Redox biology and the interface between bioenergetics, autophagy and circadian control of metabolism

Fibromyalgia is characterized by widespread musculoskeletal pain, fatigue, and depression. The aim was to analyze potential mitochondrial dysfunction or autophagy in mice after exposure to intermittent cold stress (ICS). Muscle and liver specimens were obtained from 36 mice. Lactate dehydrogenase (LDH) activity was measured. Microtubule‐associated protein light chain 3 (MAP1LC3B) and glycogen content were determined histologically; muscle ultrastructure by electron microscopy. Mitochondrial‐ and autophagy‐related markers were analyzed by RT‐qPCR and Western blotting. ATP level, cytotoxicity, and caspase 3 activity were measured in murine C2C12 myoblasts after ICS exposure. Coenzyme Q10B (COQ10B) transcript was up‐regulated in limb muscle of ICS mice, whereas its protein content was stable. Cytochrome C oxidase 4 (COX4I1) and LDH activity increased in limb muscle of male ICS mice. Glycogen content was lower in muscle and liver tissue of male ICS mice. Electron micrographs of ICS mice specimens showed mitochondrial damage and autophagic vesicles. A significant up‐regulation of autophagic transcripts of MAP1LC3B and BECLIN 1 (BECN1) was observed. Map1lc3b protein showed an aggregated distribution in ICS mice and SqSTM1/p62 (p62) protein level was stable. Furthermore, ATP level and caspase activity, detected as apoptotic marker, were significantly lowered after ICS exposure in differentiated C2C12 myoblasts. The present study shows that ICS mice are characterized by mitochondrial dysfunction, autophagic processes, and metabolic alterations. Further investigations could dissect autophagy process in the proposed model and link these mechanisms to potential therapeutic options for fibromyalgia.

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“…Furthermore, the mitochondrial metabolic process and autophagy are closely connected and monitored by circadian cycle (Wende et al. ).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, autophagy proteins are finely regulated by posttranscriptional modifications, for example, phosphorylation and lipidation, promoting their activation (Park et al 2016). Furthermore, the mitochondrial metabolic process and autophagy are closely connected and monitored by circadian cycle (Wende et al 2016).…”

Section: Vol 4 | Iss 5 | E00248mentioning

confidence: 99%

Fibromyalgia syndrome: metabolic and autophagic processes in intermittent cold stress mice

Oezel

Then

Jung

et al. 2016

Pharmacology Res & Perspec

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“…Recently it was discovered that the Nrf2 pathway (Nrf2, phase II enzymes and GSH levels) is rhythmically activated by the circadian clock [46]. For example, in rats increased GSH and GST were observed at the beginning of the active period [47].…”

Section: Discussionmentioning

confidence: 99%

The timing of caffeic acid treatment with cisplatin determines sensitization or resistance of ovarian carcinoma cell lines

2017

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Cisplatin is a widely used chemotherapeutic drug showing high efficiency in the treatment of primary tumors such as ovarian, testicular and cervical cancers. The major drawback of cisplatin is tumor resistance either acquired or intrinsic. Many mechanisms are involved in the resistance, among them is the Nrf2 pathway which regulates glutathione related enzymes. Caffeic acid, a non-toxic polyphenol which is abundant in many foods modulates glutathione S-transferase (GST) and glutathione reductase (GSR) activity, these enzymes were shown to be involved in resistance of cells towards cisplatin. Caffeic acid induces the Nrf2 pathway and can also inhibit the activity of GST and GSR.Our findings demonstrate that the co-treatment of cancer cells with cisplatin and caffeic acid can enhance cisplatin cytotoxicity and increases the amount of platinum bound to nuclear DNA. However, 6 h of pre incubation with caffeic acid prior to cisplatin treatment led to acquired resistance to cisplatin and reduced DNA binding.In conclusion, the enzyme inhibitory action of caffeic acid is dominant when the two agents are co-administered leading to increased cytotoxicity, and the Nrf2 induction is dominant when the cells are treated with caffeic acid prior to cisplatin treatment leading to resistance.The use of caffeic acid as adjuvant for cisplatin should be carefully examined due to different pharmacokinetic profiles of caffeic acid and cisplatin. Thus, it is questionable if the two agents can reach the tumors at the right time frame in vivo.

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“…Nrf2 is now shown to play an important role in mitochondrial homeostasis [27, 45, 46, 51, 52]. Nrf2 modulates mitochondrial membrane potential and fatty acid oxidation [51], and diabetes damages retinal mitochondria and alters their membrane potential [49, 53–55].…”

Section: Diabetic Retinopathy and Nrf2mentioning

confidence: 99%

Epigenetic regulation of redox signaling in diabetic retinopathy: Role of Nrf2

Kowluru

Mishra

2017

Free Radical Biology and Medicine

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Diabetic retinopathy is a major vision threatening disease among working age adults, and increased oxidative stress is one of the prime causative factors in its pathogenesis. Increased reactive oxygen species (ROS) in the cytosol damage mitochondria, and due to compromised antioxidant signaling system and dysfunctional mitochondria with damaged mitochondrial DNA, ROS continue to pile up, accelerating capillary cell loss. In addition to other cellular and enzymatic defense system, the retina is also equipped with the nuclear erythroid-2-p45-related factor-2 (Nrf2) antioxidant response element signaling pathway, which controls the expression of genes important in detoxification and elimination of ROS. However, in diabetes, its transcriptional activity is impaired, further exacerbating and exposing the retina to elevated stress. Diabetic milieu also alters epigenetic factors responsible for chromatin modifications and gene regulation, and kelch-like ECH-associated protein 1 (Keap1), important in regulating Nrf2-antioxidant signaling axis, is epigenetically modified, impeding nuclear translocation of Nrf2, and this inhibits the transcription of genes with Antioxidant Redox Element. This review discusses antioxidant signaling, especially the role of Nrf2, in diabetic retinopathy, and possible involvement of epigenetic modifications in antioxidant signaling and Nrf2 transcriptional activity. Therapies targeting Nrf2 activation, including epigenetic modifications, could prevent mitochondrial damage and inhibit the development, and progression of this sight-threatening disease which most of the patients get after 20–25 years of diabetes.

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Redox biology and the interface between bioenergetics, autophagy and circadian control of metabolism

Cited by 46 publications

References 195 publications

Fibromyalgia syndrome: metabolic and autophagic processes in intermittent cold stress mice

Fibromyalgia syndrome: metabolic and autophagic processes in intermittent cold stress mice

The timing of caffeic acid treatment with cisplatin determines sensitization or resistance of ovarian carcinoma cell lines

Epigenetic regulation of redox signaling in diabetic retinopathy: Role of Nrf2

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