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Background: Cannabidiol (CBD), extracted from Cannabis sativa, has anticancer, anti-inflammation, and analgesic effects. Nevertheless, its therapeutic effect and the mechanism by which it alleviates oral mucositis (OM) remain unclear. Aims: To explore the impact of CBD on OM in mice and on human oral keratinocyte (HOK) cells. Study Design: Expiremental study. Methods: The Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, GeneCard, DisGeNET, and Gene Expression Omnibus databases were used to conduct therapeutic target gene screening for drugs against OM. Cytoscape software was used to build networks linking components, targets, and diseases. The STRING database facilitated analysis of intertarget action relationships, and the target genes were analyzed for Kyoto Encyclopedia of Genes and Genomes pathway enrichment. Occurrence of serum inflammation-related factors, hematoxylin and eosin staining, and immunohistochemistry were used to assess OM injury. Cell proliferation, migration, pyroptosis, and apoptosis of HOK cells under different treatments were assessed. Molecular mechanisms were elucidated through western blot and quantitative real-time polymerase chain reaction analyses. Results: A total of 49 overlapping genes were pinpointed as potential targets, with NF-κB1, PIK3R1, NF-κBIA, and AKT1 being recognized as hub genes among them. Additionally, the PI3K/Akt/NF-κB and interleukin-17 signaling pathways were identified as relevant. Our in vivo experiments showed that CBD significantly reduced the proportion of lesion area, mitigated oral mucosal tissue lesions, and downregulated the expression levels of genes and levels of proteins, including NLRP3, P65, AKT, and PI3K. In vitro experiments indicated that CBD enhanced HOK cell proliferation and migration and reduced apoptosis through inhibition of the PI3K/Akt/NF-κB signaling pathway and pyroptosis. Conclusion: Our findings suggest a novel mechanism for controlling OM, in which CBD suppresses the PI3K/Akt/NF-κB signaling pathway and pyroptosis, thereby mitigating OM symptoms.
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Cannabidiol , FN-kappa B , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Piroptosis , Estomatitis , Cannabidiol/farmacología , Cannabidiol/uso terapéutico , Animales , Piroptosis/efectos de los fármacos , Ratones , Estomatitis/tratamiento farmacológico , FN-kappa B/efectos de los fármacos , FN-kappa B/análisis , Fosfatidilinositol 3-Quinasas/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Humanos , Transducción de Señal/efectos de los fármacos , Modelos Animales de EnfermedadRESUMEN
OBJECTIVE: To evaluate whether antimicrobial photodynamic therapy (aPDT) repairs bisphosphonate-related osteonecrosis of the jaw (BRONJ) modulated by the reduction of NF-kB protein in a murine model. METHODOLOGY: Male Wistar rats (N=30) were divided into the following groups (n=6/group): negative control (NC); experimental osteonecrosis (ONE); ONE + photosensitizer (PS); ONE + photobiomodulation (PBM); and ONE + aPDT. Over 8 weeks, ONE was induced by zoledronic acid 250 µg/kg injections, except in the NC group, which received sterile 0.9% saline, followed by extraction of the lower left first molar. Red light laser irradiation (wavelength ~660 nm, power 50 mW, energy of 2 J, energy dose of 66.67 J/cm2 for 40 s) was performed once a week for 4 weeks. Methylene blue 0.3% was used as PS. The animals were euthanized and examined macroscopically for the presence of exposed bone and epithelial repair and microscopically by histochemical (hematoxylin-eosin and Masson's trichrome staining) and immunohistochemical (anti-NF-kB) methods. Macroscopic and histomorphometric data were analyzed by one-way ANOVA and Tukey's post-test (p<0.05). RESULTS: Mucosal repair, viable osteocytes, and NF-kB immunostaining were observed in the NC, ONE+PS, ONE+PBM, and ONE+aPDT groups. The ONE group showed no mucosal repair, showing empty lacunae and multifocal immunostaining for NF-kB. The ONE+PBM and ONE+aPDT groups had greater deposition of extracellular matrix and less necrotic bone tissue (p<0.05). CONCLUSION: PBM and aPDT treatments for BRONJ were effective for bone and epithelial repair, in addition to reducing inflammation mediated by the decrease of NF-kB protein in the irradiated regions.
