Methotrexate treatment provokes apoptosis of proliferating keratinocyte in psoriasis patients

Elango, Tamilselvi; Thirupathi, Anand; Subramanian, Swapna; Ethiraj, Purushoth; Dayalan, Haripriya; Gnanaraj, Pushpa

doi:10.1007/s10238-016-0431-4

Cited by 39 publications

(24 citation statements)

References 48 publications

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“…Apoptosis, a genetically controlled cell death program (Shichiri et al 2000), plays a pivotal role in the development, differentiation, and defense of skin homeostasis (Elango et al 2017, Lerman et al 2011. Recent data showed that hyperproliferation of keratinocytes and decreased epidermal keratinocyte apoptosis (via the action of inflammatory mediators) are principal clinical aspects of psoriasis (Deng et al 2016, Elango et al 2017, Lerman et al 2011.…”

Section: Discussionmentioning

confidence: 99%

Roles of miR-31 and Endothelin-1 in Psoriasis Vulgaris: Pathophysiological Functions and Potential Biomarkers

Borská¹,

Andrýs²,

Chmelařová³

et al. 2017

Physiol Res

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Psoriatic lesions are characterized by hyperproliferation, aberrant differentiation of keratinocytes resistant to apoptosis and inflammation. miR-31 plays pro-proliferative, pro-differentiative and pro-inflammatory roles and modulates apoptosis in psoriatic keratinocytes. Endothelin-1 (ET-1) is produced by psoriatic keratinocytes and suppresses apoptosis. Inflammation increases the production of ET-1, which in turn leads to the chronic stimulation of keratinocyte proliferation. The aim of this study was to identify the putative link between two potential biomarkers (miR-31 and ET-1) in patients with psoriasis. The study design included experimental group (29 patients with psoriasis), and the control group (22 blood donors). The PASI score evaluated the state of the disease (median: 18.6; interquartile range 14.5-20.9). Both, the serum level of ET-1 and the whole blood level of miR-31 were significantly increased (p<0.001 and p<0.05, respectively) in patients compared to the controls. However, a significant negative relationship between ET-1 and miR-31 was observed (Spearman’s rho=-037, p=0.05). It is possible that a negative feedback loop will be present between miR-31 and ET-1. Our results indicate that miR-31 and ET-1, potential biomarkers of the disease, play significant roles in the pathophysiology of psoriasis.

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Section: Discussionmentioning

confidence: 99%

Roles of miR-31 and Endothelin-1 in Psoriasis Vulgaris: Pathophysiological Functions and Potential Biomarkers

Borská¹,

Andrýs²,

Chmelařová³

et al. 2017

Physiol Res

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“…EGF regulates keratinocyte growth, proliferation, and differentiation by binding to epidermal growth factor receptor (EGFR) and maintain high proliferative state 26,27 . Apoptosis has been proposed as a mechanism that disrupts abnormal epidermal thickness in psoriasis 28 . To investigate the role of PPL on EGF-induced hyperproliferation, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed in the presence of EGF, which showed that PPL effectively reduced the EGFstimulated cell viability of keratinocytes at both 24 ( Fig.…”

Section: Inhibitory Effects Of Ppl On Keratinocyte Hyperproliferationmentioning

confidence: 99%

Piperlongumine regulates epigenetic modulation and alleviates psoriasis-like skin inflammation via inhibition of hyperproliferation and inflammation

