Nano Today
·
2025
·
IF 10.9
Xiaomeng Ding,Qing Liu,Yueyue Mu,Yanting Pang,Jiawei Wu,Jialin Lei,Haopeng Zhang,Yuna Cao,Ting Zhang
Graphene quantum dots (GQDs), with photoluminescent properties, high stability, and excellent biocompatibility, hold tremendous potential in biomedicine. It is urgent to evaluate their safety and potential health risks to promote their clinical application. Kupffer cells (KCs), as primary immune cells encountered by foreign substances entering the liver and integral to liver immunity, have yet to be systematically studied for toxicity responses to different GQDs. This study focused on three widely used GQDs (OH-GQDs, N-GQDs, and NH 2 -GQDs), examining their effects on KCs and elucidating the underlying mechanisms. Our findings suggested that the toxicity levels of the three GQDs on KCs are ranked as OH-GQDs > N-GQDs > NH 2 -GQDs, with inflammation being the main form of toxic effect, which was a consequence of GQD-induced calcium homeostasis disruption. Specifically, cytoplasmic calcium imbalance caused by GQDs leaded to mitochondrial Ca 2 + overload, mitochondrial dysfunction, and mtROS generation, which subsequently activated the NLRP3 inflammasome-dependent inflammation. Crucially, we identified upstream mechanistic differences in calcium homeostasis disruption induced by each GQDs, with the most toxic OH-GQDs inducing ER stress-mediated Ca 2+ release, which was closely related to the depletion of GSH caused by the generation of oxygen free radicals (•OH and O 2 •−). By tracing Ca 2+ homeostasis, this work comprehensively mapped the upstream and downstream mechanisms of GQD-induced liver macrophage inflammation, providing new insights into the toxic effects of GQDs. Additionally, linking the intrinsic properties of GQDs, we identified the molecular initiating events of OH-GQDs mediated excessive inflammation in KCs, offering strategies for the de novo safe design of GQDs that target the content of oxygen-containing functional groups and the generation capacity of free radicals, which is of great significance for the development of safe, non-toxic, and efficient GQDs for clinical diagnosis and treatment.
研究领域:
生物医学
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毒理学
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免疫学
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DOI
高影响因子
ENVIRONMENTAL TOXICOLOGY
·
2022
·Vol. 37
·期 11
·2660-2672
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IF 4.109
Huiling Guo,Bingyan Huang,Ting Cui,Xuesheng Chu,Wenjing Pu,Gang Huang,Chenghong Xing,Caiying Zhang
Cadmium (Cd) is detrimental to animals, but nephrotoxic effects of Cd on duck have not been fully elucidated. To evaluate the impacts of Cd on Ca homeostasis and autophagy via PLC-IP 3 -IP 3 R pathway, primary duck renal tubular epithelial cells were exposed to 2.5 μM and 5.0 μM Cd, and combination of 5.0 μM Cd and 10.0 μM 2-APB or 0.125 μM U-73122 for 12 h (U-73122 pretreated for 1 h). These results evidenced that Cd induced [Ca 2+ ] c overload mainly came from intracellular Ca store. Cd caused [Ca 2+ ] mit and [Ca 2+ ] c overload with [Ca 2+ ] ER decrease, elevated Ca homeostasis related factors (GRP78, GRP94, CRT, CaN, CaMKII, and CaMKKβ) expression, PLC and IP 3 activities and IP 3 R expression, but subcellular Ca 2+ redistribution was reversed by 2-APB. PLC inhibitor U-73122 dramatically relieved the changes of the above indicators induced by Cd. Additionally, U-73122 obviously reduced the number of autophagosomes and LC3 accumulation spots, Atg5, LC3A, LC3B mRNA levels and LC3II/LC3I, Beclin-1 protein levels induced by Cd, and markedly elevated p62 mRNA and protein levels. Overall, the results verified that Cd induced [Ca 2+ ] c overload mainly originated from ER Ca 2+ release mediated by PLC-IP 3 -IP 3 R pathway, then triggered autophagy in duck renal tubular epithelial cells.
