DYES AND PIGMENTS
·
2020
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IF 4.613
Tingting Yang,Junyong Sun,Wu Yao,Feng Gao
To understand the relationship between endoplasmic reticulum (ER) stress and the level of hypochlorous acid (HOCl), it is highly desired to develop an ER-targetable HOCl probe to monitoring the HOCl level. In this study, a new turn-on type of two-photon ER-targetable fluorescent probe (ER-NPA) is designed for fluorescent sensing and imaging HOCl in ER using 4-hydroxy-1,8-naphthalimide as the fluorophore , p-aminophenyl ether as the recognition receptor, and methyl sulfonamide as ER-targetable group. The probe ER-NPA exhibits some intrinsic features such as excellent water solubility, good biocompatibility , significantly fast and enhanced fluorescence response to HOCl within 60 s, and detection limit as low as 6.2 nM for HOCl determination. The probe ER-NPA is successfully applied to real-time monitoring of exogenous and endogenous HOCl fluctuations in HeLa cells and zebrafish during ER stress. The developed probe ER-NPA may provide a new strategy to reveal the chemical biology roles of HOCl in ER stress-related diseases.
研究领域:
生物化学
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医学
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分子影像学
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DOI
高影响因子
Food & Function
·
2021
·Vol. 12
·期 21
·10773-10782
·
IF 5.396
Ritian Jin,Haowei Ren,Minhe Liao,Jiaqi Shang,Dangfeng Wang,Meng Li,Ning Liu
The peptide VLATSGPG (VLA) is known to inhibit dipeptidyl peptidase IV (DPP-IV), although its mechanism in relieving endoplasmic reticulum (ER) stress is unclear. In this study, we found that treating HepG2 cells with 1.0 mM VLA reduced DPP-IV activity by 73.7 ± 4.8% without changing the DPP-IV mRNA expression level. In addition, 1.0 and 0.5 mM VLA alleviated palmitic acid (PA)-induced cell death and intracellular calcium imbalances. The levels of apoptosis-related proteins (caspase-3, caspase-9, and CHOP) were reduced by VLA treatment, which was presumed to be related to ER stress. Further studies confirmed that VLA alleviated PA-induced morphological damage to the ER and reduced the levels of the ER stress marker proteins (BIP, p-PERK, and p-IRE1α). VLA alleviated PA-induced ER stress in HepG2 cells independent of DPP-IV enzymatic activity inhibition. These findings have implications for developing novel treatment approaches for liver diseases caused by ER stress.
研究领域:
分子生物学
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细胞生物学
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药理学
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肝病
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产品关联
DOI
PubMed
高影响因子
CANCER RESEARCH
·
2024
·
IF 12.5
Fang Liang,Zhang Li,Wang Mengran,He Yuhao,Yang Jiao,Huang Zengjin,Tan Ying,Fang Ke,Li Jun,Sun Zhiyuan,Li Yanping,Tang Yisen,Liang Weizheng,Cui Huanhuan,Zhu Qionghua,Wu Zhe,Li Yiming,Hu Yuhui,Chen Wei
Epithelial-mesenchymal transition (EMT) is a fundamental cellular process frequently hijacked by cancer cells to promote tumor progression, especially metastasis. EMT is orchestrated by a complex molecular network acting at different layers of gene regulation. In addition to transcriptional regulation, post-transcriptional mechanisms may also play a role in EMT. Here, we performed a pooled CRISPR screen analyzing the influence of 1547 RNA binding proteins (RBPs) on cell motility in colon cancer cells and identified multiple core components of P-bodies (PBs) as negative modulators of cancer cell migration. Further experiments demonstrated that PB depletion by silencing DDX6 or EDC4 could activate hallmarks of EMT thereby enhancing cell migration in vitro as well as metastasis formation in vivo. Integrative multi-omics analysis revealed that PBs could repress the translation of the EMT-driver gene HMGA2, which contributed to PB-meditated regulation of EMT. This mechanism is conserved in other cancer types. Furthermore, endoplasmic reticulum (ER) stress was an intrinsic signal that induced PB disassembly and translational derepression of HMGA2. Taken together, this study has identified a function of PBs in regulation of EMT in cancer.