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Osteonecrosis de los Maxilares Asociada a Difosfonatos , Modelos Animales de Enfermedad , Inmunohistoquímica , FN-kappa B , Fotoquimioterapia , Fármacos Fotosensibilizantes , Ratas Wistar , Animales , Masculino , Fotoquimioterapia/métodos , Osteonecrosis de los Maxilares Asociada a Difosfonatos/patología , FN-kappa B/análisis , Fármacos Fotosensibilizantes/farmacología , Factores de Tiempo , Reproducibilidad de los Resultados , Ácido Zoledrónico/farmacología , Resultado del Tratamiento , Imidazoles/farmacología , Difosfonatos/farmacología , Terapia por Luz de Baja Intensidad/métodos , Azul de Metileno/farmacología , Azul de Metileno/uso terapéutico , Análisis de Varianza , Distribución Aleatoria , Conservadores de la Densidad Ósea/farmacologíaRESUMEN
Parasites use different strategies of communication with their hosts. One communication channel that has been studied in recent years is the use of vesicle microRNAs to influence the host immune system by trematodes. sma-microRNA-10, secreted from Schistosoma mansoni, has been shown to influence the fate of host T-cells through manipulation of the NF-κB pathway. We have identified low molecular weight tool compounds that can interfere with this microRNA-mediated manipulation of the host immune system. We used a fragment-based screening approach by means of nuclear magnetic resonance (NMR) to identify binders to the precursor of the parasite sma-microRNA-10 present in their extracellular vesicles. The small fragments identified were used to select larger molecules. These molecules were shown to counteract the inhibition of NF-κB activity by sma-microRNA-10 in cell-based assays.
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Vesículas Extracelulares , MicroARNs , Animales , Vesículas Extracelulares/química , Interacciones Huésped-Parásitos , MicroARNs/genética , FN-kappa B/análisis , Schistosoma mansoni/genéticaRESUMEN
BACKGROUND/AIMS: Respiratory diseases are the world's biggest cause of mortality and disability. Specific nutrients have been proposed to positively affect disease progression as novel therapy alternatives to glucocorticosteroids. There has been a lot of attention in the possible health advantages of dietary assumption of Açai Seeds, popular native fruit found in the Amazon region which is rich in bioactive compounds. Until today nobody investigated the beneficial property of Açai Seeds administration in lung disease. METHODS: In our study we use two model of lung disease: for acute lung disease we use an intrapleural injection of Carrageenan; for chronic disease we used an intratracheal instillation of bleomycin. Açai Seeds was administered orally dissolved in saline. RESULTS: We found that Açai Seeds was able to reduce histological alteration, cells infiltration, pro inflammatory cytokine release, inflammation, and oxidative stress in both acute and chronic model of lung disease. CONCLUSION: Our data clearly demonstrate for the first time that Açai Seeds administration was useful against lung disease by the reduction of NF-κB nuclear translocation and by the stimulation of Nrf2/ARE pathways promoting the physiological antioxidant defense.
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Euterpe , Enfermedades Pulmonares , Antioxidantes/química , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Euterpe/química , Frutas/química , Humanos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Pulmón/metabolismo , Enfermedades Pulmonares/tratamiento farmacológico , Factor 2 Relacionado con NF-E2/análisis , FN-kappa B/análisis , Extractos Vegetales/química , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , SemillasRESUMEN
BACKGROUND: There have been few studies regarding viral involvement in the pathogenesis of renal cell carcinoma (RCC). The aim of this study was to examine the possible association of Epstein-Barr virus (EBV) infection with clinicopathological features and cellular biomarkers including p53, p16INK4a, Ki-67 and nuclear factor-kappa B (NF-κB) in RCC tumors. METHODS: In this prospective study, 122 histologically confirmed Formalin-fixed Paraffin-embedded RCC tissue specimens along with 96 specimens of their corresponding peritumoral tissues and 23 samples of blunt renal injuries were subjected to nested polymerase chain reaction (nPCR) in order to amplify EBV DNA sequences. The expression of p53, p16INK4a, Ki-67 and NF-κB was investigated by immunohistochemistry (IHC) assay. Statistical analysis was employed to demonstrate the possible associations. RESULTS: Infection with EBV was found to be significantly associated with RCC. Our results indicate that p65 NF-κB signaling pathway is probably involved in EBV-mediated RCC pathogenesis. Moreover, we found p53, Ki-67 and cytoplasmic NF-κB expression to be associated with tumor nuclear grade in RCC patients. The expression of p53 and Ki-67 was associated with primary tumor category as well. In addition, p53 overexpression was significantly more frequent among nonconventional RCC tumors than the conventional histologic type. CONCLUSIONS: Infection with EBV is likely to play an important role in the development of RCC through the constitutive and permanent activation of NF-κB p65 signaling pathway. However, more experiments and supporting data are required to reach a decisive conclusion.
