Abstract
Li-Ru-Kang (LRK), a formula of eight traditional Chinese medicines (TCM), has been used to treat hyperplasia of mammary gland (HMG) in TCM clinics. However, how LRK works in HMG patients is unclear. To explore the possible mechanisms of LRK against HMG, the network pharmacology was used to screen the potential targets and possible pathways that involved in LRK treated HMG. Rat HMG model induced by estrogen and progesterone was used to further verify the effects of the key molecules of LRK selected from the enriched pathways on HMG. Nipple heights and diameters were measured and uterus index was calculated. The histopathological changes of mammary gland tissue were detected by hematoxylin-eosin (H&E) staining. Western blot was used to detect the phosphorylation of ERK, JNK, and P38. And immunohistochemistry staining was performed to evaluate the levels of estrogen receptor α (ERα), progesterone receptor (PR), nuclear factor-(NF-)κB (p65), interleukin-1β (IL-1β), tumor necrosis factor α (TNF-α), cyclooxygenases 2 (COX-2), inducible nitric oxide synthase (iNOS), 8-hydroxy-2′deoxyguanosine (8-OHdG), and nitrotyrosine (NT). Our results indicate that LRK treatment rescues significantly nipples height and diameter, decreases uterus index and ameliorates HMG. LRK treatment also markedly attenuates the over-expression of IL-1β, TNF-α, COX-2, and iNOS, and suppressed the formation of 8-OHdG and NT. Furthermore, LRK treatment significantly inhibits the phosphorylation of JNK, ERK, and p38 and expression of NF-κB (p65), interestingly, LRK treatment has no effect on the expression of ERα and PR. Our data suggest that the LRK treatment protects the mammary glands from the damage of oxidative stress and inflammation induced by estrogen and progesterone, via suppresses of MAPK/NF-κB signaling pathways without affecting on the expression of ERα and PR.
Highlights
Hyperplasia of mammary gland (HMG), a common disease, occurs among middle-aged women with high frequency (Jia et al, 2017)
A total of 72 chemical constituents of LRK, 351 drug targets, 213 hyperplasia of mammary gland (HMG) targets and 358 interacting proteins were obtained from TCM Database@Taiwan (TDT), Herbal Ingredients’ Targets Database (HIT), Targets Database (TTD), Online Mendelian Inheritance in Man (OMIM), and Database of Interacting Proteins (DIP)
The ingredients, drug targets, disease targets and interacting proteins were connected for interaction network of “compound-target-disease” construction, which was presented with color-coded nodes (Figure 1A)
Summary
Hyperplasia of mammary gland (HMG), a common disease, occurs among middle-aged women with high frequency (Jia et al, 2017). It is a kind of pathological hyperplasia of lobules of mammary gland induced by the disorder of estrogen and progesterone (Bennett et al, 1990; Zhang et al, 2016). The morbidity of HMG is increasing nowadays with a risk of breast cancer (Chen et al, 2015). Tamoxifen is an estrogen antagonist with antiproliferative effects. It has been widely used for breast cancer as well as HMG (Cline et al, 1998; Li et al, 2018). It is important to discovery safer and more effective drugs with minimum side effects for HMG
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