EUROPEAN JOURNAL OF PHARMACOLOGY
·
2023
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IF 5
Jiangbo Nie,Yuhang Ling,Mingchao Jin,Zhuo Chen,Wei Liu,Weiyun Shen,Tianshun Fang,Jianyou Li,Ying He
Osteosarcoma (OS) is a highly fatal bone tumor characterized by high degree of malignancy and early lung metastasis. Traditional chemotherapy fails in improving the efficacy and survival rate of patients with OS. Butyrate (NaBu) has been reported as a new antitumor drug for inhibiting proliferation and inducing apoptosis in various cancer cells. However, the effect of NaBu on the ferroptosis of osteosarcoma is still unknown. This study aimed to investigate whether NaBu promotes erastin-induced ferroptosis in OS cells and to uncover the underlying mechanism. Here, we found that NaBu significantly enhanced erastin-induced ferroptosis in vitro . Compared with the group that erastin used alonely, pre-treating with NaBu exacerbated erastin-meditated GSH depletion, lipid peroxidation, and mitochondrial morphologic changes in OS cells. In a subcutaneous OS model, NaBu combined with erastin significantly reduced tumor growth and increased the levels of 4-HNE. Mechanistically, NaBu downregulated SLC7A11 transcription via regulating ATF3 expression. Overexpression of ATF3 facilitated erastin to induce ferroptosis, while ATF3 knockdown attenuated NaBu-induced ferroptosis sensitivity. In conclusion, our findings revealed a previously unidentified role of NaBu in erastin-induced ferroptosis by regulating SLC7A11, suggesting that NaBu may be a potential therapeutic agent for OS treatment.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
·
2023
·
IF 9.8
Xijuan Chao,Dezhi Yao,Chuxuan Chen,Zhiguo Sheng,Benzhan Zhu
Tetrabromobisphenol A (TBBPA), as a widely used brominated flame retardant , has been implicated as a potential neurotoxicant. However, the mechanism of TBBPA-induced neurotoxicity has not been fully elucidated yet. In this study, using mouse hippocampal neuron cell HT22 as the in vitro model, the neuronal cytotoxicity of TBBPA and the mechanism by focusing on mitophagy have been studied. We found that neuronal cytotoxic effects were indeed induced by TBBPA exposure at concentrations of >20 μM for 24 h, including decreased cell viability (to 92.38 % at 20 μM; 18.25 % at 80 μM), enhanced ROS (enhanced 53.26 % at IC 50 of 60 μM, compared with that in the control group) and mitochondrial ROS (mtROS) levels (enhanced 24.12 % at 60 μM), reduced mitochondrial membrane potential (MMP) (decreased 33.60 % at 60 μM). As a protective mechanism in cells, autophagy was initiated; however, mitophagy was inhibited, where PINK1 (PINK1-Parkin activation is critical in the depolarized MMP-induced mitophagy) expression was found to be repressed and decreased, further leading to the failure of Parkin recruitment to the damaged mitochondria. Mitophagy activator, nicotinamide mononucleotide (β-NMN) that activates the PINK1-Parkin pathway, could alleviate TBBPA-induced mitophagy deficiency and further reduce the neuronal cytotoxicity, demonstrating that TBBPA-induced PINK1-Parkin-mediated mitophagy deficiency contributed to the neuronal cytotoxicity. Furthermore, we found TBBPA caused the upregulation of Atf3 ( activating transcription factor 3 ) gene transcription and expression levels, alongside reduced Pink1 levels; whereas enhanced Pink1 transcript levels were observed after ATF3 depletion even under TBBPA treatment, demonstrating TBBPA-induced overexpression of ATF3 should be responsible for the reduced PINK1 expression. Therefore, for the first time, here we demonstrate that TBBPA can inhibit PINK1-Parkin-mediated mitophagy via upregulating ATF3 expression, which further contributes to its neuronal cytotoxicity. This study should be able to improve our understanding of the mechanism of TBBPA-induced neuronal cytotoxicity.
