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The performance of classification algorithms is mainly governed by the hyperparameter settings deployed in applications, and the search for desirable hyperparameter configurations usually is quite challenging due to the complexity of datasets. Metafeatures are a group of measures that characterize the underlying dataset from various aspects, and the corresponding recommendation algorithm fully relies on the appropriate selection of metafeatures. Metalearning (MtL), aiming to improve the learning algorithm itself, requires development in integrating features, models, and algorithm learning to accomplish its goal. In this article, we develop a multivariate sparse-group Lasso (SGLasso) model embedded with MtL capacity in recommending suitable configurations via learning. The main idea is to select the principal metafeatures by removing those redundant or irregular ones, promoting both efficiency and performance in the hyperparameter configuration recommendation. To be specific, we first extract the metafeatures and classification performance of a set of configurations from the collection of historical datasets, and then, a metaregression task is established through SGLasso to capture the main characteristics of the underlying relationship between metafeatures and historical performance. For a new dataset, the classification performance of configurations can be estimated through the selected metafeatures so that the configuration with the highest predictive performance in terms of the new dataset can be generated. Furthermore, a general MtL architecture combined with our model is developed. Extensive experiments are conducted on 136 UCI datasets, demonstrating the effectiveness of the proposed approach. The empirical results on the well-known SVM show that our model can effectively recommend suitable configurations and outperform the existing MtL-based methods and the well-known search-based algorithms, such as random search, Bayesian optimization, and Hyperband.
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Intracellular Ca2+ dysregulation is a key marker in septic cardiac dysfunction; however, regulation of the classic Ca2+ regulatory modules cannot successfully abolish this symptom. Here we show that the knockout of transient receptor potential canonical (TRPC) channel isoforms TRPC1 and TRPC6 can ameliorate LPS-challenged heart failure and prolong survival in mice. The LPS-triggered Ca2+ release from the endoplasmic reticulum both in cardiomyocytes and macrophages is significantly inhibited by Trpc1 or Trpc6 knockout. Meanwhile, TRPC's molecular partner - calmodulin - is uncoupled during Trpc1 or Trpc6 deficiency and binds to TLR4's Pococurante site and atypical isoleucine-glutamine-like motif to block the inflammation cascade. Blocking the C-terminal CaM/IP3R binding domain in TRPC with chemical inhibitor could obstruct the Ca2+ leak and TLR4-mediated inflammation burst, demonstrating a cardioprotective effect in endotoxemia and polymicrobial sepsis. Our findings provide insight into the pathogenesis of endotoxemic cardiac dysfunction and suggest a novel approach for its treatment.
Assuntos
Traumatismos Craniocerebrais , Endotoxemia , Insuficiência Cardíaca , Canais de Potencial de Receptor Transitório , Animais , Camundongos , Endotoxemia/complicações , Canal de Cátion TRPC6 , Lipopolissacarídeos/toxicidade , Receptor 4 Toll-Like , InflamaçãoRESUMO
In this study, a piezoelectric micromachined ultrasonic transducer (PMUT) is integrated with a microliter-sized volume-tunable Helmholtz resonator. The passive Helmholtz resonator is constructed using an SU8 photolithography-defined square opening plate as the neck portion, a 3D-printed hollow structure with a threaded insert nut, and a precision set screw to form the volume-controllable cavity of the Helmholtz resonator. The fabricated piezoelectric films acted as ultrasonic actuators attached to the surface of the neck SU8 plate. Experimental results show that the sound pressure level (SPL) and operation bandwidth could be effectively tuned, and a 200% SPL increase and twofold bandwidth enhancement are achieved when setting the cavity length to 0.75 mm compared with the open-cavity case. A modified Helmholtz resonator model is proposed to explain the experimental results. The adjusting factors of the effective mass and viscous damper are created to modify the existing parameters in the conventional Helmholtz resonator model. The relationship between the adjusting factors and cavity length can be described well using a two-term power series curve. This modified Helmholtz resonator model not only provides insight into this active-type Helmholtz resonator operation but also provides a useful estimation for its optimal design and fabrication.
