Development of KEAP1-targeting PROTAC and its antioxidant properties: In vitro and in vivo

Redox Biology, Journal Year: 2023, Volume and Issue: 64, P. 102783 - 102783

Published: June 16, 2023

Oxidative stress due to abnormal accumulation of reactive oxygen species (ROS) is an initiator a large number human diseases, and thus, the elimination prevention excessive ROS are important aspects preventing development such diseases. Nuclear factor erythroid 2-related 2 (NRF2) essential transcription that defends against oxidative stress, its function negatively controlled by Kelch-like ECH-associated protein 1 (KEAP1). Therefore, activating NRF2 inhibiting KEAP1 viewed as strategy for combating stress-related Here, we generated cereblon (CRBN)-based proteolysis-targeting chimera (PROTAC), which named SD2267, induces proteasomal degradation leads activation. As was intended, SD2267 bound KEAP1, recruited CRBN, induced KEAP1. Furthermore, efficacy diminished MG132 (a inhibitor) but not chloroquine (an autophagy inhibitor), suggested degradation-dependent autophagy-independent. Following degradation, nuclear translocation NRF2, led expression target genes attenuated acetaminophen (APAP) in hepatocytes. Based on vivo pharmacokinetic study, injected intraperitoneally at or 3 mg/kg APAP-induced liver injury mouse model. We observed degraded hepatic damage. Summarizing, described synthesis KEAP1-targeting PROTAC (SD2267) mode action vitro vivo. The results obtained suggest could be used treat diseases related stress.

Language: Английский

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Mitochondria in Acetaminophen-Induced Liver Injury and Recovery: A Concise Review

Livers, Journal Year: 2023, Volume and Issue: 3(2), P. 219 - 231

Published: April 10, 2023

Mitochondria are critical organelles responsible for the maintenance of cellular energy homeostasis. Thus, their dysfunction can have severe consequences in cells energy-intensive metabolic function, such as hepatocytes. Extensive research over last decades identified compromised mitochondrial function a central feature pathophysiology liver injury induced by an acetaminophen (APAP) overdose, most common cause acute failure United States. While hepatocyte oxidative and nitrosative stress coupled with induction permeability transition well recognized after APAP recent studies revealed additional details about organelle's role pathophysiology. This concise review highlights these new advances, which establish mitochondria pathophysiology, places them context earlier information literature. Adaptive alterations morphology iron importance recovery APAP-induced will be discussed.

Language: Английский

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NLRP3 deficiency protects against acetaminophen‑induced liver injury by inhibiting hepatocyte pyroptosis

Molecular Medicine Reports, Journal Year: 2024, Volume and Issue: 29(4)

Published: Feb. 20, 2024

Acetaminophen (APAP) overdose is the primary cause of drug‑induced acute liver failure in numerous Western countries. NLR family pyrin domain containing 3 (NLRP3) inflammasome activation serves a pivotal role pathogenesis various forms injury. However, cellular source for NLRP3 induction and its involvement during APAP‑induced hepatotoxicity have not been thoroughly investigated. In present study, hematoxylin eosin staining was performed to assess histopathological changes tissue. Immunohistochemistry staining(NLRP3, Caspase‑1, IL‑1β, GSDMD Caspase‑3), western blotting (NLRP3, Caspase‑3) RT‑qPCR Caspase‑1 IL‑1β) were expression NLRP3/GSDMD signaling pathway. TUNEL apoptosis The serum levels inflammatory factors (IL‑6, IL‑18, IL‑1β TNF‑α) assessed using ELISA inflammation tissue immunohistochemistry (Ly6G CD68) (TNF‑α, Il‑6, Mcp‑1, Cxcl‑1, Cxcl‑2). A Cell Counting Kit‑8 cell viability apoptosis. Protein gene analyzed by (PCNA, CCND1) (CyclinA2, CyclinD1 CyclinE1). Through investigation an injury model (AILI), study demonstrated that APAP induced cleavage gasdermin D (GSDMD) hepatocytes, both in vivo vitro. Additionally, mice with hepatocyte‑specific knockout Nlrp3 exhibited reduced lower mortality following intervention, accompanied decreased infiltration cells attenuated response. Furthermore, pharmacological blockade MCC950 or disulfiram significantly ameliorated hepatocyte death. Notably, deficiency promoted recovery enhancing proliferation. Collectively, inhibition protects against reducing pyroptosis suggests targeting may hold therapeutic potential treating AILI.

Language: Английский

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Amygdalin protects against acetaminophen-induced acute liver failure by reducing inflammatory response and inhibiting hepatocyte death

Biochemical and Biophysical Research Communications, Journal Year: 2022, Volume and Issue: 602, P. 105 - 112

Published: March 3, 2022

Language: Английский

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Hepatoprotective effects of Elaeagnus latifolia fruit extract against acetaminophen-induced hepatotoxicity in mice: Mechanistic insights

Journal of Functional Foods, Journal Year: 2024, Volume and Issue: 114, P. 106077 - 106077

Published: Feb. 20, 2024

Elaeagnus latifolia fruit extract (EE) has been reported to contain antioxidant and anti-inflammatory phytochemicals. The present study aimed examine the anti-hepatotoxic effects of EE in acetaminophen (APAP)-injected mice. Pretreatment with for 7 days APAP mice showed significant reductions levels AST ALT necrotic area, accompanied by decreases liver oxidative stress, nitric oxide, infiltrating inflammatory cells, compared APAP-only group. markedly down-regulated expression CYP2E1, JNK, Bax, NOX subunit, NF-κB target genes, up-regulated Bcl-2 Nrf2 genes livers. Furthermore, effectively lowered serum hepatic lipids, SREBP-1c/2 genes. was found phenolic compounds, flavonoids, proanthocyanidins. Therefore, mechanistic insights into EE's may be associated preventing abnormal involved toxic metabolite generation, hepatotoxic signaling, apoptosis, inflammation, lipid synthesis.

Language: Английский

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