作者机构：
Hunan Key Laboratory of Druggability and Preparation Modification for Traditional Chinese Medicine, Changsha, 410208, China;Department of Pharmaceutics, Pharmacy College, Hunan University of Tradition Chinese Medicine, Changsha, 410208, China;Supramolecular Mechanism and Mathematic-Physics Characterization for Chinese Materia Medicine, Changsha, 410208, China;[邓凯文] The First Affinity Hospital, Hunan University of Chinese Medicine, Changsha, 410007, China;[贺福元; 潘雪] Hunan Key Laboratory of Druggability and Preparation Modification for Traditional Chinese Medicine, Changsha, 410208, China, Department of Pharmaceutics, Pharmacy College, Hunan University of Tradition Chinese Medicine, Changsha, 410208, China, Supramolecular Mechanism and Mathematic-Physics Characterization for Chinese Materia Medicine, Changsha, 410208, China
通讯机构：
[He, F.-Y.] H;Hunan Key Laboratory of Druggability and Preparation Modification for Traditional Chinese Medicine, Changsha, China
作者机构：
[Hu, Jia-Qing] Second Peoples Hosp Hunan, Dept Emergency, Changsha 410007, Hunan, Peoples R China.;[Deng, Fang] Second Peoples Hosp Hunan, Dept Pharmacol, Changsha 410007, Hunan, Peoples R China.;[Hu, Xiao-Ping] Guangzhou Med Univ, Affiliated Canc Hosp, Dept Pharmacol, Guangzhou 510095, Guangdong, Peoples R China.;[Zhang, Wei] Second Peoples Hosp Hunan, Dept Radiol, Changsha, Hunan, Peoples R China.;[Zeng, Xiao-Chen] Second Peoples Hosp Hunan, Dept Surg, Changsha, Hunan, Peoples R China.
通讯机构：
[Tian, Xue-Fei] H;Hunan Univ Chinese Med, Clin Med Coll, Peoples Hosp Hunan 2, Dept Oncol, Changsha 410007, Hunan, Peoples R China.
关键词：
sirtuin;post-translational modification;apoptosis;liver cancer
摘要：
Liver cancer is the leading cause of cancer-related mortality worldwide and its incidence is increasing. Considerable effort has been made in recent decades to improve the diagnosis and treatment of liver cancer. Advanced liver cancer often exhibits a poor response to chemotherapy and poor prognosis due to acquired chemoresistance and tumor recurrence. Understanding the precise molecular mechanisms that are responsible for chemotherapeutic drug-induced cell death could potentially identify novel therapeutic targets and improve liver cancer treatment. In the present study, it was demonstrated that in response to doxorubicin, the most frequently used chemical compound for liver cancer treatment, histone deacetylase sirtuin 6 (SIRT6) is specifically downregulated. This enables forkhead box O3 (FOXO3) upregulation, translocation into the nucleus and increased expression of its target genes p27 and Bim, which further induce apoptosis. Overexpression of SIRT6, but not enzyme-inactivated mutants, prevents FOXO3 translocation into the nucleus and doxorubicin-induced cell death. SIRT6 interacts with FOXO3 and this interaction increases FOXO3 ubiquitination and decreases its stability. Finally, it was identified that the effect of SIRT6 in preventing doxorubicin-induced cell death requires FOXO3. Overexpression of SIRT6 could not prevent doxorubicin-induced cell death in FOXO3-knockdown cells. Therefore, it was concluded that SIRT6 plays a central role in determining doxorubicin-induced cell death via modulation of FOXO3 activity. Therapeutic targeting of SIRT6 and/or FOXO3 may offer novel strategies for treatment of liver cancer.
