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1.
PLoS One ; 19(5): e0302628, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38723000

RESUMO

Blood vessels permit the selective passage of molecules and immune cells between tissues and circulation. Uncontrolled inflammatory responses from an infection can increase vascular permeability and edema, which can occasionally lead to fatal organ failure. We identified mexenone as a vascular permeability blocker by testing 2,910 compounds in the Clinically Applied Compound Library using the lipopolysaccharide (LPS)-induced vascular permeability assay. Mexenone suppressed the LPS-induced downregulation of junctional proteins and phosphorylation of VE-cadherin in Bovine Aortic Endothelial Cells (BAECs). The injection of mexenone 1 hr before LPS administration completely blocked LPS-induced lung vascular permeability and acute lung injury in mice after 18hr. Our results suggest that mexenone-induced endothelial cell (EC) barrier stabilization could be effective in treating sepsis patients.


Assuntos
Células Endoteliais , Lipopolissacarídeos , Sepse , Animais , Sepse/tratamento farmacológico , Sepse/induzido quimicamente , Sepse/metabolismo , Camundongos , Bovinos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Permeabilidade Capilar/efeitos dos fármacos , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/prevenção & controle , Masculino , Caderinas/metabolismo , Camundongos Endogâmicos C57BL , Antígenos CD/metabolismo
2.
Respir Res ; 25(1): 201, 2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38725041

RESUMO

Growth differentiation factor 15 (GDF15) as a stress response cytokine is involved in the development and progression of several diseases associated with metabolic disorders. However, the regulatory role and the underlying mechanisms of GDF15 in sepsis remain poorly defined. Our study analyzed the levels of GDF15 and its correlations with the clinical prognosis of patients with sepsis. In vivo and in vitro models of sepsis were applied to elucidate the role and mechanisms of GDF15 in sepsis-associated lung injury. We observed strong correlations of plasma GDF15 levels with the levels of C-reactive protein (CRP), procalcitonin (PCT), lactate dehydrogenase (LDH), and lactate as well as Sequential Organ Failure Assessment (SOFA) scores in patients with sepsis. In the mouse model of lipopolysaccharide-induced sepsis, recombinant GDF15 inhibited the proinflammatory responses and alleviated lung tissue injury. In addition, GDF15 decreased the levels of cytokines produced by alveolar macrophages (AMs). The anti-inflammatory effect of glycolysis inhibitor 2-DG on AMs during sepsis was mediated by GDF15 via inducing the phosphorylation of the α-subunit of eukaryotic initiation factor 2 (eIF2α) and the expression of activating transcription factor 4 (ATF4). Furthermore, we explored the mechanism underlying the beneficial effects of GDF15 and found that GDF15 inhibited glycolysis and mitogen-activated protein kinases (MAPK)/nuclear factor-κB (NF-κB) signaling via promoting AMPK phosphorylation. This study demonstrated that GDF15 inhibited glycolysis and NF-κB/MAPKs signaling via activating AMP-activated protein kinase (AMPK), thereby alleviating the inflammatory responses of AMs and sepsis-associated lung injury. Our findings provided new insights into novel therapeutic strategies for treating sepsis.


Assuntos
Proteínas Quinases Ativadas por AMP , Glicólise , Fator 15 de Diferenciação de Crescimento , Macrófagos Alveolares , Camundongos Endogâmicos C57BL , Sepse , Fator 15 de Diferenciação de Crescimento/metabolismo , Animais , Camundongos , Sepse/metabolismo , Sepse/tratamento farmacológico , Masculino , Glicólise/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Humanos , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/efeitos dos fármacos , Lesão Pulmonar/metabolismo , Feminino , Pessoa de Meia-Idade
3.
Int J Mol Sci ; 25(9)2024 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-38731929

RESUMO

Sepsis-induced cardiomyopathy (SICM) is one of the leading indicators for poor prognosis associated with sepsis. Despite its reversibility, prognosis varies widely among patients. Mitochondria play a key role in cellular energy production by generating adenosine triphosphate (ATP), which is vital for myocardial energy metabolism. Over recent years, mounting evidence suggests that severe sepsis not only triggers mitochondrial structural abnormalities such as apoptosis, incomplete autophagy, and mitophagy in cardiomyocytes but also compromises their function, leading to ATP depletion. This metabolic disruption is recognized as a significant contributor to SICM, yet effective treatment options remain elusive. Sepsis cannot be effectively treated with inotropic drugs in failing myocardium due to excessive inflammatory factors that blunt ß-adrenergic receptors. This review will share the recent knowledge on myocardial cell death in sepsis and its molecular mechanisms, focusing on the role of mitochondria as an important metabolic regulator of SICM, and discuss the potential for developing therapies for sepsis-induced myocardial injury.


