ENVIRONMENTAL TOXICOLOGY
·
2022
·Vol. 37
·期 11
·2660-2672
·
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
Stem Cells International
·
2021
·
IF 5.443
Xiaoyao Huang,Zihan Li,Peisheng Liu,Meiling Wu,An-qi Liu,Chenghu Hu,Xuemei Liu,Hao Guo,Xiaoxue Yang,Xiaohe Guo,Bei Li,Xiaoning He,Kun Xuan,Yan Jin
Early orthodontic correction of skeletal malocclusion takes advantage of mechanical force to stimulate unclosed suture remodeling and to promote bone reconstruction; however, the underlying mechanisms remain largely unclear. Gli1+ cells in maxillofacial sutures have been shown to participate in maxillofacial bone development and damage repair. Nevertheless, it remains to be investigated whether these cells participate in mechanical force-induced bone remodeling during orthodontic treatment of skeletal malocclusion. In this study, rapid maxillary expansion (RME) mouse models and mechanical stretch loading cell models were established using two types of transgenic mice which are able to label Gli1+ cells, and we found that Gli1+ cells participated in mechanical force-induced osteogenesis both in vivo and in vitro. Besides, we found mechanical force-induced osteogenesis through inositol 1,4,5-trisphosphate receptor (IP3R), and we observed for the first time that inhibition of Gli1 suppressed an increase in mechanical force-induced IP3R overexpression, suggesting that Gli1+ cells participate in mechanical force-induced osteogenesis through IP3R. Taken together, this study is the first to demonstrate that Gli1+ cells in maxillofacial sutures are involved in mechanical force-induced bone formation through IP3R during orthodontic treatment of skeletal malocclusion. Furthermore, our results provide novel insights regarding the mechanism of orthodontic treatments of skeletal malocclusion.
研究领域:
正畸学
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细胞生物学
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力学生物学
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发育生物学
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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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PubMed
高影响因子
Scientific Reports
·
2023
·Vol. 13
·期 1
·1-13
·
IF 4.6
Xu Rui-Qi,Ma Ling,Chen Timson,Zhang Wei-Xiong,Chang Kuan,Wang Jing
Biosurfactants are attracting much interest due to their potential application as therapeutic agents in the medical and cosmetic field. Previous studies have demonstrated that biosurfactant such as sophorolipid (SL) exhibits immunomodulatory effects. In this article, we found the potential of sophorolipid for inhibiting histamine-induced itch and preliminarily explored its molecular basis. First, behavioral tests indicated that SL can remit the histamine-induced scratching behaviors of mice. Second, SL can suppress the the calcium influx induced by histamine, HTMT and VUF8430 in HaCaT cells. RT-PCR analysis showed that the histamine-induced upregulation of mRNA levels of phospholipase Cγ1, 1,4,5-trisphosphate receptor (IP3R), and protein kinase Cα can be inhibted by SL, suggesting that SL may impede the PLC/IP3R signaling pathway activated by histamine. In further tests, the capsaicin-induced calcium influx can also be inhibited by SL. The immunofluorescence and molecular docking analysis indicated that SL acts as an inhibitor of transient receptor potential vanilloid-1 (TRPV1) activation to decrease calcium influx against stimuli. In summary, these results revealed that SL may inhibit histamine-induced itch by decreasing PLC/IP3R signaling pathway activation and modulating TRPV1 activity. This paper indicates that SL can be a useful treatment for histamine-dependent itch.
研究领域:
药理学
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皮肤病学
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分子生物学
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治疗学
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DOI
PubMed
高影响因子
Journal of Environmental Sciences
·
2024
·
IF 5.9
Feixue Liu,Tianmeng Zhang,Yeyun Ma,Jingquan Dong,Yong Sun
Environmental residues of the fungicide difenoconazole (DFZ) have been shown to pose a threat to mammals. However, the risk assessment of DFZ for cultured carp remains unclear. The aim of this study was to investigate the adverse effects of DFZ on carp liver and their molecular mechanisms by simulating the environmental contamination concentrations of DFZ. Our results showed that DFZ induced structural damage in the liver, including edema, vacuolation, and congestion. In addition, DFZ residues were detected in liver tissues. Mechanistically, DFZ causes mitochondrial dysfunction by promoting Ca 2+ transfer from the endoplasmic reticulum (ER) to mitochondria via IP3R, leading to the onset of ROS burst and apoptosis, and the inhibition of Nrf2 antioxidant function by DFZ also results in uncontrolled ROS. Mitophagy was also activated intracellularly to counteract mitochondrial damage. Interestingly, treatment with 2-APB alleviated mitochondrial dysfunction, restored the mitochondrial membrane potential, and inhibited apoptosis by blocking the translocation of Ca 2+ from the ER to the mitochondria. Metabolomic analysis revealed that DFZ disrupted energy metabolism in carp liver, whereas 2-APB reversed DFZ-induced metabolic alterations. In conclusion, the present study elucidates the threat of DFZ to carp liver and highlights the mechanism of damage, thereby helping to explain the impact of agriculture on the aquatic environment.
