Sulforaphane prevents the development of cardiomyopathy in type 2 diabetic mice probably by reversing oxidative stress-induced inhibition of LKB1/AMPK pathway

Zhang, Zhiguo; Wang, Shudong; Zhou, Shanshan; Yan, Xiaoqing; Wang, Yonggang; Chen, Jing; Mellen, Nicholas; Kong, Maiying; Gu, Junlian; Tan, Yi; Zheng, Yang; Cai, Lu

doi:10.1016/j.yjmcc.2014.09.022

Cited by 174 publications

(122 citation statements)

References 58 publications

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“…Consistent with the previous study [17], treatment with STZ/HFD significantly increased fed and fasting glucose levels, diminished glucose and insulin tolerance, as well as elevated total cholesterol and triglyceride concentrations in both FGF21 KO mice and WT controls. However, these effects were further augmented in FGF21 KO mice compared with those in WT mice (Supplementary Figure S1).…”

Section: Loss Of Fgf21 Accelerates Cardiomyopathy In Stz/hfd-induced supporting

confidence: 91%

FGF21 ameliorates diabetic cardiomyopathy by activating the AMPK-paraoxonase 1 signaling axis in mice

Wang

Zhang

et al. 2017

Clinical Science

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The aim of the present study is to explore the molecular mechanism of fibroblast growth factor 21 (FGF21) in protecting against diabetic cardiomyopathy (DCM). Streptozotocin/high-fat diet (STZ/HFD) was used to induced diabetes in FGF21-deficient mice and their wild-type littermates, followed by evaluation of the difference in DCM between the two genotypes. Primary cultured cardiomyocytes were also used to explore the potential molecular mechanism of FGF21 in the protection of high glucose (HG)-induced cardiomyocyte injury. STZ/HFD-induced cardiomyopathy was exacerbated in FGF21 knockout mice, which was accompanied by a significant reduction in cardiac AMP-activated protein kinase (AMPK) activity and paraoxonase 1 (PON1) expression. By contrast, adeno-associated virus (AAV)-mediated overexpression of FGF21 in STZ/HFD-induced diabetic mice significantly enhanced cardiac AMPK activity, PON1 expression and its biological activity, resulting in alleviated DCM. In cultured cardiomyocytes, treatment with recombinant mouse FGF21 (rmFGF21) counteracted HG-induced oxidative stress, mitochondrial dysfunction, and inflammatory responses, leading to increased AMPK activity and PON1 expression. However, these beneficial effects of FGF21 were markedly weakened by genetic blockage of AMPK or PON1. Furthermore, inactivation of AMPK also markedly blunted FGF21-induced PON1 expression but significantly increased HG-induced cytotoxicity in cardiomyocytes, the latter of which was largely reversed by adenovirus-mediated PON1 overexpression. These findings suggest that FGF21 ameliorates DCM in part by activation of the AMPK-PON1 axis.

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Section: Loss Of Fgf21 Accelerates Cardiomyopathy In Stz/hfd-induced supporting

confidence: 91%

FGF21 ameliorates diabetic cardiomyopathy by activating the AMPK-paraoxonase 1 signaling axis in mice

Wang

Zhang

et al. 2017

Clinical Science

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“…Lower panels, immunohistochemistry of a-SYN and NQO1. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars NRF2 activator, that also promotes autophagy by regulating ERK (36) or AMPK (79). In any case, these observations collectively indicate that DMF regulates autophagy, at least in part, by regulating the NRF2/p62 axis.…”

Section: Lastres-becker Et Almentioning

confidence: 97%

Repurposing the NRF2 Activator Dimethyl Fumarate as Therapy Against Synucleinopathy in Parkinson's Disease

Lastres‐Becker

García-Yagüe

Scannevin

et al. 2016

Antioxidants & Redox Signaling

230

223

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Aims: This preclinical study was aimed at determining whether pharmacological targeting of transcription factor NRF2, a master controller of many homeostatic genes, might provide a disease-modifying therapy in the animal model of Parkinson's disease (PD) that best reproduces the main hallmark of this pathology, that is, a-synucleinopathy, and associated events, including nigral dopaminergic cell death, oxidative stress, and neuroinflammation. Results: Pharmacological activation of NRF2 was achieved at the basal ganglia by repurposing dimethyl fumarate (DMF), a drug already in use for the treatment of multiple sclerosis. Daily oral gavage of DMF protected nigral dopaminergic neurons against a-SYN toxicity and decreased astrocytosis and microgliosis after 1, 3, and 8 weeks from stereotaxic delivery to the ventral midbrain of recombinant adeno-associated viral vector expressing human a-synuclein. This protective effect was not observed in Nrf2-knockout mice. In vitro studies indicated that this neuroprotective effect was correlated with altered regulation of autophagy markers SQTSM1/p62 and LC3 in MN9D, BV2, and IMA 2.1 and with a shift in microglial dynamics toward a less pro-inflammatory and a more wound-healing phenotype. In postmortem samples of PD patients, the cytoprotective proteins associated with NRF2 expression, NQO1 and p62, were partly sequestered in Lewy bodies, suggesting impaired neuroprotective capacity of the NRF2 signature. Innovation: These experiments provide a compelling rationale for targeting NRF2 with DMF as a therapeutic strategy to reinforce endogenous brain defense mechanisms against PD-associated synucleinopathy. Conclusion: DMF is ready for clinical validation in PD. Antioxid. Redox Signal. 25, 61-77.

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“…(Paine et al 2010). Nrf2-mediated HO-1 induction contributes to antioxidant capacity has been demonstrated by multiple disease models, including cardiomyopathy in type 2 diabetic mice (Zhang et al 2014b), rat model of transient global cerebral ischaemia (Lee et al 2014), and endotoxic shock-induced acute lung injury in rabbits (Yu et al 2014). Recently, Nrf2/HO-1 activation also shows protective effect in aristolochic acid-induced acute kidney injury (Wu et al 2014a) and intestinal ischemia-reperfusion induced acute renal injury (Sun et al 2013).…”

Section: Introductionmentioning

confidence: 99%

Protective effects of curcumin on acute gentamicin-induced nephrotoxicity in rats

Peng

Zhu

et al. 2015

Can. J. Physiol. Pharmacol.

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Sulforaphane prevents the development of cardiomyopathy in type 2 diabetic mice probably by reversing oxidative stress-induced inhibition of LKB1/AMPK pathway

Cited by 174 publications

References 58 publications

FGF21 ameliorates diabetic cardiomyopathy by activating the AMPK-paraoxonase 1 signaling axis in mice

FGF21 ameliorates diabetic cardiomyopathy by activating the AMPK-paraoxonase 1 signaling axis in mice

Repurposing the NRF2 Activator Dimethyl Fumarate as Therapy Against Synucleinopathy in Parkinson's Disease

Protective effects of curcumin on acute gentamicin-induced nephrotoxicity in rats

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