Intracerebral hemorrhage (ICH) is associated with the highest rates of mortality and residual disability. To date, effective treatments to delay or prevent ICH are still lacking. Multiple forms of neuronal cell death have been discovered following ICH, including apoptosis, necrosis, autophagy, and ferroptosis. Aldo-keto reductase family 1 member C1 (AKR1C1) has been identified to act as a protective factor in ferroptosis. However, whether AKR1C1 was involved in the development of ICH was unknown. In this study, the left cerebral striatum of the Sprague-Dawley rat was injected with collagenase type IV to induce an in vivo model. Primary rat cortical neurons treated with oxygen hemoglobin (OxyHb) were applied to as an in vitro model. AKR1C1 was found to be downregulated and immunoreactivity colocalized with NeuN-positive neurons in the perihematomal region. Rats injected with lentiviral particles overexpressing AKR1C1 showed the reduction of cerebral hematoma and the remission of blood-brain barrier disruption. Moreover, AKR1C1 upregulation repressed cell apoptosis and ferroptosis induced by ICH through downregulating the expression of pro-apoptotic factors, inhibiting iron accumulation and lipid peroxidation, along with increasing the expression of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4). The results of in vitro assays were consistent with results from the in vivo . Mechanistically, P53 overexpression augmented the cellular damage in OxyHb-stimulated neurons when AKR1C1 was overexpressed. Taken together, AKR1C1 improves ICH injury by inhibiting neuronal cell death via negatively regulating P53 expression and affecting the SLC7A11/GPX4 pathway.
Runlan Wan,Xi Kong,Youzhe Yang,Siwen Tao,Youyou Chen,Alexander Tobias Teichmann,Frank Heinrich Wieland
The clinical use of the steroidal aromatase inhibitor Formestane (4-hydroxandrostenedione, 4-OHA) in the treatment of advanced ER+ breast cancer has been discontinued, and therefore, interest in this remarkable drug has vanished. As a C-19 sterol, 4-OHA can undergo extensive intracellular metabolism depending on the expression of specific enzymes in the corresponding cells. We used the metabolites 4β-hydroxyandrosterone, 4β-hydroxyepiandrosterone and its 17β-reduced derivative as standards for the proof of catalytic activity present in the cell culture medium and expressed by the isolated enzymes. All of the aldo-keto reductases AKR1C1, AKR1C2, AKR1C3 and AKR1C4 catalysed the reduction of the 3-keto-group and the Δ 4,5 double bond of 4-OHA at the same time. Molecular docking experiments using microscale thermophoresis and the examination of the kinetic behaviour of the isolated enzymes with the substrate 4-OHA proved that AKR1C3 had the highest affinity for the substrate, whereas AKR1C1 was the most efficient enzyme. Both enzymes (AKR1C1and AKR1C3) are highly expressed in adipose tissue and lungs, exhibiting 3β-HSD activity. The possibility that 4-OHA generates biologically active derivatives such as the androgen 4-hydroxytestosterone or some 17β-hydroxy derivatives of the 5α-reduced metabolites may reawaken interest in Formestane, provided that a suitable method of administration can be developed, avoiding oral or intramuscular depot-injection administration.
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