Assuntos
Cardiomiopatias , Sepse , Sepse/complicações , Sepse/metabolismo , Humanos , Cardiomiopatias/etiologia , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Animais , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Mitofagia , Metabolismo Energético , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Apoptose , Trifosfato de Adenosina/metabolismo
4.
Int J Mol Sci ; 25(9)2024 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-38731999

RESUMO

To date, several members of the transient receptor potential (TRP) channels which provide a wide array of roles have been found in the gastrointestinal tract (GI). The goal of earlier research was to comprehend the intricate signaling cascades that contribute to TRP channel activation as well as how these receptors' activity affects other systems. Moreover, there is a large volume of published studies describing the role of TRP channels in a number of pathological disorders, including inflammatory bowel disease (IBD) and sepsis. Nevertheless, the generalizability of these results is subject to certain limitations. For instance, the study of IBD relies on various animal models and experimental methods, which are unable to precisely imitate the multifactorial chronic disease. The diverse pathophysiological mechanisms and unique susceptibility of animals may account for the inconsistency of the experimental data collected. The main purpose of this study was to conduct a comprehensive review and analysis of existing studies on transient receptor potential (TRP) channels implicating specific models of colitis and sepsis, with particular emphasis on their involvement in pathological disorders such as IBD and sepsis. Furthermore, the text endeavors to evaluate the generalizability of experimental findings, taking into consideration the limitations posed by animal models and experimental methodologies. Finally, we also provide an updated schematic of the most important and possible molecular signaling pathways associated with TRP channels in IBD and sepsis.


Assuntos
Colite , Sepse , Canais de Potencial de Receptor Transitório , Sepse/metabolismo , Canais de Potencial de Receptor Transitório/metabolismo , Animais , Humanos , Colite/metabolismo , Colite/patologia , Transdução de Sinais , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/patologia , Modelos Animais de Doenças
5.
Sci Rep ; 14(1): 10477, 2024 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-38714743

RESUMO

Endothelial glycocalyx (eGC) covers the inner surface of the vessels and plays a role in vascular homeostasis. Syndecan is considered the "backbone" of this structure. Several studies have shown eGC shedding in sepsis and its involvement in organ dysfunction. Matrix metalloproteinases (MMP) contribute to eGC shedding through their ability for syndecan-1 cleavage. This study aimed to investigate if doxycycline, a potent MMP inhibitor, could protect against eGC shedding in lipopolysaccharide (LPS)-induced sepsis and if it could interrupt the vascular hyperpermeability, neutrophil transmigration, and microvascular impairment. Rats that received pretreatment with doxycycline before LPS displayed ultrastructural preservation of the eGC observed using transmission electronic microscopy of the lung and heart. In addition, these animals exhibited lower serum syndecan-1 levels, a biomarker of eGC injury, and lower perfused boundary region (PBR) in the mesenteric video capillaroscopy, which is inversely related to the eGC thickness compared with rats that only received LPS. Furthermore, this study revealed that doxycycline decreased sepsis-related vascular hyperpermeability in the lung and heart, reduced neutrophil transmigration in the peritoneal lavage and inside the lungs, and improved some microvascular parameters. These findings suggest that doxycycline protects against LPS-induced eGC shedding, and it could reduce vascular hyperpermeability, neutrophils transmigration, and microvascular impairment.


Assuntos
Doxiciclina , Glicocálix , Lipopolissacarídeos , Sepse , Glicocálix/metabolismo , Glicocálix/efeitos dos fármacos , Animais , Sepse/tratamento farmacológico , Sepse/metabolismo , Doxiciclina/farmacologia , Ratos , Masculino , Permeabilidade Capilar/efeitos dos fármacos , Pulmão/patologia , Pulmão/metabolismo , Pulmão/efeitos dos fármacos , Sindecana-1/metabolismo , Ratos Wistar , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Neutrófilos/metabolismo , Neutrófilos/efeitos dos fármacos , Inibidores de Metaloproteinases de Matriz/farmacologia
6.
Front Immunol ; 15: 1394925, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38690282

RESUMO

Sepsis is a life-threatening organ dysfunction caused by the host's dysfunctional response to infection. Abnormal activation of the immune system and disturbance of energy metabolism play a key role in the development of sepsis. In recent years, the Sirtuins (SIRTs) family has been found to play an important role in the pathogenesis of sepsis. SIRTs, as a class of histone deacetylases (HDACs), are widely involved in cellular inflammation regulation, energy metabolism and oxidative stress. The effects of SIRTs on immune cells are mainly reflected in the regulation of inflammatory pathways. This regulation helps balance the inflammatory response and may lessen cell damage and organ dysfunction in sepsis. In terms of energy metabolism, SIRTs can play a role in immunophenotypic transformation by regulating cell metabolism, improve mitochondrial function, increase energy production, and maintain cell energy balance. SIRTs also regulate the production of reactive oxygen species (ROS), protecting cells from oxidative stress damage by activating antioxidant defense pathways and maintaining a balance between oxidants and reducing agents. Current studies have shown that several potential drugs, such as Resveratrol and melatonin, can enhance the activity of SIRT. It can help to reduce inflammatory response, improve energy metabolism and reduce oxidative stress, showing potential clinical application prospects for the treatment of sepsis. This review focuses on the regulation of SIRT on inflammatory response, energy metabolism and oxidative stress of immune cells, as well as its important influence on multiple organ dysfunction in sepsis, and discusses and summarizes the effects of related drugs and compounds on reducing multiple organ damage in sepsis through the pathway involving SIRTs. SIRTs may become a new target for the treatment of sepsis and its resulting organ dysfunction, providing new ideas and possibilities for the treatment of this life-threatening disease.


