BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2022
·
IF 3.322
Weigang Yuan,Fenglei Jian,Yueguang Rong
Some traditional Chinese medicines exert roles in the therapy of liver diseases by modulating autophagy. Bifendate (DDB), a synthetic intermediate of Schisandrin C extracted from Schisandrae chinensis , is clinically used to treat hepatitis in China. While DDB is a positive control to research some potential hepatoprotective agents, its related molecular mechanisms are unknown. In this study, we show that DDB inhibited autophagosome−lysosome fusion, lysosome acidification and autophagic lysosome reformation. Moreover, DDB attenuated oleic acid-induced lipid droplet accumulation. These findings reveal the effects of DDB on the autophagy-related processes and lysosomal function, and also provide a possibility to understand the bioactivity mechanism of DDB in the future.
研究领域:
药理学
·
肝病学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CARCINOGENESIS
·
2019
·Vol. 41
·期 6
·804-816
·
IF 4.004
Wang Kai,Tu Yanbei,Wan Jian-Bo,Chen Meiwan,He Chengwei
Autophagy is an evolutionarily conserved mechanism to protect the cells from unfavorable environmental conditions. Inhibition of autophagy has been contemplated as a novel strategy to enhance anticancer efficacy of existing chemotherapeutic agents. We previously reported that pulsatilla saponin D (PSD) was a potent autophagy inhibitor. However, its anticancer potential as adjuvant and underlying mechanisms are still unknown. In this study, we identified that PSD induced the formation of autophagosome in MCF-7 and MDA-MB-231 breast cancer cells. However, PSD alone and particularly co-treatment with camptothecin remarkably increased p62 protein levels, indicating that PSD strongly inhibited the autophagic cargo degradation. The mechanistic study indicated that PSD profoundly abolished the co-localization of EGFP-LC3 and lysosomal-specific probe LysoTracker Red, suggesting that the autophagosome–lysosome fusion was blocked by PSD, which is similar to the action of chloroquine. In addition, PSD significantly increased lysosomal pH and inhibited the activation of lysosomal cathepsins in both breast cancer cell lines. Furthermore, the accrued p62 resulted in accumulation of ubiquitinated proteins owing to the interaction with p62 and delivery to the malfunctioned autophagosome by PSD. Finally, we demonstrated that PSD synergistically enhanced the anticancer activity of camptothecin (CPT) in cultured breast cancer cells and in mouse xenograft tumor models. Our results indicated that PSD inhibited autophagic flux via blocking autophagosome–lysosome fusion and lysosomal acidification, which may confer a synergistic anti-breast cancer activity of PSD and CPT.
研究领域:
肿瘤学
·
药理学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Autophagy
·
2024
·
IF 14.6
Qin Xia,Xuan Liu,Lu Zhong,Jun Qu,Lei Dong
The calcium-activated phosphatase PPP3/calcineurin dephosphorylates TFEB (transcription factor EB) to trigger its nuclear translocation and the activation of macroautophagic/autophagic targets. However, the detailed molecular mechanism regulating TFEB activation remains poorly understood. Here, we highlighted the importance of SMURF1 (SMAD specific E3 ubiquitin protein ligase 1) in the activation of TFEB for lysosomal homeostasis. SMURF1 deficiency prevents the calcium-triggered ubiquitination of the catalytic subunit of PPP3/calcineurin in a manner consistent with defective autophagic degradation of damaged lysosomes. Mechanically, PPP3CB/CNA2 plays a bridging role in the recruitment of SMURF1 by LGALS3 (galectin 3) upon lysosome damage. Importantly, PPP3CB increases the dissociation of the N-terminal tail (NT) and C-terminal carbohydrate-recognition domain (CRD) of LGALS3, which may promote the formation of open conformers in a PPP3CB dephosphorylation activity-dependent manner. In addition, PPP3CB is ubiquitinated at lysine 146 by the recruited SMURF1 in response to intracellular calcium stimulation. The K63-linked ubiquitination of PPP3CB enhances the recruitment of TFEB. Moreover, TFEB directly interacts with both PPP3CB and the regulatory subunit PPP3R1 which facilitate the conformational correction of TFEB for its activation for the transcription of TFEB-targeted genes. Altogether, our results highlighted a critical mechanism for the regulation of PPP3/calcineurin activity via its ubiquitin ligase SMURF1 in response to lysosomal membrane damage, which may account for a potential target for the treatment of stress-related diseases.
