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1.
Life Sci ; 261: 118460, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32961234

RESUMO

AIMS: The hyperpermeability of gut-vascular barrier (GVB) plays a role in gut-derived sepsis. The goal of this study was to evaluate if berberine might improve hepatic apolipoprotein M (ApoM) generation and raise plasma ApoM level to protect the compromised GVB. MATERIALS AND METHODS: The compromised GVB was induced by sepsis. Hepatic ApoM mRNA and phosphoenolpyruvate carboxykinase (PEPCK) mRNA and plasma ApoM level were assayed by qRT-PCR and ELISA, respectively. The permeability of intestinal capillary in vivo and of rat intestinal microvascular endothelial cells (RIMECs) in vitro was assayed by FITC-dextran. The blood glucose was detected by a glucometer. Plasma insulin, TNF-α and IL-1ß were assayed by ELISA. The plasmalemma vesicle-associated protein-1 (PV1), ß-catenin and occludin in RIMECs were assayed by Western blot. KEY FINDINGS: Sepsis decreased hepatic ApoM mRNA and plasma ApoM level, but raised hepatic PEPCK mRNA and plasma glucose, insulin, TNF-α, and IL-1ß levels. The increased vascular endothelial permeability was abrogated by recombinant rat ApoM in vivo or ApoM-bound S1P in vitro. ApoM-bound S1P decreased PV1 but increased occludin and ß-catenin expression in LPS-treated RIMECs. Berberine in a dose-dependent manner raised hepatic ApoM mRNA and plasma ApoM level, but decreased septic hyperglycemia, insulin resistance and plasma TNF-α and IL-1ß levels. Berberine reduced sepsis-induced PEPCK and TLR4 mRNA overexpression in the liver. SIGNIFICANCE: This study demonstrated berberine inhibited TLR4-mediated hyperglycemia, insulin resistance and proinflammatory molecule production, thereby increasing ApoM gene expression and plasma ApoM. Berberine protected the damaged GVB via modulation of ApoM/S1P pathway.


Assuntos
Apolipoproteínas M/metabolismo , Berberina/uso terapêutico , Permeabilidade Capilar/efeitos dos fármacos , Lisofosfolipídeos/metabolismo , Sepse/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Esfingosina/análogos & derivados , Animais , Berberina/farmacologia , Modelos Animais de Doenças , Trato Gastrointestinal/irrigação sanguínea , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/fisiopatologia , Células Hep G2 , Humanos , Masculino , Ratos Wistar , Sepse/metabolismo , Sepse/fisiopatologia , Esfingosina/metabolismo
3.
J Nanobiotechnology ; 18(1): 130, 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32912236

RESUMO

Fast point-of-care (POC) diagnostics represent an unmet medical need and include applications such as lateral flow assays (LFAs) for the diagnosis of sepsis and consequences of cytokine storms and for the treatment of COVID-19 and other systemic, inflammatory events not caused by infection. Because of the complex pathophysiology of sepsis, multiple biomarkers must be analyzed to compensate for the low sensitivity and specificity of single biomarker targets. Conventional LFAs, such as gold nanoparticle dyed assays, are limited to approximately five targets-the maximum number of test lines on an assay. To increase the information obtainable from each test line, we combined green and red emitting quantum dots (QDs) as labels for C-reactive protein (CRP) and interleukin-6 (IL-6) antibodies in an optical duplex immunoassay. CdSe-QDs with sharp and tunable emission bands were used to simultaneously quantify CRP and IL-6 in a single test line, by using a single UV-light source and two suitable emission filters for readout through a widely available BioImager device. For image and data processing, a customized software tool, the MultiFlow-Shiny app was used to accelerate and simplify the readout process. The app software provides advanced tools for image processing, including assisted extraction of line intensities, advanced background correction and an easy workflow for creation and handling of experimental data in quantitative LFAs. The results generated with our MultiFlow-Shiny app were superior to those generated with the popular software ImageJ and resulted in lower detection limits. Our assay is applicable for detecting clinically relevant ranges of both target proteins and therefore may serve as a powerful tool for POC diagnosis of inflammation and infectious events.


