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There is a global trend toward employing natural supplements to protect against drug-related side effects (El-Rahman et al. 2020; Hashem et al. 2020; Mohamed et al. 2019b). Specifically, many in vivo studies revealed that natural antioxidants could effectively protect against drug-induced ototoxicity (Aksoy et al. 2015; Fetoni et al. 2015; Heinrich et al. 2008). Curcumin (CCM), the Curcuma longa Linn yellow pigment, is a potent inhibitor of ROS formation (Biswas et al. 2005). As a result, CCM showed beneficial roles in a variety of health problems such as autoimmune diseases (Aggarwal and Harikumar 2009), cancer (Momtazi and Sahebkar 2016), diabetes mellitus (Pivari et al. 2019), and liver disease (Abd-Elhakim et al. 2021c; Jalali et al. 2020). Also, CCM has strong anti-inflammatory (Aggarwal and Harikumar 2009), antiapoptotic (Abd-Elhakim et al. 2021b), antigenotoxic (Saber et al. 2019), and immunostimulant (Mollazadeh et al. 2019) activities. Besides, CCM has shown important protective effects against widespread ototoxic substances and hearing disorders (Bucak et al. 2015; Soyalıç et al. 2017; Soyalıç et al. 2016). In addition, CCM protected cochlear fibroblasts from diabetes-related oxidative damage in rat models (Haryuna et al. 2017). Moreover, CCM decreased the apoptotic index in the cochlea lateral wall in ototoxic rat models produced by intratympanic injection of GEN for 18 h (Haryuna et al. 2018). Furthermore, the downregulation of NF-κB expression in the main cochlear structures has been proposed as underlying mechanism of the protective effect of CCM against cisplatin-induced ototoxicity (Paciello et al. 2020).
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Cumulative evidence verified the critical role of oxidative stress and apoptosis in GEN- and NaS-induced ototoxic effects (Park et al. 2017; Stypulkowski 1990). Herein, GEN and NaS considerably depleted CAT activity and GSH content but raised serum MDA and caspase-3 immunoexpression in inner ear tissue. In vitro and in vivo studies, GEN has been shown to enhance ROS generation and promote apoptotic events (Bustos et al. 2016; Bustos et al. 2018; Mohamed et al. 2019a). Also, GEN has been reported to deplete the antioxidant activity (Haryuna et al. 2017) but increase the apoptotic index (Haryuna et al. 2018) in the lateral wall of the cochlea fibroblasts. Despite the distinguished antioxidant effect of low doses of NaS (Yiannakopoulou and Tiligada 2009), NaS can be a prooxidant that promotes cell death at high doses. Deng et al. (2013) have documented that high NaS levels led to radical superoxide upregulation and apoptosis of spiral ganglion neurons in vitro. NaS-induced apoptosis was also demonstrated by p38-activated mitogen protein kinases leading to the Caspase-3 activation (Lee et al. 2003). The oxidative and lipid peroxidative damage and apoptotic activity caused by GEN and NaS thus elucidate the loss of hair cells detected during cochlear histopathology.
The CCM otoprotective ability may be closely related to its potent antioxidant and antiapoptotic activities. Correspondingly, CCM usage decreased cellular apoptosis and had a profound safety effect on auditory function in an acoustic trauma rat model (Soyalıç et al. 2017). CCM also stopped caspase-3 activation, modifying the expression of the Bcl-2 family in spiral ganglion neurons activated by peroxynitrite (Liu et al. 2011). Moreover, CCM significantly counteracted the apoptotic events resulting from intratympanic injection of GEN for 18 h and diabetes mellitus-induced oxidative stress in the lateral wall of the cochlea fibroblasts (Haryuna et al. 2017; Haryuna et al. 2018). One or more interactions may be part of the proposed antioxidant mechanism of CCM, like neutralizing or scavenging free radicals, preventing oxidative cascades, quenching oxygen, inhibiting oxidative enzymes, and deactivating toxicants oxidative properties (Rao 1994; Unnikrishnan and Rao 1995). Moreover, CCM's antioxidant action is closely tied to its conjugating structure, consisting of two methoxylated phenols and an enol diketone that traps radicals (Masuda et al. 2001). Besides, CCM therapy stimulates detoxification enzymes due to free radical scavenging and lysosomal release inhibition (Manikandan et al. 2004). In addition, CCM helps to protect the integrity of the cell membrane when there are toxicants by peroxidation prevention (Sankar et al. 2012).
The principal component analysis is a popular multivariate statistical approach since it separates samples using a two-dimensional projection (Granato et al. 2018). The loading plot results showed a strong correlation between the measured parameter responses. A strong positive correlation exists between hearing function indicators and antioxidants level in this study. Correspondingly, numerous previous studies have demonstrated that endogenous antioxidant deficiency is significantly associated with hearing loss (Seidman et al. 2002; Tavanai and Mohammadkhani 2017). 041b061a72