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Biomarcadores de Tumor/análisis , Carcinoma de Células Renales/virología , Infecciones por Virus de Epstein-Barr , Neoplasias Renales/virología , FN-kappa B/análisis , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Autoantígenos/análisis , Autoantígenos/genética , Biomarcadores de Tumor/genética , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/patología , Niño , Preescolar , Regulación Neoplásica de la Expresión Génica , Genes p53/genética , Humanos , Inmunohistoquímica , Neoplasias Renales/metabolismo , Neoplasias Renales/patología , Persona de Mediana Edad , FN-kappa B/genética , Clasificación del Tumor , Estudios Prospectivos , Complejo de la Endopetidasa Proteasomal/análisis , Complejo de la Endopetidasa Proteasomal/genética , Transducción de Señal , Adulto JovenRESUMEN
The transcription factor nuclear factor kappa B (NF-κB) is highly expressed in almost all types of cells. NF-κB is involved in many complex biological processes, in particular in immunity. The activation of the NF-κB signaling pathways is also associated with cancer, diabetes, neurological disorders and even memory. Hence, NF-κB is a central factor for understanding not only fundamental biological presence but also pathogenesis, and has been the subject of intense study in these contexts. Under healthy physiological conditions, the NF-κB pathway promotes synapse growth and synaptic plasticity in neurons, while in glia, NF-κB signaling can promote pro-inflammatory responses to injury. In addition, NF-κB promotes the maintenance and maturation of B cells regulating gene expression in a majority of diverse signaling pathways. Given this, the protein plays a predominant role in activating the mammalian immune system, where NF-κB-regulated gene expression targets processes of inflammation and host defense. Thus, an understanding of the methodological issues around its detection for localization, quantification, and mechanistic insights should have a broad interest across the molecular neuroscience community. In this review, we summarize the available methods for the proper detection and analysis of NF-κB among various brain tissues, cell types, and subcellular compartments, using both qualitative and quantitative methods. We also summarize the flexibility and performance of these experimental methods for the detection of the protein, accurate quantification in different samples, and the experimental challenges in this regard, as well as suggestions to overcome common challenges.
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Sistema Nervioso Central/metabolismo , FN-kappa B/análisis , Animales , Línea Celular , Humanos , FN-kappa B/metabolismoRESUMEN
AIMS: Epidemiology shows that gender affects the incidence of food allergy. However, there is a lack of evidence of gender differences in food allergies and little is known about the mechanisms. The aim of this study was to excavate potential reasons for gender differences in food allergy based on estrogen. MAIN METHODS: Female and male BALB/c mice sensitized with ovalbumin (OVA) were established to analyze the difference in food allergy. The systemic anaphylactic, including OVA-specific IgE, OVA-specific IgG, histamine, and cytokines, was assessed using an enzyme-linked immunosorbent assay (ELISA). ELISA also detected the estradiol in serum. Western blotting and immunofluorescence were used to detect the estrogen receptor. Peroxisome proliferator-activated receptor gamma (PPARγ) implicated in immune homeostasis and nuclear factor kappa-B (NF-κB) were determined by western blotting. Immunohistochemistry and hematoxylin-eosin (H&E) staining were used to detect zonula occludens-1 (ZO-1), tryptase, forkhead box protein P3 (Foxp3), and intestinal morphology, respectively. KEY FINDINGS: Female mice were more vulnerable to food allergy. Female mice treated with OVA did exhibit more serious systemic anaphylaxis than male mice. We observed increased levels of estradiol in serum, estrogen receptor, NF-κB, and decreased levels of PPAR γ in female mice. Furthermore, the intestinal mucosal integrity and intestinal permeability were more impaired in female mice treated with OVA than male mice. SIGNIFICANCE: Clarify the mechanism of gender differences in food allergies can provide targets in female mice and provide personalized diagnosis, management, and treatment of food allergy for female mice.
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Hipersensibilidad a los Alimentos/patología , Inflamación/patología , Intestinos/patología , FN-kappa B/análisis , PPAR gamma/análisis , Animales , Femenino , Hipersensibilidad a los Alimentos/etiología , Inflamación/etiología , Masculino , Ratones , Ratones Endogámicos BALB C , Caracteres Sexuales , Factores SexualesRESUMEN
The Nuclear Factor Kappa B (NFκB) pathway is an important signalling pathway in the immune system. Single gene defects in the NFκB pathway are described in a number of immunodeficiency diseases. These conditions provide a unique opportunity to investigate the mechanisms of NFκB function and how genetic mutations that disrupt this function lead to human disease. Here we describe a robust method for quantifying small differences in the functional activity of the NFκB pathway. Peripheral blood mononuclear cells from healthy donors were stimulated over several days, with a combination of anti-IgM antibody and multimeric CD40 ligand. Nuclear proteins were thereafter extracted and tested for the ability of activated transcription factors, to bind known NFκB DNA binding motifs. Repeatability experiments showed that the DNA binding Activity can be quantified with an average inter and intra assay coefficient of variation of less than 10% (RelB and p52) and less than 15% (p50 and RelA). In healthy individuals there is a significant increase in the DNA binding activity of NFκB transcription factors in response to stimulation, although the magnitude of this response varies across individuals. The kinetics of the DNA binding activity also differs between the canonical and non-canonical transcription factors. P50 and RelA DNA binding activity responds within hours of stimulation, whilst RelB and p52 response was delayed to more than a day after stimulation. Activation of NFκB signalling in response to B cell specific stimulation, can be precisely measured to distinguish individuals with differences in the functional activity of this pathway. This test may prove to be an important biomarker for investigating the functional impact of genetic variants on NFκB signalling.
