Protostemonine alleviates heat-killed methicillin-resistant Staphylococcus aureus-induced acute lung injury through MAPK and NF-κB signaling pathways.
Acute lung injury (ALI) and its most severe form acute respiratory distress syndrome (ARDS) caused by gram-positive bacteria threatens human life because effective treatments and medicines is unavailable. Protostemonine (PSN), an active alkaloid mainly isolated from the roots of Stemona sesslifolia, has anti-inflammatory effects on asthma and gram-negative bacteria-induced ALI. Here, we found that PSN exhibits anti-inflammatory effects and alleviates heat-killed methicillin-resistant Staphylococcus aureus (HKMRSA)-induced pneumonia. PSN treatment significantly attenuated HKMRSA-induced pathological injury, pulmonary neutrophil infiltration, tissue permeability and the production of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) in murine ALI model. In addition, PSN decreased the content of TNF-α, IL-1β, IL-6 and the expression of iNOS, as well as the production of NO in HKMRSA-induced bone marrow derived macrophages (BMDMs). Furthermore, treatment with PSN suppressed the activation of MAPKs (e.g. p38 MAPK, JNK and ERK) and NF-κB. Collectively, our results suggest that PSN ameliorates gram-positive bacteria-induced ALI in mice by inhibition of the MAPK and NF-κB signaling pathways, and our studies suggest that PSN might be a novel candidate for treating ALI/ARDS.
Wu Y
，Nie Y
，Huang J
，Qiu Y
，Wan B
，Liu G
，Chen J
，Chen D
，Pang Q
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Ginsenoside Rb1 ameliorates Staphylococcus aureus-induced Acute Lung Injury through attenuating NF-κB and MAPK activation.
Acute lung injury (ALI) is clinically characterized by excessive inflammation leading to acute respiratory distress syndrome (ARDS), having high morbidity and mortality both in human and animals. Ginsenoside Rb1 (Rb1) is a major primary bioactive component extracted by Panax ginseng, which has numerous pharmacological functions such as anti-cancer, anti-inflammatory, and antioxidant. However, the anti-inflammatory effects of Rb1 in Staphylococcus aureus (S. aureus)-induced ALI in mice have not been investigated. The aim of the current study was to determine the anti-inflammatory influence of Rb1 on S. aureus-induced ALI in mice, and to explore its possible underlying principle mechanisms in RAW 264.7 macrophage cells. The results of physical morphology, histopathological variation and wet-to-dry weight ratio of lungs revealed that Rb1 significantly attenuated S. aureus-induced lung injury. Furthermore, qPCR results displayed that Rb1 inhibited IL-1β, IL-6 and TNF-α production both in vivo and in vitro. The activation of Toll-like receptor 2 (TLR2) by S. aureus was inhibited by application of Rb1 as confirmed by results of immunofluorescence assay. The expression of NF-kB and MAPK signaling proteins revealed that Rb1 significantly attenuated the phosphorylation of p65, ERK, as well as JNK. Altogether, the results of this experiment presented that Rb1 has ability to protect S. aureus-induced ALI in mice by attenuating TLR-2-mediated NF-kB and MAPK signaling pathways. Consequently, Rb-1 might be a potential medicine in the treatment of S. aureus-induced lung inflammation.
Shaukat A
，Guo YF
，Jiang K
，Zhao G
，Wu H
，Zhang T
，Yang Y
，Guo S
，Yang C
，Zahoor A
，Akhtar M
，Umar T
，Shaukat I
，Rajput SA
，Hassan M
，Deng G
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Sophoricoside ameliorates methicillin-resistant Staphylococcus aureus-induced acute lung injury by inhibiting Bach1/Akt pathway.
The lack of effective treatments for methicillin-resistant Staphylococcus aureus (MRSA) infection, which often leads to severe acute lung injury (ALI), poses a grave threat to human life. Sophoricoside (SOP), an isoflavone glycoside abundant in the fruit of traditional Chinese herbal Sophora japonica l., showed anti-inflammatory effects against atopic dermatitis, allergic inflammation, and lipopolysaccharide-induced ALI. However, its effect and underlying mechanism on MRSA-induced ALI remain unclear.
The aim of this study is to assess the protective effect of SOP in MRSA-induced ALI and elucidate its underlying molecular mechanisms.