研究领域:
毒理学
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细胞生物学
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肾脏生理学
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DOI
PubMed
高影响因子
Regenerative Biomaterials
·
2025
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IF 8.1
Yu Pengcheng,Lu Weiqi,Sun Huaxin,Huang Chengchen,Zhou Xiaolin,Wang Yuxing,Zhang Zhen,Fu Guosheng,Liu Hanxiong,Ren Kefeng,Sheng Xia
Postoperative atrial fibrillation (POAF) is the most prevalent form of secondary atrial fibrillation and increase the risk of adverse cardiovascular outcomes, such as stroke, heart failure, and increased mortality. Herein, we designed an andrographolide (Andr)-loaded degradable polymer patch to deliver the drug directly to the atrial tissue for prevention of POAF. The sterile pericarditis (SP) rat model was adopted for highly relationship to clinical practice. The patch-released Andr effectively reduced the incidence of atrial fibrillation from 90% to 20%, and alleviated local atrial inflammation and oxidative stress in vivo, by using electrophysiological detection and histological analysis such as immunofluorescence, western blot, PCR and so on. In HL-1 cells, we found the use of Andr-loaded patch could strongly inhibited the cell death, reactive oxygen species (ROS) generation and mitochondrial injury caused by LPS. Meanwhile, the use of Andr-loaded patch could effectively inhibited macrophages polarize towards M1. Mechanistically, we verified that the regulation of the cytoplasm and mitochondria Ca2+ and ROS dynamic balance was quite important both in vivo and in vitro. Our strategy proved by regulating the inflammatory microenvironment, ROS balance and Ca2+ homeostasis, and the Andr-loaded atrial patch was effective for POAF in the SP rat model. The electrical signal of atrial stromal reentry in the case of this model was successfully mined, and the results of calcium channel were basically consistent with that of electrical signal channel. In addition, we have reported the infiltration and polarization of local inflammatory cells in the atrial of POAF at the tissue section level. Our study served as a new inspiration for the treatment of arrhythmic diseases and other ROS- and Ca2+- associated local illnesses.
研究领域:
心血管医学
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药理学
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生物医学工程
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DOI
PubMed
高影响因子
ENVIRONMENTAL TOXICOLOGY
·
2023
·
IF 4.5
Huiling Guo,Caiying Zhang,Wenjing Pu,Xuesheng Chu,Gang Huang,Ting Cui,Bingyan Huang,Hang Liu,Xueyan Dai
Excess molybdenum (Mo) is harmful to animals, but its nephrotoxicity has not been comprehensively explained. To appraise the influences of excess Mo on Ca homeostasis and apoptosis via PLC/IP 3 /IP 3 R axis, primary duck renal tubular epithelial cells were exposed to 480 μM and 960 μM Mo, and joint of 960 μM Mo and 10 μM 2-APB or 0.125 μM U-73122 for 12 h (U-73122 pretreated for 1 h), respectively. The data revealed that the increment of [Ca 2+ ] c induced by Mo mainly originated from intracellular Ca storage. Mo exposure reduced [Ca 2+ ] ER , elevated [Ca 2+ ] mit , [Ca 2+ ] c , and the expression of Ca homeostasis-related factors (Calpain, CaN, CRT, GRP94, GRP78 and CaMKII). 2-APB could effectively reverse subcellular Ca 2+ redistribution by inhibiting IP 3 R, which confirmed that [Ca 2+ ] c overload induced by Mo originated from ER. Additionally, PLC inhibitor U-73122 remarkably mitigated the change, and dramatically reduced the number of apoptotic cells, the expression of Bak-1, Bax, cleaved-Caspase-3/Caspase-3, and notably increased the expression of Bcl-xL, Bcl-2, and Bcl-2/Bax ratio. Overall, the results confirmed that the Ca 2+ liberation of ER via PLC/IP 3 /IP 3 R axis was the main cause of [Ca 2+ ] c overload, and then stimulated apoptosis in duck renal tubular epithelial cells.