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Regulación de la Expresión Génica/inmunología , Leucocitos Mononucleares/inmunología , FN-kappa B/metabolismo , Células 3T3 , Animales , Voluntarios Sanos , Humanos , Inmunoensayo/métodos , Inmunoglobulina M/inmunología , Inmunoglobulina M/metabolismo , Leucocitos Mononucleares/metabolismo , Ratones , FN-kappa B/análisis , Reproducibilidad de los Resultados , Transducción de Señal/genética , Transducción de Señal/inmunologíaRESUMEN
BACKGROUND: A small number of studies have confirmed the presence of oxidative damage in patients with Duchenne muscular dystrophy (DMD). Nevertheless, it is unknown if there a relationship of circulating markers of oxidative stress with a muscle injury. OBJECTIVE: We evaluated if oxidative damage and anti-oxidant markers are associated with muscle damage in DMD. METHODS: This cross-sectional study included 24 patients with DMD classified in ambulatory and non-ambulatory. Markers of muscle damage (creatine kinase [CK]), oxidative damage (malondialdehyde [MDA], and 8-isoprostane), anti-oxidant function (Thiol and mRNA of NRF2 and NF-κB) and nitric oxide (NO) were quantified in circulation. RESULTS: Total NO, MDA, and 8-isoprostane concentrations were significantly (p < 0.05) higher, and thiol concentration was lower in non-ambulatory than ambulatory patients. A significant correlation (p < 0.05) between muscle injury (evaluated by Vignos scale) with CK (r = -0.382), NO (r = 0.444), MDA (r = 0.503), 8-isoprostanes (r = 0.435) and thiol (r = -0.430) was observed. CONCLUSION: These findings suggest that non-ambulatory have high oxidative damage and low anti-oxidant function than ambulatory patients with DMD. Total nitric oxide and oxidative damage plasma markers increase, but the anti-oxidant marker thiol decreases with a muscle injury in boys with DMD. The findings of this study suggest that these markers could be considered as goods indicators of oxidative damage in longitudinal studies to evaluate the muscle injury during DMD progression. Additionally, these findings add new information about the pathophysiology of DMD.
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Músculo Esquelético/lesiones , Músculo Esquelético/metabolismo , Distrofia Muscular de Duchenne/metabolismo , Adolescente , Antioxidantes/análisis , Biomarcadores/metabolismo , Niño , Preescolar , Creatina Quinasa/análisis , Creatina Quinasa/sangre , Estudios Transversales , Dinoprost/análogos & derivados , Dinoprost/análisis , Dinoprost/sangre , Femenino , Humanos , Lactante , Masculino , Malondialdehído/análisis , Malondialdehído/sangre , México/epidemiología , Distrofia Muscular de Duchenne/fisiopatología , Factor 2 Relacionado con NF-E2/análisis , Factor 2 Relacionado con NF-E2/genética , FN-kappa B/análisis , FN-kappa B/genética , Estrés Oxidativo/fisiologíaRESUMEN
OBJECTIVE: To evaluate the role of CD68+ macrophages and inflammatory/signaling proteins in the decidua of singleton pregnancies with late-onset pre-eclampsia. PATIENTS AND METHODS: This study was designed as a prospective case-control study. Decidual tissue samples were obtained from twenty healthy pregnant women as a control group and twenty pregnant women with late-onset pre-eclampsia showing severe symptoms as the study group. We examined the abundance of CD68+ macrophages in both groups using flow cytometry. Protein and mRNA expression levels of inflammatory/signaling proteins, including inducible nitric oxide synthase, nuclear factor-κB inhibitor α, cyclooxygenase-2, and phosphorylated c-Jun N-terminal kinase, in the decidua of both groups were measured using Western blotting and Reverse Transcription-Polymerase Chain Reaction, respectively. Student's t-tests were performed for statistical analysis. RESULTS: The numbers of CD68+ macrophages were similar in the study and control groups (p=0.47). However, the levels of inducible nitric oxide synthase, nuclear factor-κB, cyclooxygenase-2, and phosphorylated c-Jun N-terminal kinase were significantly increased in the study group. Therefore, pro-inflammatory mediators and signaling proteins in the decidua during pre-eclampsia may be related to the pathogenesis of pre-eclampsia. CONCLUSIONS: Pre-eclampsia-induced alterations in the expression of inflammatory/signaling proteins in the decidua during singleton pregnancies may play a critical role in the pathogenesis of pre-eclampsia.
