Abstract
This study investigated the effect of recombinant human lactoferrin (rhLF) on the premature ovarian failure (POF) of rats. After cyclophosphamide treatments, the POF rats were divided into the following groups: normal control group (NC), low-dose group (LD), medium-dose group (MD) and high-dose group (HD) of rhLF. After drug administrations, the ovarian indexes and hormonal levels were detected. After follicle number count, the proliferation and apoptosis were analyzed with the expressions of genes related with oogenesis, reactive oxygen species (ROS) production and apoptosis detected, followed by the calculation of oxidative stress and protein expressions. After 4-hydroperoxy cyclophosphamide (4-HC) treatments, the effect of rhLF on the proliferation, ROS production and gene expressions of primary rat granulosa cells (GCs) cultured in vitro were detected. After mating, the fertilities of POF rats were recorded. The result showed that the rhLF administrations up-regulated the ovarian index with the number of developing follicles increased and the decreases of hormonal levels conferred. The Ki-67 intensities of the MD and HD groups were up-regulated with the Tunnel intensities decreased. The rhLF treatments significantly promoted the expression of oogenesis, antioxidant and anti-apoptosis related genes. The expression of Bax and Caspase 3 were decreased with the expression of Bcl-2 up-regulated after rhLF administrations. The in vitro treatments of rhLF effectively conferred the toxicity of 4-HC on primary rat GCs. The fertility assessment showed the rhLF treatments up-regulated the offspring’s’ folliculogenesis, which confirmed the ameliorative role of rhLF on the POF damages via the inhibition of ROS production in GCs.
Highlights
During the past decades, the incidence and mortality of female reproductive tumors, including cervical carcinoma, endometrial carcinoma and ovarian carcinoma have been rapidly growing worldwide [3]
The physiological states of CTX-induced premature ovarian failure (POF) rats after recombinant human lactoferrin (rhLF) administrations First of all, the body weight of each rat after CTX treatments was examined to ensure the availabilities of the following experimental data and the results showed there were no significant differences among the body weight of 80 rats after CTX treatments
The results of ovarian index analyses showed that the ovarian indexes in all rhLF administration groups were significantly increased (Fig. 1c) in comparison with the normal control group (NC) group (P < 0.05), which indicated that the rhLF administrations significantly ameliorated the abnormal estrous cycles and improved the ovarian development of CTX-induced POF rats
Summary
The incidence and mortality of female reproductive tumors, including cervical carcinoma, endometrial carcinoma and ovarian carcinoma have been rapidly growing worldwide [3]. Due to the cellular toxicity, multidrug resistance (MDR) and reproductive disorders during the long term medication of anti-cancer drugs, the present application of anti-cancer drugs and recovery after drug administration still need to be further optimized for the development of more-effective personalized therapies [9, 10, 54] Among these numerous chemotherapy drugs targeting mitochondria activities [including apoptotic related proteins, cytochrome c, caspase 3, caspase 9 and reactive oxygen species (ROS)] [1, 69, 77], endoplasmic reticulum stress (including inositol-requiring enzyme 1α, PKR-like ER kinase and activating transcription factor 6α) [8], nucleus (including nucleolar phosphorprotein, nuclear pore complex and nuclear localization signal) [28, 64], tumor microenvironments [26, 41, 71] and plasma membrane phospholipids [20, 31, 32], cyclophosphamide (CTX), as an orally active alkylating agent, has been widely used as an utilized antineoplastic drug for the clinical treatment of ovarian, breast, testicular and hematological tumors [16]. Lactoferrin (LF) has been reported with the suppression abilities of oxidative stress-induced toxicities and cellular apoptosis [17, 38, 42, 49, 50]
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