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Methyl p-coumarate (methyl p-hydroxycinnamate) (MH) is a natural compound found in a variety of plants. In the present study, we evaluated the ameliorative effects of MH on airway inflammation in an experimental model of allergic asthma (AA). In this in vitro study, MH was found to exert anti-inflammatory activity on PMA-stimulated A549 airway epithelial cells by suppressing the secretion of IL-6, IL-8, MCP-1, and ICAM-1. In addition, MH exerted an inhibitory effect not only on NF-κB (p-NF-κB and p-IκB) and AP-1 (p-c-Fos and p-c-Jun) activation but also on A549 cell and EOL-1 cell (eosinophil cell lines) adhesion. In LPS-stimulated RAW264.7 macrophages, MH had an inhibitory effect on TNF-α, IL-1ß, IL-6, and MCP-1. The results from in vivo study revealed that the increases in eosinophils/Th2 cytokines/MCP-1 in the bronchoalveolar lavage fluid (BALF) and IgE in the serum of OVA-induced mice with AA were effectively inhibited by MH administration. MH also exerted a reductive effect on the immune cell influx, mucus secretion, and iNOS/COX-2 expression in the lungs of mice with AA. The effects of MH were accompanied by the inactivation of NF-κB. Collectively, the findings of the present study indicated that MH attenuates airway inflammation in mice with AA, suggesting its potential as an adjuvant in asthma therapy.
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Asma , FN-kappa B , Animales , Ratones , Líquido del Lavado Bronquioalveolar , Citocinas/metabolismo , Modelos Animales de Enfermedad , Células Epiteliales/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Interleucina-6 , Ratones Endogámicos BALB C , FN-kappa B/metabolismo , OvalbúminaRESUMEN
Background: Cigarette smoke (CS) is considered a principal cause of chronic obstructive pulmonary disease (COPD) and is associated with mucus hypersecretion and airway inflammation. Ginsenoside compound K (CK), a product of ginsenoside metabolism, has various biological activities. Studies on the effects of CK for the treatment of COPD and mucus hypersecretion, including the underlying signaling mechanism, have not yet been conducted. Methods: To study the protective effects and molecular mechanism of CK, phorbol 12-myristate 13-acetate (PMA)-induced human airway epithelial (NCI-H292) cells were used as a cellular model of airway inflammation. An experimental mouse COPD model was also established via CS inhalation and intranasal administration of lipopolysaccharide. Mucin 5AC (MUC5AC), monocyte chemoattractant protein-1, tumor necrosis factor-α (TNF-α), and interleukin-6 secretion, as well as elastase activity and reactive oxygen species production, were determined through enzyme-linked immunosorbent assay. Inflammatory cell influx and mucus secretion in mouse lung tissues were estimated using hematoxylin and eosin and periodic acid-schiff staining, respectively. PKCδ and its downstream signaling molecules were analyzed via western blotting. Results: CK prevented the secretion of MUC5AC and TNF-α in PMA-stimulated NCI-H292 cells and exhibited a protective effect in COPD mice via the suppression of inflammatory mediators and mucus secretion. These effects were accompanied by an inactivation of PKCδ and related signaling in vitro and in vivo. Conclusion: CK suppressed pulmonary inflammation and mucus secretion in COPD mouse model through PKC regulation, highlighting the compound's potential as a useful adjuvant in the prevention and treatment of COPD.
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BACKGROUND: Since long-term or high-dose use of COPD medication causes adverse effects in patients with COPD, more effective and safer ways to manage COPD symptoms are required. Daphne kiusiana Miquel is a medicinal plant, but its anti-COPD efficacy was little studied. PURPOSE: We investigated the anti-COPD activity and molecular mechanism of action of active compounds isolated from D. kiusiana to find drug candidates for COPD. METHODS: We isolated seven compounds (1-7) in an ethyl acetate (EtOAc) fraction from D. kiusiana, and determined that seven compounds effectively control the inflammatory responsiveness in both PMA-stimulated lung epithelial cells (in vitro) and/or in COPD model mice using cigarette smoke- and lipopolysaccharides-exposed animals in vivo. RESULTS: We show that the ethyl acetate (EtOAc) fraction from D. kiusiana. suppresses inflammatory response in both PMA-stimulated human lung epithelial cells (in vitro) and COPD model mice (in vivo). The EtOAc fraction effectively suppresses various inflammatory responses, such as mucus secretion, ROS production, bronchial recruitment of inflammatory cells, and release of proinflammatory cytokines. Additionally, we isolated three compounds with anti-inflammatory efficacy from the EtOAc fraction, out of which daphnodorin C was the most effective. Finally, we demonstrated that daphnodorin C negatively regulates inflammatory gene expression by suppressing NF-κB and specific MAPK signaling pathways (JNK and p38) in vitro and in vivo. CONCLUSIONS: These results suggest that daphnodorin C could be a promising therapeutic alternative for managing COPD symptoms.
