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  • br Materials and methods br Results br Discussion

    2019-11-08


    Materials and methods
    Results
    Discussion GOS potently inhibited SRD5A1 in COS-1 cells (Fig. 4A) and rat Leydig cells (Fig. 4B), possibly attenuating testosterone activation into DHT. It has been reported that gossypol inhibited human SRD5A1 with IC50 of 7 × 10−6 M [28]. Interestingly, gossypol preferred to block human SRD5A1 to SRD5A2 (IC50 = 21 × 10−6 M [28]. GOS exerted a noncompetitive inhibition on SRD5A1 against testosterone, indicating that it reduces SRD5A1 activity after binding equally well to the enzyme whether or not it has already bound to NADPH. GOS potently inhibited AKR1C14 (Fig. 4C and Fig. 4D). GOS inhibited AKR1C14 against DHT and NADPH cofactor in a mixed mode. Interestingly, GOS blocked several steroidogenic enzymes, including rat and human 3β-hydroxysteroid dehydrogenase [22], 17β-hydroxysteroid dehydrogenase 3 [22], 11β-hydroxysteroid dehydrogenase 1 [29] and 11β-hydroxysteroid dehydrogenase 2 [29], and placental 3β-hydroxysteroid dehydrogenase 1 [5] and aromatase [5]. However, whether it is a competitive or noncompetitive inhibitor depended upon the nature of the steroidogenic enzymes. Interestingly, GOS has lower energy to bind to the AKR1C14 than DHT, suggesting that it is potent inhibitor. Indeed, it inhibited AKR1C14 with IC50 value of 0.524 ± 0.064 × 10−6 M (Fig. 4C). Molecular docking study showed that GOS mostly bound to steroid-binding site. However, it also extends to the NADPH binding site, possibly explaining the mixed mode of inhibition by this compound.
    Introduction Neurodegenerative diseases as multifactorial disorders depend on various cellular mechanism such as mitochondrial dysfunction, neuroinflammation, glutamate excitatory, oxidative stress, disruption in iron hemostasis and lipid synthesis, protein aggregation and failure of autophagy. Mitochondrial dysfunction and lipid accumulation in the DAPI hydrochloride receptor have close cross talking with each other during neurodegeneration (Jodeiri Farshbaf et al., 2016b, Schwall et al., 2012). disruption in lipid hemostasis which is caused lipid accumulation in the brain could be hallmark for some neurological diseases (Walter and van Echten-Deckert, 2013, Kim et al., 2015). Intracellular lipid droplets (LDs) are the dynamic organelles which store lipids such as triacylglycerol and cholesterol esters and more intense in the adipose tissue (Greenberg et al., 2011). In neurodegenerative disorders high amount of ROS triggers lipid accumulation in neurons (Liu et al., 2015). Transportation of lipids in nervous system is regulated by apolipoproteins E and D (ApoE, D) (Huang and Mahle, 2014). Cellular stress, including inflammation and oxidative stress have potential roles in LDs biogenesis and formation (Khatchadourian et al., 2012, Younce and Kolattukudy, 2012). Therefore, LD formation could be the biomarker for neurodegeneration by the presentation of clinical symptoms (Liu et al., 2015). In this review, we document that focusing on the mitochondrial complex II could reveal new targets for therapeutic drug development for neurodegenerative disorders because of its potential in lipid metabolism.
    Mitochondria and neurodegeneration: Contribution of the mitochondrion to the neurodegenerative disorders such as AD, PD and HD candidates this organelle as therapeutic target. Mitochondria have their own circular DNA with 16,569 base pairs. Some components of the respiratory system, specific rRNA and tRNA are encoded by mtDNA (Lin and Beal, 2006). Mitochondria have wide ranges of physiological and cellular properties such as maintaining intracellular Ca homeostasis, lipid oxidation, ATP production, reduction-oxidation potential of the cell and apoptosis which all of them relevant to neurodegenerative disorders (Martin, 2010, Nicholls, 2002). Brain by having 2% of body weight uses 20% of oxygen consumption. ROS attacks lipids, DNA and protein in the neurons and causes neurodegeneration. Superoxide anion radical (O2·−), hydroxyl radical (·OH), non-radical oxidants such as H2O2 are categorized as ROS. Superoxide has the highest capacity of oxidation in the cell (Petlicki and van de Ven, 1998). Mitochondria is the main sources of the superoxide generation. Oxygen reaction with the electrons which are leaked from mitochondrial respiratory chain is the main reaction for production of the superoxide (Loschen et al., 1974). Superoxide dismutase (SOD) catalyzes dismutaion of superoxide radical to hydrogen peroxide (Fukai and Ushio-Fukai, 2011). Mn-dependent isoform (Mn SOD, SOD2) which is in the mitochondrial matrix (Weisiter and Fridovich, 1973). Complex I and III of the respiratory chain are the main sources of the ROS generation (Mailloux, 2015).