研究领域:
细胞生物学
·
分子生物学
·
生物化学
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DOI
PubMed
高影响因子
DYES AND PIGMENTS
·
2018
·
IF 3.767
Zhuo Ye,Chao Xiong,Jian Pan,Dongdong Su,Lintao Zeng
A series of highly photostable, lysosome-targeted BODIPYs with tunable fluorescence from green to the near-infrared region was developed. The probes were found to show an accurate lysosome-targeting ability with high selectivity and high photostability under continuous excitation irradiation. The results show that these lysosome-targeted BODIPYs offer a simple and convenient tool for fluorescence imaging of lysosomes, which will be valuable for understanding the activity and function of lysosomes in related cells.
研究领域:
细胞生物学
·
生物化学
✓ 已验证
DOI
高影响因子
RSC Advances
·
2024
·Vol. 14
·期 18
·12864-12872
·
IF 3.9
Lili Zhong,Datian Fu,Jin Xu,Linyan Tan,Haimei Wu,Min Wang
Ferroptosis is a newly discovered iron-dependent form of regulated cell death associated with high levels of hydroxyl radical (˙OH) production. Meanwhile, lysosome dysfunction has been shown to be one of the causes of ferroptosis. Although a variety of ˙OH-responsive fluorescent probes have been developed for detecting intracellular ˙OH in living cells, there are still only few lysosome-targeted probes to monitor the variation in lysosomal ˙OH levels during ferroptosis. Herein, we report a novel ˙OH-specific fluorescent probe HCy-Lyso, which is composed of the hydrocyanine and morpholine moiety. Upon treatment with ˙OH, its hydrocyanine unit was converted to the corresponding cyanine group, thus leading to a large π-conjugation extension of HCy-Lyso, accompanied by a significant fluorescence off–on response. Moreover, after reacting with ˙OH in an acidic environment, the protonation product of HCy-Lyso exhibits a higher fluorescence enhancement, which is suitable for detecting lysosomal ˙OH variation. HCy-Lyso has been utilized for imaging endogenous ˙OH in living cells under phorbol myristate acetate (PMA) stimuli and monitoring the changes in lysosomal ˙OH levels during ferroptosis. Thus, our study proposes a new strategy to design lysosome-targeted and ˙OH-responsive fluorescent probes to investigate the relationship between lysosomes and ferroptosis.
研究领域:
细胞生物学
·
化学
·
生物医学工程
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产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2024
·
IF 6.2
Jixun Li,Ruzhen Feng,Wei Yang,Peiyao Liang,Tianming Qiu,Jingyuan Zhang,Xiance Sun,Qiujuan Li,Guang Yang,Xiaofeng Yao
Perfluorooctane sulfonate (PFOS) is known as a persistent organic pollutant. A significant correlation between PFOS and liver ferroptosis has been unveiled, but the precise mechanism needs to be elucidated. In prior research, we found that PFOS treatment provoked mitochondrial iron overload. In this study, we observed a gradual increase in lysosomal iron in L-O2 cells after exposure to PFOS for 0.5–24 h. In PFOS-exposed L-O2 cells, suppressing autophagy relieved the lysosomal iron overload. Inhibiting transient receptor potential mucolipin 1 (TRPML1), a calcium efflux channel on the lysosomal membrane, led to a further rise in lysosomal iron levels and decreased mitochondrial iron overload during PFOS treatment. Suppressing VDAC1, a subtype of voltage-dependent anion-selective channels (VDACs) on the outer mitochondrial membrane, had no impact on PFOS-triggered mitochondrial iron overload, whereas restraining VDAC2/3 relieved this condition. Although silencing VDAC2 relieved PFOS-induced mitochondrial iron overload, it had no effect on PFOS-triggered lysosomal iron overload. Silencing VDAC3 alleviated PFOS-mediated mitochondrial iron overload and led to an additional increase in lysosomal iron. Therefore, we regarded VDAC3 as the specific VDACs subtype that mediated the lysosomes-mitochondria iron transfer. Additionally, in the presence of PFOS, an enhanced association between TRPML1 and VDAC3 was found in mice liver tissue and L-O2 cells. Our research unveils a novel regulatory mechanism of autophagy on the iron homeostasis and the effect of TRPML1-VDAC3 interaction on lysosomes-mitochondria iron transfer, giving an explanation of PFOS-induced ferroptosis and shedding some light on the role of classic calcium channels in iron transmission.
