bims-istrec 2022-10-30 papers

bims-istrec

Biomed News

on Integrated stress response in cancer

Issue of 2022–10–30
twelve papers selected by
the Vincenzo Ciminale lab, Istituto Oncologico Veneto

Involvement of endoplasmic reticulum stress and cell death by synthesized Pa-PDT in oral squamous cell carcinoma cells.
Discovery of EMD37, a 1,2,4-oxadiazole derivative, as a novel endoplasmic reticulum stress inducer with potent anticancer activity.
DNMT2/TRDMT1 gene knockout compromises doxorubicin-induced unfolded protein response and sensitizes cancer cells to ER stress-induced apoptosis.
Pan-Aurora Kinase Inhibitor Danusertib Induces Apoptosis of Epstein-Barr Virus-transformed B-Cells Through Caspase and Endoplasmic Reticulum Stress Signaling.
Integrated profiling of endoplasmic reticulum stress-related DERL3 in the prognostic and immune features of lung adenocarcinoma.
Novel compound C150 inhibits pancreatic cancer through induction of ER stress and proteosome assembly.
4-Carbomethoxyl-10-Epigyrosanoldie E Extracted from Cultured Soft Coral Sinularia sandensis Induced Apoptosis and Autophagy via ROS and Mitochondrial Dysfunction and ER Stress in Oral Cancer Cells.
Targeting Ca2+ and Mitochondrial Homeostasis by Antipsychotic Thioridazine in Leukemia Cells.
TRIM59 guards ER proteostasis and prevents Bortezomib-mediated colorectal cancer (CRC) cells' killing.
Corrigendum: Sestrin2-mediated autophagy contributes to drug resistance via endoplasmic reticulum stress in human osteosarcoma.
Dual tumor- and subcellular-targeted photodynamic therapy using glucose-functionalized MoS2 nanoflakes for multidrug-resistant tumor ablation.
Zinc Oxide Particles Can Cause Ovarian Toxicity by Oxidative Stress in Female Mice Model.

J Dent Sci. 2022 Oct;17(4): 1722-1730

Involvement of endoplasmic reticulum stress and cell death by synthesized Pa-PDT in oral squamous cell carcinoma cells.

Hyo-Eun Yoon, Mee-Young Ahn, Yong-Chul Kim, Jung-Hoon Yoon.

   Background/purpose: Photodynamic therapy (PDT) is a therapeutic alternative for malignant tumors that uses a photosensitizer. This study examined whether synthesized Pheophorbide a (Pa) -PDT induced apoptosis and autophagy involving endoplasmic reticulum (ER) stress in oral squamous cell carcinoma (OSCC) cells.
Materials and methods: Human OSCC cells were treated with Pa-PDT, and cell proliferation was examined by MTT assay. Apoptosis and autophagy were measured using Western blot analysis. ER stress was examined using RT-PCR and Western blot analysis. In vivo murine OSCC animal model were treated with intratumoral (IT) Pa-PDT, and investigated the therapeutic effect.
Results: Pa-PDT significantly inhibited the proliferation of human OSCC cells in a dose-dependent manner. Pa-PDT induced intrinsic apoptotic cell death and also induced autophagy. Pa-PDT induced ER stress which was observed as demonstrated by the up-regulation of the ER stress marker. Inhibition of the ER stress pathway using 4-phenylbutyric acid (PBA) decreased CHOP and induced inhibition of cell deaths. In addition, the inhibition of ER stress enhanced Pa-PDT mediated autophagy. IT Pa-PDT significantly inhibited the tumor growth and induced apoptosis, autophagy and ER stress in vivo OSCC cells transplanted model.
Conclusion: This study showed that synthesized Pa-PDT induced ER stress trigger apoptosis and apoptotic cell death pathways in OSCC cells. The inhibition of ER stress declined Pa-PDT mediated cytotoxicity with an increase of autophagy. These results may provide Pa-PDT exerts anti-tumor effects through ER stress pathway in OSCC cells and may provide a basis for developing Pa-PDT targeting ER stress as a therapy for OSCC.

Keywords:  Apoptosis; Autophagy; ER stress; Oral sqaumous cell carcinoma; Pa-PDT

DOI:  https://doi.org/10.1016/j.jds.2022.02.006
Biochem Pharmacol. 2022 Oct 22. pii: S0006-2952(22)00410-5. [Epub ahead of print] 115316

Discovery of EMD37, a 1,2,4-oxadiazole derivative, as a novel endoplasmic reticulum stress inducer with potent anticancer activity.

