Author: Patel, Monika ; Vásquez-Trincado, César ; Anderson-Pullinger, Lauren ; Bekeová, Carmen ; Wang, Nadan ; Sivaramakrishnan, Aishwarya ; Tang, Hsin-Yao ; Seifert, Erin L

AbstractFriedreich’s ataxia is an inherited disorder caused by depletion of frataxin (FXN), a mitochondrial protein required for iron–sulfur cluster (ISC) biogenesis. Cardiac dysfunction is the main cause of death. Yet pathogenesis, and, more generally, how the heart adapts to FXN loss, remains poorly understood, though it is expected to be linked to an energy deficit. We modified a transgenic (TG) mouse model of inducible FXN depletion that permits phenotypic evaluation of the heart at different FXN levels and focused on substrate-specific bioenergetics and stress signaling. When FXN protein in the TG heart was 17% of normal, bioenergetics and signaling were not different from control. When, 8 weeks later, FXN was ~ 97% depleted in the heart, TG heart mass and cardiomyocyte cross-sectional area were less, without evidence of fibrosis or apoptosis. mTORC1 signaling was activated, as was the integrated stress response, evidenced by greater phosphorylation of eIF2α relative to total eIF2α, and decreased protein translation. We interpret these results to suggest that, in TG hearts, an anabolic stimulus was constrained by eIF2α phosphorylation. Cardiac contractility was maintained in the 97% FXN-depleted hearts, possibly contributed by an unexpected preservation of β-oxidation, though pyruvate oxidation was lower. Bioenergetics alterations were matched by changes in the mitochondrial proteome, including a non-uniform decrease in abundance of ISC-containing proteins. Altogether, these findings suggest that the FXN-depleted heart can suppress a major ATP-demanding process such as protein translation, which, together with some preservation of β-oxidation, could be adaptive, at least in the short term.

03 Jul 2023·Marine drugs

Protective Effect of Fucoxanthin on Zearalenone-Induced Hepatic Damage through Nrf2 Mediated by PI3K/AKT Signaling.

Article

Author: Metwally, Ashraf M ; Abu Zahra, Abdulmalek Mohammad ; Ben Ammar, Rebai ; Zahra, Hamad Abu ; Althnaian, Thnaian A ; Al-Ramadan, Saeed Y ; Abdulaziz Alamer, Sarah ; Alfwuaires, Manal

Hepatotoxic contaminants such as zearalenone (ZEA) are widely present in foods. Marine algae have a wide range of potential applications in pharmaceuticals, cosmetics, and food products. Research is ongoing to develop treatments and products based on the compounds found in algae. Fucoxanthin (FXN) is a brown-algae-derived dietary compound that is reported to prevent hepatotoxicity caused by ZEA. This compound has multiple biological functions, including anti-diabetic, anti-obesity, anti-microbial, and anti-cancer properties. Furthermore, FXN is a powerful antioxidant. In this study, we examined the effects of FXN on ZEA-induced stress and inflammation in HepG2 cells. MTT assays, ROS generation assays, Western blots, and apoptosis analysis were used to evaluate the effects of FXN on ZEA-induced HepG2 cell inflammation. Pre-incubation with FXN reduced the cytotoxicity of ZEA toward HepG2 cells. FXN inhibited the ZEA-induced production of pro-inflammatory cytokines, including IL-1 β, IL-6, and TNF-α. Moreover, FXN increased HO-1 expression in HepG2 by activating the PI3K/AKT/NRF2 signaling pathway. In conclusion, FXN inhibits ZEA-induced inflammation and oxidative stress in hepatocytes by targeting Nrf2 via activating PI3K/AKT signaling.

01 Sep 2022·Life Sciences

Protective role of ellagic acid and taurine against fluoxetine induced hepatotoxic effects on biochemical and oxidative stress parameters, histopathological changes, and gene expressions of IL-1β, NF-κB, and TNF-α in male Wistar rats

Article

Author: Meshkibaf, Mohammad-Hassan ; Kalantari-Hesari, Ali ; Beigi, Tayebeh ; Safi, Amir ; Ahmadi, Reza ; Satvati, Mahdi

PURPOSESHepatic bioactivation of fluoxetine (FXN) could increase free radicals' generation provoking hepatotoxicity. Therefore, the protective effects of ellagic acid (EA) and taurine (TAU) treatments against fluoxetine-induced liver damage in rats were examined.MATERIALS AND METHODSSixty four male Wistar rats were randomly assigned to 8 groups (n = 8). Group (1) Control, group (2) FXN, group (3) FXN + EA, group (4) FXN + TAU, group (5) FXN + EA + TAU, group (6) EA, group (7) TAU, and group (8) EA + TAU. Then, the serum and tissue parameters of the oxidative stress were examined.KEY FINDINGSFXN significantly raised serum MDA, protein carbonyl, lipid profile, ALT, AST, ALP, total bilirubin, serum IL-1β; and gene expressions of IL-1β, NF-κB, and TNF-α. Moreover, it significantly decreased HDL-C, ferric reducing antioxidant power (FRAP), catalase activity, vitamin C, and SOD activity in the liver compared to group 1. When compared to group 2, EA and TAU treatment dramatically increased antioxidant capacity and lowered hepatotoxic biochemical markers and cellular inflammation. Results also showed a protective effect of treatment against oxidative damage caused by hepatocytes' cytoarchitecture.SIGNIFICANCEOur study concluded the beneficial effects of EA and TAU on FXN-induced hepatotoxicity. These effects were derived from free radical scavenging properties and the anti-inflammatory effects related to IL-1β, NF-κB, and TNF-α gene expression inhibition.

100 Deals associated with FXN gene therapy (AavantiBio/Catalent Cell & Gene Therapy)

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Indication	Highest Phase	Country/Location	Organization	Date
Friedreich Ataxia	Preclinical	-	Aavantibio, Inc.Startup	-
Friedreich Ataxia	Preclinical	-	Catalent Cell & Gene Therapy	-
Friedreich Ataxia	Preclinical	US	Catalent Cell & Gene Therapy	-
Friedreich Ataxia	Preclinical	US	Aavantibio, Inc.Startup	-

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