研究领域:
癌症生物学
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分子生物学
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细胞生物学
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遗传学
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DOI
PubMed
高影响因子
EXPERIMENTAL CELL RESEARCH
·
2023
·
IF 3.7
Xiaohong Liu,Xiaoyu Li,Shan Su,Yujia Yuan,Wen Liu,Min Zhu,Qing Zheng,Xin Zeng,Fudong Fu,Yanrong Lu,Younan Chen
Lipotoxicity caused by excess free fatty acids , particularly saturated fatty acids (SFAs) such as palmitic acid (PA), is one of the most important pathogenesis of nonalcoholic fatty liver disease (NAFLD). However, unsaturated fatty acids (UFAs), such as oleic acid (OA), are nontoxic and can combat SFA-induced toxicity through alleviation of cell apoptosis, endoplasmic reticulum stress (ER stress) and lipids metabolism disorder. However, whether OA is able to regulate autophagy is largely unknown. So, this study aims to investigate the mechanism underlying OA mediated modulation of autophagy in hepatocytes and mice with NAFLD. In vitro, human hepatoma cell line HepG2 cells, human normal liver cells L-02 and mouse normal liver cells AML12 were treated with palmitic acid (PA)/tunicamycin (TM) or/and OA for 48 h. In vivo, C57/BL6 mice were fed with high fat diet (HFD) to induce NAFLD. And the HFD was partial replaced by olive oil to observe the protective effects of olive oil. We demonstrated that PA/TM impaired cell viability and induced cellular apoptosis in HepG2 cells and L-02 cells. Moreover, PA/TM induced autophagy impairment by reducing the nuclear translocation of transcription factor EB (TFEB) and inhibiting the activity of CTSB. However, OA substantially alleviated PA/TM induced cellular apoptosis and autophagy dysfunction in hepatocytes. Additionally, restoring autophagy function is able to reduce ER stress. Similarly, HFD for 20 weeks successfully established NAFLD model in C57/BL6 mice, and significant autophagy impairment were observed in liver tissues. Noteworthily, 30% replacement of HFD with olive oil had profoundly reversed NAFLD. It significantly impoved steatosis, and reduced autophagy dysfunction, ER stress and apoptosis in liver tissue. Conclusively, these data demonstrated that OA is able to effectively impove autophagy dysfunction under the context of both PA and ER stress inducer induced lipotoxicity, and OA mediated regulation of lysosome dysfunction through TFEB plays an important role, suggesting that the regulation of ER stress-autophagy axis is a critical mechanism in OA driven protection in NAFLD.
研究领域:
肝病学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Biology Direct
·
2024
·
IF 5.7
Hao Wang,Lei Zhang,Yunxiao Shang
Endoplasmic reticulum (ER) stress has been shown to play a pivotal role in the pathogenesis of asthma. DEPTOR (DEP Domain Containing MTOR Interacting Protein) is an endogenous mTOR inhibitor that participates in various physiological processes such as cell growth, apoptosis, autophagy, and ER homeostasis. However, the role of DEPTOR in the pathogenesis of asthma is still unknown. In this study, an ovalbumin (OVA)-induced mice model and IL-13 induced 16HBE cells were used to evaluate the effect of DEPTOR on asthma. A decreased DEPTOR expression was shown in the lung tissues of OVA-mice and IL-13 induced 16HBE cells. Upregulation of DEPTOR attenuated airway goblet cell hyperplasia, inhibited mucus hypersecretion, decreased the expression of mucin MUC5AC, and suppressed the level of inflammatory factors IL-4 and IL-5, which were all induced by OVA treatment. The increased protein expression of ER stress markers GRP78, CHOP, unfolded protein response (UPR) related proteins, and apoptosis markers in OVA mice were also inhibited by DEPTOR overexpression. In IL-13 induced 16HBE cells, overexpression of DEPTOR decreased IL-4, IL-5, and MUC5AC levels, preventing ER stress response and UPR process. Furthermore, from the proteomics results, we identified that SOD1 (Cu/Zn Superoxide Dismutase 1) may be the downstream factor of DEPTOR. Similar to DEPTOR, upregulation of SOD1 alleviated asthma progression. Rescue experiments showed that SOD1 inhibition abrogates the remission effect of DEPTOR on ER stress in vitro. In conclusion, these data suggested that DEPTOR attenuates asthma progression by suppressing endoplasmic reticulum stress through SOD1.