Assuntos
Biomarcadores/análise , Proteína C-Reativa/análise , Imunoensaio/métodos , Interleucina-6/análise , Pontos Quânticos/química , Sepse/diagnóstico , Anticorpos/imunologia , Betacoronavirus/isolamento & purificação , Proteína C-Reativa/imunologia , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/virologia , Humanos , Interleucina-6/imunologia , Limite de Detecção , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/virologia , Sistemas Automatizados de Assistência Junto ao Leito , Sepse/metabolismo , Software , Raios Ultravioleta
4.
Proc Natl Acad Sci U S A ; 117(36): 22351-22356, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32826331

RESUMO

Cytokine release syndrome (CRS) is a life-threatening complication induced by systemic inflammatory responses to infections, including bacteria and chimeric antigen receptor T cell therapy. There are currently no immunotherapies with proven clinical efficacy and understanding of the molecular mechanisms of CRS pathogenesis is limited. Here, we found that patients diagnosed with CRS from sepsis, acute respiratory distress syndrome (ARDS), or burns showed common manifestations: strikingly elevated levels of the four proinflammatory cytokines interleukin (IL)-6, IL-8, monocyte chemotactic protein-1 (MCP-1), and IL-10 and the coagulation cascade activator plasminogen activator inhibitor-1 (PAI-1). Our in vitro data indicate that endothelial IL-6 trans-signaling formed an inflammation circuit for robust IL-6, IL-8, and MCP-1 production and promoted PAI-1 production; additionally, an IL-6 signaling blockade by the human monoclonal antibody tocilizumab blunted endothelial cell activation. Plasma from severe COVID-19 patients similarly exhibited increased IL-6, IL-10, and MCP-1 levels, but these levels were not as high as those in patients with CRS from other causes. In contrast, the PAI-1 levels in COVID-19 patients were as highly elevated as those in patients with bacterial sepsis or ARDS. Tocilizumab treatment decreased the PAI-1 levels and alleviated critical illness in severe COVID-19 patients. Our findings suggest that distinct levels of cytokine production are associated with CRS induced by bacterial infection and COVID-19, but both CRS types are accompanied by endotheliopathy through IL-6 trans-signaling. Thus, the present study highlights the crucial role of IL-6 signaling in endothelial dysfunction during bacterial infection and COVID-19.


Assuntos
Síndrome da Liberação de Citocina/metabolismo , Células Endoteliais/metabolismo , Interleucina-6/metabolismo , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Transdução de Sinais , Adulto , Idoso , Anticorpos Monoclonais Humanizados/uso terapêutico , Betacoronavirus , Queimaduras/metabolismo , Queimaduras/patologia , Células Cultivadas , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/patologia , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/patologia , Citocinas/sangue , Citocinas/metabolismo , Células Endoteliais/efeitos dos fármacos , Feminino , Humanos , Inflamação , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Pandemias , Inibidor 1 de Ativador de Plasminogênio/sangue , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/metabolismo , Pneumonia Viral/patologia , Receptores de Interleucina-6/antagonistas & inibidores , Receptores de Interleucina-6/metabolismo , Síndrome do Desconforto Respiratório do Adulto/metabolismo , Síndrome do Desconforto Respiratório do Adulto/patologia , Sepse/metabolismo , Sepse/patologia
5.
DNA Cell Biol ; 39(10): 1862-1871, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32845709

RESUMO

Sepsis is a life-threatening disorder and leads to organ dysfunction and death. Therefore, searching for more alternative biomarkers is of great significance for sepsis assessment and surveillance. In our study, the gene expression profiles of 163 samples from healthy controls and septic patients were analyzed and 8 gene co-expression modules were identified by constructing weighted gene co-expression network. The blue and yellow modules showed close correlations with the phenotypic trait "days postsepsis." Besides, differentially expressed genes (DEGs) over time in septic patients were screened using Short Time-series Expression Miner (STEM) program. The intersection of genes in the blue and yellow modules and DEGs, which were significantly enriched in "HTLV-1 infection" pathway, was analyzed with protein-protein interaction network. The logistic regression model based on these eight mRNAs was constructed to determine the type of the sample reliably. Eight vital genes CECR1, ANXA2, ELANE, CTSG, AZU1, PRTN3, LYZ, and DEFA4 presented high scores and may be associated with sepsis, which provided candidate biomarkers for sepsis.


Assuntos
Sepse/genética , Transcriptoma , Adenosina Desaminase/genética , Adenosina Desaminase/metabolismo , Anexina A2/genética , Anexina A2/metabolismo , Biomarcadores/metabolismo , Catepsina G/genética , Catepsina G/metabolismo , Redes Reguladoras de Genes , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Elastase de Leucócito/genética , Elastase de Leucócito/metabolismo , Mieloblastina/genética , Mieloblastina/metabolismo , Sepse/metabolismo , Sepse/patologia , Análise de Sobrevida , alfa-Defensinas/genética , alfa-Defensinas/metabolismo
6.
Brain Behav Immun ; 89: 480-490, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32717399

