Metformin ameliorates the proinflammatory state in patients with carotid artery atherosclerosis through sirtuin 1 induction

Xu, Wei; Deng, Yangyang; Yang, Lin; Zhao, Sijia; Liu, Junhui; Zhao, Zhao; Wang, Lijun; Maharjan, Prabindra; Gao, Shanshan; Tian, Yuling; Zhuo, Xianlu; Zhao, Yan; Zhou, Juan; Yuan, Zuyi; Wu, Yue

doi:10.1016/j.trsl.2015.06.002

Cited by 47 publications

(43 citation statements)

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“…Following full text revision of remaining 289 articles, other 240 studies were excluded. Overall, 49 RCTs (Bahr et al, 2011; Bays et al, 2013; Bitzur et al, 2010; Bo et al, 2016; Breslavsky et al, 2013; Caballero et al, 2004; Chandler et al, 2014; Darghosian et al, 2015; Dawczynski et al, 2013; De Jager et al, 2005; de Jager et al, 2014; Duggan et al, 2015; Ebrahimi et al, 2009; Feher et al, 2014; Gagnon et al, 2014; Goldberg et al, 2014; Hass et al, 2014; Hutchins et al, 2013; Krysiak et al, 2011, 2013; Link et al, 2006; Magyar et al, 2012; Mazloom et al, 2013; Militaru et al, 2013; Mohamadshahi et al, 2014; Murphy et al, 2007; Nodari et al, 2011; Ogino et al, 2010; Paoli et al, 2015; Persson et al, 2006; Pooya et al, 2010; Pot et al, 2009; Pradhan et al, 2009; Rajkumar et al, 2014; Sadiya et al, 2015; Schiano et al, 2008; Shaseb et al, 2016; Sinha-Hikim et al, 2015; Sokol et al, 2012; Stricker et al, 2012; Tome-Carneiro et al, 2012; Tousoulis et al, 2008; Troseid et al, 2009; Valentini et al, 2015; van der Zijl et al, 2011; Witte et al, 2014; Xu et al, 2015; Zhao et al, 2009; Zittermann et al, 2009) were selected for the final analysis (one RCT (Rajkumar et al, 2014) was eligible among both omega −3 and probiotics). Fig.…”

Section: Resultsmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

“…Seven of 142 potential studies described the effects of metformin in 3,247 participants with mean CRP levels of 3.8 mg/L (Caballero et al, 2004; De Jager et al, 2005; de Jager et al, 2014; Goldberg et al, 2014; Krysiak et al, 2013; Pradhan et al, 2009; Xu et al, 2015). No study with the above mentioned inclusion criteria reported IL-6 levels.…”

Section: Resultsmentioning

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

View full text Add to dashboard Cite

show abstract

“…Next to glucose lowering effect, metformin was recently discussed to have anti-inflammatory and other pleiotropic effects [44, 45]. Xu et al showed, that metformin lowered hs-CRP, IL-6, and TNF-α levels in diabetics and concluded that metformin has a protective potential to ameliorate the pro-inflammatory response in patients with CAS [44]. Moreover, metformin reduced endothelial cell production of IL-6 in vitro [46] and below-the-knee arterial calcification score in type 2 diabetics [47].…”

Section: Discussionmentioning

confidence: 99%

Neutrophil gelatinase associated lipocalin (NGAL) is elevated in type 2 diabetics with carotid artery stenosis and reduced under metformin treatment

