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1.
Allergol Immunopathol (Madr) ; 50(5): 121-128, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36086972

RESUMO

BACKGROUND: Sepsis-induced acute lung injury (ALI) is a syndrome associated with inflammation. Cornus iridoid glycoside (CIG), a bioactive component isolated from Corni Fructus, exhibits anti-inflammatory activities. However, the function and underlying mechanisms of CIG in mice with sepsis-induced ALI remain elusive. METHODS: The sepsis-elicited ALI model of mice was established by the induction of cecal ligation and puncture (CLP). The wet/dry (W/D) ratio of lung tissues was examined, and the pathological alterations were determined by hematoxylin and eosin staining. The messenger RNA (mRNA) expressions and serum levels of Interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α (TNF-α) were measured by reverse transcription-quantitative polymerase chain reaction and enzyme-linked immunosorbent serologic assay, respectively. The concentrations of malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) were assessed by biochemical kits. In addition, the relative protein levels of p-p65, p65, phosphorylated- nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (p-IκBα), IκBα, nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) gene were analyzed by Western blotting analysis. RESULTS: CLP enhanced W/D ratio and aggravated pathological changes and scores in mice, which were obviously alleviated by the two concentrations of CIG treatment. CIG treatment notably decreased the CLP-induced mRNA expressions and serum levels of IL-1ß, IL-6, TNF-α, and MDA, but enhanced the decreased concentrations (caused by CLP) of SOD and GSH-Px. Moreover, CIG treatment significantly decreased the ratios of p65/p-p65 and IκBα/p-IκBα caused by CLP, but aggravated the CLP-induced relative protein levels of Nrf2 and HO-1. CONCLUSIONS: CIG obviously ameliorated the sepsis-induced ALI in mice by suppressing inflammation and oxidative stress, which was closely associated with nuclear factor kappa B (NF-κB) and Nrf2-HO-1 signaling pathways.


Assuntos
Lesão Pulmonar Aguda , Cornus , Sepse , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/etiologia , Animais , Cornus/genética , Cornus/metabolismo , Inflamação/complicações , Interleucina-6 , Glicosídeos Iridoides/efeitos adversos , Iridoides/efeitos adversos , Camundongos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Inibidor de NF-kappaB alfa , NF-kappa B/metabolismo , RNA Mensageiro , Sepse/complicações , Sepse/tratamento farmacológico , Sepse/patologia , Superóxido Dismutase/efeitos adversos , Fator de Necrose Tumoral alfa
2.
Allergol. immunopatol ; 50(5): 121-128, sept. 2022. ilus, graf
Artigo em Inglês | IBECS | ID: ibc-ADZ-13

RESUMO

Background: Sepsis-induced acute lung injury (ALI) is a syndrome associated with inflamma-tion. Cornus iridoid glycoside (CIG), a bioactive component isolated from Corni Fructus, exhibits anti-inflammatory activities. However, the function and underlying mechanisms of CIG in mice with sepsis-induced ALI remain elusive.Methods: The sepsis-elicited ALI model of mice was established by the induction of cecal ligation and puncture (CLP). The wet/dry (W/D) ratio of lung tissues was examined, and the pathological alterations were determined by hematoxylin and eosin staining. The messenger RNA (mRNA) expressions and serum levels of Interleukin (IL)-1Beta IL-6, and tumor necrosis factor-alfa(TNF-alpha) were measured by reverse transcription-quantitative polymerase chain reaction and enzyme-linked immunosorbent serologic assay, respectively. The concentrations of malondial-dehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) were assessed by biochemical kits. In addition, the relative protein levels of p-p65, p65, phosphorylated-nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (p-IκBalpha), IκBalpha, nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) gene were analyzed by Western blotting analysis.Results: CLP enhanced W/D ratio and aggravated pathological changes and scores in mice, which were obviously alleviated by the two concentrations of CIG treatment. CIG treatment notably decreased the CLP-induced mRNA expressions and serum levels of IL-1Beta, IL-6, TNF-alpha, and MDA, but enhanced the decreased concentrations (caused by CLP) of SOD and GSH-Px. Moreover, CIG treatment significantly decreased the ratios of p65/p-p65 and IκBα/p-IκBalpha caused by CLP, but...(AU)


Assuntos
Animais , Masculino , Camundongos , Lesão Pulmonar Aguda , Cornus , Sepse , Modelos Animais , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/etiologia , Cornus/genética , Cornus/metabolismo , Inflamação/complicações , Interleucina-6 , Glucosídeos Iridoides/efeitos adversos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Inibidor de NF-kappaB alfa/metabolismo , RNA Mensageiro , Sepse/complicações , Sepse/tratamento farmacológico , Sepse/patologia , Superóxido Dismutase/efeitos adversos
3.
Front Cell Infect Microbiol ; 12: 854126, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36061862

RESUMO

The pathophysiology of sepsis and its accompanying hyper-inflammatory response are key events that lead to multi-organ failure and death. A growing body of literature now suggests that the vascular endothelium plays a critical role in driving early events of sepsis progression. In this study, we demonstrate how endothelial-derived exosomes contribute to a successive pro-inflammatory phenotype of monocytes. Exosomes isolated from S. aureus infected endothelial cells drive both CD11b and MHCII expression in monocytes and contribute dysregulated cytokine production. Conversely, healthy endothelial exosomes had no major effect. microRNA (miRNA) profiling of exosomes identified miR-99 upregulation which we hypothesised as driving this phenotypic change through mechanistic target of rapamycin (mTOR). Knockdown of mTOR with miR-99a and miR-99b mimetics in S. aureus infected monocytes increased IL-6 and decreased IL-10 production. Interestingly, inhibition of miRNAs with antagomirs has the opposing effect. Collectively, endothelial exosomes are driving a pro-inflammatory phenotype in monocytes through dysregulated expression of miR-99a and miR-99b.


