SIRT2 and SIRT3 expression correlates with redox imbalance and advanced clinical stage in patients with multiple myeloma

ObjectivesSirtuins comprise seven family elements (SIRT1-7) involved in various cell signalling pathways comprising cancer inhibition and tumorigenesis. The present study aims to evaluate SIRT2 and SIRT3 gene expression and potential redox reactions in patients with multiple myeloma (MM) at onset and its correlation with disease status, extent and presence of organ damage secondary to myeloma.Design & MethodsTotal RNA was extracted from 17 MM patients and 10 controls to assess gene expression using real-time PCR. The NAD+/NADH ratio as well as the levels of glutathione peroxidase (GPx) and hydrogen peroxide (HP) in peripheral blood mononuclear cells (PBMCs) were determined using established biochemical assays.ResultsSIRT2 and SIRT3 expression is reduced in MM patients compared to healthy controls. Correlational analysis demonstrated that SIRT2 reduction is associated with advanced clinical stage and with more advanced bone lesions than in the remaining patients. SIRT3 expression is correlated with lytic bone lesions. Biochemical analysis indicated an imbalance of oxidative stress biomarkers with low concentrations of the antioxidant enzyme GPx, low amounts of NAD + and higher concentrations of pro-oxidant enzyme HP in PBMCs of MM patients compared to controls. Moreover, MM patients with bone lesions had lower concentrations of NAD + and GPx in PBMCs than patients without signs of bone disease. In addition, MM patients had higher quantities of intracellular HP than controls.ConclusionsOur results demonstrate that SIRT2 and SIRT3 are downregulated in MM and that lower concentrations correlate with an advanced stage of disease and redox imbalance. We conclude that SIRT2 and SIRT3 together with oxidative stress biomarkers, may be useful for improved risk stratification of MM patients.     

白头翁皂苷 B4调控去乙酰化酶 6对胃癌细胞转移和放疗敏感性的影响

目的探讨白头翁皂苷 B4(AB4)对胃癌细胞增殖、迁移、侵袭及放疗敏感性的影响及其分子机制。方法该研究起止时间为 2018年 4月至 2019年 10月。体外培养人正常胃黏膜上皮细胞 GES-1与胃癌细胞 HGC-27，采用不同浓度( 25、50、100 μmol/L)的 AB4处理 24 h，通过 MTT法检测细胞存活率并筛选 AB4适宜浓度用于后续研究。 Transwell实验检测 HGC-27细胞迁移及侵袭能力。细胞克隆形成实验检测 AB4对 HGC-27细胞放射敏感性的影响；蛋白质印迹法检测 AB4对 HGC-27细胞中去乙酰化酶 6(SIRT6)蛋白表达的影响；干扰 SIRT6表达联合 AB4处理后，采用上述检测方法检测 HGC-27细胞增殖、迁移、侵袭及放射敏感性；蛋白质印迹法检测 DNA激活蛋白激酶催化亚基( DNA-PKcs)、 DNA双链修复蛋白 Rad51、DNA修复酶 Ku80、基质金属蛋白酶 -2(MMP-2)、基质金属蛋白酶 -9(MMP-9)蛋白表达水平。结果与 NC组相比， AB4处理后 HGC-27细胞存活率［( 100.01±9.57)%比( 86.57±6.58)%、(65.45±8.45)%、(49.58±7.96)%］显著降低( P<0.05)，迁移细胞数［( 98.47±8.79)个比(43.57±6.53)个］与侵袭细胞数［(88.42±9.32)个比( 45.56±5.13)个］显著减少( P<0.05)MMP-2、MMP-9蛋白表达水平显著降低(P<0.05)，SIRT6蛋白表达水平(0.42±0.03比 1.03±0.15)显著升高( P<0.05)；细胞克隆形成，实验显示 AB4可降低 HGC-27细胞存活分数( P<0.05)增加增敏比，降低 Rad51、DNA-PKcs、Ku80的表达水平( P<0.05)；干扰 SIRT6表达联合 AB4处理后，迁移细胞数［(44.25±5.52)个，比( 86.47±11.16)个］与侵袭细胞数［(48.56±6.29)个比( 90.17±12.13)个］显著增多( P<0.05)，MMP-2、MMP-9 蛋白相对表达量显著升高( P<0.05)细胞存活分数显著升高( P<0.05)Rad51、DNA-PKcs、Ku80蛋白表达水平明显升高( P<0.05)。结论促进 SIRT6的表达进而发挥抑癌细胞 HGC-27增殖、迁移及侵袭的作用，并增加胃癌细胞的放射敏感性。     

Myeloid-specific SIRT1 Deletion Aggravates Hepatic Inflammation and Steatosis in High-fat Diet-fed Mice

Sirtuin 1 (SIRT1) is a mammalian NAD⁺-dependent protein deacetylase that regulates cellular metabolism and inflammatory response. The organ-specific deletion of SIRT1 induces local inflammation and insulin resistance in dietary and genetic obesity. Macrophage-mediated inflammation contributes to insulin resistance and metabolic syndrome, however, the macrophage-specific SIRT1 function in the context of obesity is largely unknown. C57/BL6 wild type (WT) or myeloid-specific SIRT1 knockout (KO) mice were fed a high-fat diet (HFD) or normal diet (ND) for 12 weeks. Metabolic parameters and markers of hepatic steatosis and inflammation in liver were compared in WT and KO mice. SIRT1 deletion enhanced HFD-induced changes on body and liver weight gain, and increased glucose and insulin resistance. In liver, SIRT1 deletion increased the acetylation, and enhanced HFD-induced nuclear translocation of nuclear factor kappa B (NF-κB), hepatic inflammation and macrophage infiltration. HFD-fed KO mice showed severe hepatic steatosis by activating lipogenic pathway through sterol regulatory element-binding protein 1 (SREBP-1), and hepatic fibrogenesis, as indicated by induction of connective tissue growth factor (CTGF), alpha-smooth muscle actin (α-SMA), and collagen secretion. Myeloid-specific deletion of SIRT1 stimulates obesity-induced inflammation and increases the risk of hepatic fibrosis. Targeted induction of macrophage SIRT1 may be a good therapy for alleviating inflammation-associated metabolic syndrome.     