Assuntos
Transdutores , Ultrassom , Desenho de Equipamento , PressãoRESUMO
Previous studies have shown that melatonin (Mel) can effectively ameliorate myocardial ischemia/reperfusion (MI/R) injury, but the mechanism is yet to be fully elucidated. Mel receptors are expressed in the paraventricular nucleus (PVN), which is also involved in regulating cardiac sympathetic nerve activity. The aim of this study was to examine whether Mel receptors in the PVN are involved in the protective effects of Mel against MI/R injury. The results of quantitative polymerase chain reaction, western blot, and immunofluorescence assays indicated that Mel receptor 2 (MT2) expression in the PVN was upregulated after MI/R. Intraperitoneal administration of Mel significantly improved post-MI/R cardiac function and reduced the infarct size, whereas shRNA silencing of MT2 in the PVN partially blocked this effect. Intraperitoneal administration of Mel reduced sympathetic nerve overexcitation caused by MI/R, whereas shRNA silencing of MT2 in the PVN partially diminished this effect. Furthermore, enzyme-linked immunosorbent assay and western blot results indicated that intraperitoneal administration of Mel lowered the levels of inflammatory cytokines in the PVN after MI/R injury, whereas the application of sh-MT2 in the PVN reduced this effect of Mel. Mel significantly reduced the levels of NF-κB after astrocyte oxygen and glucose deprivation/reoxygenation injury, and this effect was offset when MT2 was silenced. The above experimental results suggest that MT2 in the PVN partially mediated the protective effects of Mel against MI/R injury, and its underlying mechanisms may be related to postactivation amelioration of PVN inflammation and reduction of cardiac sympathetic nerve overexcitation.
Assuntos
Astrócitos/efeitos dos fármacos , Coração/inervação , Melatonina/farmacologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miocárdio/patologia , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Receptor MT2 de Melatonina/agonistas , Sistema Nervoso Simpático/fisiopatologia , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Hipóxia Celular , Células Cultivadas , Modelos Animais de Doenças , Glucose/deficiência , Masculino , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Núcleo Hipotalâmico Paraventricular/metabolismo , Núcleo Hipotalâmico Paraventricular/patologia , Núcleo Hipotalâmico Paraventricular/fisiopatologia , Receptor MT2 de Melatonina/genética , Receptor MT2 de Melatonina/metabolismo , Transdução de SinaisRESUMO
It was reported that antituberculosis medicines could induce liver damage via oxidative stress. In this study, we investigated the effects of rifampicin (RFP) on the membrane expression of multidrug resistance-associated protein 2 (MRP2) and the relationship between oxidative stress and RFP-induced endocytosis of MRP2 in HepG2 cells. We found that RFP (12.5-50 µM) dose-dependently decreased the expression and membrane localization of MRP2 in HepG2 cells without changing the messenger RNA level. RFP (50 µM) induced oxidative stress responses that further activated the PKC-ERK/JNK/p38 (protein kinase C-extracellular signal-regulated kinase/c-JUN N-terminal kinase/p38) and PI3K (phosphoinositide 3-kinase) signaling pathways in HepG2 cells. Pretreatment with glutathione reduced ethyl ester (2 mM) not only reversed the changes in oxidative stress indicators and signaling molecules but also diminished RFP-induced reduction in green fluorescence intensity of MRP2. We conducted co-immunoprecipitation assays and revealed that a direct interaction existed among MRP2, clathrin, and adaptor protein 2 (AP2) in HepG2 cells, and their expression was clearly affected by the changes in intracellular redox levels. Knockdown of clathrin or AP2 with small interfering RNA attenuated RFP-induced decreases of membrane and total MRP2. We further demonstrated that RFP markedly increased the ubiquitin-proteasome degradation of MRP2 in HepG2 cells, which was mediated by the E3 ubiquitin ligase GP78, but not HRD1 or TEB4. In conclusion, this study demonstrates that RFP-induced oxidative stress activates the PKC-ERK/JNK/p38 and PI3K signaling pathways that leads to clathrin-dependent endocytosis and ubiquitination of MRP2 in HepG2 cells, which provides new insight into the mechanism of RFP-induced cholestasis.