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Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Decidua/metabolismo , Mediadores de Inflamación/metabolismo , Preeclampsia/metabolismo , Adulto , Estudios de Casos y Controles , Ciclooxigenasa 2/análisis , Ciclooxigenasa 2/metabolismo , Decidua/patología , Femenino , Humanos , Mediadores de Inflamación/análisis , Proteínas Quinasas JNK Activadas por Mitógenos/análisis , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , FN-kappa B/análisis , FN-kappa B/metabolismo , Óxido Nítrico Sintasa/análisis , Óxido Nítrico Sintasa/metabolismo , Preeclampsia/patología , Embarazo , Estudios ProspectivosRESUMEN
PD-1/PD-L1 immune checkpoint inhibitors are promising cancer immunotherapies however responses are still limited and the development of more effective combination immunotherapy is needed. We previously reported that STAT3 activation in cancer cells and immune cells was involved in immune-resistant mechanisms. In this study, we evaluated the effect of highly absorptive forms of curcumin extracts and synthetic curcumin on anti-tumor T cell responses. The curcumin po administration resulted in the significant augmentation of in vivo induction of tumor antigen-specific T cells through restoration of dendritic cells (DCs) by inhibiting directly STAT3 in DCs and indirectly via reduced IL-6 production from STAT3 activated cancer cells in 2 syngeneic MC38 and CT26 murine tumor models. Curcumin also showed direct DC enhancing activity and enhanced T cell induction for the immunized antigens in non-tumor-bearing mice and human hosts. Curcumin restored DC functions in xenogeneic nude mouse model implanted with high IL-6-producing human clear cell ovarian cancer cells. The combination of curcumin and PD-1/PD-L1 Abs demonstrated a synergistic anti-tumor activity in MC38 murine tumor models. These results indicated that curcumin augments the induction of tumor antigen-specific T cells by restoring the T cell stimulatory activity of DCs targeting activated STAT3 in both cancer cells and immune cells. Combination immunotherapy with curcumin and PD-1/PD-L1 Ab is an attractive strategy in the development of effective immunotherapy against various cancers.
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Antineoplásicos/uso terapéutico , Curcumina/uso terapéutico , Células Dendríticas/metabolismo , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias/terapia , Factor de Transcripción STAT3/antagonistas & inhibidores , Animales , Células Dendríticas/inmunología , Quimioterapia Combinada/métodos , Femenino , Humanos , Inmunoterapia/métodos , Interferón gamma/metabolismo , Interleucina-6/biosíntesis , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Desnudos , FN-kappa B/análisis , Neoplasias/inmunología , Extractos Vegetales/uso terapéutico , Factor de Transcripción STAT3/análisis , Factor de Transcripción STAT3/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismoRESUMEN
Extensive phytochemical analysis of the CHCl3-soluble part of an ethanolic extract of branches and twigs of Broussonetia papyrifera led to the isolation of fourteen compounds, including a novel 5,11-dioxabenzo[b]fluoren-10-one derivative named broussofluorenone C (12). The isolated compounds 1-14 were characterized based on their NMR and HRMS data, and examined for their anti-inflammatory activities in LPS-stimulated THP-1 cells as well as for their cellular antioxidant effects. Compounds 7-10 and 12 showed inhibitory effects on NF-κB/AP-1 activation and compounds 7-9 were subsequently confirmed to suppress the secretion of both IL-1ß and TNF-α in LPS-stimulated THP-1 cells more significantly than the prednisone used as a positive control. In the CAA assay, compound 10 exhibited the greatest antioxidant effect, greater than that of the quercetin used as a positive control. The results show possible beneficial effects and utilization of B. papyrifera wood in the treatment of inflammatory diseases as well as oxidative stress.
