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Implication of Mitochondrial Coenzyme Q10 (Ubiquinone) in Alzheimer’s Disease *
Published in Abhai Kumar, Debasis Bagchi, Antioxidants and Functional Foods for Neurodegenerative Disorders, 2021
Sayantan Maitra, Dibyendu Dutta
Targeting directly the mitochondria with antioxidant compounds was always one of the most considered therapeutic strategies in AD. In this regard, the lipophilic antioxidant CoQ10 can be a therapeutic strategy to alleviate the conditions associated with AD. CoQ10 possesses both activities of antioxidant and component of RCC. In a rat model for AD, CoQ10 prevented the cognitive decline [49]. CoQ10 possesses low bioavailability in the brain due to its high molecular weight. To overcome this issue, the mitoquinone mesylate (MitoQ) was optimized. The conjugation of ubiquinone with triphenylphosphonium (TPP) resulted in the formation of MitoQ. TPP is necessary to direct the target to mitochondria because it helps to cross the lipid bilayers accumulating on the negative site of mitochondrial membranes. MitoQ behaved as ROS scavenger and was tested in different AD model systems. It has been reported that MitoQ prevents oxidative damage; protects RCC activity; reduces Aβ peptide levels, synaptic loss, and astrogliosis; and improves cognitive functions [50,51].
Mitochondrial Dysfunction Linking Obesity and Asthma
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Naveen K. Bhatraju, Anurag Agrawal
Oxidative stress related tissue damage in the pathophysiology of asthma and metabolic syndrome is well known. However, supplementation of general antioxidants such as α-tocopherol (vitamin E), vitamin C did not show any beneficial effects in humans despite some effects in mouse models (Hemachandra Reddy 2011). Considering the fact that mitochondria are the major source of ROS, the failure of these antioxidants could be attributed to the non-targeted nature of their activity. This has been overcome by the mitochondria-targeted antioxidants, which alone or in combination with other general antioxidants, have been shown to be beneficial both in metabolic syndrome and asthma. For instance, an 8 week supplementation of 100mg coenzyme Q10 (CoQ10), a redox component of ETC, has been shown to be effective in improving insulin resistance of MetS patients (Raygan et al. 2016). In another open-label study involving steroid-dependent asthmatics, reduction in steroid usage has been observed after supplementation with a daily antioxidant cocktail containing 120 mg CoQ10, 400 mg Vitamin E and 250 mg vitamin C (Gazdik et al. 2002; Gvozdjáková et al. 2005). Mitochondria-targeted antioxidants such as mitoquinone mesylate (mitoQ), mitochondria-targeted vitamin E (mito-vit E), contain covalently linked alkyl triphenyl phosphonium that allows them to accumulate in the mitochondrial matrix at high concentrations. This helps in scavenging ROS at the source and thus could be more effective. However, human data for their beneficial effects is awaited.
Enhanced antioxidant capacity prevents epitranscriptomic and cardiac alterations in adult offspring gestationally-exposed to ENM
Published in Nanotoxicology, 2021
Amina Kunovac, Quincy A. Hathaway, Mark V. Pinti, Andrya J. Durr, Andrew D. Taylor, William T. Goldsmith, Krista L. Garner, Timothy R. Nurkiewicz, John M. Hollander
Maternal ENM exposure during gestation interferes with fetal development and has long-term consequences for offspring that persist into adulthood (Sun et al. 2013; Hougaard et al. 2015; Bommarito, Martin, and Fry 2017; Crispi, Miranda, and Gratacos 2018). The importance of the maternal environment are outlined by the developmental origins of health and disease (DOHaD) hypothesis and supported by an increasing number of studies (Swanson et al. 2009). The current study highlights how amplifying antioxidant capacity in the maternal environment can deter the maladaptive cardiovascular changes that persist into adulthood, regardless of the progeny’s genotype. Although transgenic expression provides a limitation to clinical uses of maternal antioxidant protection, we establish a basis for investigating other potential antioxidant protective strategies. One example is mitoquinone mesylate (MitoQ), a mitochondrial-targeted antioxidant that has shown promise in improving mitochondrial dysfunction, reducing hydrogen peroxide production, and enhancing antioxidant enzyme activity (Ribeiro Junior et al. 2018; Park et al. 2020). MitoQ also has the ability to prevent the long-term impacts of maternal cigarette smoke exposure on progeny by mitigating renal total ROS in the mothers and offspring at adulthood (Sukjamnong et al. 2018). Future investigations should aim to determine whether supplementation with antioxidant-boosting therapeutics during pregnancy can provide the same protective effect to progeny as maternal mPHGPx overexpression.
New therapeutic targets in chronic kidney disease progression and renal fibrosis
Published in Expert Opinion on Therapeutic Targets, 2020
Sandra Rayego-Mateos, Jose M. Valdivielso
Some antioxidants have been studied in experimental models and patients because of its potential in reducing mitochondrial oxidative stress. The treatment of rats with Coenzyme Q10 (CoQ10) or related compounds such as mitoquinone mesylate (MitoQ) showed an improvement of renal function and tubular damage in a model of DN [45]. Furthermore, there are some clinical trials testing the role of co-Q10 in CKD, ESRD, and associated diseases such as atherosclerosis, vascular dysfunction, and diabetes (NCT03579693; NCT00908297; NCT00307996; NCT00969956; NCT02364648). The dithiol a-lipoic acid, another mitochondrial targeting agent, demonstrated renoprotective effects in an experimental model of renal disease and hypertension [46,47]. Other natural polyphenolic compounds, such as curcumin and resveratrol, efficiently alleviated the altered biochemical and histopathological features in experimental models of AKI and CKD, by modulating NRF-2, hemooxigenase-1 (HO-1) and the NF-kB signaling pathway [48–50]. Furthermore, it has been described that resveratrol improved experimental renal fibrosis by decreasing the EMT process modulated by SIRT1, MMP7, and Transforming Growth Factor- β (TGF-β) signaling pathway [51]. Regarding studies in patients, there are several clinical trials that tested the effect of resveratrol in oxidative stress, inflammation, or serum levels of microbiota-derived uremic toxins associated with CKD (NCT03352895; NCT02433925; NCT03815786). In patients with DN, the study described a beneficial effect of resveratrol, decreasing urinary albumin excretion [52].
Emerging small and large molecule therapeutics for respiratory syncytial virus
Published in Expert Opinion on Investigational Drugs, 2020
Harrison C. Bergeron, Ralph A. Tripp
An atypical therapeutic drug is the mitochondrial ROS scavenger, mitoquinone mesylate (MitoQ), which has been examined in RSV–infected Vero and human alveolar basal epithelial (A549) cells. The interplay between RSV and host mitochondria is not fully understood [97], but the treatment of Vero cells with MitoQ has been shown to reduce RSV replication. For example, in primary human bronchial epithelial cells (pBECs), treatment with MitoQ 36 hpi resulted in a decrease in viral titers and genomes [98]. Treatment of BALB/c mice infected with RSV resulted in reduced viral titers, reduced inflammatory cell infiltrates including eosinophils and mononuclear cells around the bronchial airways and perivascular regions, and reduced levels of RANTES [98]. No other studies regarding targeting host mitochondria are available.