研究领域:
毒理学
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神经科学
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细胞生物学
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DOI
PubMed
高影响因子
ENVIRONMENTAL TOXICOLOGY
·
2022
·Vol. 37
·期 5
·1093-1103
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IF 4.109
Fengfan Liu,Xiang Cheng,Shuang Wu,Bei Hu,Chen Yang,Shufen Deng,Qiwen Shi
Exposure to nickel oxide nanoparticles (NiONPs), which have been widely produced and applied in industry, leads to adverse pulmonary and systemic effects. The aim of this study is to investigate the involvement of apoptosis and ferroptosis in NiONPs-induced acute lung injury (ALI). Intratracheal instillation of NiONPs into mice elevated the levels of pro-inflammatory cytokines, neutrophils, and proteins in the bronchoalveolar lavage fluid, and triggered apoptosis and ferroptosis in the lung tissues. Consistently, NiONPs-induced apoptosis and ferroptosis were observed in in vitro experiments using human lung epithelial cells. Activating transcription factor 3 (ATF3), a stress-inducible transcription factor, was upregulated by NiONPs exposure in both murine lung tissues and human lung epithelial cells. Moreover, human lung epithelial cells with ATF3 deficiency exhibited a lower level of apoptosis and ferroptosis when exposed to NiONPs. Collectively, our findings demonstrated that ATF3 was responsive to NiONPs exposure, and promoted NiONPs-induced apoptosis and ferroptosis in lung epithelial cells, indicating that ATF3 is a potential biomarker and therapeutic target for NiONPs-associated ALI.
研究领域:
毒理学
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肺科学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2025
·
IF 8.3
Musen Lin,Yue Wang,Yan Zhao,Xiaohan Zhai,Yan Hu,Qinrong Luan,Li Lv,Zhecheng Wang,Jihong Yao
Background Acetaminophen-induced hepatotoxicity remains a clinical challenge with limited targeted therapeutic options. While recent advances have identified blood‒biliary barrier disruption as a critical pathogenic mechanism, effective interventions preserving this barrier are notably lacking. Albiflorin, a key bioactive constituent of Paeonia lactiflora Pall ., exhibits unique bile acid modulation along with antioxidant and anti-inflammatory activities, suggesting its potential efficacy in preventing acetaminophen-induced liver injury. However, its specific role and underlying mechanisms in alleviating acetaminophen-induced hepatotoxicity remain unclear. Objective This study's objective was to examine the pharmacological effects and primary molecular mechanisms of albiflorin in alleviating acetaminophen-induced liver injury. Methods An acetaminophen-induced liver injury mouse model was created using a 300 mg/kg dose of acetaminophen. The hepatoprotective effects of albiflorin were assessed through histological and biochemical analyses. Blood‒biliary barrier integrity was evaluated via Evans blue dye tests, immunofluorescence, and bile acid assays. Transcriptomic analysis, gene overexpression and interference techniques, and ChIP‒qPCR were employed to explore the molecular mechanisms underlying the protective effects of albiflorin. Results Albiflorin significantly reduced acetaminophen-induced liver injury, as evidenced by improved biochemical profiles and hepatocyte morphology. It also prevented increases in blood‒biliary barrier permeability and bile acid levels. RNA sequencing identified 3,184 differentially expressed genes, revealing critical pathways involved in maintaining blood‒biliary barrier integrity. AF reversed the acetaminophen-induced changes in the expression of genes related to the blood‒biliary barrier, particularly occludin, claudin 5, ABCG5, and ABCG8. Albiflorin protected the blood‒biliary barrier and mitigated acetaminophen-induced liver injury by enhancing ATF3 protein stability, with ATF3 identified as a critical mediator of these protective effects. Conclusion This study provides pioneering evidence that albiflorin protects against acetaminophen-induced liver injury by interacting with ATF3 to regulate blood–biliary barrier proteins and maintain the integrity of the blood–biliary barrier. These findings deepen our understanding of the role of the blood‒biliary barrier in liver diseases and suggest a therapeutic strategy for drug overdose-induced liver injury.