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Clatrina/metabolismo , Endocitose/efeitos dos fármacos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/metabolismo , Rifampina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Ubiquitina/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Células Hep G2 , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Proteína 2 Associada à Farmacorresistência Múltipla , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteína Quinase C/metabolismo , Células Tumorais Cultivadas , Ubiquitina/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
BACKGROUND Chondrocyte dysfunction and apoptosis are 2 major features during the progression of osteoarthritis. Catalpol, an iridoid glycoside isolated from the root of Rehmannia, is a valuable medication with anti-inflammatory, anti-oxidative, and anti-apoptotic effects in various diseases. However, whether catalpol protects against osteoarthritis has not been investigated. MATERIAL AND METHODS To assess the role of catalpol in osteoarthritis and the potential mechanism of action, chondrocytes were treated with interleukin (IL)-1ß and various concentrations of catalpol. Catabolic metabolism, apoptotic level and relative signaling pathway were measured by western blot, real-time polymerase chain reaction and immunofluorescence staining. Meanwhile, we assess the cartilage degeneration in an experimental rat model using Safranin O fast green staining and cartilage was graded according to the Osteoarthritis Research Society International (OARSI) system. RESULTS The results showed that catalpol prevented chondrocyte apoptotic level triggered by IL-1ß, suppressed the release of catabolic enzymes, and inhibited the degradation of extracellular matrix induced by IL-1ß. Catalpol also inhibited the nuclear factor kappa B (NF-kappaB) pathway, reduced the production of inflammatory cytokines (IL-6, tumor necrosis factor-alpha) in IL-1ß-treated chondrocytes, and partially reversed cartilage degeneration in the knee joint in animal model of osteoarthritis. CONCLUSIONS Our work suggested that catalpol treatment attenuates IL-1ß-induced inflammatory response and catabolism in rat chondrocytes by inhibiting the NF-kappaB pathway, suggesting the therapeutic potential of catalpol for the treatment of osteoarthritis.
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Apoptose/efeitos dos fármacos , Cartilagem/patologia , Condrócitos/patologia , Matriz Extracelular/metabolismo , Inflamação/patologia , Interleucina-1beta/farmacologia , Glucosídeos Iridoides/farmacologia , Proteínas ADAMTS/metabolismo , Animais , Cartilagem/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Matriz Extracelular/efeitos dos fármacos , Proteínas da Matriz Extracelular/metabolismo , Mediadores da Inflamação/metabolismo , Metaloproteinases da Matriz/genética , Metaloproteinases da Matriz/metabolismo , NF-kappa B/metabolismo , Osteoartrite/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacosRESUMO
Melatonin, the receptors for which are abundant in the hypothalamic paraventricular nucleus (PVN), can protect the heart from myocardial ischemia-reperfusion (MI/R) injury. The aim of this study was to determine whether the infusion of melatonin into the PVN protects the heart from MI/R injury by suppressing oxidative stress or regulating the balance between proinflammatory cytokines and anti-inflammatory cytokines in MI/R rats. Male Sprague-Dawley rats were treated with a bilateral PVN infusion of melatonin. MI/R operation was performed 1 week after infusion. At the end of the third week after the infusion, all the rats were euthanized. This was followed by immunohistochemistry and immunofluorescence studies of the rats. MI/R rats showed larger infarct size, increased left ventricular (LV) end-diastolic volume, and decreased LV ejection fraction and LV fractional shortening. Moreover, MI/R rats had a higher level of norepinephrine in the plasma, heart, and PVN; higher PVN levels of reactive oxygen species, NOX2, NOX4, IL-1ß, and NF-κB activity; and lower PVN levels of copper/zinc superoxide dismutase (Cu/Zn-SOD) and IL-10 compared with the sham group. Melatonin infusion in PVN reduced LV end-diastolic volume, norepinephrine, reactive oxygen species, NOX2, NOX4, IL-1ß, and NF-κB activity, and increased LV ejection fraction, LV fractional shortening, Cu/Zn-SOD, and IL-10. Overall, these results suggest that the infusion of melatonin ameliorates sympathetic nerve activity and MI/R injury by attenuating oxidative stress and inflammatory cytokines in the PVN of MI/R rats.
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Anti-Inflamatórios/administração & dosagem , Antioxidantes/administração & dosagem , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Melatonina/administração & dosagem , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Infusões Intraventriculares , Masculino , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/metabolismo , Miocárdio/patologia , Núcleo Hipotalâmico Paraventricular/metabolismo , Núcleo Hipotalâmico Paraventricular/fisiopatologia , Ratos Sprague-Dawley , Transdução de Sinais , Volume Sistólico/efeitos dos fármacos , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/metabolismo , Sistema Nervoso Simpático/fisiopatologia , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
Clustering aims at naturally grouping the data according to the underlying data distribution. The data distribution is often estimated using a parametric or nonparametric model, e.g., Gaussian mixture or kernel density estimation. Compared with nonparametric models, parametric models are statistically stable, i.e., a small perturbation of data points leads to a small change in the estimated density. However, parametric models are highly sensitive to outliers because the data distribution is far away from the parametric assumptions in the presence of outliers. Given a parametric clustering algorithm, this paper shows how to turn this algorithm into a robust one. The idea is to modify the original parametric density into a semiparametric one. The high-density data that form the core of each cluster are modeled with the original parametric density. The low-density data are often far away from the cluster cores and may have an arbitrary shape, thus are modeled using a nonparametric density. A combination of parametric and nonparametric clustering algorithms is used to group the data modeled as a semiparametric density. From the robust statistical point of view, the proposed method has good robustness properties. We test the proposed algorithm on several synthetic and 70 UCI data sets. The results indicate that the semiparametric method could significantly improve the clustering performance.
