DIGESTIVE DISEASES AND SCIENCES
·
2020
·Vol. 66
·期 10
·3375-3390
·
IF 2.751
Zhang Yu,Li Xiaozhi,Li Yaoting,Li Ying,Wang Ying,Zhu Liguo,Chen Peng,Tian Zhenyi,Qiu Yun,Feng Rui,Zeng Zhirong,He Yao,Chen Baili,Zhang Shenghong,Mao Ren,Chen Minhu
Background and Aims DNA damage-regulated autophagy modulator 1 (DRAM1) is required for induction of autophagy and apoptosis. However, the influence of DRAM1 on the pathogenesis of inflammatory bowel disease (IBD) has not been explored. Methods DRAM1 expression was examined in the intestinal mucosa of patients with IBD and colons of colitis mice. We used a recombinant adeno-associated virus carrying small hairpain DRAM1 to knock down the DRAM1 gene to treat colitis in the mice. The effect of DRAM1 on autophagy and apoptosis of intestinal epithelial cells was explored. DRAM1-mediated interaction with the c-Jun N-terminal kinase (JNK) pathway was also examined. Results DRAM1 expression in the intestinal mucosa of the IBD patients was higher than that in the control participates. DRAM1 expression in the inflammatory cells in patients with Crohn’s disease (CD) was lower than that in patients with ulcerative colitis (UC). Additionally, DRAM1 expression was correlated with the Simple Endoscopic Score for CD and the Mayo endoscopic score for UC. Serum levels of DRAM1 in the IBD group were substantially higher than those in the normal group. The knockdown of DRAM1 could alleviate colitis symptoms in mice. In in vitro experiments, knocking down DRAM1 could reduce autophagy and apoptosis levels. Mechanistically, DRAM1 may participate in the regulation of these two processes by positively regulating JNK activation. Conclusions During intestinal inflammation, the upregulation of DRAM1 may promote the activation of JNK and further aggravate intestinal epithelium damage.
研究领域:
胃肠病学
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分子生物学
·
免疫学
·
病理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Autophagy
·
2025
·
IF 14.3
Jinghong Yang,Haobin Sun,Keqing Xu,Xiaomei Zhang,Mudan Huang,Guanghui Jin,Yasong Liu,Weizhao Chen,Shunan Lin,Juan Shen,Chuan-Qi Zhong,Yan Xu,Qi Zhang,Wei Liu,Yang Yang,Jingxing Ou
Being a major contributor to cell senescence and aging, DNA damage activates macroautophagy/autophagy, but how this process is affected by aging-rewired metabolism in normal biological systems remains to be explored. Here in cultured human umbilical cord-derived mesenchymal stem cells (HsMSCs) and the mouse liver that accumulate DNA damage during aging, we found an elevation of DRAM1 (DNA damage regulated autophagy modulator 1) and DRAM1-mediated pro-senescent autophagy (DMPA). Confirming that DRAM1 activated AMPK, we sought DMPA-associated metabolic features and noted substantial enrichment of N-acetylhistamine (N-AcHA) and phosphatidylethanolamine (PE) products in the aging HsMSCs and mouse liver. Elevating DNA damage and senescence, N-AcHA supplements were sufficient to upregulate DRAM1 and DMPA in primary hepatocytes from young mice but not even in pre-senescent HsMSCs, hence reflecting the differential tolerance of these cell models toward cytotoxic metabolic cues. The effects of N-AcHA were further verified in mouse aging and post-hepatectomy liver regeneration models. In contrast, accumulating cellular PE contents via ethanolamine supplements augmented autophagy but not DNA damage and senescence despite tending to induce DRAM1. Combined treatments with N-AcHA and ethanolamine were sufficient to trigger DMPA in HsMSCs. Despite their differential cellular responses toward N-AcHA and ethanolamine supplements, in primary HsMSCs and mouse hepatocytes DMPA did not notably downregulate SQSTM1/p62 proteins, which differed from general macroautophagy and may constitutively support the fusion of SQSTM1-modified cargo-containing autophagosomes with lysosomes. Overall, this study reveals DMPA-promoting metabolic and molecular features. Thus, targeting certain metabolic pathways and DMPA may promote DNA repair and delay senescence/aging.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Microbiology Spectrum
·
2023
·Vol. 11
·期 6
·
IF 3.7
Minyu Wang,Zheng Wang,Duncan James Lessing,Min Guo,Weihua Chu
Fusobacterium nucleatum is a harmful bacterium that produces hydrogen sulfide by metabolizing sulfur-containing amino acids, both of which have been shown to promote/initiate the development of various cancers, such as colorectal cancer, liver cancer, as well as lung cancer. However, few studies have reported how F. nucleatum acts on gut microbiota, influences the autophagy process, and promotes the development of colorectal cancer through the metabolite hydrogen sulfide. It was found that HCT116 cells secreted more inflammatory factors and showed higher survival as well as migration rate when given a pathological concentration of hydrogen sulfide. Using cellular transcriptome sequencing, it could be seen that after giving HCT116 cells F. nucleatum or F. nucleatum with L-cysteine, many inflammation-related signaling pathways, including autophagic pathways, were elevated compared to the control group. In vivo, the mice in the model groups displayed cancer progression, and the expression of some of the autophagy-related genes, DRAM1, NBR1, ATG7, MAP1LC3A were also increased in mice given F. nucleatum or F. nucleatum with L-cysteine when compared to the untreated control mice. The number of certain probiotic bacteria and fungi in the mice given F. nucleatum or F. nucleatum and L-cysteine decreased significantly; in contrast, the number of potentially pathogenic bacteria and fungi increased. These findings suggest that F. nucleatum and its metabolite hydrogen sulfide can modulate intestinal microbiota and autophagy as well as promote the development and progression of colorectal cancer.
研究领域:
微生物学
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癌症生物学
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分子生物学
·
胃肠病学
✓ 已验证
DOI
高影响因子
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