研究领域:
毒理学
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细胞生物学
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肾脏生理学
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产品关联
DOI
PubMed
高影响因子
FISH & SHELLFISH IMMUNOLOGY
·
2023
·
IF 4.7
Lei Diao,Meiqi Ding,Hongzhen Sun,Yawei Xu,Rui Yin,Huijie Chen
Polystyrene microplastics (PM) is a pressing global environmental concern, posing substantial risks to aquatic ecosystems . Microalgal astaxanthin (MA), a heme pigment, safeguards cells against oxidative damage induced by free radicals, which contributes to various health conditions, including aging, inflammation and chronic diseases. Herein, we investigated the potential of MA in ameliorating the immunotoxicity of PM on carp ( Cyprinus carpio L.) based on head kidney lymphocytes treated with PM (250 μM) and/or MA (100 μM). Firstly, CCK8 results showed that PM resulted in excessive death of head kidney lymphocytes. Secondly, head kidney lymphocytes treated with PM had a higher proportion of necroptosis, and the levels of necroptosis-related genes in head kidney lymphocytes were increased. Thirdly, the relative red fluorescence intensity of JC-1 and MitoSox showed decreased mitochondrial membrane potential and increased mtROS in head kidney lymphocytes treated with PM. MitoTracker® Green FM fluorescence analysis revealed enhanced mitochondrial Ca 2+ levels in PM-treated lymphocytes, corroborating the association between PM exposure and elevated intracellular Ca 2+ dynamics. PM exposure resulted in upregulation of calcium homeostasis-related gene (Orail, CAMKIIδ and SLC8A1) in lymphocytes. Subsequent investigations revealed that PM exposure reduced miR-25-5p expression while increasing levels of MCU, MICU1, and MCUR1 . Notably, these effects were counteracted by treatment with MA. Furthermore, PM led to the elevated secretion of inflammatory factors (IFN-γ, IL-1β, IL-2 and TNF-α), thereby inducing immune dysfunction in head kidney lymphocytes. Encouragingly, MA treatment effectively mitigated the immunotoxic effects induced by PM, demonstrating its potential in ameliorating necroptosis, mitochondrial dysfunction and immune impairment via regulating the miR-25-5p/MCU axis in lymphocytes. This study sheds light on safeguarding farmed fish against agrobiological threats posed by PM, highlighting the valuable applications of MA in aquaculture.
研究领域:
环境科学
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水产养殖学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Scientific Reports
·
2025
·Vol. 15
·期 1
·1-16
·
IF 3.9
Feng Wenguang,Wang Haibin,Zhang Guoliang,Gao Wang,LI Hongcang,Liu Haibo,Sun Yanhong
Objective To explore the role and mechanism of transcription factor KLF4 in regulating mitochondrial damage and apoptosis by activating chondrocyte autophagy. Human primary chondrocytes were treated with IL-1β to establish an in vitro osteoarthritis model. KLF4 was overexpressed using lentivirus to intervene in chondrocytes. Cell apoptosis and mitochondrial membrane potential were detected by flow cytometry. Mitochondrial morphology was observed under transmission electron microscopy. Cell ATP level was detected by ELISA. Ca2 + homeostasis was detected by flow cytometry with Fluo-3/AM fluorescence labeling. The expression of autophagy-related proteins Beclin1, P62, and LC3 was detected by WB. The interaction between transcription factor KLF4 and gene p62 promoter was verified by dual luciferase assay. The interaction between p62, Beclin1 and KLF4 was verified by Chip assay. To further explore the relationship between KLF4 and autophagy, KLF4 was overexpressed and treated with autophagy inhibitor 3-MA (5mmol/L). The expression of autophagy-related proteins Beclin1, P62, and LC3 was detected by WB. Cell apoptosis level was detected by flow cytometry. The mitochondrial membrane potential level was detected by flow cytometry. Ca2 + homeostasis was detected by flow cytometry with Fluo-3/AM fluorescence labeling. In chondrocytes treated with IL-1β, TNF-α levels increased significantly, apoptosis rate rose, and ATP generation declined. However, after overexpression of KLF4, apoptosis level decreased significantly; ATP level increased significantly, and mitochondrial structure and function gradually recovered. Flow cytometry detection of mitochondrial membrane potential showed a significant decrease after KLF4 overexpression, and Ca2 + homeostasis was partially restored. WB detection of autophagy-related proteins showed a significant increase in p62 and cellular autophagy levels. Dual luciferase results indicated that transcription factor KLF4 interacted with the promoter of gene p62; Chip experiment results suggested that KLF4 may interact with the promoter regions of P62 and Beclin1. After KLF4 overexpression combined with 3-MA treatment, compared with empty load combined with 3-MA, p62 and LC3 protein expression increased significantly, apoptosis level decreased significantly, and membrane potential level decreased. Transcription factor KLF4 can regulate mitochondrial damage and apoptosis by activating chondrocyte autophagy.