研究领域:
环境科学
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毒理学
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水生生物学
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分子生物学
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DOI
PubMed
高影响因子
MOLECULAR AND CELLULAR ENDOCRINOLOGY
·
2026
·
IF 3.4
Haihui Yang,Jinming zhu,Guifang Li,Ranran Li,Ankang Peng,Hang Zhang
IP3R expression is markedly upregulated in angiotensin II-induced cardiomyocyte injury. • IP3R knockdown attenuates MAM-mediated mitochondrial Ca 2+ overload and dysfunction. • IP3R drives ER-mitochondria Ca 2+ transfer by enhancing MAM formation. • Targeting IP3R may represent a novel therapeutic strategy for heart failure. Background Heart failure (HF) is the terminal stage of various cardiovascular diseases. Mitochondrial Ca 2+ overload and dysfunction mediated by mitochondria-associated ER membranes (MAMs) are recognized contributors to HF pathogenesis; however, the underlying molecular mechanisms remain incompletely understood. Methods An in vitro model of cardiomyocyte injury was established using angiotensin II (Ang II)-stimulated H9c2 cells. IP3R was knocked down using specific siRNA. Cell viability (CCK-8), apoptosis (Annexin V/TUNEL), and hypertrophy (phalloidin staining) were assessed. IP3R expression and mitochondrial complex subunits were analyzed by western blotting. MAM formation was examined by transmission electron microscopy and immunofluorescence co-localization. Mitochondrial function was evaluated by measuring ATP levels, ROS (MitoSOX), mitochondrial membrane potential (TMRM), and Ca 2+ uptake (Rhod-2). Results Ang II stimulation reduced cell viability, induced hypertrophy and apoptosis, and promoted MAM formation. Mechanistically, Ang II upregulated IP3R expression and enhanced MAM-mediated mitochondrial Ca 2+ overload, leading to decreased mitochondrial membrane potential, elevated ROS, and reduced ATP production. Notably, genetic knockdown of IP3R attenuated these pathological changes, reducing MAM formation and mitochondrial Ca 2+ overload while restoring mitochondrial function and cell viability. Conclusion Our findings suggest that IP3R may exacerbate cardiomyocyte injury by facilitating MAM-mediated Ca 2+ transfer and mitochondrial dysfunction, indicating that targeting IP3R could represent a potential therapeutic strategy for HF. However, the upstream mechanisms of IP3R upregulation and the causal role of mitochondrial Ca 2+ uptake require further investigation.
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高影响因子
TOXICOLOGY
·
2026
·
IF 5.2
Haitao Yang,Liqing Wu,Shuyan Niu,Menghao Guo,Chenyu Liu,Tianshu Wu,Mengjing Cui,Yuying Xue
The widespread use of plastic products has elevated nanoplastics (NPs) pollution to a critical global concern, with polystyrene nanoplastics (PS-NPs) and cadmium (Cd) emerging as common environmental contaminants whose co-occurrence and combined toxicity increasingly alarm the scientific community. The intestine, as the main xenobiotic exposure site, is a primary target for PS-NPs and Cd exposure-individually or combined. While PS-NPs and Cd’s individual intestinal toxicity mechanisms are well-studied, their combined effects remain poorly understood, especially at the molecular level. This study investigated the combined effects of environmentally relevant concentrations of PS-NPs and Cd on intestinal apoptosis and the regulatory role involving the IP3R/Ca 2+ /STAT3 pathway using both C. elegans and Caco-2 cell models. In C. elegans , 72-hour PS-NPs (10 μg/L) and Cd (5 μg/L) co-exposure induced developmental retardation, intestinal structural abnormalities, and dysregulated expression of apoptosis-related genes along with key components of the IP3R/Ca 2+ /STAT3 pathway. Parallel experiments in Caco-2 cells demonstrated that 24-hour co-treatment with PS-NPs (20 μg/mL) and Cd (0.25 μg/mL) significantly elevated apoptosis rates and triggered endoplasmic reticulum stress. Molecular analyses revealed these effects were mediated through increased IP3R phosphorylation, elevated cytosolic Ca 2+ concentrations, and enhanced phosphorylation of the downstream effector STAT3. Notably, pharmacological inhibition of IP3R (2-APB, 10 μM), Ca²⁺ chelation (BAPTA, 10 μM), or STAT3 phosphorylation (stattic, 5 μM) significantly attenuated PS-NPs and Cd-induced apoptosis. These results establish the IP3R/Ca²⁺/STAT3 axis as a pivotal regulatory switch governing intestinal apoptosis under NP-heavy metal co-exposure, providing mechanistic foundations for environmental risk assessment of combined pollutant exposure.
