Osthole induced apoptosis in human normal liver cells by regulating cell proliferation and endoplasmic reticulum stress

Shen, Zhelun; Chen, Jie; Hong, Lü

doi:10.1002/tox.22743

Cited by 6 publications

(5 citation statements)

References 21 publications

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“…ER stress is mediated by three transmembrane proteins: PERK, inositol‐requiring enzyme 1 (IRE1), and ATF6 . In addition, GRP78 unbinds from the three UPR signaling pathways . In the mediation of ER stress, PERK activation ends cap‐dependent protein translation by phosphorylation of eIF2α and leads to apoptosis by CHOP induction; IRE1 stimulation leads to the unconventional splicing of XBP1 to the highly active transcription factor XBP1‐s (spliced); and ATF6, once unbound from GRP78, translocates to the Golgi complex where it is cleaved by site1/site2 proteases to form the active transcription factor .…”

Section: Discussionmentioning

confidence: 99%

“…In addition, GRP78 unbinds from the three UPR signaling pathways . In the mediation of ER stress, PERK activation ends cap‐dependent protein translation by phosphorylation of eIF2α and leads to apoptosis by CHOP induction; IRE1 stimulation leads to the unconventional splicing of XBP1 to the highly active transcription factor XBP1‐s (spliced); and ATF6, once unbound from GRP78, translocates to the Golgi complex where it is cleaved by site1/site2 proteases to form the active transcription factor . In the current study, with 8 weeks of exposure, although TiO 2 NPs increased the expression of P450s in both developing and adult mice at the early stage, the P450‐induced ER stress was observed only in the developing mice at this stage.…”

Section: Discussionmentioning

confidence: 99%

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The toxic effects of titanium dioxide nanoparticles on plasma glucose metabolism are more severe in developing mice than in adult mice

Zhang

et al. 2019

Environmental Toxicology

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Titanium dioxide nanoparticles (TiO2 NPs) are authorized food additives, and children have the highest exposure. Therefore, children are likely more susceptible to the adverse effects of TiO2 NPs than adults. Previous study showed that oral administration of 50 mg/kg body weight (bw) TiO2 NPs increase plasma glucose in mice. However, few studies have directly compared the adverse effects of exposure to TiO2 NPs on plasma glucose metabolism of different age groups. In this study, the developing (age 3 weeks) and adult mice (age 10 weeks) were orally administered with 50 mg/kg bw TiO2 NPs per day. The TiO2 NPs induced hyperglycemia earlier in the developing mice than in the adult mice. Then mechanisms were analyzed after mice were oral administration of TiO2 NPs for 8 weeks and 26 weeks, respectively. Results showed that the treatment with TiO2 NPs activated xenobiotic biodegradation in livers of both developing and adult mice at the early stage. However, only in the developing mice, TiO2 NPs induced endoplasmic reticulum (ER) stress in livers and increased reactive oxygen species in livers and sera in the early stage. The ER stress and ROS activated an inflammation response and mitogen‐activated protein kinase pathways, thereby inducing insulin resistance in the livers of developing mice at the early stage. The response of the adult mice was delayed, and these changes were observed in the late stage of the study. The results of this study all suggest that children are more susceptible than adults to the toxicity of orally administered TiO2 NPs.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The toxic effects of titanium dioxide nanoparticles on plasma glucose metabolism are more severe in developing mice than in adult mice

Zhang

et al. 2019

Environmental Toxicology

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show abstract

“…Dimerization and subsequent phosphorylation of PERK activates PERK, so it can phosphorylate eIF2α and induce the translation of ATF4, which consequently enhances the transcription of CHOP, a proapoptotic transcription factor ( 18 , 35 , 36 ). Osthole has been shown to activate the ERS signaling pathway in normal human hepatocytes and breast cancer cells ( 21 , 37 ). Similarly, the results of the present study demonstrated that the ERS signaling proteins, GRP78, p-PERK/PERK, p-elF2α/elF2α and CHOP, were upregulated following osthole treatment in the HT-29 cell line.…”

Section: Discussionmentioning

confidence: 99%

Osthole induces apoptosis of the HT‑29 cells via endoplasmic reticulum stress and autophagy

