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Rhein prevents endotoxin-induced acute kidney injury by inhibiting NF-κB activities.

ABSTRACT: This study aimed to explore the effect and mechanisms of rhein on sepsis-induced acute kidney injury by injecting lipopolysaccharide (LPS) and cecal ligation and puncture (CLP) in vivo, and on LPS-induced HK-2 cells in vitro. For histopathological analysis, rhein effectively attenuated the severity of renal injury. Rhein could significantly decrease concentration of BUN and SCr and level of TNF-α and IL-1β in two different mouse models of experimental sepsis. Moreover, rhein could markedly attenuate circulating leukocyte infiltration and enhance phagocytic activity of macrophages partly impaired at 12 h after CLP. Rhein could enhance cell viability and suppresse the release of MCP-1 and IL-8 in LPS-stimulated HK-2 cells Furthermore, rhein down regulated the expression of phosphorylated NF-κB p65, IκBα and IKKβ stimulated by LPS both in vivo and in vitro. All these results suggest that rhein has protective effects on endotoxin-induced kidney injury. The underlying mechanism of rhein on anti-endotoxin kidney injury may be closely related with its anti-inflammatory and immunomodulatory properties by decreasing NF-κB activation through restraining the expression and phosphorylation of the relevant proteins in NF-κB signal pathway, hindering transcription of NF-κB p65.These evidence suggest that rhein has a potential application to treat endotoxemia-associated acute kidney injury.

SUBMITTER: Yu C

PROVIDER: S-EPMC4493574 | biostudies-other | 2015 Jul

REPOSITORIES: biostudies-other

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Astaxanthin prevents against lipopolysaccharide-induced acute lung injury and sepsis via inhibiting activation of MAPK/NF-κB.

Project description:BackgroundEndotoxin-induced acute inflammatory diseases such as sepsis, mediated by excessive production of various pro-inflammatory cytokines remain the leading cause of mortality in critically ill patients. Lipopolysaccharide (LPS), the characteristic endotoxin found in the outer membrane of Gram-negative bacteria, can induce the innate immunity system and through Mitogen activated protein kinase (MAPK) and Nuclear Factor-κB (NF-κB), increase the production of inflammatory mediators. Astaxanthin (ASX), a xanthophyll carotenoid, exerts beneficial effects against oxidation, inflammation, and cancer. But poor evidence has been reported that whether it has protective effects on LPS-induced injury. This study aims to investigate the effects of ASX on LPS-induced sepsis and acute lung injury and to demonstrate its mechanisms.MethodsMouse prime macrophage (MPM) challenged with LPS were used for in vitro pharmacological activity and mechanistic studies. Inflammatory facors (tumor necrosis factor-alpha and interleukin-6 levels) in MPM were determined. The mouse models of LPS-induced sepsis and acute lung injury administrated with or without the compound were used for in vivo studies.ResultsPre-treatment of MPM with ASX inhibited MAPK/NF-κB signaling pathway, and attenuated LPS-increased inflammatory factors in vitro. In animal models of LPS-induced sepsis and acute lung injury, administration of ASX significantly improved survival and protected lung injury. Subsequently, ASX was shown to suppress LPS-induced inflammatory factors increase, MAPK phosphorylation, and NF-κB activation in vivo.ConclusionsASX exerts impressively protective effects on LPS-induced injury in vitro and in vivo. Taken together, it might be used as a potential candidate for clinical sepsis.

| S-EPMC6456544 | biostudies-literature

Magnesium hydride protects against acetaminophen-induced acute kidney injury by inhibiting TXNIP/NLRP3/nf-κb pathway.

Project description:Acetaminophen (APAP)-induced acute kidney injury (APAP-AKI) has turned into one of reasons for clinic obtained renal insufficiency. Magnesium hydride (MgH2), as a solid-state hydrogen source, might be potentially applied in clinical practice. The current study aimed to investigate the protective effect of MgH2 against APAP-AKI. The results showed that MgH2 improved renal function and histological injury in mice of APAP-AKI. MgH2 also had protective effects on APAP-induced cytotoxicity in HK-2 cells. In addition, the increased level of reactive oxygen species (ROS) and expressions of inflammatory cytokines (TNF-α and IL-1β) and pro-apoptotic factors (Bad, Bax, Caspase3, and CytC) induced by APAP were downregulated with MgH2 treatment. Furthermore, the expressions of molecules related to TXNIP/NLRP3/NF-κB pathway (TXNIP, NLRP3, NF-κB p65 and p-NF-κB p65) in renal tissues and HK-2 cells were enhanced by APAP overdose, which were reduced by MgH2 administration. Collectively, this study indicated that MgH2 protects against APAP-AKI by alleviating oxidative stress, inflammation and apoptosis via inhibition of TXNIP/NLRP3/NF-κB signaling pathway.

| S-EPMC10946266 | biostudies-literature

FGF18 alleviates sepsis-induced acute lung injury by inhibiting the NF-κB pathway.