研究领域:
药理学
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肝脏病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ALZHEIMERS DISEASE
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2025
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IF 3.1
Wenqiang Zhang,Fei Teng,Xifa Lan,Peihui Liu,Aiming Wang,Fan Zhang,Zhiqiang Cui,Jingwei Guan,Xiaohong Sun
BackgroundThe involvement of microglia is likely to be pivotal in the pathogenesis of Alzheimer's disease (AD) by modulating the deposition of amyloid-β (Aβ) plaques. The deletion of Dedicator of cytokinesis 8 (DOCK8) has a protective effect in mouse with neurodegenerative diseases.ObjectiveTo explore the underlying mechanism of DOCK8 in AD.MethodsIn present study, we first the detected the expression of DOCK8 in the hippocampal tissue of APP/PS1 mice. Then, the expression of DOCK8 was knocked down in the hippocampal tissue of APP/PS1 mice, and the effects of DOCK8 down-regulation on cognitive function, the microglia migration around Aβ plaques, and the cell division cycle 42 (Cdc42)/p38 mitogen-activated protein kinase (MAPK) signaling pathway were detected. Next, the effects of DOCK8 knockdown on Aβ-induced migration and activation of BV-2 cells as well as the MAPK signaling pathway were detected. Finally, the transcriptional regulation of DOCK by transcription factor 3 (ATF3) was detected by a dual luciferase reporter assay.ResultsDOCK8 expression exerts a significant upregulation in the hippocampus of APP/PS1 mice. However, following the DOCK8 knockdown, there was a significant recovery in the results of the behavioral tests and a notable reduction in microglial expression. Moreover, the high expression of DOCK8 mediated by ATF3 successfully triggered the Cdc42/p38 MAPK signaling pathway, thereby enhancing the migration and recruitment of microglia towards senile plaques, accelerating the production of Aβ plaques.ConclusionsATF3-mediated high expression of DOCK8 accelerates the production of Aβ plaques, and participates in the pathogenesis of AD.
研究领域:
神经科学
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分子生物学
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遗传学
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细胞生物学
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病理学
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DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
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2024
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IF 10.5
Xuerong Zhao,Zhuoya Wang,Guanlin Wu,Lianhong Yin,Lina Xu,Ning Wang,Jinyong Peng
Intestinal ischemia reperfusion injury (II/R injury) is a common and intractable pathophysiological process in critical patients, for which exploring new treatments and mechanisms is of great importance to improve treatment outcomes. Apigenin-7-O-Glucoside (AGL) is a sugar derivative of apigenin natural product with various pharmacological activities to protect against intestinal diseases . In this study, we synthesized two amphiphilic molecules, namely DTPA-N10–10 and mPEG-TK-DA, which can scavenge free radicals and reactive oxygen species (ROS). They were successfully encapsulated AGL through self-assembly, resulting in the formation of multi-site ROS scavenging nanoparticles called PDN@AGL. In vitro and in vivo experiments demonstrated that PDN@AGL could protect intestinal tissues by reducing lipid peroxidation, lowering ROS levels and inhibiting ferroptosis during II/R injury. Furthermore, our study revealed, for the first time, that the regulation of the ATF3/SLC7A11 pathway by PDN@AGL may play a crucial role in mitigating II/R injury. In conclusion, our study confirmed the beneficial effects of PDN@AGL in combating II/R injury through the ATF3/SLC7A11-mediated regulation of ferroptosis and oxidative stress. These findings lay the groundwork for the potential application of PDN@AGL in the treatment of II/R injury.