Assuntos
Exossomos , MicroRNAs/metabolismo , Sepse , Serina-Treonina Quinases TOR/genética , Células Endoteliais/metabolismo , Exossomos/metabolismo , Humanos , MicroRNAs/genética , Sepse/genética , Sepse/metabolismo , Sepse/patologia , Staphylococcus aureus/genética
4.
J Int Med Res ; 50(9): 3000605221118680, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36071631

RESUMO

OBJECTIVE: Sepsis is a systemic and deleterious host reaction to severe infection. Cardiac dysfunction is an established serious outcome of multiorgan failure associated with this condition. Therefore, it is important to develop drugs targeting sepsis-induced cardiac damage and inflammation. Thymoquinone (TQ) has anti-inflammatory, anti-oxidant, anti-fibrotic, anti-tumor, and anti-apoptotic effects. This study examined the effects of thymoquinone on sepsis-induced cardiac damage. METHODS: Male BALB/c mice were randomly segregated into four groups: control, TQ, cecal ligation and puncture (CLP), and CLP + TQ groups. CLP was performed after gavaging the mice with TQ for 2 weeks. After 48 hours, we estimated the histopathological changes in the cardiac tissue and the serum levels of cardiac troponin-T. We evaluated the expression of factors associated with inflammation, apoptosis, oxidative stress, and the PI3K/AKT pathway. RESULTS: TQ significantly reduced intestinal histological alterations and inhibited the upregulation of interleukin-6, tumor necrosis factor-α, Bax, NOX4, p-PI3K, and p-AKT. TQ also increased Bcl-2, HO-1, and NRF2 expression. CONCLUSION: These results suggest that TQ effectively modulates pro-inflammatory, apoptotic, oxidative stress, and PI3K/AKT pathways, making it indispensable in the treatment of sepsis-induced cardiac damage.


Assuntos
Fosfatidilinositol 3-Quinases , Sepse , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Benzoquinonas , Inflamação/complicações , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sepse/complicações , Sepse/tratamento farmacológico , Sepse/patologia
5.
Mediators Inflamm ; 2022: 8950130, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35979014

RESUMO

Background: Sepsis is a systemic inflammatory response that can elicit organ dysfunction as well as circulatory diseases in serious cases. When inflammatory responses are especially dysregulated, severe complications can arise, including sepsis-induced liver injury. Various microRNAs along with circular (circ) RNAs are involved in inflammatory responses; nevertheless, their functions in regulating sepsis-induced liver injury remain unknown. The cecal ligation and puncture (CLP) procedure can induce liver injury as well as polymicrobial sepsis. Methods: In this study, CLP was used to induce liver injury as well as polymicrobial sepsis. Then, liver function, inflammatory cytokine expression, and hepatic histopathology were evaluated. High-throughput sequencing was employed to investigate the abnormal hepatic circRNA expression after CLP. Raw264.7 cells were utilized to simulation an in vitro sepsis inflammation model with LPS induce. The relative mRNA as well as protein levels of TNF-α, IL-1ß, and IL-6 was explored by quantitative polymerase chain reaction (PCR) and enzyme-linked immunosorbent assays. We explored functional connections among circRNAs, miR-31-5p, and gasdermin D (GSDMD) using dual-luciferase reporter assays. Western blot was employed to test GSDMD, caspase-1, and NLRP3 expression in mice and cell models. Results: Our results showed that CLP-induced sepsis promoted liver injury via increasing inflammatory pyroptosis. The abnormal expression of circ-Katnal1 played an important role in CLP-induced sepsis. Downregulating circ-Katnal1 suppressed LPS-induced inflammatory pyroptosis in Raw264.7 cells. Bioinformatics and luciferase reporter results confirmed that miR-31-5p and GSDMD were downstream targets of circ-Katnal1. Inhibiting miR-31-5p or upregulating GSDMD reversed the protective effects of silencing circ-Katnal1. Conclusion: Taken together, circ-Katnal1 enhanced inflammatory pyroptosis in sepsis-induced liver injury through the miR-31-5p/GSDMD axis.


Assuntos
Doença Hepática Crônica Induzida por Substâncias e Drogas , Katanina/genética , MicroRNAs , Sepse , Animais , Apoptose , Katanina/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Piroptose , RNA Circular/genética , Sepse/patologia
6.
Front Immunol ; 13: 929316, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35958583

RESUMO

Sepsis-associated encephalopathy (SAE) is a cognitive impairment associated with sepsis that occurs in the absence of direct infection in the central nervous system or structural brain damage. Microglia are thought to be macrophages of the central nervous system, devouring bits of neuronal cells and dead cells in the brain. They are activated in various ways, and microglia-mediated neuroinflammation is characteristic of central nervous system diseases, including SAE. Here, we systematically described the pathogenesis of SAE and demonstrated that microglia are closely related to the occurrence and development of SAE. Furthermore, we comprehensively discussed the function and phenotype of microglia and summarized their activation mechanism and role in SAE pathogenesis. Finally, this review summarizes recent studies on treating cognitive impairment in SAE by blocking microglial activation and toxic factors produced after activation. We suggest that targeting microglial activation may be a putative treatment for SAE.


