JOURNAL OF HAZARDOUS MATERIALS
·
2020
·
IF 9.038
Lanqiao Wang,Lanxi Wang,Xu Shi,Shiwen Xu
Excessive chlorpyrifos (CPF) in the environment causes toxicity to nontarget organisms by triggering oxidative stress. Phosphatase and tensin homolog deleted on chromosome ten (PTEN) plays an important role in controlling apoptosis and necrosis by negatively regulating the phosphatidylinositol 3-kinase/threonine kinase (PI3K/AKT) pathway. However, the effects of different concentrations of CPF on grass fish liver cell injury and the role of the ROS/PTEN/PI3K/AKT axis remain poorly understood. In this study, L8824 cells treated with different concentrations of CPF (0, 40, 60, or 80 μM) were used as the research object. The results showed that the median inhibitory concentration (IC50) was 112.226 μM. As the CPF concentrations increased, the ROS and MDA levels increased, and the T-AOC levels and SOD/GPx/GST activities decreased. As PTEN expression increased, PI3K/AKT, BCL-2, and Caspase-8 expression dramatically decreased. Conversely, RIPK1/RIPK3/MLKL and Bax/Cyt-c/Caspase-3 expression increased. Additionally, necroptosis increased in a dose-dependent manner, while apoptosis first increased and then decreased. In conclusion, our study showed that CPF could trigger oxidative stress and induce apoptosis and necroptosis in fish liver cells by regulating the ROS/PTEN/PI3K/AKT axis, and the type of damage induced was dose-dependent. These results are meaningful for toxicological studies of CPF and efforts to protect the ecosystem.
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
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2018
·
IF 2.559
Dan Zhao,Juan Chen,Ya Zhang,Hua-Bao Liao,Zhi-Feng Zhang,Yang Zhuang,Meng-Xian Pan,Jun-Chun Tang,Rui Liu,Yang Lei,Shu Wang,Xing-Ping Qin,Yu-Gong Feng,Yun Chen,Qi Wan
Glycine has been shown to protect against ischemic stroke through various mechanisms. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) which antagonize Akt-dependent cell survival has been linked to neuronal damage. However, whether glycine has a neuroprotective property in intracerebral hemorrhage (ICH) was unknown. This study aimed to determine the protective effect of glycine in rats ICH. Adult male Sprague-Dawley (SD) rats were subjected to left striatum infusion of autologous blood. ICH animals received glycine (0.2–3 mg/kg, icv) at 1 h after ICH with or without pre-injection of Akt Inhibitor IV (100 μM, 2 μl, icv) 0.5 h prior to glycine treatment. Our results showed that in the perihematomal area PTEN was up-regulated in the early stage after ICH. However, glycine treatment decreased PTEN protein level and increased the phosphorylation level of AKT (p-AKT) in the perihematomal area. With the administration of glycine, neuronal death was significantly reduced and Evans blue leakage was alleviated as well as the brain edema after ICH. Moreover, hematoma volume was decreased and neurobehavioral outcome was improved. Nevertheless, Akt Inhibitor IV abolished the neuroprotective effects of glycine after ICH. Together, our findings demonstrate, for the first time, the protective role of glycine on ICH rats, and suggest that the neuroprotective effect of glycine was mediated through PTEN/Akt signal pathway.
