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With the application of copper nanoparticles (nano-Cu) in livestock and poultry feed addition, their biotoxicity has been gradually recognized. Therefore, it has become an urgent problem to find the effective natural antagonists to reduce the toxicity of copper nanoparticles. Here, we found that hesperidin could alleviate nano-Cu-induced pathological injury in the immune organs of chickens via the histopathological examination of the spleen, thymus, and bursa of Fabricius. Additionally, the results of western blot showed that nano-Cu exposure activated ZBP1-mediated PANoptosis in immune organs, with evidenced by the significant up-regulation of ZBP1 signal molecule and PANoptosis-related proteins (apoptosis: Caspase-7, Caspase-3, Caspase-8; pyroptosis: Caspase-1, GSDMD, GSDME; necroptosis: RIPK1 and MLKL). Besides that, immunohistochemistry and immunofluorescence also showed that the staining intensity of Caspase-9 and Caspase-8 proteins was observably elevated in nano-Cu group compared to control group, and the staining intensity of the hesperidin mixed nano-copper group was markedly lower than that of the nano-Cu group. Meanwhile, hesperidin effectively attenuated the ZBP1 expression and PANoptosis under nano-Cu exposure. These findings suggested that excessive nano-Cu could cause ZBP1-drived PANoptosis in immune organs, while hesperidin could alleviate toxic damage induced by nano-Cu exposure., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Lung cancer ranks as the second most diagnosed cancer and the leading cause of cancer-related deaths worldwide. Novel chemotherapeutic strategies are crucial to efficiently target tumor cells while minimizing toxicity to normal cells. In this study, we proposed a combination strategy using energy blocker lonidamine (LND) and cytotoxic drug nimustine (ACNU, 1-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-3-(2-chloroethyl)-3-nitrosourea) to enhance the killing of a human lung cancer cell line and investigated the potential chemo-sensitizing mechanism of LND. LND was found to remarkably increase the cytotoxicity of ACNU to A549 and H1299 cells without significantly affecting normal lung BEAS2B cells. The combination of LND and ACNU also produced significant effects on cell apoptosis, colony formation, cell migration, and invasion assays compared to single drug treatment. Mechanistically, LND decreased intracellular ATP levels by inhibiting glycolysis and inducing mitochondrial dysfunction. Furthermore, the combination of LND and ACNU could intensify cellular oxidative stress, decrease cellular GSH contents, and increase reactive oxygen species (ROS) production. Notably, LND alone dramatically downregulated the expression of DNA repair protein MGMT (O 6 -methylguanine-DNA methyltransferase), enhancing DNA interstrand cross-link formation induced by ACNU. Overall, LND represents a potential chemo-sensitizer to enhance ACNU therapy through energy inhibition, disrupting redox homeostasis and downregulating MGMT expression in human lung cancer cell line under preclinical and clinical background., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Tumor resistance seriously hinders the clinical application of chloroethylnitrosoureas (CENUs), such as O 6 -methylguanine-DNA methylguanine (MGMT), which can repair O 6 -alkyl lesions, thereby inhibiting the formation of cytotoxic DNA interstrand cross-links (ICLs). Metabolic differences between tumor and normal cells provide a biochemical basis for novel therapeutic strategies aimed at selectively inhibiting tumor energy metabolism. In this study, the energy blocker lonidamine (LND) was selected as a chemo-sensitizer of nimustine (ACNU) to explore its potential effects and underlying mechanisms in human glioblastoma in vitro and in vivo . A series of cell-level studies showed that LND significantly increased the cytotoxic effects of ACNU on glioblastoma cells. Furthermore, LND plus ACNU enhanced the energy deficiency by inhibiting glycolysis and mitochondrial function. Notably, LND almost completely downregulated MGMT expression by inducing intracellular acidification. The number of lethal DNA ICLs produced by ACNU increased after the LND pretreatment. The combination of LND and ACNU aggravated cellular oxidative stress. In resistant SF763 mouse tumor xenografts, LND plus ACNU significantly inhibited tumor growth with fewer side effects than ACNU alone. Finally, we proposed a new "HMAGOMR" chemo-sensitizing mechanism through which LND may act as a potential chemo-sensitizer to reverse ACNU resistance in glioblastoma: moderate inhibition of hexokinase (HK) activity (H); mitochondrial dysfunction (M); suppressing adenosine triphosphate (ATP)-dependent drug efflux (A); changing redox homeostasis to inhibit GSH-mediated drug inactivation (G) and increasing intracellular oxidative stress (O); downregulating MGMT expression through intracellular acidification (M); and partial inhibition of energy-dependent DNA repair (R)., Competing Interests: The authors declare no competing financial interest., (© 2024 American Chemical Society.)