MOLECULAR AND CELLULAR ENDOCRINOLOGY
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2026
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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
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2024
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IF 5.7
Quanwei Li,Pan Guo,Shaofeng Wang,Luna Su,Wenlan Yu,Jianying Guo,Liammei Hu,Hui Zhang,Jiaqiang Pan,Zhaoxin Tang,Jianzhao Liao
As an efficient alternative copper (Cu) source, copper nanoparticles (nano-Cu) have been widely supplemented into animal-producing food. Therefore, it is necessary to assess the effect of nano-Cu exposure on the biological health risk. Recently, the toxic effects of nano-Cu have been confirmed but the underlying mechanism remains unclear. This study reveals the impact of nano-Cu on endoplasmic reticulum autophagy (ER-phagy) in chicken hepatocytes and further identifies Drp1 and its downstream gene FAM134B as crucial regulators of nano-Cu-induced hepatotoxicity. Nano-Cu exposure can induce Cu ion overaccumulation and pathological injury in the liver, trigger excessive mitochondrial fission and mitochondria-associated membrane (MAM) integrity damage, and activate ER-phagy in vivo and in vitro. Interestingly, the knockdown of Drp1 markedly decreases the expression of FAM134B induced by nano-Cu. Furthermore, the expression levels of ATL3, CCPG1, SEC62, TEX264, and LC3II/LC3I induced by nano-Cu exposure are decreased by inhibiting the expression of Drp1. Simultaneously, the inhibition of FAM134B effectively alleviates nano-Cu-induced ER-phagy by downregulating the expression of ATL3, CCPG1, SEC62, TEX264, and LC3II/LC3I. Overall, these results suggest that Drp1-mediated impairment of MAM integrity leads to ER-phagy as a novel molecular mechanism involved in the regulation of nano-Cu-induced hepatotoxicity. These findings provide new ideas for future research on the mechanism of nano-Cu-induced hepatotoxicity.
研究领域:
毒理学
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细胞生物学
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分子生物学
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兽医学
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PubMed
高影响因子
TOXICOLOGY
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2024
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IF 4.8
Junke Wang,Yuexin Wei,Yuhao Wu,Tianxin Zhao,Lian Kang,Lindong Han,Jiadong Chen,Chunlan Long,Guanghui Wei,Lianju Shen,Shengde Wu
As one of the most prevalent environmental endocrine disruptors, di-(2-ethylhexyl) phthalate (DEHP) is known for its significant developmental toxicity to the male reproductive system in humans and mice. Prepubertal exposure to DEHP has been shown to cause testicular damage, but the underlying mechanisms require further investigation. To investigate this effect, prepubertal mice were exposed to 250 or 500 mg/kg body weight (bw) of DEHP for 14 days, which resulted in impaired histological structure and increased apoptosis of the testes. RNA sequencing (RNA-seq) of testicular tissue suggested that DEHP led to injury in Leydig and Sertoli cells. To further elucidate these mechanisms, we conducted experiments using immature mouse Leydig (TM3) and Sertoli (TM4) cells, and exposed them to 200 μM mono-(2-ethylhexyl) phthalate (MEHP), the primary metabolite of DEHP, for 24 h. We found that MEHP exposure induced oxidative stress injury and promoted cell apoptosis, and that cotreatment with N-acetylcysteine partially reversed these injuries. Given the close association between oxidative stress and mitochondrial calcium levels, we demonstrated that MEHP exposure disrupted mitochondria and increased mitochondrial calcium levels. This effect facilitated the formation of mitochondria-associated endoplasmic reticulum membranes (MAMs), upregulated protein expression and enhanced the interactions of the IP3R3-Grp75-VDAC1 complex. Furthermore, inhibition of calcium transfer in the IP3R3-Grp75-VDAC1-MCU axis relieved MEHP-induced mitochondrial injury, oxidative stress and apoptosis in TM3 and TM4 cells. This study highlights the importance of MAM-mediated mitochondrial calcium overload and the subsequent apoptosis of Leydig and Sertoli cells as pivotal factors contributing to testicular injury induced by prepubertal exposure to DEHP.
