RESUMEN
Thymocyte selection-associated high-mobility group box (TOX) is a transcription factor that is crucial for T cell exhaustion during chronic antigenic stimulation, but its role in inflammation is poorly understood. Here, we report that TOX extracellularly mediates drastic inflammation upon severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by binding to the cell surface receptor for advanced glycation end-products (RAGE). In various diseases, including COVID-19, TOX release was highly detectable in association with disease severity, contributing to lung fibroproliferative acute respiratory distress syndrome (ARDS). Recombinant TOX-induced blood vessel rupture, similar to a clinical signature in patients experiencing a cytokine storm, further exacerbating respiratory function impairment. In contrast, disruption of TOX function by a neutralizing antibody and genetic removal of RAGE diminished TOX-mediated deleterious effects. Altogether, our results suggest an insight into TOX function as an inflammatory mediator and propose the TOX-RAGE axis as a potential target for treating severe patients with pulmonary infection and mitigating lung fibroproliferative ARDS.
Asunto(s)
COVID-19 , Receptor para Productos Finales de Glicación Avanzada , SARS-CoV-2 , Humanos , Receptor para Productos Finales de Glicación Avanzada/metabolismo , COVID-19/inmunología , COVID-19/metabolismo , COVID-19/patología , COVID-19/complicaciones , COVID-19/virología , Animales , Ratones , Inflamación/metabolismo , Inflamación/patología , Síndrome de Dificultad Respiratoria/inmunología , Síndrome de Dificultad Respiratoria/metabolismo , Síndrome de Dificultad Respiratoria/patología , Síndrome de Dificultad Respiratoria/virología , Lesión Pulmonar/inmunología , Lesión Pulmonar/metabolismo , Lesión Pulmonar/patología , Proteínas del Grupo de Alta Movilidad/metabolismo , Proteínas del Grupo de Alta Movilidad/genética , Masculino , Pulmón/patología , Pulmón/metabolismo , Pulmón/inmunología , FemeninoRESUMEN
The inflammatory response mediated by nuclear factor κB (NF-κB) signaling is essential for host defense against pathogens. Although the regulatory mechanism of NF-κB signaling has been well studied, the molecular basis for epigenetic regulation of the inflammatory response is poorly understood. Here we identify a new signaling axis of PKCα-LSD1-NF-κB, which is critical for activation and amplification of the inflammatory response. In response to excessive inflammatory stimuli, PKCα translocates to the nucleus and phosphorylates LSD1. LSD1 phosphorylation is required for p65 binding and facilitates p65 demethylation, leading to enhanced stability. In vivo genetic analysis using Lsd1SA/SA mice with ablation of LSD1 phosphorylation and chemical approaches in wild-type mice with inhibition of PKCα or LSD1 activity show attenuated sepsis-induced inflammatory lung injury and mortality. Together, we demonstrate that the PKCα-LSD1-NF-κB signaling cascade is crucial for epigenetic control of the inflammatory response, and targeting this signaling could be a powerful therapeutic strategy for systemic inflammatory diseases, including sepsis.
Asunto(s)
Histona Demetilasas/metabolismo , Proteína Quinasa C/metabolismo , Animales , Núcleo Celular/metabolismo , Epigénesis Genética/genética , Histona Demetilasas/genética , Inflamación/metabolismo , Metilación , Ratones , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Fosforilación , Proteína Quinasa C/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal/genética , Factor de Transcripción ReIA/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Among the various cell types that constitute the liver, Kupffer cells (KCs) are responsible for the elimination of gut-derived foreign products. Protein lysine acetylation (Kac) and lactylation (Kla) are dynamic and reversible post-translational modifications, and various global acylome studies have been conducted for liver and liver-derived cells. However, no such studies have been conducted on KCs. In this study, we identified 2198 Kac sites in 925 acetylated proteins and 289 Kla sites in 181 lactylated proteins in immortalized mouse KCs using global acylome technology. The subcellular distributions of proteins with Kac and Kla site modifications differed. Similarly, the specific sequence motifs surrounding acetylated or lactylated lysine residues also showed differences. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to better understand the differentially expressed proteins in the studies by Kac and Kla. In the newly identified Kla, we found K82 lactylation in the high-mobility group box-1 protein in the neutrophil extracellular trap formation category using KEGG enrichment analyses. Here, we report the first proteomic survey of Kac and Kla in KCs.