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BACKGROUND: Berberine (BBR), a Chinese traditional herbal medicine, has many pharmacologic benefits such as anti-inflammation and anti-oxidation. It is widely used in clinical treatment of cardiovascular diseases such as hypertension. However, the mechanism of how BBR attenuates hypertension through affecting central neural system is not clear. PURPOSE: This study was designed to determine whether chronic infusion of BBR into the hypothalamic paraventricular nucleus (PVN) attenuates hypertension and sympathoexcitation via the ROS/Erk1/2/iNOS pathway. METHODS: Two-kidney, one-clip (2K1C) renovascular hypertensive rats were randomly assigned and treated with bilateral PVN infusion of BBR (2µg/h) or vehicle (artificial cerebrospinal fluid) via osmotic minipumps for 28 days. RESULTS: 2K1C rats showed higher mean arterial pressure (MAP) and PVN Fra-like activity, plasma levels of norepinephrine (NE), PVN levels of NOX2, NOX4, Erk1/2 and iNOS, and lower PVN levels of copper/zinc superoxide dismutase (Cu/Zn-SOD). Chronic infusion of BBR reduced MAP, PVN Fra-like activity and plasma levels of NE, reduced NOX2, NOX4, Erk1/2, iNOS and induced Cu/Zn-SOD in the PVN. CONCLUSIONS: These results suggest that BBR attenuates hypertension and sympathoexcitation via the ROS/Erk1/2/iNOS pathway in 2K1C renovascular hypertensive rats.
Assuntos
Berberina/farmacologia , Hipertensão/tratamento farmacológico , Sistema de Sinalização das MAP Quinases , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Animais , Pressão Arterial , Masculino , NADPH Oxidase 2/metabolismo , NADPH Oxidase 4/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Norepinefrina/sangue , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase-1/metabolismoRESUMO
Angiotensin (Ang)-(1-7) is an important biologically-active peptide of the renin-angiotensin system. This study was designed to determine whether inhibition of Ang-(1-7) in the hypothalamic paraventricular nucleus (PVN) attenuates sympathetic activity and elevates blood pressure by modulating pro-inflammatory cytokines (PICs) and oxidative stress in the PVN in salt-induced hypertension. Rats were fed either a high-salt (8% NaCl) or a normal salt diet (0.3% NaCl) for 10 weeks, followed by bilateral microinjections of the Ang-(1-7) antagonist A-779 or vehicle into the PVN. We found that the mean arterial pressure (MAP), renal sympathetic nerve activity (RSNA), and plasma norepinephrine (NE) were significantly increased in salt-induced hypertensive rats. The high-salt diet also resulted in higher levels of the PICs interleukin-6, interleukin-1beta, tumor necrosis factor alpha, and monocyte chemotactic protein-1, as well as higher gp91phox expression and superoxide production in the PVN. Microinjection of A-779 (3 nmol/50 nL) into the bilateral PVN of hypertensive rats not only attenuated MAP, RSNA, and NE, but also decreased the PICs and oxidative stress in the PVN. These results suggest that the increased MAP and sympathetic activity in salt-induced hypertension can be suppressed by blockade of endogenous Ang-(1-7) in the PVN, through modulation of PICs and oxidative stress.
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Angiotensina I/antagonistas & inibidores , Hipertensão/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Fragmentos de Peptídeos/antagonistas & inibidores , Cloreto de Sódio na Dieta/farmacologia , Angiotensina I/metabolismo , Animais , Antioxidantes/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/induzido quimicamente , Masculino , Fragmentos de Peptídeos/metabolismo , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismoRESUMO
Metformin (MET), an antidiabetic agent, also has antioxidative effects in metabolic-related hypertension. This study was designed to determine whether MET has anti-hypertensive effects in salt-sensitive hypertensive rats by inhibiting oxidative stress in the hypothalamic paraventricular nucleus (PVN). Salt-sensitive rats received a high-salt (HS) diet to induce hypertension, or a normal-salt (NS) diet as control. At the same time, they received intracerebroventricular (ICV) infusion of MET or vehicle for 6 weeks. We found that HS rats had higher oxidative stress levels and mean arterial pressure (MAP) than NS rats. ICV infusion of MET attenuated MAP and reduced plasma norepinephrine levels in HS rats. It also decreased reactive oxygen species and the expression of subunits of NAD(P)H oxidase, improved the superoxide dismutase activity, reduced components of the renin-angiotensin system, and altered neurotransmitters in the PVN. Our findings suggest that central MET administration lowers MAP in salt-sensitive hypertension via attenuating oxidative stress, inhibiting the renin-angiotensin system, and restoring the balance between excitatory and inhibitory neurotransmitters in the PVN.