研究领域:
免疫学
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肺病学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
AGING CELL
·
2021
·Vol. 20
·期 3
·e13319
·
IF 9.304
Gang Du,Zhiming Liu,Zihua Yu,Zhangpeng Zhuo,Yuedan Zhu,Juanyu Zhou,Yang Li,Haiyang Chen
As they age, adult stem cells become more prone to functional decline, which is responsible for aging-associated tissue degeneration and diseases. One goal of aging research is to identify drugs that can repair age-associated tissue degeneration. Multiple organ development-related signaling pathways have recently been demonstrated to have functions in tissue homeostasis and aging process. Therefore, in this study, we tested several chemicals that are essential for organ development to assess their ability to delay intestinal stem cell (ISC) aging and promote gut function in adult Drosophila . We found that taurine, a free amino acid that supports neurological development and tissue metabolism in humans, represses ISC hyperproliferation and restrains the intestinal functional decline seen in aged animals. We found that taurine represses age-associated ISC hyperproliferation through a mechanism that eliminated endoplasmic reticulum (ER) stress by upregulation of the target genes of unfolded protein response in the ER (UPR ER ) and inhibiting the c-Jun N-terminal kinase (JNK) signaling. Our findings show that taurine plays a critical role in delaying the aging process in stem cells and suggest that it may be used as a natural compound for the treatment of age-associated, or damage-induced intestinal dysfunction in humans.
研究领域:
衰老研究
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干细胞生物学
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分子遗传学
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产品关联
DOI
PubMed
高影响因子
Cell Reports Medicine
·
2025
·
IF 10.6
Liming Gui,Kaiwen Chen,Jingjing Yan,Ping Chen,Wei-Qiang Gao,Bin Ma
The induction of immunogenic cell death (ICD) impedes tumor progression via both tumor cell-intrinsic and -extrinsic mechanisms, representing a robust therapeutic strategy. However, ICD-targeted therapy remains to be explored and optimized. Through kinome-wide CRISPR-Cas9 screen, NUAK family SNF1-like kinase 1 (NUAK1) is identified as a potential target. The ICD-provoking effect of NUAK1 inhibition depends on the production of reactive oxygen species (ROS), consequent to the downregulation of nuclear factor erythroid 2-related factor 2 (NRF2)-mediated antioxidant gene expression. Moreover, the mevalonate pathway/cholesterol biosynthesis, activated by spliced form of X-box binding protein 1 (XBP1s) downstream of ICD-induced endoplasmic reticulum (ER) stress, functions as a negative feedback mechanism. Targeting the mevalonate pathway with CRISPR knockout or the 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibitor simvastatin amplifies NUAK1 inhibition-mediated ICD and antitumor activity, while cholesterol dampens ROS and ICD, and therefore also dampens tumor suppression. The combination of NUAK1 inhibitor and statin enhances the efficacy of anti-PD-1 therapy. Collectively, our study unveils the promise of blocking the mevalonate-cholesterol pathway in conjunction with ICD-targeted immunotherapy.