Asunto(s)
Macrófagos del Hígado , Lisina , Animales , Ratones , Lisina/metabolismo , Macrófagos del Hígado/química , Macrófagos del Hígado/metabolismo , Acetilación , Proteómica , Proteoma/análisis , Procesamiento Proteico-PostraduccionalRESUMEN
Deoxyribonuclease-I (DNase-I), a representative endonuclease, is an important biomarker for the diagnosis of infectious diseases and cancer progression. However, enzymatic activity decreases rapidly ex vivo, which highlights the need for precise on-site detection of DNase-I. Here, a localized surface plasmon resonance (LSPR) biosensor that enables the simple and rapid detection of DNase-I is reported. Moreover, a novel technique named electrochemical deposition and mild thermal annealing (EDMIT) is applied to overcome signal variations. By taking advantage of the low adhesion of gold clusters on indium tin oxide substrates, both the uniformity and sphericity of gold nanoparticles are increased under mild thermal annealing conditions via coalescence and Ostwald ripening. This ultimately results in an approximately 15-fold decrease in LSPR signal variations. The linear range of the fabricated sensor is 20-1000 ng mL-1 with a limit of detection (LOD) of 127.25 pg mL-1 , as demonstrated by spectral absorbance analyses. The fabricated LSPR sensor stably measured DNase-I concentrations from samples collected from both an inflammatory bowel disease (IBD) mouse model, as well as human patients with severe COVID-19 symptoms. Therefore, the proposed LSPR sensor fabricated via the EDMIT method can be used for early diagnosis of other infectious diseases.
Asunto(s)
Técnicas Biosensibles , COVID-19 , Nanopartículas del Metal , Animales , Ratones , Humanos , Resonancia por Plasmón de Superficie/métodos , Oro/química , Nanopartículas del Metal/química , Técnicas Biosensibles/métodos , DesoxirribonucleasasRESUMEN
High mobility group box 1 (HMGB1) is acknowledged to have critical functions; therefore, targeting this protein may have therapeutic effects. One example is potential antiseptic activity obtained by suppressing HMGB1 secretion, leading to the recovery of vascular barrier integrity. Cornuside (CN), which is a product extracted from the fruit of Cornusofficinalis Seib, is a natural bis-iridoid glycoside with the therapeutic effects of suppressing inflammation and regulating immune responses. However, the mechanism of action of CN and impact on sepsis is still unclear. We examined if CN could suppress HMGB1-induced excessive permeability and if the reduction of HMGB1 in response to LPS treatment increased the survival rate in a mouse model of sepsis. In human endothelial cells stimulated by LPS and mice with septic symptoms of cecal ligation and puncture (CLP), we examined levels of proinflammatory proteins and biomarkers as an index of tissue damage, along with decreased vascular permeability. In both LPS-treated human umbilical vein endothelial cells (HUVECs) and the CLP-treated mouse model of sepsis, we applied CN after the induction processes were over. CN suppressed excessive permeability and inhibited HMGB1 release, leading to the amelioration of vascular instability, reduced mortality, and improved histological conditions in the CLP-induced septic mouse model. Overall, we conclude that the suppressed release of HMGB1 and the increased survival rate of mice with CLP-induced sepsis caused by CN may be an effective pharmaceutical treatment for sepsis.
Asunto(s)
Glucósidos/farmacología , Proteína HMGB1/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Piranos/farmacología , Sepsis/tratamiento farmacológico , Sepsis/metabolismo , Animales , Adhesión Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Células Cultivadas , Citocinas/metabolismo , Modelos Animales de Enfermedad , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Transducción de Señal/efectos de los fármacosRESUMEN
The role of high mobility group box 1 (HMGB1) has been recognized as important, and suppression of HMGB1 release and restoration of vascular barrier integrity are regarded as potentially promising therapeutic strategies against sepsis. Hederacolchiside-E (HCE), namely 3-O-{α-L-rhamnopyranosyl (1â2)-[ß-D-glucopyranosyl(1â4)]-α-L-arabinopyranosyl}-28-O-[α-L-rhamnopyranosyl (1â4)-ß-D-glucopyranosyl(1â6)-ß-D-glucopyranosyl ester, is a bidesmosidic oleanane saponin first isolated in 1970 from the leaves of Hedera colchica. We tested our hypothesis that HCE inhibits HMGB1-induced vascular hyperpermeability and thereby increases the survival of septic mouse model from suppression of HMGB1 release upon lipopolysaccharide (LPS)-stimulation. In LPS-activated human endothelial cells and a sepsis mouse model by cecal ligation and puncture (CLP), antiseptic activity of HCE was investigated from suppression of vascular permeability, pro-inflammatory proteins, and tissue injury markers. Post-treatment of HCE significantly suppressed HMGB1 release both in LPS-activated human endothelial cells and the CLP-induced sepsis mouse model. HCE inhibited hyperpermeability and alleviated HMGB1-mediated vascular disruptions, and reduced sepsis-related mortality and tissue injury in mice. Our results suggest that reduction of HMGB1 release and septic mortality by HCE may be useful for the drug candidate of sepsis, indicating a possibility of successful repositioning of HCE.
