Oxidative testicular injury: effect of l-leucine on redox, cholinergic and purinergic dysfunctions, and dysregulated metabolic pathways

Abstract

The antioxidant and anti-proinflammatory activities of l-leucine were investigated on oxidative testicular injury, ex vivo. In vitro analysis revealed l-leucine to be a potent scavenger of free radicals, while inhibiting acetylcholinesterase activity. Oxidative injury was induced in testicular tissues using FeSO 4 . Treatment with l-leucine led to depletion of oxidativeinduced elevated levels of NO, MDA, and myeloperoxidase activity, with concomitant elevation of reduced glutathione and non-protein thiol levels, SOD and catalase activities. l-leucine caused a significant (p < 0.05) alteration of oxidative-elevated acetylcholinesterase and chymotrypsin activities, while concomitantly elevating the activities of ATPase, ENTPDase and 5′-nucleotidase. l-leucine conferred a protective effect against oxidative induced DNA damage. Molecular docking revealed molecular interactions with COX-2, IL-1 beta and iNOS. Treatment with l-leucine led to restoration of oxidative depleted ascorbic acid-2-sulfate, with concomitant depletion of the oxidative induced metabolites: D-4-Hydroxy-2-oxoglutarate, l-cystine, adenosine triphosphate, maleylacetoacetic acid, cholesteryl ester, and 6-Hydroxy flavin adenine dinucleotide. Treatment with l-leucine reactivated glycolysis while concomitantly deactivating oxidative-induced citrate cycle and increasing the impact-fold of purine metabolism pathway. l-leucine was predicted not to be an inhibitor of CYP1A2, CYP2C19, CYP2C9, CYP2D6, and CYP3A4, with a predicted LD 50 value of 5000 mg/Kg and toxicity class of 5. Additionally, l-leucine showed little or no in vitro cytotoxicity in mammalian cells. These results suggest the therapeutic potentials of l-leucine on oxidative testicular injury, as evident by its ability to attenuate oxidative stress and proinflammation, while stalling cholinergic dysfunction and modulating nucleotide hyrolysis; as well as modulate oxidative dysregulated metabolites and their pathways.

Strawberry fruit ( Fragaria x ananassa Romina) juice attenuates oxidative imbalance with concomitant modulation of metabolic indices linked to male infertility in testicular oxidative injury

“…The suppressed acetylcholinesterase activity in following treatment with strawberry fruits, therefore, indicates an improved cellular availability of acetylcholine for normal testicular physiology. This corroborates reports on the efficacy of acetylcholinesterase inhibitors for treating and managing testicular dysfunctions (Erukainure, Atolani, et al., 2021; Uzun et al., 2009). Strawberries have been reported previously for their ability to inhibit acetylcholinesterase activity (Erukainure, Salau, Oyenihi, et al., 2020; Hwang et al., 2019), and can also be attributed to the HPLC‐identified phenolics (Table 1).…”

Ocimum tenuiflorum mitigates iron‐induced testicular toxicity via modulation of redox imbalance, cholinergic and purinergic dysfunctions, and glucose metabolizing enzymes activities

“…Studies have shown the involvement of oxidative stress on enhanced acetylcholinesterase activity (Rodriguez‐Diaz et al., 2011). The elevated ACTh activity (Figure 4) on the induction of oxidative testicular injury may have emanated from oxidative stress in the testicular tissues, as described in previous studies (Erukainure, Atolani et al., 2021; Erukainure et al., 2021). Additionally, the negative binding energies of the infusion phytochemicals with ACTh protein (Table 2) may also portray its ACTh inhibitory properties.…”

“…In prostate cancer cells, elevated ATPase activity was reported to enhance motility and invasion (Michel et al., 2013). The high ATPase activity in the untreated (Figure 5) may indicate acid/base imbalance in testicular tissue owing to the oxidative onslaught as well as depleted levels of ATP (Erukainure, Atolani et al., 2021). Moreover, spermatozoa survival and functionality critically rely on the maintenance of testis tubule pH within the physiology range (Nishigaki et al., 2014).…”

Effects of varicocele and microsurgical varicocelectomy on the metabolites in semen

“…However, clinically, there are infertile patients who have improved semen quality by taking compound amino acid capsules. Also, a reduction in the levels of leucine will result in a reduction in antioxidant and anti-inflammatory ability 27 . Furthermore, a reduction of glutamic acid will lead to a reduction in acid resistance, thus making sperm vulnerable to damage 28 .…”