Project description:BackgroundAcute lung injury (ALI) is a devastating clinical disorder with a high mortality rate, and there is an urgent need for more effective therapies. Fibroblast growth factor 18 (FGF18) has potent anti-inflammatory properties and therefore has become a focus of research for the treatment of lung injury. However, the precise role of FGF18 in the pathological process of ALI and the underlying mechanisms have not been fully elucidated.MethodsA mouse model of ALI and human umbilical vein endothelial cells (HUVEC) stimulated with lipopolysaccharide (LPS) was established in vivo and in vitro. AAV-FGF18 and FGF18 proteins were used in C57BL/6J mice and HUVEC, respectively. Vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and p65 protein levels were determined by western blotting or immunofluorescent staining. Afterward, related inhibitors were used to explore the potential mechanism by which FGF18 relieves inflammation.ResultsIn this study, we found that FGF18 was significantly upregulated in LPS-induced ALI mouse lung tissues and LPS-stimulated HUVECs. Furthermore, our studies demonstrated that overexpressing FGF18 in the lung or HUVEC could significantly alleviate LPS-induced lung injury and inhibit vascular leakage.ConclusionsMechanically, FGF18 treatment dramatically inhibited the NF-κB signaling pathway both in vivo and in vitro. In conclusion, these results indicate that FGF18 attenuates lung injury, at least partially, via the NF-κB signaling pathway and therefore may be a potential therapeutic target for ALI.

| S-EPMC10902988 | biostudies-literature

LIGHT aggravates sepsis-associated acute kidney injury via TLR4-MyD88-NF-κB pathway.

Project description:Sepsis-associated acute kidney injury (SA-AKI) is a common clinical critical care syndrome. It has received increasing attention due to its high morbidity and mortality; however, its pathophysiological mechanisms remain elusive. LIGHT, the 14th member of the tumour necrosis factor (TNF) superfamily and a bidirectional immunoregulatory molecule that regulates inflammation, plays a pivotal role in disease pathogenesis. In this study, mice with an intraperitoneal injection of LPS and HK-2 cells challenged with LPS were employed as a model of SA-AKI in vivo and in vitro, respectively. LIGHT deficiency notably attenuated kidney injury in pathological damage and renal function and markedly mitigated the inflammatory reaction by decreasing inflammatory mediator production and inflammatory cell infiltration in vivo. The TLR4-Myd88-NF-κB signalling pathway in the kidney of LIGHT knockout mice was dramatically down-regulated compared to the controls. Recombinant human LIGHT aggravated LPS-treated HK-2 cell injury by up-regulating the expression of the TLR4-Myd88-NF-κB signalling pathway and inflammation levels. TAK 242 (a selective TLR4 inhibitor) reduced this trend to some extent. In addition, blocking LIGHT with soluble receptor fusion proteins HVEM-Fc or LTβR-Fc in mice attenuated renal dysfunction and pathological damage in SA-AKI. Our findings indicate that LIGHT aggravates inflammation and promotes kidney damage in LPS-induced SA-AKI via the TLR4-Myd88-NF-κB signalling pathway, which provide potential strategies for the treatment of SA-AKI.

| S-EPMC7579683 | biostudies-literature

Nimbolide protects against endotoxin-induced acute respiratory distress syndrome by inhibiting TNF-α mediated NF-κB and HDAC-3 nuclear translocation.

