Antioxidant Activity of Sestrin 2 Controls Neuropathic Pain After Peripheral Nerve Injury

Kallenborn-Gerhardt, Wiebke; Lu, Ruirui; Syhr, Katharina M.J.; Heidler, Juliana; Melchner, Harald von; Geißlinger, Gerd; Bangsow, Thorsten; Schmidtko, Achim

doi:10.1089/ars.2012.4958

Cited by 61 publications

(48 citation statements)

References 42 publications

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“…Similar studies in macrophages have shown that upregulation of SESN2 protects against H 2 O 2 -induced Prx overoxidation (38,46). In the nervous system SESN2 has been found to control ROS-dependent neuropathic pain signaling after peripheral nerve injury (47) and putatively p53-mediated antioxidant function in the retina (48). SESN2 is also needed for resveratrol, an active component in red wine, to inhibit LXR␣-mediated hepatic lipogenesis (49).…”

Section: Discussionmentioning

confidence: 85%

Gossypol Acetic Acid Prevents Oxidative Stress-Induced Retinal Pigment Epithelial Necrosis by Regulating the FoxO3/Sestrin2 Pathway

Hanus

Zhang

Chen

et al. 2015

Molecular and Cellular Biology

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The late stage of dry age-related macular degeneration (AMD), or geographic atrophy (GA), is characterized by extensive retinal pigment epithelial (RPE) cell death, and a cure is not available currently. We have recently demonstrated that RPE cells die from necrosis in response to oxidative stress, providing a potential novel mechanism for RPE death in AMD. In this study, we screened U.S. Food and Drug Administration-approved natural compounds and identified gossypol acetic acid (GAA) as a potent inhibitor of oxidative stress-induced RPE cell death. GAA induces antioxidative response and inhibits accumulation of excessive reactive oxygen species in cells, through which it prevents the activation of intrinsic necrotic pathway in response to oxidative stress. Sestrin2 (SESN2) is found to mediate GAA function in antioxidative response and RPE survival upon oxidative stress. Moreover, Forkhead box O3 transcription factor (FoxO3) is further found to be required for GAA-mediated SESN2 expression and RPE survival. Mechanistically, GAA promotes FoxO3 nuclear translocation and binding to the SESN2 enhancer, which in turn increases its transcriptional activity. Taken together, we have identified GAA as a potent inhibitor of oxidative stress-induced RPE necrosis by regulating the FoxO3/SESN2 pathway. This study may have significant implications in the therapeutics of age-related diseases, especially GA.A ge-related macular degeneration (AMD) is the leading cause of severe vision loss in people aged over 50, and its prevalence increases exponentially in people over the age of 70 (1). Currently, it is estimated that 1.75 million individuals suffer from this disease in the United States, and 7 million are said to be "at risk" (2). There are two types of AMD, the "dry" and "wet" forms, respectively. Dry AMD is a chronic disease that usually causes some degree of visual impairment and sometimes progresses to severe blindness. Dry AMD accounts for 90% of AMD cases and is currently without treatment available. The late stage of dry AMD, which is also knows as geographic atrophy (GA), is characterized by scattered or confluent areas of degeneration of retinal pigment epithelium (RPE) cells and the overlying photoreceptors that rely on the RPE for trophic support (3). AMD is a multifactorial disease with unclear etiology. Age is the most consistent risk factor associated with AMD, and genetic factors, oxidative stress, and inflammation also significantly contribute to AMD pathogenesis (4). Cigarette smoking, which induces systemic oxidative stress, has been proved to be a significant risk factor for AMD. Consistently, clinical studies have shown that the progression of AMD can be slowed with antioxidant vitamins and zinc supplements (5, 6). The retina is one of the highest oxygen-consuming tissues in the human body and, in particular, RPE is vulnerable to oxidative damage (7,8). The mechanism of RPE cell death in response to oxidative stress and in GA has been controversial. Apoptosis was suggested as a major mechanism of RPE cell ...

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Section: Discussionmentioning

confidence: 85%

Gossypol Acetic Acid Prevents Oxidative Stress-Induced Retinal Pigment Epithelial Necrosis by Regulating the FoxO3/Sestrin2 Pathway

Hanus

Zhang

Chen

et al. 2015

Molecular and Cellular Biology

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“…ROS are required for the development and maintenance of neuropathic pain, which indicated that the Sesns may protect against the neuropathic pain. In spared nerve injury model, a well characterized model of neuropathic pain, researchers found that the expression of Sesn2, but not Sesn1 or Sesn3, was up-regulated in sciatic nerves [52]. Then, they found that Sesn2 knockout ( Sesn2 –/– ) mice exhibited considerably increased latephase neuropathic pain behavior.…”

