Nicotinamide N-methyltransferase decreases 5-fluorouracil sensitivity in human esophageal squamous cell carcinoma through metabolic reprogramming and promoting the Warburg effect

Esophageal squamous cell carcinoma (ESCC) is a common malignant tumor with poor prognosis. And different individuals respond to the same drug differently. Increasing evidence has confirmed that metabolism reprogramming was involved in the drug sensitivity of tumor cells. However, the potential molecular mechanism of 5-fluorouracil (5-FU) sensitivity remains to be elucidated in ESCC cells. In this study, we found that the 5-FU sensitivity of TE1 cells was lower than that of EC1 and Eca109 cells. Gas chromatography-mass spectrometry analysis results showed that nicotinate and nicotinamide metabolism and tricarboxylic acid cycle were significantly different in these three cell lines. Nicotinamide N-methyltransferase (NNMT), a key enzyme of nicotinate and nicotinamide metabolism, was significantly higher expressed in TE1 cells than that in EC1 and Eca109 cells. Therefore, the function of NNMT on 5-FU sensitivity was analyzed in vitro and in vivo. NNMT downregulation significantly increased 5-FU sensitivity in TE1 cells. Meanwhile, the glucose consumption and lactate production were decreased, and the expression of glycolysis-related enzymes hexokinase 2, lactate dehydrogenase A, and phosphoglycerate mutase 1 were downregulated in NNMT knockdown TE1 cells. Besides, overexpression of NNMT in EC1 and Eca109 cells caused the opposite effects. Moreover, when glycolysis was inhibited by 2-deoxyglucose, the roles of NNMT on 5-FU sensitivity was weakened. In vivo experiments showed that NNMT knockdown significantly increased the sensitivity of xenografts to 5-FU and suppressed the Warburg effect. Overall, these results demonstrated that NNMT decreases 5-FU sensitivity in human ESCC cells through promoting the Warburg effect, suggesting that NNMT may contribute to predict the treatment effects of the clinical chemotherapy in ESCC.     

The effect of acetylation on the protein stability of BmApoLp‐III in the silkworm,Bombyx mori

Acetylation is an important, reversible posttranslational modification to a protein. In a previous study, we found that there were a large number of acetylated sites in various nutrient storage proteins of the silkworm haemolymph. In this study, we confirmed that acetylation can affect the stability of nutrient storage protein Bombyx mori apolipophorin‐III (BmApoLp‐III). First, the expression of BmApoLp‐III could be upregulated when BmN cells were treated with the deacetylase inhibitor panobinostat (LBH589); similarly, the expression was downregulated when the cells were treated with the acetylase inhibitor C646. Furthermore, the increase in acetylation by LBH589 could inhibit the degradation and improve the accumulation of BmApoLp‐III in BmN cells treated with cycloheximide and MG132 respectively. Moreover, we found that an increase in acetylation could decrease the ubiquitination of BmApoLp‐III and vice versa; therefore, we predicted that acetylation could improve the stability of BmApoLp‐III by competing for ubiquitination and inhibiting the protein degradation pathway mediated by ubiquitin. Additionally, BmApoLp‐III had an antiapoptosis function that increased after LBH589 treatment, which might have been due to the improved protein stability after acetylation. These results have laid the foundation for further study on the mechanism of acetylation in regulating the storage and utilization of silkworm nutrition.     

Prevalence and clinical impact of TP53 germline mutations in Chinese women with breast cancer