RESUMO

The incidence of infectious diseases affecting the central nervous system (CNS) has been increasing over the last several years. Among the reasons for the expansion of these diseases and the appearance of new neuropathogens are globalization, global warming, and the increased proximity between humans and wild animals due to human activities such as deforestation. Neurotropism affecting normal brain function is shared by organisms such as viruses, bacteria, fungi, and parasites. Neuroinfections caused by these agents activate immune responses, inducing neuroinflammation, excitotoxicity, and neurodegeneration. Purinergic signaling is an evolutionarily conserved signaling pathway associated with these neuropathologies. During neuroinfections, host cells release ATP as an extracellular danger signal with pro-inflammatory activities. ATP is metabolized to its derivatives by ectonucleotidases such as CD39 and CD73; ATP and its metabolites modulate neuronal and immune mechanisms through P1 and P2 purinergic receptors that are involved in pathophysiological mechanisms of neuroinfections. In this review we discuss the beneficial or deleterious effects of various components of the purinergic signaling pathway in infectious diseases that affect the CNS, including human immunodeficiency virus (HIV-1) infection, herpes simplex virus type 1 (HSV-1) infection, bacterial meningitis, sepsis, cryptococcosis, toxoplasmosis, and malaria. We also provide a description of this signaling pathway in emerging viral infections with neurological implications such as Zika and SARS-CoV-2.


Assuntos
Infecções do Sistema Nervoso Central/metabolismo , Receptores Purinérgicos P1/metabolismo , Receptores Purinérgicos P2X/metabolismo , Receptores Purinérgicos P2Y/metabolismo , Complexo AIDS Demência/metabolismo , Betacoronavirus , Infecções por Coronavirus/metabolismo , Encefalite por Herpes Simples/metabolismo , Humanos , Malária/metabolismo , Meningites Bacterianas/metabolismo , Meningite Criptocócica/metabolismo , Pandemias , Pneumonia Viral/metabolismo , Sepse/metabolismo , Transdução de Sinais , Toxoplasmose Cerebral/metabolismo , Infecção por Zika virus/metabolismo
7.
Int J Mol Sci ; 21(13)2020 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-32629817

RESUMO

By attaching to the angiotensin converting enzyme 2 (ACE2) protein on lung and intestinal cells, Sudden Acute Respiratory Syndrome (SARS-CoV-2) can cause respiratory and homeostatic difficulties leading to sepsis. The progression from acute respiratory failure to sepsis has been correlated with the release of high-mobility group box 1 protein (HMGB1). Lack of effective conventional treatment of this septic state has spiked an interest in alternative medicine. This review of herbal extracts has identified multiple candidates which can target the release of HMGB1 and potentially reduce mortality by preventing progression from respiratory distress to sepsis. Some of the identified mixtures have also been shown to interfere with viral attachment. Due to the wide variability in chemical superstructure of the components of assorted herbal extracts, common motifs have been identified. Looking at the most active compounds in each extract it becomes evident that as a group, phenolic compounds have a broad enzyme inhibiting function. They have been shown to act against the priming of SARS-CoV-2 attachment proteins by host and viral enzymes, and the release of HMGB1 by host immune cells. An argument for the value in a nonspecific inhibitory action has been drawn. Hopefully these findings can drive future drug development and clinical procedures.


Assuntos
Betacoronavirus/fisiologia , Proteína HMGB1/metabolismo , Insuficiência Respiratória/patologia , Sepse/patologia , Proteína HMGB1/antagonistas & inibidores , Humanos , Macrófagos/citologia , Macrófagos/metabolismo , Macrófagos/virologia , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Exsudatos de Plantas/química , Exsudatos de Plantas/farmacologia , Plantas Medicinais/química , Plantas Medicinais/metabolismo , Insuficiência Respiratória/metabolismo , Insuficiência Respiratória/prevenção & controle , Sepse/metabolismo , Sepse/prevenção & controle , Internalização do Vírus/efeitos dos fármacos
8.
Life Sci ; 258: 118161, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32730835

RESUMO

AIMS: Tubulointerstitial inflammation is recognized as a key determinant of progressive sepsis-induced acute kidney injury (AKI). Schisantherin A (SchA) has been shown to be capable of regulating inflammatory processes. In the present study, we explored the possibility of SchA in preventing lipopolysaccharide (LPS)-induced kidney inflammation and injury. MATERIALS AND METHODS: AKI was induced by a single intraperitoneal injection of LPS in CD1 mice, administration of SchA was used for treatment. The protective effect of SchA on renal function and inflammation were analyzed respectively; the NRK-52E cell line was employed for the in vitro study and relative molecular mechanism was explored. KEY FINDINGS: Administration with SchA markedly attenuated LPS-induced damage on renal function and histopathological changes of the kidney. Additionally, pretreatment with SchA could inhibit the expression of inflammatory factors in the kidneys. In NRK-52E cells, SchA treatment significantly inhibited LPS-induced NF-κB activation and pro-inflammatory cytokine expression. Moreover, SchA could promote NRF2 pathway activation, and further blockade of NRF2 activation reversed the SchA-induced inhibition of NF-κB activation. SIGNIFICANCE: These presented results indicated that SchA may have great potential for protecting against sepsis-induced AKI.