Section: Sesns In the Nervous Systemmentioning

confidence: 99%

“…Then, they found that Sesn2 knockout ( Sesn2 –/– ) mice exhibited considerably increased latephase neuropathic pain behavior. The increased ROS levels and increased expression of activating transcription factor 3 may contribute to the exacerbated neuropathic pain behavior in Sesn2 –/– mice [52]. In PC12 cells, a widely used neuron-like cell model for studying neurotoxicity and neuroprotection, researchers found that the expression of Sesn2 was induced by H 2 O 2 in a time-dependent and dose-dependent manner through the c-Jun NH (2)-terminal kinase (JNK)/c-Jun pathway [53].…”

Section: Sesns In the Nervous Systemmentioning

confidence: 99%

Recent Insights into the Biological Functions of Sestrins in Health and Disease

Wang

Liu

et al. 2017

Cell Physiol Biochem

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Sestrins (Sesns) have been identified as a family of highly conserved stress-inducible proteins that are strongly up-regulated by various stresses, including DNA damage, oxidative stress, and hypoxia. The Sesns play protective roles in most physiological and pathological conditions mainly through the regulation of oxidative stress, inflammation, autophagy, endoplasmic reticulum stress, and metabolic homeostasis. In this review, we discussed the possible regulators of Sesns expression, such as p53, forkhead box O, nuclear factor erythroid 2 like 2 (Nrf2), NH (2)-terminal kinase (JNK)/c-Jun pathway and hypoxia-inducible factor-1α (Hif-1α), and the downstream pathways regulated by the Sesns including AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling, mitogen-activated protein kinases (MAPKs) signaling, Nrf2 signaling, NADPH oxidase signaling and transforming growth factor β (TGF-β) signaling in heart diseases, lung diseases, gastrointestinal tract diseases, liver and metabolism diseases, neurological diseases, kidney diseases and immunological diseases. This review aims to provide a comprehensive understanding the protective effects of Sesns.

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“…For example, a recent report revealed the protective effect of sestrin2 induction against neurotoxicity associated with MPP + , a mitochondrial complex I inhibitor, in neuroblastoma SH-SY5Y cells [17]. Sestrin2 also controls reactive oxygen species (ROS)-dependent neuropathic pain signaling after peripheral nerve injury [18]. Together, these findings point to the neuroprotective potential of sestrin2, at least in part via attenuation of oxidative stress, in the experimental models mimicking neurodegeneration.…”

Section: Introductionmentioning

confidence: 97%

Nuclear Factor-kappaB-Dependent Sestrin2 Induction Mediates the Antioxidant Effects of BDNF Against Mitochondrial Inhibition in Rat Cortical Neurons

Chen

Yin

et al. 2015

Mol Neurobiol

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Brain-derived neurotrophic factor (BDNF), in addition to its neurotrophic action, also possesses antioxidant activities. However, the underlying mechanisms remain to be fully defined. Sestrin2 is a stress-responsive gene implicated in the cellular defense against oxidative stress. Currently, the potential functions of sestrin2 in nervous system, in particular its correlation with neurotrophic factors, have not been well established. In this study, we hypothesized that BDNF may enhance sestrin2 expression to confer neuronal resistance against oxidative stress induced by 3-nitropropionic acid (3-NP), an irreversible mitochondrial complex II inhibitor, and characterized the molecular mechanisms underlying BDNF induction of sestrin2 in primary rat cortical cultures. We found that BDNF-mediated sestrin2 expression in cortical neurons required formation of nitric oxide (NO) with subsequent production of 3',5'-cyclic guanosine monophosphate (cGMP) and activation of cGMP-dependent protein kinase (PKG). BDNF induced localization of nuclear factor-kappaB (NF-κB) subunits p65 and p50 into neuronal nuclei that required PKG activities. Interestingly, BDNF exposure led to formation of a protein complex containing at least PKG-1 and p65/p50, which bound to sestrin2 promoter with resultant upregulation of its protein products. Finally, BDNF preconditioning mitigated production of reactive oxygen species (ROS) as a result of 3-NP exposure; this antioxidative effect of BDNF was dependent upon PKG activity, NF-κB, and sestrin2. Taken together, our results indicated that BDNF enhances sestrin2 expression to confer neuronal resistance against oxidative stress induced by 3-NP through attenuation of ROS formation; furthermore, BDNF induction of sestrin2 requires activation of a pathway involving NO/PKG/NF-κB.

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Antioxidant Activity of Sestrin 2 Controls Neuropathic Pain After Peripheral Nerve Injury

Cited by 61 publications

References 42 publications

Gossypol Acetic Acid Prevents Oxidative Stress-Induced Retinal Pigment Epithelial Necrosis by Regulating the FoxO3/Sestrin2 Pathway

Gossypol Acetic Acid Prevents Oxidative Stress-Induced Retinal Pigment Epithelial Necrosis by Regulating the FoxO3/Sestrin2 Pathway

Recent Insights into the Biological Functions of Sestrins in Health and Disease

Nuclear Factor-kappaB-Dependent Sestrin2 Induction Mediates the Antioxidant Effects of BDNF Against Mitochondrial Inhibition in Rat Cortical Neurons

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