当前位置：
X-MOL 学术
›
Cell Death Dis.
›
论文详情
Our official English website, www.x-mol.net, welcomes your
feedback! (Note: you will need to create a separate account there.)
Piperlongumine regulates epigenetic modulation and alleviates psoriasis-like skin inflammation via inhibition of hyperproliferation and inflammation.
Cell Death & Disease ( IF 8.1 ) Pub Date : 2020-01-10 , DOI: 10.1038/s41419-019-2212-y Sowjanya Thatikonda 1 , Venkatesh Pooladanda 1 , Dilep Kumar Sigalapalli 2 , Chandraiah Godugu 1
Cell Death & Disease ( IF 8.1 ) Pub Date : 2020-01-10 , DOI: 10.1038/s41419-019-2212-y Sowjanya Thatikonda 1 , Venkatesh Pooladanda 1 , Dilep Kumar Sigalapalli 2 , Chandraiah Godugu 1
Affiliation
|
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 ROS-mediated 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.
中文翻译：
Piperlongumine 通过抑制过度增殖和炎症来调节表观遗传调节并减轻牛皮癣样皮肤炎症。
牛皮癣是一种自身免疫性皮肤病，由于过度的细胞因子信号传导、异常分化和逃避角质形成细胞凋亡而导致的慢性免疫反应在介导异常角质形成细胞过度增殖中发挥着至关重要的作用。从治疗的角度来看，具有强抗增殖和抗炎特性的分子可能具有巨大的相关性。在这项研究中，我们证明胡椒长明（PPL）治疗通过诱导ROS介导的晚期细胞凋亡和线粒体膜电位的丧失，有效地消除了角质形成细胞的过度增殖和分化。此外，由于DNA断裂，细胞周期停滞在Sub-G1期。从分子角度来看，STAT3 和 Akt 信号传导受到抑制，PCNA、ki67 和 Cyclin D1 等增殖标志物以及抗凋亡 Bcl-2 蛋白表达减少。角蛋白 17 是角质形成细胞分化的关键调节因子，并且发现 PPL 显着下调角蛋白 17。此外，通过抑制脂多糖（LPS）/咪喹莫特（IMQ）诱导的p65 NF-κB信号级联反应，观察到显着的抗炎作用，并强烈抑制参与银屑病样皮肤炎症的细胞因子风暴的产生，从而导致恢复正常表皮结构，减少表皮增生和脾肿大。此外，PPL 表观遗传抑制组蛋白修饰酶，包括通过免疫印迹和 HDAC 酶测定试剂盒评估的 I 类 (HDAC1-4) 和 II 类 (HDAC6) 组蛋白脱乙酰酶 (HDAC)。 此外，我们的结果表明，PPL 有效抑制 p65 和组蛋白调节剂 HDAC3 的核转位，从而隔离在巨噬细胞的细胞质中。此外，PPL 有效增强了 HDAC3 和 p65 与 IκBα 的蛋白质-蛋白质相互作用，这种相互作用被 LPS 刺激破坏，并通过 Co-IP 和分子模型进行了评估。总的来说，我们的研究结果表明胡椒长明可以作为一种抗增殖和抗炎剂，并且可以作为治疗牛皮癣的潜在治疗选择。
更新日期：2020-01-10
中文翻译：
Piperlongumine 通过抑制过度增殖和炎症来调节表观遗传调节并减轻牛皮癣样皮肤炎症。
牛皮癣是一种自身免疫性皮肤病，由于过度的细胞因子信号传导、异常分化和逃避角质形成细胞凋亡而导致的慢性免疫反应在介导异常角质形成细胞过度增殖中发挥着至关重要的作用。从治疗的角度来看，具有强抗增殖和抗炎特性的分子可能具有巨大的相关性。在这项研究中，我们证明胡椒长明（PPL）治疗通过诱导ROS介导的晚期细胞凋亡和线粒体膜电位的丧失，有效地消除了角质形成细胞的过度增殖和分化。此外，由于DNA断裂，细胞周期停滞在Sub-G1期。从分子角度来看，STAT3 和 Akt 信号传导受到抑制，PCNA、ki67 和 Cyclin D1 等增殖标志物以及抗凋亡 Bcl-2 蛋白表达减少。角蛋白 17 是角质形成细胞分化的关键调节因子，并且发现 PPL 显着下调角蛋白 17。此外，通过抑制脂多糖（LPS）/咪喹莫特（IMQ）诱导的p65 NF-κB信号级联反应，观察到显着的抗炎作用，并强烈抑制参与银屑病样皮肤炎症的细胞因子风暴的产生，从而导致恢复正常表皮结构，减少表皮增生和脾肿大。此外，PPL 表观遗传抑制组蛋白修饰酶，包括通过免疫印迹和 HDAC 酶测定试剂盒评估的 I 类 (HDAC1-4) 和 II 类 (HDAC6) 组蛋白脱乙酰酶 (HDAC)。 此外，我们的结果表明，PPL 有效抑制 p65 和组蛋白调节剂 HDAC3 的核转位，从而隔离在巨噬细胞的细胞质中。此外，PPL 有效增强了 HDAC3 和 p65 与 IκBα 的蛋白质-蛋白质相互作用，这种相互作用被 LPS 刺激破坏，并通过 Co-IP 和分子模型进行了评估。总的来说，我们的研究结果表明胡椒长明可以作为一种抗增殖和抗炎剂，并且可以作为治疗牛皮癣的潜在治疗选择。
京公网安备 11010802027423号