Asunto(s)
Lesión Pulmonar Aguda/tratamiento farmacológico , Proteína HMGB1/antagonistas & inhibidores , Saponinas/uso terapéutico , Sepsis/tratamiento farmacológico , Lesión Pulmonar Aguda/metabolismo , Animales , Permeabilidad Capilar/efectos de los fármacos , Adhesión Celular/efectos de los fármacos , Moléculas de Adhesión Celular/metabolismo , Movimiento Celular/efectos de los fármacos , Citocinas/metabolismo , Proteína HMGB1/metabolismo , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Células Endoteliales de la Vena Umbilical Humana/fisiología , Humanos , Lipopolisacáridos/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Neutrófilos/efectos de los fármacos , Neutrófilos/fisiología , Saponinas/farmacología , Sepsis/metabolismo , Sirtuina 1/metabolismoRESUMEN
Particulate matter 2.5 (PM2.5), aerodynamic diameter ≤ 2.5 µm, is the primary air pollutant that plays the key role for lung injury resulted from the loss of vascular barrier integrity. Cudratricusxanthone O (CTXO) is a novel xanthone compound isolated from the root of Cudrania tricuspidata Bureau. Here, we investigated the beneficial effects of CTXO against PM-induced lung endothelial cell (EC) barrier disruption and pulmonary inflammation. Permeability, leukocyte migration, activation of proinflammatory proteins, generation of reactive oxygen species (ROS), and histology were examined in PM2.5-treated ECs and mice. CTXO significantly scavenged PM2.5-induced ROS and inhibited the ROS-induced activation of p38 mitogen-activated protein kinase (MAPK). Concurrently, CTXO activated Akt, which helped maintain endothelial integrity. Furthermore, CTXO reduced vascular protein leakage, leukocyte infiltration, and proinflammatory cytokine release in the bronchoalveolar lavage fluid in PM-induced lung tissues. These results indicated that CTXO may exhibit protective effects against PM-induced inflammatory lung injury and vascular hyperpermeability.
Asunto(s)
Contaminantes Atmosféricos/efectos adversos , Lesión Pulmonar/prevención & control , Material Particulado/efectos adversos , Neumonía/prevención & control , Sustancias Protectoras/farmacología , Xantonas/farmacología , Animales , Células Endoteliales/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos BALB C , Moraceae/químicaRESUMEN
BACKGROUND: Since its first detection in December 2019, coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 infection has spread rapidly around the world. Although there have been several studies investigating prognostic factors for severe COVID-19, there have been no such studies in Korea. METHODS: We performed a retrospective observational study of 110 patients with confirmed COVID-19 hospitalized at a tertiary hospital in Daegu, Korea. Demographic, clinical, laboratory, and outcome data were collected and analyzed. Severe disease was defined as a composite outcome of acute respiratory distress syndrome, intensive care unit care, or death. RESULTS: Diabetes mellitus (odds ratio [OR], 19.15; 95% confidence interval [CI], 1.90-193.42; P = 0.012), body temperature ≥ 37.8°C (OR, 10.91; 95% CI, 1.35-88.36; P = 0.025), peripheral oxygen saturation < 92% (OR, 33.31; 95% CI, 2.45-452.22; P = 0.008), and creatine kinase-MB (CK-MB) > 6.3 (OR, 56.84; 95% CI, 2.64-1,223.78, P = 0.010) at admission were associated with higher risk of severe COVID-19. The likelihood of development of severe COVID-19 increased with an increasing number of prognostic factors. CONCLUSION: In conclusion, we found that diabetes mellitus, body temperature ≥ 37.8°C, peripheral oxygen saturation < 92%, and CK-MB > 6.3 are independent predictors of severe disease in hospitalized COVID-19 patients. Appropriate assessment of prognostic factors and close monitoring to provide the necessary interventions at the appropriate time in high-risk patients may reduce the case fatality rate of COVID-19.