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Daphne , Enfermedad Pulmonar Obstructiva Crónica , Animales , Benzopiranos , Humanos , Inflamación/tratamiento farmacológico , Pulmón , Ratones , FN-kappa B , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , HumoRESUMEN
Methyl phydroxycinnamate (MH), an esterified derivative of pCoumaric acid exerts antiinflammatory effects on lipopolysaccharide (LPS)stimulated RAW264.7 macrophages. Based on these effects, the present study investigated the protective role of MH in a mouse model of LPSinduced acute respiratory distress syndrome (ARDS). The results demonstrated that administration of LPS (5 mg/kg intranasally) markedly increased the neutrophil/macrophage numbers and levels of inflammatory molecules (TNFα, IL6, IL1ß and reactive oxygen species) in the bronchoalveolar lavage ï¬uid (BALF) of mice. On histological examination, the presence of inflammatory cells was observed in the lungs of mice administered LPS. LPS also notably upregulated the secretion of monocyte chemoattractant protein1 and protein content in BALF as well as expression of inducible nitric oxide synthase in the lungs of mice; it also caused activation of p38 mitogenactivated protein kinase (MAPK) and NFκB signaling. However, MH treatment significantly suppressed LPSinduced upregulation of inflammatory cell recruitment, inflammatory molecule levels and p38MAPK/NFκB activation, and also led to upregulation of heme oxygenase1 (HO1) expression in the lungs of mice. In addition, the ability of MH to induce HO1 expression was confirmed in RAW264.7 macrophages. Taken together, the findings of the present study indicated that MH may exert protective effects against airway inflammation in ARDS mice by inhibiting inflammatory cell recruitment and the production of inflammatory molecules.
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Antiinflamatorios/farmacología , Cinamatos/farmacología , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Inflamación/prevención & control , Lipopolisacáridos/toxicidad , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Animales , Inflamación/etiología , Inflamación/metabolismo , Inflamación/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Células RAW 264.7 , Síndrome de Dificultad Respiratoria/inducido químicamente , Síndrome de Dificultad Respiratoria/metabolismo , Síndrome de Dificultad Respiratoria/patología , Transducción de SeñalRESUMEN
Microglia play an important role in the maintenance and neuroprotection of the central nervous system (CNS) by removing pathogens, damaged neurons, and plaques. Recent observations emphasize that the promotion and development of neurodegenerative diseases (NDs) are closely related to microglial activation. In this review, we summarize the contribution of microglial activation and its associated mechanisms in NDs, such as epilepsy, Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), based on recent observations. This review also briefly introduces experimental animal models of epilepsy, AD, PD, and HD. Thus, this review provides a better understanding of microglial functions in the development of NDs, suggesting that microglial targeting could be an effective therapeutic strategy for these diseases.
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Lagerstroemia ovalifolia Teijsm. & Binn. (LO) (crape myrtle) has reportedly been used as traditional herbal medicine (THM) in Java, Indonesia. Our previous study revealed that the LO leaf extract (LOLE) exerted anti-inflammatory effects on lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Based on this finding, the current study aimed to evaluate the protective effects of LOLE in a mouse model of LPS-induced acute lung injury (ALI). The results showed that treatment with LPS enhanced the inflammatory cell influx into the lungs and increased the number of macrophages and the secretion of the inflammatory cytokines in the bronchoalveolar lavage fluid (BALF) of mice. However, these effects were notably abrogated with LOLE pretreatment. Furthermore, the increase of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and monocyte chemoattractant protein-1 (MCP-1) expression in the lung tissues of mice with ALI was also reversed by LOLE. In addition, LOLE significantly suppressed the LPS-induced activation of the MAPK/NF-κB signaling pathway and led to heme oxygenase-1 (HO-1) induction in the lungs. Additionally, in vitro experiments showed that LOLE enhanced the expression of HO-1 in RAW264.7 macrophages. The aforementioned findings collectively indicate that LOLE exerts an ameliorative effect on inflammatory response in the airway of ALI mice.