Assuntos
Metabolismo Energético , Estresse Oxidativo , Sepse , Sirtuínas , Humanos , Sepse/tratamento farmacológico , Sepse/imunologia , Sepse/metabolismo , Animais , Sirtuínas/metabolismo , Metabolismo Energético/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Inflamação/tratamento farmacológico , Inflamação/imunologia
7.
Front Immunol ; 15: 1373876, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38715602

RESUMO

Objective: The objective of this study was to investigate the impact of electro-acupuncture (EA) on sepsis-related intestinal injury and its relationship with macrophage polarization. Methods: A sepsis model was established using cecal ligation and puncture (CLP) to assess the effectiveness of EA. The extent of pathological injury was evaluated using Chiu's score, the expression of ZO-1 and Ocludin, and the impact on macrophage polarization was examined through flow cytometry and immunofluorescence staining. The expression of spermidine, one type of polyamine, and ornithine decarboxylase (ODC) was measured using ELISA and PCR. Once the efficacy was determined, a polyamine depletion model was created, and the role of polyamines was reassessed by evaluating efficacy and observing macrophage polarization. Results: EA treatment reduced the Chiu's score and increased the expression of ZO-1 and Ocludin in the intestinal tissue of septic mice. It inhibited the secretion of IL-1ß and TNF-α, promoted the polarization of M2-type macrophages, increased the secretion of IL-10, and upregulated the expression of Arg-1, spermidine, and ODC. However, after depleting polyamines, the beneficial effects of EA on alleviating intestinal tissue damage and modulating macrophage polarization disappeared. Conclusion: The mechanism underlying the alleviation of intestinal injury associated with CLP-induced sepsis by EA involves with the promotion of M2-type macrophage polarization mediated by spermidine expression.


Assuntos
Modelos Animais de Doenças , Eletroacupuntura , Macrófagos , Poliaminas , Sepse , Animais , Sepse/terapia , Sepse/metabolismo , Sepse/imunologia , Camundongos , Macrófagos/imunologia , Macrófagos/metabolismo , Eletroacupuntura/métodos , Poliaminas/metabolismo , Masculino , Ativação de Macrófagos , Intestinos/patologia , Intestinos/imunologia , Camundongos Endogâmicos C57BL , Citocinas/metabolismo
8.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 40(4): 319-326, 2024 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-38710516

RESUMO

Objective To investigate the impact of the cannabinoid receptor agonist arachidonyl-2'-chloroethylamide (ACEA) on cognitive function in mice with sepsis-associated encephalopathy (SAE). Methods C57BL/6 mice were randomly divided into artificial cerebrospinal fluid (ACSF) and lipopolysaccharide (LPS) groups. The SAE model was established by intraventricular injection of LPS. The severity of sepsis in mice was assessed by sepsis severity score (MSS) and body mass changes. Behavioral paradigms were used to evaluate motor ability (open field test) and cognitive function (contextual fear conditioning test, Y-maze test). To evaluate the effects of ACEA intervention on SAE, mice were randomly assigned to ACSF group, ACEA intervention combined with ACSF group, LPS group, and ACEA intervention combined with LPS group. The dosage of ACEA intervention was 1.5 mg/kg. Real-time quantitative PCR was used to measure the mRNA expression levels of interleukin 1ß (IL-1ß), IL-6, and tumor necrosis factor α (TNF-α) in mouse hippocampal tissues. Western blot analysis was used to assess the protein levels of IL-6 and TNF-α in the hippocampus. Nissl staining was performed to examine neuronal damage in the CA1 region of the mouse hippocampus. Behavioral paradigms were again employed to evaluate motor ability and cognitive function. Results Three days after intraventricular LPS injection, mice exhibited significant cognitive dysfunction, confirming SAE modeling. Compared to the control group, the LPS group showed significant increases in mRNA of inflammatory factors such as IL-6, TNF-α, and IL-1ß, together with significant increases in IL-6 and TNF-α protein levels in the hippocampus, a decrease in Nissl bodies in the CA1 region, and significant cognitive dysfunction. Compared to the LPS group, the ACEA intervention group showed a significant decrease in the mRNA of IL-6, TNF-α, and IL-1ß, a significant reduction in IL-6 and TNF-α protein levels, an increase in Nissl bodies, and improved cognitive function. Conclusion ACEA improves cognitive function in SAE mice by inhibiting the expression levels of inflammatory factors IL-6 and TNF-α.


Assuntos
Ácidos Araquidônicos , Camundongos Endogâmicos C57BL , Encefalopatia Associada a Sepse , Animais , Encefalopatia Associada a Sepse/tratamento farmacológico , Encefalopatia Associada a Sepse/metabolismo , Camundongos , Masculino , Ácidos Araquidônicos/farmacologia , Agonistas de Receptores de Canabinoides/farmacologia , Lipopolissacarídeos/efeitos adversos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/genética , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Receptor CB1 de Canabinoide/genética , Receptor CB1 de Canabinoide/metabolismo , Receptor CB1 de Canabinoide/agonistas , Cognição/efeitos dos fármacos , Sepse/tratamento farmacológico , Sepse/complicações , Sepse/metabolismo
9.
J Biosci ; 492024.
Artigo em Inglês | MEDLINE | ID: mdl-38726820

