Scientific Reports
·
2024
·Vol. 14
·期 1
·1-12
·
IF 3.8
Hu Deliang,Yang Yuqing,Fang Lei,Fan Shijie,Lin Ling,Luo Puying,Xiong Yuanhuan,Su Yufang
Isoliquiritigenin (ISL), a naturally occurring flavonoid derived from licorice root, exhibits antioxidant, anticancer, anti-inflammatory, and anti-allergic properties, and is frequently detected in both environmental and human samples. Previous studies from our lab have demonstrated that ISL exposure can lead to developmental deformities and aberrant immune responses. However, the molecular mechanisms underlying ISL toxicity in zebrafish embryos remain incompletely elucidated. Therefore, this study aimed to elucidate the effects of ISL exposure on endoplasmic reticulum (ER) stress in zebrafish embryos by assessing the expression levels of ER stress markers HSPA5 and CHOP , along with associated apoptosis factors, under various ISL concentrations, with tunicamycin (TM) serving as a positive control. Furthermore, targeted analyses of ER stress-related pathways were conducted using RNA transcriptome sequencing, and the up-regulated gene was verified by western blot. The results revealed that ISL exposure significantly elevated the expression levels of HSPA5 and CHOP , concomitantly activating ER stress pathways, including pPERK-eIF2α-ATF4 and ATF6 pathways in zebrafish embryos. These findings suggest that the activation of endoplasmic reticulum stress signaling pathways may contribute to the developmental deformities observed in zebrafish embryos following ISL exposure, thereby highlighting the potential ecological risks associated with ISL usage.
研究领域:
毒理学
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发育生物学
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分子生物学
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环境科学
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DOI
PubMed
高影响因子
ONCOLOGY REPORTS
·
2021
·Vol. 46
·期 5
·1-14
·
IF 3.906
Zhiwei Wang,Mingxing Li,Yuanfeng Liu,Zhentao Qiao,Tao Bai,Ling Yang,Bo Liu
Dihydroartemisinin (DHA), an artemisinin derivate, has been investigated as a potential antitumor drug in primary liver cancer (PLC). Ferroptosis is a form of iron‑dependent cell death that can be driven by lipid peroxidation inducers. The present study aimed to determine whether and how DHA could promote the death of PLC cells by inducing ferroptosis. In total, four PLC cell lines with different p53 statuses, including Hep3B (p53 null), Huh7 (p53 mutant), PLC/PRF/5 (p53 mutant) and HepG2 (p53 wild‑type), were treated with various concentrations of DHA. The effects of DHA on all three branches of the unfolded protein response (UPR) were evaluated. To deactivate the UPRs, small interfering RNA was used to knockdown the expression of activating transcription factor (ATF)4, X‑box binding protein 1 (XBP1) or ATF6 in PLC cells. The effect of DHA on the promoter activity of Chac glutathione specific γ‑glutamylcyclotransferase 1 (CHAC1) was evaluated using a dual luciferase reporter assay. The results revealed that DHA‑induced death in PLC cells was irrelevant of the p53 status. PLC cells exposed to DHA displayed classic features of ferroptosis, such as increased lipid reactive oxygen species and malondialdehyde levels, an iron overload, and decreased activity or expression of glutathione (GSH), glutathione peroxidase 4, solute carrier family (SLC) 7 member 11 and SLC family 3 member 2. The antitumor effects of DHA in PLC cells were significantly weakened by two typical ferroptosis inhibitors, ferrostatin‑1 and deferoxamine mesylate salt, whereas the antitumor effects were augmented following iron overload. Furthermore, DHA activated all three branches of the UPR (eukaryotic translation initiation factor 2 α kinase 3/eukaryotic translation initiation factor 2A/ATF4, inositol‑requiring transmembrane kinase/endoribonuclease 1α/XBP1 and ATF6 branches) in vitro. Notably, DHA‑induced ferroptosis was significantly attenuated following the knockdown of ATF4, XBP1 or ATF6 expression. In addition, the promoter activity of CHAC1, a gene capable of degrading GSH, was enhanced by DHA, but weakened when the aforementioned three UPR transcription factors were knocked down. In conclusion, the findings of the present study suggested that DHA may effectively induce ferroptosis in PLC cells through the activation of anti‑survival UPRs and the upregulation of CHAC1 expression.
