Hepatocellular carcinoma (HCC) is one of the most common tumor types and remains a major clinical challenge. Increasing evidence has revealed that mitophagy inhibitors can enhance the effect of chemotherapy on HCC. Ho...Hepatocellular carcinoma (HCC) is one of the most common tumor types and remains a major clinical challenge. Increasing evidence has revealed that mitophagy inhibitors can enhance the effect of chemotherapy on HCC. However, few mitophagy inhibitors have been approved for clinical use in humans. Pyrimethamine (Pyr) is used to treat infections caused by protozoan parasites. Recent studies have reported that Pyr may be beneficial in the treatment of various tumors. However, its mechanism of action is still not clearly defined. Here, we found that blocking mitophagy sensitized cells to Pyr-induced apoptosis. Mechanistically, Pyr potently induced the accumulation of autophagosomes by inhibiting autophagosome-lysosome fusion in human HCC cells. In vitro and in vivo studies revealed that Pyr blocked autophagosome-lysosome fusion by upregulating BNIP3 to inhibit synaptosomal-associated protein 29 (SNAP29)-vesicle-associated membrane protein 8 (VAMP8) interaction. Moreover, Pyr acted synergistically with sorafenib (Sora) to induce apoptosis and inhibit HCC proliferation in vitro and in vivo. Pyr enhances the sensitivity of HCC cells to Sora, a common chemotherapeutic, by inhibiting mitophagy. Thus, these results provide new insights into the mechanism of action of Pyr and imply that Pyr could potentially be further developed as a novel mitophagy inhibitor. Notably, Pyr and Sora combination therapy could be a promising treatment for malignant HCC.展开更多
Current guidelines recommend cold snare polypectomy for polyps less than 10 mm in size.Conversely,endoscopic mucosal resection is still the preferred technique for larger polyps.Concerns regarding cold snare polypecto...Current guidelines recommend cold snare polypectomy for polyps less than 10 mm in size.Conversely,endoscopic mucosal resection is still the preferred technique for larger polyps.Concerns regarding cold snare polypectomy for larger polyps revolve around the difficulty in conducting en-bloc resection(resulting in piecemeal removal),and the potential for local residual polyp tissue and a high rate of recurrence.On the other hand,cold snare technique has the advantages of shortening procedure time,reducing delayed bleeding risks and lowering cost of treatment.Numerous ongoing and recent studies are focused on evaluating the risks and benefits of this technique for polyps larger than 10 mm,with the goal of providing clear guidelines in the near future.The aim of this editorial is to provide our readers with an overview regarding this subject and the latest developments surrounding it.展开更多
在真核生物细胞中,各细胞器间物质和信息的交流是细胞生命活动的基本保证,而囊泡转运是细胞器之间物质和信息交流的主要方式。大多数的囊泡融合过程是由可溶性的N-乙基马来酰亚胺敏感因子连接物复合体(Soluble N-ethyl-maleimide-sensit...在真核生物细胞中,各细胞器间物质和信息的交流是细胞生命活动的基本保证,而囊泡转运是细胞器之间物质和信息交流的主要方式。大多数的囊泡融合过程是由可溶性的N-乙基马来酰亚胺敏感因子连接物复合体(Soluble N-ethyl-maleimide-sensitive fusion protein attachment protein receptors,SNAREs)介导的,物种间的SNAREs具有高度保守的特性。与其他真核生物相比,植物的基因组编码更多的SNAREs。研究证明,植物的SNAREs是一个多功能的蛋白家族,在植物的许多生理过程中都有着重要的作用。本文对植物SNAREs作用的分子机理及生物学功能的最新研究进展做一概述。展开更多
基金supported by the National Natural Science Foundation of China(Grant No:81903643)the“Young Talent Support Plan”of Xi'an Jiaotong University,the Shaanxi Province Science and Technology Development Plan Project(Grant No.:2022ZDLSF05-05)+1 种基金the Project of Shaanxi Provincial Administration of Traditional Chinese Medicine(Project No.:2021-03-ZZ-002)the Shaanxi Province Science Fund for Distinguished Young Scholars(Grant No:2023-JC-JQ-59).
文摘Hepatocellular carcinoma (HCC) is one of the most common tumor types and remains a major clinical challenge. Increasing evidence has revealed that mitophagy inhibitors can enhance the effect of chemotherapy on HCC. However, few mitophagy inhibitors have been approved for clinical use in humans. Pyrimethamine (Pyr) is used to treat infections caused by protozoan parasites. Recent studies have reported that Pyr may be beneficial in the treatment of various tumors. However, its mechanism of action is still not clearly defined. Here, we found that blocking mitophagy sensitized cells to Pyr-induced apoptosis. Mechanistically, Pyr potently induced the accumulation of autophagosomes by inhibiting autophagosome-lysosome fusion in human HCC cells. In vitro and in vivo studies revealed that Pyr blocked autophagosome-lysosome fusion by upregulating BNIP3 to inhibit synaptosomal-associated protein 29 (SNAP29)-vesicle-associated membrane protein 8 (VAMP8) interaction. Moreover, Pyr acted synergistically with sorafenib (Sora) to induce apoptosis and inhibit HCC proliferation in vitro and in vivo. Pyr enhances the sensitivity of HCC cells to Sora, a common chemotherapeutic, by inhibiting mitophagy. Thus, these results provide new insights into the mechanism of action of Pyr and imply that Pyr could potentially be further developed as a novel mitophagy inhibitor. Notably, Pyr and Sora combination therapy could be a promising treatment for malignant HCC.
文摘Current guidelines recommend cold snare polypectomy for polyps less than 10 mm in size.Conversely,endoscopic mucosal resection is still the preferred technique for larger polyps.Concerns regarding cold snare polypectomy for larger polyps revolve around the difficulty in conducting en-bloc resection(resulting in piecemeal removal),and the potential for local residual polyp tissue and a high rate of recurrence.On the other hand,cold snare technique has the advantages of shortening procedure time,reducing delayed bleeding risks and lowering cost of treatment.Numerous ongoing and recent studies are focused on evaluating the risks and benefits of this technique for polyps larger than 10 mm,with the goal of providing clear guidelines in the near future.The aim of this editorial is to provide our readers with an overview regarding this subject and the latest developments surrounding it.
文摘在真核生物细胞中,各细胞器间物质和信息的交流是细胞生命活动的基本保证,而囊泡转运是细胞器之间物质和信息交流的主要方式。大多数的囊泡融合过程是由可溶性的N-乙基马来酰亚胺敏感因子连接物复合体(Soluble N-ethyl-maleimide-sensitive fusion protein attachment protein receptors,SNAREs)介导的,物种间的SNAREs具有高度保守的特性。与其他真核生物相比,植物的基因组编码更多的SNAREs。研究证明,植物的SNAREs是一个多功能的蛋白家族,在植物的许多生理过程中都有着重要的作用。本文对植物SNAREs作用的分子机理及生物学功能的最新研究进展做一概述。