Assuntos
Lesão Renal Aguda/tratamento farmacológico , Lesão Renal Aguda/etiologia , Anti-Inflamatórios/uso terapêutico , Ciclo-Octanos/uso terapêutico , Dioxóis/uso terapêutico , Lignanas/uso terapêutico , Fator 2 Relacionado a NF-E2/metabolismo , Sepse/complicações , Lesão Renal Aguda/metabolismo , Lesão Renal Aguda/patologia , Animais , Linhagem Celular , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Masculino , Camundongos , Ratos , Sepse/tratamento farmacológico , Sepse/metabolismo , Sepse/patologia , Transdução de Sinais/efeitos dos fármacos
9.
PLoS One ; 15(7): e0236038, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32658933

RESUMO

The attenuation of hyper-inflammation in sepsis with the administration of anti-inflammatory macrophages is an interesting adjuvant therapy for sepsis. Because the induction of anti-inflammatory macrophages by microRNA (miR), a regulator of mRNA, has been mentioned, the exploration on miR-induced anti-inflammatory macrophages was performed. The over-expression of miR-223 and miR-146a in RAW264.7 induced M2 macrophage-polarization (anti-inflammatory macrophages) as evaluated by the enhanced expression of Arginase-1 and Fizz. However, miR-223 over-expressed cells demonstrated the more potent anti-inflammatory property against LPS stimulation as lesser iNOS expression, lower supernatant IL-6 and higher supernatant IL-10 compared with miR-146a over-expressed cells. Interestingly, LPS stimulation in miR-223 over-expressed cells, compared with LPS-stimulated control cells, demonstrated lower activity of glycolysis pathway and higher mitochondrial respiration, as evaluated by the extracellular flux analysis, and also down-regulated HIF-1α, an important enzyme of glycolysis pathway. In addition, the administration of miR-223 over-expressed macrophages with IL-4 pre-conditioning, but not IL-4 stimulated control cells, attenuated sepsis severity in LPS injected mice as evaluated by serum creatinine, liver enzymes, lung histology and serum cytokines. In conclusion, miR-223 interfered with the glycolysis pathway through the down-regulation of HIF-1α, resulting in the anti-inflammatory status. The over-expression of miR-223 in macrophages prevented the conversion into M1 macrophage polarization after LPS stimulation. The administration of miR-223 over-expressed macrophages, with IL-4 preconditioning, attenuated sepsis severity in LPS model. Hence, a proof of concept in the induction of anti-inflammatory macrophages through the cell-energy interference for sepsis treatment was proposed as a basis of cell-based therapy in sepsis.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos/métodos , Glicólise , Inflamação/prevenção & controle , Lipopolissacarídeos/toxicidade , Macrófagos/transplante , MicroRNAs/genética , Sepse/prevenção & controle , Animais , Modelos Animais de Doenças , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Ativação de Macrófagos , Macrófagos/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sepse/induzido quimicamente , Sepse/metabolismo , Sepse/patologia
10.
Gene ; 755: 144897, 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32561323

RESUMO

The integrity of the intestinal barrier is critical for protecting the host against the intestinal lumen and pathogens. The roles of circRNAs in the intestinal barrier dysfunction in sepsis remained unclear. The present study aims to investigate the role of circ_0001105 in the intestinal mucosal permeability, oxidative damage and morphological changes during sepsis. We found that upregulation of circ_0001105 decreased the levels of serum D-lactic acid, diamine oxidase and fluorescence isothiocyanate dextran in septic rats. Upregulation of circ_0001105 also decreased the malondialdehyde content but enhanced superoxide dismutase activity in the intestinal tissues. Upregulation of circ_0001105 reduced the production of tumor necrosis factor α, interleukin (IL)-6, and IL-1ß and the expression of YAP1. Furthermore, upregulation of circ_0001105 improved the survival of rats with sepsis. In summary, our findings showed that circ_0001105 protects the intestinal barrier function of septic rats by inhibiting intestinal inflammation, oxidative damage and YAP1 expression. Our results provide a novel insight for developing sepsis treatment.


