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Atrial fibrosis is associated with the occurrence of atrial fibrillation (AF) and regulated by the transforming growth factor-ß1 (TGF-ß1)/Smad2/3 signalling pathway. Unfortunately, the mechanisms of regulation of TGF-ß1/Smad2/3-induced atrial fibrosis and vulnerability to AF remain still unknown. Previous studies have shown that sirtuin3 (SIRT3) sulfhydration has strong anti-fibrotic effects. We hypothesised that SIRT3 sulfhydration inhibits angiotensin II (Ang-II)-induced atrial fibrosis via blocking the TGF-ß1/Smad2/3 signalling pathway. In this study, we found that SIRT3 expression was decreased in the left atrium of patients with AF compared to that in those with sinus rhythm (SR). In vitro, SIRT3 knockdown by small interfering RNA significantly expanded Ang-II-induced atrial fibrosis and TGF-ß1/Smad2/3 signalling pathway activation, whereas supplementation with Sodium Hydrosulfide (NaHS, exogenous hydrogen sulfide donor and sulfhydration agonist) and SIRT3 overexpression using adenovirus ameliorated Ang-II-induced atrial fibrosis. Moreover, we observed suppression of the TGF-ß1/Smad2/3 pathway when Ang-II was combined with NaHS treatment, and the effect of this co-treatment was consistent with that of Ang-II combined with LY3200882 (Smad pathway inhibitor) on reducing atrial fibroblast proliferation and cell migration in vitro. Supplementation with dithiothreitol (DTT, a sulfhydration inhibitor) and adenovirus SIRT3 shRNA blocked the ameliorating effect of NaHS and AngII co-treatment on atrial fibrosis in vitro. Finally, continued treatment with NaHS in rats ameliorated atrial fibrosis and remodelling, and further improved AF vulnerability induced by Ang-II, which was reversed by DTT and adenovirus SIRT3 shRNA, suggesting that SIRT3 sulfhydration might be a potential therapeutic target in atrial fibrosis and AF.
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BACKGROUND: Hypertension may result in atrial fibrillation (AF) and lipid metabolism disorders. The Sirtuins3 (SIRT3) / AMP-activated protein kinase (AMPK) signaling pathway has the capacity to regulate lipid metabolism disorders and the onset of AF. We hypothesize that the SIRT3/AMPK signaling pathway suppresses lipid metabolism disorders, thereby mitigating salt-sensitive hypertension (SSHT)-induced susceptibility to AF. METHODS: The study involved 7-week-old male Dahl salt-sensitive that were fed either high-salt diet (8% NaCl; DSH group) or normal diet (0.3% NaCl; DSN group). Then DSH group were administered either oral metformin (MET, an AMPK agonist) or intraperitoneal injection of Honokiol (HK, a SIRT3 agonist). This experimental model allowed for the measurement of SBP, the expression levels of lipid metabolism-related biomarker, pathological examination of atrial fibrosis and lipid accumulation, as well as AF inducibility and AF duration. RESULTS: DSH decrease SIRT3, phosphorylation-AMPK and VLCAD expression, increased FASN and FABP4 expression and concentrations of FFA and TG, atrial fibrosis and lipid accumulation in atrial tissue, enhanced level of SBP, promoted AF induction rate and prolonged AF duration, which are blocked by MET and HK. Our results also showed that the degree of atrial fibrosis was negatively correlated with VLCAD expression, but positively correlated with the expression of FASN and FABP4. CONCLUSIONS: We have confirmed that high-salt diet can result in hypertension, associated atrial tissue lipid metabolism dysfunction. This condition is linked to the inhibition of the SIRT3/AMPK signaling pathway, which plays a significant role in the progression of susceptibility to AF in SSHT rats.