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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DOI
PubMed
高影响因子
Drug Design Development and Therapy
·
2022
·
IF 4.319
Nianxiu Tian,Yanbin Gao,Xiaolei Wang,Xiaoming Wu,Dawei Zou,Zhiyao Zhu,ZheJi Han,Tao Wang,Yimin Shi
Background Endoplasmic reticulum stress is associated with podocyte apoptosis in the pathogenesis of diabetic nephropathy (DN). A previous study has demonstrated that emodin has a protective effect in the kidney by suppressing proliferation of mesangial cells and inhibiting the renal tubular epithelial-to-mesenchymal transition. However, the effects of emodin on the podocyte apoptosis in DN and its mechanisms are unknown.Aim This study aimed to explore the effect of emodin on DN model KK-Ay mice and high glucose induced podocytes apoptosis via the PERK–eIF2α pathway.Methods KK-Ay mice model of DN were treated with emodin at dose of 40 and 80 mg/kg/day for 8 weeks. Urine albumin, serum creatinine, blood urea nitrogen levels and the renal histopathology in mice were performed. In vitro, conditionally immortalized mouse podocytes exposed to HG (30mM) were incubated with emodin. Cell viability was measured by CCK-8 assay. Additionally, we performed RNA interference and measured the apoptosis in cultured podocytes treated with emodin. Immunohistochemistry, immunofluorescence, western blot, and real-time PCR were used to detect gene and protein expression both in vivo and in vitro.Results The results showed that emodin treatment ameliorated urine albumin, serum creatinine, and blood urea nitrogen of DN mice. The pathological damage of kidney tissue was also improved after treatment with emodin. Moreover, emodin increased nephrin expression. Podocytes apoptosis and endoplasmic reticulum stress markers (GRP78) were significantly reduced upon emodin treatment. Furthermore, emodin treatment decreased the expression of phosphorylated protein kinase RNA-like endoplasmic reticulum kinase (P-PERK), phosphorylated P-eIF2α, ATF4, and CHOP. In vitro, emodin treatment was further found to decrease the GRP78 level induced by high glucose or tunicamycin (TM). Besides, emodin and PERK knockdown inhibited the apoptosis of podocytes cultured in high glucose by counteracting the upregulation of phosphorylated PERK, phosphorylated eIF2α, ATF4, and CHOP.Conclusion Overall, the findings indicate that emodin mitigates podocytes apoptosis by inhibiting the PERK-eIF2α signaling pathway in vivo and in vitro, and, therefore, exerts a protective action on podocytes in DN.
研究领域:
药理学
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肾病学
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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
ACS Omega
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2024
·
IF 3.7
Chenxin Xu,Yinghua Chen,Zhuoen Zhou,Ying Yan,Wenying Fu,Peng Zou,Daoyong Ni
Lung cancer is one of the leading causes of death. Celastrol is a natural product that has shown anticancer activity but has not yet been applied in clinical settings due to its narrow therapeutic window. In this study, we discovered that celastrol stimulates an abnormal rise in the reactive oxygen species (ROS) level in lung cancer cells and that the ROS scavenger N-acetylcysteine (NAC) could counteract the cell death caused by celastrol. At the same time, celastrol upregulated the expression of cytoprotective transcription factor Nrf2 and its downstream proteins, which are effective in preventing the oxidative damage caused by ROS accumulation. Notably, we found that the overexpression of Nrf2 enhances the tolerance of lung cancer cells to celastrol and that lung cancer cells H460 with a Keap1 mutation are insensitive to celastrol. This indicates that the increase in Nrf2 contributes to the survival of lung cancer cells. Thus, we brought in an Nrf2 inhibitor ML385 to suppress the activation of Nrf2. We found that when ML385 and celastrol were added together the survival rates of lung cancer cells decreased more and the detected ROS level became much higher compared to treatment with celastrol alone. We also discovered that ML385 suppressed the expression of HO-1 and GCLC, which amplified celastrol-induced ATF4/CHOP-dependent endoplasmic reticulum stress (ER stress). Above all, our study found that ML385 enhanced celastrol-induced increases in ROS and ER stress, leading to lung cancer cell death. This research provides a potential strategy for the preclinical investigation of celastrol.