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Antiinflamatorios/farmacología , Antioxidantes/farmacología , Broussonetia/química , Antiinflamatorios/química , Antiinflamatorios/aislamiento & purificación , Antioxidantes/química , Antioxidantes/aislamiento & purificación , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Humanos , Interleucina-1beta/antagonistas & inhibidores , Interleucina-1beta/biosíntesis , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Estructura Molecular , FN-kappa B/análisis , FN-kappa B/antagonistas & inhibidores , FN-kappa B/biosíntesis , Estrés Oxidativo/efectos de los fármacos , Relación Estructura-Actividad , Células THP-1 , Factor de Transcripción AP-1/análisis , Factor de Transcripción AP-1/antagonistas & inhibidores , Factor de Transcripción AP-1/biosíntesis , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
Roflumilast is an inhibitor of phosphodiesterase-4 (PDE4) and can suppress the hydrolysis of cAMP in inflammatory cells, conferring anti-inflammatory effects. This study aimed to investigate the protective effects of roflumilast on hyperoxia-induced acute lung injury (HALI) in a rat model. Male Sprague-Dawley rats were randomly assigned into: control group; HALI group; 2.5 mg/kg roflumilast group; and 5 mg/kg roflumilast group. Rats were pressurized to 250 kPa with pure oxygen to induce lung injury. In the roflumilast groups, rats were orally administered with roflumilast at 2.5 or 5 mg/kg once before hyperoxia exposure and once daily for two days after exposure. Rats were sacrificed 72 hours after hyperoxia exposure. The lung tissues were collected for the detection of lung water content, inflammatory cytokines and NF-κB/p-NF-κB protein expression, and the bronchoalveolar lavage fluid was harvested for the measurement of protein concentration and lactate dehydrogenase activity. Results showed roflumilast at different doses could significantly reduce lung edema, improve lung pathology and reduce the expression of inflammatory cytokines in the lung. The protective effects seemed to be related to the dose of roflumilast. Our study indicates roflumilast has the potential as a medication for the treatment of HALI.
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Aminopiridinas/uso terapéutico , Benzamidas/uso terapéutico , Hiperoxia/complicaciones , Lesión Pulmonar/prevención & control , Inhibidores de Fosfodiesterasa 4/uso terapéutico , Proteínas/análisis , Aminopiridinas/administración & dosificación , Animales , Benzamidas/administración & dosificación , Agua Corporal , Líquido del Lavado Bronquioalveolar/química , Ciclopropanos/administración & dosificación , Ciclopropanos/uso terapéutico , Interleucina-10/análisis , Interleucina-1beta/análisis , Interleucina-6/análisis , L-Lactato Deshidrogenasa/análisis , Pulmón/química , Pulmón/patología , Lesión Pulmonar/etiología , Lesión Pulmonar/patología , Masculino , FN-kappa B/análisis , Inhibidores de Fosfodiesterasa 4/administración & dosificación , Edema Pulmonar/prevención & control , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Factor de Necrosis Tumoral alfa/análisisRESUMEN
Cytarabine is effectively used in the treatment of adult acute leukemia, but it has a dose-limiting side effect of fatal pulmonary oedema because it increases the vascular permeability of the alveolar capillaries. The aim of the present study was to conduct a radiological, biochemical and histopathological investigation of the effect of rutin on cytarabine-associated pulmonary oedema in rats. Rats were treated with a combination of rutin+cytarabine by administering oral rutin at a dose of 50 mg/kg; other rat groups were orally administered the same volume of physiological saline. One hour after administration of rutin or saline, the rutin+cytarabine and cytarabine groups received an intraperitoneal injection of cytarabine (200 mg/kg). This administration procedure was repeated once a day for 14 days. Radiologically, 50% of the animals given cytarabine alone showed lung oedema, but the rutin+cytarabine group showed no oedema. The inclusion of rutin decreased the amounts of cytarabine-associated malondialdehyde, tumour necrosis factor-α, and nuclear factor-κB in the lung tissue. Rutin also inhibited the reduction of total glutathione by nitric oxide. These findings suggest that rutin may be a beneficial adjunct that can minimise the development of cytarabine-associated pulmonary oedema.
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Antiinflamatorios/uso terapéutico , Antioxidantes/uso terapéutico , Citarabina/efectos adversos , Edema Pulmonar/tratamiento farmacológico , Rutina/uso terapéutico , Animales , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Masculino , FN-kappa B/análisis , Oxidantes/sangre , Estrés Oxidativo/efectos de los fármacos , Edema Pulmonar/inducido químicamente , Edema Pulmonar/patología , Ratas , Ratas Wistar , Rutina/farmacología , Factor de Necrosis Tumoral alfa/análisisRESUMEN
Aim: The objective of this study was to evaluate the possible protective effects of probiotic bacteria, especially Bifidobacterium and Lactobacillus strains, on 4,4'-dichlorodiphenyltrichloroethane (DDT)-induced toxicity. For this reason, we evaluated the relationship between probiotics and toxicity by checking immunological and immunohistochemical parameters. Materials & methods: Probiotic pretreatment was applied to 36 Wistar albino rats for 12 consecutive days. Serum aspartate aminotransferase and alanine aminotransferase levels were detected. CD3 and NF-κB staining methods were then performed by immunohistochemistry. Finally, pro- and anti-inflammatory cytokines were measured by ELISA. Results: DDT caused a serious increase/decrease in some cytokine parameters. The effective dose was 1 × 1011 colony-forming unit probiotic treatment. CD3 and NF-κB positivity were intense in DDT group whereas the intensity was reduced in probiotic treatment groups. Discussion: The probiotic mixture has a potential to prevent inflammatory and oxidative stress related organ injuries. Further studies should be performed to explain the possible mechanisms.
