Blockade of cyclophilin D rescues dexamethasone-induced oxidative stress in gingival tissue

Abstract

Glucocorticoids (GCs) are frequently used for the suppression of inflammation in chronic inflammatory diseases. Excessive GCs usage is greatly associated with several side effects, including gingival ulceration, the downward migration of the epithelium, attachment loss and disruption of transeptal fibers. The mechanisms underlying GCs-induced impairments in gingival tissue remains poorly understood. Mitochondrial dysfunction is associated with various oral diseases, such as chronic periodontitis, age-related alveolar bone loss and hydrogen peroxide-induced cell injury in gingival. Here, we reported an unexplored role of cyclophilin D (CypD), the major component of mitochondrial permeability transition pore (mPTP), in dexamethasone (Dex)-induced oxidative stress accumulation and cell dysfunctions in gingival tissue. We demonstrated that the expression level of CypD significantly increased under Dex treatment. Blockade of CypD by pharmaceutical inhibitor cyclosporine A (CsA) significantly protected against Dex-induced oxidative stress accumulation in gingival tissue. And the protective effects of blocking CypD in Dex-induced gingival fibroblasts dysfunction were evidenced by rescued mitochondrial function and suppressed production of reactive oxygen species (ROS). In addition, blockade of CypD by pharmaceutical inhibitor CsA or gene knockdown also restored Dex-induced cell toxicity in HGF-1 cells, as shown by suppressed mitochondrial ROS production, increased CcO activity and decreased apoptosis. We also suggested a role of oxidative stress-mediated p38 signal transduction in this event, and antioxidant N-acety-l-cysteine (NAC) could obviously blunted Dex-induced oxidative stress. These findings provide new insights into the role of CypD-dependent mitochondrial pathway in the Dex-induced gingival injury, indicating that CypD may be potential therapeutic strategy for preventing Dex-induced oxidative stress and cell injury in gingival tissue.

Cyclophilin D deficiency attenuates mitochondrial perturbation and ameliorates hepatic steatosis

“…CypD overexpression may cause apoptosis . Our results showed that CypD overexpression can increase hepatic steatosis, especially TG contents when TG contents have been normalized by the corresponding tissue weight or protein .…”

“…CypD overexpression may cause apoptosis. (35,36) Our results showed that CypD overexpression can increase hepatic steatosis, especially TG contents when TG contents have been normalized by the corresponding tissue weight or protein. (37) So we think we eliminate the possibility that CypD-induced steatosis is secondary to elevated apoptosis, at least to a certain degree.…”

An energetic view of stress: Focus on mitochondria

“…In cultured neurons, the synthetic glucocorticoid dexamethasone exerts biphasic effects on mitochondrial function in which physiological levels of glucocorticoids promote Ca 2+ sequestration, moderate oxidation and maintain mitochondrial membrane potential while supra-physiological glucocorticoid levels start to do so but fail after 24 h and lead to a failure of all three measures (Du et al, 2009). In other cell types, chronic glucocorticoid treatment can reduce the activity of specific mitochondrial electron transport chain complexes and increase mitochondrial ROS production (Tome et al, 2012; He et al, 2017). The underlying mechanisms for these effects are not fully understood, but there are three glucocorticoid response elements (GREs) on the circular mtDNA (Psarra and Sekeris, 2009), where GR likely bind and influence mtDNA gene expression (Psarra and Sekeris, 1813; Hunter et al, 2016).…”

Phosphorylation of cyclophilin D at serine 191 regulates mitochondrial permeability transition pore opening and cell death after ischemia-reperfusion

“…The prolyl isomerase cyclophilin D (CypD) in the matrix is an important regulator of mPTP opening 10,11 . CypD was identified as a target of the cyclosporine A (CsA) drug, which inhibits mPTP opening 12 .…”