TNF-α Increases Production of Reactive Oxygen Species through Cdk5 Activation in Nociceptive Neurons

Sandoval, Rodrigo; Lazcano, Pablo; Ferrari, Franco; Pinto-Pardo, Nicolás; González-Billault, Christian; Utreras, Elías

doi:10.3389/fphys.2018.00065

Cited by 59 publications

(40 citation statements)

References 65 publications

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“…In dental pulp inflammation, the accumulation of reactive oxygen species (ROS) was considered to be one possible reason for mitochondrial damage and active mitophagy. Damaged mitochondria can produce ROS, the accumulation of ROS could be harmful to healthy mitochondria and cause continuously damage to cell (Sandoval et al, ). We detected excessive ROS generation in preodontoblasts under LPS stimulation.…”

Section: Discussionmentioning

confidence: 99%

Activation of mitophagy in inflamed odontoblasts

Yang

Duan

et al. 2019

Oral Diseases

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Objectives Mitophagy is an important mitochondrial quality control mechanism. In this study, we investigated the mitochondrial damage and mitophagy occurred in inflammatory human dental pulp and lipopolysaccharide‐stimulated preodontoblasts. Materials and Methods In dental pulp tissues and lipopolysaccharide‐stimulated preodontoblasts, immunofluorescences and Western blot were performed to detect the expression of mitochondrial and mitophagy‐related proteins, and autophagy markers were also examined. Reactive oxygen species generated by mitochondria were examined by MitoSOX. Transmission electron microscope (TEM) was used to examine the morphology of mitochondria in lipopolysaccharide‐stimulated preodontoblasts. Results The active fission activity of mitochondria and mitophagy in inflammatory dental pulp was observed. In lipopolysaccharide‐treated preodontoblasts, mitophagy‐related proteins were also upregulated. Moreover, increased reactive oxygen species in the inflamed preodontoblasts were observed. Additionally, single‐membrane autolysosomes containing partially degraded mitochondria with swollen inner membranes in lipopolysaccharide‐treated preodontoblasts were observed by TEM. Conclusions These results indicate that mitochondria were damaged and mitophagy might be activated to degrade impaired mitochondria in inflamed odontoblasts.

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Section: Discussionmentioning

confidence: 99%

Activation of mitophagy in inflamed odontoblasts

Yang

Duan

et al. 2019

Oral Diseases

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“…TNFα and ROS may also show specific positive feedback, because not only do ROS increase TNFα production, TNFα also increases ROS production. Additionally, TNFα is not only a ligand for TNFR, but also binds other receptors, such as Cdk5, which induces higher NADPH oxidase (NOX) expression, increasing ROS generation [18]. Moreover, complexes I and III of the mitochondrial respiratory chain are sensitive to TNFα, which enhances the increase in ROS production [19], which are capable of activating many apoptosis pathways directly related to the action of lipid mediators, so their excessive generation through activation of TNFR1 is an additional mechanism for the activation of apoptosis.…”

Section: Receptor Pathwaymentioning

confidence: 99%

Involvement of Metabolic Lipid Mediators in the Regulation of Apoptosis

et al. 2020

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Apoptosis is the physiological mechanism of cell death and can be modulated by endogenous and exogenous factors, including stress and metabolic alterations. Reactive oxygen species (ROS), as well as ROS-dependent lipid peroxidation products (including isoprostanes and reactive aldehydes including 4-hydroxynonenal) are proapoptotic factors. These mediators can activate apoptosis via mitochondrial-, receptor-, or ER stress-dependent pathways. Phospholipid metabolism is also an essential regulator of apoptosis, producing the proapoptotic prostaglandins of the PGD and PGJ series, as well as the antiapoptotic prostaglandins of the PGE series, but also 12-HETE and 20-HETE. The effect of endocannabinoids and phytocannabinoids on apoptosis depends on cell type-specific differences. Cells where cannabinoid receptor type 1 (CB1) is the dominant cannabinoid receptor, as well as cells with high cyclooxygenase (COX) activity, undergo apoptosis after the administration of cannabinoids. In contrast, in cells where CB2 receptors dominate, and cells with low COX activity, cannabinoids act in a cytoprotective manner. Therefore, cell type-specific differences in the pro- and antiapoptotic effects of lipids and their (oxidative) products might reveal new options for differential bioanalysis between normal, functional, and degenerating or malignant cells, and better integrative biomedical treatments of major stress-associated diseases.

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“…Some evidence demonstrated that Cdk5 acts a key role in mediating heat hyperalgesia induced by inflammation [9][10][11]. Moreover, previous results obtained by other investigators suggest that Cdk5 is a key regulator in mediation of neurotransmitters, including glutamate in the central nervous system [12].…”

Section: Discussionmentioning

confidence: 95%

“…e activities of Cdk5 and p35 in the spinal cord were significantly increased following peripheral injection of complete Freund's adjuvant (CFA). Furthermore, both Cdk5 kinase activity and heat hyperalgesia were inhibited by Cdk5/p35 knockdown or intrathecal administration of roscovitine [9][10][11]. Previous studies have suggested that presynaptic Cdk5 is the primary regulator of neurotransmitter release in the central nervous system [12].…”

Section: Introductionmentioning

confidence: 99%

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VGLUT2/Cdk5/p25 Signaling Pathway Contributed to Inflammatory Pain by Complete Freund’s Adjuvant

Tang

Peng

Tao

et al. 2020

Pain Research and Management

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Vesicular glutamate transporter type 2 (VGLUT2) is known to play an important role in mediating heat hyperalgesia induced by inflammation. However, the underlying mechanism for this activity is poorly understood. Cyclin-dependent kinase 5 (Cdk5), serving as a key regulator in modulating release of glutamate, acted a key player in the formation of heat hyperalgesia of inflammatory pain. However, it remains unknown whether there is a bridge between Cdk5 and VGLUT2 for mediating inflammatory pain. Therefore, we designed the experiment to determine whether VGLUT2 signaling pathway is involved in inflammatory pain mediated by Cdk5 in the inflammatory pain model induced by complete Freund’s adjuvant (CFA). Our results showed that the coexpression of Cdk5/VGLUT2 in small- and medium-sized neuronal cells of the dorsal root ganglion (DRG) and spinal cord between days 1 and 3 following subcutaneous injection of CFA was significantly increased. Moreover, our study revealed that the expression of VGLUT2 protein in the DRG and spinal cord was remarkably increased between days 1 and 3 following CFA injection and was significantly reduced by roscovitine, a selective antagonist of Cdk5. Additionally, p25 but not p35, an activator of Cdk5, protein was significantly increased by CFA and reduced by roscovitine. Our findings suggested that VGLUT2/Cdk5 signaling pathway contributes to inflammatory pain mediated by Cdk5/p25.

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TNF-α Increases Production of Reactive Oxygen Species through Cdk5 Activation in Nociceptive Neurons

Cited by 59 publications

References 65 publications

Activation of mitophagy in inflamed odontoblasts

Activation of mitophagy in inflamed odontoblasts

Involvement of Metabolic Lipid Mediators in the Regulation of Apoptosis

VGLUT2/Cdk5/p25 Signaling Pathway Contributed to Inflammatory Pain by Complete Freund’s Adjuvant

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