Metformin inhibits nuclear factor κB activation and decreases serum high-sensitivity C-reactive protein level in experimental atherogenesis of rabbits

Li, Songnan; Xiang, Wu; Zeng, Qiutang; Feng, Yan; Cheng, Xiang; Mao, Xiaobo; Wang, Tianhong; Deng, Heping

doi:10.1007/s00380-008-1137-7

Cited by 86 publications

(65 citation statements)

References 48 publications

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“…[22][23][24] Consistent with previous studies, [25][26][27][28][29] our study also indicates that metformin prevents activation of NF-jB. In the present study, we have shown that the expression of LPS-induced NF-jB in ciliary bodies as well as retinal tissues was suppressed in metfomin-treated rats.…”

Section: Discussionsupporting

confidence: 81%

Antidiabetic Drug Metformin Suppresses Endotoxin-Induced Uveitis in Rats

Kalariya

Mohammed

Ansari

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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PURPOSE.To investigate the therapeutic effects of metformin, a commonly used antidiabetic drug, in preventing endotoxininduced uveitis (EIU) in rats.METHODS. EIU in Lewis rats was developed by subcutaneous injection of lipopolysaccharide (LPS; 150 lg). Metformin (300 mg/kg body weight, intraperitoneally) or its carrier was injected either 12 hours before or 2 hours after LPS induction. Three and 24 hours after EIU, eyes were enucleated and aqueous humor (AqH) was collected. The MILLIPLEX-MAG Rat cytokine-chemokine magnetic bead array was used to determine inflammatory cytokines. The expression of Cox-2, phosphorylation of AMPK, and NF-jB (p65) were determined immunohistochemically. Primary human nonpigmented ciliary epithelial cells (HNPECs) were used to determine the in vitro efficacy of metformin.RESULTS. Compared with controls, the EIU rat AqH had significantly increased number of infiltrating cells and increased levels of various cytokines and chemokines (TNF-a, MCP-1, IL-1b, MIP-1a, IL-6, Leptin, and IL-18) and metformin significantly prevented the increase. Metformin also prevented the expression of Cox-2 and phosphorylation of p65, and increased the activation of AMPK in the ciliary bodies and retinal tissues. Moreover, metformin prevented the expression of Cox-2, iNOS, and activation of NF-kB in the HNPECs and decreased the levels of NO and PGE2 in cell culture media. CONCLUSIONS.Our results for the first time demonstrate a novel role of the antidiabetic drug, metformin, in suppressing uveitis in rats and suggest that this drug could be developed to prevent uveitis complications. (Invest Ophthalmol Vis Sci.

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Section: Discussionsupporting

confidence: 81%

Antidiabetic Drug Metformin Suppresses Endotoxin-Induced Uveitis in Rats

Kalariya

Mohammed

Ansari

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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“…This is in line with some findings from experimental models in which metformin reduced levels of several inflammatory mediators (IL-6, IL-1β, TNF-α, prostaglandin E2, nitric oxide) in a dose-dependent manner (Hyun et al, 2013). Also for metformin, one of the biological mechanisms underpinning this anti-inflammatory effect was the inhibition of transcription factor NF-κB (Hyun et al, 2013; Li et al, 2009). Taken together these findings indicate metformin as a potential alternative strategy to caloric restriction in reducing inflammaging.…”

Section: Discussionmentioning

confidence: 99%

Evidence-based nutritional and pharmacological interventions targeting chronic low-grade inflammation in middle-age and older adults: A systematic review and meta-analysis

