RESUMEN
Type I interferons (IFNs) are the first frontline of the host innate immune response against invading pathogens. Herein, we characterized an unknown protein encoded by phospholipase A2 inhibitor and LY6/PLAUR domain-containing (PINLYP) gene that interacted with TBK1 and induced type I IFN in a TBK1- and IRF3-dependent manner. Loss of PINLYP impaired the activation of IRF3 and production of IFN-ß induced by DNA virus, RNA virus, and various Toll-like receptor ligands in multiple cell types. Because PINLYP deficiency in mice engendered an early embryonic lethality in mice, we generated a conditional mouse in which PINLYP was depleted in dendritic cells. Mice lacking PINLYP in dendritic cells were defective in type I IFN induction and more susceptible to lethal virus infection. Thus, PINLYP is a positive regulator of type I IFN innate immunity and important for effective host defense against viral infection.
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Células Dendríticas/inmunología , Inhibidores Enzimáticos/inmunología , Inmunidad Innata , Interferón beta/inmunología , Animales , Línea Celular , Infecciones por Virus ADN/genética , Infecciones por Virus ADN/inmunología , Virus ADN/genética , Virus ADN/inmunología , Humanos , Interferón beta/genética , Ratones , Ratones Noqueados , Infecciones por Virus ARN/genética , Infecciones por Virus ARN/inmunología , Virus ARN/genética , Virus ARN/inmunologíaRESUMEN
Severe trauma can lead to numerous serious complications, threating the well-being and vitality of the afflicted. The quantity and functionality of PMNs undergo rapid transformations in response to severe trauma, playing a pivotal role in the trauma response. The absence of CCAAT/enhancer-binding protein ε (C/EBPε) profoundly impairs the functionality of polymorphonuclear neutrophils (PMNs), a function of paramount importance in trauma. In this study, by generating mice with C/EBPε knocked out or overexpressed, we substantiate that C/EBPε ensures the restoration of PMN function, enhancing the expression of antimicrobial proteins and thereby promoting trauma recovery. Furthermore, diminished expression of C/EBPε is observed in trauma patients, with levels displaying a negative correlation with ISS and APACHE II scores, suggesting its potential as a prognostic indicator for clinical treatment. Mechanistically, we uncover the upregulation of SIRT1 and the inhibition of P300 participating in the suppression of C/EBPε acetylation, consequently reducing the resilience of mice to trauma. As therapeutic interventions, whether through the sole administration of PMN, NAM treatment, or their combination, all result in an increased survival rate in traumatic mice. In conclusion, our study elucidates the role of C/EBPε in enhancing the resilience to trauma and identifies C/EBPε acetylation as a critical regulatory mechanism, offering potential therapeutic approaches involving PMN transfusion and NAM treatment.
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Bacterial wound infection has emerged as a pivotal threat to human health worldwide, and the situation has worsened owing to the gradual increase in antibiotic-resistant bacteria caused by the improper use of antibiotics. To reduce the use of antibiotics and avoid the increase in antibiotic-resistant bacteria, researchers are increasingly paying attention to photodynamic therapy, which uses light to produce reactive oxygen species to kill bacteria. Treating bacteria-infected wounds by photodynamic therapy requires fixing the photosensitizer (PS) at the wound site and maintaining a certain level of wound humidity. Hydrogels are materials with a high water content and are well suited for fixing PSs at wound sites for antibacterial photodynamic therapy. Therefore, hydrogels are often loaded with PSs for treating bacteria-infected wounds via antibacterial photodynamic therapy. In this review, we systematically summarised the antibacterial mechanisms and applications of PS-loaded hydrogels for treating bacteria-infected wounds via photodynamic therapy. In addition, the recent studies and the research status progresses of novel antibacterial hydrogels are discussed. Finally, the challenges and future prospects of PS-loaded hydrogels are reviewed.
