P2X7 receptor deletion attenuates oxidative stress and liver damage in sepsis

Larrouyet-Sarto, Maria Luciana; Tamura, Augusto Shuiti; Alves, Vinícius Santos; Santana, Patrícia Teixeira; Ciarlini-Magalhães, Roberta; Rangel, Thuany Prado; Siebert, Cassiana; Hartwig, Josiane Rutz; Santos, Tiago Marcon dos; Wyse, Ângela T. S.; Takiya, Christina Maeda; Coutinho‐Silva, Robson; Savio, Luiz Eduardo Baggio

doi:10.1007/s11302-020-09746-7

Cited by 20 publications

(11 citation statements)

References 60 publications

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“…Some proteins and receptors had been proved to be related with oxidative stress, oxygen species metabolic process, etc., during sepsis. For example, heat shock protein 70 in the intracellular environment was reported to have chaperone activity, correcting damaged proteins and modulating inflammatory response ( Sulzbacher et al, 2020 ); P2X7 receptor blockers were reported to limit oxidative damage and inflammations in sepsis ( Larrouyet-Sarto et al, 2020 ); the overexpression of protein kininogen-1 (KNG1) could strengthen inflammation and oxidation in sepsis-induced acute lung injury ( Hu et al, 2020 ). LPS was reported to effect diminishing the intracellular alkalization and change neutrophil size induced by platelet-activating factor (PAF), which was an important mediator of the systemic inflammatory response ( Hug et al, 2021 ), and have an effect on the phagocytosis and reactive oxygen species (ROS) production of neutrophils ( Messerer et al, 2020 ).…”

Section: Resultsmentioning

confidence: 99%

Detecting Critical Functional Ingredients Group and Mechanism of Xuebijing Injection in Treating Sepsis

Yin

et al. 2021

Front. Pharmacol.

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Sepsis is a systemic inflammatory reaction caused by various infectious or noninfectious factors, which can lead to shock, multiple organ dysfunction syndrome, and death. It is one of the common complications and a main cause of death in critically ill patients. At present, the treatments of sepsis are mainly focused on the controlling of inflammatory response and reduction of various organ function damage, including anti-infection, hormones, mechanical ventilation, nutritional support, and traditional Chinese medicine (TCM). Among them, Xuebijing injection (XBJI) is an important derivative of TCM, which is widely used in clinical research. However, the molecular mechanism of XBJI on sepsis is still not clear. The mechanism of treatment of “bacteria, poison and inflammation” and the effects of multi-ingredient, multi-target, and multi-pathway have still not been clarified. For solving this issue, we designed a new systems pharmacology strategy which combines target genes of XBJI and the pathogenetic genes of sepsis to construct functional response space (FRS). The key response proteins in the FRS were determined by using a novel node importance calculation method and were condensed by a dynamic programming strategy to conduct the critical functional ingredients group (CFIG). The results showed that enriched pathways of key response proteins selected from FRS could cover 95.83% of the enriched pathways of reference targets, which were defined as the intersections of ingredient targets and pathogenetic genes. The targets of the optimized CFIG with 60 ingredients could be enriched into 182 pathways which covered 81.58% of 152 pathways of 1,606 pathogenetic genes. The prediction of CFIG targets showed that the CFIG of XBJI could affect sepsis synergistically through genes such as TAK1, TNF-α, IL-1β, and MEK1 in the pathways of MAPK, NF-κB, PI3K-AKT, Toll-like receptor, and tumor necrosis factor signaling. Finally, the effects of apigenin, baicalein, and luteolin were evaluated by in vitro experiments and were proved to be effective in reducing the production of intracellular reactive oxygen species in lipopolysaccharide-stimulated RAW264.7 cells, significantly. These results indicate that the novel integrative model can promote reliability and accuracy on depicting the CFIGs in XBJI and figure out a methodological coordinate for simplicity, mechanism analysis, and secondary development of formulas in TCM.

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Section: Resultsmentioning

confidence: 99%

Detecting Critical Functional Ingredients Group and Mechanism of Xuebijing Injection in Treating Sepsis

Yin

et al. 2021

Front. Pharmacol.