Assuntos
Disfunção Cognitiva , Encefalopatia Associada a Sepse , Sepse , Encéfalo/patologia , Disfunção Cognitiva/patologia , Humanos , Microglia/patologia , Sepse/complicações , Sepse/patologia , Encefalopatia Associada a Sepse/patologia , Encefalopatia Associada a Sepse/terapia
7.
Mediators Inflamm ; 2022: 7659282, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35935811

RESUMO

Human neutrophil peptides 1-3 (HNP1-3), also known as human α-defensins, are the most abundant neutrophil granule proteins. The genes that encode HNP1-3, DEFA1/DEFA3, exhibit extensive copy number variations, which correlate well with their protein levels. Human and mouse studies have shown that increased copy numbers of DEFA1/DEFA3 worsen sepsis outcomes. Additionally, high concentrations of HNP1-3 in body fluids have been reported in patients with sepsis. However, direct evidence for the pathogenic role of HNP1-3 proteins during sepsis progression is lacking. In current study, sepsis was induced by means of cecal puncture and ligation. Various doses of HNP-1 (low dose with 0.5 mg/kg body weight and high dose with 10 mg/kg body weight) or phosphate buffer saline were intraperitoneally administered to mice at six hours after sepsis onset. Survival rate was monitored, and vascular permeability, endothelial cell pyroptosis, and immunofluorescence of endothelial adherens junction protein vascular endothelial-cadherin were evaluated. The administration of a high dose of HNP-1 after sepsis onset led to increased mortality, more severe liver injury, and increased vascular permeability in the liver and mesentery. The injection of high dose of HNP-1 did not directly induce liver endothelial cell death but destroyed interendothelial junctions in the liver. Moreover, genetic deficiency of nucleotide-binding oligomerization domain-like receptor protein-3 or caspase-1 abrogated the high mortality and disrupted liver interendothelial junctions caused by high dose of HNP-1 during sepsis. This study directly demonstrates that neutrophil defensins play a key role in regulating endothelial stability during sepsis development.


Assuntos
Sepse , alfa-Defensinas , Animais , Peso Corporal , Variações do Número de Cópias de DNA , Defensinas , Humanos , Fígado/patologia , Camundongos , Neutrófilos , Sepse/patologia , alfa-Defensinas/genética
8.
Mol Immunol ; 149: 119-128, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35810663

RESUMO

BACKGROUND: Acute lung injury (ALI) is a severe organ dysfunction caused by sepsis. WIN55212-2 (WIN) is a cannabinoid receptor agonist. Activation of cannabinoid type 2 receptor can alleviate septic lung injury. Therefore, the effects of WIN on sepsis-related ALI were evaluated. METHODS: MiR-29b-3p, FOXO3 and PFKFB3 levels, as well as M1 and M2 macrophage markers were assessed by RT-qPCR in MH-S cells after lipopolysaccharide (LPS) and WIN treatment. ChIP and dual luciferase reporter assays determined molecules interactions. Glycolysis-related proteins were evaluated by Western blotting assay. Lactic acid and ATP were also tested. Furthermore, the effect of WIN was tested in sepsis mice model. HE staining evaluated the histopathological changes in mouse lung tissues. The number of inflammatory cells and macrophages, protein concentration and lactic acid content were detected in mouse bronchoalveolar lavage fluid. RESULTS: We found that WIN suppressed M1 polarization and glycolysis in alveolar macrophages induced by LPS. Moreover, WIN inhibited FOXO3 by up-regulating miR-29b-3p. Furthermore, we verified that FOXO3 induced macrophage M1 polarization and glycolysis through activating PFKFB3. In vivo, WIN alleviated ALI in mice with sepsis. CONCLUSION: Our results reveal that WIN inhibits macrophage glycolysis through the miR-29b-3p/ FOXO3/PFKFB3 axis, suggesting new therapeutic targets to alleviate sepsis-related ALI.


Assuntos
Lesão Pulmonar Aguda , MicroRNAs , Sepse , Lesão Pulmonar Aguda/patologia , Animais , Benzoxazinas , Glicólise , Ácido Láctico/efeitos adversos , Lipopolissacarídeos/metabolismo , Macrófagos/metabolismo , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Morfolinas , Naftalenos , Sepse/patologia
9.
Klin Monbl Augenheilkd ; 239(7): 857-866, 2022 Jul.
Artigo em Inglês, Alemão | MEDLINE | ID: mdl-35858596

RESUMO

Microbial, infectious keratitis is a relevant indication for penetrating keratoplasty. The requirement for transplantation results in histopathological examination of the entire thickness of the cornea. Although the clinical diagnosis is not always possible to confirm, pathology can support diagnostic evidence of clinical presentation and pathogenesis. This is achieved with multiple methods from cytology, histochemistry, immunohistology, molecular pathology and in rare cases electron microscopy. These allow tissue-based detection of previous and parallel diseases and the responsible pathogens. The failure of satisfactory clinicopathological correlation raises the question whether a suspected pathogen was not ultimately responsible for destroyed corneal tissue. The pathogenesis of keratitis requiring transplantation is not yet completely understood, also on the experimental level. The development of such a keratitis can lead to a clinical symptomatology which can be described as "threatening organ dysfunction", a term used in sepsis research. Considering recent literature, possible correlations between sepsis and microbial keratitis and their relation to histopathology are discussed.


