SCIENCE OF THE TOTAL ENVIRONMENT
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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.
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PHYTOTHERAPY RESEARCH
·
2023
·
IF 7.2
Haili Xiao,Chao Wei,Huiying Liu,Zhiqiang Li,Cihua Zheng,Jun Luo
Lentinan, a natural drug with wide-ranging pharmacological activities, can regulate autophagy—the process through which Schwann cells (SCs) eliminate myelin fragments after peripheral nerve injury (PNI). However, the effect of lentinan after PNI and the role of accelerated myelin debris removal via autophagy in this process are unclear. This study examined the effect of lentinan on rat sciatic nerve repair following crush injury and the underlying mechanisms. After the successful establishment of the sciatic nerve compression injury model, group-specific treatments were performed. The treatment group received 20 mg/kg lentinan via intraperitoneal injection, while the model group was treated with normal saline. The recovery in each group was then evaluated. Further, a rat SC line (RSC96) was cultured in medium with/without lentinan after supplementation with homogenous myelin fractions to evaluate the removal of myelin particles. Our results showed that lentinan promotes autophagic flux in vivo via the AMPK/mTOR signaling pathway, accelerates the clearance of myelin debris by SCs, and inhibits neuronal apoptosis, thereby promoting neurological recovery. Similarly, in vitro experiments showed that lentinan promotes the phagocytosis of myelin debris by SCs. In conclusion, our results suggest that lentinan primarily promotes nerve regeneration by accelerating the autophagic clearance of myelin debris in SCs, and this process is likely regulated by the AMPK/mTOR signaling pathway. Therefore, this study provides compelling evidence that lentinan may be a cost-effective and natural treatment agent for PNI.
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JOURNAL OF HAZARDOUS MATERIALS
·
2023
·
IF 13.6
Yanli Zhang,Yulin Zhang,Ye Lei,Junrong Wu,Yiyuan Kang,Shuo Zheng,Longquan Shao
During pregnancy, the human body is quite vulnerable to external stimuli. Zinc oxide nanoparticles (ZnO-NPs) are widely used in daily life, and they enter the human body via environmental or biomedical exposure, thus having potential risks. Although accumulating studies have demonstrated the toxic effects of ZnO-NPs, few studies have addressed the effect of prenatal ZnO-NP exposure on fetal brain tissue development. Here, we systematically studied ZnO-NP-induced fetal brain damage and the underlying mechanism. Using in vivo and in vitro assays, we found that ZnO-NPs could cross the underdeveloped blood brain barrier and enter fetal brain tissue, where they could be endocytosed by microglia. ZnO-NP exposure impaired mitochondrial function and induced autophagosome overaccumulation by downregulation of Mic60, thus inducing microglial inflammation. Mechanistically, ZnO-NPs increased Mic60 ubiquitination by activating MDM2, resulting in imbalanced mitochondrial homeostasis. Inhibition of Mic60 ubiquitination by MDM2 silencing significantly attenuated the mitochondrial damage induced by ZnO-NPs, thereby preventing autophagosome overaccumulation and reducing ZnO-NP-mediated inflammation and neuronal DNA damage. Our results demonstrate that ZnO-NPs are likely to disrupt mitochondrial homeostasis, inducing abnormal autophagic flux and microglial inflammation and secondary neuronal damage in the fetus. We hope the information provided in our study will improve the understanding of the effects of prenatal ZnO-NP exposure on fetal brain tissue development and draw more attention to the daily use of and therapeutic exposure to ZnO-NPs among pregnant women.
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Molecular Therapy-Nucleic Acids
·
2023
·
IF 8.8
Xin Chang,Chang Liu,Yu-Mo Han,Qiu-Ling Li,Bin Guo,Hu-Lin Jiang
Pulmonary fibrosis (PF) is an interstitial lung disease with complex pathological mechanism, and there is currently a lack of therapeutics that can heal it completely. Using gene therapy with drugs provides promising therapeutic strategies for synergistically reversing PF. However, improving the intracellular accumulation and transfection efficiency of therapeutic nucleic acids is still a critical issue that urgently needs to be addressed. Herein, we developed lipid nanoparticles (PEDPs) with high transfection efficiency coloaded with pDNA of nuclear factor erythroid 2-related factor 2 (pNrf2) and pirfenidone (PFD) for PF therapy. PEDPs can penetrate biological barriers, accumulate at the target, and exert therapeutic effects, eventually alleviating the oxidative stress imbalance in type II alveolar epithelial cells (AECs II) and inhibiting myofibroblast overactivation through the synergistic effects of Nrf2 combined with PFD, thus reversing PF. In addition, we systematically engineered various liposomes (LNPs), demonstrated that reducing the polyethylene glycol (PEG) proportion could significantly improve the uptake and transfection efficiency of the LNPs, and proposed a possible mechanism for this influence. This study clearly reveals that controlling the composition ratio of PEG in PEDPs can efficiently deliver therapeutics into AECs II, improve pNrf2 transfection, and synergize with PFD in a prospective strategy to reverse PF.