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Antibacterianos , Vendajes , Hidrogeles , Fármacos Fotosensibilizantes , Infección de Heridas , Humanos , Antibacterianos/farmacología , Antibacterianos/administración & dosificación , Infecciones Bacterianas/tratamiento farmacológico , Hidrogeles/farmacología , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/farmacología , Cicatrización de Heridas/efectos de los fármacos , Infección de Heridas/tratamiento farmacológico , Infección de Heridas/microbiologíaRESUMEN
PURPOSE: Vibrio vulnificus (V. Vulnificus) infection is characterized by rapid onset, aggressive progression, and challenging treatment. Bacterial resistance poses a significant challenge for clinical anti-infection treatment and is thus the subject of research. Enhancing host infection tolerance represents a novel infection prevention strategy to improve patient survival. Our team initially identified cytochrome P4501A1 (CYP1A1) as an important target owing to its negative modulation of the body's infection tolerance. This study explored the superior effects of the CYP1A1 inhibitor bergamottin compared to antibiotic combination therapy on the survival of mice infected with multidrug-resistant V. Vulnificus and the protection of their vital organs. METHODS: An increasing concentration gradient method was used to induce multidrug-resistant V. Vulnificus development. We established a lethal infection model in C57BL/6J male mice and evaluated the effect of bergamottin on mouse survival. A mild infection model was established in C57BL/6J male mice, and the serum levels of creatinine, urea nitrogen, aspartate aminotransferase, and alanine aminotransferase were determined using enzyme-linked immunosorbent assay to evaluate the effect of bergamottin on liver and kidney function. The morphological changes induced in the presence of bergamottin in mouse organs were evaluated by hematoxylin and eosin staining of liver and kidney tissues. The bacterial growth curve and organ load determination were used to evaluate whether bergamottin has a direct antibacterial effect on multidrug-resistant V. Vulnificus. Quantification of inflammatory factors in serum by enzyme-linked immunosorbent assay and the expression levels of inflammatory factors in liver and kidney tissues by real-time quantitative polymerase chain reaction were performed to evaluate the effect of bergamottin on inflammatory factor levels. Western blot analysis of IκBα, phosphorylated IκBα, p65, and phosphorylated p65 protein expression in liver and kidney tissues and in human hepatocellular carcinomas-2 and human kidney-2 cell lines was used to evaluate the effect of bergamottin on the nuclear factor kappa-B signaling pathway. One-way ANOVA and Kaplan-Meier analysis were used for statistical analysis. RESULTS: In mice infected with multidrug-resistant V. Vulnificus, bergamottin prolonged survival (p = 0.014), reduced the serum creatinine (p = 0.002), urea nitrogen (p = 0.030), aspartate aminotransferase (p = 0.029), and alanine aminotransferase (p = 0.003) levels, and protected the cellular morphology of liver and kidney tissues. Bergamottin inhibited interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α expression in serum (IL-1ß: p = 0.010, IL-6: p = 0.029, TNF-α: p = 0.025) and inhibited the protein expression of the inflammatory factors IL-1ß, IL-6, TNF-α in liver (IL-1ß: p = 0.010, IL-6: p = 0.011, TNF-α: p = 0.037) and kidney (IL-1ß: p = 0.016, IL-6: p = 0.011, TNF-α: p = 0.008) tissues. Bergamottin did not affect the proliferation of multidrug-resistant V. Vulnificus or the bacterial load in the mouse peritoneal lavage fluid (p = 0.225), liver (p = 0.186), or kidney (p = 0.637). CONCLUSION: Bergamottin enhances the tolerance of mice to multidrug-resistant V. Vulnificus infection. This study can serve as a reference and guide the development of novel clinical treatment strategies for V. Vulnificus.