研究领域:
肿瘤学
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药理学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
INDUSTRIAL CROPS AND PRODUCTS
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2021
·
IF 5.645
Mingming Zhou,Siew Young Quek,Xulan Shang,Shengzuo Fang
This research investigated the variations of triterpenoid contents in Cyclocarya paliurus leaves and their underlying anticancer activity and mechanism. Leaf samples were collected from twelve geographical locations in China for the experiments. Significant variation in the triterpenoid content and growth inhibition on HeLa cells were observed among the C. paliurus populations. Antiproliferation effects of the leaf samples were significantly affected by the pentacyclic triterpenoids contents except for oleanolic acid. Among the pentacyclic triterpenoids, hederagenin exhibited the best anticancer activity with IC 50 of 17.42 μg/mL. Based on the results, pentacyclic triterpenoids may induce HeLa cell apoptosis via mitochondrial pathway. RNA sequencing indicated that the ACTB , ATF4 , TUBA1B and TUBA1C genes might be the key ones involved in the apoptosis induction by cyclocaric acid B and hederagenin. These results provided useful information for application of C. paliurus in functional beverage and pharmaceutical industries.
研究领域:
药理学
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植物科学
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分子生物学
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癌症研究
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DOI
高影响因子
Frontiers in Endocrinology
·
2025
·
IF 4.6
Congrong Wu,Maomao Sun,Yue He,Jie Jiang,Luran Wang,Yanni Wang,Yonghui Yu
Background: Clinical research has identified a correlation between hypertensive disorders of pregnancy (HDP) and subclinical hypothyroidism during gestation. But the potential influence of HDP on thyroid hormone synthesis remains undetermined.Aims: This study aims to elucidate the impact of HDP on thyroid hormone synthesis and to delineate the underlying mechanisms.Methods: 20 pregnancy SD rats were stratified at random into the HDP group and the Control group. The HDP group was subjected to NG-Nitro-L-arginine-methylester administration from gestational days 13 to 20, while the Control group received saline. Subsequent assessments encompassed serum FT4, FT3, and TSH concentrations, morphological examination of the thyroid, as well as quantification of essential proteins pivotal to thyroid hormone synthesis and markers indicative of endoplasmic reticulum stress.Results: The HDP group exhibited a statistically significant augmentation in serum TSH concentrations (p<0.05), while FT3 and FT4 levels manifested no discernible statistical variations. H&E staining highlighted a pronounced hyperplasia of the follicular epithelial cells and a diminution in the follicle lumen area. Electron microscopy unveiled pronounced endoplasmic reticulum markedly swelling and expansion within the HDP group. Molecular evaluations revealed a decrement in Tg expression within thyroid tissue, concomitant with an upregulated expression of p-PERK, P-eIF2α, and ATF4.Conclusion: This investigation suggests that HDP might modulate Tg expression within thyroid tissue, possibly mediated through the PERK/eIF2α signaling cascade. This perturbation may compromise thyroid hormone synthesis, thereby predisposing pregnant rats to subclinical hypothyroidism.