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Lesión Pulmonar Aguda/tratamiento farmacológico , Lagerstroemia/química , Proteínas Quinasas Activadas por Mitógenos/metabolismo , FN-kappa B/metabolismo , Extractos Vegetales/farmacología , Lesión Pulmonar Aguda/inducido químicamente , Animales , Antiinflamatorios/farmacología , Quimiocina CCL2 , Ciclooxigenasa 2 , Citocinas/metabolismo , Hemo-Oxigenasa 1 , Indonesia , Macrófagos/efectos de los fármacos , Masculino , Proteínas de la Membrana , Ratones , Ratones Endogámicos C57BL , Óxido Nítrico Sintasa de Tipo II , Hojas de la Planta/química , Células RAW 264.7 , Transducción de Señal/efectos de los fármacosRESUMEN
3,4,5Trihydroxycinnamic acid (THCA) exhibits antiinflammatory activity in acute or chronic inflammatory disorders, such as acute lung injury and asthma. The present study investigated the antiinflammatory activity of THCA in a tumor necrosis factorα/interferonγ (TI) mixturestimulated human keratinocyte cell line. The results of ELISA and reverse transcriptionquantitative PCR revealed that THCA reduced the secretion and mRNA expression levels of interleukin (IL)6; IL8; thymus and activationregulated chemokine; macrophagederived chemokine; regulated upon activation, normal T cell expressed and secreted; and monocyte chemoattractant protein1 in TI mixturestimulated HaCaT cells. In addition, the results of western blot analysis demonstrated that THCA exerted inhibitory activity on the activation of AKT, ERK and nuclear factorκB in TI mixturestimulated HaCaT cells. Furthermore, THCA upregulated the expression levels of heme oxygenase1 and NAD(P)H:quinone oxidoreductase 1, and the activation of nuclear factor erythroid 2related factor 2 in HaCaT cells. These results demonstrated that THCA may exhibit antiinflammatory activity in activated HaCaT cells.
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Antiinflamatorios/farmacología , Cinamatos/farmacología , Interferón gamma/farmacología , Queratinocitos/efectos de los fármacos , Factor de Necrosis Tumoral alfa/farmacología , Proteínas ADAM/genética , Proteínas ADAM/metabolismo , Quimiocina CCL17/genética , Quimiocina CCL17/metabolismo , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Quimiocina CCL5/genética , Quimiocina CCL5/metabolismo , Células HaCaT , Hemo-Oxigenasa 1/metabolismo , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Interleucina-8/genética , Interleucina-8/metabolismo , Proteínas Quinasas Activadas por Mitógenos/metabolismo , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factor de Transcripción ReIA/metabolismo , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
Macrophages play an important role in the innate and adaptive immune responses of organ systems, including the lungs, to particles and pathogens. Cumulative results show that macrophages contribute to the development and progression of acute or chronic inflammatory responses through the secretion of inflammatory cytokines/chemokines and the activation of transcription factors in the pathogenesis of inflammatory lung diseases, such as acute lung injury (ALI), acute respiratory distress syndrome (ARDS), ARDS related to COVID-19 (coronavirus disease 2019, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)), allergic asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF). This review summarizes the functions of macrophages and their associated underlying mechanisms in the development of ALI, ARDS, COVID-19-related ARDS, allergic asthma, COPD, and IPF and briefly introduces the acute and chronic experimental animal models. Thus, this review suggests an effective therapeutic approach that focuses on the regulation of macrophage function in the context of inflammatory lung diseases.