Project description:Acute respiratory distress syndrome (ARDS) is characterized by an excessive acute inflammatory response in lung parenchyma, which ultimately leads to refractory hypoxemia. One of the earliest abnormalities seen in lung injury is the elevated levels of inflammatory cytokines, among them, the soluble tumor necrosis factor (TNF-α) has a key role, which exerts cytotoxicity in epithelial and endothelial cells thus exacerbates edema. The bacterial lipopolysaccharide (LPS) was used both in vitro (RAW 264.7, THP-1, MLE-12, A549, and BEAS-2B) and in vivo (C57BL/6 mice), as it activates a plethora of overlapping inflammatory signaling pathways involved in ARDS. Nimbolide is a chemical constituent of Azadirachta indica, which contains multiple biological properties, while its role in ARDS is elusive. Herein, we have investigated the protective effects of nimbolide in abrogating the complications associated with ARDS. We showed that nimbolide markedly suppressed the nitrosative-oxidative stress, inflammatory cytokines, and chemokines expression by suppressing iNOS, myeloperoxidase, and nitrotyrosine expression. Moreover, nimbolide mitigated the migration of neutrophils and mast cells whilst normalizing the LPS-induced hypothermia. Also, nimbolide modulated the expression of epigenetic regulators with multiple HDAC inhibitory activity by suppressing the nuclear translocation of NF-κB and HDAC-3. We extended our studies using molecular docking studies, which demonstrated a strong interaction between nimbolide and TNF-α. Additionally, we showed that treatment with nimbolide increased GSH, Nrf-2, SOD-1, and HO-1 protein expression; concomitantly abrogated the LPS-triggered TNF-α, p38 MAPK, mTOR, and GSK-3β protein expression. Collectively, these results indicate that TNF-α-regulated NF-κB and HDAC-3 crosstalk was ameliorated by nimbolide with promising anti-nitrosative, antioxidant, and anti-inflammatory properties in LPS-induced ARDS.

| S-EPMC6349848 | biostudies-literature

Melittin Ameliorates Endotoxin-Induced Acute Kidney Injury by Inhibiting Inflammation, Oxidative Stress, and Cell Death in Mice.

Project description:Sepsis-related acute kidney injury (AKI) is a worldwide health problem, and its pathogenesis involves multiple pathways. Lipopolysaccharide (LPS) is an endotoxin that induces systemic inflammatory responses. Melittin, a main constituent of bee venom, exerts several biological activities such as antioxidant, anti-inflammatory, and antiapoptotic actions. However, whether melittin protects against endotoxin-induced AKI remains undetermined. Here, we aimed to examine the potential action of melittin on LPS-induced renal injury and explore the mechanisms. We showed that acute renal failure and structural damage after injection of LPS were markedly attenuated by administration of melittin. The peptide also suppressed expression of markers of direct tubular damage in kidneys of the LPS-treated mice. Mechanistically, melittin reduced systemic and renal levels of cytokines and inhibited renal accumulation of immune cells with concomitant suppression of nuclear factor kappa-B pathway. Increased amounts of lipid peroxidation products after LPS treatment were largely decreased by melittin. Additionally, the peptide decreased expression of nicotinamide adenine dinucleotide phosphate oxidase 4 and enhanced nuclear factor erythroid-2-related factor 2-mediated antioxidant defenses. Moreover, melittin inhibited apoptotic and necroptotic cell death after LPS treatment. Lastly, we showed that melittin improved the survival rate of LPS-injected mice. These results suggest that melittin ameliorates endotoxin-induced AKI and mortality through inhibiting inflammation, oxidative injury, and apoptotic and necroptotic death of tubular epithelial cells.

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Low-Dose Aspirin Prevents Kidney Damage in LPS-Induced Preeclampsia by Inhibiting the WNT5A and NF-κB Signaling Pathways.

Project description:Preeclampsia (PE) is a serious pregnancy-related disease, and patients usually present with a high inflammatory response. Previous studies have suggested that aspirin (ASP) may have a role in alleviating the pathogenesis of preeclampsia. However, whether ASP can improve kidney damage and the mechanism for improving it is currently unclear. Here we optimized a lipopolysaccharide (LPS)-induced PE mouse model to identify the role of ASP in renal protection. We found that ASP treatment ameliorated LPS-induced renal failure and pathological changes, the tubular injury was significantly attenuated by ASP. Administration of ASP decreased the renal expression of pro-inflammatory factors, resulting in reduced kidney inflammation. The number of GALECTIN-3-positive cells was reduced, and the up-regulation of IL-6 and TNF-α was decreased. In addition, ASP also suppressed renal cell apoptosis and oxidative stress. An in vitro study indicated that ASP relieved LPS-induced HK-2 cell damage by inhibiting WNT5A/NF-κB signaling. Collectively, our data suggest that ASP is a useful therapeutic option for PE-related kidney injury.

| S-EPMC8006287 | biostudies-literature

Wogonin Alleviates Kidney Tubular Epithelial Injury in Diabetic Nephropathy by Inhibiting PI3K/Akt/NF-κB Signaling Pathways.