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Hipertensão/tratamento farmacológico , Metformina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Cloreto de Sódio na Dieta/farmacologia , Animais , Antioxidantes/uso terapêutico , Pressão Arterial/efeitos dos fármacos , Hipertensão/induzido quimicamente , Infusões Intraventriculares , Masculino , Metformina/administração & dosagem , Neurotransmissores/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismoRESUMO
Researchers have shown that the level of immunoglobulin D (IgD) is often elevated in patients with autoimmune diseases. The possible roles of IgD on the function of human T cell activation are still unclear. Paeoniflorin-6'-O-benzene sulfonate (code: CP-25), the chemistry structural modifications of paeoniflorin, was a novel drug of anti-inflammation and immunomodulation. The aims of this study were to determine if human CD4+ T cells could be activated by IgD via the IgD receptor (IgDR)-Lck pathway and whether the novel compound CP-25 could affect the activation of T cells by regulating Lck. Human CD4+ T cells were purified from peripheral blood mononuclear cells using microbeads. T cell viability and proliferation were detected by Cell Counting Kit-8 and CFSE Cell Proliferation Kit. Cytokines secreted by T cells were assessed with the Quantibody Human Inflammation Array. The binding affinity and expression of IgDR on T cells were detected by flow cytometry, and protein expression of IgDR, Lck, and P-Lck were analyzed by western blot. IgD was shown to bind to IgDR on CD4+ T cells in a concentration-dependent manner and stimulate the activation and proliferation of these cells by enhancing phosphorylation of the activating tyrosine residue of Lck (Tyr394). CP-25 inhibited the IgD-stimulated activation and proliferation of CD4+ T cells, as well as the production of inflammatory cytokines; it was thus suggested that this process might be related to the downregulation of Lck (Tyr394) phosphorylation. These results demonstrate that IgD amplifies the activation of CD4+ T cells, which could be mediated by Lck phosphorylation. Further, CP-25, via its ability to modulate Lck, is a novel potential therapeutic agent for the treatment of human autoimmune diseases.
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The endotoxin lipopolysaccharide (LPS)-induced pulmonary endothelial barrier disruption is a key pathogenesis of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). However, the molecular mechanisms underlying LPS-impaired permeability of pulmonary microvascular endothelial cells (PMVECs) are not fully understood. Gap junctions, particularly Connexin40 (Cx40), are necessary for the maintenance of normal vascular function. In this study, we for the first time investigated the role of Cx40 in LPS-impaired permeability of PMVECs and provided potential therapeutic approaches based on mechanistic findings of Cx40 regulation by LPS stimuli. Rat PMVECs were isolated, cultured and identified with cell morphology, specific markers, ultrastructural characteristics and functional tests. Western blot analysis demonstrated that Cx40 is the major connexin highly expressed in PMVECs. Furthermore, by inhibiting Cx40 in a time-dependent manner, LPS impaired gap junction function and induced permeability injury of PMVECs. The key role of Cx40 decline in mediating detrimental effects of LPS was further confirmed in rescue experiments through Cx40 overexpression. Mechanistically, LPS stress on PMVECs inhibited the protein kinase C (PKC) pathway, which may synergize with the inflammatory nuclear factor kappaB (NFκB) signaling activation in suppressing Cx40 expression level and phosphorylation. Moreover, through pharmacological PKC activation or NFκB inhibition, Cx40 activity in PMVECs could be restored, leading to maintained barrier function under LPS stress. Our findings uncover a previously unrecognized role of Cx40 and its regulatory mechanisms in impaired endothelial integrity under endotoxin and inflammation, shedding light on intervention approaches to improve pulmonary endothelial barrier function in ALI and ARDS.
