Cell Death & Disease
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2025
·Vol. 16
·期 1
·1-15
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IF 9.6
Cen Junjie,Zhao Dongliang,Shi Xin,Chen Jinlong,Zhou Hang,Liang Yanping,Gui Chengpeng,Chen Wei,Luo Junhang,Chen Xu
Renal cell carcinoma (RCC) remains a significant clinical challenge due to its increasing incidence and resistance to conventional therapy. This study identifies an unprecedented mechanism by which mesencephalic astrocyte-derived neurotrophic factor (MANF) contributes to RCC progression. From single-cell transcriptome, we observed a significant upregulation of MANF in RCC compared to its progenitor cells, the proximal tubular cells. Mechanistically, decreased N6-methyladenosine (m6A) modification on MANF mRNA, mediated by the upregulation of the m6A demethylase ALKBH5, led to reduced RNA degradation and increased MANF protein expression. Furthermore, while the common von Hippel-Lindau (VHL) deletion in RCC results in the accumulation of misfolded proteins and endoplasmic reticulum (ER) stress, increased MANF efficiently mitigated ER stress by binding to phosphorylated inositol-requiring enzyme-1 alpha (IRE1α) and inhibited its phosphorylation, indicating that MANF-mediated ER stress resistance compensates for the negative effects of VHL depletion and contributes to the survival of RCC. Our findings highlight a potential therapeutic strategy for RCC by targeting the m6A-mediated regulation, directly degrading MANF protein or inhibiting its function.
研究领域:
分子生物学
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癌症研究
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生物化学
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细胞生物学
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转化医学
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DOI
PubMed
高影响因子
Autophagy
·
2024
·
IF 14.6
Zhenchong Xiong,Lin Yang,Chao Zhang,Weiling Huang,Wenjing Zhong,Jiarong Yi,Jikun Feng,Xiazi Zouxu,Libing Song,Xi Wang
During tumor expansion, breast cancer (BC) cells often experience reactive oxygen species accumulation and mitochondrial damage because of glucose shortage. However, the mechanism by which BC cells deal with the glucose-shortage-induced oxidative stress remains unclear. Here, we showed that MANF (mesencephalic astrocyte derived neurotrophic factor)-mediated mitophagy facilitates BC cell survival under glucose-starvation conditions. MANF-mediated mitophagy also promotes fatty acid oxidation in glucose-starved BC cells. Moreover, during glucose starvation, SENP1-mediated de-SUMOylation of MANF increases cytoplasmic MANF expression through the inhibition of MANF’s nuclear translocation and hence renders mitochondrial distribution of MANF. MANF mediates mitophagy by binding to PRKN (parkin RBR E3 ubiquitin protein ligase), a key mitophagy regulator, in the mitochondria. Under conditions of glucose starvation, protein oxidation inhibits PRKN activity; nevertheless, the CXXC motif of MANF alleviates protein oxidation in RING II-domain of PRKN and restores its E3 ligase activity. Furthermore, MANF-PRKN interactions are essential for BC tumor growth and metastasis. High MANF expression predicts poor outcomes in patients with BC. Our results highlight the prosurvival role of MANF-mediated mitophagy in BC cells during glucose starvation, suggesting MANF as a potential therapeutic target.
研究领域:
肿瘤学
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细胞生物学
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分子生物学
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癌症生物学
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DOI
PubMed
高影响因子
International Journal of Pharmaceutics-X
·
2025
·
IF 6.4
Jie-Zhou,Tian-Le Li,Bo-Wei,Yue-Feng Ruan,Ye-Qin Wang,Jiao-Yan Liu,Meng-Meng Song,Yu-Xian Shen
Midbrain astrocyte-derived neurotrophic factor (MANF) is a secreted protein induced by endoplasmic reticulum stress. Previous studies have indicated that intravenous administration of 1 mg/kg/day recombinant human MANF protein with His tag (His-MANF) for 3 days can ameliorate acute ulcerative colitis in mice. However, long-term intravenous therapy has many disadvantages. In this paper, His-MANF protein was successfully encapsulated into alginate and hyaluronic acid hybrid hydrogel microcapsules in one step using the gas shear method and then coated by Eudragit S100 to construct an oral colon-targeted delivery system (MSH@E). The MSH@E microcapsules exhibited controlled and sustained release behavior and colon-targeting properties. Both fluorescent imaging and immunohistochemistry staining results showed that His-MANF protein could accumulate in the colitis colon for a longer residence time after oral delivery. In vivo studies demonstrated that oral administration of MSH@E microcapsules could alleviate DSS-induced colitis in mice without systemic toxicity. Importantly, even if the oral His-MANF dose was half of the intravenous His-MANF dose, oral delivery was still much more effective than intravenous injection, suggesting the development of the oral colon-targeted delivery system (MSH@E) has great significance and makes a breakthrough from intravenous to oral administration for His-MANF treatment of ulcerative colitis (UC).
研究领域:
药剂学
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胃肠病学
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药物递送系统
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生物医学工程
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DOI
PubMed
高影响因子
PHYTOMEDICINE
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2022
·
IF 6.656
Qiang-Ming Li,Xiang Li,Shuang-Qiao Su,Yu-Tong Wang,Tong Xu,Xue-Qiang Zha,Li-Hua Pan,Zhen-Zi Shang,Feng-Yun Zhang,Jian-Ping Luo
Background Parkinson's disease (PD) is an age-related neurodegenerative disorder without effective treatments. Mesencephalic astrocyte-derived neurotrophic factor (MANF) has been suggested to be capable of protecting against PD by inhibiting endoplasmic reticulum (ER) stress-mediated neuronal apoptosis. Purpose This study was aimed to evaluate the antiparkinsonian effect of dendrobine and reveal its underlying mechanisms from the perspective of MANF-mediated ER stress suppression. Methods Behavioral assessments of PD mice as well as LDH/CCK-8 assay in SH-SY5Y cells and primary midbrain neurons were carried out to detect the antiparkinsonian effect of dendrobine. Immunofluorescence, western blot, flow cytometry and shRNA-mediated MANF knockdown were used to determine the apoptosis of dopaminergic neurons and the expressions of ER stress-related proteins for investigating the underlying mechanism of dendrobine. Results Dendrobine significantly ameliorated the motor performance of PD mice and attenuated the injuries of dopaminergic neurons. Dendrobine could also relieve neuronal apoptosis, up-regulate MANF expression and inhibit ER stress, which were largely abolished by shRNA-mediated MANF knockdown in PD model. Conclusion Dendrobine might protect against PD by inhibiting dopaminergic neuron apoptosis, which was achieved by facilitating MANF-mediated ER stress suppression. Our study suggested that dendrobine could act as a MANF up-regulator to protect against PD, and provided a potential candidate for exploring etiological agents of PD.
研究领域:
神经科学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
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