Background: Hyperthermia has proved successful in treating cutaneous human papillomavirus infectious diseases such as plantar wart and condyloma acuminata (CA). Moreover, this treatment provides improved therapeutic efficacy in these conditions as compared with conventional therapies.
Objectives: To investigate the global proteome changes in CA in response to hyperthermia and achieve a better understanding of the mechanisms of hyperthermia therapy against HPV-infectious diseases.
Methods: CA tissue was obtained from patients undergoing pathological examinations. Diagnosis was verified as based on results of both HE staining and HPV-DNA PCR assay. Hyperthermia was achieved with a 44?°C water bath. Differentially expressed proteins (DEPs) were identified by iTRAQ labeling, SCX chromatography and LC-MS/MS assay. Validation of proteomic results was performed using real-time qPCR and western blot, while bioinformatic analysis of DEPs was accomplished by R 3.4.1, STRING and Cytoscape softwares.
Results: In response to hyperthermia, a total of 102 DEPs were identified with 37 being upregulated and 65 downregulated. Among these DEPs, hyperthermia induced proteins involved with anti-viral processes such as OAS1, MX1, BANF1, CANX and AP1S1, whereas it inhibited proteins that participated in cellular metabolism, such as GALT, H6PD, EXOSC4 and EXOSC6; protein translation, such as RPS4Y1; as well as keratinocyte differentiation, such as KRT5, KRT27, KRT75, KRT76 and H2AFY2.
Conclusions: Hyperthermia inhibited enzymes and molecules responsible for metabolism modulation and keratinocyte differentiation in CA tissue, whereas it promoted factors involved in anti-viral responses. Such effects may, in part, contribute to the efficacy of local hyperthermia therapy against HPV infection. 相似文献
Melatonin has been previously shown to prevent nonalcoholic fatty liver disease (NAFLD), yet the underlying mechanisms are poorly understood. Here, we identified a previously unknown regulatory action of melatonin on apoptosis signal‐regulating kinase 1 (ASK1) signaling pathway in the pathogenesis and development of NAFLD. Although melatonin administration did not alter food intake, it significantly alleviated fatty liver phenotypes, including the body weight gain, insulin resistance, hepatic lipid accumulation, steatohepatitis, and fibrosis in a high‐fat diet (HFD)‐induced NAFLD mouse model (in vivo). The protection of melatonin against NAFLD was not affected by inactivation of Kupffer cell in this model. In NAFLD mice liver, ASK1 signal cascade was substantially activated, evidence by the enhancement of total ASK1, phospho‐ASK1, phospho‐MKK3/6, phospho‐p38, phospho‐MKK4/7, and phospho‐JNK. Melatonin treatment significantly suppressed the ASK1 upregulation and the phosphorylation of ASK1, MKK3/6, MKK4/7, p38, and JNK. Mechanistically, we found that lipid stress triggered the interaction between ASK1 and TNF receptor‐associated factors (TRAFs), including TRAF1, TRAF2, and TRAF6, which resulted in ASK1 deubiquitination and thereby increased ASK1 protein stability. Melatonin did not alter ASK1 mRNA level; however, it activated a scaffold protein β‐arrestin‐1 and enabled it to bind to ASK1, which antagonized the TRAFs‐mediated ASK1 deubiquitination, and thus reduced ASK1 protein stability. Consistent with these findings, knockout of β‐arrestin‐1 in mice partly abolished the protection of melatonin against NAFLD. Taken together, our results for the first time demonstrate that melatonin safeguards against NAFLD by eliminating ASK1 activation via inhibiting TRAFs‐mediated ASK1 deubiquitination and stabilization in a β‐arrestin‐1 dependent manner. 相似文献