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Lesión Pulmonar Aguda/patología , COVID-19/patología , Macrófagos/patología , Neumonía/patología , Enfermedad Pulmonar Obstructiva Crónica/patología , Síndrome de Dificultad Respiratoria/patología , Lesión Pulmonar Aguda/inmunología , Animales , Asma/inmunología , Asma/patología , COVID-19/inmunología , Enfermedad Crónica , Humanos , Fibrosis Pulmonar Idiopática/inmunología , Fibrosis Pulmonar Idiopática/patología , Pulmón/inmunología , Pulmón/patología , Macrófagos/inmunología , Neumonía/inmunología , Enfermedad Pulmonar Obstructiva Crónica/inmunología , Síndrome de Dificultad Respiratoria/inmunología , SARS-CoV-2/inmunologíaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Callicarpa japonica Thunb., as an herbal medicine has been used for the treatment of inflammatory diseases in China and Korea. MATERIALS AND METHODS: Ultra performance liquid chromatography-photodiode array-quadrupole time-of-flight mass spectrometer (UPLC-PDA-QTof MS) was used to detect the major phenylethanoid glycosides in the C. japonica extract. BALB/c mice were intraperitoneally sensitized by ovalbumin (OVA) (on days 0 and 7) and challenged by OVA aerosol (on days 11-13) to induce airway inflammatory response. The mice were also administered with C. japonica Thunb. (CJT) (20 and 40 mg/kg Per oral) on days 9-13. CJT pretreatment was conducted in lipopolysaccharide (LPS)-stimulated RAW264.7 or phorbol 12-myristate 13-acetate (PMA)-stimulated A549 cells. RESULTS: CJT administration significantly reduced the secretion of Th2 cytokines, TNF-α, IL-6, immunoglobulin E (IgE) and histamine, and the recruitment of eosinophils in an OVA-exposed mice. In histological analyses, the amelioration of inflammatory cell influx and mucus secretion were observed with CJT. The OVA-induced airway hyperresponsiveness (AHR), iNOS expression and NF-κB activation were effectively suppressed by CJT administration. In addition, CJT led to the upregulation of HO-1 expression. In an in vitro study, CJT pretreatment suppressed the LPS-induced TNF-α secretion in RAW264.7 cells and attenuated the PMA-induced IL-6, IL-8 and MCP-1 secretion in A549 cells. These effects were accompanied by downregulated NF-κB phosphorylation and by upregulated HO-1 expression. CONCLUSION: These results suggested that CJT has protective activity against OVA-induced airway inflammation via downregulation of NF-κB activation and upregulation of HO-1, suggesting that CJT has preventive potential for the development of allergic asthma.
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Antiasmáticos/farmacología , Antiinflamatorios/farmacología , Asma/prevención & control , Hiperreactividad Bronquial/prevención & control , Callicarpa , Hemo-Oxigenasa 1/metabolismo , Pulmón/efectos de los fármacos , Proteínas de la Membrana/metabolismo , FN-kappa B/metabolismo , Extractos Vegetales/farmacología , Células A549 , Animales , Antiasmáticos/aislamiento & purificación , Antiinflamatorios/aislamiento & purificación , Asma/inducido químicamente , Asma/enzimología , Asma/fisiopatología , Hiperreactividad Bronquial/inducido químicamente , Hiperreactividad Bronquial/enzimología , Hiperreactividad Bronquial/fisiopatología , Broncoconstricción/efectos de los fármacos , Callicarpa/química , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Pulmón/enzimología , Pulmón/fisiopatología , Ratones , Ratones Endogámicos BALB C , Ovalbúmina , Extractos Vegetales/aislamiento & purificación , Células RAW 264.7 , Transducción de Señal , Regulación hacia ArribaRESUMEN
3,4,5-Trihydroxycinnamic acid (THCA) has been reported to possess anti-inflammatory activity. However, the effect of THCA for treating allergic asthma was unknown. Therefore, in the present study, the anti-asthmatic effects of THCA were studied in both in vitro and in vivo studies. In phorbol 12-myristate 13-acetate (PMA)-stimulated A549 airway epithelial cells, THCA pretreatment decreased the mRNA expression and secretion of interleukin (IL)-8, monocyte chemoattractant protein-1 (MCP-1), and intercellular adhesion molecules 1 (ICAM-1), and reduced the mRNA expression of matrix metalloproteinase 9 (MMP-9). THCA also inhibited PMA-induced protein kinase B (AKT), mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) activation in A549 cells. In lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages, THCA pretreatment suppressed the mRNA expression of ICAM-1 and MMP-9. In addition, THCA suppressed the adhesion of EOL and A549 cells. In ovalbumin (OVA)-administered asthmatic mice, THCA exerted inhibitory activity on IL-5, IL-13, and MCP-1 in bronchoalveolar lavage fluid (BALF) and on OVA-specific immunoglobulin E (IgE) in serum. THCA attenuated the numbers of inflammatory cells in BALF and the influx of inflammatory cell in lung tissues. Furthermore, THCA downregulated the levels of inducible nitric oxide (iNOS), cyclooxygenase-2 (COX-2), and leukotriene B4 (LTB4) expression, mucus production and CREB phosphorylation as well as Penh value. These effects were accompanied by suppression of AKT, extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and NF-κB activation. Therefore, the results of the current study suggest that THCA may be a valuable adjuvant or therapeutic in the prevention or treatment of allergic asthma.