Asunto(s)
Infecciones por Coronavirus/patología , Complicaciones de la Diabetes/virología , Diabetes Mellitus/patología , Fiebre/patología , Hipoxia/patología , Neumonía Viral/patología , Adolescente , Adulto , Anciano , Betacoronavirus , COVID-19 , Niño , Preescolar , Femenino , Hospitalización , Humanos , Lactante , Recién Nacido , Unidades de Cuidados Intensivos , Masculino , Persona de Mediana Edad , Pandemias , Pronóstico , República de Corea , Síndrome de Dificultad Respiratoria/etiología , Estudios Retrospectivos , Factores de Riesgo , SARS-CoV-2 , Adulto JovenRESUMEN
BACKGROUND: The case fatality rate of coronavirus disease 2019 (COVID-19) is estimated to be between 4.3% and 11.0%. Currently there is no effective antiviral treatment for COVID-19. Thus, early recognition of patients at high risk is important. METHODS: We performed a retrospective observational study of 110 patients with severe acute respiratory syndrome coronavirus 2 infection. We compared the effectiveness of three scoring systems: the Systemic Inflammatory Response Syndrome (SIRS), quick Sequential Organ Failure Assessment (qSOFA), and National Early Warning Score (NEWS) systems, for predicting the prognosis of COVID-19. The area under the receiver operating characteristic curve (AUROC) was used for these assessments, and Kaplan-Meier survival curves were used to identify the cumulative risk for 28-day mortality according to the NEWS stratification. RESULTS: For predicting 28-day mortality, NEWS was superior to qSOFA (AUROC, 0.867 vs. 0.779, P < 0.001), while there was no significant difference between NEWS and SIRS (AUROC, 0.867 vs. 0.639, P = 0.100). For predicting critical outcomes, NEWS was superior to both SIRS (AUROC, 0.918 vs. 0.744, P = 0.032) and qSOFA (AUROC, 0.918 vs. 0.760, P = 0.012). Survival time was significantly shorter for patients with NEWS ≥ 7 than for patients with NEWS < 7. CONCLUSION: Calculation of the NEWS at the time of hospital admission can predict critical outcomes in patients with COVID-19. Early intervention for high-risk patients can thereby improve clinical outcomes in COVID-19 patients.
Asunto(s)
Deterioro Clínico , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/mortalidad , Insuficiencia Multiorgánica/diagnóstico , Puntuaciones en la Disfunción de Órganos , Neumonía Viral/diagnóstico , Neumonía Viral/mortalidad , Anciano , Betacoronavirus , COVID-19 , Infecciones por Coronavirus/patología , Diagnóstico Precoz , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/patología , Pronóstico , Estudios Retrospectivos , SARS-CoV-2RESUMEN
The screening of biologically active chemical compound libraries can be an efficient way to reposition Food and Drug Adminstration (FDA)-approved drugs or to discover new therapies for human diseases. Particulate matter with an aerodynamic diameter equal to or less than 2.5 µm (PM2.5) is a form of air pollutant that causes significant lung damage when inhaled. This study illustrates drug repositioning with biapenem (BIPM) for the modulation of PM-induced lung injury. Biapenem was used for the treatment of severe infections. Mice were treated with BIPM via tail-vein injection after the intratracheal instillation of PM2.5. Alterations in the lung wet/dry weight, total protein/total cell count and lymphocyte count, inflammatory cytokines in the bronchoalveolar lavage fluid (BALF), vascular permeability, and histology were monitored in the PM2.5-treated mice. BIPM effectively reduced the pathological lung injury, lung wet/dry weight ratio, and hyperpermeability caused by PM2.5. Enhanced myeloperoxidase (MPO) activity by PM2.5 in the pulmonary tissue was inhibited by BIPM. Moreover, increased levels of inflammatory cytokines and total protein by PM2.5 in the BALF were also decreased by BIPM treatment. In addition, BIPM markedly suppressed PM2.5-induced increases in the number of lymphocytes in the BALF. Additionally, the activity of mammalian target of rapamycin (mTOR) was increased by BIPM. Administration of PM2.5 increased the expression levels of toll-like receptor 4 (TLR4), MyD88, and the autophagy-related proteins LC3 II and Beclin 1, which were suppressed by BIPM. In conclusion, these findings indicate that BIPM has a critical anti-inflammatory effect due to its ability to regulate both the TLR4-MyD88 and mTOR-autophagy pathways, and may thus be a potential therapeutic agent against diesel PM2.5-induced pulmonary injury.
