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Breaking the vicious loop between inflammation, oxidative stress and coagulation, a novel anti-thrombus insight of nattokinase by inhibiting LPS-induced inflammation and oxidative stress.

ABSTRACT: Thrombosis is a principle cause of cardiovascular disease, the leading cause of morbidity and mortality worldwide; however, the conventional anti-thrombotic approach often leads to bleeding complications despite extensive clinical management and monitoring. In view of the intense crosstalk between inflammation and coagulation, plus the contributing role of ROS to both inflammation and coagulation, it is highly desirable to develop safer anti-thrombotic agent with preserved anti-inflammatory and anti-oxidative stress activities. Nattokinase (NK) possesses many beneficial effects on cardiovascular system due to its strong thrombolytic and anticoagulant activities. Herein, we demonstrated that NK not only effectively prevented xylene-induced ear oedema in mice, but also remarkably protected against LPS-induced acute kidney injury in mice through restraining inflammation and oxidative stress, a central player in the initiation and progression of inflammation. Fascinatingly, in line with our in vivo data, NK elicited prominent anti-inflammatory activity in RAW264.7 macrophages via suppressing the LPS-induced TLR4 and NOX2 activation, thereby repressing the corresponding ROS production, MAPKs activation, and NF-?B translocation from the cytoplasm to the nucleus, where it mediates the expression of pro-inflammatory mediators, such as TNF-?, IL-6, NO, and PAI-1 in activated macrophage cells. In particular, consistent with the macrophage studies, NK markedly inhibited serum PAI-1 levels induced by LPS, thereby blocking the deposition of fibrin in the glomeruli of endotoxin-treated animals. In summary, we extended the anti-thrombus mechanism of NK by demonstrating the anti-inflammatory and anti-oxidative stress effects of NK in ameliorating LPS-activated macrophage signaling and protecting against LPS-stimulated AKI as well as glomeruler thrombus in mice, opening a comprehensive anti-thrombus strategy by breaking the vicious cycle between inflammation, oxidative stress and thrombosis.

SUBMITTER: Wu H

PROVIDER: S-EPMC7078552 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Breaking the vicious loop between inflammation, oxidative stress and coagulation, a novel anti-thrombus insight of nattokinase by inhibiting LPS-induced inflammation and oxidative stress.

Wu Hao H Wang Ying Y Zhang Yupeng Y Xu Feng F Chen Jiepeng J Duan Lili L Zhang Tingting T Wang Jian J Zhang Fengjiao F

Redox biology 20200311

Thrombosis is a principle cause of cardiovascular disease, the leading cause of morbidity and mortality worldwide; however, the conventional anti-thrombotic approach often leads to bleeding complications despite extensive clinical management and monitoring. In view of the intense crosstalk between inflammation and coagulation, plus the contributing role of ROS to both inflammation and coagulation, it is highly desirable to develop safer anti-thrombotic agent with preserved anti-inflammatory and ...[more]

PMID: 32193146

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Project description:BackgroundAcute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), are devastating clinical disorders with high mortality, and for which more effective therapies are urgently needed. FGF1, the prototype member of the FGF family, is shown to exert protective effects against injurious stimuli in multiple disease models. Here we aimed to evaluate whether FGF1 pretreatment is protective against LPS-induced ALI and elucidate the potential underlying mechanisms.MethodsFor drug-treated groups, C57B/6 mice received a single i.p. injection of FGF1 (1 mg/kg) 1 h before the LPS challenge or not. To induce the ALI model, the mice were treated by intratracheal instillation of LPS (5 mg/kg). Then, histopathological changes in lung tissues were assessed by hematoxylin and eosin staining and transmission electron microscopy. ELISA and qPCR assays were used to detect pro-inflammatory cytokine levels in BALF and lung tissues, respectively. The total number of inflammatory cells (neutrophils and macrophages) in BALF were counted using the Wright-Giemsa method. The expressions of reactive oxygen species (ROS) and malondialdehyde (MDA) were measured using their respective kits. Western blot and immunostaining were used to evaluate the expressions of antioxidants (Nrf-2, HO-1, SOD2, GPX4, and Catalase), as well as the inflammatory and/or apoptosis-related factors (TLR4, NF-κB, and Cleaved- caspase 3).ResultsFGF1 pretreatment significantly ameliorated the LPS-induced histopathological changes, reduced lung wet/dry ratios, ROS and MDA levels, total BALF protein, inflammatory cell infiltration, proinflammatory cytokine levels, and significantly increased the expression of antioxidant proteins (Nrf-2, HO-1, Catalase, and SOD2). In addition, FGF1 pretreatment significantly reduced the expression of TLR4 and cleaved- caspase 3, inhibited NF-κB activation, and reduced LPS-induced cell apoptosis.ConclusionsAltogether, our results suggest that FGF1 pretreatment is protective against LPS-induced ALI through mediating anti-inflammatory and antioxidant effects, which may be attributed to the downregulation of TLR4 expression and inhibition of NF-κB activation, as well as promotion of antioxidant defenses. Therefore, FGF1 administration may prove beneficial in preventative strategies for ALI/ARDS.

Project description:Sepsis causes severe dysregulation of organ functions, via the development of oxidative stress and inflammation. These pathophysiological mechanisms are mimicked in mice injected with bacterial lipopolysaccharide (LPS). Here, protective properties of argan oil against LPS-induced oxidative stress and inflammation are explored in the murine model. Mice received standard chow, supplemented with argan oil (AO) or olive oil (OO) for 25 days, before septic shock was provoked with a single intraperitoneal injection of LPS, 16 hours prior to animal sacrifice. In addition to a rise in oxidative stress and inflammatory markers, injected LPS also caused hepatotoxicity, accompanied by hyperglycemia, hypercholesterolemia and hyperuremia. These LPS-associated toxic effects were blunted by AO pretreatment, as corroborated by normal plasma parameters and cell stress markers (glutathione: GSH) and antioxidant enzymology (catalase, CAT; superoxide dismutase, SOD and glutathione peroxidase, GPx). Hematoxylin-eosin staining revealed that AO can protect against acute liver injury, maintaining a normal status, which is pointed out by absent or reduced LPS-induced hepatic damage markers (i.e., alanine aminotransferase (ALT) and aspartate transaminase (AST)). Our work also indicated that AO displayed anti-inflammatory activity, due to down-regulations of genes encoding pro-inflammatory cytokines Interleukin-6 (IL-6) and Tumor Necrosis Factor-? (TNF-?) and in up-regulations of the expression of anti-inflammatory genes encoding Interleukin-4 (IL-4) and Interleukin-10 (IL-10). OO provided animals with similar, though less extensive, protective changes. Collectively our work adds compelling evidence to the protective mechanisms of AO against LPS-induced liver injury and hence therapeutic potentialities, in regard to the management of human sepsis. Activations of IL-4/Peroxisome Proliferator-Activated Receptors (IL-4/PPARs) signaling and, under LPS, an anti-inflammatory IL-10/Liver X Receptor (IL-10/LXR) route, obviously indicated the high potency and plasticity of the anti-inflammatory properties of argan oil.

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Dataset Information

Breaking the vicious loop between inflammation, oxidative stress and coagulation, a novel anti-thrombus insight of nattokinase by inhibiting LPS-induced inflammation and oxidative stress.

Publications

Breaking the vicious loop between inflammation, oxidative stress and coagulation, a novel anti-thrombus insight of nattokinase by inhibiting LPS-induced inflammation and oxidative stress.

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