Amal Kamal Abdel-Aziz, Eman M E Dokla, Khaled A M Abouzid, Saverio Minucci.

  Targeting endoplasmic reticulum (ER) stress presents a promising strategy in cancer therapy. We previously reported a series of 1,2,4-oxadiazole derivatives that induced the degradation of EGFR and c-Met which are implicated in tumorigenesis. Based on our previous SAR studies, herein, we report the discovery of EMD37, a novel 1,2,4-oxadiazole derivative, which demonstrated potent anticancer activity against NCI-60 cancer cell lines panel compared to its parent/lead compounds. Anti-proliferative assays revealed preferential cytotoxicity of EMD37 on cancer cells compared to normal cells. Delving deeper, we exploited unbiased genome-wide transcriptome profiling of EMD37-treated cancer cells. Gene Ontology and gene set enrichment analyses revealed that EMD37 promoted ER stress and unfolded protein response (UPR) machinery which was confirmed using RT-qPCR. Mining drug signature databases also confirmed the enrichment of the signature of canonical UPR inducers. Knocking down ER stress transcription factors compromised at least partly the anticancer activity of EMD37. Immunoblot analysis showed that EMD37 induced the accumulation of polyubiquitinated proteins and inhibited mTOR signaling. EMD37 induced G2/M cell cycle arrest and apoptosis of human cancer cells. Inhibiting apoptosis evidently abrogated the anticancer efficacy of EMD37. Altogether, this study introduces EMD37 as a novel ER inducer which warrants further investigation as a potentially relevant anti-cancer therapy.

Keywords:  Bioinformatics; Cancer; Drug discovery; ER stress; Oxadiazole; mTOR

DOI:  https://doi.org/10.1016/j.bcp.2022.115316
Apoptosis. 2022 Oct 23.

DNMT2/TRDMT1 gene knockout compromises doxorubicin-induced unfolded protein response and sensitizes cancer cells to ER stress-induced apoptosis.

Jagoda Adamczyk-Grochala, Dominika Bloniarz, Klaudia Zielinska, Anna Lewinska, Maciej Wnuk.

  The acidic, hypoxic and nutrient-deprived tumor microenvironment may induce endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) may exert an important cytoprotective role by promoting folding of newly synthesized proteins and cancer cell survival. The lack of DNMT2/TRDMT1 methyltransferase-mediated C38 tRNA methylation compromises translational fidelity that may result in the accumulation of misfolded and aggregated proteins leading to proteotoxic stress-related cell death. In the present study, DNMT2/TRDMT1 gene knockout-mediated effects were investigated during doxorubicin (DOX)-induced ER stress and PERK-, IRE1- and ATF6-orchestrated UPR in four genetically different cellular models of cancer (breast and cervical cancer, osteosarcoma and glioblastoma cells). Upon DOX stimulation, DNMT2/TRDMT1 gene knockout impaired PERK activation and modulated NSUN and 5-methylcytosine RNA-based responses and microRNA profiles. The lack of DNMT2/TRDMT1 gene in DOX-treated four cancer cell lines resulted in decreased levels of four microRNAs, namely, miR-23a-3p, miR-93-5p, miR-125a-5p and miR-191-5p involved in the regulation of several pathways such as ubiquitin-mediated proteolysis, amino acid degradation and translational misregulation in cancer. We conclude that DNMT2/TRDMT1 gene knockout, at least in selected cellular cancer models, affects adaptive responses associated with protein homeostasis networks that during prolonged ER stress may result in increased sensitivity to apoptotic cell death.

Keywords:  Cancer cells; DNMT2/TRDMT1; Doxorubicin; ER stress; MicroRNA expression

DOI:  https://doi.org/10.1007/s10495-022-01779-0
Anticancer Res. 2022 Nov;42(11): 5265-5274

Pan-Aurora Kinase Inhibitor Danusertib Induces Apoptosis of Epstein-Barr Virus-transformed B-Cells Through Caspase and Endoplasmic Reticulum Stress Signaling.

Jin Soo Kim, Dae Young Hur.