研究领域:
内分泌学
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生殖医学
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分子生物学
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DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2022
·
IF 3.322
Jing Cong,Yuehui Zhang,Xinming Yang,Yu Wang,Hui He,Mengying Wang
Polycystic ovary syndrome (PCOS) is a complicated endocrinopathy affecting women at reproductive age. Increasing evidence has shown the anti-PCOS effect of electroacupuncture (EA), a modified approach of traditional Chinese medical therapy “acupuncture”. However, the underlying mechanism of EA-alleviated PCOS waits further explored. In this study, experimental PCOS were induced in rats by dehydroepiandrosterone (DHEA) injection. Testosterone (T)-induced human ovarian granulosa cell (GC) line KGN was used to mimic PCOS in vitro . EA significantly alleviated histological changes and hormone disruption in PCOS rats. Besides, EA inhibited cell apoptosis, autophagy and the activation of endoplasmic reticulum (ER) stress-related PERK/eIF2α/ATF4/CHOP signaling in ovaries of PCOS rats. More interestingly, intermedin (IMD), a member of calcitonin gene-related peptide (CGRP), was evidently up-regulated in ovarian GCs after EA treatment, and its main bioactive form IMD 1-53 suppressed cell apoptosis, autophagy and PERK/eIF2α/ATF4/CHOP signaling in T-induced KGN cells. Consistent with IMD 1-53 , ER stress inhibitor 4-PBA exerted an inhibitory effect on T-induced cell apoptosis and autophagy in KGN cells. Collectively, this study validates the protective effect of EA on DHEA-induced PCOS, and proposes that IMD relieved apoptosis and autophagy in T-induced granulosa cells via inhibiting ER stress.
研究领域:
生殖医学
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内分泌学
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分子生物学
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中医学
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DOI
PubMed
高影响因子
CELLULAR SIGNALLING
·
2023
·
IF 4.8
Xiaoyu Liu,Beike Wang,Maolin Chang,Xiaocen Zhang,Hao Zou,Zhen Zhang,Guangli Han
The bone formation (osteogenesis) of human periodontal ligament cells (hPDLCs) under tension stress is essential for alveolar bone remodeling during orthodontic tooth movement (OTM). Deubiquitinating enzymes (DUBs) remove ubiquitin from target proteins, affecting their function and mediating cell survival and differentiation. However, whether and how DUBs regulate hPDLC function under tension force is poorly understood. In this study, we first investigated the expression of DUBs in hPDLCs under cyclic tension stimulation (CTS). Up-regulation of USP12 was observed in hPDLCs and at the tension side of molar teeth in OTM C57BL6 mice models. Knockdown (KD) of USP12 led to enhanced osteogenesis of hPDLCs under CTS. RNA-seq analysis suggested that the unfolded protein response (UPR) was the prevailing biological process in hPDLCs with USP12 KD, indicating that USP12 depletion triggered endoplasmic reticulum (ER) stress. The three major UPR-related signaling branches, namely PERK/eIF2α/ATF4, IRE1α/XBP1s, and ATF6 axis, were activated in hPDLCs with USP12 KD. By utilizing specific inhibitors, we proved that the PERK/eIF2α/ATF4 axis predominantly mediated the enhanced osteogenesis in hPDLCs with USP12 KD under CTS. In summary, our study demonstrates that USP12 serves as a key regulator for CTS-induced osteogenesis in hPDLCs, suggesting that USP12 upregulation serves as an adaptive mechanism for hPDLCs to alleviate ER stress during OTM.