研究领域:
癌症研究
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免疫学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2021
·Vol. 19
·期 1
·1-18
·
IF 10.435
Hu Hongzhi,Yang Wenbo,Liang Zihui,Zhou Zezhu,Song Qingcheng,Liu Weijian,Deng Xiangtian,Zhu Jian,Xing Xin,Zhong Binglong,Wang Baichuan,Wang Shangyu,Shao Zengwu,Zhang Yingze
Background Despite advances of surgery and neoadjuvant chemotherapy during the past few decades, the therapeutic efficacy of current therapeutic protocol for osteosarcoma (OS) is still seriously compromised by multi-drug resistance and severe side effects. Amplification of intracellular oxidative stress is considered as an effective strategy to induce cancer cell death. The purpose of this study was to develop a novel strategy that can amplify the intracellular oxidative stress for synergistic cascade cancer therapy.Methods and resultsA novel nanocomposite, composed of folic acid (FA) modified mesoporous silica–coated gold nanostar (GNS@MSNs-FA) and traditional Chinese medicine lycorine (Ly), was rationally designed and developed. Under near-infrared (NIR) irradiation, the obtained GNS@MSNs-FA/Ly could promote a high level of ROS production via inducing mitochondrial dysfunction and potent endoplasmic reticulum (ER) stress. Moreover, glutathione (GSH) depletion during ER stress could reduce ROS scavenging and further enable efficient amplification of intracellular oxidative stress. Both in vitro and in vivo studies demonstrated that GNS@MSNs-FA/Ly coupled with NIR irradiation exhibited excellent antitumor efficacy without noticeable toxicity in MNNG/HOS tumor-bearing mice.Conclusion All these results demonstrated that GNS@MSNs-FA/Ly coupled with NIR irradiation could dramatically amplify the intra-tumoral oxidative stress, exhibiting excellent antitumor ability without obvious systemic toxicity. Taken together, this promising strategy provides a new avenue for the effective cancer synergetic therapy and future clinical translation.
研究领域:
癌症治疗
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纳米技术
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药理学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2024
·
IF 5.7
Shan Su,Xiaohong Liu,Min Zhu,Wen Liu,Jingyi Liu,Yujia Yuan,Fudong Fu,Zhiyong Rao,Jingping Liu,Yanrong Lu,Younan Chen
Nonalcoholic fatty liver disease (NAFLD), characterized by hepatic lipid deposition, is one of the most prevalent chronic metabolic disorders globally, and its pharmaceutical treatments are still limited. Excessive lipid accumulation triggers endoplasmic reticulum (ER) stress and autophagy flux dysfunction, which are important mechanisms for NAFLD. Trehalose (Tre), a natural disaccharide, has been identified to reduce hepatic steatosis and glucose intolerance. However, its underlying mechanisms for NAFLD remain unclear. In this study, a high-fat-diet (HFD)-induced mouse NAFLD model and a saturated fatty acid palmitic acid (PA)-stimulated cell model were constructed. The results indicated that Tre supplementation ameliorated hepatocyte lipid deposition in vitro, as well as hepatic steatosis and hyperlipidemia in vivo. Mechanistically, Tre alleviated both autophagy flux dysfunction and endoplasmic reticulum (ER) stress. Under the stimulation of HFD or PA, Tre remarkably increased the expression and nucleic translocation of the lysosomal master protein transcription factor EB (TFEB), while decreasing the accumulation of p62 and also decreasing the ER stress markers (inositol-requiring enzyme 1 (IRE1α), XBP-1, CHOP, and BIP). Similar results were observed in an ER stressor tunicamycin (TM)-induced in vivo and in vitro models. In addition, the transcriptomic analysis of NAFLD patients revealed significant differences in ER stress-related and autophagy-related biomarkers, including TFEB, ATG7, IRE1α, and CHOP. Molecular docking results demonstrated a strong affinity between Tre and both IRE1α and TFEB. Overall, Tre protected hepatocytes from lipotoxicity-related ER stress and autophagy dysfunction, and its regulatory effect on the IRE1α–TFEB signaling pathway may be a critical mechanism. These findings suggest that Tre, as a bioactive substance with significant medicinal potential, holds considerable promise for drug development and clinical application in treating NAFLD.
