Abstract
The major component of the Solenocera crassicornis head protein hydrolysates-fraction 1 (SCHPs-F1) are low molecular weight peptides (MW < 1 kDa). In this study, we investigated the potential renoprotective effects of SCHPs-F1 in a cyclophosphamide (CTX) toxicity mouse model. In brief, 40 male mice were randomly divided into 5 groups and received either saline or 80 mg/kg body weight (BW) CTX by intraperitoneal injection for 5 days, followed by either saline or SCHPs-F1 (100, 200, and 400 mg/kg BW) by intragastric administration for 15 days. SCHPs-F1 treatment significantly reversed the CTX-induced decreases in the levels of blood urea nitrogen (BUN), creatinine (CRE), and cytochrome P450 (CYP450), as well as the renal histological lesions. Furthermore, the results indicated that SCHPs-F1 potentially alleviated CTX-induced nephrotoxicity through mitigating inflammatory responses, oxidative stress, and apoptosis status of the kidneys, as evidenced by decreased levels of malondialdehyde (MDA), interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ and increased levels of total antioxidant capacity (T-AOC), catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). Moreover, overexpression of pro-apoptotic proteins pair B-cell lymphoma-2 (Bcl-2)-associated X (Bax)/Bcl-2, cysteinyl aspartate specific proteinase (caspase)-3 and caspase-9 in renal tissues were suppressed by treatment with SCHPs-F1. In addition, the protein levels of the antioxidant factor nuclear factor erythroid-2 related factor 2 (Nrf2) and the expression levels of its downstream target genes heme-oxygenase (HO-1), glutamate-cysteine ligase modifier subunit (GCLM) and NAD(P)H dehydrogenase (quinone) 1 (NQO-1) were stimulated by treatment with SCHPs-F1 in the CTX-induced renal injury model. Taken together, our data suggested that SCHPs-F1 could provide a novel potential strategy in mitigating the nephrotoxicity caused by CTX.
Highlights
Cyclophosphamide (CTX) is the most extensively used drug in clinical cancer chemotherapy, with a high therapeutic index and broad-spectrum anti-cancer effect
We further examined the effect of SCHPs-F1 on nephrocyte apoptosis in CTX-treated mice using the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay
The downstream antioxidant proteins HO-1, glutamate-cysteine ligase modifier subunit (GCLM), and NAD(P)H dehydrogenase (quinone) 1 (NQO-1), which are associated with nuclear factor erythroid-2 related factor 2 (Nrf2) protein expression, were notably up-regulated compared with mice that were treated with SCHPs-F1 only. These results revealed that SCHPs-F1 were able to mitigate renal oxidative stress following CTX-induction by increased Nrf2 expression and by up-regulating the activities of HO-1, GCLM, and NQO-1
Summary
Cyclophosphamide (CTX) is the most extensively used drug in clinical cancer chemotherapy, with a high therapeutic index and broad-spectrum anti-cancer effect. CTX needs to be converted into active metabolites to properly function in vivo [1]. Antioxidants 2020, 9, 745 organ toxicity caused by its metabolites has seriously limited the role of CTX in the comprehensive treatment of cancer [2]. The mechanism underlying the multiple organ toxicity of CTX has been examined in numerous studies, and it has been found to correlate with oxidative stress, inflammation, and apoptosis [3,4,5]. CTX exposure perturbs the redox balance and exhausts the antioxidant defense system of the kidneys, resulting in oxidative damage to the renal tissue. Inflammatory cascades were subsequently activated and involved in the up-regulation of apoptosis, leading to nephrocyte necrosis and apoptosis, disorganization of renal tissue, and renal dysfunction [6,7,8,9]
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