Anti-inflammatory Mechanism of Ginseng Saponin Metabolite Rh3 in Lipopolysaccharide-Stimulated Microglia: Critical Role of 5′-Adenosine Monophosphate-Activated Protein Kinase Signaling Pathway

Lee, Yu Young; Park, Jin-Sun; Lee, Eun Jung; Lee, Sang-Yun; Kim, Dong Hyun; Kang, Jihee Lee; Kim, Hee Sun

doi:10.1021/jf506110y

Cited by 64 publications

(44 citation statements)

References 39 publications

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“…Interestingly, recent studies have also revealed that inflammatory defenses can be regulated by AMPK, which does not directly target NF‐κB but rather mediates the inhibition of NF‐κB by modulating SIRT1, PGC‐1α, p53, or FoxO . Rh3 inhibits neuroinflammation accompanied by microglial activation at least partially by upregulating AMPK/SIRT1 and inhibiting the phosphorylation of its downstream kinases PI3K/Akt and JAK1/STAT1; this is eventually associated with the inhibition of NF‐κB and enhancement of Nrf2 pathways . Rg1 was found to alleviate inflammation‐based liver damage caused by CCl4, which was attributed to the stimulation of AMPK/SIRT1 and suppression of the NF‐κB pathway …”

Section: Cellular Stress Response Mechanisms Regulated By Ginsenosidesmentioning

confidence: 97%

Cellular stress response mechanisms as therapeutic targets of ginsenosides

2017

Medicinal Research Reviews

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Ginseng, one of the most widely used traditional herbal medicines and dietary supplements, has historically been recognized as a tonic herb and adaptogen that can enhance the body's tolerance to various adversities. Ginsenosides are a diverse group of steroidal saponins that comprise the major secondary metabolites of ginseng and are responsible for its multiple pharmacological effects. Emerging evidence suggests that hormetic phytochemicals produced by environmentally stressed plants can activate the moderate cellular stress response mechanisms at a subtoxic level in humans, which may enhance tolerance against severe dysfunction or disease. In this review, we initially describe the role of ginsenosides in the chemical defense of plants from the genus Panax suffering from biotic and abiotic stress. Next, we summarize the diverse evolutionarily conserved cellular stress response pathways regulated by ginsenosides and the subsequent stress tolerance against various dysfunctions or diseases. Finally, the structure-activity relationship involved in the effect of ginsenosides is also analyzed. The evidence presented in this review implicates that ginseng as "the King of all herbs" could be regarded as a well-characterized example of the critical role of cellular stress response mechanisms in understanding the health benefits provided by herbal medicines from an evolutionary and ecological perspective.

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Section: Cellular Stress Response Mechanisms Regulated By Ginsenosidesmentioning

confidence: 97%

Cellular stress response mechanisms as therapeutic targets of ginsenosides

2017

Medicinal Research Reviews

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“…Recent studies show that AMPK regulates both energy homeostasis and inflammatory defense [11–13]. Activation of AMPK inhibits ATP-consuming anabolic processes (such as protein translation) mainly via inhibiting mammalian target of rapamycin (mTOR) signaling [14].…”

Section: Introductionmentioning

confidence: 99%

“…In the brain, AMPK activation inhibits lipopolysaccharide (LPS)-induced pro-inflammatory cytokines expression by modulating NF-κB in primary rat microglia [16]. AMPK activation also inhibits the expression of pro-inflammatory mediators in the cerebral cortex of LPS-injected rats [11]. Thus, AMPK may be an interesting target for neuroprotective drugs in inflammatory conditions, such as morphine tolerance.…”

Section: Introductionmentioning

confidence: 99%

Metformin reduces morphine tolerance by inhibiting microglial-mediated neuroinflammation