Assuntos
Proteínas Reguladoras de Apoptose/biossíntese , Mucosa Intestinal/metabolismo , RNA Circular/metabolismo , Sepse/metabolismo , Amina Oxidase (contendo Cobre)/sangue , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Regulação para Baixo , Inflamação/genética , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Perfuração Intestinal/metabolismo , Ácido Láctico/sangue , Masculino , Estresse Oxidativo/fisiologia , Permeabilidade , RNA Circular/biossíntese , RNA Circular/genética , Ratos , Ratos Sprague-Dawley , Sepse/genética , Fator de Necrose Tumoral alfa/metabolismo
11.
PLoS One ; 15(6): e0234039, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32555710

RESUMO

Sepsis is characterized by organ dysfunction due to a dysregulated immune response to infection. Currently, no effective treatment for sepsis exists. Platelets are recognized as mediators of the immune response and may be a potential therapeutic target for the treatment of sepsis. We previously demonstrated that NLRP3 inflammasome activation in sepsis-induced activated platelets was associated with multi-organ injury in the cecal-ligation puncture (CLP) rat model of sepsis. In this study, we tested the hypothesis that inhibition of NLRP3 would inhibit platelet activation and attenuate multi-organ injury in the CLP rat. CLP (n = 10) or Sham (n = 10) surgery were performed in male and female Sprague-Dawley rats. A subset of CLP rats were treated with MCC950 (50mg/kg/d), a specific NLRP3 inhibitor (CLP+MCC950, n = 10). At 72 hrs. post-CLP, blood and organs were harvested for analysis of platelet activation, NLRP3 activation, inflammation and end organ damage. Platelet activation increased from 8±0.8% in Sham to 16±1% in CLP, and was reduced to 9±1% in CLP+M rats (p<0.05). NLRP3 activation was also increased in platelets of CLP vs Sham. NLRP3 expression was unchanged in kidney and lung after CLP, but Caspase 1 expression and IL-1ß were increased. MCC950 treatment attenuated NLRP3 activation in platelets. Plasma, kidney, and lung levels of NLRP3 inflammasome associated cytokines, IL-1ß and IL-18, were significantly increased in CLP compared to Sham rats. Inhibition of NLRP3 normalized cytokine levels. Glomerular injury, pulmonary edema, and endothelial dysfunction markers were increased in CLP rats vs Sham. MCC950 treatment significantly decreased renal and pulmonary injury and endothelial dysfunction in CLP+M. Our results demonstrate a role for NLRP3 in contributing to platelet activation and multi-organ injury in sepsis.


Assuntos
Ceco/cirurgia , Inflamassomos/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Ativação Plaquetária/efeitos dos fármacos , Punções/efeitos adversos , Sepse/tratamento farmacológico , Sepse/fisiopatologia , Animais , Caspase 1/metabolismo , Citocinas/metabolismo , Endotélio/efeitos dos fármacos , Endotélio/metabolismo , Feminino , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/fisiopatologia , Ligadura/efeitos adversos , Masculino , Permeabilidade/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica/efeitos dos fármacos , Sepse/metabolismo
13.
Am J Physiol Renal Physiol ; 319(2): F229-F244, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32538150

RESUMO

Sepsis-associated acute kidney injury (s-AKI) has a staggering impact in patients and lacks any treatment. Incomplete understanding of the pathogenesis of s-AKI is a major barrier to the development of effective therapies. We address the gaps in knowledge regarding renal oxygenation, tubular metabolism, and mitochondrial function in the pathogenesis of s-AKI using the cecal ligation and puncture (CLP) model in mice. At 24 h after CLP, renal oxygen delivery was reduced; however, fractional oxygen extraction was unchanged, suggesting inefficient renal oxygen utilization despite decreased glomerular filtration rate and filtered load. To investigate the underlying mechanisms, we examined temporal changes in mitochondrial function and metabolism at 4 and 24 h after CLP. At 4 h after CLP, markers of mitochondrial content and biogenesis were increased in CLP kidneys, but mitochondrial oxygen consumption rates were suppressed in proximal tubules. Interestingly, at 24 h, proximal tubular mitochondria displayed high respiratory capacity, but with decreased mitochondrial content, biogenesis, fusion, and ATP levels in CLP kidneys, suggesting decreased ATP synthesis efficiency. We further investigated metabolic reprogramming after CLP and observed reduced expression of fatty acid oxidation enzymes but increased expression of glycolytic enzymes at 24 h. However, assessment of functional glycolysis revealed lower glycolytic capacity, glycolytic reserve, and compensatory glycolysis in CLP proximal tubules, which may explain their susceptibility to injury. In conclusion, we demonstrated significant alterations in renal oxygenation, tubular mitochondrial function, and metabolic reprogramming in s-AKI, which may play an important role in the progression of injury and recovery from AKI in sepsis.