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Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Citocinas/sangre , DDT/toxicidad , Probióticos , Bazo/efectos de los fármacos , Animales , Bifidobacterium , Complejo CD3/análisis , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Femenino , Inflamación/prevención & control , Lactobacillus , Hígado/química , Hígado/efectos de los fármacos , Hígado/inmunología , FN-kappa B/análisis , Estrés Oxidativo , Ratas , Ratas Wistar , Bazo/química , Bazo/inmunologíaRESUMEN
Twelve metabolites were obtained from the culture media of Chaetomium nigricolor, including a new furan derivative, methyl succinyl Sumiki's acid (1), and two new atropisomers of the previously reported bis-naphtho-γ-pyrones, (aS)-asperpyrone A and (aS)-fonsecinone A (2 and 3). The structures were elucidated by spectroscopic, chemical, and chiroptical techniques. Compounds 2 and 3 inhibited nitric oxide production in lipopolysaccharide-stimulated RAW 264.7 macrophages. Compound 2 was found to inhibit nuclear factor-kappa B and c-Jun N-terminal kinase activation, in turn suppressing pro-inflammatory mediators and cytokines including nitric oxide, prostaglandin E2, interleukin (IL)-1ß, tumor necrosis factor-α, IL-6, and IL-12.
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Antiinflamatorios/química , Antiinflamatorios/farmacología , Chaetomium/química , Animales , Supervivencia Celular/efectos de los fármacos , Citocinas/antagonistas & inhibidores , Dinoprostona/biosíntesis , Activación Enzimática , Furanos/aislamiento & purificación , Furanos/farmacología , Mediadores de Inflamación/antagonistas & inhibidores , Isomerismo , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Lipopolisacáridos/farmacología , Espectroscopía de Resonancia Magnética , Ratones , FN-kappa B/análisis , Óxido Nítrico/biosíntesis , Células RAW 264.7RESUMEN
PURPOSE: To examine the therapeutic effect of external adenosine on an acetic acid-induced acute ulcerative colitis model in rats. METHODS: Thirty male mature rats were divided into three groups as control, acute colitis (AC) and AC+adenosine group (AC+AD). AC was induced by rectal administration of 4% acetic acid (AA). 5mg/kg/day adenosine was performed i.p for 4 weeks to AC+AD group. Rectum and colon were excised for microscopic and histopathological histopathologic evaluations, and immunohistochemical analysis of nuclear factor kappa B (NF-kB). Blood samples were collected for biochemical detection of TNF-α, Pentraxin-3 and malondialdehyde (MDA) levels. RESULTS: AC group had generalized hyperemia and hemorrhage with increased macroscopic and histopathological scores compared with control (P <0.0001) while adenosine treatment decreased these scores significantly (P <0.001), with reduced distribution of disrupted epithelium, leukocyte infiltrates, and focal hemorrhage. AC group showed significantly increased immunoexpression of NF-kB in rectum, plasma and tissue levels of TNF-α, plasma Pentraxin-3 and MDA levels (P <0.0001) while adenosine reduced these levels (P < 0.05). CONCLUSION: Adenosine appears to promote healing of colon and rectum exposed to AA-induced AC, suggesting a boosting effect of adenosine on the intestinal immune system to cure ulcerative colitis.
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Adenosina/uso terapéutico , Antiinflamatorios/uso terapéutico , Colitis Ulcerosa/tratamiento farmacológico , Ácido Acético , Enfermedad Aguda , Animales , Proteína C-Reactiva/análisis , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/patología , Colon/patología , Ensayo de Inmunoadsorción Enzimática , Inmunohistoquímica , Masculino , Malondialdehído/sangre , FN-kappa B/análisis , Ratas Sprague-Dawley , Recto/patología , Valores de Referencia , Reproducibilidad de los Resultados , Componente Amiloide P Sérico/análisis , Sustancias Reactivas al Ácido Tiobarbitúrico , Factores de Tiempo , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/análisisRESUMEN
The Mediterranean Diet, characterized by higher intakes of plant foods including plant proteins, monounsaturated fat, fish, and lower consumption of animal products and saturated fat, has long been associated with reduced cardiovascular risk, but the molecular mechanisms underlying these associations have not been fully elucidated. We conducted a pilot study to evaluate associations of an Alternate Mediterranean Diet Score, reflective of adherence to this diet pattern and adapted for US populations, and its components, with markers of endothelial inflammation directly measured in endothelial cells harvested from a diverse sample of women (nâ¯=â¯25, mean⯱â¯SD age 33⯱â¯10.5y, 68% racial/ethnic minorities). Cardiovascular risk markers including nuclear factor kappa B (NF-κB)-a marker of inflammation, as well as oxidative stress and endothelial nitric oxide synthase (eNOS) gene expression-markers of endothelial function, were evaluated in harvested endothelial cells. We hypothesized that the Mediterranean diet pattern would be associated with lower inflammation and oxidative stress and higher eNOS expression in endothelial cells. Results showed that lower oxidative stress was associated with higher plant-based protein (Exp(ß)â¯=â¯0.96; Pâ¯=â¯.007), overall protein (Exp(ß)â¯=â¯0.99; Pâ¯=â¯.007), and red and processed meat intake (Exp(ß)â¯=â¯0.93; Pâ¯=â¯.012). Lower NF-κB was associated with higher legume (Exp(ß)â¯=â¯0.79; Pâ¯=â¯.045) intake, and higher eNOS was associated with higher red and processed meat intake (Exp(ß)â¯=â¯1.13; Pâ¯=â¯.005). Our findings suggest potential novel mechanisms through which certain Mediterranean dietary components may influence pre-clinical vascular alterations that may be associated with cardiovascular risk through lower endothelial oxidative stress, lower inflammation, and greater endothelial functioning. These findings warrant confirmation, prospectively in a larger sample.