Eilenberg

Stojković

Piechota-Polańczyk

et al. 2017

Cardiovasc Diabetol

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BackgroundNeutrophil gelatinase-associated lipocalin (NGAL), an acute phase protein released by neutrophils, has been described as biomarker of inflammatory states. Type 2 diabetes mellitus (T2DM) is characterized by increased inflammation and an elevated risk for embolization of carotid artery stenosis (CAS). We aimed to explore the role of NGAL systemically and in plaques of diabetics undergoing carotid endarterectomy. Moreover, the potential anti-inflammatory effect of metformin on NGAL was addressed in diabetics.MethodsSerum NGAL and matrix metalloproteinase (MMP)-9/NGAL levels were measured in 136 patients (67 with T2DM vs. 69 non-diabetics) by specific ELISA. Endarterectomy samples were graded histologically according to the American Heart Association´s classification. NGAL mRNA expression was detected using RealTime-PCR in carotid endarterectomy specimens.ResultsSerum NGAL [median 107.4 ng/ml (quartiles: 75.2–145.0) vs. 64.4 (50.4 –81.3), p < 0.0001] and MMP-9/NGAL [41.5 ng/ml (20.8–63.9) vs. 27.6 (16.0–42.4), p = 0.017] were significantly elevated in diabetics compared to non-diabetics, as were leukocytes, neutrophils, C-reactive protein and fibrinogen (all p < 0.05). In patients with symptomatic and asymptomatic CAS diabetics had higher NGAL levels compared to non-diabetics [128.8 ng/ml (100.8–195.6) vs. 64.8 (48.9–82.2] and [101.6 ng/ml (70.1–125.3) vs. 63.8 (51.0–81.3), respectively, both p < 0.0001]. Presence of T2DM and type VI plaques (with surface defect, hemorrhage or thrombus) had a profound impact on NGAL levels (both p < 0.01) in multiple linear regression analysis. NGAL mRNA was detectable in 95% of analyzed carotid artery lesions of diabetics compared to 5% of non-diabetics (p < 0.0001). Accordingly, cerebral embolization was more frequent in diabetics (52.2% vs. 29%, p = 0.006). Metformin treatment was associated with decreased NGAL [60.7 ng/ml (51.9–69.2) vs. 121.7 (103.7–169.9), p < 0.0001] and MMP-9/NGAL [20.8 ng/ml (12.1–26.5) vs. 53.7 (27.4–73.4), p = 0.007] in diabetics and reduced leukocyte infiltration in carotid lesions of diabetics.ConclusionsHigher NGAL levels in serum and plaques are associated with T2DM in patients with CAS. Metformin significantly reduced the inflammatory burden including NGAL in diabetics. Early treatment of these patients may be recommended, as elevated NGAL levels were linked with vulnerable plaques prone for embolization.

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“…In addition, results from a double-blind placebo-controlled study in patients with carotid artery atherosclerosis indicated that metformin treatment attenuated the proinflammation state in peripheral blood mononuclear cells through SIRT1 induction, p65 acetylation reduction, and NF-jB blockade (201).…”

Section: Sirt1 and Sirt6 Pharmacological Modulators In The Preclinicamentioning

confidence: 99%

SIRT1 and SIRT6 Signaling Pathways in Cardiovascular Disease Protection

D’Onofrio¹,

Servillo²,

Balestrieri³

2018

Antioxidants & Redox Signaling

295

238

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Significance: Oxidative stress represents the common hallmark of pathological conditions associated with cardiovascular disease (CVD), including atherosclerosis, heart failure, hypertension, aging, diabetes, and other vascular system-related diseases. The sirtuin (SIRT) family, comprising seven proteins (SIRT1-SIRT7) sharing a highly conserved nicotinamide adenine dinucleotide (NAD + )-binding catalytic domain, attracted a great attention for the past few years as stress adaptor and epigenetic enzymes involved in the cellular events controlling aging-related disorder, cancer, and CVD. Recent Advances: Among sirtuins, SIRT1 and SIRT6 are the best characterized for their protective roles against inflammation, vascular aging, heart disease, and atherosclerotic plaque development. This latest role has been only recently unveiled for SIRT6. Of interest, in recent years, complex signaling networks controlled by SIRT1 and SIRT6 common to stress resistance, vascular aging, and CVD have emerged. Critical Issues: We provide a comprehensive overview of recent developments on the molecular signaling pathways controlled by SIRT1 and SIRT6, two post-translational modifiers proven to be valuable tools to dampen inflammation and oxidative stress at the cardiovascular level. Future Directions: A deeper understanding of the epigenetic mechanisms through which SIRT1 and SIRT6 act in the signalings responsible for onset and development CVD is a prime scientific endeavor of the upcoming years. Multiple ''omic'' technologies will have widespread implications in understanding such mechanisms, speeding up the achievement of selective and efficient pharmacological modulation of sirtuins for future applications in the prevention and treatment of CVD. Antioxid. Redox Signal. 28, 711-732.

show abstract

Metformin ameliorates the proinflammatory state in patients with carotid artery atherosclerosis through sirtuin 1 induction

Cited by 47 publications

References 30 publications

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

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

Neutrophil gelatinase associated lipocalin (NGAL) is elevated in type 2 diabetics with carotid artery stenosis and reduced under metformin treatment

SIRT1 and SIRT6 Signaling Pathways in Cardiovascular Disease Protection

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