研究领域:
分子生物学
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风湿病学
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细胞生物学
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转化医学
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骨骼疾病
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信号转导
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基因调控
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线粒体功能
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产品关联
DOI
PubMed
高影响因子
CHEMOSPHERE
·
2021
·
IF 7.086
Siyan Che,Sunni Chen,Shiqi Li,Zheng Ruan
Decabromodiphenyl ether (BDE-209) tends to accumulate in lipid-rich tissues and targets the liver since its high lipophilicity. This study aimed to investigate the effects of BDE-209 on mouse liver and reveal the underlying toxicological mechanisms. Here we firstly confirmed that treatment of BDE-209 could lead to an imbalance of redox and promote apoptosis with a mitochondria-dependent manner in mice livers. Next, the transmission electron microscope (TEM) image revealed BDE-209 induced changes in mitochondrial morphology and increased endoplasmic reticulum (ER) - mitochondrial contact. ER stress was involved in the apoptosis process, which was displayed by the enhancive ER stress makers . Finally, from the increased abundance of cellular pivotal Ca 2+ signals transducer CaM, activating Ca 2+ release channel Sig-1R and IP3R1, and the stronger fluorescence density of mitochondria-specifically Ca 2+ labeled probe Rhod-2 in vitro , we summarized that there was overloaded mitochondrial Ca 2+ in hepatocytes of BDE-209 treated mice. In conclusion, these results partly illustrated evidence to reveal a potential mechanism of BDE-209-induced hepatoxicity, where oxidative stress-induced-ER stress led to the over-release of Ca 2+ , followed by the overloaded mitochondrial Ca 2+ , and cell apoptosis initiated. Our findings provided a theoretical basis for further studying.
研究领域:
毒理学
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细胞生物学
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肝病学
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产品关联
DOI
PubMed
高影响因子
TOXICOLOGY LETTERS
·
2018
·
IF 3.166
Lin Li,Jiahui Cui,Zi Liu,Xuejiao Zhou,Zengqiang Li,Yang Yu,Yuanyuan Jia,Daiying Zuo,Yingliang Wu
Silver nanoparticles (AgNPs) have many medical and commercial applications, but their effects on human health are poorly understood. The aim of this study was to assess the effect of AgNPs on the human neuroblastoma cell line SH-SY5Y and to explore their potential mechanisms of action. We found that AgNPs decreased SH-SY5Y cell viability in a dose- and time-dependent manner. Exposure to AgNPs activated endoplasmic reticulum (ER) stress, as reflected by upregulated expression of glucose-regulated protein 78 (GRP78), phosphorylated PKR-like endoplasmic reticulum kinase (p-PERK), phosphorylated eukaryotic translation initiation factor 2α (p-eIF2α), C/EBP homology protein (CHOP), spliced X-box binding protein-1 (XBP1), and phosphorylated inositol-requiring enzyme (p-IRE), all of which are involved in the cellular unfolded protein response. Prolonged exposure of cells to AgNPs damaged calcium (Ca 2+ ) homeostasis, increased the length of contact sites between the ER and mitochondria, altered IP 3 R function by the increased levels of phosphatase and tensin homolog deleted on chromosome ten (PTEN) in the ER and enhanced mitochondrial Ca 2+ uptake. Finally, Ca 2+ overload and disrupted homeostasis in the mitochondria triggered apoptotic cell death. Our results suggest that caution should be exercised in the use of AgNPs in humans.