The prevalence and clinical relevance of TP53 germline mutations in a large unselected breast cancer series are largely unknown. Here, we determined TP53 germline mutations in a large cohort of 10,053 unselected breast cancer patients through multigene panel-based next-generation and/or Sanger sequencing assays. We found that 0.5% of patients (50 cases) carried a pathogenic TP53 germline mutation in this large series of 10,053 unselected breast cancer patients, and the prevalence of TP53 germline mutation was 3.8% in very early onset breast cancer (age ≤30 years) in this large cohort. TP53 mutation carriers were significantly more likely to have early onset cancer (p < 0.001) and bilateral breast cancer (p = 0.03), they and were significantly more likely to respond to carboplatin-based neoadjuvant chemotherapy compared to anthracycline- or taxane-based regimen in terms of pathologic complete response (50% vs. 0%, p = 0.006). At the median follow-up of 54 months, TP53 mutation was an independent unfavorable factor for recurrence-free survival (RFS), distant recurrence-free survival (DRFS), and overall survival (OS) (RFS, adjusted hazard ratio [HR]: 2.24, 95% confidence interval [CI]: 1.15–4.33, p = 0.02; DRFS, adjusted HR: 2.73, 95% CI: 1.41–5.30, p = 0.003; OS, adjusted HR: 4.60, 95% CI: 2.26–9.41, p < 0.001) in multivariate analyses. Our study suggested that TP53 germline mutations occur more frequently in very early onset unselected breast cancer patients; and TP53 germline mutation carriers have a very poor survival and may benefit from carboplatin-based neoadjuvant chemotherapy in unselected breast cancer patients.     

黄酮类化合物及其纳米制剂在肿瘤防治中的研究进展

传统的肿瘤治疗方法依然存在肿瘤组织可及性差和药物不良反应普遍的问题。黄酮类化合物已被证实对多种类型肿瘤有效，但其安全性和作用部位特异性尚未被评估。然而，膳食黄酮类化合物因溶解度小、代谢快、口服吸收差等特点限制了其在体内抗肿瘤活性的发挥。此外，黄酮类化合物在某些情况下还能通过生物转化等作用与药物相互作用而影响生物利用度。纳米载体因可改变药物的药动学和药效学特征而被设计用于靶向药物传递，提高难溶性药物的生物利用度，将大分子传递到细胞内的作用位点，同时还能减少药物不良反应。体内、外研究均表明，纳米类黄酮制剂，特别是槲皮素、柚皮素、芹菜素、儿茶素和非瑟酮等在多种肿瘤的预防和治疗方面具有潜在作用，但其临床应用价值仍有待阐明。本文就纳米类黄酮制剂在提高生物利用度、肿瘤治疗效果和安全性方面的作用展开综述，为肿瘤治疗药物的开发利用提供新思路。     

下瘀血汤加减辅助TACE 治疗原发性肝癌肝热血瘀证临床研究

目的:观察下瘀血汤加减治疗对行经皮肝动脉化疗栓塞术(TACE)的原发性肝癌(PLC)肝热血瘀证患者中医证候、血清基质金属蛋白酶(MMP)、肝功能、生活质量及化疗毒副反应的影响。方法:选取78例行TACE治疗的PLC肝热血瘀证患者,按住院先后顺序随机分为观察组和对照组各39例。对照组术后给予复方甘草酸苷胶囊治疗,观察组在对照组基础上给予下瘀血汤加减治疗,均治疗12周。比较2组中医证候积分、临床疗效、血清MMP-1及MMP-9水平、Child-Pugh分级、卡氏评分(KPS评分)、化疗毒副反应发生情况。结果:治疗后,2组中医证候积分均较治疗前降低,观察组中医证候积分低于对照组,差异均有统计学意义(P0.05)。观察组总有效率为89.74%,高于对照组的71.79%(P0.05)。治疗后,2组血清MMP-1、MMP-9水平均较治疗前降低(P0.05),观察组血清MMP-1、MMP-9水平均比对照组降低更明显(P0.05)。治疗后,2组Child-Pugh分级A级比率均较治疗前升高(P0.05),观察组Child-Pugh分级A级比率高于对照组(P0.05)。治疗后,2组KPS评分均较治疗前升高(P0.05),观察组KPS评分比对照组升高更明显(P0.05)。治疗6周、12周,观察组血小板下降、谷丙转氨酶升高情况均优于对照组,差异均有统计学意义(P0.05)。结论:下瘀血汤加减用于治疗PLC肝热血瘀证行TACE术后患者,可改善其中医证候,降低血清MMP-1、MMP-9水平,改善患者的肝功能和生活质量,减少化疗毒副反应。