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Transcription suppressor Musculin (MSC) is enriched in pro-inflammatory Th17 and IL-22-producing ILC3s. While MSC+/+ mice survived DSS-induced colitis, MSC-/- mice showed elevated pro-inflammatory cytokines with severer pathology, reduced body weight, and earlier death. Reversal of colitis symptoms in MSC-/- mice by IL-22 antagonism suggests the existence of MSC:IL-22 regulatory axis.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/inmunología , Colitis/inmunología , Citocinas/inmunología , Mediadores de Inflamación/inmunología , Interleucinas/inmunología , Linfocitos/inmunología , Células Th17/inmunología , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Colitis/inducido químicamente , Colitis/genética , Citocinas/metabolismo , Sulfato de Dextran , Inmunidad Innata/inmunología , Mediadores de Inflamación/metabolismo , Interleucina-17/inmunología , Interleucina-17/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Linfocitos/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Células Th17/metabolismo , Interleucina-22RESUMEN
BACKGROUND Sepsis has emerged as a leading cause of death in the intensive care unit. A growing number of studies have shown that genetic variants, especially single nucleotide polymorphisms, are key determinants of inter-individual variation in sepsis response. Therefore, early prediction of the onset and progression of sepsis, along with early intervention in high-risk patients, should be performed to effectively reduce the morbidity and mortality of the disease. MATERIAL AND METHODS A total of 581 Chinese patients were enrolled in this study, including 271 patients with sepsis and 310 patients without. We measured gene polymorphisms of MBL2 and serum levels of MBL2, tumor necrosis factor (TNF-alpha), interleukin (IL)-6, IL-4, and IL-10 in all patients. The effects of site mutations on the binding of MBL2 to mannose-associated serine protease 1 (MASP1) and MASP2 were also analyzed. RESULTS Of 3 site mutations in the MBL2 gene (rs5030737, rs1800450, and rs1800451), only rs1800450 had a mutant (G/A) genotype. The frequency of the GA genotype and A allele in the sepsis group was higher than that in the non-sepsis group. Furthermore, rs1800450G/A was associated with decreased serum MBL2 and IL-10 levels and decreased MBL2-MASP1 and MBL2-MASP2 interactions. Bioinformatics analysis showed that rs1800450G/A reduced the structural stability of the MBL2 protein and affected its function. CONCLUSIONS MBL2 rs1800450G/A was associated with a higher risk of sepsis, which possibly involved a decreased level of serum MBL2 that broke the balance of inflammation and weakened the binding of MBL2 to MASP1 and MASP2.
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Lectina de Unión a Manosa , Sepsis , China , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Interleucina-10/genética , Lectina de Unión a Manosa/genética , Serina Proteasas Asociadas a la Proteína de Unión a la Manosa/genética , Polimorfismo de Nucleótido Simple/genética , Sepsis/genéticaRESUMEN
BACKGROUND AND OBJECTIVES: To optimize the pretreatment method of colorectal cancer tissue samples for metabolomics research based on solid-phase nuclear magnetic resonance (NMR). METHODS AND STUDY DESIGN: The mucosal tissues of colorectal cancer were classified into five groups with a volume of 0.2 cm*0.2 cm*0.2 cm. The pretreatment methods for each group were as follows: I. Preservation with liquid nitrogen alone. Samples were also treated with liquid nitrogen for 10 (II), 20 (III), and 30 min (IV), respectively, immediately after isolation and then transferred to a -80â refrigerator; V. Only -80â refrigerator storage. No more than 30 minutes should pass between isolation and pretreatment of tumor samples. The tissue sample testing process was carried out on Bruker AVII-600 NMR Spectrometer. NMR signals were collected and analysed using partial least-squares discrimination analysis (PLS-DA) to explore the effects of different pretreatment methods on the metabolic changes of samples. RESULTS: The levels of pelargonic acid, stearic acid, D-Ribose, heptadecanoic acid, pyruvic acid, succinate, sarcosine, glycine, creatine, and L-lactate in the group I (only liquid nitrogen) were significantly lower than the other groups (p<0.05); the content of glycerophosphocholine in the group I (only liquid nitrogen) was lower than that in the other groups (p=0.055). These indicated that the glucose and choline phospholipid metabolism levels of the liquid nitrogen group were significantly lower than those of the other four groups. CONCLUSIONS: Liquid nitrogen storage can stop the metabolic process of glucose and choline phospholipid in colorectal cancer tissue samples in vitro, thus maintaining the metabolic state of tissue samples in vivo as much as possible.
