## 7 Mechanism of Action of _M. oleifera_ Extract on Oxidative Stress and Male Fertility  
_Moringa oleifera_ extracts possess anti-oxidative, anti-inflammatory, anti-diabetic, anti-obesity and anti-apoptotic properties [86; 126], which have been attributed to its polyphenols, flavonoids (particularly quercetin and kaempfer), phenolic acids, caffeoylquinic acid and isothi cyanates [127; 128]. The alkaloids, flavonoids, saponins, triterpenoids/steroids and tannins in _M. oleifera_ extract are powerful anti-oxidants that acts to prevent new free radicals and chain reactions and protects the cells from oxidative damage [129]. Figure 3 shows some mechanisms through which _M. oleifera_ extract inhibit the damaging effects of oxidative stress, thereby preventing male infertility. indicates increase; white arrows pointing downwards indicates a decrease. Indicated the regulatory/inhibitory role of Moringa oleifera extract. Obesity activates the adipocytes to further produce leptin and could lead to leptin resistance, which has been shown to inhibit the GnRH neurons due to the suppression of KISS1 neuron activities and increased NPY levels [130]. This, consequently, affects the HPG axis, by the impairment of the release of GnRH, FSH and LH, and ultimately impairs the functions of the reproductive cells, testosterone release and development and maturation of the spermatozoa [131]. Besides the reduction of food intake, the anti-obesity and anti-hyperglycaemic activities of _M. oleifera_ are brought about by the reduction of leptin levels by down regulating mRNA expression of leptin and resistin [132]. Additionally, hyperglycaemia may occur due to oxidative stress associated with obesity as it impedes the functioning of insulin and glucose utilisation by peripheral tissue [133]. Flavonoids, particularly quercetin, in the extracts has been shown to act as an apical inhibitor of glucose transporter 2, demonstrating its anti-hyperglycaemic activity [134]. Furthermore, the anti-hyperglycaemic activity of the plant extract is noted by the inhibition of \(\alpha\)-glucosidase, pancreatic \(\alpha\)-amylase and intestinal sucrose [135]. Figure 3: Mechanism of action of _Moringa oleifera_ (MO) extract on oxidative stress and male infertility. Abbreviations: CAT-catalase; FSH-follicle stimulating hormone; COX-2-cyclooxygenase -2; GLUT2-glucose transporter 2; G-6-pase-glucose 6-phosphatase; GPx-glutathione peroxidase; GSH-glutathione; HPA-hypothalamic-pituitary-adrenal axis; HPG-hypothalamic-pituitary-gonadal axis; IL-6-interleukin 6; iNOS-inducible nitric oxide synthase; LH-luteinizing hormone; mRNA-messenger RNA; NF-K9-nuclear factor kappa-light-chain-enhancer of activated B cells; NO-nitric oxide; ROS-reactive oxygen species; SOD-superoxide dismutase; StAR-steroidogenic acute regulatory protein, TAC-total anti-oxidant capacity; TNF-\(\alpha\)-tumour necrosis factor alpha. White arrows pointing up indicates increase; white arrows pointing downwards indicates a decrease. Indicated the regulatory/inhibitory role of Moringa oleifera extract. Inflammatory cytokines, including IL-1\(\beta\) and TNF-\(\alpha\), can increase the production of prostaglandin E2 (PGE-2), nitric oxide (NO), inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2) and microsomal PGE synthase-1 (mPGES-1) as well as their expression in target cells [136]. _M. Oleifera_ has also been shown to reduce the production of inflammatory cytokines, such as of TNF-\(\alpha\) and IL-6 [126], as well as inhibit the expression of RelA, a gene involved in NF-kB p65 signalling during inflammation [137]. Cortisol and leptin, respectively, produce a primary and secondary negative feedback mechanism for the HPA axis [138], which is critical in maintaining equilibrium under stressful conditions. Chronic psychological stress, for instance, can bring about dysregulation of cortisol [139]. The high levels of ROS result in the release of cortisol (stress hormone), which is usually activated by the HPA axis.