Asunto(s)
Reposicionamiento de Medicamentos , Lesión Pulmonar , Pulmón , Material Particulado/toxicidad , Tienamicinas/farmacología , Animales , Beclina-1/inmunología , Lavado Broncoalveolar , Citocinas/inmunología , Pulmón/inmunología , Pulmón/patología , Lesión Pulmonar/inducido químicamente , Lesión Pulmonar/tratamiento farmacológico , Lesión Pulmonar/inmunología , Lesión Pulmonar/patología , Linfocitos/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Proteínas Asociadas a Microtúbulos/inmunología , Factor 88 de Diferenciación Mieloide/inmunología , Serina-Treonina Quinasas TOR/inmunología , Receptor Toll-Like 4/inmunologíaRESUMEN
The larva of Allomyrina dichotoma (family Scarabaeidae) is an edible insect that is registered in the Korean Food Standards Codex as a food resource. The chemical study on the larvae of A. dichotoma resulted in the isolation of three new tetrahydroquinolines, allomyrinaines A-C (1-3), one new dopamine derivative, allomyrinamide A (4), and four known compounds (5-8). The structures were elucidated on the basis of 1D and 2D nuclear magnetic resonance (NMR) and MS spectroscopic data analysis. Allomyrinaines A-C (1-3) possessed three stereogenic centers at C-2, C-3, and C-4, whose relative configurations were determined by analyses of the coupling constants and the nuclear Overhauser enhancement spectroscopy (NOESY) data, as well as DP4+ calculation. The anti-inflammatory effects of compounds 1-4 were evaluated in human endothelial cells. Allomyrinaines A-C (1-3) could stabilize vascular barrier integrity on lipopolysaccharide (LPS)-induced vascular inflammation via inhibition of the nuclear factor-κB (NF-κB) pathway. The physiologically relevant concentration was confirmed by Q-TOF-MS-based quantitative analysis on allomyrinaines A-C in crude extract. This study suggests that allomyrinaines A-C (1-3) are bioactive constituents of A. dichotoma to treat vascular inflammatory disorder.
Asunto(s)
Escarabajos/química , Insectos Comestibles/química , Inflamación/prevención & control , Quinolinas/farmacología , Animales , Antiinflamatorios/química , Antiinflamatorios/farmacología , Citocinas/metabolismo , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Humanos , Inflamación/inducido químicamente , Inflamación/metabolismo , Lipopolisacáridos , Espectroscopía de Resonancia Magnética , Masculino , Ratones Endogámicos C57BL , Estructura Molecular , FN-kappa B/metabolismo , Sustancias Protectoras/química , Sustancias Protectoras/farmacología , Quinolinas/químicaRESUMEN
Inhibition of high mobility group box 1 (HMGB1) and restoration of endothelial integrity are emerging as attractive therapeutic strategies for the management of severe vascular inflammatory diseases. Recently, we found that JH-4, a synthesized decursin derivative, exhibited a strong anti-Hutchinson-Gilford progeria syndrome by efficiently blocking progerin-lamin A/C binding. In this study, we examined the effects of JH-4 on HMGB1-mediated septic responses and the survival rate in a mouse sepsis model. The anti-inflammatory activities of JH-4 were monitored based on its effects on lipopolysaccharide- or cecal ligation and puncture (CLP)-mediated release of HMGB1. The antiseptic activities of JH-4 were determined by measuring permeability, leukocyte adhesion, migration, and the activation of proinflammatory proteins in HMGB1-activated human umbilical vein endothelial cells and mice. JH-4 inhibited the release of HMGB1 and downregulated HMGB1-dependent inflammatory responses in human endothelial cells. JH-4 also inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice. In addition, treatment with JH-4 reduced CLP-induced release of HMGB1, sepsis-related mortality, and pulmonary injury in vivo. Our results indicate that JH-4 is a possible therapeutic agent to treat various severe vascular inflammatory diseases via the inhibition of the HMGB1 signaling pathway.
Asunto(s)
Antiinfecciosos Locales/uso terapéutico , Antiinflamatorios/uso terapéutico , Benzopiranos/uso terapéutico , Butiratos/uso terapéutico , Proteína HMGB1/metabolismo , Extractos Vegetales/uso terapéutico , Sepsis/tratamiento farmacológico , Sepsis/mortalidad , Angelica/química , Animales , Antiinfecciosos Locales/farmacología , Antiinflamatorios/farmacología , Benzopiranos/farmacología , Butiratos/farmacología , Permeabilidad Capilar/efectos de los fármacos , Adhesión Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Modelos Animales de Enfermedad , Proteína HMGB1/antagonistas & inhibidores , Proteína HMGB1/farmacología , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Leucocitos/metabolismo , Lipopolisacáridos/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Extractos Vegetales/farmacología , Sepsis/metabolismo , Tasa de SupervivenciaRESUMEN
Inhalation of fine particulate matter (PM2.5) is associated with elevated pulmonary injury attributed to the loss of vascular barrier integrity. Black ginseng (BG), steamed 9 times and dried ginseng, and its major protopanaxatriol type ginsenosides (ginsenoside Rg4, Rg6, Rh4, Rh1, and Rg2) exhibited various biological activities including anti-septic, anti-diabetic, wound healing, immune-stimulatory, and anti-antioxidant activity. The aim of this study was to investigate the beneficial effects of Rgx365 (a protopanaxatriol type rare ginsenosides fraction) on PM-induced lung endothelial cell (EC) barrier disruption and pulmonary inflammation. Permeability, leukocyte migration, activation of proinflammatory proteins, generation of reactive oxygen species (ROS), and histology were examined in PM2.5-treated EC and mice. Rgx365 significantly scavenged PM2.5-induced ROS, inhibited ROS-induced activation of p38 mitogen-activated protein kinase (MAPK), activated Akt in purified pulmonary EC, which helped maintain endothelial integrity. Further, Rgx365 reduced vascular protein leakage, leukocyte infiltration, and proinflammatory cytokine release in bronchoalveolar lavage fluids in PM-induced mouse lung tissues. Data suggested that Rgx365 might exhibit protective effects in PM-induced inflammatory lung injury and vascular hyperpermeability.