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Neoplasias Colorrectales , Ácido Pirúvico , Colina , Creatina , Glucosa , Glicerilfosforilcolina , Humanos , Lactatos , Nitrógeno , Ribosa , Sarcosina , SuccinatosRESUMEN
Sepsis, which is characterized by multiple organ dysfunctions as a result of an unbalanced host-inflammatory response to pathogens, is potentially a life-threatening condition and a major cause of death in the intensive care units (ICUs). However, effective treatment or intervention to prevent sepsis-associated lethality is still lacking. Human umbilical cord mesenchymal stem cell (hUC-MSC) transplantation has been shown to have potent immunomodulatory properties and improve tissue repair yet lacks direct antibacterial and endotoxin clearance activities. In this study, we engineered hUC-MSCs to express a broad-spectrum antibacterial fusion peptide containing BPI21 and LL-37 (named BPI21/LL-37) and confirmed that the BPI21/LL-37 modification did not affect the stemness and immunoregulatory capacities of hUC-MSCs but remarkably, enhanced its antibacterial and toxin-neutralizing activities in vitro. Furthermore, we showed that administration of BPI21/LL-37-engineered hUC-MSCs significantly reduces serum levels of tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß), and IL-6, whereas increases that of IL-10 in cecal ligation and puncture (CLP)-induced sepsis mouse model. Administration of BPI21/LL-37-engineered hUC-MSCs significantly reduced systemic endotoxin (lipopolysaccharide [LPS]) levels and organ bacterial load, ameliorated damage to multiple organs, and improved survival. Taken together, our study demonstrates that BPI21/LL-37-engineered hUC-MSCs might offer a novel therapeutic strategy to prevent or treat sepsis via enhanced antimicrobial and anti-inflammatory properties to preserve organ functions better.
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Antibacterianos/farmacología , Péptidos Catiónicos Antimicrobianos/farmacología , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Proteínas Recombinantes de Fusión/farmacología , Sepsis/terapia , Cordón Umbilical/citología , Animales , Terapia Combinada , Modelos Animales de Enfermedad , Endotoxinas/inmunología , Ingeniería Genética , Humanos , Inmunomodulación/efectos de los fármacos , Trasplante de Células Madre Mesenquimatosas/efectos adversos , Trasplante de Células Madre Mesenquimatosas/métodos , Células Madre Mesenquimatosas/citología , Ratones , Sepsis/etiología , Sepsis/mortalidadRESUMEN
OBJECTIVES: The knowledge that agmatine is found in the human body has existed for several years; however, its role in sepsis has not yet been studied. In the present study, we investigate the role of agmatine in the progression and treatment of sepsis. DESIGN: Clinical/laboratory investigations. SETTING: Medical centers/University-based research laboratory. SUBJECTS: Elective ICU patients with severe sepsis and healthy volunteers; C57BL/6 mice weighing 18-22 g. INTERVENTIONS: Serum agmatine level and its associations with inflammatory markers were assessed in patients with sepsis. Agmatine was administered intraperitoneally to mice before a lipopolysaccharide challenge. Human peripheral blood mononuclear cells and murine macrophages were pretreated with agmatine followed by lipopolysaccharide stimulation. MEASUREMENTS AND MAIN RESULTS: Serum agmatine levels were significantly decreased in patients with sepsis and lipopolysaccharide-induced mice, and correlated with Acute Physiology and Chronic Health Evaluation II score, procalcitonin, tumor necrosis factor-α, and interleukin-6 levels. In a therapeutic experiment, exogenous agmatine attenuated the cytokine production of peripheral blood mononuclear cells from patients with sepsis and healthy controls. Agmatine also exerted a significant beneficial effect in the inflammatory response and organ damage and reduced the death rate in lipopolysaccharide-induced mice. Imidazoline I2 receptor agonist 2-benzofuran-2-yl blocked the pharmacological action of agmatine; whereas, other imidazoline receptor ligands did not. Furthermore, agmatine significantly impaired the inflammatory response by inactivating nuclear factor-κB, but not protein 38 mitogen-activated protein kinase, c-Jun N-terminal kinase, extracellular signal-regulated kinase, and inducible nitric oxide synthase signaling in macrophages. Activation of imidazoline I2 receptor or knockdown of ribosomal S6 kinase 2 counteracted the effects of agmatine on phosphorylation and degradation of inhibitor of nuclear factor-κBα. CONCLUSIONS: Endogenous agmatine metabolism correlated with the progression of sepsis. Supplemental exogenous agmatine could ameliorate the lipopolysaccharide-induced systemic inflammatory responses and multiple organ injuries through the imidazoline I2 receptor-ribosomal S6 kinase 2-nuclear factor-κB pathway. Agmatine could be used as both a clinical biomarker and a promising pharmaconutrient in patients with severe sepsis.