研究领域:
纳米技术
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细胞生物学
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毒理学
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神经科学
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产品关联
DOI
PubMed
高影响因子
MARINE POLLUTION BULLETIN
·
2025
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IF 4.9
Yuyao Jiang,Yujia Yan,Yanru Guan,Jason T. Magnuson,Zijie Ding,Qingqing Ke,Aoxue Wang,Kun Qiao,Shuying Li,Wenjun Gui,Daniel Schlenk
The pervasive presence of pentachlorophenol (PCP) in aquatic-benthic ecosystems poses a threat to organisms. However, the toxicological mechanisms of PCP in benthic organisms are limited. In this study, Tegillarca granosa , a representative bivalve species, was treated with environmentally relevant concentrations of PCP (1, 10, and 100 μg/kg) and positive control for 28 days via sediment exposure to investigate bioaccumulation potential, metabolomic profiles, and histopathology. The biota-sediment bioaccumulation factor for PCP was 9.1. Given the capability of PCP to act as an uncoupler of oxidative phosphorylation, studies were performed to determine key events in the adverse outcome pathway associated with this molecular initiating event. Metabolic profiles indicated a disruption in lipid metabolism, as well as imbalances in the quantity of calcium, which was associated with the synthesis of reactive oxygen species (ROS). A reduction in adenosine-5′-triphosphate (ATP) levels were seen in clams treated with PCP and in animals treated with carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone (FCCP), which served as a positive control. When clams were co-exposed to 100 μg/kg PCP and 500 μg/kg ATP, PCP toxicity was diminished and levels of mitochondrial calcium, as well as ROS, were reduced. These results suggest that mitochondrial impairment is a key event in the toxic mechanism of PCP to T. granosa .
研究领域:
环境毒理学
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海洋生物学
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代谢组学
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生态毒理学
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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 Environmental Sciences
·
2023
·
IF 6.9
Hongge Li,Jingcai Liu,Weihua Nong,Mengying Shen,Sheng Dou,Shaochen Sun,Junli Wang
Aluminum (Al) can lead to an exposure of creature in varieties ways for its universality, and it could disturb normal physiological metabolism, with the damage to multisystem including reproduction. Since the oocyte quality is critical for female reproduction, we inspected the toxicity of Al on mouse oocyte maturation. We constructed in vitro exposure mouse model, and we found that 5 mmol/L Al had adverse effects on oocyte maturation by impairing organelle and cytoskeleton. Aberrant spindle and misaligned chromosomes which might be considered to be caused by elevated levels of acetylation , as well as abnormal distribution of actin dynamics could hinder normal meiosis of oocytes. Organelle dysfunction indicated that Al affected proteins synthesis , transport and digestion, which would further damage oocyte maturation. In order to explore the mechanism of Al toxicity, our further investigation demonstrated that Al caused mitochondrial dysfunction and imbalance calcium homeostasis , resulting in limited energy supply. Moreover, high level of reactive oxygen species , DNA damage and apoptosis caused by oxidative stress were also the manifestation of Al toxicity on oocytes. In conclusion, our study provided the evidence that Al exposure affected oocyte quality through its effects on spindle organization, actin dynamics, organelle function and the induction of DNA damage-related apoptosis with mouse model.