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Asma/inducido químicamente , Asma/tratamiento farmacológico , Cinamatos/farmacología , Macrófagos/efectos de los fármacos , Animales , Adhesión Celular/efectos de los fármacos , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/metabolismo , Línea Celular Tumoral , Quimiocinas/genética , Quimiocinas/metabolismo , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Ratones , Ratones Endogámicos BALB C , Ovalbúmina/toxicidad , Células RAW 264.7 , Distribución AleatoriaRESUMEN
A number of species of the genus Trichilia (Meliaceae) exhibit anti-inflammatory effects. However, the effect of Trichilia martiana C. DC. (TM) on lipopolysaccharide (LPS)-induced inflammation has not, to the best of our knowledge, yet been determined. Therefore, in the present study, the antiinflammatory effect of TM on LPS-stimulated RAW264.7 macrophages was evaluated. The ethanol extract of TM (TMEE) significantly inhibited LPS-induced nitric oxide (NO), prostaglandin 2 (PGE2), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). TMEE also reduced the levels of inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1ß and IL-6. The upregulation of mitogen-activated protein kinases (MAPKs) and NF-κB activation was revealed to be downregulated following TMEE pretreatment. Furthermore, TMEE was indicated to lead to the nucleus translocation of nuclear factor erythroid-derived 2-related factor 2 (Nrf2) and the expression of heme oxygenase-1 (HO-1). In H292 airway epithelial cells, the pretreatment of TMEE significantly downregulated the production of LPS-stimulated IL-1ß, and TMEE was indicated to increase the expression of HO-1. In animal models exhibiting LPS-induced acute lung injury (ALI), treatment with TMEE reduced the levels of macrophages influx and TNF-α production in the bronchoalveolar lavage fluid (BALF) of ALI mice. Additionally, TMEE significantly downregulated the activation of ERK, JNK and IκB, and upregulated the expression of HO-1 in the lungs of ALI mice. In conclusion, the results of the current study demonstrated that TMEE could exert a regulatory role in the prevention or treatment of the endotoxin-mediated inflammatory response.
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Antiinflamatorios/farmacología , Células Epiteliales/efectos de los fármacos , Lipopolisacáridos/efectos adversos , Macrófagos/efectos de los fármacos , Meliaceae/química , Extractos Vegetales/farmacología , Lesión Pulmonar Aguda/inducido químicamente , Animales , Ciclooxigenasa 2 , Citocinas/metabolismo , Modelos Animales de Enfermedad , Hemo-Oxigenasa 1 , Inflamación/tratamiento farmacológico , Interleucina-1beta , Interleucina-6 , Pulmón , Lesión Pulmonar/inducido químicamente , Lesión Pulmonar/tratamiento farmacológico , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Prostaglandinas , Células RAW 264.7 , Transducción de Señal/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
3,4,5-Trihydroxycinnamic acid (THCA), a derivative of hydroxycinnamic acid, has been reported to exert anti-inflammatory and antioxidant activities. However, its anti-inflammatory effects in chronic obstructive pulmonary disease (COPD) have not yet been elucidated. Therefore, we explored the protective effects of THCA on pulmonary inflammation in an experimental COPD model elicited by cigarette smoke (CS) and lipopolysaccharide (LPS). Oral administration of THCA significantly inhibited the activity of elastase, the release of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1), myeloperoxidase (MPO) and the numbers of neutrophils and macrophages in the bronchoalveolar lavage fluid (BALF) of experimental COPD mice. THCA also exerted inhibitory effects on the recruitment of inflammatory cells, the levels of PAS positive cells and cAMP-response-element-binding protein (CREB) activation, and the expression of phosphodiesterase 4 (PDE4) in the lungs of experimental COPD mice. In addition, THCA exerted a regulatory effect on the activation of p38, ERK and nuclear factor-κB (NF-κB) in the lungs of experimental COPD mice. THCA also significantly upregulated the expression of NAD(P)H dehydrogenase (quinone 1) 1 (NQO1) and the activation of nuclear factor erythroid-derived 2-related factor 2 (Nrf2) in the lungs of mice. Furthermore, THC restored the reduction of NAD-dependent protein deacetylase sirtuin-1 (SIRT1) in the lungs of experimental COPD mice. In phorbol myristate acetate (PMA)-stimulated A549 or H292 airway epithelial cells, pretreatment of THCA dose-dependently inhibited the generation of IL-6. THCA also led to increased NQO1 expression in H292 cells. Collectively, these protective effects of antioxidant THCA were notably excellent and are thought to be associated with the downregulation of MAPK (partial)/NF-κB signaling and upregulation of NQO1 and SIRT1 expression.