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Agmatina/uso terapéutico , Receptores de Imidazolina/fisiología , FN-kappa B/fisiología , Proteínas Quinasas S6 Ribosómicas 90-kDa/fisiología , Sepsis/tratamiento farmacológico , Transducción de Señal/fisiología , Agmatina/farmacología , Animales , Células Cultivadas , Progresión de la Enfermedad , Humanos , Receptores de Imidazolina/efectos de los fármacos , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/fisiología , Macrófagos/efectos de los fármacos , Macrófagos/fisiología , Ratones , Ratones Endogámicos C57BL , FN-kappa B/efectos de los fármacos , Proteínas Quinasas S6 Ribosómicas 90-kDa/efectos de los fármacos , Transducción de Señal/efectos de los fármacosRESUMEN
The polarization of macrophages is critical to inflammation and tissue repair, with unbalanced macrophage polarization associated with critical dysfunctions of the immune system. Cytochrome P450 1A1 (CYP1A1) is a hydroxylase mainly controlled by the inflammation-limiting aryl hydrocarbon receptor (AhR), which plays a critical role in mycoplasma infection, oxidative stress injury, and cancer. Arginase-1 (Arg-1) is a surrogate for polarized alternative macrophages and is important to the production of nitric oxide (NO) by the modulation of arginine. In the present study, we found CYP1A1 to be upregulated in IL-4-stimulated mouse peritoneal macrophages (PMs) and human peripheral blood monocytes. Using CYP1A1-overexpressing RAW264.7 cells (CYP1A1/RAW) we found that CYP1A1 augmented Arg-1 expression by strengthening the activation of the JAK1/STAT6 signaling pathway in macrophages treated with IL-4. 15(S)-HETE, a metabolite of CYP1A1 hydroxylase, was elevated in IL-4-induced CYP1A1/RAW cells. Further, in macrophages, the loss-of-CYP1A1-hydroxylase activity was associated with reduced IL-4-induced Arg-1 expression due to impaired 15(S)-HETE generation. Of importance, CYP1A1 overexpressing macrophages reduced the inflammation associated with LPS-induced peritonitis. Taken together, these findings identified a novel signaling axis, CYP1A1-15(S)-HETE-JAK1-STAT6, that may be a promising target for the proper maintenance of macrophage polarization and may also be a means by which to treat immune-related disease due to macrophage dysfunction.
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Arginasa/biosíntesis , Citocromo P-450 CYP1A1/fisiología , Janus Quinasa 1/antagonistas & inhibidores , Macrófagos Peritoneales/efectos de los fármacos , Peritonitis/prevención & control , Factor de Transcripción STAT6/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico/farmacología , Traslado Adoptivo , Animales , Araquidonato 15-Lipooxigenasa/fisiología , Arginasa/genética , Citocromo P-450 CYP1A1/biosíntesis , Citocromo P-450 CYP1A1/genética , Endotoxinas/toxicidad , Humanos , Ácidos Hidroxieicosatetraenoicos/biosíntesis , Ácidos Hidroxieicosatetraenoicos/genética , Ácidos Hidroxieicosatetraenoicos/farmacología , Interleucina-4/farmacología , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/trasplante , Macrófagos Peritoneales/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Peritonitis/inducido químicamente , Células RAW 264.7 , Interferencia de ARN , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Receptores Citoplasmáticos y Nucleares/biosíntesis , Receptores Citoplasmáticos y Nucleares/genética , Células THP-1 , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Neutrophilic granule protein (NGP) belongs to the cystatin superfamily. Even though this superfamily is critically involved in cancer biology and adaptive immunity, the relationship of macrophage NGP to inflammation and phagocytosis remains poorly understood. In this study, we observed a significant increase of NGP in peritoneal macrophages (PMs) isolated from mice challenged with E. coli or lipopolysaccharide (LPS), as judged by NGP mRNA microarray. We also found changes in NGP to be mainly Toll-like receptor 4 (TLR4)-dependent. By western blot and electrophoretic mobility shift assay, we demonstrated NGP overexpression to reduce TNF-α and IL-1ß production by LPS-induced RAW264.7 cells (RAW) via suppression of the NF-κB (p65 and p50) signalling pathway, rather than the JNK1/AP-1 (fos and jun) signalling pathway. NGP overexpression by LPS-induced RAW also induced IL-10, an anti-inflammatory cytokine, which was partially involved in the anti-inflammatory effect produced by NGP overexpression. Moreover, upregulated NGP enhanced the phagocytosis of E. coli by RAW. Taken together, these results demonstrated NGP to be an important host defense component that regulates inflammatory responses and phagocytosis by activated macrophages. As such, NGP may be useful for the treatment of inflammatory based disease.