研究领域:
生殖生物学
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毒理学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2024
·
IF 6.2
Guoqing Li,Caiyun Sun,Le Zhu,Yan Zeng,Jinquan Li,Yufei Mei
Cadmium (Cd) is a neurotoxicant that gradually accumulates in the human body with age. High Cd burden is correlated with adult hippocampal neurogenesis (AHN) and memory deficits in mammals. However, little knowledge is known about the mechanism by which Cd exposure impairs neurogenesis and cognition. Here, we investigated the roles of store-operated calcium entry (SOCE)-mediated calcium dyshomeostasis in Cd-induced AHN and memory deficits as well as therapeutic potential for the prevention of Cd-induced neurotoxicity. To achieve this goal, 8 weeks-old C57BL/6 J mice were subjected to different concentrations of cadmium chloride (0, 5, 10, 20 ppm) in drinking water for 8 weeks, we then examined the AHN, calcium homeostasis, SOCE channel and memory in Cd-exposed mice by using immunohistochemistry, calcium imaging, Y-maze and fear conditioning test. Our results indicated that chronic Cd exposure markedly increased Cd levels in serum and cerebrospinal fluid by almost 10-fold, and inhibited the proliferation and differentiation of hippocampal adult neural stem cells in a dose-dependent manner. Additionally, Cd exposure impaired the maturation of hippocampal neural stem cells without inducing gliosis. Transcriptome analysis revealed that Cd exposure inhibited the proliferation of neuroblastoma via alteration of calcium signaling pathway, and attenuated SOCE channels played a pivotal role in mediating Cd-induced cytoplasmic calcium overload and depletion of endoplasmic reticulum calcium stores. Activation of SOCE by hyperforin, a natural derivative from medicinal plant, restored intracellular calcium homeostasis and improved AHN and memory in Cd-exposed mice. Together, this study provided novel insights into the mechanism that Cd exposure impaired AHN and memory by prompting neuronal SOCE-mediated calcium dyshomeostasis, and offered a new therapeutic approach for prevention of Cd-induced neurotoxicity.
研究领域:
神经科学
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药理学
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毒理学
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DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2023
·
IF 8
Xiao Lei,Guodong Tan,Yiming Wang,Li Chen,Yuan Cao,Bingxin Si,Zhen Zhen,Bei Li,Yan Jin,Wei Wang,Fang Jin
Introduction Osteoarthritis (OA) is a chronic degenerative joint disease accompanied by an elevated macrophage proinflammatory phenotype, which is triggered by persistent pathologically elevated calcium ion levels in mitochondria. However, existing pharmacological compounds targeting the inhibition of mitochondrial calcium ion (m[Ca2+]) influx are currently limited in terms of plasma membrane permeability and low specificity for ion channels and transporters. In the present study, we synthesized mesoporous silica nanoparticle-amidated (MSN)-ethylenebis (oxyethylenenitrilo)tetraacetic acid (EGTA)/triphenylphosphine (TPP)-polyethylene glycol (PEG) [METP] nanoparticles (NPs), which specifically target mitochondria and block excess calcium ion influx.Methods m[Ca2+] overload in OA mouse bone marrow-derived macrophages (BMDMs) was detected by a fluorescence probe. A tissue in situ fluorescence colocalization assay was used to evaluate METP NP uptake by macrophages. BMDMs from healthy mice were pretreated with a concentration gradient of METP NPs followed by lipopolysaccharide (LPS) stimulation and detection of m[Ca2+] levels in vitro. The optimal METP NP concentration was further applied, and the endoplasmic reticulum (ER) and cytoplasm calcium levels were detected. The inflammatory phenotype was measured by surface markers, cytokine secretion and intracellular inflammatory gene/protein expression. A Seahorse cell energy metabolism assay was performed to elucidate the mechanism by which METP NPs reverse the BMDM proinflammatory phenotype.Results The present study identified calcium overload in BMDM mitochondria of OA mice. We demonstrated that METP NPs reversed the increased m[Ca2+] levels in mitochondria and the proinflammatory phenotype of BMDMs, with both in vivo and in vitro experiments, via the inhibition of the mitochondrial aspartate-arginosuccinate shunt and ROS production.Conclusion We demonstrated that METP NPs are effective and highly specific regulators of m[Ca2+] overload. In addition, we demonstrated that these METP NPs reverse the macrophage proinflammatory phenotype by restoring m[Ca2+] homeostasis, thereby inhibiting the tissue inflammatory response and achieving a therapeutic effect for OA.
研究领域:
药理学
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纳米技术
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免疫学
·
骨科
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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