Sirt1 Protects against Oxidative Stress-Induced Apoptosis in Fibroblasts from Psoriatic Patients: A New Insight into the Pathogenetic Mechanisms of Psoriasis

Abstract

Psoriasis, a multisystem chronic disease characterized by abnormal keratinocyte proliferation, has an unclear pathogenesis where systemic inflammation and oxidative stress play mutual roles. Dermal fibroblasts, which are known to provide a crucial microenvironment for epidermal keratinocyte function, represented the selected experimental model in our study which aimed to clarify the potential role of SIRT1 in the pathogenetic mechanisms of the disease. We firstly detected the presence of oxidative stress (lipid peroxidation and total antioxidant capacity), significantly reduced SIRT1 expression level and activity, mitochondrial damage and apoptosis (caspase-3, -8 and -9 activities) in psoriatic fibroblasts. Upon SIRT1 activation, redox balance was re-established, mitochondrial function was restored and apoptosis was no longer evident. Furthermore, we examined p38, ERK and JNK activation, which was strongly altered in psoriatic fibroblasts, in response to SIRT1 activation and we measured caspase-3 activity in the presence of specific MAPK inhibitors demonstrating the key role of the SIRT1 pathway against apoptotic cell death via MAPK modulation. Our results clearly demonstrate the involvement of SIRT1 in the protective mechanisms related to fibroblast injury in psoriasis. SIRT1 activation exerts an active role in restoring both mitochondrial function and redox balance via modulation of MAPK signaling. Hence, SIRT1 can be proposed as a specific tool for the treatment of psoriasis.

Evaluation of changes in expression pattern of oxidative stress genes under the influence of adalimumab

“…Thus, one can conclude on the important role of p38 MAPK in the emergence of keratinocyte responses to cellular stress. What is also important is the use of the p38 inhibitor results in a decrease in apoptosis that confirms the important role of the described trail in this process (Becatti et al, ).…”

Redox status assessment in infertile patients with non‐obstructive azoospermia undergoing testicular sperm extraction: A prospective study

“…It is based on the thiobarbituric acid as an optimal reagent able to react with lipoperoxidation products (after 1 h at 95°C), leading to the formation of a chromophore adduct measured spectrofluorometrically with excitation at 530 nm and emission at 550 nm in a Microplate Fluorometer (Biotek Synergy H1). Results were expressed in terms of malondialdehyde, MDA (nmol/mL) …”

The Oxidative Stress-Induced miR-200c Is Upregulated in Psoriasis and Correlates with Disease Severity and Determinants of Cardiovascular Risk

“…Although early concepts of psoriasis pathogenesis focused primarily on keratinocyte hyperproliferation, the current view identifies dysregulation of immune responses and systemic inflammation as key pathogenic events [1]; moreover, an increase in reactive oxygen species production and decreased antioxidant potential in psoriasis have been also described [3,4]. As a result, psoriasis is now considered a systemic disease in which oxidative stress and inflammation are widespread [3][4][5][6]. Importantly, life expectancy is reduced in severe psoriasis by up to 4 years, largely because of the high incidence of CVD and CeVD [6][7][8].…”