摘要：
Curcumin has been revealed to inhibit liver cancer, however, no studies have reported that the mechanism of curcumin's action on liver cancer is related to damage-associated molecular pattern (DAMP) molecules heat shock protein 70 (HSP70) and the toll-like receptor 4 (TLR4) signaling. This study aimed to investigate whether the activation of TLR4 signaling by HSP70 could be inhibited by curcumin, thus investigating the possible mechanism of curcumin in the inhibition of liver cancer. Western blotting was used to evaluate the expression of the HSP70 and TLR4 in HepG2 cells and ELISA was used to detect the concentration of HSP70 in cell culture medium. A thermal tolerance HepG2 (HepG2TT) cell model was established to simulate HSP70 accumulation in the microenvironment. A certain concentration of curcumin was co-cultured with HepG2 and HepG2TT cells to observe the changes of HSP70 and TLR4. Our results revealed that heat stress significantly increased the expression of extracellular HSP70 (eHSP70) and TLR4 (P<0.01), but significantly reduced the expression of intracellular HSP70 (P<0.01). Curcumin inhibited proliferation, invasion, and metastasis of HepG2 cells, caused cells to remain in the DNA S phase, promoted apoptosis, and significantly reduced intracellular HSP70, eHSP70 and TLR4 levels of HepG2TT cells. Following the removal of curcumin, eHSP70 increased again. In summary, our results demonstrated that the antitumor effect of curcumin was related to the inhibition HSP70-TLR4 signaling.
摘要：
目的 以姜黄提取物为参照研究姜黄素对大鼠血栓模型的影响及其与损伤相关模式分子(DAM P)热休克蛋白70(HSP70)的关系.方法 分别对大鼠进行姜黄素及姜黄提取物灌胃14 d后用物理方法建立大鼠血栓模型,以假手术组、蒸馏水灌胃血栓模型组(血栓模型组)大鼠为对照,获取各组大鼠血液标本和血管组织,采用ELISA法检测各组大鼠血浆HSP70水平,采用免疫组化法检测各组大鼠血管组织中HSP70的表达.结果 血栓模型组大鼠血浆H S P70水平显著高于假手术组大鼠(P=0.003),姜黄素低、高剂量灌胃血栓模型组大鼠血浆HSP70均显著降低(P=0.005、0.002),而姜黄提取物灌胃血栓模型组大鼠血浆HSP70水平无明显变化;与假手术组大鼠相比,血栓模型组大鼠血管组织中H S P70表达增强,姜黄素灌胃使血栓模型大鼠血管组织中H S P70表达增强,而姜黄提取物没有此作用.结论 姜黄素抗炎作用与增加细胞内H S P70表达,降低细胞外H S P70有关,姜黄提取物的抗炎作用可能是通过其他机制.
摘要：
Aims: Neutrophil extracellular traps (NETs) comprise a unique form of non-apoptotic cell death exhibited by neutrophils, which occurs in a stepwise process termed NETosis. It has been postulated that NETosis plays an important role in the pathogenesis of autoimmune disorders. The aim of this study was to evaluate serum levels of NET remnants in patients with rheumatoid arthritis (RA), as well as potential associations between NET remnants and indicators of RA. Methods: Serum levels of myeloperoxidase (MPO)-DNA complexes (NET remnants) were examined in 74 RA patients and 50 healthy controls using a modified enzyme-linked immunosorbent assay. Associations between the levels of these complexes and indicators of RA were then statistically evaluated. Results: RA patients exhibited significantly higher levels of MPO-DNA complexes than the healthy controls, and these levels were associated with increased neutrophil counts and positivity for rheumatoid factor (RF) and anti-citrullinated protein/peptide antibodies (ACPA). Among the 63 ACPA-positive RA patients examined, those with ACPA titers > 1600 U/mL showed significantly increased MPO-DNA levels. Receiver operating characteristic analysis determined that the area under the curve for all 74 RA patients was 0.798, with a sensitivity of 91.9% and a specificity of 56.0%, while that for the ACPA-negative patients was 0.891, with a sensitivity and specificity of 81.8% and 84.0%, respectively. Conclusions: The results of this study suggest that the disease status of RA is associated with increased NETosis. In particular, evaluation of serum MPO-DNA levels may comprise a useful complementary tool for discriminating RA patients from healthy individuals.
