作者: Angelin, Alessia ; Jurado, Kellie A. ; Keith, Kelsey ; Widjaja, Gabrielle A. ; McManus, Meagan J. ; Potluri, Prasanth ; Taylor, Deanne ; Zhu, Yi ; Albrecht, Yentli E. Soto ; Guarnieri, Joseph W. ; Kilbaugh, Todd J. ; Murdock, Deborah G. ; Hewin, Peter ; Lie, Timothy ; Wallace, Douglas C.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection inhibits mitochondrial oxidative phosphorylation (OXPHOS) and elevates mitochondrial reactive oxygen species (ROS, mROS) which activates hypoxia-inducible factor-1alpha (HIF-1α), shifting metabolism toward glycolysis to drive viral biogenesis but also causing the release of mitochondrial DNA (mtDNA) and activation of innate immunity. To determine whether mitochondrially targeted antioxidants could mitigate these viral effects, we challenged mice expressing human angiotensin-converting enzyme 2 (ACE2) with SARS-CoV-2 and intervened using transgenic and pharmacological mitochondrially targeted catalytic antioxidants. Transgenic expression of mitochondrially targeted catalase (mCAT) or systemic treatment with EUK8 decreased weight loss, clinical severity, and circulating levels of mtDNA; as well as reduced lung levels of HIF-1α, viral proteins, and inflammatory cytokines. RNA-sequencing of infected lungs revealed that mCAT and Eukarion 8 (EUK8) up-regulated OXPHOS gene expression and down-regulated HIF-1α and its target genes as well as innate immune gene expression. These data demonstrate that SARS-CoV-2 pathology can be mitigated by catalytically reducing mROS, potentially providing a unique host-directed pharmacological therapy for COVID-19 which is not subject to viral mutational resistance.

2024-06-01·Journal of Pharmacological Sciences

Proteasome inhibitors induce apoptosis by superoxide anion generation via NADPH oxidase 5 in human neuroblastoma SH-SY5Y cells

Article

作者: Yoshioka, Yasuhiro ; Iyama, Takumi ; Ishimaru, Yuki ; Yamamuro-Tanabe, Akiko ; Oshima, Yu

The ubiquitin-proteasome system (UPS) is a major proteolytic system that plays an important role in the regulation of various cell processes, such as cell cycle, stress response, and transcriptional regulation, especially in neurons, and dysfunction of UPS is considered to be a cause of neuronal cell death in neurodegenerative diseases. However, the mechanism of neuronal cell death caused by UPS dysfunction has not yet been fully elucidated. In this study, we investigated the mechanism of neuronal cell death induced by proteasome inhibitors using human neuroblastoma SH-SY5Y cells. Z-Leu-D-Leu-Leu-al (MG132), a proteasome inhibitor, induced apoptosis in SH-SY5Y cells in a concentration- and time-dependent manner. Antioxidants N-acetylcysteine and EUK-8 attenuated MG132-induced apoptosis. Apocynin and diphenyleneiodonium, inhibitors of NADPH oxidase (NOX), an enzyme that produces superoxide anions, also attenuated MG132-induced apoptosis. It was also found that MG132 treatment increased the expression of NOX5, a NOX family member, and that siRNA-mediated silencing of NOX5 and BAPTA-AM, which inhibits NOX5 by chelating calcium, suppressed MG132-induced apoptosis and production of reactive oxygen species in SH-SY5Y cells. These results suggest that MG132 induces apoptosis in SH-SY5Y cells through the production of superoxide anion by NOX5.

2023-02-01·Journal of Inorganic Biochemistry

ROS scavenging of SOD/CAT mimics probed by EPR and reduction of lipid peroxidation in S. cerevisiae and mouse liver, under severe hydroxyl radical stress condition

Article

作者: Horn, Adolfo ; Mattos, Larissa M de M ; Segat, Bruna B ; Latini, Alexandra ; Fernandes, Christiane ; Pires, Daniele C ; Hottum, Hyan M ; Pereira, Marcos D ; Tolentino, Hugo ; Menezes, Lucas B

The interaction between Cu^II, Fe^III and Mn^II complexes, derived from the ligands 1-[bis(pyridine-2-ylmethyl)amino]-3-chloropropan-2-ol (hpclnol) and bis(pyridine-2-ylmethyl)amine (bpma), and the free radical 2,2-diphenyl-1-(2,4,6-trinitrophenyl)hydrazyl (DPPH) and reactive oxygen species (ROS), was investigated by colorimetric and EPR (Electron Paramagnetic Resonance) techniques. A comparison between these results and those reported to [Mn(salen)Cl] or EUK-8 was also addressed. EPR studies allowed us the identification of intermediates species such as superoxide‑copper(I) and superoxide‑copper(II), a mixed-valence Fe^IIIFe^II species and a 16-line feature attributed to Mn^III-oxo-Mn^IV species. The biomarker malondialdehyde (MDA) was determined by TBARS assay in S. cerevisiae cells, and the determination of the IC₅₀ indicate that the antioxidant activity shown dependence on the metal center (Cu^II ≈ Fe^III > Mn^II ≈ [Mn(salen)Cl]. The lipid peroxidation attenuation was also investigated in liver homogenates obtained from Swiss mice and the IC₅₀ values were in the nanomolar concentrations. We demonstrated here that all the complexes interact with the free radical DPPH and with ROS (H₂O₂, O₂^•- and hydroxyl radical), enhancing the cellular protection against oxidative stress generated by hydroxyl radical, employing two experimental model systems, S. cerevisiae (in vivo) and mouse liver (ex vivo).

100 项与 EUK-8 相关的药物交易

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