研究领域:
药理学
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纳米技术
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胃肠病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
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2023
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IF 5.1
Xinyu Qian,Lin Zhu,Mengzhen Xu,Haoli Liu,Xinyan Yu,Qiuyue Shao,Jing Qin
Small cell lung cancer (SCLC) is a subtype of lung cancer with a very poor overall survival rate due to its extremely high proliferation and metastasis predilection. Shikonin is an active ingredient extracted from the roots of Lithospermum erythrorhizon, and exerts multiple anti-tumor functions in many cancers. In the present study, the role and underlying mechanism of shikonin in SCLC were investigated for the first time. We found that shikonin effectively suppressed cell proliferation , apoptosis , migration, invasion, and colony formation and slightly induced apoptosis in SCLC cells. Further experiment indicated the shikonin could also induced ferroptosis in SCLC cells. Shikonin treatment effectively suppressed the activation of ERK, the expression of ferroptosis inhibitor GPX4 , and elevated the level of 4-HNE, a biomarker of ferroptosis. Both total ROS and lipid ROS were increased, while the GSH levels were decreased in SCLC cells after shikonin treatment. More importantly, our data identified that the function of shikonin was dependent on the up-regulation of ATF3 by performing rescue experiments using shRNA to silence the expression of ATF3, especially in the total and lipid ROS accumulaiton. Xenograft model was established using SBC-2 cells, and the results revealed that shikonin also significantly inhibited tumor growth by inducing ferroptosis. Finally, our data further confirmed that shikonin activated ATF3 transcription by impairing the recruitment of HDAC1 mediated by c-myc on the ATF3 promoter , and subsequently elevating of histone acetylation . Our data documented that shikonin suppressed SCLC by inducing ferroptosis in a ATF3-dependent manner. Shikonin upregulated the expression of ATF3 expression via promoting the histone acetylation by inhibiting c-myc-mediated HDAC1 binding on ATF3 promoter.
研究领域:
肿瘤学
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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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产品关联
DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
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2024
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IF 12.2
Lixiao Zhou,Renjie Li,Fu Wang,Ruiqi Zhou,Yinyin Xia,Xuejun Jiang,Shuqun Cheng,Fanghong Wang,Danyang Li,Jun Zhang,Lejiao Mao,Xuemei Cai,Hongyang Zhang,Jingfu Qiu,Xin Tian,Zhen Zou,Chengzhi Chen
Excessive exposure to metals in daily life has been proposed as an environmental risk factor for neurological disorders. Oxidative stress is an inevitable stage involved in the neurotoxic effects induced by metals, nevertheless, the underlying mechanisms are still unclear. In this study, we used arsenic as a representative environmental heavy metal to induce neuronal oxidative stress and demonstrated that both in vitro and in vivo exposure to arsenic significantly increased the level of N6-methyladenosine (m6A) by down-regulating its demethylase FTO. Importantly, the results obtained from FTO transgenic mice and FTO overexpressed/knockout cells indicated that FTO likely regulated neuronal oxidative stress by modulating activating transcription factor 3 (ATF3) in a m 6 A-dependent manner. We also identified the specific m6A reader protein, YTHDC1, which interacted with ATF3 and thereby affecting its regulatory effects on oxidative stress. To further explore potential intervention strategies, cerebral metabolomics was conducted and we newly identified myo-inositol as a metabolite that exhibited potential in protecting against arsenic-induced oxidative stress and cognitive dysfunction. Overall, these findings provide new insights into the importance of the FTO-ATF3 signaling axis in neuronal oxidative stress from an m 6 A perspective, and highlight a beneficial metabolite that can counteract the oxidative stress induced by arsenic.
