Bergenin Monohydrate Attenuates Inflammatory Response via MAPK and NF-κB Pathways Against Klebsiella pneumonia Infection.
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SUBMITTER: Tang Q
PROVIDER: S-EPMC8129520 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background: Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a common respiratory disease characterized by persistent hypoxemia and an uncontrolled inflammatory response. Valsartan, an angiotensin II type 1 receptor antagonist, is clinically used to treat hypertension and has anti-inflammatory and antioxidant effects on gefitinib-induced pneumonia in rats. However, the potential therapeutic effects of valsartan on lipopolysaccharide (LPS)-induced ALI remain unclear. This study investigated the protective role of valsartan in LPS-induced ALI and its underlying mechanisms. Methods: LPS-treated BEAS-2B cells and ALI mouse model were established. BEAS-2B cells were treated with LPS (10 μg/mL) for 24h, with or without valsartan (20, 40, and 80 µM). For ALI mouse models, LPS (5 mg/kg) was administered through intratracheal injection to treat the mice for 24h, and valsartan (10 or 30 mg/kg) was injected intraperitoneally twice 2 h before and 12 h after the LPS injection. Pulmonary functional parameters were examined by an EMKA pulmonary system. Hematoxylin and eosin staining, flow cytometry, CCK-8 assay, qRT-PCR, ELISA, immunofluorescence, Western blotting, and related commercial kits were used to assess the pathological damage to the lungs, neutrophil recruitment in the lung tissue and bronchoalveolar lavage fluid (BALF), cell viability, inflammation, oxidative activity, and mucus production, respectively. Potential mechanisms were further explored using network pharmacology and Western blotting. Results: Valsartan rescued LPS-reduced cell viability of BEAS-2B cells, improved the pulmonary function, ameliorated pathological lung injury in mice with ALI, ameliorated LPS-induced neutrophil recruitment in BALF and lung tissue of mice, attenuated oxidative stress by increasing the level of SOD and decreasing that of MDA and GSSG, inhibited LPS-induced MUC5AC overproduction, decreased the LPS-induced increase in expression of pro-inflammatory cytokines/chemokines including TNF-α, IL-6, IL-1β, CXCL-1 and CXCL-2, and restored the expression of anti-inflammatory IL-10. Mechanistic studies showed that valsartan inhibits LPS-induced phosphorylation of nuclear factor-kappa B (NF-κΒ) and mitogen-activated protein kinases (MAPKs) including P38, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK) in both LPS-treated cells and the mouse model of ALI. Conclusion: Valsartan protects against LPS-induced ALI by attenuating oxidative stress, reducing MUC5AC production, and attenuating the inflammatory response that may involve MAPK and NF-κΒ pathways.
| S-EPMC10822936 | biostudies-literature
Project description:Background and purpose: Fengshi Gutong capsule (FSGTC), a traditional herbal formula, has been used clinically in China for the treatment of arthritis. However, the mechanism underlying the therapeutic effects of FSGTC on osteoarthritis (OA) has not been elucidated. The present study investigated the function and mechanisms of FSGTC in rat OA model and interleukin (IL)-1β-stimulated synovial cells. Materials and methods: Rat OA model was established by intra-articular injection containing 4% papain. IL-1β-induced SW982 cells were used as an OA cell model. Safranin-O-Fast green (S-O) and hematoxylin-eosin (HE) stainings were used to observe the changes in cartilage morphology. Enzyme-linked immunosorbent assay (ELISA) and real-time quantitative PCR (qPCR) detected the expression of inflammatory cytokines. In addition, molecular mechanisms were analyzed by Western blot in the OA cell model. Results: FSGTC treatment significantly relieved the degeneration of cartilage and reduced the contents of tumor necrosis factor-α (TNF-α) and IL-6 in the serum in papain-induced OA rats. FSGTC also reduced the protein and mRNA levels of IL-6 and IL-8 in IL-1β-stimulated SW982 cells. Moreover, it inhibited the phosphorylation levels of ERK (extracellular signal-related kinase), JNK (c-Jun N-terminal kinase), p38, Akt (protein kinase B), and c-Jun. It also decreased the extent of IκBα degradation and p65 protein translocation into the nucleus. Conclusion: The current data confirmed the protective effects of FSGTC in the rat and OA cell models. The results suggested that FSGTC reduced the production of inflammatory mediators via restraining the activation of mitogen-activated protein kinases (MAPK), nuclear factor kappa B (NF-κB), activator protein-1 (AP-1), and Akt.