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Mediadores de Inflamación/metabolismo , Inflamación/inducido químicamente , Inflamación/metabolismo , Lipopolisacáridos/farmacología , Macrófagos Peritoneales/metabolismo , Fagocitosis/fisiología , Animales , Línea Celular , Cistatinas/metabolismo , Citocinas/metabolismo , Escherichia coli/metabolismo , Inflamación/patología , Macrófagos Peritoneales/patología , Masculino , Ratones , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Células RAW 264.7 , Transducción de Señal/fisiología , Receptor Toll-Like 4/metabolismo , Factor de Transcripción ReIA/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
An amendment to this paper has been published and can be accessed via the original article.
RESUMEN
The hydroxylase cytochrome P450 1A1 (CYP1A1) is regulated by the inflammation-limiting aryl hydrocarbon receptor (AhR), but CYP1A1 immune functions remain unclear. We observed CYP1A1 overexpression in peritoneal macrophages (PMs) isolated from mice following LPS or heat-killed Escherichia. coli (E. coli) challenge. CYP1A1 overexpression augmented TNF-α and IL-6 production in RAW264.7 cells (RAW) by enhancing JNK/AP-1 signalling. CYP1A1 overexpression also promoted 12S-hydroxy-5Z,8Z,10E,14Z-eicosatetraenoic acid (12(S)-HETE) production in activated RAW, while a 12(S)-HETE antibody attenuated and 12(S)-HETE alone induced inflammatory responses. Macrophages harbouring hydroxylase-deficient CYP1A1 demonstrated reduced 12(S)-HETE generation and LPS-induced TNF-α/IL-6 secretion. CYP1A1 overexpression also impaired phagocytosis of bacteria via decreasing the expression of scavenger receptor A (SR-A) in PMs. Mice injected with CYP1A1-overexpressing PMs were more susceptible to CLP- or E. coli-induced mortality and bacteria invading, while Rhapontigenin, a selective CYP1A1 inhibitor, improved survival and bacteria clearance of mice in sepsis. CYP1A1 and 12(S)-HETE were also elevated in monocytes and plasma of septic patients and positively correlated with SOFA scores. Macrophage CYP1A1 disruption could be a promising strategy for treating sepsis. Video abstract.
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Citocromo P-450 CYP1A1/fisiología , MAP Quinasa Quinasa 4/metabolismo , Macrófagos Peritoneales , Fagocitosis , Sepsis/metabolismo , Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico/metabolismo , Adulto , Anciano , Animales , Escherichia coli , Humanos , Inflamación , Macrófagos Peritoneales/metabolismo , Macrófagos Peritoneales/microbiología , Macrófagos Peritoneales/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Células RAW 264.7 , Adulto JovenRESUMEN
Sepsis is one of the most challenging health problems worldwide. Our previous study showed that chronic schistosoma japonica (SJ) infection might increase serum anti-inflammatory factors to play a protective role, thus improving the survival rate of septic mice. Further research revealed that SJ infection promoted J774A.1 macrophage differentiation into M2 macrophages; suppressed LPS-induced activation of M1 macrophages; up-regulated CD163, IL-10, and TGF-ß1 expression; inhibited TNF-α and iNOS expression; and blocked the effect of LPS-promoted TNF-α and iNOS expression. Furthermore, adoptive transfer of ex vivo programed M2 macrophages significantly increased the survival rate of septic mice. In vitro studies suggested that soluble egg antigen (SEA) from SJ played the same role as worm infection but had no impact on M1 macrophages. SEA reduced LPS-induced TNF-α and iNOS expression, decreased the inhibitory effect of LPS on IL-10 and TGF-ß1 expression, increased STAT6 phosphorylation, and up-regulated PI3K and Akt expression but inhibited SOCS1 expression. When PI3K inhibitors were added, SEA-induced expression of CD163, IL-10, and arg1 might be reduced. Therefore, worm infection has a protective effect in septic mice in which SEA may play a key role via the STAT6 and PI3K pathways. This finding may provide a favorable solution for the treatment of sepsis, especially early cases. J. Cell. Biochem. 118: 4230-4239, 2017. © 2017 Wiley Periodicals, Inc.