研究领域:
神经科学
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毒理学
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分子生物学
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代谢组学
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产品关联
DOI
PubMed
高影响因子
APOPTOSIS
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2024
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IF 6.1
Li Ziyao,Tian Ye,Zong Huafeng,Wang Xuelei,Li Dongyang,Keranmu Adili,Xin Shiyong,Ye Bowen,Bai Rong,Chen Weihua,Yang Guosheng,Ye Lin,Wang Siyan
Dysregulation of deubiquitination contributes to various diseases, including cancer, and aberrant expression of deubiquitinating enzymes is involved in carcinoma progression. As a member of the ovarian tumor (OTU) deubiquitinases, OTUD4 is considered a tumor suppressor in many kinds of malignancies. The biological characteristics and mechanisms of OTUD4 in clear cell renal cell carcinoma (ccRCC) remain unclear. The downregulation of OTUD4 in ccRCC was confirmed based on the TCGA database and a validation cohort of 30-paired ccRCC and para-carcinoma samples. Moreover, OTUD4 expression was detected by immunohistochemistry in 50 cases of ccRCC tissues, and patients with lower levels of OTUD4 showed larger tumor size ( p = 0.015). TCGA data revealed that patients with high expression of OTUD4 had a longer overall survival rate. In vitr o and in vivo studies revealed that downregulation of OTUD4 was essential for tumor cell growth and metastasis in ccRCC, and OTUD4 overexpression inhibited these malignant phenotypes. We further found that OTUD4 sensitized ccRCC cells to Erastin-induced ferroptosis, and ferrostain-1 inhibited OTUD4-induced ferroptotic cell death. Mechanistic studies indicated that OTUD4 functioned as an anti-proliferative and anti-metastasic factor through the regulation of RNA-binding protein 47 (RBM47)-mediated activating transcription factor 3 (ATF3). OTUD4 directly interacted with RBM47 and promoted its stability via deubiquitination events. RBM47 was critical in ccRCC progression by regulating ATF3 mRNA stability, thereby promoting ATF3-mediated ferroptosis. RBM47 interference abolished the suppressive role of OTUD4 overexpression in ccRCC. Our findings provide mechanistic insight into OTUD4 of ccRCC progression and indicate a novel critical pathway OTUD4/RBM47/ATF3 may serve as a potential therapeutic pathway for ccRCC.
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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肿瘤学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2023
·Vol. 24
·期 2
·1667
·
IF 5.6
Shengqi Huo,Qian Wang,Wei Shi,Lulu Peng,Yue Jiang,Mengying Zhu,Junyi Guo,Dewei Peng,Moran Wang,Lintong Men,Bingyu Huang,Jiagao Lv,Li Lin
Cuproptosis resulting from copper (Cu) overload has not yet been investigated in diabetic cardiomyopathy (DCM). Advanced glycosylation end products (AGEs) induced by persistent hyperglycemia play an essential role in cardiotoxicity. To clarify whether cuproptosis was involved in AGEs-induced cardiotoxicity, we analyzed the toxicity of AGEs and copper in AC16 cardiomyocytes and in STZ-induced or db/db-diabetic mouse models. The results showed that copper ionophore elesclomol induced cuproptosis in cardiomyocytes. It was only rescued by copper chelator tetrathiomolybdate rather than by other cell death inhibitors. Intriguingly, AGEs triggered cardiomyocyte death and aggravated it when incubated with CuCl2or elesclomol–CuCl2. Moreover, AGEs increased intracellular copper accumulation and exhibited features of cuproptosis, including loss of Fe–S cluster proteins (FDX1, LIAS, NDUFS8 and ACO2) and decreased lipoylation of DLAT and DLST. These effects were accompanied by decreased mitochondrial oxidative respiration, including downregulated mitochondrial respiratory chain complex, decreased ATP production and suppressed mitochondrial complex I and III activity. Additionally, AGEs promoted the upregulation of copper importer SLC31A1. We predicted that ATF3 and/or SPI1 might be transcriptional factors of SLC31A1 by online databases and validated that by ATF3/SPI1 overexpression. In diabetic mice, copper and AGEs increases in the blood and heart were observed and accompanied by cardiac dysfunction. The protein and mRNA profile changes in diabetic hearts were consistent with cuproptosis. Our findings showed, for the first time, that excessive AGEs and copper in diabetes upregulated ATF3/SPI1/SLC31A1 signaling, thereby disturbing copper homeostasis and promoting cuproptosis. Collectively, the novel mechanism might be an alternative potential therapeutic target for DCM.Keywords:cuproptosis;advanced glycosylation end products;diabetic cardiomyopathy;SLC31A1