Assuntos
Ceratite , Sepse , Córnea/patologia , Humanos , Ceratite/cirurgia , Ceratoplastia Penetrante , Estudos Retrospectivos , Sepse/diagnóstico , Sepse/patologia , Sepse/cirurgia
10.
Eur J Histochem ; 66(3)2022 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-35726572

RESUMO

Mitochondrial dysfunction has a role in sepsis-associated acute kidney injury (S-AKI), so the restoration of normal mitochondrial homeostasis may be an effective treatment strategy. Transcription factor nuclear factor erythroid 2 p45-related factor 2 (NRF2) is a main regulator of cell-redox homeostasis, and recent studies reported that NRF2 activation helped to preserve mitochondrial morphology and function under conditions of stress. However, the role of NRF2 in the process of S-AKI is still not well understood. The present study investigated whether NRF2 regulates mitochondrial homeostasis and influences mitochondrial function in S-AKI. We demonstrated activation of NRF2 in an in vitro model: lipopolysaccharide (LPS) challenge of ductal epithelial cells of rat renal tubules (NRK-52e cells), and an in vivo model: cecal ligation and puncture (CLP) of rats. Over-expression of NRF2 attenuated oxidative stress, apoptosis, and the inflammatory response; enhanced mitophagy and mitochondrial biogenesis; and mitigated mitochondrial damage in the in vitro model. In vivo experiments showed that rats treated with an NRF2 agonist had higher adenosine triphosphate (ATP) levels, lower blood urea nitrogen and creatinine levels, fewer renal histopathological changes, and higher expression of mitophagy-related proteins [PTEN-induced putative kinase 1 (PINK1), parkin RBR E3 ubiquitin protein ligase (PRKN), microtubule-associated protein 1 light chain 3 II (LC3 II)] and mitochondrial biogenesis-related proteins [peroxisome proliferator-activated receptor γ coactivator-1 (PGC-1α) and mitochondrial transcription factor A (TFAM)]. Electron microscopy of kidney tissues showed that mitochondrial damage was alleviated by treatment with an NRF2 agonist, and the opposite response occurred upon treatment with an NRF2 antagonist. Overall, our findings suggest that mitochondria have an important role in the pathogenesis of S-AKI, and that NRF2 activation restored mitochondrial homeostasis and function in the presence of this disease. This mitochondrial pathway has the potential to be a novel therapeutic target for the treatment of S-AKI.


Assuntos
Injúria Renal Aguda , Mitocôndrias , Fator 2 Relacionado a NF-E2 , Sepse , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Animais , Homeostase , Fator 2 Relacionado a NF-E2/metabolismo , Ratos , Sepse/complicações , Sepse/metabolismo , Sepse/patologia
11.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 34(4): 400-406, 2022 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-35692206