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Frontiers in Molecular Biosciences
·
2023
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IF 5
Shi Hanqiang,Xiong Lie,Yan Guang,Du Shuqin,Liu Jie,Shi Yanbo
The clinical therapeutics of cervical cancer is limited due to the drug resistance and metastasis of tumor. As a novel target for antitumor therapy, ferroptosis is deemed to be more susceptible for those cancer cells with resistance to apoptosis and chemotherapy. Dihydroartemisinin (DHA), the primary active metabolites of artemisinin and its derivatives, has exhibited a variety of anticancer properties with low toxicity. However, the role of DHA and ferroptosis in cervical cancer remained unclear. Here, we showed that DHA could time-dependently and dose-dependently inhibit the proliferation of cervical cancer cells, which could be alleviated by the inhibitors of ferroptosis rather than apoptosis. Further investigation confirmed that DHA treatment initiated ferroptosis, as evidenced by the accumulation of reactive oxygen species (ROS), malondialdehyde (MDA) and liquid peroxidation (LPO) levels and simultaneously depletion of glutathione peroxidase 4 (GPX4) and glutathione (GSH). Moreover, nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy was also induced by DHA leading to subsequent increases of intracellular labile iron pool (LIP), exacerbated the Fenton reaction resulting in excessive ROS production, and enhanced cervical cancer ferroptosis. Among them, we unexpectedly found that heme oxygenase-1 (HO-1) played an antioxidant role in DHA-induced cell death. In addition, the results of synergy analysis showed that the combination of DHA and doxorubicin (DOX) emerged a highly synergistic lethal effect for cervical cancer cells, which was related also to ferroptosis. Overall, our data revealed the molecular mechanisms that DHA triggered ferritinophagy-dependent ferroptosis and sensitized to DOX in cervical cancer, which may provide novel avenues for future therapy development.
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PHYSIOLOGICAL RESEARCH
·
2023
·
IF 2.1
T Wang,Q Wang,G Pan,G Jia,X Li,C Wang,L Zhang,C Zuo
The acidic tumor microenvironment (TME) of pancreatic cancer affects the physiological function of pancreatic stellate cells (PSCs), which in turn promotes cancer progression. Acid-sensing ion channel 1a (ASIC1a) is responsible for acidosis-related physiopathological processes. In this study, we investigated the effect of acid exposure on the activation and autophagy of PSCs, and the role of ASIC1a in these events. The results showed that acidic medium upregulated the expression of ASIC1a, induced PSCs activation and autophagy, which can be suppressed by inhibiting ASIC1a using PcTx1 or ASIC1a knockdown, suggesting that ASIC1a involves these two processes. In addition, the acid-induced activation of PSCs was impaired after the application of autophagy inhibitor alone or in combination with ASIC1a siRNA, meaning a connection between autophagy and activation. Collectively, our study provides evidence for the involvement of ASIC1a in the acid-caused PSCs activation, which may be associated with autophagy induction.
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JOURNAL OF HAZARDOUS MATERIALS
·
2023
·
IF 13.6
Jinzhe Li,Chuyun Fu,Qiufeng Lin,Tao Zeng,Da Wang,Xinwen Huang,Shuang Song,Cong Li,Feilong Dong
Ferrate (Fe(VI), FeO 4 2- ) has been widely used in the degradation of micropollutants with the advantages of high redox potential , no secondary pollution and inhibition of disinfection byproducts . However, the low transformation of Fe(V) and/or Fe(IV) by Fe(VI) and incomplete mineralization of pollutants limit their application. In this work, we designed a photo electric cell with TiO 2 nanotubes (TNTs) and Pt serving as the anode and cathode to enhance the utilization of Fe(VI) (Fe(VI)-TNTs system). TNTs accelerated the generation of •OH via h VB + oxidation of OH - and photogenerated electrons at Pt boosted the transformation of Fe(VI) to Fe(V) and/or Fe(IV), resulting in a 22.2 % enhancement of chloroquine (CLQ) removal compared to Fe(VI) alone. The results from EPR and quenching tests showed that Fe(VI), Fe(V), Fe(IV), •OH, O 2 •- and h VB + coexisted in the Fe(VI)-TNTs system, among which Fe(V) and Fe(IV) were testified as the primary reactive substances accounting for 59 % of CLQ removal. The performance tests and recycling tests demonstrated that the Fe(VI)-TNTs system maintained excellent performance in an authentic water environment. The plausible degradation pathway of CLQ oxidized in the Fe(VI)-TNTs system was proposed with nine identified oxidation products via N-C cleavage, electrophilic addition and carboxylation processes. Based on the ECOSAR calculation, the constructed reaction system allowed a decrease in acute and chronic toxicity. Our findings provide a highly efficient and cost-effective strategy to enhance Fe(VI) application for micropollutant degradation in the future.