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Antiinflamatorios/uso terapéutico , Antioxidantes/uso terapéutico , Cinamatos/uso terapéutico , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Animales , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Líquido del Lavado Bronquioalveolar/citología , Línea Celular , Cinamatos/farmacología , Citocinas/inmunología , Humanos , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Inflamación/patología , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/patología , Ratones Endogámicos C57BL , Modelos Animales , Enfermedad Pulmonar Obstructiva Crónica/inmunología , Enfermedad Pulmonar Obstructiva Crónica/patología , Humo/efectos adversos , NicotianaRESUMEN
Persistent infection by human papillomaviruses (HPVs), small, double-stranded DNA viruses that infect keratinocytes of the squamous epithelia, can lead to the development of cervical and other cancers. The viral oncoprotein E7 contributes to viral persistence in part by regulating host gene expression through binding host transcriptional regulators, although mechanisms responsible for E7-mediated transcriptional regulation are incompletely understood. Type I IFN signaling promotes the expression of anti-viral genes, called interferon-stimulated genes (ISGs), through the phosphorylation and activation of STAT1. In this study, we have observed that the CR3 domain of E7 contributes to the episomal maintenance of viral genomes. Transcriptome analysis revealed that E7 transcriptionally suppresses a subset of ISGs but not through regulation of STAT1 activation. Instead, we discovered that E7 associates with Mediator kinase CDK8 and this is correlated with the recruitment of CDK8 to ISG promoters and reduced ISG expression. E7 fails to suppress ISGs in the absence of CDK8, indicating that CDK8 function contributes to the suppression of ISGs by E7. Altogether, E7/CDK8 association may be a novel mechanism by which E7 inhibits innate immune signaling.
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Quinasa 8 Dependiente de Ciclina/genética , Quinasa 8 Dependiente de Ciclina/metabolismo , Papillomavirus Humano 16/metabolismo , Interferones/metabolismo , Proteínas E7 de Papillomavirus/metabolismo , Línea Celular , Expresión Génica , Regulación de la Expresión Génica , Papillomavirus Humano 16/genética , Humanos , Queratinocitos/virología , Mutación , Proteínas Oncogénicas Virales/metabolismo , Proteínas E7 de Papillomavirus/genética , Infecciones por Papillomavirus/virología , Fosforilación , Factor de Transcripción STAT1 , Transducción de SeñalRESUMEN
Pistacia weinmannifolia (Anacardiaceae) has been used in herbal medicine for the treatment of influenza, dysentery and enteritis in China. It was recently observed that P. weinmannifolia root extract (PWRE) exerts antiinflammatory effects both in in vitro and in vivo models. Based on the results from previous studies, the present study investigated the protective effect of PWRE on airway inflammation and mucus hypersecretion. Treatment with PWRE significantly decreased the number of eosinophils and the levels of Th2 cytokines, such as interleukin (IL)4, IL5 and IL13, in the bronchoalveolar lavage fluid (BALF) of OVAexposed mice. PWRE decreased the high serum levels of total and OVAspecific immunoglobulin E. PWRE also effectively inhibited the influx of inflammatory cells into the lung, as well as airway mucus hypersecretion. In addition, the increased level of monocyte chemoattractant protein1 was significantly decreased with the PWRE treatment in the BALF of OVAexposed mice and in lipopolysaccharidestimulated RAW264.7 macrophages. These protective effects of PWRE on OVAinduced pulmonary inflammation were accompanied by the downregulation of mitogen associated protein kinases and nuclear factorκB activation. Thus, the results from the present study indicate that PWRE could be valuable adjuvant for the treatment of asthma.
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Asma/tratamiento farmacológico , Pistacia/química , Extractos Vegetales/farmacología , Neumonía/tratamiento farmacológico , Animales , Antiasmáticos/farmacología , Asma/inducido químicamente , Asma/patología , Modelos Animales de Enfermedad , Expresión Génica/efectos de los fármacos , Humanos , Pulmón/efectos de los fármacos , Pulmón/patología , Ratones , FN-kappa B/genética , Ovalbúmina/toxicidad , Extractos Vegetales/química , Raíces de Plantas/química , Neumonía/inducido químicamente , Neumonía/patología , Células RAW 264.7RESUMEN
Linalool is a natural product present in fruits and aromatic plants with biological activities. Researchers have reported that the inhalation of linalool exerts anti-inflammatory activities. In this study, we examined the therapeutic effects of linalool on airway inflammation and mucus overproduction in mice with allergic asthma. Oral administration of linalool significantly inhibited the levels of eosinophil numbers, Th2 cytokines and immunoglobulin E (IgE) caused by ovalbumin (OVA) exposure. Linalool exerted preventive effects against the influx of inflammatory cells and mucus hypersecretion in the lung tissues. Linalool also dose-dependently decreased the levels of inducible nitric oxide synthase (iNOS) expression and protein kinase B (AKT) activation in the lung tissues. Linalool effectively downregulated the activation of mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB) caused by OVA exposure. Furthermore, linalool exerted inhibitory effect on OVA-induced airway hyperresponsiveness (AHR). In the in vitro study, the increased secretion of MCP-1 was attenuated with linalool treatment in lipopolysaccharide (LPS)-stimulated H292 airway epithelial cells. In conclusion, linalool effectively exerts a protective role in OVA-induced airway inflammation and mucus hypersecretion, and its protective effects are closely related to the downregulation of inflammatory mediators and MAPKs/NF-κB signaling.
