Kaempferol reduces K63-linked polyubiquitination to inhibit nuclear factor-κB and inflammatory responses in acute lung injury in mice

Qian, Jianchang; Chen, Xuemei; Chen, Xiaojun; Sun, Chao; Jiang, Yuchen; Qian, Yuanyuan; Zhang, Yali; Khan, Zia A.; Zhang, Jianmin; Liang, Guang; Cheng, Zheng

doi:10.1016/j.toxlet.2019.02.005

Cited by 40 publications

(30 citation statements)

References 36 publications

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“…According to the degree of the nodes in the compound-target network, we identified eight compounds as potential active ingredients that might participate in the regulatory processes of LJF in ALI. Obviously, the active ingredients chrysoeriol ( Wei et al, 2019 ), luteolin ( Rungsung et al, 2018 ), kaempferol ( Chen et al, 2012 ; Qian et al, 2019 ), and quercetin ( Wang et al, 2018 ) have well-established roles in lung inflammation. ALI-related genes were acquired using the GeneCard database.…”

Section: Discussionmentioning

confidence: 99%

An integrated network pharmacology and RNA-Seq approach for exploring the preventive effect of Lonicerae japonicae flos on LPS-induced acute lung injury

Liu

Yin

Feng

et al. 2021

Journal of Ethnopharmacology

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Ethnopharmacological relevance Lonicerae japonicae flos (LJF, the dried flower bud or newly bloomed flower of Lonicera japonica Thunb.), a typical herbal medicine, targets the lung, heart and stomach meridian with the function of clearing heat and detoxication. It ameliorated inflammatory responses and protected against acute lung inflammation in animal models. Acute lung injury (ALI) is a kind of inflammatory disease in which alveolar cells are damaged. However, a network pharmacology study to thoroughly investigate the mechanisms preventing ALI has not been performed. Aim of the study In this study, we examined the main active ingredients in LJF and the protective effects of LJF on LPS-induced ALI in rats. Materials and methods First, the main active ingredients of LJF were screened in the TCMSP database, and the ALI-associated targets were collected from the GeneCards database. Then, we used compound-target and target-pathway networks to uncover the preventive mechanisms of LJF. Furthermore, we assessed the preventive effects of LJF in an LPS-induced rat model with the RNA-Seq technique to validate the possible molecular mechanisms of the effects of LJF in the treatment of ALI. Results The network pharmacology results identified 28 main active compounds in LJF, and eight chemical components highly related to the potential targets, which were potential active compounds in LJF. In all, 94 potential targets were recognized, including IL6, TNF, PTGS2, APP, F2, and GRM5. The pathways revealed that the possible targets of LJF involved in the regulation of the IL-17 signalling pathway. Then, in vivo experiments indicated that LJF decreased the levels of proinflammatory cytokines (TNF-, IL-1, and IL-6) in serum and bronchoalveolar lavage fluid, decreased the levels of oxidative stress factors (MDA and MPO) and increased the activities of SOD and GSH-Px in lung tissue. The RNA-Seq results revealed that 7811, 775 and 3654 differentially expressed genes (DEGs) in Ctrl (control group), ALI-LJF (Lonicerae japonicae flos group) and ALI-DXSM (dexamethasone group), respectively. KEGG pathway analysis showed that the DEGs associated with immune response and inflammation signalling pathways and the IL-17 signalling pathway were significantly enriched in LJF. Compared with those in ALI, the expression of CXCL2, CXCL1, CXCL6, NFKBIA, IFNG, IL6, IL17A, IL17F, IL17C, MMP9 and TNFAIP3, which are involved in the IL-17 signalling pathway, were significantly decreased in the LJF group according to the qRT-PCR analyses. Conclusions In view of the network pharmacology and RNA-Seq results, the study identified the main active ingredient and potential targets of LJF involved in protecting against ALI, which suggests directions for further research on LJF.

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Section: Discussionmentioning

confidence: 99%

An integrated network pharmacology and RNA-Seq approach for exploring the preventive effect of Lonicerae japonicae flos on LPS-induced acute lung injury

Liu

Yin

Feng

et al. 2021

Journal of Ethnopharmacology

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“…Kaempferol can improve myocardial fibroblast inflammation through inhibiting NF-kB activity by regulating p65 and IkB a, the major related proteins of NF-kB signaling pathway (Tang et al, 2015). Kaempferol also can protect lung from acute injury in mice by inhibiting LPS-mediated NF-kB activation (Qian et al, 2019). In mouse retinal I/R injury, kaempferol suppressed NOD like receptor protein (NLRP) 1/NLRP3 inflammasomes and caspase-8 via c-Jun N-terminal kinase (JNK) and NF-kB pathways to attenuate retinal ganglion cell death (Lin et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Kaempferol Improves Lung Ischemia-Reperfusion Injury via Antiinflammation and Antioxidative Stress Regulated by SIRT1/HMGB1/NF-κB Axis

Chen

Yang

et al. 2020

Front. Pharmacol.

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Trauma, organ transplantation, and thromboembolism are the main causes of lung ischemia-reperfusion injury (LIRI), and new therapies and drugs are urgent to relieve LIRI. In preliminary experiment, authors found that kaempferol could improve LIRI in rats, and the current study further explored its possible mechanism. The model of rat LIRI was established and appropriate research methods were implemented. Results shown that kaempferol could significantly improve LIRI, inhibit release of inflammatory factors including interleukin (IL) 6 and tumor necrosis factor (TNF) a in bronchoalveolar lavage fluid, and reduce oxidative stress reaction. Western blotting was used to detect protein expression levels and found that kaempferol could up-regulate the protein expressions of phosphorylated (p-) p65 and p65, and down-regulate the protein expression of sirtuin (SIRT) 1. Immunofluorescence was used to localize the expression of high mobility group box (HMGB) 1 and found its higher expression in outside of nucleus. However, the above effects of kaempferol on LIRI markedly attenuated by EX 527, a selective inhibitor of SIRT 1. Taken together, we first reported the protective effect of kaempferol on rat LIRI and confirmed that kaempferol's antiinflammation and antioxidative stress involving the SIRT1/ HMGB1/NF-kB axis.

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“…ex Paxt., showed inhibitory effects on inflammatory responses and oxidative stress. At 100 mg/kg, kaempferol exhibited inhibitory effects on lung pathological changes and lung edema in mice with LPS-induced ALI, which was likely induced by regulating the polyubiquitination of TRAF6 as well as inhibiting the MAPK and NF-κB signaling pathways [ 123 , 124 ]. Another study found that kaempferol also inhibited H9N2 virus-induced ALI through inhibiting TLR4/MyD88-mediated NF-κB and MAPKs pathways [ 125 ].…”

Section: Natural Compounds That Exert Anti-ali Effectsmentioning

confidence: 99%

Natural product derived phytochemicals in managing acute lung injury by multiple mechanisms

Zhou

et al. 2021

Pharmacological Research

224

121

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Kaempferol reduces K63-linked polyubiquitination to inhibit nuclear factor-κB and inflammatory responses in acute lung injury in mice

Cited by 40 publications

References 36 publications

An integrated network pharmacology and RNA-Seq approach for exploring the preventive effect of Lonicerae japonicae flos on LPS-induced acute lung injury

An integrated network pharmacology and RNA-Seq approach for exploring the preventive effect of Lonicerae japonicae flos on LPS-induced acute lung injury

Kaempferol Improves Lung Ischemia-Reperfusion Injury via Antiinflammation and Antioxidative Stress Regulated by SIRT1/HMGB1/NF-κB Axis

Natural product derived phytochemicals in managing acute lung injury by multiple mechanisms

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