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高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2023
·
IF 5.8
Xu Yao,Jie Zhu,Lin Li,Bo Yang,Bixia Chen,Endong Bao,Xiaohui Zhang
Severe heat stress can cause human and animal heart failure and sudden death, which is an important issue of public health worldwide. Our previous studies in animals showed that myocardial cells injury was critical in the above process, and Hsp90 induction has a definite anti-myocardial injury effect, especially through aspirin (ASA). But the mechanism has not been fully clarified. In this study, an in vitro heat stress model of chicken primary myocardial cells (CPMCs) most sensitive to heat stress was used to explore the cell injuries and corresponding molecular resistance mechanism. We found that heat stress resulted in serious oxidation stress and calcium overload in mitochondria, which destroyed the mitochondrial structure and function and then triggered the cell death mechanism of CPMCs. Hsp90 was proven to be a central regulator for resisting heat-stress injury in CPMCs mitochondria using its inhibitor and inducer (geldanamycin and ASA), respectively. The mechanism involved that Hsp90 could activate Akt and PKM2 signals to promote Bcl-2 translocation into mitochondria and its phosphorylation, thereby preventing ROS production and subsequent cell apoptosis . In addition, Hsp90 inhibited mitochondrial calcium overload to overcome MPTP opening and MMP suppression through the inhibitory effect of Raf-1-ERK activation on the CREB-IP3R pathway. This study is the first to reveal a pivotal reason for heat-stressed damage in chicken myocardial cells at subcellular level and identify an effective regulator, Hsp90, and its protective mechanisms responsible for maintaining mitochondrial homeostasis.
研究领域:
细胞生物学
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分子生物学
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心脏病学
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应激生物学
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PubMed
高影响因子
SHOCK
·
2023
·Vol. 60
·期 5
·713
·
IF 3.1
Zhao Jinghong,Hu Jilin,Zhang Rongyi,Deng Jianping
Hypertension seems to inevitably cause cardiac remodeling, increasing the mortality of patients. This study aimed to explore the molecular mechanism of CCAAT/enhancer-binding protein delta (CEBPD)–mediated oxidative stress and inflammation in hypertensive cardiac remodeling. The hypertensive murine model was established through angiotensin-II injection, and hypertensive mice underwent overexpressed CEBPD vector injection, cardiac function evaluation, and observation of histological changes. The cell model was established by angiotensin-II treatment and transfected with overexpressed CEBPD vector. Cell viability and surface area and oxidative stress (reactive oxygen species/superoxide dismutase/lactate dehydrogenase/malondialdehyde) were assessed, and inflammatory factors (TNF-α/IL-1β/IL-6/IL-10) were determined both in vivo and in vitro . The levels of CEBPD, miR-96-5p, inositol 1,4,5-trisphosphate receptor 1 (IP3R), natriuretic peptide B, and natriuretic peptide A, collagen I, and collagen III in tissues and cells were determined. The binding relationships of CEBPD/miR-96-5p/IP3R 3′ untranslated region were validated. CEBPD was reduced in cardiac tissue of hypertensive mice, and CEBPD upregulation improved cardiac function and attenuated fibrosis and hypertrophy, along with reductions of reactive oxygen species/lactate dehydrogenase/malondialdehyde/TNF-α/IL-1β/IL-6 and increases in superoxide dismutase/IL-10. CEBPD enriched on the miR-96-5p promoter to promote miR-96-5p expression, whereas CEBPD and miR-96-5p negatively regulated IP3R. miR-96-5p silencing/IP3R overexpression reversed the alleviative role of CEBPD overexpression in hypertensive mice. In summary, CEBPD promoted miR-96-5p to negatively regulate IP3R expression to inhibit oxidative stress and inflammation, thereby alleviating hypertensive cardiac remodeling.