研究领域:
神经科学
·
药理学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
Theranostics
·
2025
·Vol. 15
·期 16
·8488
·
IF 13.3
Jiyuan Chen,Luyao Gong,Simeng Cao,Guanshan Song,Yeheng Peng,Yuanyuan Wang,Yan-Ru Lou,Teemu J Murtola,Yao Wu,Ganjun Yu,Yuan Gao
Rationale: Enzalutamide (Enz) is the first-line therapy for castration-resistant prostate cancer (CRPC). However, drug resistance has hindered its further application. Moreover, CRPC is frequently prone to metastasis, particularly to bone (BmCRPC). Methods: To investigate the involvement of phosphatase and tensin homolog deleted on chromosome 10 ( PTEN ) deletion and C-X-C motif chemokine receptor 2 (CXCR2) overexpression in Enz-resistant CRPC and BmCRPC, we constructed a bisphosphonate (BP) lipid-like material with high bone affinity (GB4-BPL) for the codelivery of a PTEN plasmid (pPTEN) and CXCR2 siRNA (siCXCR2) to BmCRPC. Results: GB4-BPL demonstrated twice the bone metastasis-targeting ability of GB4-lipo (which lacks bisphosphonate modification) while maintaining a gene transfection efficiency comparable to that of Lipo8000 and exhibiting significantly lower cytotoxicity. Moreover, siCXCR2 and pPTEN loaded in GB4-BPL (GB4-BPL@siCXCR2/pPTEN) synergistically inhibited tumor growth and metastasis, highly enhancing the effect of Enz by 69.45% in the Enz-resistant model. Furthermore, GB4-BPL@siCXCR2/pPTEN significantly reduced the numbers of MDSCs, Tregs, and M2-like TAMs by 55.01%, 64.75%, and 52.53%, respectively, while increasing the proportions of M1 macrophages, NK cells, and CD8 + T cells by 1.65-, 1.40-, and 4.60-fold, respectively. In addition, this nanosystem reduced skeletal-related events. Conclusions: Our studies demonstrated the potential of GB4-BPL for delivering siCXCR2/pPTEN to tumor and bone metastatic sites. GB4-BPL@siCXCR2/pPTEN alone or in combination with Enz could provide a new strategy for the treatment of drug-resistant BmCRPC.
研究领域:
肿瘤学
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分子治疗
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药理学
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生物信息学
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纳米技术
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF NEUROSCIENCE RESEARCH
·
2025
·Vol. 103
·期 7
·e70064
·
IF 3.4
Sun Hong,Liu GuoYan,Wu JiaWen,Yu Xin,Zhan ShuQin,Reng HongWei,Chen MengYing,Cheng YuXuan
Chronic epilepsy is mainly characterized by spontaneous recurrent seizures (SRS). The peroxisome proliferator activated receptor gamma/phosphatase and tensin homolog/protein kinase B (PPARγ/PTEN/Akt) pathway is involved in the pathogenesis of SRS and neuronal loss. Curcumin is a natural compound, and previous studies have shown it provides neuroprotection via anti-inflammation and anti-oxidant effects in many central nervous system (CNS) diseases. In the present study, we show that curcumin regulates the abnormal expression of PTEN and Akt in the SRS phase, improves the neuronal loss in the hippocampus, and suppresses SRS development and seizure spike activity in epileptic rats. More importantly, these effects are reversed by the PPARγ antagonist, T0070907, suggesting that curcumin exerts neuroprotective and anti-epileptic effects through the PPARγ/PTEN/Akt signaling pathway. Other studies have shown that curcumin can cross the BBB and has a safety profiles and pleiotropic pharmacological effects. Thus, our data support the proposition that curcumin might be a potential neuroprotective and anti-epileptic agent for chronic epilepsy.
