Anthocyanins from Lycium ruthenicum Murray Mitigate Cadmium-Induced Oxidative Stress and Testicular Toxicity by Activating the Keap1/Nrf2 Signaling Pathway

Abstract

Cadmium (Cd) is a hazardous heavy metal environmental pollutant that has carcinogenic, teratogenic, and mutagenic properties. Excessive exposure to Cd can induce oxidative stress, which greatly harms the male reproductive system. Anthocyanins have remarkable antioxidative, anti-inflammatory, and anti-stress properties. In this study, we investigated the effects of anthocyanins and the underlying mechanisms through which anthocyanins mitigate Cd-induced reproductive damage. We isolated and purified Lycium ruthenicum Murray anthocyanin extract (LAE) and performed UHPLC-MS/MS to identify 30 different anthocyanins. We established an ICR mouse Cd injury model by administering 5 mg/kg/day CdCl2 for 28 consecutive days. LAE at 500 mg/kg/day effectively ameliorated testicular damage and preserved spermatogenesis. The mice in the LAE-treated group had elevated testosterone and inhibin B levels. Additionally, the treatment restored the activity of antioxidant enzymes, including T-SOD, CAT, and GR, and substantially increased the levels of the non-enzymatic antioxidant GSH. Research findings indicate that LAE can activate the SIRT1/Nrf2/Keap1 antioxidant pathway. This activation is achieved through the upregulation of both the SIRT1 gene and protein levels, leading to the deacetylation of Nrf2. Moreover, LAE reduces the expression of Keap1, alleviating its inhibitory effect on Nrf2. This, in turn, facilitates the uncoupling process, promoting the translocation of Nrf2 to the nucleus, where it governs downstream expression, including that of HO-1 and GPX1. LAE effectively mitigated toxicity to the reproductive system associated with exposure to the heavy metal Cd by alleviating oxidative stress in the testes.

Petanin Potentiated JNK Phosphorylation to Negatively Regulate the ERK/CREB/MITF Signaling Pathway for Anti-Melanogenesis in Zebrafish

“…Zolamide and methoxomicillin could significantly increase the activities of CAT and POD in zebrafish [ 31 ]. Anthocyanins could significantly reduce the activities of CAT and GR but could significantly restore the activities of oxidoreductase [ 32 ]. The coenzyme Q10 and ellagic acid down-regulate the α-MSH signaling pathway and/or induce Nrf2/ARE-mediated depigmentation activity of antioxidant genes; phenolics reduce melanogenesis in B16F10 cells, and zebrafish indicate that oxidative stress has an important effect on melanogenesis [ 33 , 34 , 35 ].…”

“…doreductase [32]. The coenzyme Q10 and ellagic acid down-regulate the α-MSH signaling pathway and/or induce Nrf2/ARE-mediated depigmentation activity of antioxidan genes; phenolics reduce melanogenesis in B16F10 cells, and zebrafish indicate that oxida tive stress has an important effect on melanogenesis [33][34][35].…”

Type 1 diabetes impairs the activity of rat testicular somatic and germ cells through NRF2/NLRP3 pathway-mediated oxidative stress

“…Worthy of note is that NRF2 seems to be a vital regulator of the molecular mechanisms that cause male infertility. In fact, several studies suggest that the function of NRF2 plays a crucial role in protecting spermatogenesis when an excessive amount of ROS is produced ( 77 ) as in the case of exposure to environmental pollutants ( 78 , 79 ), aging ( 80 ), and metabolic disorder ( 17 , 81 ). This protection, in turn, preserves specific sperm functions, particularly motility, which could otherwise be compromised under conditions of increased ROS exposure.…”

Protective Effects of Lycium ruthenicum Murray against Acute Alcoholic Liver Disease in Mice via the Nrf2/HO-1/NF-κB Signaling Pathway

“…The TAC was represented by the equivalent of petunia (Pt g/100 g) and determined by Formula (1): where, Δ A is the difference between pH 1.0 (A 532 nm–A 700 nm) and pH 4.5 (A 532 nm–A 700 nm); MW represents the molecular weight (Pt’s molar mass is 912.7 g/mol). DF indicates the dilution coefficient; V represents the volume extracted (mL); ε is the molar extinction coefficient (29,591 for Pt, L·mol –1 ·cm –1 ); 1 is the cupola thickness (1 cm); m is the sample weight in g; and 10 is the conversion factor from g to 100 g [ 18 , 74 ].…”

“…Thus, it helps the body protect against oxidative stress and reduce free radical damage [ 15 , 16 , 17 ]. Dong Mingran et al [ 18 ] discovered that LRM can activate the antioxidant pathway SIRT1/Nrf2/Keap1, thereby reducing the reproductive toxicity caused by exposure to the heavy metal Cd by easing oxidative stress in the testes. LRM likely modulates inflammatory factors, such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) [ 19 , 20 , 21 ], and inhibits inflammatory pathways with its bioactive components.…”