研究领域:
牙科
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细胞生物学
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分子生物学
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正畸学
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DOI
PubMed
高影响因子
ENDOCRINE
·
2019
·Vol. 64
·期 3
·512-524
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IF 3.296
Liu Xiaohong,Zeng Xin,Chen Xuanming,Luo Ruixi,Li Linzhao,Wang Chengshi,Liu Jingping,Cheng Jingqiu,Lu Yanrong,Chen Younan
Purpose It is demonstrated that unsaturated fatty acids can counteract saturated fatty acids-induced lipotoxicity, but the molecular mechanisms are unclear. In this study, we investigated the protective effects of monounsaturated oleic acid (OA) against saturated palmitic acid (PA)-induced cytotoxicity in rat β cells as well as islets, and mechanistically focused on its regulation on endoplasmic reticulum (ER) stress. Methods Rat insulinoma cell line INS-1E cells and primary islets were treated with PA with or without OA for 24 h to determine the cell viability, apoptosis, and ER stress. SD rats were fed with high-fat diet (HFD) for 16 w, then, HFD was half replaced by olive oil to observe the protective effects of monounsaturated fatty acids rich diet. Results We demonstrated that PA impaired cell viability and insulin secretion of INS-1E cells and rat islets, but OA robustly rescued cells from cell death. OA substantially alleviated either PA or chemical ER stressors (thapsigargin or tunicamycin)-induced ER stress. Importantly, OA attenuated the activity of PERK-eIF2α-ATF4-CHOP pathway and regulated the ER Ca 2+ homeostasis. In vivo, only olive oil supplementation did not cause significant changes, while high-fat diet (HFD) for 32 w obviously induced islets ER stress and impaired insulin sensitivity in SD rats. Half replacement of HFD with olive oil (a mixed diet) has ameliorated this effect. Conclusion OA alleviated PA-induced lipotoxicity in INS-1E cells and improved insulin sensitivity in HFD rats. The amelioration of PA triggered ER stress may be responsible for its beneficial effects in β cells.
研究领域:
细胞生物学
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内分泌学
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营养学
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DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2021
·Vol. 9
·期 38
·8109-8120
·
IF 6.331
Hao Liu,Haolin Chen,Xiaoying Liu,Luoqi Mo,Chao Chen,Zhouyi Guo,Zhiming Liu
1T-phase niobium telluride (NbTe2) nanosheets are becoming increasingly important in emerging fields, such as spintronics, sensors and magneto-optoelectronics, due to their excellent physical and chemical properties. However, exploration on their biomedical applications are limited. Herein, ultrathin 1T-phase NbTe2 single-crystalline nanosheets with excellent photothermal performance, high drug-loading rate, near-infrared (NIR) light/acidic pH-triggered drug release, and low toxicity were developed for potentiated photothermal therapy. Importantly, they showed excellent biocompatibility in vivo and in vitro. NbTe2 nanosheets loaded with integrated stress response inhibitors (ISRIB) could achieve chemo-photothermal therapy of tumors through the ATF4–ASNS signaling axis. Ultrathin 1T-phase NbTe2 single-crystalline nanosheets with unique photothermal properties, drug loading rate and safety provide dramatic possibilities in biomedical applications, such as tissue imaging, photothermal therapeutics and pharmaceutics.
研究领域:
生物医学工程
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纳米技术
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癌症治疗
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材料科学
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DOI
PubMed
高影响因子
TOXICOLOGY AND INDUSTRIAL HEALTH
·
2022
·
IF 1.851
Junyu Shen,Lushan Wang,Xuxu Wang,Jiafei Xie,Tingting Yao,Yue Yu,Qi Wang,Zhen Ding,Jinpeng Zhang,Meirong Zhang,Lichun Xu
Cypermethrin, an extensively used pyrethroid pesticide, is regarded as one of many endocrine-disrupting chemicals (EDCs) with anti-androgenic activity to damage male reproductive systems. We previously found cypermethrin-induced apoptosis in mouse Sertoli cells TM4. We hypothesized cypermethrin-induced TM4 apoptosis by the endoplasmic reticulum (ER) pathway. This study aimed to explore the roles of the ER pathway in cypermethrin-induced apoptosis in TM4 cells. The cells were treated with cypermethrin for 24 h at various concentrations (0 µM, 10 µM, 20 µM, 40 µM, and 80 µM). Flow cytometry was used to test for apoptosis. Western blot was used to test protein expressions in the ER stress pathway. The results showed that the apoptosis rate of TM4 cells increased with increased concentrations of cypermethrin, and a significant difference was detected in the 80-μM group. The protein expressions of glucose-regulated protein 78 (GRP78), protein kinase R (PKR)-like ER kinase (PERK), p-PERK, α subunit of eukaryotic initiation factor (eIF2α), p-eIF2α, activating transcription factor 4 (ATF4), C/EBP homologous protein (CHOP), caspase-12, caspase-9, and caspase-3 increased with increased concentrations of cypermethrin. The results suggested cypermethrin-induced apoptosis in TM4 cells regulated by the ER pathway involving PERK-eIF2α-ATF4-CHOP. The study provides a new insight into cypermethrin-induced apoptosis in Sertoli cells.
