Abstract

   Resveratrol and quercetin have effects on polycystic ovary syndrome
   (PCOS). Hence, resveratrol combined with quercetin may have better
   effects on it. However, because of the limitations in animal and human
   experiments, the pharmacological and molecular mechanism of
   quercetin-resveratrol combination (QRC) remains to be clarified. In
   this research, a systematic pharmacological approach comprising
   multiple compound target collection, multiple potential target
   prediction, and network analysis was used for comparing the
   characteristic of resveratrol, quercetin and QRC, and exploring the
   mechanism of QRC. After that, four networks were constructed and
   analyzed: (1) compound-compound target network; (2) compound-potential
   target network; (3) QRC-PCOS PPI network; (4) QRC-PCOS-other human
   proteins (protein-protein interaction) PPI network. Through GO and
   pathway enrichment analysis, it can be found that three compounds focus
   on different biological processes and pathways; and it seems that QRC
   combines the characteristics of resveratrol and quercetin. The in-depth
   study of QRC further showed  more PCOS-related biological processes and
   pathways. Hence, this research not only offers clues to the researcher
   who is interested in comparing the differences among resveratrol,
   quercetin and QRC, but also provides hints for the researcher who wants
   to explore QRC’s various synergies and its pharmacological and
   molecular mechanism.

   Subject terms: Reproductive disorders, Medical research

Introduction

   Polycystic ovary syndrome (PCOS) is one of the most common female
   endocrine diseases characterized by hyperandrogenism, menstrual
   disorders and infertility. The prevalence of PCOS is estimated at
   6–18%^[33]1,[34]2. PCOS is associated with a variety of factors, such
   as systemic inflammation, endothelial dysfunction, endocrine and
   metabolic disorders and dyslipidemia^[35]3,[36]4. Currently, lots of
   evidence has shown that PCOS is usually associated with hyperlipidemia,
   decreased glucose tolerance, cardiovascular disease, type 2 diabetes,
   cancer and hypertension^[37]5,[38]6. In clinical, the main pharmacology
   options of PCOS are anti-androgen, oral contraceptives and so on.
   However, the treatment of PCOS remains a major challenge in obstetrics
   and gynecology. For example, metformin, as a first-line treatment for
   PCOS, can reduce peripheral blood glucose and insulin levels; however,
   long-term use may result in side effects such as gastrointestinal
   discomfort.

   Although the etiology of PCOS is still unclear, plenty of evidence has
   suggested that hyperandrogenism and inflammation are the key
   factors^[39]7–[40]10. Evidence also suggests that resveratrol and
   quercetin, the nature polyphenolic compounds, may be the potential
   novel drugs for hyperandrogenism. Latest clinical trials have found
   that resveratrol can significantly reduce ovarian and adrenal
   androgens, and improve insulin sensitivity^[41]11. Animal experiments
   also show that in PCOS rat models, resveratrol can improve plasma
   anti-Mullerian hormone levels, IGF-1 levels and oxidative stress
   parameters; and it also reduces rat theca-interstitial cell growth in
   vitro and inhibits insulin-induced rat theca-interstitial cell
   growth^[42]12,[43]13. Another clinical trial about quercetin shows that
   quercetin effectively improves adiponectin - mediated insulin
   resistance^[44]14. And the animal experiments also suggest that in PCOS
   rat models, quercetin can inhibit Toll-like receptor/NF-κB signaling
   pathway and improve the ovarian inflammatory microenvironment
   (Interleukin [IL] 1β, IL-6 and tumor necrosis factor [TNF] -α).
   Moreover, quercetin can also inhibit phosphoinositide 3-kinase (PI3K)
   inhibition and decrease CYP17A1 gene expression^[45]15.

   According to these references, it appears that resveratrol combined