Assuntos
Lesão Renal Aguda/patologia , Rim/lesões , Mitocôndrias/metabolismo , Sepse/complicações , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/metabolismo , Animais , Modelos Animais de Doenças , Rim/metabolismo , Túbulos Renais Proximais/metabolismo , Camundongos Endogâmicos C57BL , Sepse/metabolismo
14.
Mol Immunol ; 123: 97-105, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32474254

RESUMO

Myeloid-derived suppressor cells (MDSCs) contribute to high mortality rates during sepsis, but how sepsis induces MDSCs is unclear. Previously we reported that microRNA (miR)-21 and miR-181b reprogram MDSCs in septic mice by increasing levels of DNA binding transcription factor, nuclear factor 1 (NFI-A). Here, we provide evidence that miR-21 and miR-181b stabilize NFI-A mRNA and increase NFI-A protein levels by recruiting RNA-binding proteins HuR and Ago1 to its 3' untranslated region (3'UTR). We also find that the NFI-A GU-rich element (GRE)-binding protein CUGBP1 counters miR-21 and miR-181b dependent NFI-A mRNA stabilization and decreases protein production by replacing 3'UTR bound Ago1 with Ago2. We confirmed the miR-21 and miR-181b dependent reprogramming pathway in MDSCs transfected with a luciferase reporter construct containing an NFI-A 3'UTR fragment with point mutations in the miRNA binding sites. These results suggest that targeting NFI-A in MDSCs during sepsis may enhance resistance to uncontrolled infection.


Assuntos
Proteína Semelhante a ELAV 1/fisiologia , MicroRNAs/fisiologia , Células Supressoras Mieloides/metabolismo , Fatores de Transcrição NFI/genética , Sepse/genética , Animais , Células Cultivadas , Masculino , Camundongos , Camundongos Endogâmicos BALB C , MicroRNAs/genética , Células Supressoras Mieloides/patologia , Fatores de Transcrição NFI/metabolismo , Sepse/metabolismo , Sepse/patologia , Ativação Transcricional , Regulação para Cima/genética
15.
Am J Physiol Lung Cell Mol Physiol ; 319(2): L228-L238, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32460519

RESUMO

Clinical studies indicate that sepsis-induced diaphragm dysfunction is a major contributor to respiratory failure in mechanically ventilated patients. Currently there is no drug to treat this form of diaphragm weakness. Sepsis-induced muscle dysfunction is thought to be triggered by excessive mitochondrial free radical generation; we therefore hypothesized that therapies that target mitochondrial free radical production may prevent sepsis-induced diaphragm weakness. The present study determined whether MitoTEMPOL, a mitochondrially targeted free radical scavenger, could reduce sepsis-induced diaphragm dysfunction. Using an animal model of sepsis, we compared four groups of mice: 1) sham-operated controls, 2) animals with sepsis induced by cecal ligation puncture (CLP), 3) sham controls given MitoTEMPOL (10 mg·kg-1·day-1 ip), and 4) CLP animals given MitoTEMPOL. At 48 h after surgery, we measured diaphragm force generation, mitochondrial function, proteolytic enzyme activities, and myosin heavy chain (MHC) content. We also examined the effects of delayed administration of MitoTEMPOL (by 6 h) on CLP-induced diaphragm weakness. The effects of MitoTEMPOL on cytokine-mediated alterations on muscle cell superoxide generation and cell size in vitro were also assessed. Sepsis markedly reduced diaphragm force generation. Both immediate and delayed MitoTEMPOL administration prevented sepsis-induced diaphragm weakness. MitoTEMPOL reversed sepsis-mediated reductions in mitochondrial function, activation of proteolytic pathways, and decreases in MHC content. Cytokines increased muscle cell superoxide generation and decreased cell size, effects that were ablated by MitoTEMPOL. MitoTEMPOL and other compounds that target mitochondrial free radical generation may be useful therapies for sepsis-induced diaphragm weakness.