RESUMO

We investigated the relationship between neutrophil apoptosis and endoplasmic reticulum stress (ERS) in sepsis and its mechanism. A prospective cohort study was conducted by recruiting a total of 58 patients with sepsis. Peripheral blood samples were collected on 1, 3, 5 and 7 days after admission to the ICU. The expressions of endoplasmic reticulum specific glucose regulatory protein 78 (GRP78), C/EBP homologous protein (CHOP), apoptosis signal-regulating kinase 1 (ASK1), Bcl-2-like 11 (BIM), death receptor 5 (DR5), c-Jun N-terminal kinases (JNK) and p38 were detected by Western blot and PCR. The subcellular location of CHOP and GRP78 was observed by immunofluorescence analysis. Spearman correlation was used to analyze the correlation between the expression of chop protein and the apoptosis rate of peripheral blood neutrophils. Healthy volunteers in the same period were selected as the healthy control group. The expression of GRP78 protein was significantly elevated on the first day of ICU admission and showed a decreasing trend on the third, fifth and seventh day, but was significantly higher than the corresponding healthy control group. The expression of CHOP protein reached the highest level on the third day. The expression of chop protein in each group was significantly higher than that in the corresponding healthy control group. Immunofluorescence staining clearly showed that the CHOP protein accumulated in the nucleus, with an elevation in the intensity of GRP78. The neutrophil apoptosis rate of sepsis patients on the 1st, 3rd, 5th and 7th day of ICU stay was significantly higher than that of the healthy control group, with the highest apoptosis rate on the 3rd day, and then decreased gradually. CHOP protein expression level was significantly positively correlated with neutrophil apoptosis rate in sepsis patients. Endoplasmic reticulum stress occurs in neutrophils during the development of sepsis. GRP78 protein and CHOP protein may be involved in the pathological process of neutrophil apoptosis in sepsis.


Assuntos
Apoptose , Chaperona BiP do Retículo Endoplasmático , Estresse do Retículo Endoplasmático , Retículo Endoplasmático , Proteínas de Choque Térmico , Neutrófilos , Sepse , Fator de Transcrição CHOP , Humanos , Fator de Transcrição CHOP/metabolismo , Fator de Transcrição CHOP/genética , Neutrófilos/metabolismo , Neutrófilos/patologia , Sepse/patologia , Sepse/metabolismo , Sepse/genética , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Masculino , Feminino , Pessoa de Meia-Idade , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/patologia , Retículo Endoplasmático/genética , Idoso , Adulto , Regulação da Expressão Gênica , Estudos Prospectivos
10.
Wiad Lek ; 77(3): 497-505, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38691792

RESUMO

OBJECTIVE: Aim: The aim of this research is to clarify the potential effect of CDDO-EA against experimentally sepsis induced lung injury in mice. PATIENTS AND METHODS: Materials and Methods: Mice have divided into four groups: Sham group CLP group, Vehicle-treatment group, CDDO-EA-treated group: mice in this group received CDDO-EA 2mg/kg intraperitoneally, 1hr before CLP, then the animals were sacrificed 24hr after CLP. After exsAngpuinations, tissue samples of lung were collected, followed by markers measurement including, TNF-α, IL-1ß, VEGF, MPO, caspase11, Angp-1and Angp-2 by ELISA, gene expression of TIE2 and VE-cadherin by qRT-PCR, in addition to histopathological study. RESULTS: Results: A significant elevation (p<0.05) in TNF-α, IL-1ß, MPO, ANGP-2, VEGF, CASPASE 11 in CLP and vehicle groups when compared with sham group. CDDO-EA group showed significantly lower levels p<0.05, level of ANGP-1 was significantly lower p<0.05 in the CLP and vehicle groups as compared with the sham group. Quantitative real-time PCR demonstrated a significant decrement in mRNA expression of TIE2&ve-cadherin genes p<0.05 in sepsis & vehicle. CONCLUSION: Conclusions: CDDO-EA has lung protective effects due to its anti-inflammatory and antiAngpiogenic activity, additionally, CDDO-EA showes a lung protective effect as they affect tissue mRNA expression of TIE2 and cadherin gene. Furthermore, CDDO-EA attenuate the histopathological changes that occur during polymicrobial sepsis thereby lung protection effect.


Assuntos
Lesão Pulmonar Aguda , Modelos Animais de Doenças , Endotoxemia , Sepse , Animais , Camundongos , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Endotoxemia/metabolismo , Sepse/complicações , Sepse/metabolismo , Masculino , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Pulmão/patologia , Pulmão/metabolismo , Interleucina-1beta/metabolismo
11.
Commun Biol ; 7(1): 562, 2024 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-38734709

RESUMO

MiRNAs in mesenchymal stem cells (MSCs)-derived exosome (MSCs-exo) play an important role in the treatment of sepsis. We explored the mechanism through which MSCs-exo influences cognitive impairment in sepsis-associated encephalopathy (SAE). Here, we show that miR-140-3p targeted Hmgb1. MSCs-exo plus miR-140-3p mimic (Exo) and antibiotic imipenem/cilastatin (ABX) improve survival, weight, and cognitive impairment in cecal ligation and puncture (CLP) mice. Exo and ABX inhibit high mobility group box 1 (HMGB1), IBA-1, interleukin (IL)-1ß, IL-6, iNOS, TNF-α, p65/p-p65, NLRP3, Caspase 1, and GSDMD-N levels. In addition, Exo upregulates S-lactoylglutathione levels in the hippocampus of CLP mice. Our data further demonstrates that Exo and S-lactoylglutathione increase GSH levels in LPS-induced HMC3 cells and decrease LD and GLO2 levels, inhibiting inflammatory responses and pyroptosis. These findings suggest that MSCs-exo-mediated delivery of miR-140-3p ameliorates cognitive impairment in mice with SAE by HMGB1 and S-lactoylglutathione metabolism, providing potential therapeutic targets for the clinical treatment of SAE.