研究领域:
毒理学
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细胞生物学
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环境科学
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产品关联
DOI
PubMed
高影响因子
Nanoscale
·
2020
·Vol. 12
·期 24
·13010-13016
·
IF 6.895
Qiaoling Liu,Xiuyun Niu,Yan Zhang,Ying Zhao,Kaixin Xie,Boru Yang,Qing He,Shiyou Lv,Lin Li
The abnormal concentrations of both biothiols and pH in lysosomes are seriously related to many major diseases, such as Parkinson's and Alzheimer's diseases. Up to now, there are few reports that clearly illustrate the relationship between lysosomal pH and biothiols via fluorescence assay. Herein, novel carbon dots (Scy-CDs) are prepared with good water dispersibility and excellent photostability, and a large Stokes shift of 106 nm is exhibited under an excitation wavelength of 450 nm. The remarkable pH-dependent behavior of Scy-CDs is presented with the fluorescence quenching based on the donor-excited photoinduced electron transfer (d-PET) process. The pKa value is 5.30, which is in good agreement with the range of the normal and abnormal lysosomal pH. Upon the addition of cysteine (Cys) or homocysteine (Hcy), the d-PET process is effectively inhibited with fluorescence recovery totally. The significant co-localization of Scy-CDs with Lyso-Tracker Deep Red in HEp-2 cells and the Pearson correlation coefficient 0.88 strongly suggest that the Scy-CDs can target lysosomal pH and Cys/Hcy in living cells.
研究领域:
细胞生物学
·
医学
·
分析化学
✓ 已验证
DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2021
·
IF 3.575
Wenli Shi,Danyi Lu,Chunlei Wu,Meiqing Li,Zhihao Ding,Yanyan Li,Binghua Chen,Xian Lin,Wu Su,Ximing Shao,Zhihui Xia,Lijing Fang,Ke Liu,Hongchang Li
Natural products are useful tools for biological mechanism research and drug discovery. Due to the excellent tumor cell growth inhibitory profile and sub-nanomolar potency, Coibamide A (CA), an N-methyl-stabilized depsipeptide isolated from marine cyanobacterium , has been considered as a promising lead compound for cancer treatment. However, the molecular anti-cancer mechanism of the action of CA remains unclear. Here, we showed that CA treatment induced caspase-independent cell death in breast cancer cells. CA treatment also led to severe lysosome defects, which was ascribed to the impaired glycosylation of lysosome membrane protein LAMP1 and LAMP2 . As a consequence, the autophagosome-lysosome fusion was blocked upon CA treatment. In addition, we presented evidence that this autophagy defect partially contributed to the CA treatment-induced tumor cell death. Together, our work uncovers a novel mechanism underlying the anti-cancer action of CA, which will promote its further application for cancer therapy.
研究领域:
癌症生物学
·
药理学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2022
·
IF 18.027
Yufei Wang,Yi-Feng Wang,Xianlei Li,Yuqing Wang,Qianqian Huang,Xiaowei Ma,Xing-Jie Liang
Precise subcellular manipulation remains challenging in quantitative biological studies. After target modification and hierarchical assembly, nanoparticles can be functionalized for intracellular investigation. However, it remains unclear whether nanoparticles themselves can progressively manipulate subcellular processes, especially organellar networks. Mitochondria act as the energetic supply, whose fission dynamics are often modulated by molecular reagents. Here, using different-sized gold nanoparticles (AuNPs) as a model, we demonstrated the nanoparticle-driven controllable regulation on mitochondria. Compared with molecular reagents, AuNPs could induce size-dependent mitochondrial fission without detectable cell injury, and this process was reversible along with intracellular AuNPs’ clearance. Mechanistically, it was attributed to the AuNPs-induced enhanced organelle interactome between lysosomes and mitochondria. Lysosomal accumulation of AuNPs induced lysosomal swelling and lysosomal motility alterations, promoting mitochondrial fission through the increased “kiss” events during the “kiss-and-run” moving of the lysosome–mitochondria interactome. This study highlights the fundamental understanding to fully explore the intrinsic capability of nanoparticles by engineering their basic properties. Also, it provides practical guidance to investigate the delicate nanolevel regulation on biological processes.