RESUMO

OBJECTIVE: To explore the protective effect and mechanism of scutellarin (Scu) on sepsis associated-acute kidney injury (SA-AKI). METHODS: (1) In vivo experiment: 36 male C57BL/6 mice were divided into normal saline (NS) control group, lipopolysaccharide (LPS) induced SA-AKI model group (LPS group), 20 mg/kg Scu control group (Scu 20 control group), and 5, 10, 20 mg/kg Scu pretreatment groups by random number table with 6 mice in each group. The SA-AKI model was reproduced by intraperitoneal injection of 10 mg/kg LPS. The NS control group was injected with NS intraperitoneally. The Scu pretreatment groups were intraperitoneally injected with different doses of Scu every day before LPS injection for 1 week. Scu 20 control group was injected with 20 mg/kg Scu for 1 week. After 24 hours of LPS treatment, mice in each group were sacrificed, kidney tissues were collected, and kidney injury was detected by hematoxylin-eosin (HE) staining. Western blotting was used to detect the protein expression levels of nuclear factor-κB (NF-κB) signaling pathway related molecules, apoptosis-related proteins and cysteine-rich protein 61-connective tissue growth factor-nephroblastoma overexpressed gene 1 (CCN1). (2) In vitro experiment: human renal tubular epithelial cell line HK-2 was cultured in vitro and used for experiment when the cells fused to 80%. In the cells without LPS treatment and after 100 g/L LPS treatment, pcDNA3.1-CCN1 and small interfering RNA (siRNA) CCN1 sequence were transfected to overexpress and inhibit CCN1 expression, respectively, to observe whether CCN1 was involved in NF-κB signaling pathway activation and apoptosis. In addition, 100g/L LPS and 20 µmol/L Scu were added into HK-2 cells transfected with and without CCN1 siRNA to investigate the mechanism of protective effect of Scu on LPS-induced HK-2 cells injury. RESULTS: (1) The results of in vivo experiment: the renal function of SA-AKI mice induced by LPS was significantly decreased, and had kidney histological damage and severely damaged renal tubules. Scu could alleviate renal function and histological damage in a dose-dependent manner. Western blotting results showed Scu could reduce the protein expression of NF-κB signaling pathway related molecules and CCN1 in the renal tissue, and had a significant alleviating effect on apoptosis, indicating that CCN1 was involved in NF-κB signaling pathway activation and apoptosis. (2) The results of in vitro experiment: in HK-2 cells not treated with LPS, CCN1 overexpression had no effect on apoptosis related protein and pro-inflammatory factors of NF-κB signaling pathway. In HK-2 cells treated with LPS, overexpression of CCN1 significantly inhibited the mRNA expressions of interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1), with significant differences as compared with cells stimulated only by LPS [IL-1ß mRNA (2-ΔΔCT): 3.20±0.57 vs. 4.88±0.69, TNF-α mRNA (2-ΔΔCT): 2.99±0.44 vs. 5.00±0.81, MCP-1 mRNA (2-ΔΔCT): 2.81±0.50 vs. 5.41±0.75, all P < 0.05], and the apoptosis-related protein was significantly down-regulated. However, when siRNA was used to inhibit the expression of CCN1, the mRNA expressions of pro-inflammatory factors were significantly increased as compared with cells stimulated only by LPS [IL-1ß mRNA (2-ΔΔCT): 6.01±1.13 vs. 4.88±0.69, TNF-α mRNA (2-ΔΔCT): 5.15±0.86 vs. 5.00±0.81, all P < 0.05], and apoptosis-related protein was significantly up-regulated. In the LPS-induced HK-2 cells, the mRNA expressions of pro-inflammatory factors were significantly down-regulated after Scu treatment as compared with cells stimulated only by LPS [IL-1ß mRNA(2-ΔΔCT): 2.55±0.50 vs. 6.15±1.04, TNF-α mRNA (2-ΔΔCT): 2.58±0.40 vs. 3.95±0.52, MCP-1 mRNA (2-ΔΔCT): 2.64±0.44 vs. 6.21±0.96, all P < 0.05], and apoptosis-related protein was also significantly reduced. When the expression of CCN1 was inhibited by siRNA, the protective effect of Scu on cells was weakened, which showed that the mRNA expressions of pro-inflammatory factors in cells was significantly up-regulated compared with the cells without inhibition of CCN1 expression [IL-1ß mRNA (2-ΔΔCT): 5.34±0.76 vs. 2.55±0.50, TNF-α mRNA (2-ΔΔCT): 3.66±0.54 vs. 2.58±0.40, MCP-1 mRNA (2-ΔΔCT): 5.15±0.79 vs. 2.64±0.44, all P < 0.05], and the expression of apoptosis related protein was also significantly up-regulated. CONCLUSIONS: Scu could protect the renal function in SA-AKI mice, and the protective effect is associated with NF-κB signaling pathway and CCN1. Thus, Scu could alleviate LPS-induced kidney injury by regulating the NF-κB signaling pathway.


Assuntos
Injúria Renal Aguda , Sepse , Tumor de Wilms , Injúria Renal Aguda/induzido quimicamente , Animais , Apigenina , Fator de Crescimento do Tecido Conjuntivo , Proteína Rica em Cisteína 61/genética , Glucuronatos , Rim/metabolismo , Lipopolissacarídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , RNA Mensageiro , RNA Interferente Pequeno , Sepse/patologia , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo , Tumor de Wilms/patologia
12.
PLoS One ; 17(6): e0269924, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35696412

RESUMO

Septic patients commonly present with central nervous system (CNS) disorders including impaired consciousness and delirium. Today, the main mechanism regulating sepsis-induced cerebral disorders is believed to be neuroinflammation. However, it is unknown how another component of the CNS, the spinal cord, is influenced during sepsis. In the present study, we intraperitoneally injected mice with lipopolysaccharide (LPS) to investigate molecular and immunohistochemical changes in the spinal cord of a sepsis model. After LPS administration in the spinal cord, pro-inflammatory cytokines including interleukin (IL)-1ß, IL-6, and tumor necrosis factor alpha mRNA were rapidly and drastically induced. Twenty-four-hour after the LPS injection, severe neuronal ischemic damage spread into gray matter, especially around the anterior horns, and the anterior column had global edematous changes. Immunostaining analyses showed that spinal microglia were significantly activated and increased, but astrocytes did not show significant change. The current results indicate that sepsis induces acute neuroinflammation, including microglial activation and pro-inflammatory cytokine upregulation in the spinal cord, causing drastic neuronal ischemia and white matter edema in the spinal cord.