研究领域:
神经病学
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分子生物学
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药理学
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转化医学
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中枢神经系统疾病
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产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2023
·
IF 17.1
Shibo Fu,Shunqian Yi,Qinfei Ke,Kai Liu,He Xu
Electrical stimulation therapy (EST) has been established as an effective strategy to accelerate wound healing by stimulating cell proliferation and migration, ultimately promoting re-epithelialization and vascularization, two key processes that significantly influence the rate of wound healing. Phosphatase and tensin homologue (PTEN), a widely expressed protein in somatic cells, works as a “brake” regulating cell differentiation, proliferation, and migration. Given that this “brake” also works in cell electrical responses, there is a hypothesis that PTEN inhibition may amplify the efficacy of EST in wound treatment. However, long-term inhibition of PTEN may result in DNA damage and reduce DNA repair, which poses a significant challenge to the safe use of PTEN inhibitors. To address this issue, we developed a system that combines PTEN inhibitor loaded electro-responsive hydrogel (BPV@PCP) with a wearable direct current pulse piezoelectric nanogenerator (PENG). The PENG converts the rat’s motions into electric fields that synchronously charge the wound edge tissue and BPV@PCP. Electric field intensity was lower when the rat was quiet or anesthetized, which is insufficient to trigger an effective PTEN inhibitor release. However, when the rat was in action, the electric field intensity exceeded 625 mV/mm, resulting in a rapid drug release. This on-demand PTEN inhibition accelerated wound healing by amplifying cell electric responsiveness while avoiding negative effects associated with continuous overinhibition of PTEN. Notably, this system improves vascularization not only by improving endothelial cell electric responsiveness but also through the paracrine pathway, in which electrical stimulation and PTEN inhibition synergically promote VEGF secretion.
研究领域:
生物医学工程
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组织工程
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纳米技术
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药学
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再生医学
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产品关联
DOI
PubMed
高影响因子
EXPERIMENTAL CELL RESEARCH
·
2023
·
IF 3.7
Hai-Tao Yang,Guan Wang,Peng-Cheng Zhu,Zhao-Yang Xiao
Pulmonary vascular remodeling caused by the excessive proliferation of pulmonary arterial smooth muscle cells (PASMCs) is the hallmark feature of pulmonary arterial hypertension (PAH). Eukaryotic initiation factor 3 subunit A (EIF3A) exhibited proliferative activity in multiple cell types. The present study investigated the role of EIF3A in the progression of PAH. A monocrotaline (MCT)-induced PAH rat model was constructed, and adeno-associated virus type 1 (AAV1) carrying EIF3A shRNA was intratracheally delivered to PAH rats to block EIF3A expression. PASMCs were isolated from rats and treated with PDGF-BB to simulate PASMC proliferation , and shRNA for EIF3 was conducted to investigate the mechanism behind the role of EIF3A in PASMC function in vitro . EIF3A expression was upregulated in pulmonary arteries, and EIF3A inhibition effectively improved pulmonary hypertension and right ventricular hypertrophy and suppressed MCT-induced vascular remodeling in vivo . In addition, we found that genetic knockdown of EIF3A reduced PDGF-triggered proliferation and arrested cell cycle, accompanied by downregulated proliferation-related protein expression in PASMCs. Mechanistically, the histone deacetylase 1 (HDAC1)-mediated PTEN/PI3K/AKT pathway was recognized as a primary mechanism in PAH progression. Silencing EIF3A decreased HDAC1 expression, and further inhibited the excessive proliferation of PASMCs by increasing the phosphatase and tension homolog (PTEN) expression and suppressing the AKT phosphorylation. Notably, HDAC1 expression reversed the effect of silencing EIF3A on PAH and PTEN/PI3K/AKT pathway. Collectively, silencing EIF3A improved PAH by decreasing PASMC proliferation through the HDAC1-mediated PTEN/PI3K/AKT pathway. These findings suggest that targeting EIF3A may represent a potential approach for the treatment of PAH.
研究领域:
心血管疾病
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分子生物学
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药理学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
CytoJournal
·
2024
·
IF 2.5
Yan Li,Zhenwei Jia,Xiaoyang Kong,Hongbo Zhao,Xiaoyan Liu,Guirong Cui,Jianmin Luo
Objective:
We currently face a sharp increase of T-cell acute lymphoblastic leukemia (T-ALL) incidence and a challenge of unmasking its complex etiology. The deoxycytidine analog 5-Aza-2’-deoxycytidine (5-Aza-dC) is currently the most common nucleoside methyltransferase inhibitor. The objective of this study was to clarify the role of 5-Aza-dC in T-ALL cell biological behaviors and phosphatase and tensin homolog deleted on chromosome ten (PTEN) expression.