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“…Physiologically, homeostatic inflammatory processes take place and are tightly regulated in a coordinated way, which is essential to maintain tissue and organ homeostasis (Protzer et al, 2012;Robinson et al, 2016). However, when exposed to systemic and excessive inflammation, the liver plays a central role in the initiation of sepsis by magnifying oxidative stress and inflammatory cytokines (Cichoż-Lach and Michalak, 2014;Larrouyet-Sarto et al, 2020). On the other hand, studies also suggested that the alterations of hepatic metabolism contributed to sepsis-related liver injury (Feng et al, 2013;Geng et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Estrogen-Related Receptor γ Agonist DY131 Ameliorates Lipopolysaccharide-Induced Acute Liver Injury

Liu

et al. 2021

Front. Pharmacol.

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Sepsis-associated liver dysfunction remains a challenge in clinical practice with high mortality and limited specific therapies. DY131 is a pharmacological agonist of the orphan receptor estrogen-related receptor (ERR) γ which plays a crucial role in regulating energy generation, oxidative metabolism, cell apoptosis, inflammatory responses, etc. However, its role in acute liver injury is unknown. In this study, we evaluated the effect of DY131 on lipopolysaccharide (LPS)-induced liver injury. Mice were pretreated with DY131 through intraperitoneal injection at a dose of 5 mg/kg/day for 3 days prior to LPS challenge (10 mg/kg). 24 h later, they were anesthetized and sacrificed. Blood and liver tissues were collected for further studies. In a separate experiment, mice were treated with saline (vehicle) or DY131 for 3 days to evaluate the toxicity of DY131. We found that ERRγ was downregulated in the liver tissues from LPS-treated mice. Pretreatment with DY131 ameliorated LPS-induced liver injury as demonstrated by reduced liver enzyme release (ALT, AST, and LDH), improved liver morphological damage, and attenuated oxidative stress, inflammation and apoptosis. Meanwhile, DY131 had no significant side effects on hepatic and renal functions in mice. Finally, transcriptomics analysis revealed that the dysregulated pathways associated with inflammation and metabolism were significantly reversed by DY131 in LPS-treated mice, providing more evidence in favor of the protective effect of DY131 against LPS-induced liver injury. Altogether, these findings highlighted the protective effect of DY131 on LPS-induced hepatotoxicity possibly via suppressing oxidative stress, inflammation, and apoptosis.

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“…In bacterial sepsis, P2X7 and P2X4-mediated ROS production may be necessary to pathogen control in phagocytes [ 142 ]. However, excessive ROS and NO production in sepsis result in oxidative stress, tissue damage, organ dysfunction, and poor outcomes [ 8 , 143 , 144 ]. In this context, P2X7 receptor deletion attenuated ROS and RNS production in the mice liver and brain, promoting increased SOD and catalase (CAT) activity, which diminishes oxidative stress and protection from organ injury [ 143 , 144 ].…”

Section: P2 Receptors Signaling In Redox Biologymentioning

confidence: 99%

Purinergic signaling in the modulation of redox biology

et al. 2021

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Purinergic signaling is a cell communication pathway mediated by extracellular nucleotides and nucleosides. Tri- and diphosphonucleotides are released in physiological and pathological circumstances activating purinergic type 2 receptors (P2 receptors): P2X ion channels and P2Y G protein-coupled receptors. The activation of these receptors triggers the production of reactive oxygen and nitrogen species and alters antioxidant defenses, modulating the redox biology of cells. The activation of P2 receptors is controlled by ecto-enzymes named ectonucleotidases, E-NTPDase1/CD39 and ecto-5’-nucleotidase/CD73) being the most relevant. The first enzyme hydrolyzes adenosine triphosphate (ATP) and adenosine diphosphate (ADP) into adenosine monophosphate (AMP), and the second catalyzes the hydrolysis of AMP to adenosine. The activity of these enzymes is diminished by oxidative stress. Adenosine actives P1 G-coupled receptors that, in general, promote the maintenance of redox hemostasis by decreasing reactive oxygen species (ROS) production and increase antioxidant enzymes. Intracellular purine metabolism can also contribute to ROS generation via xanthine oxidase activity, which converts hypoxanthine into xanthine, and finally, uric acid. In this review, we describe the mechanisms of redox biology modulated by purinergic signaling and how this signaling may be affected by disturbances in the redox homeostasis of cells.

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P2X7 receptor deletion attenuates oxidative stress and liver damage in sepsis

Cited by 20 publications

References 60 publications

Detecting Critical Functional Ingredients Group and Mechanism of Xuebijing Injection in Treating Sepsis

Detecting Critical Functional Ingredients Group and Mechanism of Xuebijing Injection in Treating Sepsis

Estrogen-Related Receptor γ Agonist DY131 Ameliorates Lipopolysaccharide-Induced Acute Liver Injury

Purinergic signaling in the modulation of redox biology

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