Assuntos
Sepse , Animais , Citocinas , Humanos , Lipopolissacarídeos , Camundongos , Microglia , Doenças Neuroinflamatórias , Sepse/patologia , Medula Espinal/patologia
13.
Biochem Biophys Res Commun ; 618: 133-140, 2022 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-35724457

RESUMO

Sepsis is a life-threatening organ function dysfunction featured by stimulated oxidative stress and inflammatory responses, in which about 40%-60% of sepsis patients are accompanied with cardiac dysfunction. Mesenchymal stem cells (MSCs)-derived exosomes exert critical roles in the treatment of multiple diseases through transferring non-coding RNAs. Circular RNA (circRNA) is a novel form of functional RNAs that involves in the progression of multiple cardiac pathological condition. Nevertheless, the function of MSCs-derived exosomal circRTN4 in sepsis-induced myocardial injury is still obscure. Significantly, FISH assay demonstrated the location of circRTN4 in cytoplasm of cardiomyocytes. The expression of circRTN4 was reduced in the cardiac tissues from caecal ligation and puncture (CLP) rats and LPS-treated cardiomyocytes. CircRTN4 could be delivered to cardiomyocytes cells via MSCs-derived exosomes. The cardiac injury and apoptosis were induced in the CLP rats and the treatment of MSCs-derived exosomal circRTN4 relieved the phenotypes. MSCs-derived exosomal circRTN4 notably suppressed the upregulated ROS level in the CLP rats. The activity of SOD and GSH was repressed in CLP rats, in which MSCs-derived exosomal circRTN4 rescued the activity in the rats. The upregulated IL-1ß, IL-6, and TNF-α levels in CLP rats were reduced by the treatment of MSCs-derived exosomal circRTN4. MSCs-derived exosomal circRTN4 improved cell survival and suppressed apoptosis of LPS-treated cardiomyocytes. CircRTN4 direct interact with miR-497-5p to upregulate MG53 expression in cardiomyocytes. MSCs-derived exosomal circRTN4 relieves LPS-stimulated cardiomyocyte damage via targeting miR-497-5p/MG53 axis. Therefore, we determine that MSCs-derived exosomes prevent sepsis-induced myocardial injury by a circRTN4/miR-497-5p/MG53 pathway. Our data provides novel insight into the regulatory mechanism by which MSCs-derived exosomal circRTN4 regulates sepsis-induced myocardial injury. MSCs-derived exosomal circRTN4 may be applied as a promising therapeutic approach for sepsis-induced myocardial injury.


Assuntos
Exossomos , Células-Tronco Mesenquimais , MicroRNAs , Miocárdio , RNA Circular , Sepse , Animais , Apoptose/fisiologia , Exossomos/genética , Exossomos/metabolismo , Lipopolissacarídeos/farmacologia , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , RNA Circular/administração & dosagem , RNA Circular/genética , RNA Circular/metabolismo , Ratos , Sepse/metabolismo , Sepse/patologia , Transdução de Sinais , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismo
14.
Int J Mol Sci ; 23(12)2022 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-35743025

RESUMO

Immune suppression is known to occur during sepsis. Endotoxin tolerance is considered a mechanism of immune suppression in sepsis. However, the timing and serial changes in endotoxin tolerance have not been fully investigated. In this study, we investigated serial changes in endotoxin tolerance in a polymicrobial sepsis model. Herein, we used a rat model of fecal slurry polymicrobial sepsis. After induction of sepsis, endotoxin tolerance of peripheral blood mononuclear cells (PBMCs) and splenocytes was measured at various time points (6 h, 12 h, 24 h, 48 h, 72 h, 5 days, and 7 days), through the measurement of TNF-α production after stimulation with lipopolysaccharide (LPS) in an ex vivo model. At each time point, we checked for plasma tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-10 levels. Moreover, we analyzed reactive oxygen species (ROS) as measured by 2',7'-dichlorodihydrofluorescein, plasma lactate, serum alanine aminotransferase (ALT), and creatinine levels. Nuclear factor (NF)-κB, IL-1 receptor-associated kinase (IRAK)-M, and cleaved caspase 3 levels were measured in the spleen. Endotoxin tolerance, measured by TNF-α production stimulated through LPS in PBMCs and splenocytes, was induced early in the sepsis model, starting from 6 h after sepsis. It reached a nadir at 24 to 48 h after sepsis, and then started to recover. Endotoxin tolerance was more prominent in the severe sepsis model. Plasma cytokines peaked at time points ranging from 6 to 12 h after sepsis. ROS levels peaked at 12 h and then decreased. Lactate, ALT, and serum creatinine levels increased up to 24 to 48 h, and then decreased. Phosphorylated p65 and IRAK-M levels of spleen increased up to 12 to 24 h and then decreased. Apoptosis was prominent 48 h after sepsis, and then recovered. In the rat model of polymicrobial sepsis, endotoxin tolerance occurred earlier and started to recover from 24 to 48 h after sepsis.