| S-EPMC6107711 | biostudies-literature
Project description:Gefitinib is an effective treatment for patients with locally advanced non-small cell lung cancer. However, it is associated with cardiotoxicity that can limit its clinical use. Liraglutide, a glucagon-like peptide 1 receptor agonist, showed potent cardioprotective effects with the mechanism is yet to be elucidated. Therefore, this study aimed to determine the efficiency of liraglutide in protecting the heart from damage induced by gefitinib. Adult male Wistar rats were randomly divided into control group, liraglutide group (200 µg/kg by i.p. injection), gefitinib group (30 mg/kg orally) and liraglutide plus gefitinib group. After 28 days, blood and tissue samples were collected for histopathological, biochemical, gene and protein analysis. We demonstrated that gefitinib treatment (30 mg/kg) resulted in cardiac damage as evidenced by histopathological studies. Furthermore, serum Creatine kinase-MB (CK-MB), N-terminal pro B-type natriuretic peptide (NT-proBNP) and cardiac Troponin-I (cTnI) were markedly elevated in gefitinib group. Pretreatment with liraglutide (200 µg/kg), however, restored the elevation in serum markers and diminished gefitinib-induced cardiac damage. Moreover, liraglutide improved the gene and protein levels of anti-oxidant (superoxide dismutase) and decreased the oxidative stress marker (NF-κB). Mechanistically, liraglutide offered protection through upregulation of the survival kinases (ERK1/2 and Akt) and downregulation of stress-activated kinases (JNK and P38). In this study, we provide evidence that liraglutide protects the heart from gefitinib-induced cardiac damage through its anti-oxidant property and through the activation of survival kinases.
| S-EPMC7132601 | biostudies-literature
Project description:Conventional treatments for chronic periodontitis are less effective in controlling inflammation and often relapse. Therefore, it is necessary to explore an immunomodulatory medication as an adjuvant. Ginsenoside Rb3 (Rb3), one of the most abundant active components of ginseng, has been found to possess anti-inflammatory and immunomodulatory properties. Here, we detected the anti-inflammatory effect of Rb3 on Porphyromonas gingivalis LPS-stimulated human periodontal ligament cells and experimental periodontitis rats for the first time. We found that the expression of pro-inflammatory mediators, including IL-1β, IL-6 and IL-8, upregulated by lipopolysaccharide (LPS) stimulation was remarkably downregulated by Rb3 treatment in a dose-dependent manner at both transcriptional and translational levels. Network pharmacological analysis of Rb3 showed that the mitogen-activated protein kinase (MAPK) signaling pathway had the highest richness and that p38, JNK, and ERK molecules were potential targets of Rb3 in humans. Western blot analysis revealed that Rb3 significantly suppressed the phosphorylation of p38 MAPK and p65 NF-κB, as well as decreased the expression of total AKT. In experimental periodontitis rat models, reductions in alveolar bone resorption and osteoclast generation were observed in the Rb3 treatment group. Thus, we can conclude that Rb3 ameliorated Porphyromonas gingivalis LPS-induced inflammation by inhibiting the MAPK/AKT/NF-κB signaling pathways and attenuated alveolar bone resorption in experimental periodontitis rats.
| S-EPMC7588009 | biostudies-literature
Project description:Daeshiho-tang (DSHT), a traditional herbal formula with diverse pharmacological effects, has shown promise in medicine owing to its anti-hypertensive, anti-diabetic, and anti-inflammatory properties. However, the precise molecular mechanism underlying these effects remains unclear. Thus, we investigated the effect of DSHT on inflammatory response and oxidative stress to understand its molecular mechanism using lipopolysaccharide (LPS)-induced macrophage (RAW 264.7) cells. DSHT decreased the contents of nitric oxide (NO) and prostaglandin E2 (PGE2) through downregulating inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein expressions. DSHT suppressed the LPS-induced TLR4 as well as MyD88, subsequently suppressing the NF-κB activation and the phosphorylation of MAPK (p38, ERK, and JNK). Radical scavenging activity results revealed a dose-dependent response of DSHT with diminished ABTS activity, a hallmark of oxidative stress potential. Furthermore, DSHT enhanced Nrf2 and HO-1 expression in response to LPS. Collectively, our findings indicated that DSHT exert anti-inflammatory effect and regulating oxidative stress by modulating TLR4/MyD88, NF-κB, MAPK, and Nrf2/HO-1 pathways, consequently can provide potential therapeutic strategy for the prevention and treatment of inflammation and oxidative stress-related diseases.
