos , Camundongos , Apoptose/genética , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Citocinas/metabolismo , Células Endoteliais/metabolismo , Inflamação/patologia , Camundongos Knockout , Camundongos Knockout para ApoE , NF-kappa B/genética , NF-kappa B/metabolismo , Estresse Oxidativo/genética , Receptores do Fator Natriurético Atrial/genética , Receptores do Fator Natriurético Atrial/metabolismoRESUMO
CD4+CD25+ regulatory T cells (Tregs) have been shown to protect against abdominal aortic aneurysm (AAA) progression. Statins have immunomodulatory properties, and their effect on AAA partly depends on immune-related mechanisms. In this study, we aimed to explore whether there is an association between statins and Tregs in AAA progression. Sixty ApoE-/- mice were randomly divided into four groups (n = 15 per group): A, saline group; B, control group; C, simvastatin group (intragastric administration of simvastatin); and D, PC61 group (simvastatin combined with an intraperitoneal injection of 100 µg CD25-depleting antibody PC61). After 2 weeks of simvastatin treatment, the mice received a continuous subcutaneous infusion of angiotensin II (Ang II; B, C, and D groups) or saline (A group) for 28 days. Simvastatin therapy for 6 weeks significantly decreased the incidence and severity of AAA and inhibited the apoptosis of smooth muscle cells and generation of reactive oxygen species, which was partly abolished after the injection of PC61 antibody. Importantly, simvastatin increased the number of Tregs and the levels of Treg-associated cytokines (TGF-ß and IL-10) and decreased the level of IL-17 both in aortic tissues and serum. Interestingly, simvastatin attenuated Ang II-induced gut microbial dysbiosis, which might be associated with the accumulation of Tregs. In conclusion, simvastatin therapy prevented the development of AAA induced by Ang II in ApoE-/- mice, which might be partly due to the induction of Treg accumulation. In addition, simvastatin regulated gut microbial dysbiosis, which might also be associated with Treg generation.
Assuntos
Aneurisma da Aorta Abdominal , Inibidores de Hidroximetilglutaril-CoA Redutases , Angiotensina II/farmacologia , Animais , Aneurisma da Aorta Abdominal/prevenção & controle , Apolipoproteínas E/genética , Modelos Animais de Doenças , Disbiose/complicações , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Camundongos , Camundongos Knockout , Sinvastatina/uso terapêutico , Linfócitos T ReguladoresRESUMO
MATERIAL AND METHODS: A cohort of 123 patients diagnosed with gliomas (World Health Organization grades II-IV) who underwent surgery and was treated at our center between January 2016 and July 2020, was enrolled in this retrospective study. Radiomics features were extracted from MR T1WI, T2WI, T2FLAIR, CE-T1WI, and ADC images. Patients were randomly split into training and validation sets at a ratio of 4:1. A radiomics signature was constructed using the least absolute shrinkage and selection operator (LASSO) to train the SVM model using the training set. The prediction accuracy and area under curve and other evaluation indexes were used to explore the performance of the model established in this study for predicting the ATRX mutation state. RESULTS: Fifteen radiomic features were selected to generate an ATRX-associated radiomic signature using the LASSO logistic regression model. The area under curve for ATRX mutation (ATRX(-)) on training set was 0.93 (95% confidence interval [CI]: 0.87-1.0), with the sensitivity, specificity and accuracy being 0.91, 0.82 and 0.88, while on the validation set were 0.84 (95% CI: 0.63-0.91), with the sensitivity, specificity and accuracy of 0.73, 0.86, and 0.79, respectively. CONCLUSIONS: These results indicate that radiomic features derived from preoperative MRI facilitat efficient prediction of ATRX status in gliomas, thus providing a novel evaluation method for noninvasive imaging biomarkers.
Assuntos
Glioma , Glioma/diagnóstico por imagem , Glioma/genética , Humanos , Imageamento por Ressonância Magnética/métodos , Mutação , Curva ROC , Estudos Retrospectivos , Proteína Nuclear Ligada ao X/genéticaRESUMO
Background: According to the integrated theoretical model, adolescents' behaviors were the outcome of the complex interplay between multiple levels. Non-suicidal self-injury (NSSI) is a serious and high prevalent problem among adolescents with mood disorders. However, a systematic perspective on psychosocial correlates among Chinese clinical adolescents is still rare. Method: The impact of several factors at the individual (i.e., sex, age, self-esteem, and psychological distress), family (i.e., family structure, family income, and family support), and social level (i.e., living environment, peer support, and teacher support) on the frequency of NSSI behaviors were investigated in the current study. This research included 621 Chinese adolescents with mood disorders from 20 hospitals. Results: Three-steps hierarchical regression analyses indicated that lower levels of psychological distress and higher levels of self-esteem were most associated with less frequency of NSSI behaviors. In addition, family support was negatively associated with the frequency of NSSI behaviors. After controlling the factors at individual and family levels, no significant association was found between the factors at the social level and the frequency of NSSI behaviors. Conclusion: These findings provide preliminary support for the notion that adolescent self-esteem and family support may effectively shield them from problematic behavior; nevertheless, adolescents suffering from more emotional pain can be even riskier. Thus, further intervention strategies should consider the non-independence of individual capacities, co-combinatory effects of mood disorder, and family environment in treating those vulnerable Chinese adolescents.