   BACKGROUND/AIM: Evidence for the relevance of Epstein-Barr virus (EBV) in various types of cancer has expanded; however, the definitive mechanism of EBV-induced oncogenesis remains ambiguous. The purpose of this study was to identify the relevance of aurora kinases in EBV-induced carcinogenesis, and the cellular responses to danusertib, a pan-aurora kinase inhibitor. The underlying signaling mechanism in EBV-transformed B-cells was also investigated.
MATERIALS AND METHODS: Western blotting was performed on EBV-transformed B-cells and EBV-positive lymphoma cells to identify aurora kinase expression. Cellular responses of EBV-transformed B-cells to danusertib were investigated using AlamaBlue assay and apoptosis analysis. To evaluate the underlying signaling mechanisms of danusertib-induced apoptosis, cleavage of caspase cascade molecules, endoplasmic reticulum (ER) stress-associated molecule activation, and intracellular Ca2+ levels were evaluated using western blotting, flow cytometry, and inhibition assays.
RESULTS: Expression of both aurora kinase A and B was gradually increased in EBV-infected B-cells and two EBV-positive B lymphoma cell lines. Danusertib significantly suppressed EBV-transformed B-cell proliferation in a dose-dependent manner. Danusertib induced apoptosis and cell cycle arrest through disruption of mitochondrial membrane potential in EBV-transformed B-cells in a dose-dependent and time-dependent manner. Moreover, danusertib induced cleavage of caspases, ER stress-associated molecule activation, and intracellular Ca2+ release from ER to cytoplasm in EBV-transformed B-cells, while BAPTA-AM, a calcium chelator, inhibited danusertib-induced apoptosis.
CONCLUSION: Danusertib treatment led to apoptosis of EBV-transformed B-cells through ER stress-associated proteins and mitochondrial caspase activation. These results suggest that aurora kinases may be valuable targets for potential therapeutic agents against EBV-associated carcinoma.

Keywords:  Aurora kinase inhibitor; Epstein–Barr virus-transformed B-cells; apoptosis; cell-cycle arrest; endoplasmic reticulum stress

DOI:  https://doi.org/10.21873/anticanres.16033
Front Immunol. 2022 ;13 906420

Integrated profiling of endoplasmic reticulum stress-related DERL3 in the prognostic and immune features of lung adenocarcinoma.

Lanlan Lin, Guofu Lin, Hai Lin, Luyang Chen, Xiaohui Chen, Qinhui Lin, Yuan Xu, Yiming Zeng.

   Background: DERL3 has been implicated as an essential element in the degradation of misfolded lumenal glycoproteins induced by endoplasmic reticulum (ER) stress. However, the correlation of DERL3 expression with the malignant phenotype of lung adenocarcinoma (LUAD) cells is unclear and remains to be elucidated. Herein, we investigated the interaction between the DERL3 and LUAD pathological process.
Methods: The Cancer Genome Atlas (TCGA) database was utilized to determine the genetic alteration of DERL3 in stage I LUAD. Clinical LUAD samples including carcinoma and adjacent tissues were obtained and were further extracted to detect DERL3 mRNA expression via RT-qPCR. Immunohistochemistry was performed to evaluate the protein expression of DERL3 in LUAD tissues. The GEPIA and TIMER website were used to evaluate the correlation between DERL3 and immune cell infiltration. We further used the t-SNE map to visualize the distribution of DERL3 in various clusters at the single-cell level via TISCH database. The potential mechanisms of the biological process mediated by DERL3 in LUAD were conducted via KEGG and GSEA.
Results: It was indicated that DERL3 was predominantly elevated in carcinoma compared with adjacent tissues in multiple kinds of tumors from the TCGA database, especially in LUAD. Immunohistochemistry validated that DERL3 was also upregulated in LUAD tissues compared with adjacent tissues from individuals. DERL3 was preliminarily found to be associated with immune infiltration via the TIMER database. Further, the t-SNE map revealed that DERL3 was predominantly enriched in plasma cells of the B cell population. It was demonstrated that DERL3 high-expressed patients presented significantly worse response to chemotherapy and immunotherapy. GSEA and KEGG results indicated that DERL3 was positively correlated with B cell activation and unfolded protein response (UPR).
Conclusion: Our findings indicated that DERL3 might play an essential role in the endoplasmic reticulum-associated degradation (ERAD) process in LUAD. Moreover, DERL3 may act as a promising immune biomarker, which could predict the efficacy of immunotherapy in LUAD.