Assuntos
Disfunção Cognitiva , Exossomos , Proteína HMGB1 , Células-Tronco Mesenquimais , MicroRNAs , Encefalopatia Associada a Sepse , MicroRNAs/genética , MicroRNAs/metabolismo , Proteína HMGB1/metabolismo , Proteína HMGB1/genética , Animais , Encefalopatia Associada a Sepse/metabolismo , Encefalopatia Associada a Sepse/genética , Camundongos , Exossomos/metabolismo , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/genética , Disfunção Cognitiva/metabolismo , Masculino , Células-Tronco Mesenquimais/metabolismo , Humanos , Camundongos Endogâmicos C57BL , Sepse/genética , Sepse/metabolismo , Sepse/complicações , Modelos Animais de Doenças
12.
Int J Mol Sci ; 25(9)2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38732114

RESUMO

Extracellular vesicles (EVs) are tools for intercellular communication, mediating molecular transport processes. Emerging studies have revealed that EVs are significantly involved in immune processes, including sepsis. Sepsis, a dysregulated immune response to infection, triggers systemic inflammation and multi-organ dysfunction, posing a life-threatening condition. Although extensive research has been conducted on animals, the complex inflammatory mechanisms that cause sepsis-induced organ failure in humans are still not fully understood. Recent studies have focused on secreted exosomes, which are small extracellular vesicles from various body cells, and have shed light on their involvement in the pathophysiology of sepsis. During sepsis, exosomes undergo changes in content, concentration, and function, which significantly affect the metabolism of endothelia, cardiovascular functions, and coagulation. Investigating the role of exosome content in the pathogenesis of sepsis shows promise for understanding the molecular basis of human sepsis. This review explores the contributions of activated immune cells and diverse body cells' secreted exosomes to vital organ dysfunction in sepsis, providing insights into potential molecular biomarkers for predicting organ failure in septic shock.


Assuntos
Biomarcadores , Exossomos , Insuficiência de Múltiplos Órgãos , Sepse , Humanos , Exossomos/metabolismo , Sepse/metabolismo , Insuficiência de Múltiplos Órgãos/metabolismo , Insuficiência de Múltiplos Órgãos/imunologia , Insuficiência de Múltiplos Órgãos/etiologia , Animais
13.
Circ Res ; 134(10): 1330-1347, 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38557119

RESUMO

BACKGROUND: Tetraspanin CD151 is highly expressed in endothelia and reinforces cell adhesion, but its role in vascular inflammation remains largely unknown. METHODS: In vitro molecular and cellular biological analyses on genetically modified endothelial cells, in vivo vascular biological analyses on genetically engineered mouse models, and in silico systems biology and bioinformatics analyses on CD151-related events. RESULTS: Endothelial ablation of Cd151 leads to pulmonary and cardiac inflammation, severe sepsis, and perilous COVID-19, and endothelial CD151 becomes downregulated in inflammation. Mechanistically, CD151 restrains endothelial release of proinflammatory molecules for less leukocyte infiltration. At the subcellular level, CD151 determines the integrity of multivesicular bodies/lysosomes and confines the production of exosomes that carry cytokines such as ANGPT2 (angiopoietin-2) and proteases such as cathepsin-D. At the molecular level, CD151 docks VCP (valosin-containing protein)/p97, which controls protein quality via mediating deubiquitination for proteolytic degradation, onto endolysosomes to facilitate VCP/p97 function. At the endolysosome membrane, CD151 links VCP/p97 to (1) IFITM3 (interferon-induced transmembrane protein 3), which regulates multivesicular body functions, to restrain IFITM3-mediated exosomal sorting, and (2) V-ATPase, which dictates endolysosome pH, to support functional assembly of V-ATPase. CONCLUSIONS: Distinct from its canonical function in strengthening cell adhesion at cell surface, CD151 maintains endolysosome function by sustaining VCP/p97-mediated protein unfolding and turnover. By supporting protein quality control and protein degradation, CD151 prevents proteins from (1) buildup in endolysosomes and (2) discharge through exosomes, to limit vascular inflammation. Also, our study conceptualizes that balance between degradation and discharge of proteins in endothelial cells determines vascular information. Thus, the IFITM3/V-ATPase-tetraspanin-VCP/p97 complexes on endolysosome, as a protein quality control and inflammation-inhibitory machinery, could be beneficial for therapeutic intervention against vascular inflammation.