Clinical significance of sirtuin 1 level in sepsis: correlation with disease risk,severity, and mortality risk

This study aimed to investigate the value of sirtuin 1 (SIRT1) in differentiating sepsis patients from healthy controls (HCs), and its correlation with inflammation, disease severity, as well as prognosis in sepsis patients. Serum samples were collected from 180 sepsis patients and 180 age- and gender-matched HCs. The SIRT1 level in the serum samples was detected by enzyme-linked immunoassay. The clinical data of the sepsis patients were documented, and their disease severity scores and 28-day mortality rate were assessed. SIRT1 was decreased in sepsis patients compared with HCs, and the receiver operating characteristic curve (ROC) showed that SIRT1 distinguished sepsis patients from HCs (area under the curve (AUC): 0.901; 95% confidence interval (CI): 0.868-0.934). In sepsis patients, SIRT1 negatively correlated with serum creatinine (Scr), white blood cells (WBC), C-reactive protein (CRP), acute physiology, and chronic health evaluation II (APACHE II) score, and sequential organ failure assessment (SOFA) score, while it positively correlated with albumin. No correlation of SIRT1 with primary infection site or primary organism was observed. Furthermore, SIRT1 was reduced in 28-day non-survivors compared with 28-day survivors, and subsequent ROC showed that SIRT1 predicted 28-day mortality of sepsis patients (AUC: 0.725; 95% CI: 0.651-0.800), and its prognostic value was not inferior to Scr, albumin, WBC, and CRP, but was less than SOFA score and APACHE II score. In conclusion, measurement of serum SIRT1 might assist with the optimization of disease assessment, management strategies, and survival surveillance in sepsis patients.     

Effects of dairy products consumption on inflammatory biomarkers among adults: A systematic review and meta-analysis of randomized controlled trials

AimsThis study aimed to summarize earlier studies on the effects of dairy consumption on inflammatory biomarkers in adults and to quantify these effects through meta-analysis.Data synthesisA comprehensive search of all relevant articles, published up to December 2019 indexed in PubMed, ISI (Institute for Scientific Information), EmBase, Scopus, and Google Scholar was done using relevant keywords. Randomized controlled trials (RCTs) that examined the effect of dairy products consumption, compared with low or no dairy intake, on inflammatory biomarkers in adults were included. Overall, 11 RCTs with 663 participants were included in this meta-analysis. We found that high consumption of dairy products, compared with low or no dairy intake, might significantly reduce CRP [weighed mean difference (WMD): −0.24 mg/L; 95% CI, −0.35, −0.14], TNF-α (WMD:- 0.66 pg/mL; 95% CI, −1.23, −0.09), IL-6 (WMD: −0.74 pg/mL; 95% CI, −1.36, −0.12), and MCP concentrations (WMD: −25.58 pg/mL; 95% CI, −50.31, −0.86). However, when the analyses were confined to cross-over trials, no such beneficial effects of dairy intake on inflammation were observed. In addition, high dairy intake might result in increased adiponectin levels (WMD: 2.42 μg/mL; 95% CI, 0.17, 4.66). No significant effect of dairy consumption on serum leptin (WMD: −0.32 ng/mL; 95% CI, −3.30, 2.65), ICAM-1 (WMD: −3.38 ng/ml; 95% CI, −15.57, 8.96) and VCAM-1 (WMD: 3.1 ng/mL; 95% CI, −21.38, 27.58) levels was observed.ConclusionsIn summary, the current meta-analysis indicated that dairy intake might improve several inflammatory biomarkers in adults. In most subgroups without heterogeneity, effects tended to be null. Study design and participants’ age were the main sources of heterogeneity. More research, with a particular focus on fat content of dairy foods, is recommended.     

沉默信息调节因子2相关酶1在炎症反应中的调节机制研究进展

沉默信息调节因子相关酶1(SIRT1)是酵母沉默信息调节因子2(Sir2)的哺乳动物同源体,是一种高度保守的NAD+依赖的组蛋白去乙酰化酶.SIRT1的作用底物众多,不仅可以对组蛋白进行去乙酰化作用,还可与多种转录因子和信号分子相互作用.SIRT1的去乙酰化酶活性影响细胞的存活、分化、衰老和凋亡,因而现在已成为生命科学研究的热点.最近几年发现其在炎症反应的发生发展中也发挥着重要调节作用.     

The hinge region in androgen receptor control

The region between the DNA-binding domain and the ligand-binding domain of nuclear receptors is termed the hinge region. Although this flexible linker is poorly conserved, diverse functions have been ascribed to it. For the androgen receptor (AR), the hinge region and in particular the (629)RKLKKL(634) motif, plays a central role in controlling AR activity, not only because it acts as the main part of the nuclear translocation signal, but also because it regulates the transactivation potential and intranuclear mobility of the receptor. It is also a target site for acetylation, ubiquitylation and methylation. The interplay between these different modifications as well as the phosphorylation at serine 650 will be discussed here. The hinge also has an important function in AR binding to classical versus selective androgen response elements. In addition, the number of coactivators/corepressors that might act via interaction with the hinge region is still growing. The importance of the hinge region is further illustrated by the different somatic mutations described in patients with androgen insensitivity syndrome and prostate cancer. In conclusion, the hinge region serves as an integrator for signals coming from different pathways that provide feedback to the control of AR activity.