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Dieta Mediterránea , Células Endoteliales/fisiología , Etnicidad , Inflamación/prevención & control , Proyectos Piloto , Adulto , Dieta Vegetariana , Células Endoteliales/química , Endotelio Vascular/fisiopatología , Fabaceae , Femenino , Expresión Génica , Humanos , Inflamación/fisiopatología , FN-kappa B/análisis , Óxido Nítrico Sintasa de Tipo III/genética , Estrés Oxidativo/fisiología , Proteínas de Plantas/administración & dosificación , Estados UnidosRESUMEN
Ependymomas show poor correlation between World Health Organization grade and clinical outcome. A subgroup of supratentorial ependymomas are characterized by C11orf95-RELA fusions, presumed to be secondary to chromothripsis of chromosome 11, resulting in constitutive activation of the NF-κB signaling pathway and overexpression of cyclin D1, p65, and L1 cell adhesion molecule (L1CAM). These RELA-fused ependymomas are recognized as a separate, molecularly defined World Health Organization entity and might be associated with poor clinical outcome. In this study, we show that immunohistochemistry for NF-κB signaling components, such as L1CAM, p65, and cyclin D1, can help distinguish RELA-fused from non-RELA-fused supratentorial ependymomas. Furthermore, these three markers can reliably differentiate RELA-fused ependymomas from a variety of histologic mimics. Lastly, we report that RELA-fused ependymomas may be associated with different chromosomal copy number changes and molecular alterations compared to their non-RELA-fused counterparts, providing additional insight into the genetic pathogenesis of these tumors and potential targets for directed therapies.
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Ependimoma/genética , FN-kappa B/análisis , Proteínas/genética , Neoplasias Supratentoriales/genética , Factor de Transcripción ReIA/genética , Adolescente , Adulto , Biomarcadores de Tumor/análisis , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fusión de Oncogenes , Proteínas de Fusión Oncogénica/genética , Adulto JovenRESUMEN
Edaravone is a potent free radical scavenger that has a promising role in combating many acute lung injuries. Ischemia/reperfusion process is a serious condition that may lead to multiple organ dysfunctions. This work was designed to investigate novel mechanisms underlying ischemia/reperfusion-induced lung injury and to evaluate the protective role of edaravone. Thirty adult male rats were divided into three experimental groups; operated with no ischemia (Sham-group), ischemia/reperfusion (I/R) group and edaravone-I/R group. Hind limb ischemia was carried out by clamping the femoral artery. After two hours of ischemia for the hind limb, the rat underwent 24h of reperfusion. Rats in the edaravone-I/R group received edaravone (3mg/kg), 30min before induction of ischemia. At the end of the I/R trial, specimens from the lungs were processed for histological, immunohistochemical, enzyme assay, and RT-qPCR studies. Specimens from I/R group showed focal disruption of the alveolar architecture. Extensive mononuclear cellular infiltration particularly with neutrophils and dilated congested blood capillaries were observed. A significant increase in iNOS, NF-κB, and COX-2 immunoreaction was detected and confirmed by RT-qPCR. Ultrastructural examination showed RBCs and fluid inside alveoli, cellular infiltration, and vacuolations of the inter-alveolar septum. In addition to the presence of extravasated neutrophils and RBCs within the inter-alveolar septum. In contrast, minimal changes were observed in rats which received edaravone before the onset of the ischemia. It could be concluded that edaravone exerted a potent protective effect against lung injury induced by a hind limb I/R in rats through its antioxidant and anti-inflammatory activities.