Zhou

Kang

Zhong³

et al. 2021

Oncol Lett

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Endoplasmic reticulum stress (ERS) and autophagy are important pathways, which induce apoptosis of tumor cells. Osthole has been demonstrated to exert anticancer effects via the induction of apoptosis in several human colon cancer lines, but the mechanism underlying its involvement in the induction of ERS and autophagy in the human HT-29 colorectal cancer cell line remains unknown. The present study aimed to identify the possible signaling pathways involved in osthole-induced apoptosis of HT29 cells. Methodologically, colony formation and Cell Counting Kit-8 assays were used to assess cell proliferation and viability, respectively, while flow cytometry was performed to investigate apoptosis. Signaling pathways, including apoptosis, autophagy and ERS, were also investigated in the HT-29 cell line using western blot analysis. The results demonstrated that osthole inhibited cellular proliferation and viability in a dose-dependent manner. In addition, osthole induced the expression level of proteins associated with mitochondria-mediated cell apoptosis, autophagy and ERS. The association between autophagy and ERS in osthole-induced apoptosis in the HT-29 cell line was further clarified. Inhibiting cell autophagy with the inhibitor, 3-methyladenine, suppressed osthole-induced cell apoptosis and enhanced osthole-induced ERS. By contrast, alleviating ERS with the inhibitor, 4-phenylbutyric acid attenuated osthole-induced cell apoptosis and autophagy. In conclusion, osthole could significantly suppress the proliferation and viability of the HT-29 colorectal cancer cell line and induce cell apoptosis via autophagy and ERS. Furthermore, ERS may play a more important role in osthole-induced cell apoptosis.

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“…In addition to the drugs mentioned above, liver injury caused by traditional herbal medicines remains an important concern. Fructus Cnidium can induce apoptosis by activating ERS and inhibiting the proliferation of LO2 cells [ 93 ]. Oxymatrine in Sophora flavescens can also induce the occurrence of ERS and the phosphorylation of c-JNK through the excessive accumulation of reactive oxygen species, causing LO2 apoptosis, which can be alleviated by 4-PBA [ 94 ].…”

Section: The Important Role Of Endoplasmic Reticulum Stress In Liver ...mentioning

confidence: 99%

Endoplasmic reticulum stress-mediated cell death in liver injury

et al. 2022

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The endoplasmic reticulum is an important intracellular organelle that plays an important role in maintaining cellular homeostasis. Endoplasmic reticulum stress (ERS) and unfolded protein response (UPR) are induced when the body is exposed to adverse external stimuli. It has been established that ERS can induce different cell death modes, including autophagy, apoptosis, ferroptosis, and pyroptosis, through three major transmembrane receptors on the ER membrane, including inositol requirement enzyme 1α, protein kinase-like endoplasmic reticulum kinase and activating transcription factor 6. These different modes of cell death play an important role in the occurrence and development of various diseases, such as neurodegenerative diseases, inflammation, metabolic diseases, and liver injury. As the largest metabolic organ, the liver is rich in enzymes, carries out different functions such as metabolism and secretion, and is the body’s main site of protein synthesis. Accordingly, a well-developed endoplasmic reticulum system is present in hepatocytes to help the liver perform its physiological functions. Current evidence suggests that ERS is closely related to different stages of liver injury, and the death of hepatocytes caused by ERS may be key in liver injury. In addition, an increasing body of evidence suggests that modulating ERS has great potential for treating the liver injury. This article provided a comprehensive overview of the relationship between ERS and four types of cell death. Moreover, we discussed the mechanism of ERS and UPR in different liver injuries and their potential therapeutic strategies.

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Osthole induced apoptosis in human normal liver cells by regulating cell proliferation and endoplasmic reticulum stress

Cited by 6 publications

References 21 publications

The toxic effects of titanium dioxide nanoparticles on plasma glucose metabolism are more severe in developing mice than in adult mice

The toxic effects of titanium dioxide nanoparticles on plasma glucose metabolism are more severe in developing mice than in adult mice

Osthole induces apoptosis of the HT‑29 cells via endoplasmic reticulum stress and autophagy

Endoplasmic reticulum stress-mediated cell death in liver injury

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