研究领域:
毒理学
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细胞生物学
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内分泌学
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产品关联
DOI
PubMed
高影响因子
Italian Journal of Animal Science
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2021
·
IF 2.217
Yi Ma,Mawda Elmhadi,Chao Wang,Hao Zhang,Hongrong Wang
Several studies have demonstrated that high-concentrate (HC) diet with thiamine supplementation can alleviate rumen epithelium inflammation and protecting the barrier function in goats. This study aimed to investigate the effects of dietary supply of thiamine on mitophagy and endoplasmic reticulum stress (ERS) during high-concentrate diet feeding. Twenty-four Boer goats (35.62 ± 2.4 kg) were used in this study, goats were subsequently assigned to 3 treatment groups (8 goats in each group) as follows: a low-concentrate diet (CON; concentrate: forage 30:70), a high-concentrate diet (HC; concentrate: forage 70:30) and high-concentrate diet with 200 mg thiamine/kg DMI (HCT; concentrate: forage 70:30) for 12 weeks. Compared with the HC group, the goats of HCT group had a markedly higher final weight, net weight gain, and average daily gain (ADG). The blood physiological and biochemical results showed that the HCT group expressed a lower the content of lymphocytes and leukocytes but a higher total protein and monocytes compared with that of HC group. The rumen epithelial mitochondrial membrane potential change (ΔΨm), relative mitochondrial DNA (mtDNA) content, adenosine triphosphate (ATP) level, together with the activities of the respiratory complexes I, III, and IV were markedly higher in the HCT group relative to HC ones. Relative to the HC group, the unc-51 like autophagy activating kinase 1 (ULK1), microtubule-associated protein 1 light chain 3 (LC3), autophagy-related 5 (ATG5), autophagy related 7 (ATG7), Beclin1, PTEN induced putative kinase 1 (PINK1), PERK (PKR-Endoplasmic Reticulum Kinase), activating transcription factor 4 (ATF4), activating transcription factor 6 (ATF6), X-box binding protein 1 (XBP1), heat shock 70 kDa protein 5 (HSPA5), DNA damage-inducible transcript 3 (DDIT3) and DNA damage-inducible transcript 4 (DDIT4) mRNA levels were decreased, but the breast cancer 1 (BRCA1), ataxia telangiectasia mutated (ATM), heat shock factor binding protein 1 (HSBP1) were increased in rumen epithelium of the HCT group. The results of transmission electron micrographs showed that the cell structure of the HCT group was higher integrity than that in the HC group, and the damage degree of mitochondria as well as endoplasmic reticulum being lower than the HC group. These results demonstrated that dietary thiamine could enhance rumen epithelial integrity by suppressing the responses of ERS and mitophagy during long-term HC diet feeding.HIGHLIGHTSThis study is the first to demonstrate that the reduction of inflammatory response is related to the down-regulation of autophagy and endoplasmic reticulum stress in goats.Thiamine has good anti-inflammatory and anti-oxidation properties, which can be applied in intensive industry to reduce the negative effects caused by long-term high-concentrate diet.
研究领域:
动物营养
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分子生物学
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兽医学
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营养基因组学
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DOI
高影响因子
危险品化学品经营许可证（带存储）