Assuntos
Lipopolissacarídeos , Sepse , Animais , Tolerância à Endotoxina , Interleucina-6 , Lactatos , Leucócitos Mononucleares , Lipopolissacarídeos/farmacologia , NF-kappa B , Ratos , Espécies Reativas de Oxigênio , Sepse/patologia , Fator de Necrose Tumoral alfa
15.
Cells ; 11(11)2022 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-35681439

RESUMO

Decompensated cirrhosis (DC) is susceptible to infections and sepsis. Neutrophils and monocytes provide the first line of defense to encounter infection. We aimed to evaluate proteins related to neutrophils functionality in sepsis. 70 (DC), 40 with sepsis, 30 without (w/o) sepsis and 15 healthy controls (HC) plasma was analyzed for proteomic analysis, cytokine bead array, endotoxin, cell free DNA and whole blood cells were analyzed for nCD64-mHLADR index, neutrophils-monocytes, functionality and QRT-PCR. nCD64-mHLADR index was significantly increased (p < 0.0001) with decreased HLA-DR expression on total monocytes in sepsis (p = 0.045). Phagocytic activity of both neutrophils and monocytes were significantly decreased in sepsis (p = 0.002 and p = 0.0003). Sepsis plasma stimulated healthy neutrophils, showed significant increase in NETs (neutrophil extracellular traps) and cell free DNA (p = 0.049 and p = 0.04) compared to w/o sepsis and HC. Proteomic analysis revealed upregulated- DNAJC13, TMSB4X, GPI, GSTP1, PNP, ANPEP, COTL1, GCA, APOA1 and PGAM1 while downregulated- AHSG, DEFA1,SERPINA3, MPO, MMRN1and PROS1 proteins (FC > 1.5; p < 0.05) associated to neutrophil activation and autophagy in sepsis. Proteins such as DNAJC13, GPI, GSTP1, PNP, ANPEP, COTL1, PGAM1, PROS1, MPO, SERPINA3 and MMRN1 showed positive correlation with neutrophils activity and number, oxidative burst activity and clinical parameters such as MELD, MELD Na and Bilirubin. Proteomic analysis revealed that faulty functionality of neutrophils may be due to the autophagy proteins i.e., DNAJC13, AHSG, TMSB4X, PROS1 and SERPINA3, which can be used as therapeutic targets in decompensated cirrhosis patients with sepsis.


Assuntos
Cirrose Hepática , Neutrófilos , Proteoma , Sepse , Ácidos Nucleicos Livres , Humanos , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Neutrófilos/metabolismo , Neutrófilos/patologia , Proteômica , Sepse/patologia
16.
Oxid Med Cell Longev ; 2022: 9148246, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35528525

RESUMO

Current evidences indicate that both inflammation and oxidative stress contribute to the pathogenesis of sepsis-associated skeletal muscle atrophy. However, the interaction between inflammation and oxidative stress has not been completely understood in sepsis-associated skeletal muscle atrophy. Here in the present study, a murine model of sepsis has been established by cecal ligation and puncture (CLP) with wild-type and interleukin- (IL-) 6 knockout (KO) mice. Our results suggested that IL-6 KO largely attenuated skeletal muscle atrophy as reflected by reduced protein degradation, increased cross-sectional area (CSA) of myofibers, and improved muscle contractile function (all P < 0.05). In addition, we observed that IL-6 KO promoted the expression of peroxisome proliferator-activated receptor γ coactivator-1alpha (PGC-1α) and inhibited CLP-induced mitochondrial reactive oxygen species (ROS) production in skeletal muscles (all P < 0.05). However, the knockdown of PGC-1α abolished the protective effects of IL-6 KO in CLP-induced skeletal muscle atrophy and reversed the changes in mitochondrial ROS production (all P < 0.05). Ex vivo experiments found that exogenous IL-6 inhibited PGC-1α expression, promoted mitochondrial ROS production, and induced proteolysis in C2C12 cells (all P < 0.05). Together, these results suggested that IL-6 deficiency attenuated skeletal muscle atrophy by inhibiting mitochondrial ROS production through the upregulation of PGC-1α expression in septic mice.


Assuntos
Interleucina-6 , Doenças Musculares , Sepse , Animais , Inflamação/patologia , Interleucina-6/deficiência , Camundongos , Músculo Esquelético/metabolismo , Atrofia Muscular/metabolismo , Doenças Musculares/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sepse/patologia , Fatores de Transcrição/metabolismo , Regulação para Cima
17.
Front Immunol ; 13: 843782, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35529856

RESUMO

Acute kidney injury (AKI) may be induced by different causes, including renal ischemia-reperfusion injury and sepsis, which represent the most common reasons for AKI in hospitalized patients. AKI is defined by reduced urine production and/or increased plasma creatinine. However, this definition does not address the molecular mechanisms of different AKI entities, and uncertainties remain regarding distinct pathophysiological events causing kidney injury in the first place. In particular, sepsis-induced AKI is considered not to be associated with leukocyte infiltration into the kidney, but a direct investigation of this process is missing to this date. In this study, we used two murine AKI models induced by either renal ischemia-reperfusion injury (IRI) or cecal ligation and puncture (CLP) to investigate the contribution of neutrophils to tissue injury and kidney function. By using VEC-Y731F mice, in which neutrophil recruitment is impaired, we analyzed the specific contribution of neutrophil recruitment to the pathogenesis of IRI- and CLP-induced AKI. We observed that the degree of renal injury evaluated by plasma creatinine, urinary biomarkers and histological analyses, following IRI-induction was dependent on neutrophil migration into the kidney, whereas the pathogenesis of CLP-induced AKI was independent of neutrophil recruitment. Furthermore, plasma transfer experiments suggest that the pathogenesis of CLP-induced AKI relies on circulating inflammatory mediators. These results extend our knowledge of the AKI pathogenesis and may help in the development of prophylactic and therapeutic treatments for AKI patients.