| S-EPMC10622541 | biostudies-literature
Project description:Cigarette smoke (CS) is the main cause of chronic obstructive pulmonary disease (COPD), and continuous CS exposure causes lung inflammation and deterioration. To investigate the protective effects of Artemisia gmelinii against lung inflammation in this study, cigarette smoke extract (CSE)/lipopolysaccharide (LPS)-treated alveolar macrophages (AMs) and mice stimulated with CSE/porcine pancreas elastase (PPE) were used. Artemisia gmelinii ethanol extract (AGE) was effective in decreasing the levels of cytokines, chemokine, inducible nitric oxide synthase, and cyclooxygenase-2 by inhibiting mitogen-activated protein (MAP) kinases/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway in AMs. Additionally, oral administration of AGE suppressed inflammatory cells' infiltration and secretion of inflammatory cytokines, chemokines, matrix metallopeptidase 9, and neutrophil extracellular traps in bronchoalveolar lavage fluid from the COPD model. Moreover, the obstruction of small airways, the destruction of the lung parenchyma, and expression of IL-6, TNF-α, IL-1β, and MIP-2 were suppressed by inhibiting NF-κB activation in the lung tissues of the AGE group. These effects are associated with scopolin, chlorogenic acid, hyperoside, 3,4-di-O-caffeoylquinic acid, 3,5-di-O-caffeoylquinic acid, and 4,5-di-O-caffeoylquinic acid, which are the main components of AGE. These data demonstrate the mitigation effect of AGE on lung inflammation via inhibition of MAPK and NF-κB pathways, suggesting that AGE may be instrumental in improving respiratory and lung health.
| S-EPMC8944700 | biostudies-literature
Project description:ObjectivesA role for the type II arginine methyltransferase PRMT5 in various human diseases has been identified. In this study, the potential mechanism underlying the involvement of PRMT5 in the pathological process leading to osteoarthritis (OA) was investigated.MethodsPRMT5 expression in cartilage tissues from patients with OA and control individuals was assessed by immunohistochemical staining. The regulatory and functional roles of PRMT5 in the chondrocytes of patients with OA and control individuals were determined by western blotting and reverse transcription polymerase chain reaction. The effects of the PRMT5 inhibitor EPZ on interleukin-1β-induced inflammation were examined in the chondrocytes of patients with OA and in the destabilized medial meniscus (DMM) of a mouse model of OA.ResultsPRMT5 was specifically upregulated in the cartilage of patients with OA. Moreover, adenovirus-mediated overexpression of PRMT5 in human chondrocytes caused cartilage degeneration. This degeneration was induced by elevated expression levels of matrix-degrading enzymes (matrix metalloproteinase-3 (MMP-3) and matrix metalloproteinase-13 (MMP-13)) in chondrocytes. The activation of the MAPK and nuclear factor κB signaling pathways was evidenced by elevated levels of p-p65, p-p38, and p-JNK. These effects were attenuated by inhibiting the expression of PRMT5. In the mouse model, EPZ inhibited PRMT5 expression, thus protecting mouse cartilage from DMM-induced OA.ConclusionsOur results demonstrate that PRMT5 is a crucial regulator of OA pathogenesis, implying that EPZ has therapeutic value in the treatment of this cartilage-destroying disease.
| S-EPMC7650297 | biostudies-literature
Project description:Globally, gastric ulcer is a vital health hazard for a human. Rabdosia inflexa (RI) has been used in traditional medicine for inflammatory diseases. The present study aimed to investigate the protective effect and related molecular mechanism of RI using lipopolysaccharide (LPS)-induced inflammation in RAW 246.7 cells and HCl/EtOH-induced gastric ulcer in mice. We applied 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), nitric oxide (NO), reactive oxygen species (ROS), histopathology, malondialdehyde (MDA), quantitative real-time polymerase chain reaction (qPCR), immunohistochemistry (IHC), and Western blot analyses to evaluate the protective role of RI. Study revealed that RI effectively attenuated LPS-promoted NO and ROS production in RAW 246.7 cells. In addition, RI mitigated gastric oxidative stress by inhibiting lipid peroxidation, elevating NO, and decreasing gastric inflammation. RI significantly halted elevated gene expression of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), inducible nitric oxide synthetase (iNOS), and cyclooxygenase-2 (COX-2) in gastric tissue. Likewise, RI markedly attenuated the mitogen-activated protein kinases (MAPKs) phosphorylation, COX-2 expression, phosphorylation and degradation of inhibitor kappa B (IκBα) and activation of nuclear factor kappa B (NF-κB). Thus, experimental findings suggested that the anti-inflammatory and gastroprotective activities of RI might contribute to regulating pro-inflammatory cytokines and MAPK/NF-κB signaling pathways.