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MOLECULAR NUTRITION & FOOD RESEARCH
·
2019
·Vol. 63
·期 18
·1801255
·
IF 4.653
Peng Cao,Yu Zhang,Zi Huang,Mitchell A. Sullivan,Zihao He,Jinglin Wang,Zehong Chen,Huiping Hu,Kaiping Wang
Scope Autophagy plays an important role in alleviating alcoholic liver disease (ALD). In this study, it is discovered that a dimer procyanidin (DPC) significantly prevented ALD by promoting hepatic autophagy. Methods and results Both cell and animal disease models stimulated by excessive ethanol are employed to evaluate the protective actions of DPC. Specifically, in vitro, DPC significantly decreased intracellular lipid deposition, diminished reactive oxygen species (ROS) formation, and elevated the level of mitochondrial membrane potential. These beneficial effects can be remarkably blocked by 3-methyladenine, a potent autophagy inhibitor, suggesting the autophagy-dependent protective role of DPC. In vivo, DPC pretreatment can also significantly reduce lipid accumulation, ROS overproduction, and elevated GSH content in the liver. Similarly, these protective effects of DPC can be partially reversed by chloroquine, a lysosomal inhibitor used to block the late-stage autophagy flux. Moreover, the determinations of LC3 and p62 protein expressions, autophagic flux assessments, and transmission electron microscopy observation further demonstrate the pro-autophagic effect of DPC. Conclusions DPC may activate hepatic autophagy to eliminate lipid droplets and damaged mitochondria, thereby reducing hepatic lipid disposition and ROS overproduction. This study demonstrates that DPC is a protective reagent on ALD, providing a novel strategy of fighting ALD.
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JOURNAL OF CELLULAR BIOCHEMISTRY
·
2019
·Vol. 120
·期 8
·13121-13132
·
IF 3.448
Xiaoxiao Liang,Zhiqiang Hou,Yuanlong Xie,Feifei Yan,Sisi Li,Xiaobin Zhu,Lin Cai
Osteoporosis (OP) results from the impaired function of endogenous bone marrow mesenchymal stem cells (BMSCs). Icariin (ICA) has shown potential osteoprotective effects. However, the molecular mechanism for the anabolic action of ICA remains largely unknown. The objective of the present study is to investigate whether ICA prevents bone loss by acting on BMSCs via affecting the level of autophagy after ovariectomy (OVX). The BMSCs were extracted from BALB/c mice treated with ICA, chloroquine (CQ, an autophagy inhibitor) or ICA + CQ. The OVX mice were injected with ICA, CQ, or ICA + CQ for 1 month. We performed Alizarin Red staining and alkaline phosphatase staining to detect osteogenic differentiation of BMSCs. Micro-CT, hematoxylin and eosin staining, Oil Red O staining, and tartrate-resistant acid phosphatase staining were used to assess the bone mass, lipid droplets and osteoclasts in femurs. Autophagy activity in BMSCs from different groups was evaluated by Western blot analysis. The osteogenic differentiation of BMSCs from OVX-induced OP mice was decreased. Treatment with ICA reduced bone loss and formation of osteoclasts and increased osteogenic differentiation of BMSCs in vitro and vivo. In addition, autophagy was enhanced in BMSCs of OVX mice treated with ICA. Our results indicate that ICA prevents OVX-induced bone loss possibly by strengthening the osteogenic differentiation of BMSCs via increasing autophagic activity.
