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HDAC inhibitors promote pancreatic stellate cell apoptosis and relieve pancreatic fibrosis by upregulating miR-15/16 in chronic pancreatitis.

HDAC 抑制剂通过上调慢性胰腺炎 miR-15/16 促进胰腺星状细胞凋亡,缓解胰腺纤维化。

  • 影响因子:2.15
  • DOI:10.1007/s13577-020-00387-x
  • 作者列表:"Ji T","Feng W","Zhang X","Zang K","Zhu X","Shang F
  • 发表时间:2020-06-11
Abstract

:In chronic pancreatitis, PSCs are activated by proinflammatory cytokines to induce pancreatic fibrogenesis. HDAC inhibition protected against the pancreatic fibrosis and the apoptosis of PSCs through induced apoptosis and depressed inflammation. In our study, we found that miR-15 and miR-16 decreased significantly in chronic pancreatitis and HDAC inhibition could recover the levels of these two miRNAs. HDAC regulated the transcription of miR-15 and miR-16, which then modulate the apoptosis and fibrosis of PSCs. And we proved that Bcl-2 and Smad5 were the target genes of miR-15 and miR-16, which illustrated how HDAC inhibition alleviated the apoptosis and fibrogenesis of PSCs in chronic pancreatitis. These results suggested that HDAC inhibition protects against CP by promoting apoptosis and TGF-β/Smads signaling pathways, and indicated that HDAC inhibition is a potential therapy to alleviate CP patients in clinic, and these need to be explored further.

摘要

: 在慢性胰腺炎中,PSCs 被促炎细胞因子激活以诱导胰腺纤维化。HDAC 抑制通过诱导细胞凋亡和抑制炎症来保护胰腺纤维化和 PSCs 的凋亡。在我们的研究中,我们发现慢性胰腺炎时 miR-15 和 miR-16 显著降低,HDAC 抑制可以恢复这两种 miRNAs 的水平。HDAC 调控 miR-15 和 miR-16 的转录,进而调控 PSCs 的凋亡和纤维化。证明了 Bcl-2 和 Smad5 是 miR-15 和 miR-16 的靶基因,说明 HDAC 抑制可减轻慢性胰腺炎 PSCs 的凋亡和纤维化。这些结果表明 HDAC 抑制通过促进细胞凋亡和 TGF-β/Smads 信号通路保护 CP,并表明 HDAC 抑制是临床上缓解 CP 患者的潜在疗法。这些需要进一步探讨。

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发表时间:2020-01-27
来源期刊:Aging
DOI:10.18632/aging.102776
作者列表:["Akula SM","Ruvolo PP","McCubrey JA"]

METHODS::Pancreatic ductal adenocarcinoma (PDAC) is a disease of aging. The TP53 gene product regulates cell growth, aging, and cancer. To determine the important targets of TP53 in PDAC, we examined the expression of 440 proteins on a reverse phase protein array (RPPA) in PDAC-derived MIA-PaCa-2 cells which either had WT-TP53 or lacked WT-TP53. MIA-PaCa-2 cells have a TP53 mutation as well as mutant KRAS and represent a good in vitro model to study PDAC. RPPA analysis demonstrated expression of tumor promoting proteins in cells that lacked WT-TP53; and this feature could be reversed significantly when the cells were transfected with vector encoding WT-TP53 or treated with berberine or a modified berberine (BBR). Expression of miR-34a-associated signaling was elevated in cells expressing WT-TP53 compared to cells expressing mTP53. Results from in vivo studies using human PDAC specimens confirmed the in vitro results as the expression of miR-34a and associated signaling was significantly decreased in PDAC specimens compared to non-cancerous tissues. This study determined SERPINE1 as a miR-34a target with relevance to the biology of PDAC. Thus, we have identified a key target (SERPINE1) of the TP53/miR-34a axis that may serve as a potential biomarker for early detection of pancreatic cancer.

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影响因子:5.13
发表时间:2020-01-28
DOI:10.1080/17425247.2020.1723544
作者列表:["Kou L","Huang H","Lin X","Jiang X","Bao S","Luo Q","Sun J","Yao Q","Ganapathy V","Chen R"]

METHODS::Background: SLC6A14 (ATB0,+), a Na+/Cl-coupled transporter for neutral/cationic amino acids, is overexpressed in many cancers; It has been investigated as a target for improved liposomal drug delivery to treat liver cancer.Research design and methods: Here we explored the mechanism of ATB0,+-mediated entry of such liposomes. As ATB0,+ is highly-expressed in pancreatic cancer, we also examined the therapeutic utility of ATB0,+-targeted liposomal drug delivery to treat this cancer.Results: The uptake of lysine-conjugated liposomes (LYS-LPs) was greater in ATB0,+-positive MCF7 cells. The uptake process consisted of two steps: binding and internalization. The binding of LYS-LPs to MCF7 cells was higher than that of bare liposomes, and the process was dependent on Na+ and Cl-, and inhibitable by ATB0,+ substrates or blocker. In contrast, the internalization step was independent of lysine. The cellular entry of LYS-LPs facilitated by ATB0,+ occurred via endocytosis with transient endosomal degradation of ATB0,+ protein with subsequent recovery. Moreover, LYS-LPs also enhanced the uptake and cytotoxicity of gemcitabine in these cells in an ATB0,+-dependent manner.Conclusions: We conclude that ATB0,+ could be exploited for targeted drug delivery in the form of lysine-conjugated liposomes and that the approach represents a novel strategy for enhanced pancreatic cancer therapy.

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影响因子:2.30
发表时间:2020-01-28
DOI:10.1007/s00423-020-01857-4
作者列表:["Okada KI","Kawai M","Hirono S","Kojima F","Tanioka K","Terada M","Miyazawa M","Kitahata Y","Iwahashi Y","Ueno M","Hayami S","Murata SI","Shimokawa T","Yamaue H"]

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