Assuntos
Antioxidantes/farmacologia , Diafragma/efeitos dos fármacos , Depuradores de Radicais Livres/farmacologia , Mitocôndrias/efeitos dos fármacos , Debilidade Muscular/etiologia , Debilidade Muscular/prevenção & controle , Sepse/complicações , Animais , Ceco/efeitos dos fármacos , Ceco/metabolismo , Citocinas/metabolismo , Diafragma/metabolismo , Modelos Animais de Doenças , Ligadura/métodos , Masculino , Camundongos , Mitocôndrias/metabolismo , Debilidade Muscular/metabolismo , Cadeias Pesadas de Miosina/metabolismo , Proteólise/efeitos dos fármacos , Sepse/metabolismo
16.
PLoS One ; 15(5): e0233738, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32470072

RESUMO

Sepsis is an important cause of morbidity and mortality in pediatric patients. Increased expression of olfactomedin-4 (OLFM4), a glycoprotein contained within a subpopulation of neutrophils, has been associated with complicated course in sepsis. The factors that regulate OLFM4 expression are unknown. Here, we followed children undergoing bone marrow transplantation (BMT) to document the percentage of neutrophils that express OLFM4 over time. This population was selected because of the ability to observe nascent neutrophils following engraftment, perform frequent blood sampling, and the children are at high risk for clinical complications that may associate with changes in percentage of OLFM4+ neutrophils. We found a surprising degree of variability of OLFM4 expression between patients. In the weeks following initial neutrophil recovery we also saw great variability in OLFM4 expression within individual patients, indicating that multiple external factors may modify OLFM4 expression. We identified decreased expression of CD64 (a marker associated with response to infection), in OLFM4+ neutrophils. This is the first study to demonstrate fluctuation in OLFM4 expression within patients and provides insight into possible mechanisms for OLFM4 regulation in nascent neutrophils.


Assuntos
Biomarcadores/metabolismo , Transplante de Medula Óssea/efeitos adversos , Fator Estimulador de Colônias de Granulócitos/metabolismo , Neutrófilos/metabolismo , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , Masculino , Neutrófilos/patologia , Receptores de IgG/metabolismo , Sepse/etiologia , Sepse/metabolismo , Adulto Jovem
17.
Am J Physiol Renal Physiol ; 319(1): F8-F18, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32421349

RESUMO

Sepsis is the leading cause of acute kidney injury in critically ill patients. Tumor necrosis factor-α (TNF-α) has been implicated in the pathogenesis of septic kidney injury; however, the sites and mechanisms of renal TNF-α production during sepsis remain to be defined. In the present study, we showed that TNF-α expression is increased in medullary thick ascending limbs (MTALs) of mice with sepsis induced by cecal ligation and puncture. Treatment with lipopolysaccharide (LPS) for 3 h in vitro also increased MTAL TNF-α production. Sepsis and LPS increased MTAL TNF-α expression through activation of the myeloid differentiation factor 88 (MyD88)-IL-1 receptor-associated kinase 1-ERK signaling pathway. Pretreatment with monophosphoryl lipid A (MPLA), a nontoxic immunomodulator that protects against bacterial infection, eliminated the sepsis- and LPS-induced increases in MTAL TNF-α production. The suppressive effect of MPLA on TNF-α was mediated through activation of a phosphatidylinositol 3-kinase-dependent pathway that inhibits MyD88-dependent ERK activation. This likely involves MPLA-phosphatidylinositol 3-kinase-mediated induction of Tollip, which negatively regulates the MyD88-ERK pathway by inhibiting activation of IL-1 receptor-associated kinase 1. These regulatory mechanisms are similar to those previously shown to mediate the effect of MPLA to prevent sepsis-induced inhibition of MTAL [Formula: see text] absorption. These results identify the MTAL as a site of local TNF-α production in the kidney during sepsis and identify molecular mechanisms that can be targeted to attenuate renal TNF-α expression. The ability of MPLA pretreatment to suppress MyD88-dependent ERK signaling in the MTAL during sepsis has the dual beneficial effects of protecting tubule transport functions and attenuating harmful proinflammatory responses.


Assuntos
Citocinas/metabolismo , Medula Renal/efeitos dos fármacos , Lipídeo A/análogos & derivados , Alça do Néfron/efeitos dos fármacos , Sepse/metabolismo , Animais , Medula Renal/metabolismo , Lipídeo A/farmacologia , Lipopolissacarídeos/farmacologia , Alça do Néfron/metabolismo , Masculino , Camundongos , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Transdução de Sinais/efeitos dos fármacos
18.
Genes Cells ; 25(7): 443-449, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32394600

RESUMO

Histamine is a bioactive monoamine that is synthesized by the enzymatic activity of histidine decarboxylase (HDC) in basophils, mast cells, gastric enterochromaffin-like (ECL) cells and histaminergic neuronal cells. Upon a series of cellular stimuli, these cells release stored histamine, which elicits allergies, inflammation, and gastric acid secretion and regulates neuronal activity. Recent studies have shown that certain other types of myeloid lineage cells also produce histamine with HDC induction under various pathogenic stimuli. Histamine has been shown to play a series of pathophysiological roles by modulating immune and inflammatory responses in a number of disease conditions, whereas the mechanistic aspects underlying induced HDC expression remain elusive. In the present review, we summarize the current understanding of the regulatory mechanism of Hdc gene expression and the roles played by histamine in physiological contexts as well as pathogenic processes. We also introduce a newly developed histaminergic cell-monitoring transgenic mouse line (Hdc-BAC-GFP) that serves as a valuable experimental tool to identify the source of histamine and dissect upstream regulatory signals.