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TOXICOLOGY LETTERS
·
2019
·
IF 3.499
Lingmin Zhang,Qingqing Xia,Yingying Zhou,Jie Li
Excessive accumulation of cadmium (Cd) in retina plays an important role in tobacco smoking-associated age-related macular degeneration (AMD). Plenty of evidence has revealed that the retinal pigment epithelium (RPE) is the primary site of pathology in AMD. Our current study demonstrated that Cd induced apoptosis in a human RPE cell line ARPE-19 cells, as it dose-dependently caused cell viability loss and activated caspase-3. The reactive oxygen species (ROS) were confirmed to be important mediators for Cd-triggered cell death in ARPE-19 cells. We found that endoplasmic reticulum (ER) stress was activated as its marker BiP was remarkably upregulated by Cd-exposure. Whereas the antioxidants N-acetylcysteine (NAC) and Tempol significantly suppressed the expression of BiP and CHOP, suggesting that ROS generation is an early trigger of Cd-activated ER stress. Furthermore, we found that Cd-induced oxidative stress significantly increased autophagic flux and p62 expression. A temporal impact of Cd exposure is possibly existed in p62 expression in ARPE-19 cells. Moreover, an ER stress inhibitor salubrinal diminished Cd-induced LC3BII expression and attenuated cytotoxicity, indicating that ER stress mediates autophagy and was implicated in apoptosis of Cd-exposed ARPE-19 cells. However, CHOP expression may not exert impact on the regulation of Cd-caused autophagy. Additionally, inhibition of autophagy with si-Beclin 1 and 3-Methyladenine significantly ameliorated Cd-induced CHOP expression and cytotoxicity, indicating that autophagy was detrimental in Cd-accumulated ARPE-19 cells, and a positive feedback regulation mechanism may exist between Cd-triggered ER stress and autophagy. Taken together, these results suggest that Cd-caused ER stress and autophagy are implicated in RPE cell death associated retinopathies especially related to smoking.
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Nanoscale
·
2018
·Vol. 10
·期 26
·12788-12796
·
IF 7.233
Shuang E,Quan-Xing Mao,Xiao-Li Yuan,Xiao-Lei Kong,Xu-Wei Chen,Jian-Hua Wang
Organelles play crucial roles in cellular activities and the functions of organelles are related greatly to the pH values, therefore, the bio-imaging of targeted organelles and their related pH sensing is of great importance in biological assays. Herein we report the fluorescence imaging of specific organelles, i.e., lysosomes and endoplasmic reticulum, and their pH sensing with surface regulated carbon dots (CDs). Carbon dots functionalized with amine groups (ACDs) are first prepared by hydrothermal treatment of citric acid and urea, and then laurylamine functionalized CDs (LCDs) are obtained via the conjugation of laurylamine with ACDs. The as-prepared ACDs and LCDs provide clear and bright imaging results for the lysosome and endoplasmic reticulum, respectively. The subcellular targeting features of the two CDs are attributed to their surface chemistries and cellular uptake pathways. Moreover, both the CDs are pH responsive within a certain pH range, i.e., 4.0–5.4 for ACDs and 6.2–7.2 for LCDs. The ACDs and LCDs are thus successfully applied to visualize the pH fluctuations of the lysosome and endoplasmic reticulum in MCF-7 cells.
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SEPARATION AND PURIFICATION TECHNOLOGY
·
2024
·
IF 8.1
Boqiang Gao,Haoge Liang,Jie Wang,Yan Huang,Jingzhen Wang,Jia Song,Pan Hu,Hu Yang,Shuanglong Ma
Hydroxychloroquine (HCQ) as an antiviral pharmaceutical has been widely detected in the aquatic environment. Adsorption is an effective method for removal of HCQ, but the quantitative study of the adsorption interactions is unclear. In this study, a carboxylated lignin-based sponge (PLC) was fabricated, and the adsorption contributions of electrostatic attraction (EA), hydrogen bond (HB), and π-π electron donor–acceptor (π-π EDA) interactions were quantitatively investigated. The results showed that PLC exhibited excellent adsorption performance under wide pH range (4.0 < pH < 11.0), with the highest adsorption capacity of 0.165 mmol/g. Inhibitor and molecular probe experiments showed that EA and HB were the main contributors to adsorption at neutral and basic pH ranges, respectively. A linear correlation model of the carboxyl groups of lignin-based sponges with the adsorption capacity of EA, HB, and π-π EDA interactions of HCQ ( R 2 > 0.822) and three molecular probes ( R 2 > 0.749) was established, respectively. The optimal adsorption capacity was achieved by the synergistic combination of the deprotonated carboxyl of PLC with the HB of Ka1 amino, EA of Ka2 amino, and the π-π EDA of the quinoline ring. This study provided a new strategy for the quantitative construction of structure–activity relationships of adsorbents.
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危险品化学品经营许可证（带存储）