Material and Methods:
T-ALL cell lines were divided into the experimental group with 5-Aza-dC solution treatment, and the control group without treatment. PTEN methylation was detected using methylation-specific polymerase chain reaction (MS-PCR). Following the measurement of cell proliferation, viability, apoptosis, invasion, migration, etc., quantitative reverse transcription-polymerase chain reaction (PCR) was conducted to detect PTEN, DNA methyl-transferases (DNMT1), DNMT3a, MBD2, and MeCP2 expressions; Western blot to detect PTEN, PI3K, AKT, and mTOR protein expressions. In addition, rescue experiments to inhibit and restore the expression of PTEN in different groups were performed for further identification of the results in the former parts.
Results:
MS-PCR results showed that in Jurkat cells, the target band was amplified using methylated primers for the PTEN gene promoter region; moreover, at 10 μmol/L of 5-Aza-dC for 24 h, PTEN methylation was completely removed without any un-methylated band observed. The experimental group had significantly lower cell proliferation and viability rates, higher apoptosis rates, decreased cell proportion in S phase, reduced invasion and migration; increased PTEN expression, decreased DNMT1, DNMT3a, MBD2, and MeCP2 mRNA expressions; and decreased PI3K, AKT, and mTOR protein expressions than those in the control group (all P < 0.05). Furthermore, according to the rescue experiment, silenced PTEN expression weakened the beneficial roles of 5-Aza-dC treatment, and resulted in significantly higher cell proliferation and viability rates, lower apoptosis rates, increased cell proportion in S phase, increased cell invasion and migration; decreased PTEN expression, elevated DNMT1, DNMT3a, MBD2, and MeCP2 mRNA expressions, and higher PI3K, AKT, and mTOR protein expressions (all P < 0.05). While restored PTEN expression enhanced functions of 5-Aza-dC treatment, leading to obviously lower cell proliferation and viability rates, higher apoptosis rates, increased cell proportion in G1 phase, and reduced cell invasion and migration; as well as increased PTEN expression, decreased DNMT1, DNMT3a, MBD2, and MeCP2 mRNA expressions, and lower PI3K, AKT, and mTOR protein expressions (all P < 0.05).
Conclusion:
Demethylation treatment with 5-Aza-dC can inhibit T-ALL cell malignant biological behaviors and enhance the sensitivity to chemotherapy agents possibly, which may be related to the inhibited expressions of DNMT1, DNMT3a, MBD2, and MeCP2, and restored expression activity of PTEN to negatively regulate the PI3K/AKT signal transduction. Our silencing and restoration of PTEN expressions further support our findings, highlighting that demethylation with 5-Aza-dC to restore the anti-tumor activity of the tumor suppressor gene PTEN may be a promising therapeutic option for treating T-ALL.
Keywords: 5-Aza-2’-deoxycytidine, T-cell acute lymphoblastic leukemia, PTEN, Tumor cell biological behaviors, Demethylation
研究领域:
肿瘤学
·
分子生物学
·
血液学
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产品关联
DOI
PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
·
2021
·
IF 6.025
Bangrong Cai,Mengya Liu,Jinxing Li,Dujuan Xu,Jiansheng Li
Chronic obstructive pulmonary disease (COPD) is widely recognized as a global public health problem and the third leading cause of mortality worldwide by 2020. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a dual-specificity protein and lipid phosphatase that plays an important role in COPD. However, the redox regulation of PTEN in the development of COPD was poorly studied. Our results showed that cigarette smoke extract (CSE) could oxidize PTEN in a time-dependent manner in BEAS-2B cells, whereas PTEN oxidation exposed to CSE was delayed compared to that of H 2 O 2. Additionally, we found that ROS derived from DUOX1 and 2 of NADPH oxidases were mainly responsible for oxidative inactivation PTEN, also simultaneously led to Trx-1 inactivation by dimerization . Oxidative mechanism of PTEN exposed to CSE was mediated by forming a disulfide bond between Cys 71 and Cys 124 , similar to H 2 O 2 . Inactivation of PTEN resulted in the increased phosphorylation of Akt. In conclusion, CSE exposure could elevate the intracellular ROS mainly from DUOX1 and 2 to oxidize PTEN and Trx-1 resulting in Akt activation, eventually cause the occurrence of COPD, suggesting that PTEN is a potential target for new therapies in COPD.