研究领域:
环境科学
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毒理学
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生殖生物学
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细胞生物学
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内分泌学
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PubMed
高影响因子
Food & Function
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2021
·Vol. 12
·期 21
·10741-10749
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IF 5.396
Yi Zhao,Jia-Gen Cui,Hao Zhang,Xue-Nan Li,Mu-Zi Li,Milton Talukder,Jin-Long Li
Di (2-ethylhexyl) phthalate (DEHP) is a hazardous compound used as a plasticizer in plastic products. As a natural carotenoid, lycopene (LYC) is considered an effective protective agent against various types of organ damage. The present study aimed to investigate the role of mitochondria-endoplasmic reticulum (ER) coupling in LYC preventing DEHP-induced hepatotoxicity. The mice were treated with LYC (5 mg kg−1) and/or DEHP (500 or 1000 mg kg−1). In the present study, LYC prevented DEHP-induced histopathological changes including fibrosis and glycogen storage in the liver. Additionally, LYC alleviated DEHP-induced ultrastructural injury of mitochondria and ER. LYC had the underlying preventability against DEHP-induced mitochondrial dynamics imbalance including an increase in fission and a decrease in fusion. Furthermore, DEHP induced mitochondria-associated endoplasmic reticulum membrane (MAM) disorder-induced ER stress through the ER unfolded protein response (UPRER), but LYC alleviated these alterations. Therefore, LYC prevented DEHP-induced hepatic mitochondrial dynamics and MAM disorder, leading to ER stress. The present study provides novel evidence of mitochondria-ER coupling as a target for LYC that prevents DEHP-induced hepatotoxicity.
研究领域:
毒理学
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药理学
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细胞生物学
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PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2024
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IF 5.7
Yi Zhao,Yuan-Hang Chang,Hao-Ran Ren,Ming Lou,Fu-Wei Jiang,Jia-Xin Wang,Ming-Shan Chen,Shuo Liu,Yu-Sheng Shi,Hong-Mei Zhu,Jin-Long Li
Di-(2-ethylhexyl) phthalate (DEHP), as the most common phthalate, has been extensively used as a plasticizer to improve the plasticity of agricultural products, which pose severe harm to human health. Mitochondrial dynamics and endoplasmic reticulum (ER) homeostasis are indispensable for maintaining mitochondria-associated ER membrane (MAM) integrity. In this study, we aimed to explore the effect of DEHP on the nervous system and its association with the ER–mitochondria interaction. Here, we showed that DEHP caused morphological changes, motor deficits, cognitive impairments, and blood–brain barrier disruption in the brain. DEHP triggered ER stress, which is mainly mediated by protein kinase R-like endoplasmic reticulum kinase (PERK) signaling. Moreover, DEHP-induced mitofusin-2 (Mfn2) downregulation results in imbalance of the mitochondrial dynamics. Interestingly, DEHP exposure impaired MAMs by inhibiting the Mfn2-PERK interaction. Above all, this study elucidates the disruption of the Mfn2-PERK axis-mediated ER–mitochondria interaction as a phthalate-induced neurotoxicity that could be potentially developed as a novel therapy for neurological diseases.
研究领域:
神经科学
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毒理学
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细胞生物学
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药理学
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PubMed
高影响因子
EUROPEAN POLYMER JOURNAL
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2023
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IF 6
Haojie Qian,Xiaowen Xu
Fluorescent hydrogels with fluorescent dyes are widely used for anti-counterfeiting encryption. However, developing highly stretchable and remarkable tear-resistant hydrogels with reusable fluorescence for anti-counterfeiting purposes remains challenging. In this study, we fabricated and characterized double network (DN) hydrogels comprising polyvinyl alcohol-borax (PVA-borax) as the first network and poly(methacrylamide- co -polyethylene glycol- co -pyrenylmethyl acrylate) (P(MAM- co -PEGMA- co -PyMA)) as the second network with varying MAM to PEGMA ratios. SEM images showed the hydrogels had 3D porous structures. FT-IR and thermal properties analysis (DSC and TGA) indicated the presence of hydrogen bonds between PVA-borax and P(MAM- co -PEGMA- co -PyMA) without any chemical bonds. The red shift in characteristic absorption bands at 841 and 710 cm −1 further confirmed the presence of π-π* interactions between pyrene moieties. XRD analysis revealed no significant changes in crystalline phase of the hydrogels, which facilitated the formation of a 3D network due to abundant hydrogen bond presence. When the MAM to PEGMA ratio was adjusted to 9:2, the resulting hydrogels exhibited remarkable properties such as ultra-high stretchability (strain over 3300 %), excellent notch-insensitivity, and exceptional tear resistance (tearing energy over 3.25 × 10 5 J/m 2 ). Importantly, the hydrogel's fluorescence intensity could be reversibly changed by alternatively adding Fe 3+ and EDTA-2Na. It could be reused more than 10 times while maintaining a fluorescence intensity of around 80 %, demonstrating its reliability as a versatile hydrogel probe for Fe 3+ detection with “ON-OFF-ON” fluorescence behavior. Furthermore, the hydrogels demonstrated exceptional 2D encryption and decryption capabilities, highlighting their potential applications in information storage and data security. To improve the level of anti-counterfeiting, multiple encryption approaches such as QR codes and ASCII binary codes were rationally designed. Overall, this study successfully developed a universal DN hydrogel platform with ultra-high stretchability and remarkable tear resistance, capable of rapid encoding and decoding of complex information for smart anti-counterfeiting.
研究领域:
材料科学
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化学
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纳米技术
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防伪技术
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高影响因子
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