Custodero

Mankowski

Lee

et al. 2018

Ageing Research Reviews

129

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Growing evidence suggests chronic low-grade inflammation (LGI) as a possible mechanism underlying the aging process. Some biological and pharmaceutical compounds may reduce systemic inflammation and potentially avert functional decline occurring with aging. The aim of the present meta-analysis was to examine the association of pre-selected interventions on two established biomarkers of inflammation, interleukin-6 (IL-6), and C-reactive protein (CRP) in middle-age and older adults with chronic LGI. We reviewed the literature on potential anti-inflammatory compounds, selecting them based on safety, tolerability, acceptability, innovation, affordability, and evidence from randomized controlled trials. Six compounds met all five inclusion criteria for our systematic review and meta-analysis: angiotensin II receptor blockers (ARBs), metformin, omega-3, probiotics, resveratrol and vitamin D. We searched in MEDLINE, PubMed and EMBASE database until January 2017. A total of 49 articles fulfilled the selection criteria. Effect size of each study and pooled effect size for each compound were measured by the standardized mean difference. I2 was computed to measure heterogeneity of effects across studies. The following compounds showed a significant small to large effect in reducing IL-6 levels: probiotics (−0.68 pg/ml), ARBs (−0.37 pg/ml) and omega-3 (−0.19 pg/ml). For CRP, a significant small to medium effect was observed with probiotics (−0.43 mg/L), ARBs (−0.2 mg/L), omega-3 (−0.17 mg/L) and metformin (−0.16 mg/L). Resveratrol and vitamin D were not associated with any significant reductions in either biomarker. These results suggest that nutritional and pharmaceutical compounds can significantly reduce established biomarkers of systemic inflammation in middle-age and older adults. The findings should be interpreted with caution, however, due to the evidence of heterogeneity across the studies.

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“…However, metformin inhibition of complex 1 function in isolated mitochondria requires very high metformin concentrations (18). In the context of atherosclerosis, metformin inhibits NF-κB activation and decreases C-reactive protein levels (20), and it inhibits the inflammatory response via a pathway involving AMPK and the tumor suppressor PTEN (21). Not much is known about how metformin mediates any of its anticancer effects.…”

mentioning

confidence: 99%

Metformin inhibits the inflammatory response associated with cellular transformation and cancer stem cell growth

Hirsch

Iliopoulos

Struhl

2012

Proc. Natl. Acad. Sci. U.S.A.

395

285

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Metformin, the first-line drug for treating diabetes, inhibits cellular transformation and selectively kills cancer stem cells in breast cancer cell lines. In a Src-inducible model of cellular transformation, metformin inhibits the earliest known step in the process, activation of the inflammatory transcription factor NF-κB. Metformin strongly delays cellular transformation in a manner similar to that occurring upon a weaker inflammatory stimulus. Conversely, inhibition of transformation does not occur if metformin is added after the initial inflammatory stimulus. The antitransformation effect of metformin can be bypassed by overexpression of Lin28B or IL1β, downstream targets of NF-κB. Metformin preferentially inhibits nuclear translocation of NF-κB and phosphorylation of STAT3 in cancer stem cells compared with non-stem cancer cells in the same population. The ability of metformin to block tumor growth and prolong remission in xenografts in combination with doxorubicin is associated with decreased function of the inflammatory feedback loop. Lastly, metformin-based combinatorial therapy is effective in xenografts involving inflammatory prostate and melanoma cell lines, whereas it is ineffective in noninflammatory cell lines from these lineages. Taken together, our observations suggest that metformin inhibits a signal transduction pathway that results in an inflammatory response. As metformin alters energy metabolism in diabetics, we speculate that metformin may block a metabolic stress response that stimulates the inflammatory pathway associated with a wide variety of cancers.cancer treatment | inflammation | cancer prevention

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Metformin inhibits nuclear factor κB activation and decreases serum high-sensitivity C-reactive protein level in experimental atherogenesis of rabbits

Cited by 86 publications

References 48 publications

Antidiabetic Drug Metformin Suppresses Endotoxin-Induced Uveitis in Rats

Antidiabetic Drug Metformin Suppresses Endotoxin-Induced Uveitis in Rats

Evidence-based nutritional and pharmacological interventions targeting chronic low-grade inflammation in middle-age and older adults: A systematic review and meta-analysis

Metformin inhibits the inflammatory response associated with cellular transformation and cancer stem cell growth

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