Assuntos
Permeabilidade Capilar/efeitos dos fármacos , Conexinas/metabolismo , Células Endoteliais/efeitos dos fármacos , Lipopolissacarídeos/toxicidade , Pulmão/irrigação sanguínea , Microvasos/efeitos dos fármacos , Animais , Células Cultivadas , Conexinas/genética , Relação Dose-Resposta a Droga , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Junções Comunicantes/efeitos dos fármacos , Junções Comunicantes/metabolismo , Junções Comunicantes/patologia , Microvasos/metabolismo , Microvasos/patologia , NF-kappa B/metabolismo , Fosforilação , Proteína Quinase C/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Proteína alfa-5 de Junções ComunicantesRESUMO
An innovative natriuretic peptide analog named CNAAC (structurally consisting of the C-terminus and ring of ANP and the N-terminus of CNP) that has been shown to exhibit potent vasodilatory, diuretic, and hypotensive effects in our previous study was evaluated for the treatment of left ventricular dysfunction following myocardial infarction. The temporal relaxation effect and metabolic status of CNAAC were determined. A myocardial ischemic model was established. Rats were randomly divided into Sham, MI, MI-ANP, MI-CNP, MI-VNP, and MI-CNAAC groups. Humoral factors were measured; echocardiography and hemodynamics methods were employed to assess the cardiac function at the fourth week after modeling. The results showed that CNAAC had a potent relaxant effect and longer duration of action than ANP, CNP, or VNP. The stability of CNAAC in blood was higher than other three NPs. Four weeks of NP administration ameliorated diastolic and systolic dysfunction, the hypertrophic index, myocardial fibrosis, and infarct size; it also restored the abnormal changes in humoral factors. These results demonstrate that CNAAC has a potent cardioprotective effect against left ventricular dysfunction after myocardial infarction. The results may lay the foundation for the clinical application of this newly designed NP chimera in the treatment and prevention of heart failure.
Assuntos
Fator Natriurético Atrial/farmacologia , Cardiotônicos/farmacologia , Infarto do Miocárdio/complicações , Peptídeo Natriurético Tipo C/farmacologia , Proteínas Recombinantes de Fusão/farmacologia , Disfunção Ventricular Esquerda/tratamento farmacológico , Animais , Aorta Abdominal/efeitos dos fármacos , Fator Natriurético Atrial/sangue , Ecocardiografia , Hemodinâmica , Masculino , Peptídeo Natriurético Tipo C/sangue , Peptídeos Natriuréticos , Ratos Sprague-Dawley , Proteínas Recombinantes de Fusão/sangue , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Disfunção Ventricular Esquerda/prevenção & controleRESUMO
Excessive oxidative stress and inflammation in hypothalamic paraventricular nucleus (PVN) are implicated in the pathogenesis of hypertension. It is reported that tert-butylhydroquinone (tBHQ), a nuclear factor erythroid 2-related factor 2(Nrf2)-inducer, has a variety of pharmacological activities such as anti-oxidation and anti-inflammatory effect. The objective of this study was to investigate the effects of tBHQ in high salt induced hypertension and to identify whether the beneficial effects were induced by inhibiting PVN oxidative stress and inflammation. Male Sprague-Dawley rats were fed with high salt diet (HS, 8% NaCl) or normal salt diet (NS, 0.3% NaCl). These rats were administration of tBHQ (150mg/kg/d) by oral gavage for 16 weeks. Our results showed that high salt intake resulted in higher mean arterial pressure, cardiac hypertrophy as well as increased plasma level of norepinephrine and interleukin (IL)-1ß, IL-6 compared with NS rats. It increased PVN level of reactive oxygen species, gp91phox, IL-1ß, IL-6, p-IKKß and nuclear factor-kappa B (NF-κB) activity, decreased PVN level of Nrf2 and Cu/Zn-SOD. Chronic administration of tBHQ significantly attenuated these changes in HS rats. These data suggest that the protective effects of tBHQ in salt induced hypertension are partly due to inhibiting oxidative stress and inflammation in PVN.