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BACKGROUND: Hypertension is a risk factor for atrial fibrillation (AF), and brain and muscle arnt-like protein 1 (Bmal1) regulate circadian blood pressure and is implicated in several fibrotic disorders. Our hypothesis that Bmal1 inhibits atrial fibrosis and susceptibility to AF in salt-sensitive hypertension (SSHT) and our study provides a new target for the pathogenesis of AF induced by hypertension. METHODS: The study involved 7-week-old male Dahl salt-sensitive that were fed either a high-salt diet (8% NaCl; DSH group) or a normal diet (0.3% NaCl; DSN group). An experimental model was used to measure systolic blood pressure (SBP), left atrial ejection fraction (LAEF), left atrial end-volume index (LAEVI), left atrial index (LAFI), AF inducibility, AF duration, and atrial fibrosis pathological examination and the expression of Baml1 and fibrosis-related proteins (TNF-α and α-SMA) in left atrial tissue. RESULTS: DSH increased TNF-α and α-SMA expression in atrial tissue, level of SBP and LAESVI, atrial fibrosis, AF induction rate, and AF duration, and decreased Bmal1 expression in atrial tissue, the circadian rhythm of hypertension, and level of LAEF and LAFI. Our results also showed that the degree of atrial fibrosis was negatively correlated with Bmal1 expression, but positively correlated with the expression of TNF-α and α-SMA. CONCLUSIONS: We demonstrated that a high-salt diet leads to circadian changes in hypertension due to a reduction of Bmal1 expression, which plays a crucial role in atrial fibrosis and increased susceptibility to AF in SSHT rats.
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Factores de Transcripción ARNTL , Fibrilación Atrial , Presión Sanguínea , Modelos Animales de Enfermedad , Fibrosis , Atrios Cardíacos , Hipertensión , Ratas Endogámicas Dahl , Cloruro de Sodio Dietético , Animales , Factores de Transcripción ARNTL/metabolismo , Factores de Transcripción ARNTL/genética , Fibrilación Atrial/metabolismo , Fibrilación Atrial/etiología , Fibrilación Atrial/prevención & control , Fibrilación Atrial/fisiopatología , Masculino , Cloruro de Sodio Dietético/efectos adversos , Hipertensión/metabolismo , Hipertensión/fisiopatología , Atrios Cardíacos/metabolismo , Atrios Cardíacos/patología , Atrios Cardíacos/fisiopatología , Atrios Cardíacos/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Ratas , Factor de Necrosis Tumoral alfa/metabolismo , Remodelación Atrial/efectos de los fármacosRESUMEN
BACKGROUND AND AIMS: Tripartite motif (TRIM65) is an important member of the TRIM protein family, which is a newly discovered E3 ligase that interacts with and ubiquitinates various substrates and is involved in diverse pathological processes. However, the function of TRIM65 in atherosclerosis remains unarticulated. In this study, we investigated the role of TRIM65 in the pathogenesis of atherosclerosis, specifically in vascular smooth muscle cells (VSMCs) phenotype transformation, which plays a crucial role in formation of atherosclerotic lesions. METHODS AND RESULTS: Both non-atherosclerotic and atherosclerotic lesions during autopsy were collected singly or pairwise from each individual (n = 16) to investigate the relationship between TRIM65 and the development of atherosclerosis. In vivo, Western diet-fed ApoE-/- mice overexpressing or lacking TRIM65 were used to assess the physiological function of TRIM65 on VSMCs phenotype, proliferation and atherosclerotic lesion formation. In vitro, VSMCs phenotypic transformation was induced by platelet-derived growth factor-BB (PDGF-BB). TRIM65-overexpressing or TRIM65-abrogated primary mouse aortic smooth muscle cells (MOASMCs) and human aortic smooth muscle cells (HASMCs) were used to investigate the mechanisms underlying the progression of VSMCs phenotypic transformation, proliferation and migration. Increased TRIM65 expression was detected in α-SMA-positive cells in the medial and atherosclerotic lesions of autopsy specimens. TRIM65 overexpression increased, whereas genetic knockdown of TRIM65 remarkably inhibited, atherosclerotic plaque development. Mechanistically, TRIM65 overexpression activated PI3K/Akt/mTOR signaling, resulting in the loss of the VSMCs contractile phenotype, including calponin, α-SMA, and SM22α, as well as cell proliferation and migration. However, opposite phenomena were observed when TRIM65 was deficient in vivo or in vitro. Moreover, in cultured PDGF-BB-induced TRIM65-overexpressing VSMCs, inhibition of PI3K by treatment with the inhibitor LY-294002 for 24 h markedly attenuated PI3K/Akt/mTOR activation, regained the VSMCs contractile phenotype, and blocked the progression of cell proliferation and migration. CONCLUSIONS: TRIM65 overexpression enhances atherosclerosis development by promoting phenotypic transformation of VSMCs from contractile to synthetic state through activation of the PI3K/Akt/mTOR signal pathway.
