Fisetin ameliorates oxidative glutamate testicular toxicity in rats via central and peripheral mechanisms involving SIRT1 activation

Abstract

Objectives This study aimed to evaluate the potential mitigating effect of fisetin on monosodium glutamate (MSG)-induced testicular toxicity and investigate the possible involvement of silent mating type information regulation 2 homolog 1 (SIRT1) in this effect. Methods Forty male rats were divided into normal control, fisetin-treated, MSG-treated, and fisetin + MSG-treated groups. Testosterone, GnRH, FSH, and LH were measured in plasma, as well as SIRT1 and phosphorylated AMP-activated protein kinase (pAMPK) levels in testicular tissues using ELISA. Hydrogen peroxide (H 2 O 2 ), nitric oxide (NO), and reduced glutathione (GSH) were measured colorimetrically, while Nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) expression was relatively quantified using RT–PCR in testicular tissues. Results After 30 days, fisetin could ameliorate MSG-induced testicular toxicity by acting centrally on the hypothalamic-pituitary-gonadal axis, increasing plasma levels of GnRH, FSH, LH, and testosterone. Peripheral actions of fisetin on the testis were indicated as it increased testicular SIRT1 and pAMPK. Furthermore, it antagonized glutamate-induced oxidative stress by significantly lowering H 2 O 2 , NO, and relative NOX4 expression while significantly increasing reduced GSH levels. It also improved the architecture of the seminiferous tubules, reduced sperm abnormality, and increased sperm count. Discussion Fisetin ameliorates MSG-induced testicular toxicity via central and peripheral mechanisms making it a promising therapeutic target for male infertility.

Fisetin Delays Postovulatory Oocyte Aging by Regulating Oxidative Stress and Mitochondrial Function through Sirt1 Pathway

“…Sirt1 plays a crucial role during postovulatory oocyte aging [ 17 , 18 ] and has been shown to be upregulated by fisetin [ 25 , 26 ]. However, it is unknown whether fisetin can affect Sirt1 expression in oocytes.…”

“…Thus, Sirt1 may exert protective functions by regulating histone acetylation in oocytes. Fisetin can inhibit IL-1β-induced inflammatory responses, oxidative stress, and hepatic steatosis in humans and mice by increasing SIRT1 activity [ 25 , 26 , 27 ]. However, it is still unknown whether fisetin affects Sirt1 in oocytes.…”

Fisetin regulates the biological effects of rat nucleus pulposus mesenchymal stem cells under oxidative stress by sirtuin‐1 pathway

“…Fis has been tested as an activator of SIRT1, and the effects on SIRT1 have been found in many studies 38,39 . A recent study found that Fis activates SIRT1 to ameliorate oxidative glutamate testicular toxicity 40 . Also, it has been reported that Fis ameliorates alcohol‐induced liver injury by regulating SIRT1 41 .…”

“… 38 , 39 A recent study found that Fis activates SIRT1 to ameliorate oxidative glutamate testicular toxicity. 40 Also, it has been reported that Fis ameliorates alcohol‐induced liver injury by regulating SIRT1. 41 However, the potential protective effects of Fis on NPMSCs are unclear, and the mechanism of Fis function in NPMSCs is significant for us to research.…”

Natural Phytochemicals as SIRT Activators—Focus on Potential Biochemical Mechanisms

“…Interestingly, fisetin, as an activator of SIRT1, prevented germ cells from apoptosis caused by hydrogen peroxide. This effect was possibly achieved by the degradation of the transcription factor FOXO3a, which is the inductor of apoptosis [ 167 ]. The abovementioned studies allow us to imply that fisetin can lower the risk of oxidative stress-related degenerative diseases [ 168 ] and metabolic syndrome with its potential for the suppression of fat accumulation in obesity [ 162 ].…”