Assuntos
Hidroquinonas/farmacologia , Hipertensão/tratamento farmacológico , Inflamação/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Cloreto de Sódio na Dieta/efeitos adversos , Animais , Antioxidantes/farmacologia , Pressão Arterial , Modelos Animais de Doenças , Hipertensão/induzido quimicamente , Interleucina-1beta/sangue , Interleucina-6/sangue , Masculino , Glicoproteínas de Membrana/sangue , NADPH Oxidase 2 , NADPH Oxidases/sangue , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Norepinefrina/sangue , Núcleo Hipotalâmico Paraventricular/metabolismo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Cloreto de Sódio na Dieta/administração & dosagem , Superóxido Dismutase/metabolismoRESUMO
Immunoglobulin IgD might play an important role in autoimmune diseases, but the function of IgD has remained elusive, despite multiple attempts to define its biological function. Fibroblast-like synoviocytes (FLSs) are specialized cells of the synovium that play a key role in the pathogenesis of rheumatoid arthritis (RA). In this study we explored the possible roles of excessive IgD expression on the function of FLSs from RA patients (RA-FLSs). We showed that IgD Fc receptor (IgDR) was constitutively expressed on FLSs, and was significantly elevated in RA-FLSs compared with FLSs prepared from synovial tissues of healthy controls (HC-FLSs). Furthermore, IgDR was mainly detected on the cell surface and in the cytoplasm. We further detected the intrinsic binding affinity of IgD to IgDR on HC-FLSs with an equilibrium dissociation constant (KD) of 0.067 nmol/L. Incubation of RA-FLSs with IgD (1-10 µg/mL) for 48 h dose-dependently promoted the expression of IgDR, and stimulated the production of inflammatory cytokines and chemokines, such as IL-1ß, IL-6, monocyte chemotactic protein (MCP)-1, TNF-α and receptor activator of nuclear factor-κB ligand (RANKL), thus potentially contributing to IgD-IgDR crosslinking. Moreover, incubation with IgD (0.1-10 µg/mL) for 48 h dose-dependently enhanced viability for both HC-FLSs and RA-FLSs. Our results demonstrate that IgDR is expressed on RA-FLSs and contributes to the activation of FLSs, and suggest that IgD-IgDR is a potential novel immunotherapeutic target for the management of RA.
Assuntos
Artrite Reumatoide/metabolismo , Fibroblastos/metabolismo , Receptores Fc/metabolismo , Membrana Sinovial/metabolismo , Sinoviócitos/metabolismo , Artrite Reumatoide/imunologia , Estudos de Casos e Controles , Células Cultivadas , Quimiocinas/metabolismo , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Fibroblastos/efeitos dos fármacos , Fibroblastos/imunologia , Humanos , Imunoglobulina D/metabolismo , Imunoglobulina D/farmacologia , Receptores Fc/efeitos dos fármacos , Receptores Fc/imunologia , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/imunologia , Sinoviócitos/efeitos dos fármacos , Sinoviócitos/imunologia , Fatores de Tempo , Regulação para CimaRESUMO
Brain renin-angiotensin system (RAS) could regulate oxidative stress in the paraventricular nucleus (PVN) in the development of hypertension. This study was designed to explore the precise mechanisms of RAS acting on reactive oxygen species (ROS) in salt-induced hypertension. Male Wistar rats were administered with a high-salt diet (HS, 8.0% NaCl) for 8 weeks to induced hypertension. Those rats were received PVN infusion of AT1R antagonist losartan (LOS, 10 µg/h) or microinjection of small interfering RNAs for protein kinase C γ (PKCγ siRNA) once a day for 2 weeks. High salt intake resulted in higher levels of AT1R, PKCγ, Rac1 activity, superoxide and malondialdehyde (MDA) activity, but lower levels of copper/zinc superoxide dismutase (Cu/Zn-SOD), superoxide dismutase (SOD) and glutathione (GSH) in PVN than control animals. PVN infusion of LOS not only attenuated the PVN levels of AT1R, PKCγ, Rac1 activity, superoxide and decreased the arterial pressure, but also increased the PVN antioxidant capacity in hypertension. PVN microinjection of PKCγ siRNA had the same effect on LOS above responses to hypertension but no effect on PVN level of AT1R. These results, for the first time, identified that the precise signaling pathway of RAS regulating ROS in PVN is via AT1R/PKCγ/Rac1 in salt-induced hypertension.