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Aterosclerosis , Proteínas Proto-Oncogénicas c-akt , Humanos , Ratones , Animales , Becaplermina/genética , Becaplermina/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Músculo Liso Vascular/patología , Fosfatidilinositol 3-Quinasas/metabolismo , Movimiento Celular , Transducción de Señal , Proliferación Celular , Serina-Treonina Quinasas TOR/metabolismo , Aterosclerosis/patología , Miocitos del Músculo Liso/patología , Fenotipo , Células Cultivadas , Proteínas de Motivos Tripartitos/genética , Proteínas de Motivos Tripartitos/metabolismo , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
Chromatin accessibility profiles at single cell resolution can reveal cell type-specific regulatory programs, help dissect highly specialized cell functions and trace cell origin and evolution. Accurate cell type assignment is critical for effectively gaining biological and pathological insights, but is difficult in scATAC-seq. Hence, by extensively reviewing the literature, we designed scATAC-Ref (https://bio.liclab.net/scATAC-Ref/), a manually curated scATAC-seq database aimed at providing a comprehensive, high-quality source of chromatin accessibility profiles with known cell labels across broad cell types. Currently, scATAC-Ref comprises 1 694 372 cells with known cell labels, across various biological conditions, >400 cell/tissue types and five species. We used uniform system environment and software parameters to perform comprehensive downstream analysis on these chromatin accessibility profiles with known labels, including gene activity score, TF enrichment score, differential chromatin accessibility regions, pathway/GO term enrichment analysis and co-accessibility interactions. The scATAC-Ref also provided a user-friendly interface to query, browse and visualize cell types of interest, thereby providing a valuable resource for exploring epigenetic regulation in different tissues and cell types.
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Secuenciación de Inmunoprecipitación de Cromatina , Cromatina , Bases de Datos Genéticas , Análisis de la Célula Individual , Cromatina/genética , Epigénesis Genética , Humanos , AnimalesRESUMEN
Pulmonary fibrosis (PF) is a fatal and irreversible respiratory disease accompanied by excessive fibroblast activation. Previous studies have suggested that cAMP signaling pathway and cGMP-PKG signaling pathway are continuously down-regulated in lung fibrosis, whereas PDE10A has a specifically expression in fibroblasts/myofibroblasts in lung fibrosis. In this study, we demonstrated that overexpression of PDE10A induces myofibroblast differentiation, and papaverine, as a PDE10A inhibitor used for vasodilation, inhibits myofibroblast differentiation in human fibroblasts, Meanwhile, papaverine alleviated bleomycin-induced pulmonary fibrosis and amiodarone-induced oxidative stress, papaverine downregulated VASP/ß-catenin pathway to reduce the myofibroblast differentiation. Our results first demonstrated that papaverine inhibits TGFß1-induced myofibroblast differentiation and lung fibrosis by VASP/ß-catenin pathway.
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Sistema Cardiovascular , Hiperemia , Humanos , Hiperemia/diagnóstico , Factores de Riesgo , Corazón , Hemorragia , Endotelio VascularRESUMEN
Polo-like kinase 1 (PLK1) is a serine/threonine kinase involving lipid metabolism and cardiovascular disease. However, its role in atherogenesis has yet to be determined. The aim of this study was to observe the impact of PLK1 on macrophage lipid accumulation and atherosclerosis development and to explore the underlying mechanisms. We found a significant reduction of PLK1 expression in lipid-loaded macrophages and atherosclerosis model mice. Lentivirus-mediated overexpression of PLK1 promoted cholesterol efflux and inhibited lipid accumulation in THP-1 macrophage-derived foam cells. Mechanistic analysis revealed that PLK1 stimulated the phosphorylation of AMP-activated protein kinase (AMPK), leading to activation of the peroxisome proliferator-activated receptor γ (PPARγ)/liver X receptor α (LXRα) pathway and up-regulation of ATP binding cassette transporter A1 (ABCA1) and ABCG1 expression. Injection of lentiviral vector expressing PLK1 increased reverse cholesterol transport, improved plasma lipid profiles and decreased atherosclerotic lesion area in apoE-deficient mice fed a Western diet. PLK1 overexpression also facilitated AMPK and HSL phosphorylation and enhanced the expression of PPARγ, LXRα, ABCA1, ABCG1 and LPL in the aorta. In summary, these data suggest that PLK1 inhibits macrophage lipid accumulation and mitigates atherosclerosis by promoting ABCA1- and ABCG1-dependent cholesterol efflux via the AMPK/PPARγ/LXRα pathway.