Keywords:  B cell; DERL3; endoplasmic reticulum stress; immune infiltration; lung adenocarcinoma

DOI:  https://doi.org/10.3389/fimmu.2022.906420
Front Oncol. 2022 ;12 870473

Novel compound C150 inhibits pancreatic cancer through induction of ER stress and proteosome assembly.

Tao Wang, Ping Chen, Scott Weir, Michael Baltezor, Frank J Schoenen, Qi Chen.

  Pancreatic cancer is a devastating disease with a dismal prognosis and poor treatment outcomes. Searching for new agents for pancreatic cancer treatment is of great significance. We previously identified a novel activity of compound C150 to inhibit pancreatic cancer epithelial-to-mesenchymal transition (EMT). Here, we further revealed its mechanism of action. C150 induced ER stress in pancreatic cancer cells and subsequently increased proteasome activity by enhancing proteasome assembly, which subsequently enhanced the degradation of critical EMT transcription factors (EMT-TFs). In addition, as cellular responses to ER stress, autophagy was elevated, and general protein synthesis was inhibited in pancreatic cancer cells. Besides EMT inhibition, the C150-induced ER stress resulted in G2/M cell cycle arrest, which halted cell proliferation and led to cellular senescence. In an orthotopic syngeneic mouse model, an oral dose of C150 at 150 mg/kg 3× weekly significantly increased survival of mice bearing pancreatic tumors, and reduced tumor growth and ascites occurrence. These results suggested that compound C150 holds promises in comprehensively inhibiting pancreatic cancer progression.

Keywords:  ER stress; autophagy; cell senescence; pancreatic cancer; proteasome

DOI:  https://doi.org/10.3389/fonc.2022.870473
Oxid Med Cell Longev. 2022 ;2022 3017807

4-Carbomethoxyl-10-Epigyrosanoldie E Extracted from Cultured Soft Coral Sinularia sandensis Induced Apoptosis and Autophagy via ROS and Mitochondrial Dysfunction and ER Stress in Oral Cancer Cells.

Yun-Ying She, Jen-Jie Lin, Jui-Hsin Su, Ting-Shou Chang, Yu-Jen Wu.

Oral cancer is a malignant neoplasia that is more common in Asian than other regions, and men are at higher risk than women. Currently, clinical treatment for oral cancer consists of radiation therapy combined with chemotherapy. Therefore, it is important to find a drug that can inhibit the growth of cancer cells more effectively and safely. In this study, we examined the cytotoxicity of 4-carbomethoxyl-10-epigyrosanoldie E extracted from cultured soft coral Sinularia sandensis towards oral cancer cells. MTT cell proliferation and colony formation assays were used to evaluate cell survival, and immunofluorescence staining and Western blotting were employed to analyze the effects of 4-carbomethoxyl-10-epigyrosanoldie E on apoptosis and autophagy. 4-Carbomethoxyl-10-epigyrosanoldie E treatment also induced the formation of reactive oxygen species (ROS), which are associated with 4-carbomethoxyl-10-epigyrosanoldie E-induced cell death. In addition, the 4-carbomethoxyl-10-epigyrosanoldie E-induced antiproliferation effects on Ca9-22 and Cal-27 cells were associated with the release of cytochrome c from mitochondria, activation of proapoptotic proteins (such as caspase-3/-9, Bax, and Bad), and inhibition of antiapoptotic proteins (Bcl-2, Bcl-xl, and Mcl-1). 4-Carbomethoxyl-10-epigyrosanoldie E treatment also triggered endoplasmic reticulum (ER) stress, leading to activation of the PERK/elF2α/ATF4/CHOP apoptotic pathway. Moreover, increased expressions of Beclin-1, Atg3, Atg5, Atg7, Atg12, Atg 16, LC3-I, and LC3-II proteins indicated that 4-carbomethoxyl-10-epigyrosanoldie E triggered autophagy in oral cancer cells. In conclusion, our findings demonstrated that 4-carbomethoxyl-10-epigyrosanoldie E suppressed human oral cancer cell proliferation and should be further investigated with regard to its potential use as a chemotherapy drug for the treatment of human oral cancer.

DOI: https://doi.org/10.1155/2022/3017807
Life (Basel). 2022 Sep 23. pii: 1477. [Epub ahead of print]12(10):

Targeting Ca2+ and Mitochondrial Homeostasis by Antipsychotic Thioridazine in Leukemia Cells.