Asunto(s)
Ginsenósidos/farmacología , Lesión Pulmonar/tratamiento farmacológico , Material Particulado/efectos adversos , Sustancias Protectoras/farmacología , Animales , Técnicas de Cultivo de Célula , Células Endoteliales , Masculino , Ratones , Ratones Endogámicos BALB C , Sapogeninas/químicaRESUMEN
Particulate matter 2.5 (PM2.5), with an aerodynamic diameter of ≤2.5 µm, is the primary air pollutant that plays a key role associated with lung injury produced by loss of vascular barrier integrity. Dioscorea batatas Decne (Chinese yam), a perennial plant belonging to Dioscoreaceae family, is widely cultivated in tropical and subtropical regions across Asia. Both aerial parts and root of D. batatas are consumed for nutritional and medicinal purposes. The aim of this study was to (1) identify the bioactive compounds present in D. batatas peel which may be responsible for inhibition of PM2.5-induced pulmonary inflammation in mice and (2) examine in vitro mechanisms underlying the observed effects of these compounds on mouse lung microvascular endothelial cells. The measured parameters include permeability, leukocyte migration, proinflammatory protein activation, reactive oxygen species (ROS) generation, and histology. Two phenanthrene compounds, 2,7-dihydroxy-4,6-dimethoxyphenanthrene (1) and 6,7-dihydroxy-2,4-dimethoxyphenanthrene (2) were isolated from D. batatas peels. Both these phenanthrene compounds exhibited significant scavenging activity against PM2.5-induced ROS and inhibited ROS-induced activation of p38 mitogen-activated protein kinase. In addition, enhancement of Akt pathway, involved in the maintenance of endothelial integrity, was noted. These phenanthrene compounds also reduced vascular protein leakage, leukocyte infiltration, and proinflammatory cytokine release in the bronchoalveolar lavage fluid obtained from PM2.5-induced lung tissues. Evidence thus indicates that phenanthrene compounds derived from D. batatas may exhibit protective effects against PM2.5-induced inflammatory lung injury and vascular hyperpermeability in mice.
Asunto(s)
Dioscorea/química , Lesión Pulmonar/inducido químicamente , Material Particulado/toxicidad , Fenantrenos/farmacología , Extractos Vegetales/farmacología , Animales , Líquido del Lavado Bronquioalveolar , Frutas/química , Regulación de la Expresión Génica/efectos de los fármacos , Lesión Pulmonar/prevención & control , Masculino , Ratones , Ratones Endogámicos BALB C , Estructura Molecular , Tamaño de la Partícula , Fenantrenos/química , Fenantrenos/uso terapéutico , Fosforilación , Extractos Vegetales/química , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismoRESUMEN
Inhalation of fine particulate matter (PM2.5) is associated with elevated pulmonary injury caused by the loss of vascular barrier integrity. A traditional herbal prescription, Kyung-Ok-Ko (KOK), has long been used in Oriental medicine as a tonic for age-related diseases. In this study, we investigated the beneficial effects of KOK on PM-induced lung endothelial cell (EC) barrier disruption and pulmonary inflammation. Permeability, leukocyte migration, activation of proinflammatory proteins, generation of reactive oxygen species (ROS), and histology were examined in PM2.5-treated EC and mice. KOK significantly scavenged PM2.5-induced ROS and inhibited the ROS-induced activation of p38 mitogen-activated protein kinase (MAPK). Concurrently, KOK activated Akt, which helped maintain endothelial integrity. Furthermore, KOK reduced vascular protein leakage, leukocyte infiltration, and proinflammatory cytokine release in bronchoalveolar lavage fluids in PM-induced lung tissues. These data suggested that KOK might exhibit protective effects in PM-induced inflammatory lung injury and vascular hyperpermeability.