研究领域:
心脏病学
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糖尿病
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分子生物学
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细胞信号传导
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病理生理学
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产品关联
DOI
PubMed
高影响因子
Biomaterials Research
·
2023
·Vol. 27
·期 1
·1-15
·
IF 11.3
Shi Jiachen,Ma Qiuling,Su Wenting,Liu Congyan,Zhang Huangqin,Liu Yuping,Li Xiaoqi,Jiang Xi,Ge Chang,Kong Fei,Chen Yan,Qu Ding
Background Conventional dissolving microneedles (DMNs) face significant challenges in anti-melanoma therapy due to the lack of active thrust to achieve efficient transdermal drug delivery and intra-tumoral penetration.Methods In this study, the effervescent cannabidiol solid dispersion-doped dissolving microneedles (Ef/CBD-SD@DMNs) composed of the combined effervescent components (CaCO3 & NaHCO3) and CBD-based solid dispersion (CBD-SD) were facilely fabricated by the “one-step micro-molding” method for boosted transdermal and tumoral delivery of cannabidiol (CBD).Results Upon pressing into the skin, Ef/CBD-SD@DMNs rapidly produce CO2 bubbles through proton elimination, significantly enhancing the skin permeation and tumoral penetration of CBD. Once reaching the tumors, Ef/CBD-SD@DMNs can activate transient receptor potential vanilloid 1 (TRPV1) to increase Ca2+ influx and inhibit the downstream NFATc1-ATF3 signal to induce cell apoptosis. Additionally, Ef/CBD-SD@DMNs raise intra-tumoral pH environment to trigger the engineering of the tumor microenvironment (TME), including the M1 polarization of tumor-associated macrophages (TAMs) and increase of T cells infiltration. The introduction of Ca2+ can not only amplify the effervescent effect but also provide sufficient Ca2+ with CBD to potentiate the anti-melanoma efficacy. Such a “one stone, two birds” strategy combines the advantages of effervescent effects on transdermal delivery and TME regulation, creating favorable therapeutic conditions for CBD to obtain stronger inhibition of melanoma growth in vitro and in vivo.Conclusion sThis study holds promising potential in the transdermal delivery of CBD for melanoma therapy and offers a facile tool for transdermal therapies of skin tumors.
研究领域:
药学
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生物医学工程
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肿瘤学
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药物递送系统
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产品关联
DOI
PubMed
高影响因子
MOLECULAR CELL
·
2024
·
IF 14.5
Huihui An,Yifan Hong,Yeek Teck Goh,Casslynn W.Q. Koh,Shahzina Kanwal,Yi Zhang,Zhaoqi Lu,Phoebe M.L. Yap,Suat Peng Neo,Chun-Ming Wong,Alice S.T. Wong,Yang Yu,Jessica Sook Yuin Ho,Jayantha Gunaratne,Wee Siong Sho Goh
N 6 ,2′-O-dimethyladenosine (m 6 Am) is an abundant mRNA modification that impacts multiple diseases, but its function remains controversial because the m 6 Am reader is unknown. Using quantitative proteomics, we identified transcriptional terminator premature cleavage factor II (PCF11) as a m 6 Am-specific reader in human cells. Direct quantification of mature versus nascent RNAs reveals that m 6 Am does not regulate mRNA stability but promotes nascent transcription. Mechanistically, m 6 Am functions by sequestering PCF11 away from proximal RNA polymerase II (RNA Pol II). This suppresses PCF11 from dissociating RNA Pol II near transcription start sites, thereby promoting full-length transcription of m 6 Am-modified RNAs. m 6 Am’s unique relationship with PCF11 means m 6 Am function is enhanced when PCF11 is reduced, which occurs during all- trans -retinoic-acid (ATRA)-induced neuroblastoma-differentiation therapy. Here, m 6 Am promotes expression of ATF3, which represses neuroblastoma biomarker MYCN. Depleting m 6 Am suppresses MYCN repression in ATRA-treated neuroblastoma and maintains their tumor-stem-like properties. Collectively, we characterize m 6 Am as an anti-terminator RNA modification that suppresses premature termination and modulates neuroblastoma’s therapeutic response.
研究领域:
分子生物学
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癌症生物学
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转录组学
✓ 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）