Vivian W R Moraes, Vivian M Santos, Eloah R Suarez, Letícia S Ferraz, Rayssa de Mello Lopes, Giuliana P Mognol, Joana D Campeiro, João A Machado-Neto, Fabio D Nascimento, Mirian A F Hayashi, Ivarne L S Tersariol, Donald D Newmeyer, Tiago Rodrigues.

  Mitochondria have pivotal roles in cellular physiology including energy metabolism, reactive oxygen species production, Ca2+ homeostasis, and apoptosis. Altered mitochondrial morphology and function is a common feature of cancer cells and the regulation of mitochondrial homeostasis has been identified as a key to the response to chemotherapeutic agents in human leukemias. Here, we explore the mechanistic aspects of cytotoxicity produced by thioridazine (TR), an antipsychotic drug that has been investigated for its anticancer potential in human leukemia cellular models. TR exerts selective cytotoxicity against human leukemia cells in vitro. A PCR array provided a general view of the expression of genes involved in cell death pathways. TR immediately produced a pulse of cytosolic Ca2+, followed by mitochondrial uptake, resulting in mitochondrial permeabilization, caspase 9/3 activation, endoplasmic reticulum stress, and apoptosis. Ca2+ chelators, thiol reducer dithiothreitol, or CHOP knockdown prevented TR-induced cell death. TR also exhibited potent cytotoxicity against BCL-2/BCL-xL-overexpressing leukemia cells. Additionally, previous studies have shown that TR exhibits potent antitumor activity in vivo in different solid tumor models. These findings show that TR induces a Ca2+-mediated apoptosis with involvement of mitochondrial permeabilization and ER stress in leukemia and it emphasizes the pharmacological potential of TR as an adjuvant in antitumor chemotherapy.

Keywords:  apoptosis; calcium; endoplasmic reticulum stress; leukemia; mitochondria; phenothiazine

DOI:  https://doi.org/10.3390/life12101477
Invest New Drugs. 2022 Oct 28.

TRIM59 guards ER proteostasis and prevents Bortezomib-mediated colorectal cancer (CRC) cells' killing.

Xuejia Feng, Gui Yang, Litian Zhang, Shishi Tao, Joong Sup Shim, Liang Chen, Qingxia Wu.

  The endoplasmic reticulum (ER) is a critical organelle that preserves the protein homeostasis of cells. Under various stress conditions, cells evolve a degree of capacity to maintain ER proteostasis, which is usually augmented in tumor cells, including colorectal cancer (CRC) cells, to bolster their survival and resistance to apoptosis. Bortezomib (BTZ) is a promising drug used in CRC treatment; however, its main limitation result from drug resistance. Here, we identified the role of tripartite motif-containing protein 59 (TRIM59)-a protein localized on the ER membrane- in the prevention of BTZ-mediated CRC killing. Depletion of TRIM59 is associated with the enhancement of ER stress and a remarkable increase in unfolded protein response (UPR) signaling. Besides, TRIM59 strengthens ER-associated degradation (ERAD) and alleviates the generation of ROS. Of note, TRIM59 knockdown synergizes with the anti-cancer effect of BTZ both in vitro and in vivo. Our findings revealed a role for TRIM59 in the ER by guarding ER proteostasis and represents a novel therapeutic target of CRC.

Keywords:  Bortezomib; Colorectal cancer; ER-associated degradation; ER-stress; TRIM59; Unfolded protein response

DOI:  https://doi.org/10.1007/s10637-022-01306-7
Front Cell Dev Biol. 2022 ;10 882270

Corrigendum: Sestrin2-mediated autophagy contributes to drug resistance via endoplasmic reticulum stress in human osteosarcoma.

Zhen Tang, Xinghui Wei, Tian Li, Wei Wang, Hao Wu, Hui Dong, Yichao Liu, Feilong Wei, Lei Shi, Xiaokang Li, Zheng Guo, Xin Xiao.

  [This corrects the article DOI: 10.3389/fcell.2021.722960.].

Keywords:  Sestrin2; apoptosis; autophagy; drug resistance; endoplasmic reticulum stress

DOI:  https://doi.org/10.3389/fcell.2022.882270
Biomaterials. 2022 Oct 12. pii: S0142-9612(22)00484-7. [Epub ahead of print]290 121844

Dual tumor- and subcellular-targeted photodynamic therapy using glucose-functionalized MoS2 nanoflakes for multidrug-resistant tumor ablation.