In vivo experiments were conducted using wild-type mice to establish MRSA-induced ALI mouse model, and the effects of SOP on ALI were evaluated by hematoxylin-eosin staining, flow cytometry, quantitative real-time polymerase chain reaction, and several biochemical indicators. Adoptive transfer experiments and BTB and CNC homology 1 knockout (Bach1-/-) mice were also utilized in this study. In vitro studies employed murine macrophages RAW264.7 cells, primary bone marrow-derived macrophages (BMDMs), and primary lung macrophages to explore the underlying molecular mechanisms.
The administration of SOP ameliorated MRSA-induced ALI by improving pulmonary histological damages, reducing neutrophil infiltration, suppressing oxidative stress levels, and decreasing the expression of inflammatory cytokines. In isolation experiments with ALI mouse lung macrophages and macrophage adoptive transfer experiments, SOP prevented macrophage activation, thereby reducing the production of proinflammatory cytokines. In vitro experiments demonstrated that SOP decreased the expression of inflammatory mediators in lipoteichoic acid (LTA)-stimulated RAW264.7 cells, BMDMs, and primary lung macrophages. Additionally, SOP inhibited protein kinase B (Akt) phosphorylation and treatment with MK2206-a specific inhibitor of Akt-eliminated SOP's ability to suppress LTA-stimulated macrophage inflammation. Furthermore, stimulation with LTA or MRSA up-regulated Bach1 expression; however, deletion of Bach1 abolished the inhibitory effect of SOP on p-Akt activation as well as inflammation and ALI development.
This study provides the first evidence that SOP effectively mitigates MRSA-induced ALI via suppressing macrophage activation through the inhibition of Bach1/Akt pathway. These findings highlight the potential of SOP as a novel therapeutic agent for treating MRSA-induced ALI.
Wu Y
，He S
，Zhang Y
，Li S
，Liu R
，Zhang Y
，Jing Y
，Chen D
，Tong Y
，Wang Z
，Wang Q
，Pang Q
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Protective effect of Jie-Geng-Tang against Staphylococcus aureus induced acute lung injury in mice and discovery of its effective constituents.
Jie-Geng-Tang (JGT), a famous traditional Chinese medicine prescription, consists of Platycodonis Radix and Glycyrrhizae Radix et Rhizoma. According to traditional medicinal theory, JGT exerts various effects, including apocenosis, detoxifying, moisturizing the lung and relieving sore throat. It is often used to treat throat inflammation and lung diseases.
To determine the protective effect of JGT on Staphylococcus aureus (S. aureus)-induced acute lung injury (ALI) in mice and to identify the compounds in the prescription that may be responsible for antibacterial activity.
The protective effect of JGT was assessed using S. aureus-induced ALI mice (i.g., 2.7 g/kg/day). Bacterial burden, pathological morphology, cytokine levels of TNF-α, IL-1β, KC, and MIP-2 were evaluated in the lung and bronchoalveolar lavage fluid at 24 h post-infection, respectively. Twenty three compounds in the prescription were evaluated for their minimum inhibitory concentration (MIC) in vitro by means of microbroth dilution method against S. aureus. The antibacterial effects in vitro of licochalcone A and isoliquiritigenin were also investigated by transmission electron microscopy. In vivo antibacterial activities of licochalcone A and isoliquiritigenin were evaluated by survival rates, bacterial burden, and pathological morphology of lung tissues on S. aureus-induced ALI in mice (i.p., 160 mg/kg/day).
Pretreatment with JGT significantly improved the pathological morphology of lung tissues on S. aureus-induced ALI in mice, accompanied with the reduced bacterial burden in the lungs and inhibited expression of inflammatory cytokine levels at 24 h post-infection. Five compounds, namely licochalcone A, licoisoflavone B, glyasperin A, isoliquiritigenin, and licochalcone B from Jie-Geng-Tang displayed good antibacterial activities against S. aureus (MIC < 128 μg/mL). Furthermore, applications of licochalcone A and isoliquiritigenin resulted in the increased survival rates, reduced bacterial burden in the lungs, and improved pathological morphology of lung tissues in S. aureus infected mice.
The study demonstrated that Jie-Geng-Tang presented protective role of acute lung injury, which supported its traditional use for the treatment of lung diseases. Licochalcone A, isoliquiritigenin, licoisoflavone B, glyasperin A, and licochalcone B might contribute to the antibacterial activity of JGT on S. aureus-induced acute lung injury. The anti-S. aureus activity of licoisoflavone B, glyasperin A, and licochalcone B in vitro, as well as the anti-S. aureus activity of licochalcone A in vivo, were first reported in this study.
Liu Y
，Hong Z
，Qian J
，Wang Y
，Wang S
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