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Antígenos Helmínticos/inmunología , Citocinas , Macrófagos/metabolismo , Esquistosomiasis Japónica/complicaciones , Sepsis/complicaciones , Transducción de Señal , Animales , Macrófagos/inmunología , Ratones , Óxido Nítrico Sintasa de Tipo II , Fosfatidilinositol 3-Quinasas/metabolismo , Factor de Transcripción STAT6/metabolismo , Esquistosomiasis Japónica/inmunología , Esquistosomiasis Japónica/metabolismo , Sepsis/mortalidad , Tasa de SupervivenciaRESUMEN
The enzyme complex IκB kinase (IKK) is an essential activator of NF-κB signaling pathway involved in propagating the cellular response to inflammation. The complex contains two functional subunits IKKα and IKKß, which are structurally conserved kinases and selective inhibition of them would result in distinct biological effects. However, most existing IKK inhibitors show moderate or high promiscuity for the two homologous kinases. Understanding of the molecular mechanism and biological implication underlying the specific interactions in IKK-ligand recognition is thus fundamentally important for the rational design of selective IKK inhibitors. In the current work, we integrated molecular docking, quantum mechanics/molecular mechanics calculation and Poisson-Boltzmann/surface area analysis to investigate the structural basis and energetic property of the selective binding of small-molecule ligands to IKKα and IKKß. It was found that the selectivity is primarily determined by the size and topology difference in ATP-binding pocket of IKKα and IKKß kinase domains; bulky inhibitor molecules commonly have, respectively, low and appropriate affinities towards IKKα and IKKß, and thus exhibit relatively high selectivity for IKKß over IKKα, whereas small ligands can only bind weakly to both the two kinases with low selectivity. In addition, the conformation, arrangement and distribution of residues in IKK pockets are also responsible for constituting the exquisite specificity of ligand binding to KKα and IKKß. Next, a novel quantitative structure-selectivity relationship model was developed to characterize the relative contribution of each kinase residue to inhibitor selectivity and to predict the selectivity and specificity for a number of known IKK inhibitors. Results showed that the active-site residues contribute significantly to the selectivity by directly interacting with inhibitor ligands, while those protein portions far away from the kinase active sites may also play an important role in determining the selectivity through long-range non-bonded forces and indirect allosteric effect.
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Quinasa I-kappa B/antagonistas & inhibidores , FN-kappa B/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Secuencia de Aminoácidos , Dominio Catalítico , Humanos , Quinasa I-kappa B/química , Quinasa I-kappa B/genética , Modelos Moleculares , Simulación de Dinámica Molecular , Datos de Secuencia Molecular , Inhibidores de Proteínas Quinasas/química , Estructura Terciaria de Proteína , Relación Estructura-Actividad Cuantitativa , Teoría Cuántica , Transducción de Señal/efectos de los fármacos , Homología Estructural de ProteínaRESUMEN
PURPOSE: To evaluate the usefulness and information collecting ability of speckle tracking imaging techniques in the assessment of myocardial regional ventricular contractility in a rabbit model with blunt cardiac injury. METHODS: Fifteen healthy New Zealand rabbits weighing (2.70 ±0.28) kg were anesthetized (3% pentobarbital sodium/i.v) and impacted using the BIM-II biological impact machine to induce myocardial contusion (MC). Hemodynamic parameters, such as heart rate, systolic pressure, mean arterial pressure, diastolic pressure and central venous pressure, were determined before and after MC. Further, parameters reflecting left ventricular functions, such as left ventricular end systolic pressure, left ventricular end diastolic pressure, isovolumic pressure (IP) and the maximal increasing/decreasing rate of left intraventricular pressure (±dp/dtmax), were also determined before and after MC. Left ventricular functions were determined either by two dimensional transthoracic echocardiography or by speckle tracking imaging for segmental abnormal ventricular wall motions. RESULTS: Heart rate, systolic pressure, diastolic pressure and mean arterial pressure decreased significantly but transiently, while central venous pressure markedly increased after MC. In contrast to significant changes in diastolic functions, there was no significant change in cardiac systolic functions after MC. The speckle tracking imaging demonstrated that strain values of different myocardial segment significantly decreased post impact, and that of the ventricular segment decreased from segment to segment. CONCLUSION: Speckle tracking imaging is useful and informative to assess myocardial regional dysfunctions post MC.