Shaohui Xu, Pan Zhang, Isabelle Heing-Becker, Junmei Zhang, Peng Tang, Raju Bej, Sumati Bhatia, Yinan Zhong, Rainer Haag.

  Photodynamic therapy (PDT) is emerging as an efficient strategy to combat multidrug-resistant (MDR) cancer. However, the short half-life and limited diffusion of reactive oxygen species (ROS) undermine the therapeutic outcomes of this therapy. To address this issue, a tumor-targeting nanoplatform was developed to precisely deliver mitochondria- and endoplasmic reticulum (ER)-targeting PDT agents to desired sites for dual organelle-targeted PDT. The nanoplatform is constructed by functionalizing molybdenum disulfide (MoS2) nanoflakes with glucose-modified hyperbranched polyglycerol (hPG), and then loading the organelle-targeting PDT agents. The resultant nanoplatform Cy7.5-TG@GPM is demonstrated to mediate both greatly enhanced internalization within MDR cells and precise subcellular localization of PDT agents, facilitating in situ near-infrared (NIR)-triggered ROS generation for augmented PDT and reversal of MDR, causing impressive tumor shrinkage in a HeLa multidrug-resistant tumor mouse model. As revealed by mechanistic studies of the synergistic mitochondria- and ER-targeted PDT, ROS-induced ER stress not only activates the cytosine-cytosine-adenosine-adenosine thymidine/enhancer-binding protein homologous protein (CHOP) pro-apoptotic signaling pathway, but also cooperates with ROS-induced mitochondrial dysfunction to trigger cytochrome C release from the mitochondria and induce subsequent cell death. Furthermore, the mitochondrial dysfunction reduces ATP production and thereby contributes to the reversal of MDR. This nanoplatform, with its NIR-responsive properties and ability to target tumors and subcellular organelles, offers a promising strategy for effective MDR cancer therapy.

Keywords:  Endoplasmic reticulum stress; Mitochondrial dysfunction; Molybdenum disulfide; Photodynamic therapy; Reversal of tumor multidrug-resistance; precise subcellular organelle targeting

DOI:  https://doi.org/10.1016/j.biomaterials.2022.121844
Int J Nanomedicine. 2022 ;17 4947-4960

Zinc Oxide Particles Can Cause Ovarian Toxicity by Oxidative Stress in Female Mice Model.

Yuanyuan Xu, Yu Zhao, Shanji Liu, Sidi Lv, Ling Chen, Wanzhen Wang, Yueying Feng, Fen Fu, Hengyi Xu.

   Introduction: Zinc oxide nanoparticles (ZnO NPs) participate in all aspects of our lives, but with their wide application, more and more disadvantages are exposed. The goal of this study was to investigate the toxicity of ZnO NPs in female mice ovaries and explore its potential mechanism.
Methods: In this study, adult female mice were orally exposed to 0, 100, 200, and 400 mg/kg ZnO NPs for 7 days. We explored the underlying mechanisms via the intraperitoneal injection of N-acetyl-cysteine (NAC), an inhibitor of oxidative stress, and salubrinal (Sal), an inhibitor of endoplasmic reticulum (ER) stress.
Results: The results indicated that serum estradiol and progesterone levels declined greatly with increasing ZnO NPs dosage. Hematoxylin and eosin (HE) staining revealed increased atretic follicles and exfoliated follicular granulosa cells. Moreover, at the transcriptional level, antioxidant-related genes such as Keap1 and Nrf2, and ER stress-related genes PERK, eIF2α, and ATF4 were markedly upregulated. In addition, the expression of Caspase12, Caspase9, and Caspase3, which are genes related to apoptosis, was also upregulated in all ZnO NPs treatment groups. Serum malondialdehyde (MDA) content was remarkably up-regulated, whereas superoxide dismutase (SOD) activity was down-regulated. The 400 mg/kg ZnO NPs treatment group suffered the most substantial harm. However, ovarian damage was repaired when NAC and Sal were added to this group.
Conclusion: ZnO NPs had toxic effects on the ovary of female mice, which were due to oxidative stress, ER stress, and the eventual activation of apoptosis.

Keywords:  apoptosis; endoplasmic reticulum stress; ovary; oxidative stress; zinc oxide nanoparticles

DOI:  https://doi.org/10.2147/IJN.S373147