Assuntos
COVID-19 , Endossomos , Lisossomos , Tetraspanina 24 , Animais , Lisossomos/metabolismo , Tetraspanina 24/metabolismo , Tetraspanina 24/genética , Humanos , Camundongos , COVID-19/metabolismo , COVID-19/imunologia , COVID-19/patologia , Endossomos/metabolismo , Camundongos Knockout , Vasculite/metabolismo , Camundongos Endogâmicos C57BL , SARS-CoV-2 , Inflamação/metabolismo , Inflamação/patologia , Sepse/metabolismo
14.
Aging (Albany NY) ; 16(8): 6937-6953, 2024 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-38643461

RESUMO

AIMS: This study aimed to evaluate the effects of VC on SIMI in rats. METHODS: In this study, the survival rate of high dose VC for SIMI was evaluated within 7 days. Rats were randomly assigned to three groups: Sham group, CLP group, and high dose VC (500 mg/kg i.v.) group. The animals in each group were treated with drugs for 1 day, 3 days or 5 days, respectively. Echocardiography, myocardial enzymes and HE were used to detect cardiac function. IL-1ß, IL-6, IL-10 and TNF-α) in serum were measured using ELISA kits. Western blot was used to detect proteins related to apoptosis, inflammation, autophagy, MAPK, NF-κB and PI3K/Akt/mTOR signaling pathways. RESULTS: High dose VC improved the survival rate of SIMI within 7 days. Echocardiography, HE staining and myocardial enzymes showed that high-dose VC relieved SIMI in rats in a time-dependent manner. And compared with CLP group, high-dose VC decreased the expressions of pro-apoptotic proteins, while increased the expression of anti-apoptotic protein. And compared with CLP group, high dose VC decreased phosphorylation levels of Erk1/2, P38, JNK, NF-κB and IKK α/ß in SIMI rats. High dose VC increased the expression of the protein Beclin-1 and LC3-II/LC3-I ratio, whereas decreased the expression of P62 in SIMI rats. Finally, high dose VC attenuated phosphorylation of PI3K, AKT and mTOR compared with the CLP group. SIGNIFICANCE: Our results showed that high dose VC has a good protective effect on SIMI after continuous treatment, which may be mediated by inhibiting apoptosis and inflammatory, and promoting autophagy through regulating MAPK, NF-κB and PI3K/AKT/mTOR pathway.


Assuntos
Apoptose , Autofagia , NF-kappa B , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Ratos Sprague-Dawley , Sepse , Transdução de Sinais , Serina-Treonina Quinases TOR , Animais , Serina-Treonina Quinases TOR/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Apoptose/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Autofagia/efeitos dos fármacos , NF-kappa B/metabolismo , Masculino , Fosfatidilinositol 3-Quinases/metabolismo , Sepse/tratamento farmacológico , Sepse/complicações , Sepse/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/administração & dosagem , Miocárdio/metabolismo , Miocárdio/patologia
15.
Int Immunopharmacol ; 133: 112130, 2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38648712

RESUMO

Neutrophils and T lymphocytes are closely related to occurrence of immunosuppression in sepsis. Studies have shown that neutrophil apoptosis decreases and T lymphocyte apoptosis increases in sepsis immunosuppression, but the specific mechanism involved remains unclear. In the present study, we found Toll-like Receptor 2 (TLR2) and programmed death-ligand 1 (PD-L1) were significantly activated in bone marrow neutrophils of wild-type mice after LPS treatment and that they were attenuated by treatment with C29, an inhibitor of TLR2. PD-L1 activation inhibits neutrophil apoptosis, whereas programmed death protein 1 (PD-1)activation promotes apoptosis of T lymphocytes, which leads to immunosuppression. Mechanistically, when sepsis occurs, pro-inflammatory factors and High mobility group box-1 protein (HMGB1) passively released from dead cells cause the up-regulation of PD-L1 through TLR2 on neutrophils. The binding of PD-L1 and PD-1 on T lymphocytes leads to increased apoptosis of T lymphocytes and immune dysfunction, eventually resulting in the occurrence of sepsis immunosuppression. In vivo experiments showed that the HMGB1 inhibitor glycyrrhizic acid (GA) and the TLR2 inhibitor C29 could inhibit the HMGB1/TLR2/PD-L1 pathway, and improving sepsis-induced lung injury. In summary, this study shows that HMGB1 regulates PD-L1 and PD-1 signaling pathways through TLR2, which leads to immunosuppression.


Assuntos
Apoptose , Antígeno B7-H1 , Proteína HMGB1 , Camundongos Endogâmicos C57BL , Neutrófilos , Sepse , Linfócitos T , Receptor 2 Toll-Like , Animais , Receptor 2 Toll-Like/metabolismo , Proteína HMGB1/metabolismo , Sepse/imunologia , Sepse/metabolismo , Antígeno B7-H1/metabolismo , Apoptose/efeitos dos fármacos , Neutrófilos/imunologia , Neutrófilos/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/efeitos dos fármacos , Camundongos , Masculino , Tolerância Imunológica , Ácido Glicirrízico/farmacologia , Ácido Glicirrízico/uso terapêutico , Lipopolissacarídeos/imunologia , Transdução de Sinais , Terapia de Imunossupressão
16.
Int Immunopharmacol ; 133: 112123, 2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38663314

RESUMO

The NOD-like receptor family protein 3 (NLRP3) inflammasome is a crucial complex for the host to establish inflammatory immune responses and plays vital roles in a series of disorders, including Alzheimer's disease and acute peritonitis. However, its regulatory mechanism remains largely unclear. Zinc finger antiviral protein (ZAP), also known as zinc finger CCCH-type antiviral protein 1 (ZC3HAV1), promotes viral RNA degradation and plays vital roles in host antiviral immune responses. However, the role of ZAP in inflammation, especially in NLRP3 activation, is unclear. Here, we show that ZAP interacts with NLRP3 and promotes NLRP3 oligomerization, thus facilitating NLRP3 inflammasome activation in peritoneal macrophages of C57BL/6 mice. The shorter isoform of ZAP (ZAPS) appears to play a greater role than the full-length isoform (ZAPL) in HEK293T cells. Congruously, Zap-deficient C57BL/6 mice may be less susceptible to alum-induced peritonitis and lipopolysaccharide-induced sepsis in vivo. Therefore, we propose that ZAP is a positive regulator of NLRP3 activation and a potential therapeutic target for NLRP3-related inflammatory disorders.