Assuntos
Comportamento do Adolescente , Comportamento Autodestrutivo , Adolescente , Comportamento do Adolescente/psicologia , Povo Asiático , Humanos , Transtornos do Humor/epidemiologia , Prevalência , Comportamento Autodestrutivo/epidemiologia , Comportamento Autodestrutivo/psicologiaRESUMO
Objective: The objective of this trial is to evaluate and compare the acute toxicity in patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) treated with docetaxel plus cisplatin, or docetaxel, or cisplatin concurrently with helical tomotherapy during concurrent chemoradiotherapy (CCRT). Methods: In a prospective, single-center, open-label, randomized phase II study, after 2 cycles of induction chemotherapy with docetaxel plus cisplatin regimen, 125 patients with LA-NPC (stage III and IVA, UICC eighth) diagnosed pathologically from June 2017 to November 2019 were randomized into CCRT with docetaxel plus cisplatin group (25 patients), CCRT with docetaxel group (50 patients), and CCRT with cisplatin group (50 patients). The incidence of grade 3 or 4 acute toxicities and clinical efficacy were analyzed among the 3 groups. Results: Safety evaluation was completed in all the 125 patients, during the CCRT period, 66.4% of patients completed 3 cycles of chemotherapy, 24.0% completed 2 cycles of chemotherapy, and 9.6% completed 1 cycle of chemotherapy according to the research plan. The incidence of grade 3 or 4 acute toxicity in CCRT with docetaxel plus cisplatin (DP), docetaxel (D), and cisplatin (P) groups was 88.0%, 72.0%, and 56.0%, respectively. The incidence of grade 3 or 4 acute toxicities in the DP group was significantly higher than that in the D and P groups (P = .015), no significant difference was detected between the D and P groups (P = .096). The most common toxicities were mucositis (40.0%), leukopenia (29.6%), neutropenia (26.4%), and pharyngo-esophagitis (12.0%); compared to D and P groups, DP group did not significantly improved the 3-year overall survival (96.0% vs 87.0% and 87.6%), progression-free survival (92.0% vs 79.7% and,76.9%), locoregional failure-free survival (96.0% vs 91.8% and 92.7%), and distant failure-free survival (100% vs 90.0% and 89.0%), there were no significant difference in survival data among the 3 groups (all P > .05). Conclusions: Higher survival benefits did not achieve from intensified CCRT with DP, CCRT with P or D obtained similar short-term survival outcomes with similar acceptable toxicities in LA-NPC patients.
Assuntos
Neoplasias Nasofaríngeas , Radioterapia de Intensidade Modulada , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimiorradioterapia/efeitos adversos , Cisplatino , Docetaxel/efeitos adversos , Fluoruracila , Humanos , Carcinoma Nasofaríngeo/radioterapia , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/patologia , Estudos Prospectivos , Radioterapia de Intensidade Modulada/efeitos adversosRESUMO
BACKGROUND: Identifying the risk factors of suicide attempts(SA) in adolescents with mood disorders(MD) who engage in non-suicidal self-injury(NSSI) is of great significance for suicide prevention. The aim of the present study was to explore the psychological characteristics and risk factors of SA among MD adolescents engaged in NSSI. METHODS: We recruited MD outpatients accompany with NSSI aged 12-18 years. SA, NSSI methods and function, suicidal ideation(SI), psychological distress(PD), self-esteem, stress mindset and perceived social support were assessed by valid scales. Classification and regression tree analysis (CART) was employed to explore the characteristics and risk factors of SA among MD adolescent with NSSI. RESULTS: We included 658 participants in this study. Of 58.1% participants reported SA during the past 12 months. Compared with the adolescents without SA, the attempters used more different NSSI methods and reported more frequent NSSI. SA, SI, PD, self-esteem and amount of thinking time before engaging in self-injury were risk factors of SA among MD adolescents. Interactions between the four risk factors resulted in varying degrees of risk of SA. Compared to adolescents with the characteristics of low level of SI - little consideration before self-injury, adolescents who having multiple characteristics of the high level of SI -high level of PD - low self-esteem were associated with a 15.1-fold increased risk of SA(P < 0.001), and those with the characteristics of high SI - deliberated before engaging in self-injury were associated with a 28.1-fold increased risk of attempted suicide(P < 0.001). CONCLUSIONS: Our findings identify multiple correlates for SA in MD adolescents accompany with NSSI, including SI, PD, self-esteem and deliberate time they thought before self-injury, which may contribute to the development of suicidal behaviors in an interactive manner.
Assuntos
Comportamento Autodestrutivo , Tentativa de Suicídio , Adolescente , Humanos , Transtornos do Humor , Fatores de Risco , Comportamento Autodestrutivo/epidemiologia , Ideação SuicidaRESUMO
Acute respiratory distress syndrome (ARDS) is a common critical illness in respiratory care units with a huge public health burden. Despite tremendous advances in the prevention and treatment of ARDS, it remains the main cause of intensive care unit (ICU) management, and the mortality rate of ARDS remains unacceptably high. The poor performance of ARDS is closely related to its heterogeneous clinical syndrome caused by complicated pathophysiology. Based on the different pathophysiology phases, drugs, protective mechanical ventilation, conservative fluid therapy, and other treatment have been developed to serve as the ARDS therapeutic methods. In recent years, there has been a rapid development in nanomedicine, in which nanoparticles as drug delivery vehicles have been extensively studied in the treatment of ARDS. This study provides an overview of pharmacologic therapies for ARDS, including conventional drugs, natural medicine therapy, and nanomedicine. Particularly, we discuss the unique mechanism and strength of nanomedicine which may provide great promises in treating ARDS in the future.