Asunto(s)
Contaminantes Atmosféricos/toxicidad , Medicamentos Herbarios Chinos/uso terapéutico , Células Endoteliales/efectos de los fármacos , Pulmón/efectos de los fármacos , Material Particulado/toxicidad , Sustancias Protectoras/uso terapéutico , Animales , Permeabilidad Capilar/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Células Cultivadas , Medicamentos Herbarios Chinos/farmacología , Células Endoteliales/fisiología , Leucocitos/efectos de los fármacos , Leucocitos/fisiología , Pulmón/patología , Pulmón/fisiología , Masculino , Ratones Endogámicos BALB C , Sustancias Protectoras/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Cudratricusxanthone A (CTXA), a natural bioactive compound extracted from the roots of Cudraniatricuspidata Bureau, is known to possess antithrombotic, antiproliferative, and antiinflammatory activities. It remains unclear that CTXA can improve hepatoprotective activity in vivo. The objective of this study was to investigate the effect of CTXA on lipopolysaccharide (LPS)-induced liver failure in mice, and to elucidate its underlying molecular mechanisms. Liver failure was induced by LPS (15 mg/kg, i.p.) in mice, and 12 hr later, they were treated intravenously with CTXA. Administration of LPS significantly increased mortality, serum levels of alanine transaminase (ALT), aspartate transaminase (AST), and serum inflammatory cytokines. CTXA treatment effectively countered these effects of LPS. Further, LPS treatment markedly increased the expression of myeloperoxidase, phosphorylation of p38, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK), and expressions of nuclear proteins, such as nuclear factor (NF)-κB and phosphorylated c-Jun. Additionally, LPS increased the serum levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6. All these effects of LPS were attenuated by CTXA. Moreover, CTXA increased the expression of sirtuin-1 (SIRT1) and reduced the expression of acetylated forkhead box O1 box O1 (Ac-FoxO1), acetylated Ac-p53, and acetylated nuclear factor-kappa beta (Ac-NF-κB). In conclusion, CTXA alleviates LPS-induced liver injury by reducing inflammatory responses and the potential mechanism is associated with SIRT1 signaling activation and finally could be used to treat liver diseases.
Asunto(s)
Hígado/efectos de los fármacos , Moraceae/química , Sepsis/tratamiento farmacológico , Xantonas/administración & dosificación , Acetilación , Animales , Citocinas/genética , Proteína Forkhead Box O1/genética , Humanos , Lipopolisacáridos/toxicidad , Hígado/lesiones , Hígado/patología , Fallo Hepático/inducido químicamente , Ratones , FN-kappa B/genética , Sepsis/complicaciones , Sepsis/patología , Proteína p53 Supresora de Tumor/genética , Xantonas/químicaRESUMEN
The development of new sepsis-specific biomarkers is mandatory to improve the detection and monitoring of the disease. Testican-1 is a highly conserved, multidomain proteoglycan that is most prominently expressed in the thalamus of the brain, and is upregulated in activated astroglial cells of the cerebrum. The aim of this study was to evaluate blood levels of Testican-1 in septic patients. A prospective study of 82 patients with sepsis was conducted. Furthermore, C57BL/6 mice were administrated with lipopolysaccharide (LPS), high mobility group box 1 (HMGB1) protein or subjected to cecal ligation and puncture (CLP) surgery. Alternatively, human umbilical vein endothelial cells (HUVECs) or C57BL/6 mice were exposed to LPS (100 ng/mL) or HMGB1 (1 µg/mL). LPS, HMGB1, or CLP enhanced the synthesis and secretion of Testican-1 in HUVECs and mice. In patients admitted to the intensive care unit (ICU) with sepsis, circulating levels of Testican-1 were significantly high (sepsis, 20.44-63.37 ng/mL, n = 30; severe sepsis, 41.30-98.69 ng/mL, n = 22; septic shock, 98.10-151.85 ng/mL, n = 30) when compared to the levels of control donors (6.97-8.77 ng/mL, n = 21), reflecting the severity of the disease. These results suggest that in septic patients, Testican-1 blood level is related to the severity of sepsis and Testican-1 could be used as a biomarker to determine the severity of sepsis.