Assuntos
Inflamassomos , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR , Peritonite , Animais , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Humanos , Inflamassomos/metabolismo , Inflamassomos/imunologia , Células HEK293 , Peritonite/imunologia , Peritonite/induzido quimicamente , Camundongos , Lipopolissacarídeos/imunologia , Camundongos Knockout , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/metabolismo , Sepse/imunologia , Sepse/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Masculino , Multimerização Proteica
17.
Int Immunopharmacol ; 133: 112153, 2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38678669

RESUMO

LPS induced sepsis is a complex process involving various immune cells and signaling molecules. Dysregulation of macrophage polarization and ROS production contributed to the pathogenesis of sepsis. PGP is a transmembrane transporter responsible for the efflux of a number of drugs and also expressed in murine macrophages. Natural products have been shown to decrease inflammation and expression of efflux transporters. However, no treatment is currently available to treat LPS induced sepsis. Verapamil and Tangeretin also reported to attenuate lipopolysaccharide-induced inflammation. However, the effects of verapamil or tangeretin on lipopolysaccharide (LPS)-induced sepsis and its detailed anti-inflammatory mechanism have not been reported. Here, we have determined that verapamil and tangeretin protects against LPS-induced sepsis by suppressing M1 macrophages populations and also through the inhibition of P-glycoprotein expression via downregulating STAT1/STAT3 and upregulating SOCS3 expression in macrophages. An hour before LPS (10 mg/kg) was administered; mice were given intraperitoneal injections of either verapamil (5 mg/kg) or tangeretin (5 mg/kg). The peritoneal macrophages from different experimental groups of mice were isolated. Hepatic, pulmonary and splenic morphometric analyses revealed that verapamil and tangeretin decreased the infiltration of neutrophils into the tissues. Verapamil and tangeritin also enhanced the activity of SOD, CAT, GRX and GSH level in all the tissues tested. verapamil or tangeretin pre-treated mice shifted M1 macrophages to M2 type possibly through the inhibition of P-glycoprotein expression via downregulating STAT1/STAT3 and upregulating SOCS3 expression. Hence, both these drugs have shown protective effects in sepsis via suppressing iNOS, COX-2, oxidative stress and NF-κB signaling in macrophages. Therefore, in our study we can summarize that mice were treated with either Vera or Tan before LPS administration cause an elevated IL-10 by the macrophages which enhances the SOCS3 expression, and thereby able to limits STAT1/STAT3 inter-conversion in the macrophages. As a result, NF-κB activity is also getting down regulated and ultimately mitigating the adverse effect of inflammation caused by LPS in resident macrophages. Whether verapamil or tangeretin offers such protection possibly through the inhibition of P-glycoprotein expression in macrophages needs clarification with the bio availability of these drugs under PGP inhibited conditions is a limitation of this study.


Assuntos
Flavonas , Lipopolissacarídeos , Fator de Transcrição STAT1 , Fator de Transcrição STAT3 , Proteína 3 Supressora da Sinalização de Citocinas , Verapamil , Animais , Verapamil/farmacologia , Fator de Transcrição STAT1/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas/genética , Flavonas/farmacologia , Flavonas/uso terapêutico , Camundongos , Fator de Transcrição STAT3/metabolismo , Masculino , Sepse/tratamento farmacológico , Sepse/imunologia , Sepse/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Regulação para Baixo/efeitos dos fármacos , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/metabolismo , Macrófagos Peritoneais/imunologia , Células Cultivadas , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/imunologia , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
18.
Int Immunopharmacol ; 133: 112111, 2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38678672

RESUMO

BACKGROUND: Brain and muscle arnt-like protein-1 (BMAL1) deficiency is associated with myocardial dysfunction and suppressed sirtuin 1 (SIRT1). However, whether BMAL1 promotes mitophagy via SIRT1 to alleviate myocardial injury in sepsis remains unknown. METHODS: An in vitro myocardial injury model was established using lipopolysaccharide (LPS)-treated H9C2 cells. Knockdown or overexpression of genes was performed using plasmid transfection. Gene and protein expression was assessed by qRT-PCR and Western blot, respectively. Cell proliferation was evaluated using cell counting kit-8, and cellular apoptosis and reactive oxygen species (ROS) levels were analyzed using flow cytometry. An in vivo myocardial injury model of sepsis was established by cecal ligation and puncture in rats. Myocardial function was characterized by analyzing the damage-associated proteins, inflammatory factors, ejection fraction, and fraction shortening. RESULTS: sgBMAL1 significantly decreased BMAL1 levels and remarkably increased the sensitivity of H9C2 cells to LPS stimulation, consequently enhancing LPS-induced apoptosis, inflammation, and ROS levels. These effects were further attenuated by BMAL1 overexpression. BMAL1 knockdown inhibited the expression of SIRT1 and mitophagy-associated proteins. SIRT1 overexpression reversed the enhancement of shBMAL1 on cell proliferation and inflammation. In the rat model of sepsis, BMAL1 overexpression decreased the myocardial injury-associated proteins to recover the myocardial function and suppressed inflammatory activities by promoting mitophagy via SIRT1. CONCLUSION: BMAL1 enhances mitophagy dependent on SIRT1, thereby alleviating myocardial injury in sepsis.