研究领域:
肺科学
·
分子生物学
·
细胞生物学
·
氧化应激
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药理学
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产品关联
DOI
PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
·
2024
·
IF 3.9
Yiren Xiong,Jiayi He,Shanshan He,Zuqing Hu,Di Ouyang,Renyi Liu,Zhenjie Gao,Weiguang Zhang,Zhujun Kang,Shuyi Lan,Yang Wang,Fatoumata Diallo,Dalin Hu
Lead is a ubiquitous environmental chemical with various toxic damage to human body. This investigation aimed to explore the intervention effect of human umbilical cord mesenchymal stem cells derived exosomes (HUC-MSC-exo) on the neurotoxicity of lead and the relevant mechanism. Differential gradient ultracentrifugation was adopted to isolate HUC-MSC-exo. Nanoparticle tracking assay (NTA), Transmission electron microscope (TEM) technology and exosomal specific biomarkers CD9, CD63 and CD81 were adopted for exosomal characterization. Human neuroblastoma cell (SH-SY5Y) was used as the recipient cell. Confocal laser scanning microscope analysis was conducted to confirm the intake of HUC-MSC-exo by SH-SY5Y cells. Cell migration ability, apoptosis, IL-6, IL-1β and TNF-α were analyzed. The role of miR-26a-5p/PTEN axis was assessed. The result showed that the exposure of SH-SY5Y cells to lead activated the miR-26a-5p/PTEN pathway by down-regulating miR-26a-5p and up-regulating PTEN expression, which was related to the significantly decreased cell migration and increased apoptosis, as well as significantly enhanced levels of inflammatory cytokine as compared with the control. While HUC-MSC-exo could significantly alleviate the cytotoxicity, apoptosis and inflammatory effects induced by lead on SH-SY5Y cells via partially restoring miR-26a-5p/PTEN pathway. Herein, we conclude that HUC-MSC-exo can alleviate lead-induced toxic effects on SH-SY5Y cells partially through miR-26a-5p/PTEN pathway.
研究领域:
毒理学
·
干细胞研究
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神经科学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL TOXICOLOGY
·
2022
·Vol. 37
·期 8
·1840-1852
·
IF 4.109
Huijie Chen,Yue Zhang,Mengmeng Zou,Xiaowei Sun,Xiaodan Huang,Shiwen Xu
Dibutyl phthalate (DBP) is a phthalic acid ester (PAE) that has posed a health hazard to the organisms. Naringenin (NRG) is a flavanone compound that has shown protection against several environmental chemicals through suppression of oxidative stress and activation of phosphatidylinositol 3-kinase/threonine kinase (PI3K/AKT) signaling pathway. Herein, swine testis (ST) cells were treated with 1.8 μM of DBP or/and 25.39 nM of NRG for 24 h, we described the discovery path of NRG inhibition on apoptosis in DBP-exposed ST cells through targeting phosphatase and tensin homologue deleted on chromosome 10 (PTEN). We first found that the anti-apoptosis effect of NRG is dependent on mitochondrial pathway through flow cytometry and related gene/protein expression, and then we detected PI3K/AKT pathway-related gene/protein expression, and established a computational docking assay between NRG and PTEN. We found that NRG specifically binds to three basic residues (His93, Lys125, Lys128) of P loop in PTEN, as well as phosphatase domains (Asp92, His93, Cys124, Lys125, Ala126, Lys128, and Arg130) in active dephosphorylation pockets, thereby reducing PTEN level and activating PI3K/AKT signaling pathway, and further inhibiting oxidative stress and mitochondrial pathway apoptosis. Taken together, our results push forward that NRG deserves further attention as a potential antagonistic therapy against DBP through targeting PTEN to inhibit oxidative stress and activate PI3K/AKT signaling pathway.