Asunto(s)
Ecocardiografía , Lesiones Cardíacas/fisiopatología , Función Ventricular , Heridas no Penetrantes/fisiopatología , Animales , Femenino , Lesiones Cardíacas/diagnóstico por imagen , Hemodinámica , Masculino , Contracción Miocárdica , Conejos , Heridas no Penetrantes/diagnóstico por imagenRESUMEN
Infection is a common medical problem at present. Different pathogens can lead to different infections. Severe infections can ultimately lead to sepsis, resulting in multiple organ dysfunction and the high mortality of patients. Therefore, studying the occurrence and development of severe infections is essential to improve the survival rate of patients. More and more studies have revealed the important role of connection between intestine and liver in infectious diseases. The maintenance of intestinal mechanical barrier and biological barrier function and the regulation of intestinal flora metabolites can reduce infectious liver injury. Bile acids are important metabolites in the liver, which can inhibit the progression of certain infectious intestinal injuries and promote intestinal damage caused by certain pathogens. In this article, the mechanism of action of the intestinal-liver axis in infection was reviewed to find a new target for the treatment of clinical infection.
Asunto(s)
Intestinos , Hígado , Humanos , Hígado/metabolismo , Ácidos y Sales Biliares/metabolismo , Hepatopatías/metabolismo , Hepatopatías/etiología , Mucosa Intestinal/metabolismo , Microbioma GastrointestinalRESUMEN
Polyimides (PIs) are a class of polymers characterized by strong covalent bonds, which offer the advantages of high thermal weight, low weight, good electronic properties and superior mechanical properties. They have been successfully used in the fields of microelectronics, aerospace engineering, nanomaterials, lasers, energy storage and painting. Their biomedical applications have attracted extensive attention, and they have been explored for use as an implantable, detectable, and antibacterial material in recent years. This article summarizes the progress of PI in terms of three aspects: synthesis, properties, and application. First, the synthetic strategies of PI are summarized. Next, the properties of PI as a biological or medical material are analyzed. Finally, the applications of PI in electrodes, biosensors, drug delivery systems, bone tissue replacements, face masks or respirators, and antibacterial materials are discussed. This review provides a comprehensive understanding of the latest progress in PI, thereby providing a basis for developing new potentially promising materials for medical applications.
RESUMEN
The interaction of gut microbiota and its metabolites with the host not only plays an important role in maintaining gut homeostasis and host health, but also is a key link in responding to pathogen infections. A thorough understanding of the changes in gut microbiota and its metabolites during infection, as well as their role and mechanism in host defense against infection, is helpful to guide anti-infection treatment. This review focuses on the role of gut microbiota and their metabolites in host defense against bacterial, fungal, and viral infections, and reveals that they can exert anti-infection effects through resistance mechanisms (inducing antimicrobial substances, training immunity, inhibiting pathogen respiration, directly neutralizing pathogens, immune regulation) and tolerance mechanisms (altering energy metabolism patterns of microbiota, cell proliferation and tissue damage repair, maintaining physiological signal transduction in extraintestinal organs, inflammation regulation, maintaining the integrity of the intestinal barrier), and also summarizes measures to regulate gut microbiota against pathogen infections, in order to provide more ideas for novel anti-infection prevention and treatment strategies targeting gut microbiota and its metabolites.