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

Abstract

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.

Transcriptomic Analysis of the Mechanisms for Alleviating Psoriatic Dermatitis Using Taodan Granules in an Imiquimod-Induced Psoriasis-like Mouse Model

“…Ki67 and PCNA are classical markers of cell proliferation in a variety of diseases ( Alhosaini et al, 2021 ; Cai et al, 2021 ). As expected, following TDG treatment, the number of Ki67 and PCNA-positive cells in IMQ-induced psoriasis-like mice decreased significantly ( Figure 2 ; Supplementary Figure S1 ), which is consistent with the results of previous studies ( Ru et al, 2020 ; Thatikonda et al, 2020 ; Tomalin et al, 2020 ). Accordingly, we speculated that TDGs could mitigate the excessive proliferation of KCs to effectively alleviate psoriasis.…”

Biotechnologically Produced Lavandula angustifolia Mill. Extract Rich in Rosmarinic Acid Resolves Psoriasis-Related Inflammation Through Janus Kinase/Signal Transducer and Activator of Transcription Signaling

“…The PI3K/AKT signaling is activated in psoriatic keratinocytes and reflect cell growth promotion, induction of hyperproliferation and hyper-keratinization ( Engelman et al, 2006 ; Li et al, 2019 ; Thatikonda et al, 2020 ). Data from the gene expression analysis indicated that both LV extract and pure RA downregulated AKT .…”

Anti-Apoptotic Role of Sanhuang Xiexin Decoction and Anisodamine in Endotoxemia

“…In addition, endotoxemia can also induce apoptosis through oxidative stress. For example, piperlongumine exhibits prominent anti-inflammatory effects by inhibiting the ETX-induced p65 NF-κB signaling cascade and markedly suppresses cytokine storm production, which is closely associated with ROS-mediated induction of late apoptosis and reduced expression of antiapoptotic Bcl2 protein (Thatikonda et al, 2020). To sum up, Figure 4 reveals how the recognition signals of endotoxin, inflammation, and oxidative stress responses induce apoptosis directly or indirectly.…”