The present study aimed to elucidate the effect of sulforaphane (a natural isothiocyanate) on oxidative stress and mitochondrial dysfunction during and at selected periods following status epilepticus (SE) induced in immature 12-day-old rats by Li-pilocarpine. Dihydroethidium was employed for the detection of superoxide anions, immunoblot analyses for 3-nitrotyrosine (3-NT) and 4-hydroxynonenal (4-HNE) levels and respiratory chain complex I activity for evaluation of mitochondrial function. Sulforaphane was given i.p. in two doses (5 mg/kg each), at PD 10 and PD 11, respectively. The findings of the present study indicate that both the acute phase of SE and the early period of epileptogenesis (1 week and 3 weeks following SE induction) are associated with oxidative stress (documented by the enhanced superoxide anion production and the increased levels of 3-NT and 4-HNE) and the persisting deficiency of complex I activity. Pretreatment with sulforaphane either completely prevented or significantly reduced markers of both oxidative stress and mitochondrial dysfunction. Since sulforaphane had no direct anti-seizure effect, the findings suggest that the ability of sulforaphane to activate Nrf2 is most likely responsible for the observed protective effect. Nrf2-ARE signaling pathway can be considered a promising target for novel therapies of epilepsy, particularly when new compounds, possessing inhibitory activity against protein-protein interaction between Nrf2 and its repressor protein Keap1, with less "off-target" effects and, importantly, with an optimal permeability and bioavailability properties, become available commercially.

• Klíčová slova
• Immature rats, Mitochondrial dysfunction, Oxidative stress, Protection, Status epilepticus, Sulforaphane,
• MeSH
• faktor 2 související s NF-E2 * metabolismus   MeSH
• isothiokyanatany farmakologie   MeSH
• KEAP-1 metabolismus   MeSH
• krysa rodu Rattus MeSH
• mitochondrie metabolismus   MeSH
• oxidační stres MeSH
• status epilepticus * metabolismus   MeSH
• sulfoxidy metabolismus   farmakologie   MeSH
• superoxidy metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• faktor 2 související s NF-E2 * MeSH
• isothiokyanatany MeSH
• KEAP-1 MeSH
• sulforaphane MeSH Prohlížeč
• sulfoxidy MeSH
• superoxidy MeSH

Nrf2 (nuclear factor erythroid 2 (NF-E2)-related factor 2) transcription factor is recognized for its pro-survival and cell protective role upon exposure to oxidative, chemical, or metabolic stresses. Nrf2 controls a number of cellular processes such as proliferation, differentiation, apoptosis, autophagy, lipid synthesis, and metabolism and glucose metabolism and is a target of activation in chronic diseases like diabetes, neurodegenerative, and inflammatory diseases. The dark side of Nrf2 is revealed when its regulation is imbalanced (e.g., via oncogene activation or mutations) and under such conditions constitutively active Nrf2 promotes cancerogenesis, metastasis, and radio- and chemoresistance. When there is no stress, Nrf2 is instantly degraded via Keap1-Cullin 3 (Cul3) pathway but despite this, cells exhibit a basal activation of Nrf2 target genes. It is yet not clear how Nrf2 maintains the expression of its targets under homeostatic conditions. Here, we found a stable 105 kDa Nrf2 form that is resistant to Keap1-Cul3-mediated degradation and translocates to the nucleus of lung cancer cells. RNA-Seq analysis indicate that it might originate from the exon 2 or exon 3-truncated transcripts. This stable 105 kDa Nrf2 form might help explain the constitutive activity of Nrf2 under normal cellular conditions.

• Klíčová slova
• Nrf2 antibodies, Nrf2 detection, Nrf2 migration in SDS-PAGE,
• Publikační typ
• časopisecké články MeSH

NF-E2-related factor 2 (NRF2) is a basic leucine zipper transcription factor, a master regulator of redox homeostasis regulating a variety of genes for antioxidant and detoxification enzymes. NRF2 was, therefore, initially thought to protect the liver from oxidative stress. Recent studies, however, have revealed that mutations in NRF2 cause aberrant accumulation of NRF2 in the nucleus and exert the upregulation of NRF2 target genes. Moreover, among all molecular changes in hepatocellular carcinoma (HCC), NRF2 activation has been revealed as a more prominent pathway contributing to the progression of precancerous lesions to malignancy. Nevertheless, how its activation leads to poor prognosis in HCC patients remains unclear. In this review, we provide an overview of how aberrant activation of NRF2 triggers HCC development. We also summarize the emerging roles of other NRF family members in liver cancer development.

• Klíčová slova
• NF-E2-related factor 2, hepatocellular carcinoma, oxidative stress, redox homeostasis, transcription factor,
• MeSH
• aktivace transkripce * MeSH
• analýza přežití MeSH
• faktor 2 související s NF-E2 genetika   metabolismus   MeSH
• genové regulační sítě MeSH
• hepatocelulární karcinom diagnóza   genetika   mortalita   patologie   MeSH
• karcinogeneze genetika   metabolismus   patologie   MeSH
• KEAP-1 genetika   metabolismus   MeSH
• lidé MeSH
• mutace MeSH
• nádorové buněčné linie MeSH
• nádory jater diagnóza   genetika   mortalita   patologie   MeSH
• oxidace-redukce MeSH
• oxidační stres MeSH
• prognóza MeSH
• regulace genové exprese u nádorů * MeSH
• signální transdukce MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• faktor 2 související s NF-E2 MeSH
• KEAP-1 MeSH
• KEAP1 protein, human MeSH Prohlížeč
• NFE2L2 protein, human MeSH Prohlížeč