Pan

Sun

Jiang

et al. 2016

J Neuroinflammation

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BackgroundTolerance seriously impedes the application of morphine in clinical medicine. Thus, it is necessary to investigate the exact mechanisms and efficient treatment. Microglial activation and neuroinflammation in the spinal cord are thought to play pivotal roles on the genesis and maintaining of morphine tolerance. Activation of adenosine monophosphate-activated kinase (AMPK) has been associated with the inhibition of inflammatory nociception. Metformin, a biguanide class of antidiabetic drugs and activator of AMPK, has a potential anti-inflammatory effect. The present study evaluated the effects and potential mechanisms of metformin in inhibiting microglial activation and alleviating the antinociceptive tolerance of morphine.MethodsThe microglial cell line BV-2 cells and mouse brain-derived endothelial cell line bEnd3 cells were used. Cytokine expression was measured using quantitative polymerase chain reaction. Cell signaling was assayed by western blot and immunohistochemistry. The antinociception and morphine tolerance were assessed in CD-1 mice using tail-flick tests.ResultsWe found that morphine-activated BV-2 cells, including the upregulation of p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation, pro-inflammatory cytokines, and Toll-like receptor-4 (TLR-4) mRNA expression, which was inhibited by metformin. Metformin suppressed morphine-induced BV-2 cells activation through increasing AMPK phosphorylation, which was reversed by the AMPK inhibitor compound C. Additionally, in BV-2 cells, morphine did not affect the cell viability and the mRNA expression of anti-inflammatory cytokines. In bEnd3 cells, morphine did not affect the mRNA expression of interleukin-1β (IL-1β), but increased IL-6 and tumor necrosis factor-α (TNF-α) mRNA expression; the effect was inhibited by metformin. Morphine also did not affect the mRNA expression of TLR-4 and chemokine ligand 2 (CCL2). Furthermore, systemic administration of metformin significantly blocked morphine-induced microglial activation in the spinal cord and then attenuated the development of chronic morphine tolerance in mice.ConclusionsMetformin significantly attenuated morphine antinociceptive tolerance by suppressing morphine-induced microglial activation through increasing AMPK phosphorylation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0754-9) contains supplementary material, which is available to authorized users.

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“…3B). MAPKs play critical roles in cell proliferation, differentiation, and apoptosis [23], [24]. Therefore, these results demonstrate that inhibition of the MAPKs-apoptosis signaling cascade plays a critical role in mediating the renoprotective effect of ginsenoside Rh3.…”

Section: Resultsmentioning

confidence: 62%

Protective effect of ginsenoside Rh3 against anticancer drug-induced apoptosis in LLC-PK1 kidney cells

Lee

Kang

2017

Journal of Ginseng Research

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BackgroundGinsenosides are active components of Panax ginseng that exert various health benefits including kidney protection effect. The medicinal activity of ginsenosides can be enhanced by modulating their stereospecificity by heat processing. Ginsenosides Rk2 and Rh3 represent positional isomers of the double bond at C-20(21) or C-20(22).MethodsThe present study investigated the kidney-protective effects of ginsenosides Rk2 and Rh3 against cisplatin, a platinum based anticancer drug, induced apoptotic damage in renal proximal LLC-PK1 cells.ResultsAs a result, ginsenoside Rh3 shows a stronger protective effect than that shown by Rk2. Cisplatin-induced elevated protein levels of phosphorylated c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), p38, and cleaved caspase-3 decreased after cotreatment with ginsenoside Rh3. The increase in the percentage of apoptotic LLC-PK1 cells induced by cisplatin treatment also significantly reduced after cotreatment with ginsenoside Rh3.ConclusionThese results demonstrate that inhibition of the JNK and ERK mitogen-activated protein kinase signaling cascade plays a critical role in mediating the renoprotective effect of ginsenoside Rh3.

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Anti-inflammatory Mechanism of Ginseng Saponin Metabolite Rh3 in Lipopolysaccharide-Stimulated Microglia: Critical Role of 5′-Adenosine Monophosphate-Activated Protein Kinase Signaling Pathway

Cited by 64 publications

References 39 publications

Cellular stress response mechanisms as therapeutic targets of ginsenosides

Cellular stress response mechanisms as therapeutic targets of ginsenosides

Metformin reduces morphine tolerance by inhibiting microglial-mediated neuroinflammation

Protective effect of ginsenoside Rh3 against anticancer drug-induced apoptosis in LLC-PK1 kidney cells

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