et al. 2020

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Psoriasis is an autoimmune skin disease, where chronic immune responses due to exaggerated cytokine signaling, abnormal differentiation, and evasion of keratinocytes apoptosis plays a crucial role in mediating abnormal keratinocytes hyperproliferation. From the therapeutic perspective, the molecules with strong anti-proliferative and anti-inflammatory properties could have tremendous relevance. In this study, we demonstrated that piperlongumine (PPL) treatment effectively abrogated the hyperproliferation and differentiation of keratinocytes by inducing ROSmediated late apoptosis with loss of mitochondrial membrane potential. Besides, the arrest of cell cycle was found at Sub-G1 phase as a result of DNA fragmentation. Molecularly, inhibition of STAT3 and Akt signaling was observed with a decrease in proliferative markers such as PCNA, ki67, and Cyclin D1 along with anti-apoptotic Bcl-2 protein expression. Keratin 17 is a critical regulator of keratinocyte differentiation, and it was found to be downregulated with PPL significantly. Furthermore, prominent anti-inflammatory effects were observed by inhibition of lipopolysaccharide (LPS)/Imiquimod (IMQ)-induced p65 NF-κB signaling cascade and strongly inhibited the production of cytokine storm involved in psoriasis-like skin inflammation, thus led to the restoration of normal epidermal architecture with reduction of epidermal hyperplasia and splenomegaly. In addition, PPL epigenetically inhibited histone-modifying enzymes, which include histone deacetylases (HDACs) of class I (HDAC1-4) and class II (HDAC6) evaluated by immunoblotting and HDAC enzyme assay kit. In addition, our results show that PPL effectively inhibits the nuclear translocation of p65 and a histone modulator HDAC3, thus sequestered in the cytoplasm of macrophages. Furthermore, PPL effectively enhanced the protein-protein interactions of HDAC3 and p65 with IκBα, which was disrupted by LPS stimulation and were evaluated by Co-IP and molecular modeling. Collectively, our findings indicate that piperlongumine may serve as an anti-proliferative and anti-inflammatory agent and could serve as a potential therapeutic option in treating psoriasis.

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“…In PsO, a dysregulation of cytochrome c has been demonstrated. Indeed, a higher serum and mitochondrial levels were observed compared to healthy skin; this contributes to epidermal hyperplasia ( 37 ). Concerning PsA, the result is synovial inflammation and joint destruction ( 38 ).…”

Section: Potential Role Of Cytochrome C and Tryptase In Psoriasis Andmentioning

confidence: 99%

Potential Role of Cytochrome c and Tryptase in Psoriasis and Psoriatic Arthritis Pathogenesis: Focus on Resistance to Apoptosis and Oxidative Stress

et al. 2018

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Psoriasis (PsO) is an autoimmune disease characterized by keratinocyte proliferation, chronic inflammation and mast cell activation. Up to 42% of patients with PsO may present psoriatic arthritis (PsA). PsO and PsA share common pathophysiological mechanisms: keratinocytes and fibroblast-like synoviocytes are resistant to apoptosis: this is one of the mechanism facilitating their hyperplasic growth, and at joint level, the destruction of articular cartilage, and bone erosion and/or proliferation. Several clinical studies regarding diseases characterized by impairment of cell death, either due to apoptosis or necrosis, reported cytochrome c release from the mitochondria into the extracellular space and finally into the circulation. The presence of elevated cytochrome c levels in serum has been demonstrated in diseases as inflammatory arthritis, myocardial infarction and stroke, and liver diseases. Cytochrome c is a signaling molecule essential for apoptotic cell death released from mitochondria to the cytosol allowing the interaction with protease, as the apoptosis protease activation factor, which lead to the activation of factor-1 and procaspase 9. It has been demonstrated that this efflux from the mitochondria is crucial to start the intracellular signaling responsible for apoptosis, then to the activation of the inflammatory process. Another inflammatory marker, the tryptase, a trypsin-like serine protease produced by mast cells, is released during inflammation, leading to the activation of several immune cells through proteinase-activated receptor-2. In this review, we aimed at discussing the role played by cytochrome c and tryptase in PsO and PsA pathogenesis. To this purpose, we searched pathogenetic mechanisms in PUBMED database and review on oxidative stress, cytochrome c and tryptase and their potential role during inflammation in PsO and PsA. To this regard, the cytochrome c release into the extracellular space and tryptase may have a role in skin and joint inflammation.

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Methotrexate treatment provokes apoptosis of proliferating keratinocyte in psoriasis patients

Cited by 39 publications

References 48 publications

Roles of miR-31 and Endothelin-1 in Psoriasis Vulgaris: Pathophysiological Functions and Potential Biomarkers

Roles of miR-31 and Endothelin-1 in Psoriasis Vulgaris: Pathophysiological Functions and Potential Biomarkers

Piperlongumine regulates epigenetic modulation and alleviates psoriasis-like skin inflammation via inhibition of hyperproliferation and inflammation

Potential Role of Cytochrome c and Tryptase in Psoriasis and Psoriatic Arthritis Pathogenesis: Focus on Resistance to Apoptosis and Oxidative Stress

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