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Aterosclerosis , Proteínas de Ciclo Celular , Proteínas Serina-Treonina Quinasas , Proteínas Proto-Oncogénicas , Proteínas Quinasas Activadas por AMP/genética , Proteínas Quinasas Activadas por AMP/metabolismo , Transportador 1 de Casete de Unión a ATP/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1/genética , Animales , Apolipoproteínas E/metabolismo , Aterosclerosis/metabolismo , Proteínas de Ciclo Celular/genética , Colesterol/metabolismo , Receptores X del Hígado/genética , Receptores X del Hígado/metabolismo , Ratones , PPAR gamma/genética , PPAR gamma/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Proto-Oncogénicas/genética , Serina , Quinasa Tipo Polo 1RESUMEN
Atrial fibrosis is the basis for the occurrence and development of atrial fibrillation (AF) and is closely related to the Warburg effect, endoplasmic reticulum stress (ERS) and mitochondrion dysfunctions-induced cardiomyocyte apoptosis. Hydrogen sulfide (H2S) is a gaseous signalling molecule with cardioprotective, anti-myocardial fibrosis and improved energy metabolism effects. Nevertheless, the specific mechanism by which H2S improves the progression of atrial fibrosis to AF remains unclear. A case-control study of patients with and without AF was designed to assess changes in H2S, the Warburg effect, and ERS in AF. The results showed that AF can significantly reduce cystathionine-γ-lyase (CSE) and 3-mercaptopyruvate thiotransferase (3-MST) expression and the H2S level, induce cystathionine-ß-synthase (CBS) expression; increase the Warburg effect, ERS and atrial fibrosis; and promote left atrial dysfunction. In addition, AngII-treated SD rats had an increased Warburg effect and ERS levels and enhanced atrial fibrosis progression to AF compared to wild-type SD rats, and these conditions were reversed by sodium hydrosulfide (NaHS), dichloroacetic acid (DCA) or 4-phenylbutyric acid (4-PBA) supplementation. Finally, low CSE levels in AngII-induced HL-1 cells were concentration- and time-dependent and associated with mitochondrial dysfunction, apoptosis, the Warburg effect and ERS, and these effects were reversed by NaHS, DCA or 4-PBA supplementation. Our research indicates that H2S can regulate the AngII-induced Warburg effect and ERS and might be a potential therapeutic drug to inhibit atrial fibrosis progression to AF.
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BACKGROUND: Lower body positive pressure (LBPP) treadmill has potential applications for improving the gait of patients after stroke, but the related mechanism remains unclear. CASE SUMMARY: A 62-year-old male patient suffered from ischemic stroke with hemiplegic gait. He was referred to our hospital because of a complaint of left limb weakness for 2 years. The LBPP training was performed one session per day and six times per week for 2 wk. The dynamic plantar pressure analysis was taken every 2 d. Meanwhile, three-digital gait analysis and synchronous electromyography as well as clinical assessments were taken before and after LBPP intervention and at the 4-wk follow-up. During LBPP training, our patient not only improved his lower limb muscle strength and walking speed, but more importantly, the symmetry index of various biomechanical indicators improved. Moreover, the patient's planter pressure transferring from the heel area to toe area among the LBPP training process and the symmetry of lower body biomechanical parameters improved. CONCLUSION: In this study, we documented a dynamic improvement of gait performance in a stroke patient under LBPP training, which included lower limb muscle strength, walking speed, and symmetry of lower limb biomechanics. Our study provides some crucial clues about the potential dynamic mechanism for LBPP training on gait and balance improvement, which is related to rebuilding foot pressure distribution and remodeling symmetry of biomechanics of the lower limb.
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N6-methyladenine RNA modification (m6A) is an RNA methylation modification catalyzed by methyltransferase at the 6th position nitrogen atom of adenine (A), which is the most common chemical modification of eukaryotic messenger RNA (mRNA). Recently, m6A has been found to play an important role in the dynamic regulation of RNA, which is crucial for some physiological and pathophysiological processes such as adipogenesis, cell differentiation, and the immune/inflammatory response. Metabolic diseases are a series of chronic inflammatory disorders caused by metabolic dysfunction of proteins, glucose, and lipids. Emerging studies have shown that m6A plays an important role in the process of metabolic diseases such as obesity, type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVDs) via regulation of glucose/lipid metabolism and the immune/inflammatory response. In this review, we will summarize the role of m6A in metabolic diseases, which may provide new ideas for the prevention and treatment of metabolic diseases.