研究领域:
毒理学
·
细胞生物学
·
药理学
✓ 已验证
DOI
PubMed
高影响因子
OncoTargets and Therapy
·
2022
·
IF 4.345
Ping Chen,Xiaoyong Zhao,Hui Wang,Mengdan Zheng,Qinghua Wang,Wenjuan Chang
Purpose LncRNAs are important regulators in cancers. In this study, we investigated the role of lncRNA PCAT18 in gastric cancer (GC).Patients and Methods The level of PCAT18 in GC tissues and cells was determined by qRT-PCR. The cellular behaviors of GC cells with knockdown or overexpression of PCAT18 were respectively detected by CCK-8 assays, colony formation assays, flow cytometry and Western blot. A GC mice model was established by subcutaneous injection of MGC-803 and HGC-27 cells with the knockdown or overexpression of PCAT18. The tumor size and weight were measured, and IHC was performed to determine ki-67 level. Predicted by bioinformatics software and confirmed by dual-luciferase reporter assay, PCAT18 was involved in miR-107/PTEN axis, thus, the expression of and relationship among PCAT18, miR-107 and PTEN pathway were explored in clinical cases and GC cell lines. Rescue assay was performed in GC cells by co-transfection with miR-107 mimic or PCAT18. The PTEN/PI3K/AKT pathway was then detected by Western blot.Results PCAT18 was down-regulated in GC tissues and cells, and it had a significant diagnostic value for GC. The expression of PCAT18 was highly associated with tumor size, and PCAT18 was found to inhibit GC growth in vitro and in vivo. It was also found that PCAT18 was involved in PTEN/PI3K/AKT signaling pathway through targeting miR-107.Conclusion PCAT18 inhibits the progression of GC via miR-107/PTEN/PI3K/AKT signaling pathway. Additionally, PCAT18 is possibly a promising target for treatment of GC.
研究领域:
肿瘤学
·
分子生物学
·
癌症研究
·
细胞生物学
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产品关联
DOI
PubMed
高影响因子
COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY C-TOXICOLOGY & PHARMACOLOGY
·
2023
·
IF 3.9
Guangxing Li,Yang Chen,Menglin Wu,Kaiting Chen,Di Zhang,Ruili Zhang,Guijun Yang,Xiaodan Huang
Di (2-ethyl) hexyl phthalate (DEHP) is a common environmental endocrine disruptor that induces oxidative stress, posing a significant threat to human and animal health. Oxidative stress can activate the PTEN/PI3K/AKT pathway, which is closely related to cell apoptosis. However, it is unclear whether DEHP induces apoptosis of chicken liver cells by regulating the PTEN/PI3K/AKT pathway through oxidative stress. In this experiment, male laying hens were continuously exposed to 400 mg/kg, 800 mg/kg, and 1600 mg/kg DEHP for 14 d, 28 d, and 42 d. The results showed that liver injury was aggravated with the dose of DEHP gavage, and the ROS/MDA levels in L, M, and H DEHP exposure groups were significantly increased, while the T-AOC/T-SOD/GSH-PX levels were decreased. Meanwhile, DEHP exposure up-regulated the mRNA and protein expression levels of PTEN/Bax/Caspase-9/Caspase-3 and down-regulated the mRNA and protein expression levels of PI3K/AKT/BCL-2, indicating that DEHP may lead to hepatocyte apoptosis through ROS regulation of PTEN/PI3K/AKT axis. In order to further clarify the relationship between oxidative stress and liver injury, we treated chicken hepatocellular carcinoma cell line (LMH) with 2.5 mM N -acetylcysteine (NAC). NAC attenuated these phenomena. In summary, our study suggests that DEHP can induce apoptosis of chicken liver through ROS activation of the PTEN/PI3K/AKT axis.
研究领域:
毒理学
·
细胞生物学
·
环境科学
✓ 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）