Assuntos
Histamina/metabolismo , Histidina Descarboxilase/metabolismo , Receptores Histamínicos/metabolismo , Sepse/imunologia , Animais , Cromossomos Artificiais Bacterianos , Regulação Enzimológica da Expressão Gênica/imunologia , Histamina/fisiologia , Histidina Descarboxilase/genética , Histonas/metabolismo , Metilação , Camundongos , Camundongos Transgênicos , Células Mieloides/metabolismo , Sepse/metabolismo
19.
Crit Care ; 24(1): 134, 2020 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-32264946

RESUMO

High-density lipoproteins (HDLs) represent a family of particle characterized by the presence of apolipoprotein A-I (apoA-I) and by their ability to transport cholesterol from peripheral tissues back to the liver conferring them a cardioprotective function. HDLs also display pleiotropic properties including antioxidant, anti-apoptotic, anti-thrombotic, anti-inflammatory, or anti-infectious functions. Clinical data demonstrate that HDL cholesterol levels decrease rapidly during sepsis and that these low levels are correlated with morbi-mortality. Experimental studies emphasized notable structural and functional modifications of HDL particles in inflammatory states, including sepsis. Finally, HDL infusion in animal models of sepsis improved survival and provided a global endothelial protective effect. These clinical and experimental studies reinforce the potential of HDL therapy in human sepsis. In this review, we will detail the different effects of HDLs that may be relevant under inflammatory conditions and the lipoprotein changes during sepsis and we will discuss the potentiality of HDL therapy in sepsis.


Assuntos
Lipoproteínas HDL/fisiologia , Sepse/metabolismo , Sepse/terapia , Animais , Anti-Inflamatórios , Apolipoproteína A-I , Modelos Animais de Doenças , Humanos , Sepse/imunologia
20.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 36(1): 20-25, 2020 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-32314720

RESUMO

Objective To investigate the role of CXCR2 in the cerebral endothelial activation and migration of neutrophils into the brain in septic encephalopathy (SE) induced by lipopolysaccharide (LPS). Methods C57BL/6J mice and CXCR2-knockout mice were randomly divided into a normal control group, a wildtype mice group with LPS treatment and CXCR2-knockout mice group with LPS treatment. Mouse SE models were induced by intraperitoneal LPS injection. Naphthol AS-D chloroacetate histochemical staining of the brain section was performed to quantitate the neutrophils infiltrating into the cerebral cortex. TNF-α and CXCL1 concentrations in the brain and plasma were determined by ELISA. After the stimulation of LPS (1 µg/mL) and TNF-α (200 ng/mL), the levels of CXCR2 protein in the primary mouse brain microvascular endothelial cells isolated from the cerebral cortex were detected by Western blotting. The levels of F-actin and vascular cell adhesion molecule 1 (VCAM-1) protein in the primary mouse brain microvascular endothelial cells stimulated by CXCL1 (100 ng/mL) were detected by Western blotting. Results After intraperitoneal LPS injection, there was a significant increase in the level of TNF-α in the brain and plasma and there was also an evident increase in the level of CXCL1 in the brain of wild type mice (C57BL/6J mice). And intraperitoneal LPS injection caused increased neutrophil infiltration into the cerebral cortex in the wild type mice (C57BL/6J mice). But CXCR2-knockout mice displayed evidently reduced neutrophil infiltration into the cerebral cortex compared with the wildtype mice. In vitro LPS and TNF-α upregulated the expression of CXCR2 in the primary brain microvascular endothelial cells. CXCL1 increased remarkably the expression of endothelial F-actin and VCAM-1. Conclusion In the SE model, CXCR2 participates in the cerebral endothelial activation and neutrophil migration into the brain.


Assuntos
Encefalopatias/metabolismo , Movimento Celular , Células Endoteliais/citologia , Neutrófilos/citologia , Receptores de Interleucina-8B/metabolismo , Sepse/metabolismo , Actinas/metabolismo , Animais , Encefalopatias/patologia , Lipopolissacarídeos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Distribuição Aleatória , Sepse/patologia , Molécula 1 de Adesão de Célula Vascular/metabolismo
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