Project description:IntroductionKidney tubular epithelial injury is one of the key factors in the progression of diabetic nephropathy (DN). Wogonin is a kind of flavonoid, which has many pharmacological effects, such as anti-inflammation, anti-oxidation and anti-fibrosis. However, the effect of wogonin in renal tubular epithelial cells during DN is still unknown.Materials and methodsSTZ-induced diabetic mice were given doses of wogonin (10, 20, and 40 mg/kg) by intragastric administration for 16 weeks. The metabolic indexes from blood and urine and pathological damage of renal tubules in mice were evaluated. Human tubular epithelial cells (HK-2) were cultured in high glucose (HG) condition containing wogonin (2μM, 4μM, 8μM) for 24 h. Tubular epithelial cell inflammation and autophagic dysfunction both in vivo and in vitro were assessed by Western blot, qRT-PCR, IHC, and IF analyses.ResultsThe treatment of wogonin attenuated urinary albumin and histopathological damage in tubulointerstitium of diabetic mice. We also found that wogonin down-regulated the expression of pro-inflammatory cytokines and autophagic dysfunction in vivo and in vitro. Molecular docking and Cellular Thermal Shift Assay (CETSA) results revealed that mechanistically phosphoinositide 3-kinase (PI3K) was the target of wogonin. We then found that inhibiting PI3K eliminated the protective effect of wogonin. Wogonin regulated autophagy and inflammation via targeting PI3K, the important connection point of PI3K/Akt/NF-κB signaling pathway.ConclusionOur study is the first to demonstrate the novel role of wogonin in mitigating tubulointerstitial fibrosis and renal tubular cell injury via regulating PI3K/Akt/NF-κB signaling pathway-mediated autophagy and inflammation. Wogonin might be a latent remedial drug against tubular epithelial injury in DN by targeting PI3K.

| S-EPMC8291679 | biostudies-literature

Knockdown of P2Y4 ameliorates sepsis-induced acute kidney injury in mice <i>via</i> inhibiting the activation of the NF-κB/MMP8 axis.

Project description:Sepsis-induced acute kidney injury (S-AKI) has emerged as a frequent and life-threatening complication in critically ill patients, which is characterized by a systematic inflammatory response and a rapid decline in kidney function. P2Y4, a member of G protein-coupled P2Y nucleotide receptor family, has been reported to serve as a crucial player in inflammatory responses during the development of neurocognitive disorder and myocardial infarction. Nonetheless, the biological role of P2Y4 in S-AKI remains largely unclear. This study aimed to decipher the biological role of P2Y4 in S-AKI and illuminate the potential mechanisms. In this study, S-AKI models were successfully established in mice via cecal ligation and puncture. Results showed that the kidney tissues from S-AKI mouse models exhibited a higher P2Y4 expression level than from the sham-operated group. Knockdown of P2Y4 was found to remarkably alleviate kidney damage and reduce inflammatory response in mice of S-AKI models. Moreover, P2Y4 ablation inhibited the activation of the NF-κB/MMP-8 signaling axis. Additionally, mechanistic studies revealed that rescuing MMP-8 reversed the alleviating effects of P2Y4 knockdown against renal cell damage. Collectively, our findings indicate that P2Y4 knockdown ameliorated S-AKI in mice via inhibiting the activation of the NF-κB/MMP-8 axis and that P2Y4 may represent a novel therapeutic target for S-AKI patients.

| S-EPMC9467379 | biostudies-literature

Hispidulin Ameliorates Endotoxin-Induced Acute Kidney Injury in Mice.

Project description:Lipopolysaccharide (LPS) is an endotoxin that plays a crucial role in septic acute kidney injury (AKI). Hispidulin is a natural flavonoid that possesses various biological activities. Recent studies have shown that hispidulin administration alleviates various inflammatory diseases in animal models. This study aimed to investigate the renoprotective effect of hispidulin on LPS-induced AKI. Male C57BL/6 mice were administered LPS (10 mg/kg) with or without hispidulin (50 mg/kg). Hispidulin administration attenuated renal dysfunction, histological alterations, and the upregulation of neutrophil gelatinase-associated lipocalin. This flavonoid also reduced cytokine production and Toll-like receptor 4 expression, inhibited nuclear factor-κB and mitogen-activated protein kinase cascades, and alleviated immune cell infiltration. The oxidation of lipids and DNA was also inhibited by hispidulin administration. This antioxidant effect of hispidulin was associated with the downregulation of NADPH oxidase 4, the activation of catalase and superoxide dismutase activities, and the restoration of glutathione levels. Moreover, hispidulin administration attenuated tubular cell apoptosis by inhibiting caspase-3 pathway. These data suggest that hispidulin ameliorates endotoxin-induced kidney injury by suppressing inflammation, oxidative stress, and tubular cell death.

| S-EPMC8948942 | biostudies-literature

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