Abstract
BackgroundDiminished ovarian reserve (DOR) significantly increases the risk of female infertility and contributes to reproductive technology failure. Recently, the role of melatonin in improving ovarian reserve (OR) has attracted widespread attention. However, details on the pharmacological targets and mechanisms of melatonin-improved OR remain unclear.ObjectiveA systems pharmacology strategy was proposed to elucidate the potential therapeutic mechanism of melatonin on DOR at the molecular, pathway, and network levels.MethodsThe systems pharmacological approach consisted of target identification, data integration, network construction, bioinformatics analysis, and molecular docking.ResultsFrom the molecular perspective, 26 potential therapeutic targets were identified. They participate in biological processes related to DOR development, such as reproductive structure development, epithelial cell proliferation, extrinsic apoptotic signaling pathway, PI3K signaling, among others. Eight hub targets (MAPK1, AKT1, EGFR, HRAS, SRC, ESR1, AR, and ALB) were identified. From the pathway level, 17 significant pathways, including the PI3K-Akt signaling pathway and the estrogen signaling pathway, were identified. In addition, the 17 signaling pathways interacted with the 26 potential therapeutic targets to form 4 functional modules. From the network point of view, by regulating five target subnetworks (aging, cell growth and death, development and regeneration, endocrine and immune systems), melatonin could exhibit anti-aging, anti-apoptosis, endocrine, and immune system regulation effects. The molecular docking results showed that melatonin bound well to all hub targets.ConclusionThis study systematically and intuitively illustrated the possible pharmacological mechanisms of OR improvement by melatonin through anti-aging, anti-apoptosis, endocrine, and immune system regulation effects.
Highlights
Infertility affects a significant proportion of humanity and is regarded as a global public health issue by the World Health Organization [1, 2]
From the molecular perspective, 26 potential therapeutic targets were identified. They participate in biological processes related to Diminished ovarian reserve (DOR) development, such as reproductive structure development, epithelial cell proliferation, extrinsic apoptotic signaling pathway, PI3K signaling, among others
The 17 signaling pathways interacted with the 26 potential therapeutic targets to form 4 functional modules
Summary
Infertility affects a significant proportion of humanity and is regarded as a global public health issue by the World Health Organization [1, 2]. Diminished ovarian reserve (DOR), defined as a reduction in both oocyte quality and quantity, is one of the most common causes of female infertility and poor ovarian response to controlled ovarian stimulation with a rapidly increasing occurrence rate [3, 4]. Devine et al reported that the prevalence of DOR increased from 19 to 26% in the past few years, representing a major challenge in reproductive medicine [8, 9]. Diminished ovarian reserve (DOR) significantly increases the risk of female infertility and contributes to reproductive technology failure. The role of melatonin in improving ovarian reserve (OR) has attracted widespread attention. Details on the pharmacological targets and mechanisms of melatonin-improved OR remain unclear
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