Asunto(s)
Monoterpenos Acíclicos/uso terapéutico , Antiinflamatorios/uso terapéutico , Asma/tratamiento farmacológico , Hipersensibilidad/tratamiento farmacológico , Pulmón/metabolismo , Hipersensibilidad Respiratoria/tratamiento farmacológico , Células Th2/inmunología , Administración Oral , Alérgenos/inmunología , Animales , Células Cultivadas , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Inmunoglobulina E/metabolismo , Pulmón/patología , Ratones , Ratones Endogámicos BALB C , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Ovalbúmina/inmunología , Mucosa Respiratoria/metabolismo , Mucosa Respiratoria/patologíaRESUMEN
Fascaplysin, a natural product isolated from marine sponges, is a potential candidate for the development of anti-cancer drugs. However, the mechanism underlying its therapeutic effect of strengthening anti-cancer efficacy of other drugs is poorly understood. Here, we found that fascaplysin increases phosphorylation of protein kinase B (PKB), also known as AKT, and adenosine monophosphate-activated protein kinase (AMPK), which are considered therapeutic targets for cancer treatment due to their anti-apoptotic or pro-survival functions in cancer. A cell viability assay revealed that pharmacological suppression of AKT using LY294002 enhanced the anti-cancer effect of fascaplysin in various cancer cells. Similarly, fascaplysin was observed to have improved anti-cancer effects in combination with compound C, a selective AMPK inhibitor. Another challenge showed that fascaplysin increased the efficacy of methotrexate (MTX)-mediated cancer therapy by suppressing genes related to folate and purine metabolism. Overall, these results suggest that fascaplysin may be useful for improving the anti-cancer efficacy of targeted anti-cancer drugs, such as inhibitors of phosphoinositide 3-kinase AKT signaling, and chemotherapeutic agents, such as MTX.
Asunto(s)
Adenilato Quinasa/antagonistas & inhibidores , Antineoplásicos/farmacología , Indoles/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Adenilato Quinasa/metabolismo , Línea Celular Tumoral , Daño del ADN , Sinergismo Farmacológico , Activación Enzimática/efectos de los fármacos , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Metotrexato/farmacología , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Estrés Fisiológico/efectos de los fármacosRESUMEN
High-risk human papillomaviruses (HPVs) encode oncoproteins which manipulate gene expression patterns in the host keratinocytes to facilitate viral replication, regulate viral transcription, and promote immune evasion and persistence. In some cases, oncoprotein-induced changes in host cell behavior can cause progression to cancer, but a complete picture of the functions of the viral oncoproteins in the productive HPV life cycle remains elusive. E7 is the HPV-encoded factor most responsible for maintaining cell cycle competence in differentiating keratinocytes. Through interactions with dozens of host factors, E7 has an enormous impact on host gene expression patterns. In this review, we will examine the role of E7 specifically as a regulator of transcription. We will discuss mechanisms of regulation of cell cycle-related genes by E7 as well as genes involved in immune regulation, growth factor signaling, DNA damage responses, microRNAs, and others pathways. We will also discuss some unanswered questions about how transcriptional regulation by E7 impacts the biology of HPV in both benign and malignant conditions.