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Adenina/análogos & derivados , Enfermedades Metabólicas/genética , Enfermedades Metabólicas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Adenina/química , Animales , Humanos , Metilación , Metiltransferasas/metabolismo , Procesamiento Postranscripcional del ARN/genética , Procesamiento Postranscripcional del ARN/fisiología , ARN Mensajero/químicaRESUMEN
Air pollution events frequently occur in China during the winter. Most investigations of pollution studies have focused on the physical and chemical properties of PM2.5. Many of these studies have indicated that PM2.5 exacerbates asthma or eosinophil inflammation. However, few studies have evaluated the relationship between bacterial loads in PM2.5, and especially pathogenic bacteria and childhood asthma. Airborne PM2.5 samples from heavily polluted air were collected in Hangzhou, China between December 2014 and January 2015. PM2.5 and ovalbumin (OVA) were intratracheally administered twice in 4-week intervals to induce the allergic pulmonary inflammation in adolescent C57/BL6 mice. PM2.5 exposure caused neutrophilic alveolitis and bronchitis. In the presence of OVA, the levels of the Th2 cytokines IL-4, IL-12, and IL-17 were significantly increased in bronchoalveolar lavage fluids (BALF) after PM2.5 exposure, while eosinophil infiltration and mucin secretion were also induced. In addition to adjuvant effects on OVA-induced allergic inflammation, PM2.5 exposure also led to the maturation of dendritic cells. These results suggest that PM2.5 exposure may aggravate lung eosinophilia and that PM2.5-bound microbial can exacerbate allergic and inflammatory lung diseases.
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Microbiología del Aire , Pulmón/microbiología , Material Particulado/toxicidad , Neumonía/microbiología , Eosinofilia Pulmonar/microbiología , Hipersensibilidad Respiratoria/microbiología , Factores de Edad , Animales , Carga Bacteriana , Células Cultivadas , Técnicas de Cocultivo , Citocinas/metabolismo , Células Dendríticas/metabolismo , Células Dendríticas/microbiología , Modelos Animales de Enfermedad , Pulmón/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Ovalbúmina , Tamaño de la Partícula , Neumonía/inducido químicamente , Neumonía/metabolismo , Eosinofilia Pulmonar/inducido químicamente , Eosinofilia Pulmonar/metabolismo , Hipersensibilidad Respiratoria/inducido químicamente , Hipersensibilidad Respiratoria/metabolismo , Células Th2/metabolismo , Células Th2/microbiologíaRESUMEN
The present study aimed to investigate the potent inhibitory effects and possible biochemical basis of the novel phosphodiesterase 4 (PDE4) inhibitor ciclamilast, which is a derivative of piclamilast (RP 73401), on PDE4 and allergic inflammation. Ciclamilast was orally administered to allergic rats, their lungs and bronchoalveolar lavage fluid (BALF) were harvested, and their levels of inflammation and goblet cell hyperplasia, particularly cAMPPDE activity, and expression and distribution of PDE4 subtypes were determined. The results suggested that oral administration of ciclamilast significantly reduced the total leukocyte number and eosinophil number in BALF and suppressed lung histology changes, including the infiltration of inflammatory cells into the perivascular and peribronchial spaces, structural changes and goblet cell hyperplasia. For eosinophil infiltration, ciclamilast exhibited improved selectivity compared with piclamilast. Furthermore, ciclamilast significantly inhibited the upregulated activity of cAMPPDE and showed improved selective inhibition of the protein expression of PDE4B than piclamilast in a dosedependent manner. The mRNA expression of PDE4D was significantly increased in allergic rats, but PDE4B was not. PDE4B was mainly distributed in the cytoplasm, whereas PDE4D was mainly distributed in the cell membrane. The improved antiinflammatory activity of ciclamilast compared with piclamilast may be due to its higher level of inhibition of the activity, mRNA and protein expression of PDE4, particularly its effect on PDE4B.