Assuntos
Hipertensão/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sistema Renina-Angiotensina , Transdução de Sinais , Animais , Hipertensão/induzido quimicamente , Hipertensão/fisiopatologia , Masculino , Núcleo Hipotalâmico Paraventricular/fisiopatologia , Proteína Quinase C/metabolismo , Ratos , Ratos Sprague-Dawley , Cloreto de Sódio na Dieta/efeitos adversos , Proteínas rac1 de Ligação ao GTP/metabolismoRESUMO
Hydrogen sulfide (H2S) is an important gaseous signaling molecule in neuro-modulation, anti-inflammatory, anti-oxidant and anti-hypertensive effects. The paraventricular nucleus (PVN) is a major integrative nucleus in regulating BP and SNA. The aim of this study is to explore whether endogenous or exogenous H2S changed by hydroxylamine hydrochloride (HA) or GYY4137 infused in the PVN affects RSNA and MAP by regulating oxidative stress or the balance between pro-inflammatory cytokines (PICs) and anti-inflammatory cytokines in high salt-induced hypertensive rats. Male Dahl rats were fed by high-salt or normal-salt diet. At the end of the 4th week, GYY4137, HA or vehicle was microinjected into bilateral PVN for 6 weeks. The levels of MAP, HR, plasma norepinephrine (NE), reactive oxygen species (ROS), NOX2, NOX4 and IL-1ß were increased significantly in high salt-induced hypertensive rats. Higher levels of these parameters were detected in the group treated by HA, but lower levels in the GYY4137 group. The trends of H2S, CBS, IL-10 and Cu/Zn SOD were opposite to the parameters described above. These findings suggest that endogenous or exogenous H2S in the PVN attenuates sympathetic activity and hypertensive response, which are partly due to decrease of ROS and PICs within the PVN in high salt-induced hypertension.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Sulfeto de Hidrogênio/farmacologia , Hipertensão/sangue , Estresse Oxidativo/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Cloreto de Sódio na Dieta/efeitos adversos , Animais , Anti-Inflamatórios/farmacologia , Cistationina beta-Sintase/antagonistas & inibidores , Cistationina beta-Sintase/genética , Cistationina beta-Sintase/metabolismo , Regulação para Baixo , Frequência Cardíaca/efeitos dos fármacos , Hidroxilamina/farmacologia , Hipertensão/induzido quimicamente , Hipertensão/tratamento farmacológico , Interleucina-10/genética , Interleucina-10/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Morfolinas/farmacologia , NADPH Oxidase 2 , NADPH Oxidase 4 , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Norepinefrina/sangue , Compostos Organotiofosforados/farmacologia , Núcleo Hipotalâmico Paraventricular/metabolismo , Ratos , Ratos Endogâmicos Dahl , Espécies Reativas de Oxigênio/metabolismo , Cloreto de Sódio na Dieta/administração & dosagem , Cloreto de Sódio na Dieta/sangue , Superóxido Dismutase/sangueRESUMO
The imbalance of neurotransmitters and excessive oxidative stress responses contribute to the pathogenesis of hypertension. In this study, we determined whether blockade of p44/42 MAPK pathway in the hypothalamic paraventricular nucleus (PVN) ameliorates the development of hypertension through modulating neurotransmitters and attenuating oxidative stress. Dahl salt-sensitive (S) rats received a high-salt diet (HS, 8% NaCl) or a normal-salt diet (NS, 0.3% NaCl) for 6 weeks and were treated with bilateral PVN infusion of PD-98059 (0.025 µg/h), a p44/42 MAPK inhibitor, or vehicle via osmotic minipump. HS resulted in higher mean arterial pressure (MAP) and Fra-like (Fra-LI) activity, and plasma and PVN levels of norepinephrine (NE), tyrosine hydroxylase (TH), NOX2 and NOX4, lower PVN levels of gamma-aminobutyric acid (GABA), copper/zinc superoxide dismutase (Cu/Zn-SOD) and the 67-kDa isoform of glutamate decarboxylase (GAD67), as compared with NS group. PD-98059 infusion reduced NE, TH, NOX2 and NOX4 in the PVN, and induced Cu/Zn-SOD and GAD67 in the PVN. It suggests that PVN blockade of p44/42 MAPK attenuates hypertension through modulating neurotransmitters and attenuating oxidative stress.
Assuntos
Hipertensão/induzido quimicamente , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Neurotransmissores/metabolismo , Estresse Oxidativo , Núcleo Hipotalâmico Paraventricular/enzimologia , Cloreto de Sódio/metabolismo , Animais , Modelos Animais de Doenças , Núcleo Hipotalâmico Paraventricular/fisiologia , Ratos Endogâmicos Dahl , Transdução de SinaisRESUMO
Choosing suitable kernels plays an important role in the performance of kernel methods. Recently, a number of studies were devoted to developing nonparametric kernels. Without assuming any parametric form of the target kernel, nonparametric kernel learning offers a flexible scheme to utilize the information of the data, which may potentially characterize the data similarity better. The kernel methods using nonparametric kernels are referred to as nonparametric kernel methods. However, many nonparametric kernel methods are restricted to transductive learning, where the prediction function is defined only over the data points given beforehand. They have no straightforward extension for the out-of-sample data points, and thus cannot be applied to inductive learning. In this paper, we show how to make the nonparametric kernel methods applicable to inductive learning. The key problem of out-of-sample extension is how to extend the nonparametric kernel matrix to the corresponding kernel function. A regression approach in the hyper reproducing kernel Hilbert space is proposed to solve this problem. Empirical results indicate that the out-of-sample performance is comparable to the in-sample performance in most cases. Experiments on face recognition demonstrate the superiority of our nonparametric kernel method over the state-of-the-art parametric kernel methods.