Assuntos
Fatores de Transcrição ARNTL , Mitofagia , Ratos Sprague-Dawley , Sepse , Transdução de Sinais , Sirtuína 1 , Animais , Sirtuína 1/metabolismo , Sirtuína 1/genética , Sepse/metabolismo , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Ratos , Masculino , Linhagem Celular , Apoptose , Lipopolissacarídeos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Espécies Reativas de Oxigênio/metabolismo , Autofagia , Miocárdio/patologia , Miocárdio/metabolismo , Mitocôndrias/metabolismo , Modelos Animais de Doenças
19.
Clinics (Sao Paulo) ; 79: 100354, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38640751

RESUMO

AIM: The study was to clarify the mechanism of miR-1258 targeting Prep1 (pKnox1) to control Transforming Growth Factor ß1 (TGF-ß1)/SMAD3 pathway in septic Acute Lung Injury (ALI)-induced oxidative stress and inflammation. METHODS: BEAS-2B cells and C57BL/6 mice were used to make in vitro and in vivo septic ALI models, respectively. miR-1258 expression was checked by RT-qPCR. After transfection in the in vitro experimental model, inflammation, oxidative stress, viability, and apoptosis were observed through ELISA, MTT, and flow cytometry. RESULTS: In the in vivo model after miR-1258 overexpression treatment, inflammation, oxidative stress, and lung injury were further investigated. The targeting relationship between miR-1258 and Pknox1 was tested. Low miR-1258 was expressed in septic ALI patients, LPS-treated BEAS-2B cells, and mice. Upregulated miR-1258 prevented inflammation, oxidative stress, and apoptosis but enhanced the viability of LPS-treated BEAS-2B cells. The impact of upregulated miR-1258 on LPS-treated BEAS-2B cells was mitigated by inhibiting Pknox1 expression. MiR-1258 overexpression had the alleviating effects on inflammation, oxidative stress, and lung injury of LPS-injured mice through suppressing Pknox1 expression and TGF-ß1/SMAD3 cascade activation. CONCLUSIONS: The study concludes that miR-1258 suppresses oxidative stress and inflammation in septic ALI through the Pknox1-regulated TGF-ß1/SMAD3 cascade.


Assuntos
Lesão Pulmonar Aguda , Apoptose , Camundongos Endogâmicos C57BL , MicroRNAs , Estresse Oxidativo , Sepse , Proteína Smad3 , Fator de Crescimento Transformador beta1 , Animais , Humanos , Masculino , Camundongos , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/metabolismo , Modelos Animais de Doenças , Inflamação/metabolismo , MicroRNAs/metabolismo , MicroRNAs/genética , Sepse/complicações , Sepse/metabolismo , Sepse/genética , Transdução de Sinais , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Regulação para Cima
20.
Metabolomics ; 20(3): 46, 2024 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-38641695

RESUMO

INTRODUCTION: Cardiac dysfunction after sepsis the most common and severe sepsis-related organ failure. The severity of cardiac damage in sepsis patients was positively associated to mortality. It is important to look for drugs targeting sepsis-induced cardiac damage. Our previous studies found that 4-phenylbutyric acid (PBA) was beneficial to septic shock by improving cardiovascular function and survival, while the specific mechanism is unclear. OBJECTIVES: We aimed to explore the specific mechanism and PBA for protecting cardiac function in sepsis. METHODS: The cecal ligation and puncture-induced septic shock models were used to observe the therapeutic effects of PBA on myocardial contractility and the serum levels of cardiac troponin-T. The mechanisms of PBA against sepsis were explored by metabolomics and network pharmacology. RESULTS: The results showed that PBA alleviated the sepsis-induced cardiac damage. The metabolomics results showed that there were 28 metabolites involving in the therapeutic effects of PBA against sepsis. According to network pharmacology, 11 hub genes were found that were involved in lipid metabolism and amino acid transport following PBA treatment. The further integrated analysis focused on 7 key targets, including Comt, Slc6a4, Maoa, Ppara, Pparg, Ptgs2 and Trpv1, as well as their core metabolites and pathways. In an in vitro assay, PBA effectively inhibited sepsis-induced reductions in Comt, Ptgs2 and Ppara after sepsis. CONCLUSIONS: PBA protects sepsis-induced cardiac injury by targeting Comt/Ptgs2/Ppara, which regulates amino acid metabolism and lipid metabolism. The study reveals the complicated mechanisms of PBA against sepsis.


Assuntos
Cardiopatias , Fenilbutiratos , Sepse , Choque Séptico , Aminoácidos/metabolismo , Ciclo-Oxigenase 2/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Cardiopatias/tratamento farmacológico , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolômica , Fenilbutiratos/farmacologia , Fenilbutiratos/uso terapêutico , Sepse/complicações , Sepse/tratamento farmacológico , Sepse/metabolismo , Choque Séptico/complicações , Choque Séptico/tratamento farmacológico , Animais , Camundongos , Modelos Animais de Doenças , Catecol O-Metiltransferase/efeitos dos fármacos , Catecol O-Metiltransferase/metabolismo , PPAR alfa/efeitos dos fármacos , PPAR alfa/metabolismo
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