Asunto(s)
Evasión Inmune , Papillomaviridae/genética , Proteínas E7 de Papillomavirus/genética , Infecciones por Papillomavirus/virología , Neoplasias Cutáneas/virología , Transcripción Genética , Carcinogénesis/genética , Carcinogénesis/inmunología , Carcinogénesis/patología , Ciclo Celular/genética , Ciclo Celular/inmunología , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/inmunología , Diferenciación Celular , Línea Celular , Regulación de la Expresión Génica , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/inmunología , Queratinocitos/inmunología , Queratinocitos/virología , Papillomaviridae/crecimiento & desarrollo , Papillomaviridae/patogenicidad , Proteínas E7 de Papillomavirus/inmunología , Infecciones por Papillomavirus/genética , Infecciones por Papillomavirus/inmunología , Infecciones por Papillomavirus/patología , Transducción de Señal , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Replicación ViralRESUMEN
UNLABELLED: The immediate early 62 protein (IE62) of varicella-zoster virus (VZV), a major viral trans-activator, initiates the virus life cycle and is a key component of pathogenesis. The IE62 possesses several domains essential for trans-activation, including an acidic trans-activation domain (TAD), a serine-rich tract (SRT), and binding domains for USF, TFIIB, and TATA box binding protein (TBP). Transient-transfection assays showed that the VZV IE62 lacking the SRT trans-activated the early VZV ORF61 promoter at only 16% of the level of the full-length IE62. When the SRT of IE62 was replaced with the SRT of equine herpesvirus 1 (EHV-1) IEP, its trans-activation activity was completely restored. Herpes simplex virus 1 (HSV-1) ICP4 that lacks a TAD very weakly (1.5-fold) trans-activated the ORF61 promoter. An IE62 TAD-ICP4 chimeric protein exhibited trans-activation ability (10.2-fold), indicating that the IE62 TAD functions with the SRT of HSV-1 ICP4 to trans-activate viral promoters. When the serine and acidic residues of the SRT were replaced with Ala, Leu, and Gly, trans-activation activities of the modified IE62 proteins IE62-SRTΔSe and IE62-SRTΔAc were reduced to 46% and 29% of wild-type activity, respectively. Bimolecular complementation assays showed that the TAD of IE62, EHV-1 IEP, and HSV-1 VP16 interacted with Mediator 25 in human melanoma MeWo cells. The SRT of IE62 interacted with the nucleolar-ribosomal protein EAP, which resulted in the formation of globular structures within the nucleus. These results suggest that the SRT plays an important role in VZV viral gene expression and replication. IMPORTANCE: The immediate early 62 protein (IE62) of varicella-zoster virus (VZV) is a major viral trans-activator and is essential for viral growth. Our data show that the serine-rich tract (SRT) of VZV IE62, which is well conserved within the alphaherpesviruses, is needed for trans-activation mediated by the acidic trans-activation domain (TAD). The TADs of IE62, EHV-1 IEP, and HSV-1 VP16 interacted with cellular Mediator 25 in bimolecular complementation assays. The interaction of the IE62 SRT with nucleolar-ribosomal protein EAP resulted in the formation of globular structures within the nucleus. Understanding the mechanisms by which the TAD and SRT of IE62 contribute to the function of this essential regulatory protein is important in understanding the gene program of this human pathogen.
Asunto(s)
Herpesvirus Humano 3/fisiología , Proteínas Inmediatas-Precoces/metabolismo , Transactivadores/metabolismo , Proteínas del Envoltorio Viral/metabolismo , Replicación Viral , Sustitución de Aminoácidos , Línea Celular , Análisis Mutacional de ADN , Prueba de Complementación Genética , Humanos , Proteínas Inmediatas-Precoces/genética , Eliminación de Secuencia , Transactivadores/genética , Proteínas del Envoltorio Viral/genéticaRESUMEN
The diameter and collapsibility of the inferior vena cava (IVC) should be interpreted in consideration with other clinical and echocardiographic parameters before drawing definitive diagnostic conclusions. We report a case of a 46-year-old female with isolated IVC dilation and diminished inspiratory collapse without other abnormalities, and provide a brief review of the literature.
Asunto(s)
Vena Cava Inferior/patología , Función del Atrio Derecho , Presión Atrial , Cateterismo Cardíaco , Dilatación Patológica , Ecocardiografía Doppler en Color , Femenino , Humanos , Persona de Mediana Edad , Flebografía/métodos , Mecánica Respiratoria , Tomografía Computarizada por Rayos X , Vena Cava Inferior/diagnóstico por imagen , Vena Cava Inferior/fisiopatologíaRESUMEN
Aorta-right atrial tunnel is a rare and distinct congenital anomaly. It is a vascular channel that originates from one of the sinuses of Valsalva with a tortuous course anterior or posterior to the ascending aorta, and terminates either in the superior vena cava or in the right atrium (RA). We report a 42-year-old female briefly with aorta-right atrial tunnel in which the left coronary artery arose from the tunnel and terminated into the RA.