研究领域:
心脏病学
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分子生物学
·
药理学
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PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2024
·
IF 6.9
Zefeng Jiang,Xiaowei Wen,Qin Mao,Gang Wang,Zhuo Wang,Yu Yan,Shan Gao,Xiaoqian Sun,Miao Zhang,Jiajing Liu,Rong Zhang,Baofeng Yang
Myocardial infarction (MI) is a leading cause of morbidity and mortality worldwide, and endoplasmic reticulum stress (ERS) and mitochondrial Ca 2+ overload have been involved in apoptotic cardiomyocyte death during MI. 13-Methylpalmatine (13-Me-PLT) is a natural isoquinoline alkaloid isolated from Coptis chinensis and has not been systematically studied for their potential pharmacological effects in cardiovascular diseases. We conducted the present study to elucidate whether 13-Me-PLT modulates MI pathology in animal MI and cellular hypoxic models, employing state-of-the-art molecular techniques. The results demonstrated that 13-Me-PLT preserved post-ischemic cardiac function and alleviated cardiomyocyte apoptosis. 13-Me-PLT decreased ERS and the communication between ER and mitochondria, which serves as a protective mechanism against mitochondrial Ca 2+ overload and structural and functional injuries to mitochondria. Our data revealed mitigating mitochondrial Ca 2+ overload and apoptosis by inhibiting CHOP-mediated Ca 2+ transfer between inositol 1,4,5-trisphosphate receptor (IP 3 R) in ER and VDAC1 in mitochondria as an underlying mechanism for 13-Me-PLT action. Furthermore, 13-Me-PLT produced superior effects in alleviating cardiac dysfunction and apoptosis post-MI to diltiazem and palmatine. Collectively, our research suggests that the CHOP/IP 3 R/VDAC1 signaling pathway mediates ER-mitochondrial Ca 2+ transfer and 13-Me-PLT activates this axis to maintain cellular and organellar Ca 2+ homeostasis, protecting against ischemic myocardial injury. These findings may offer an opportunity to develop new agents for the therapy of ischemic heart disease.
研究领域:
药理学
·
心脏病学
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分子生物学
·
细胞生物学
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DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
·
2021
·Vol. 35
·期 6
·3181-3193
·
IF 5.882
Rui Liu,Shiling Hu,Yuanyuan Ding,Jue Wang,Yuejin Wang,Jiapan Gao,Langchong He
Anaphylactoid reactions are potentially fatal allergic diseases caused by mast cells (MCs), which release histamine and lipid mediators under certain stimuli. Therefore, there is an urgent need to develop new drug candidates to treat anaphylactoid reactions. The MrgX2 receptor mediates anaphylactoid reactions that cause inflammatory diseases. Cortex dictamni is a Chinese herb used for treating allergy-related diseases; however, its active compound is still unknown and its mechanism of action has not yet been reported. The aim of this study was to screen the anti-anaphylactoid compound from C . dictamni extracts. An MrgX2/CMC-HPLC method was established for screening MrgX2-specific compounds retained from the alcohol extract of C . dictamni . A mouse model of hindpaw extravasation was used to evaluate the anti-anaphylactoid effect of this ingredient. Intracellular Ca 2+ mobilization was assessed using a calcium imaging assay. Enzyme immunoassays were performed to measure cytokine and chemokine release levels. The molecular signaling pathways were explored by western blotting. As a result, dictamnine was identified as an effective compound using the MrgX2/CMC method, which remarkably suppressed MC intracellular Ca 2+ mobilization and the release of de novo degranulated substances, and inhibited PKC-PLCγ-IP3R-associated protein signaling molecules. Hence, dictamnine is a novel therapeutic candidate for anaphylactoid reactions via MrgX2.
研究领域:
药理学
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免疫学
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中药学
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分子生物学
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PubMed
高影响因子
BIOMATERIALS
·
2023
·
IF 14
Fengying Shao,Jianyu Han,Zhaoyan Tian,Zhi Wang,Songqin Liu,Yafeng Wu
Taking advantage of endogenous Ca 2+ to upregulate intramitochondrial Ca 2+ level has become a powerful mean for mitochondrial dysfunction-mediated tumor therapy. However, the Ca 2+ entered into mitochondria is limited ascribing to the uncontrollability and non-selectivity of endogenous Ca 2+ transport. It remains a great challenge to make the maximum use of endogenous Ca 2+ to ensure sufficient Ca 2+ overloading in mitochondria. Herein, we smartly fabricate an intracellular Ca 2+ directional transport channel to selectively transport endogenous Ca 2+ from endoplasmic reticulum (ER) to mitochondria based on cascade release nanoplatform ABT-199@liposomes/doxorubicin@Fe III -tannic acid (ABT@Lip/DOX@Fe-TA). In tumor acidic microenvironment , Fe 3+ ions are firstly released and reduced by tannic acid (TA) to Fe 2+ for ROS generation. Subsequently, under the NIR light irradiation, the released ABT-199 molecules combine with ROS contribute to the formation of IP3R-Grp75-VDAC1 channel between ER and mitochondria, thus Ca 2+ ions are directionally delivered and intramitochondrial Ca 2+ level is significantly upregulated. The synergetic ROS generation and mitochondrial Ca 2+ overloading effectively intensifies mitochondrial dysfunction, thereby achieving efficient tumor inhibition. This work presents a new insight and promising avenue for endogenous Ca 2+ -involved tumor therapies.
研究领域:
肿瘤学
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药学
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生物医学工程
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PubMed
高影响因子
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