Assuntos
Injúria Renal Aguda , Traumatismo por Reperfusão , Sepse , Injúria Renal Aguda/patologia , Animais , Creatinina , Feminino , Humanos , Isquemia/patologia , Rim/patologia , Masculino , Camundongos , Infiltração de Neutrófilos , Reperfusão/efeitos adversos , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/patologia , Sepse/patologia
18.
Int J Immunopathol Pharmacol ; 36: 3946320221090021, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35603454

RESUMO

Sepsis caused by aggressive infection is a severe clinical problem with an increasing incidence worldwide. Toll-like receptors and their common adapter myeloid differentiation factor 88 (MyD88) can activate immune responses by recognizing a foreign microbe's product. This study aimed to identify the different time expression of TLR four signaling pathway in an experimental rodent model of polymicrobial sepsis. A randomized animal study was investigated in rats with septic peritonitis induced by cecal ligation and puncture (CLP). The expressions of MyD88-dependent pathway biomarkers, including MyD88, nuclear factor-κB (NF-κB), and serum tumor necrosis factor-α (TNF-α), were analyzed and compared to the sham controls at the different time points after CLP surgery. CLP-induced sepsis increased liver MyD88 mRNA expression and protein expression compared to the control groups at 2 h after surgery. The MyD88 mRNA and protein expressions in rats with CLP-induced sepsis marked increased at 4 and 6 h, and their NF-κB activities and serum TNF-α levels also increased at 4 h after CLP surgery (both p < .05). The different serial expression of MyD88-ependent pathway during sepsis may be used as biomarkers during sepsis. These results may provide further helpful information for using pro-inflammatory biomarkers of innate immunity such as MyD88 and TNF-α in clinical sepsis or related abdominal surgical emergency in the future.


Assuntos
Sepse , Receptor 4 Toll-Like , Animais , Modelos Animais de Doenças , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , RNA Mensageiro , Ratos , Ratos Sprague-Dawley , Sepse/patologia , Transdução de Sinais , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
19.
J Immunol ; 208(11): 2515-2522, 2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-35534212

RESUMO

The cannabinoid receptor 2 (CB2) is a receptor mainly expressed in immune cells and believed to be immunosuppressive in infective or inflammatory models. However, its role in sepsis has not been fully elucidated. In this study, we delineate the function and mechanism of CB2 in the cecal ligation and puncture-induced septic model in mice. The activation of CB2 signaling with HU308 led to decreased survival rates and more severe lung injury in septic mice, and lower IL-10 levels in peritoneal lavage fluid were observed in the CB2 agonist group. The mice with conditional knockout of CB2-encoding gene CNR2 in CD4+ T cells (CD4 Cre CNR2fl/fl) improved survival, enhanced IL-10 production, and ameliorated pulmonary damage in the sepsis model after CB2 activation. In addition, double-knockout of the CNR2 gene (Lyz2 Cre CD4 Cre CNR2fl/fl) decreased the susceptibility to sepsis compared with Lyz2 Cre CNR2fl/fl mice. Mechanistically, the blockade of IL-10 with the anti-IL-10 Ab abolished its protection in CD4 Cre CNR2fl/fl mice. In accordance with the animal study, in vitro results revealed that the lack of CNR2 in CD4+ cells elevated IL-10 production, and CB2 activation inhibited CD4+ T cell-derived IL-10 production. Furthermore, in the clinical environment, septic patients expressed enhanced CB2 mRNA levels compared with healthy donors in PBMCs, and their CB2 expression was inversely correlated with IL-10. These results suggested that the activation of CD4+ T cell-derived CB2 increased susceptibility to sepsis through inhibiting IL-10 production.


Assuntos
Linfócitos T CD4-Positivos , Interleucina-10 , Receptor CB2 de Canabinoide , Sepse , Animais , Ligadura , Camundongos , Camundongos Endogâmicos C57BL , Receptor CB2 de Canabinoide/genética , Sepse/patologia
20.
Int J Biol Sci ; 18(8): 3337-3357, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35637949

RESUMO

Neutrophil extracellular traps (NETs) production is a major strategy employed by polymorphonuclear neutrophils (PMNs) to fight against microbes. NETs have been implicated in the pathogenesis of various lung injuries, although few studies have explored NETs in sepsis-associated acute lung injury (SI-ALI). Here, we demonstrate a major contribution of NETs to the pathology of sepsis-associated ALI by inducing ferroptosis of alveolar epithelial cells. Using both in vitro and in vivo studies, our findings show enhanced NETs accumulation in sepsis-associated ALI patients and mice, as well as the closely related upregulation of ferroptosis, the induction of which depends on METTL3-induced m6A modification of GPX4. Using a CLP-induced sepsis-associated ALI mouse model established with METTL3-/- versus WT mice, in addition to METTL3 knockout and overexpression in vitro, we elucidated and confirmed the critical role of ferroptosis in NETs-induced ALI. These findings support a role for NETs-induced METTL3 modification and the subsequent induction of ferroptosis in the pathogenesis of sepsis-associated ALI.


Assuntos
Lesão Pulmonar Aguda , Armadilhas Extracelulares , Ferroptose , Sepse , Lesão Pulmonar Aguda/patologia , Células Epiteliais Alveolares , Animais , Humanos , Metiltransferases , Camundongos , Sepse/complicações , Sepse/patologia
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