研究领域:
药理学
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分子生物学
·
代谢紊乱
·
肝病学
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DOI
PubMed
高影响因子
Signal Transduction and Targeted Therapy
·
2023
·Vol. 8
·期 1
·1-16
·
IF 39.3
Cui Bopei,Song Lifang,Wang Qian,Li Kelei,He Qian,Wu Xing,Gao Fan,Liu Mingchen,An Chaoqiang,Gao Qiushuang,Hu Chaoying,Hao Xiaotian,Dong Fangyu,Zhou Jiuyue,Liu Dong,Song Ziyang,Yan Xujia,Zhang Jialu,Bai Yu,Mao Qunying,Yang Xiaoming,Liang Zhenglun
With the continuous in-depth study of the interaction mechanism between viruses and hosts, the virus has become a promising tool in cancer treatment. In fact, many oncolytic viruses with selectivity and effectiveness have been used in cancer therapy. Human enterovirus is one of the most convenient sources to generate oncolytic viruses, however, the high seroprevalence of some enteroviruses limits its application which urges to exploit more oncolytic enteroviruses. In this study, coxsackievirus B5/Faulkner (CV-B5/F) was screened for its potential oncolytic effect against non-small cell lung cancers (NSCLCs) through inducing apoptosis and autophagy. For refractory NSCLCs, DNA-dependent protein kinase (DNA-PK) or ataxia telangiectasia mutated protein (ATM) inhibitors can synergize with CV-B5/F to promote refractory cell death. Here, we showed that viral infection triggered endoplasmic reticulum (ER) stress-related pro-apoptosis and autophagy signals, whereas repair for double-stranded DNA breaks (DSBs) contributed to cell survival which can be antagonized by inhibitor-induced cell death, manifesting exacerbated DSBs, apoptosis, and autophagy. Mechanistically, PERK pathway was activated by the combination of CV-B5/F and inhibitor, and the irreversible ER stress-induced exacerbated cell death. Furthermore, the degradation of activated STING by ERphagy promoted viral replication. Meanwhile, no treatment-related deaths due to CV-B5/F and/or inhibitors occurred. Conclusively, our study identifies an oncolytic CV-B5/F and the synergistic effects of inhibitors of DNA-PK or ATM, which is a potential therapy for NSCLCs.
研究领域:
肿瘤学
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病毒学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2022
·
IF 7.129
Zhihui Liu,Yingying Shangguan,Penglin Zhu,Yousef Sultan,Yiyi Feng,Xiaoyu Li,Junguo Ma
Glyphosate (GLY) induces developmental toxicity in fish, but research on the toxicity mechanism is limited. In this study, zebrafish embryos were exposed for 120 hpf to 0.7, 7, and 35 mg L -1 GLY. The results show that GLY treatment induced developmental toxicity in the fish, including premature hatching, reduced heartbeats, pericardial and yolk sac oedema, swim bladder deficiency, and shortened body length, which was possibly due to a significantly decreased triiodothyronine (T3)/thyroxine (T4) ratio and the abnormal expression patterns of hypothalamic-pituitary-thyroid (HPT) ( crh , tshβ , tr α , tr β , and t tr ) and growth hormone/insulin-like growth factor (GH/IGF) axis-related genes ( gh , ghrα , ghrβ , igf1 , igf1rα , and igf1rβ ) in larvae exposed to GLY. In addition, GLY exposure altered the levels of SOD and CAT, increased ROS, promoted malondialdehyde (MDA) content, and significantly altered the levels of endoplasmic reticulum (ER) stress signalling pathway factors ( perk , eif2α , gadd34 , atf4 , ire1α , xbp1 , atf6 , hspa5 , and chop ), suggesting that GLY treatment induced oxidative injury and ER stress in the larvae. Further research showed that treatment with a higher concentration of GLY upregulated the levels of iNOS, IL-1β, and TNF-α while inhibiting the expression of IL-10 and TGF-β, suggesting that GLY causes an inflammatory reaction in the larvae. In addition, we also found that apoptosis was induced in the larvae, which was determined by acridine orange staining and abnormal expression of p53 , caspase-3 , -8 , and -9 . Taken together, our results demonstrate that GLY exposure altered the T3/T4 ratio, disturbed the expression patterns of HPT and GH/IGF axis-related genes, and induced oxidative and ER stress, inflammatory reactions, and apoptosis in the zebrafish larvae. This investigation contributes to improved understanding of the developmental toxicity mechanism of GLY in fish.
研究领域:
毒理学
·
发育生物学
·
环境科学
·
鱼类生物学
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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）