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Benzamidas/administración & dosificación , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/genética , Hipersensibilidad/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Piridinas/administración & dosificación , Animales , Recuento de Células Sanguíneas , Líquido del Lavado Bronquioalveolar , AMP Cíclico/genética , Modelos Animales de Enfermedad , Eosinófilos/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Células Caliciformes/efectos de los fármacos , Células Caliciformes/patología , Humanos , Hiperplasia/tratamiento farmacológico , Hiperplasia/patología , Hipersensibilidad/genética , Hipersensibilidad/patología , Inflamación/genética , Inflamación/patología , Leucocitos/efectos de los fármacos , Pulmón/efectos de los fármacos , Pulmón/patología , Inhibidores de Fosfodiesterasa/administración & dosificación , RatasRESUMEN
Quercetin (Que) as an abundant flavonol element possesses potent antioxidative properties and has protective effect in lipopolysaccharide (LPS)-induced acute lung injury (ALI), but the specific mechanism is still unclear, so we investigated the effect of Que from in vivo and in vitro studies and the related mechanism of cAMP-PKA/Epac pathway. The results in mice suggested that Que can inhibit the release of inflammatory cytokine, block neutrophil recruitment, and decrease the albumin leakage in dose-dependent manners. At the same time, Que can increase the cAMP content of lung tissue, and Epac content, except PKA. The results in epithelial cell (MLE-12) suggested that Que also can inhibit the inflammatory mediators keratinocyte-derived chemokines release after LPS stimulation; Epac inhibitor ESI-09 functionally antagonizes the inhibitory effect of Que; meanwhile, PKA inhibitor H89 functionally enhances the inhibitory effect of Que. Overexpression of Epac1 in MLE-12 suggested that Epac1 enhance the effect of Que. All those results suggested that the protective effect of quercetin in ALI is involved in cAMP-Epac pathway.
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Acetilcisteína/análogos & derivados , Lesión Pulmonar Aguda/inducido químicamente , AMP Cíclico/metabolismo , Eritromicina/análogos & derivados , Quercetina/farmacología , Acetilcisteína/metabolismo , Animales , Línea Celular , Eritromicina/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Mediadores de Inflamación/antagonistas & inhibidores , Lipopolisacáridos , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Ratones , Sustancias Protectoras/farmacologíaRESUMEN
This paper indicated that inactivated Bordetella pertussis (iBp) can enhance the lung airway hyperreactivity of the rats sensitized and challenged with OVA. The mechanisms were involved in the upregulation of cAMP-PDE activity and PDE4A, PDE4D, and PDE3 gene expression in the lungs. But only PDE4 activity was different between the OVA and OVA+iBp groups, and PDE4D expression was significantly increased in iBp rats alone. So, our data suggested that cosensitization with OVA and iBp affects lung airway reactivity by modulating the lung cAMP-PDE activity and PDE4D gene expression.
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Pulmón/enzimología , Vacuna contra la Tos Ferina/farmacología , Hidrolasas Diéster Fosfóricas/metabolismo , 3',5'-AMP Cíclico Fosfodiesterasas/metabolismo , Animales , Bordetella pertussis/inmunología , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 3/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Pulmón/inmunología , Masculino , Ovalbúmina/inmunología , Vacuna contra la Tos Ferina/inmunología , Ratas , Ratas Sprague-Dawley , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/inmunología , Vacunas de Productos InactivadosRESUMEN
cAMP-specific phosphodiesterase type 4 (PDE4) is one of the hot targets for treatment of inflammatory diseases. PDE4 inhibitors can suppress inflammation by increasing the concentration of cAMP in inflammatory cells. The efficacy and safety evaluations of several PDE4 inhibitors are currently carried on in clinical trials, for example GSK256066 in asthma, roflumilast and GSK256066 in chronic obstructive pulmonary disease, tetomilast in inflammatory bowel disease, and apremilast in dermatitis and arthritis etc. This article reviews the recent progress on PDE4-targeted therapy for inflammatory diseases.
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Inflamación/tratamiento farmacológico , Inhibidores de Fosfodiesterasa 4/farmacología , Aminopiridinas/farmacología , Aminoquinolinas/farmacología , Artritis/tratamiento farmacológico , Asma/tratamiento farmacológico , Benzamidas/farmacología , Ciclopropanos/farmacología , Dermatitis/tratamiento farmacológico , Humanos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Sulfonas/farmacología , Talidomida/análogos & derivados , Talidomida/farmacología , Tiazoles/farmacologíaRESUMEN
In order to determine whether local anesthetics directly affect the propagation and strength of myometrial contractions, we compared the effects of bupivacaine, ropivacaine, lidocaine and tetracaine on the contractions of myometrium isolated from pregnant and non-pregnant rats. Full-thickness myometrial strips were obtained from 18- to 21-day pregnant and non-pregnant Sprague-Dawley rats and incubated in an organ bath. When spontaneous contractions became regular, strips were exposed to cumulative concentrations of the four local anesthetics ranging from 0.01 to 300 µmol/L and the amplitude and frequency of contraction were recorded. All four compounds caused a concentration-dependent inhibition of the contractility of pregnant and non-pregnant uterine muscle. In pregnant myometrium, the concentration that caused 50% inhibition (IC(50)) was 100 µmol/L for bupivacaine, 157 µmol/L for ropivacaine, > 1000 µmol/L for lidocaine, and 26.3 µmol/L for tetracaine. In non-pregnant myometrium, the IC(50) was 26.9 µmol/L for bupivacaine, 40 µmol/L for ropivacaine, 384 µmol/L for lidocaine, and 7.4 µmol/L for tetracaine. These results suggested that local anesthetics do inhibit myometrial contractions in pregnant and non-pregnant rats in a concentration-dependent manner.
