Metformin Inhibits Chemokine Expression Through the AMPK/NF-κB Signaling Pathway

Ye, Jinhui; Zhu, Na; Sun, Ruipu; Liao, Wenjian; Fan, Shipan; Shi, Fuli; Lin, Hui; Jiang, Shuping; Ying, Ying

doi:10.1089/jir.2018.0061

Cited by 35 publications

(24 citation statements)

References 32 publications

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“…Increasing evidence have shown that MET exerts its anti-oxidative and anti-inflammatory activities via suppression of NF-κB while activation of Nrf2 signaling pathways ( Chiang et al., 2017 ; Ye et al., 2018 ). We next wan to elucidate whether NF-κB and Nrf2 signaling pathways are independent or crosstalk with each other under the GDM condition.…”

Section: Resultsmentioning

confidence: 99%

Metformin Ameliorates Gestational Diabetes Mellitus-Induced Endothelial Dysfunction via Downregulation of p65 and Upregulation of Nrf2

et al. 2020

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Gestational diabetes mellitus (GDM) causes oxidative stress in mothers and infants and causes vascular endothelial dysfunction, which is a key factor for maternal and fetal cardiovascular diseases in the later stage of GDM, seriously threatening the life and health of mothers and infants. Nowadays, metformin (MET) has been discovered to improve endothelial function, but studies regarding the mechanism of MET improving endothelial cell function and alleviating endothelial function under hyperglycemia are still extremely limited. We aimed to investigate whether MET exerts its protective role against hyperglycemia-induced endothelial dysfunction through p65 and Nrf2. In our studies, applying cell migration assay and tube formation assay, we observed an obvious improvement of endothelial function under MET-treated, as characterized by that MET accelerated GDM-attenuated migration and angiogenesis of HUVECs. And ELISA assay results uncovered that Nrf2 expression level was decreased in GDM placenta, HVUECs and maternal serum comparing with normal group, however activation Nrf2 largely ameliorated tube formation under hyperglycemic condition. Furthermore, MET elevated the Nrf2 expression level and the level of nuclear Nrf2 accumulation in hyperglycemic HUVECs. Besides, preliminary evidence predicted that Nrf2 expression was modulated by transcription factor p65, which was increased in GDM peripheral blood, placenta and HUVECs, and suppression of p65 could recover GDM-induced suppression of angiogenesis. In addition, we also confirmed MET restores the GDM-induced angiogenesis impairment may via downregulation of p65 and upregulation of Nrf2. Taken together, the endothelial protective effect of MET under GDM (HG) conditions could be partly attributed to its role in downregulating p65 and upregulating Nrf2.

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Section: Resultsmentioning

confidence: 99%

Metformin Ameliorates Gestational Diabetes Mellitus-Induced Endothelial Dysfunction via Downregulation of p65 and Upregulation of Nrf2

et al. 2020

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“…There are several possible mechanisms to explain how the activators of AMPK could suppress the functions of MDSCs in cancer therapy. For instance, it is known that AMPK activators downregulate the chemokine signaling in macrophages [189, 190] which might impair the chemokine-driven accumulation of MDSCs into tumors. Given that AMPK activators have displayed beneficial effects in cancer combination therapies [191], it would be important to clarify whether they could improve cancer immunotherapies by inhibiting the MDSC-induced immunosuppression.…”

Section: Introductionmentioning

confidence: 99%

AMPK activation inhibits the functions of myeloid-derived suppressor cells (MDSC): impact on cancer and aging

2019

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AMP-activated protein kinase (AMPK) has a crucial role not only in the regulation of tissue energy metabolism but it can also control immune responses through its cooperation with immune signaling pathways, thus affecting immunometabolism and the functions of immune cells. It is known that AMPK signaling inhibits the activity of the NF-κB system and thus suppresses proinflammatory responses. Interestingly, AMPK activation can inhibit several major immune signaling pathways, e.g., the JAK-STAT, NF-κB, C/EBPβ, CHOP, and HIF-1α pathways, which induce the expansion and activation of myeloid-derived suppressor cells (MDSC). MDSCs induce an immunosuppressive microenvironment in tumors and thus allow the escape of tumor cells from immune surveillance. Chronic inflammation has a key role in the expansion and activation of MDSCs in both tumors and inflammatory disorders. The numbers of MDSCs also significantly increase during the aging process concurrently with the immunosenescence associated with chronic low-grade inflammation. Increased fatty acid oxidation and lactate produced by aerobic glycolysis are important immunometabolic enhancers of MDSC functions. However, it seems that AMPK signaling regulates the functions of MDSCs in a context-dependent manner. Currently, the activators of AMPK signaling are promising drug candidates for cancer therapy and possibly for the extension of healthspan and lifespan. We will describe in detail the AMPK-mediated regulation of the signaling pathways controlling the expansion and activation of immunosuppressive MDSCs. We will propose that the beneficial effects mediated by AMPK activation, e.g., in cancers and the aging process, could be induced by the inhibition of MDSC functions.

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“…After IκB is degraded, the NF-κB complex is phosphorylated and translocated to the nucleus. Then, various mRNAs including MMP3 , MMP13 , and COX-2 are upregulated [ 60 , 62 , 63 ]. Activation of the NF-κB signaling pathway leads to the degradation of articular cartilage and increases the expression of catabolic factors that can lead to arthritis [ 64 ].…”

Section: Discussionmentioning

confidence: 99%

Schisandrol A Suppresses Catabolic Factor Expression by Blocking NF-κB Signaling in Osteoarthritis

et al. 2021

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Schisandrol A possesses pharmacological properties and is used to treat various diseases; however, its effects on osteoarthritis (OA) progression remain unclear. Here, we investigated Schisandrol A as a potential therapeutic agent for OA. In vitro, Schisandrol A effects were confirmed based on the levels of expression of catabolic factors (MMPs, ADAMTS5, and Cox2) induced by IL-1β or Schisandrol A treatment in chondrocytes. In vivo, experimental OA in mice was induced using a destabilized medial meniscus (DMM) surgical model or oral gavage of Schisandrol A in a dose-dependent manner, and demonstrated using histological analysis. In vitro and in vivo analyses demonstrated that Schisandrol A inhibition attenuated osteoarthritic cartilage destruction via the regulation of Mmp3, Mmp13, Adamts5, and Cox2 expression. In the NF-κB signaling pathway, Schisandrol A suppressed the degradation of IκB and the phosphorylation of p65 induced by IL-1β. Overall, and Schisandrol A reduced the expression of catabolic factors by blocking NF-κB signaling and prevented cartilage destruction. Therefore, Schisandrol A attenuated OA progression, and can be used to develop novel OA drug therapies.

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Metformin Inhibits Chemokine Expression Through the AMPK/NF-κB Signaling Pathway

Cited by 35 publications

References 32 publications

Metformin Ameliorates Gestational Diabetes Mellitus-Induced Endothelial Dysfunction via Downregulation of p65 and Upregulation of Nrf2

Metformin Ameliorates Gestational Diabetes Mellitus-Induced Endothelial Dysfunction via Downregulation of p65 and Upregulation of Nrf2

AMPK activation inhibits the functions of myeloid-derived suppressor cells (MDSC): impact on cancer and aging

Schisandrol A Suppresses Catabolic Factor Expression by Blocking NF-κB Signaling in Osteoarthritis

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