Asunto(s)
Células Endoteliales de la Vena Umbilical Humana/metabolismo , Proteoglicanos/sangre , Sepsis/sangre , Sepsis/diagnóstico , Animales , Células Endoteliales de la Vena Umbilical Humana/patología , Humanos , Lipopolisacáridos/toxicidad , Masculino , Ratones , Sepsis/inducido químicamente , Sepsis/patologíaRESUMEN
Only a few isoflavones have been isolated from plants of the genus Abronia. The biological properties of compounds isolated from Abronia species have not been well established, and their antisepsis effects have not been reported yet. In the present study, a new C-methylcoumarinochromone, was isolated from Abronia nana suspension cultures. Its structure was deduced as 9,11-dihydroxy-10-methylcoumarinochromone (boeravinone Y, 1) by spectroscopic data analysis and verified by chemical synthesis. The potential inhibitory effects of 1 against high mobility group box 1 (HMGB1)-mediated septic responses were investigated. Results showed that 1 effectively inhibited lipopolysaccharide-induced release of HMGB1 and suppressed HMGB1-mediated septic responses, in terms of reduction of hyperpermeability, leukocyte adhesion and migration, and cell adhesion molecule expression. In addition, 1 increased the phagocytic activity of macrophages and exhibited bacterial clearance effects in the peritoneal fluid and blood of mice with cecal ligation and puncture-induced sepsis. Collectively, these results suggested that 1 might have potential therapeutic activity against various severe vascular inflammatory diseases via inhibition of the HMGB1 signaling pathway.
Asunto(s)
Cromonas/química , Cromonas/farmacología , Nyctaginaceae/química , Sepsis/tratamiento farmacológico , Animales , Antisepsia/métodos , Adhesión Celular/efectos de los fármacos , Técnicas de Cultivo de Célula , Movimiento Celular/efectos de los fármacos , Cromonas/aislamiento & purificación , Proteína HMGB1/metabolismo , Células Endoteliales de la Vena Umbilical Humana , Humanos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Lipopolisacáridos/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Fagocitosis/efectos de los fármacos , Sepsis/inducido químicamente , Sepsis/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Protaetia brevitarsis seulensis (Kolbe) has been temporarily registered as a food material by the Ministry of Food and Drug Safety of Korea (MFDS). The current study aimed to discover small antithrombotic molecules from this edible insect. Five indole alkaloids, 5-hydroxyindolin-2-one (1), (1R,3S)-1-methyl-1,2,3,4-tetrahydro-ß-carboline-3-carboxylic acid (2), (1S,3S)-1-methyl-1,2,3,4-tetrahydro-ß-carboline-3-carboxylic acid (3), (3S)-1,2,3,4-tetrahydro-ß-carboline-3-carboxylic acid (4) and L-tryptophan (5), were isolated from the insect. Among them, compounds 1 and 2 prolonged aPTT and PT and impaired thrombin and FXa generation on HUVEC surface. Moreover, these compounds inhibited platelet aggregation. Antithrombotic effects of compounds 1 and 2 were further confirmed in pre-clinical models of pulmonary embolism and arterial thrombosis. Collectively, these results demonstrated that compounds 1 and 2 could be effective antithrombotic agents and serve as new scaffolds for the development of antithrombotic drug.
Asunto(s)
Alcaloides Indólicos/farmacología , Agregación Plaquetaria/efectos de los fármacos , Trombosis/tratamiento farmacológico , Animales , Escarabajos/química , Células Endoteliales de la Vena Umbilical Humana , Humanos , Alcaloides Indólicos/química , Alcaloides Indólicos/aislamiento & purificación , Insectos/química , Trombosis/patologíaRESUMEN
High mobility group box 1 (HMGB1) is considered a late mediator of sepsis and the inhibition of HMGB1-mediated severe inflammatory responses and restoration of endothelial integrity have emerged as attractive therapeutic strategies for the management of sepsis. Zingerone (ZGR), a phenolic alkanone isolated from ginger, has been reported to possess various pharmacological activities. We examined the effects of ZGR on HMGB1-mediated septic responses and survival rate in a mouse model of sepsis. ZGR was administered after HMGB1 challenge. The antiseptic activity of ZGR was determined from the measurements of permeability, leukocyte adhesion and migration, activation of pro-inflammatory proteins, and the production of tissue injury markers in HMGB1-activated HUVECs and mice. ZGR significantly reduced HMGB1 release in LPS-activated HUVECs via the SIRT1-mediated deacetylation of HMGB1. And, ZGR suppressed the production of TNF-α and IL-6 and the activation of NF-κB and ERK 1/2 by HMGB1. ZGR also inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice. In addition, treatment with ZGR reduced the CLP-induced release of HMGB1, sepsis-related mortality, and tissue injury in vivo. Our results indicated that ZGR might be useful in the treatment of sepsis by targeting HMGB1.