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Anestésicos Locales/farmacología , Contracción Uterina/efectos de los fármacos , Amidas/farmacología , Animales , Bupivacaína/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Técnicas In Vitro , Lidocaína/farmacología , Embarazo , Ratas , Ratas Sprague-Dawley , Ropivacaína , Tetracaína/farmacologíaRESUMEN
To investigate the changes in drug sensitivity of miR-122 transfected BEL-7402/5-FU cells. MiR-122 and negative miRNA expression vectors were constructed and stably transfected into BEL-7402/5-FU cells. Real-time RT-PCR was used to detect the level of miR-122, Bcl-XL, Bcl-2 and P53 mRNA. Western Blotting was used to detect Bcl-2, Bcl-XL and P53 protein expression. Drug sensitivity of the cells to 5-fluorouracil (5-FU) was analyzed with MTT and flow cytometry. Compared with negative miRNA transfectants or untreated cells, mRNA and protein expression level of Bcl-2, Bcl-XL in stable miR-122 transfectants were decreased. Accordingly, P53 protein expression showed a significant up-regulation; MTT results showed that after incubation with 5-FU, miR-122 transfectants had higher cell inhibitory rates than negative miRNA or untreated cells; flow cytometry results demonstrated that apoptosis rate increased in miR-122 transfected cells, compared with negative miRNA or untreated cells. After addition of 5-FU (10 and 100 micromol/I), miR-122 transfected cells showed higher apoptosis rate than negative miRNA or untreated cells. MiR-122 can specifically down-regulate the expression of Bcl-2 and Bcl-XL, and increase P53 activity in BEL-7402/5-FU cells, which increased cells spontaneous apoptosis and sensitize cells to 5-FU. Therefore, MiR-122 can be used as a potential therapy agent against human hepatoblastoma.
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Antimetabolitos/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Fluorouracilo/farmacología , MicroARNs/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-bcl-2/biosíntesis , Western Blotting , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Colorantes , Regulación hacia Abajo/efectos de los fármacos , Citometría de Flujo , Vectores Genéticos , Humanos , Análisis por Micromatrices , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Sales de Tetrazolio , Tiazoles , Transfección , Proteína p53 Supresora de Tumor/biosíntesis , Proteína bcl-X/biosíntesisRESUMEN
Monoammonium glycyrrhizinate (MAG) was the aglycone of glycyrrhizin derived from licorice. In this study, the anti-inflammatory effects of MAG on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice and the possible mechanisms involved in this protection were investigated. Pretreatment with MAG prior to the administration of intratracheal LPS significantly induced a decrease in lung wet weight/dry weight ratio, in total leukocyte number and neutrophil percent in the BALF, and in myeloperoxidase (MPO) activity of lung in dose-dependent manners. At the same time, pretreatment with MAG also significantly improved the super oxide dismutase (SOD) activity and induced the malondialdehyde (MDA) content in the bronchoalveolar lavage fluid (BALF). Importantly, pretreatment with MAG prevented an increase in cyclic adenosine monophosphate-phosphodiesterase (cAMP-PDE) activity of lung in a dose-dependent manner. In addition, it can up-regulate the interleukin-10 (IL-10) level and down-regulate the tumor neurosis factor-α (TNF-α) level in the lung tissue of ALI mice. These results showed that anti-inflammatory effects of MAG against the LPS-induced ALI may be due to its ability of primary inhibition of cAMP-PDE activity, oxidative stress and its regulation of cytokine effects. Thus the results support that use of MAG is beneficial in the treatment of ALI and ARDS.