| S-EPMC5855806 | biostudies-literature
Project description:BackgroundStephania yunnanensis H. S. Lo is widely used as an antipyretic, analgesic and anti-inflammatory herbal medicine in SouthWest China. In this study, we investigated the anti-inflammatory activity and mechanism of sinoacutine (sino), one of the primary components extracted from this plant.MethodsA RAW264.7 cell model was established using lipopolysaccharide (LPS) induced for estimation of cytokines in vitro, qPCR was used to estimate gene expression, western blot analysis was used to estimate protein level and investigate the regulation of NF- κB, JNK and MAPK signal pathway. In addition, an acute lung injury model was established to determine lung index and levels of influencing factors.ResultsUsing the RAW264.7 model, we found that sino reduced levels of nitric oxide (NO), tumour necrosis factor-α (TNF-α), interleukin (IL)-1β and prostaglandin E2 (PGE2) but increased levels of IL-6. qPCR analysis revealed that sino (50, 25 μg/ml) inhibited gene expression of nitric oxide synthase (iNOS). western blot analysis showed that sino significantly inhibited protein levels of both iNOS and COX-2. Further signalling pathway analysis validated that sino also inhibited phosphorylation of p65 in the NF-κB and c-Jun NH2 terminal kinase (JNK) signalling pathways but promoted the phosphorylation of extracellular signal regulated kinase (ERK) and p38 in the MAPK signalling pathway. In addition, in a mouse model induced by LPS, we determined that sino reduced the lung index and the levels of myeloperoxidase (MPO), NO, IL-6 and TNF-α in lung tissues and bronchoalveolar lavage fluid (BALF) in acute lung injury (ALI).ConclusionTaken together, our results demonstrate that sino is a promising drug to alleviate LPS-induced inflammatory reactions.
| S-EPMC8605577 | biostudies-literature
Project description:BackgroundAnti-nerve growth factor (NGF) monoclonal antibodies (anti-NGF mAbs) have been reported to significantly attenuate pain, but the mechanism involved has not been fully elucidated, and the serious adverse events associated with mAbs seriously limit their clinical use. This study further investigated the mechanism by which peripheral NGF is involved in neuropathic pain and found safe, natural compounds that target NGF to attenuate neuropathic pain.MethodsNociception was assessed by the Von Frey hair and Hargreaves' methods. Western-blotting, qPCR and immunofluorescence were used to detect the cell signaling pathway. RAW264.7 macrophages and RSC96 Schwann cells were cultured for in vitro evaluation.ResultsIntraplantar administration of anti-NGF mAbs suppressed the expression of phosphorylated transforming growth factor-β-activated kinase 1 (TAK1) in the dorsal root ganglion (DRG) and sciatic nerve. Intraplantar administration of a TAK1 inhibitor attenuated CCI-induced neuropathic pain and suppressed the expression of phosphorylated mitogen-activated protein kinases (MAPKs) in the DRG and sciatic nerve. Perisciatic nerve administration of levo-corydalmine (l-CDL) on the operated side obviously attenuated CCI-induced neuropathic pain and suppressed the expression of mNGF and proNGF. In addition, l-CDL-induced antinociception was reversed by intraplantar administration of NGF. Further results indicated that l-CDL-induced suppression of phosphorylated TAK1, MAPKs, and p65 and expression of the proinflammatory cytokines TNF-α and IL-1β in the DRG and sciatic nerve were all abolished by NGF. In addition, in vitro experiments indicated that l-CDL suppressed the secretion of NGF and proNGF in RAW264.7 macrophages and RSC96 Schwann cells, which was abolished by AP-1 and CREB agonists, respectively.ConclusionsThis study showed NGF inhibition suppressed TAK1 in the periphery to attenuate CCI-induced neuropathic pain through inhibition of downstream MAPK and p65 signaling. The natural compound l-CDL inhibited NGF secretion by macrophages and Schwann cells and downstream TAK1-MAPK/NF-κB signaling in the periphery to attenuate CCI-induced neuropathic pain. Video abstract Proposed mechanisms underlying the effect of l-CDL in periphery of CCI rats. In CCI rats, macropahages and Schwann cells could secret NGF to act on the receptors in the periphery to activate TAK1-MAPK/NF-κB axis and promote the release of proinflammatory cytokines, including TNF-α and IL-1β to promote neuropathic pain. l-CDL decreased the secretion of NGF through inhibiting AP-1 and CREB respectively in RAW264.7 and RSC96 Schwann cells to attenuate CCI-induced neuropathic pain by inhibiting the TAK1-p38 MAPK/NF-κB signaling pathway.
| S-EPMC7171864 | biostudies-literature