研究领域:
纳米技术
·
细胞生物学
·
生物物理学
✓ 已验证
DOI
PubMed
高影响因子
BIOMATERIALS
·
2023
·
IF 14
Wei Jiang,Zuoxiu Tie,Chi Yu,Yu Chen,Dan Liu,Bin Li
Although inhibiting the energy metabolism of tumor cells has become an effective measure to enhance chemotherapy, tumor cells can still escape the lethal effect of chemotherapy by entering a dormancy state with low-energy expenditure. Herein, the glutathione (GSH)-responsive nanoplatform (C-A-D NPs) were constructed to inhibit energy metabolism and lysosomal activity of tumor cells, thereby forcing tumor cells to remain vulnerable to cisplatin . In this system, cisplatin prodrug was reduced to cisplatin by GSH, and D-peptide and apoptozole (Az) were released to inhibit the energy metabolism and autophagy-lysosome pathway of tumor cells. The suppressed autophagy-lysosome pathway prevents tumor cells from entering a low-energy dormancy state, resulting in the loss of resistance to the lethal effect of cisplatin with high-energy expenditure and insufficient energy supply. Such engineered nanoplatform effectively enhances the chemotherapeutic effect of cisplatin by inhibiting intracellular energy metabolism and lysosomal activity, showing great clinical prospects.
研究领域:
肿瘤学
·
药学
·
纳米技术
·
化疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
SENSORS AND ACTUATORS B-CHEMICAL
·
2021
·
IF 7.46
Yinghua Guo,Xinru Wang,Yan Feng,Xiao Luo,Xiangming Meng,Xuhong Qian,Youjun Yang
Autophagy is a physiological process governing proteostasis and implicated in many diseases. Enhanced ROS levels was known to be associated with lysosomal autophagy and therefore a lyso-specific ROS probe could find applications in autophagy related studies. Following the probe-design principle of bridging-group modification, we previously developed a ROS probe capable of detect a broader range of reactive species than the existing probes. Additional merits of the probe include ratiometry-capability, minimal probe-product spectral crosstalk, resistance toward autoxidation at lysosomal acidity, and structural simplicity. It is the aim of this manuscript to render this probe lyso-specificity and examine its potentials to monitor autophagy-related ROS generation in HeLa cells treated by H 2 O 2 or 6-OHDA.
研究领域:
细胞生物学
·
生物化学
·
医学研究
✓ 已验证
DOI
高影响因子
CELL
·
2025
·
IF 42.5
Nan Zhou,Jingzhi Chen,Meiqin Hu,Na Wen,Weijie Cai,Ping Li,Liding Zhao,Yaping Meng,Dongdong Zhao,Xiaotong Yang,Siyu Liu,Fangqian Huang,Cheng Zhao,Xinghua Feng,Zikai Jiang,Enjun Xie,Hongxu Pan,Zhidong Cen,Xinhui Chen,Wei Luo,Beisha Tang,Junxia Min,Fudi Wang,Junsheng Yang,Haoxing Xu
Lysosomes maintain an acidic pH of 4.5–5.0, optimal for macromolecular degradation. Whereas proton influx is produced by a V-type H + ATPase, proton efflux is mediated by a fast H + leak through TMEM175 channels, as well as an unidentified slow pathway. A candidate screen on an orphan lysosome membrane protein (OLMP) library enabled us to discover that SLC7A11, the protein target of the ferroptosis-inducing compound erastin, mediates a slow lysosomal H + leak through downward flux of cystine and glutamate, two H + equivalents with uniquely large but opposite concentration gradients across lysosomal membranes. SLC7A11 deficiency or inhibition caused lysosomal over-acidification, reduced degradation, accumulation of storage materials, and ferroptosis, as well as facilitated α-synuclein aggregation in neurons. Correction of abnormal lysosomal acidity restored lysosome homeostasis and prevented ferroptosis. These studies have revealed an unconventional H + transport conduit that is integral to lysosomal flux of protonatable metabolites to regulate lysosome function, ferroptosis, and Parkinson’s disease (PD) pathology.
研究领域:
细胞生物学
·
医学
·
神经科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）