Protective effect of quercetin on lipopolysaccharide‑induced miscarriage based on animal experiments and network pharmacology

Wu,Shuangyu; Wu,Shuangyu; Tian,Ye; Tian,Ye; Zhang,Qiying; Zhang,Qiying; Fu,Zhujing; Fu,Zhujing; Lan,Huizhen; Lan,Huizhen; Zhou,Xuanle; Zhou,Xuanle; Ma,Ling; Ma,Ling; Lou,Yiyun; Lou,Yiyun

doi:10.3892/mmr.2024.13223

Protective effect of quercetin on lipopolysaccharide‑induced miscarriage based on animal experiments and network pharmacology

Authors:
- Shuangyu Wu
- Ye Tian
- Qiying Zhang
- Zhujing Fu
- Huizhen Lan
- Xuanle Zhou
- Ling Ma
- Yiyun Lou
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Affiliations: Department of Gynecology, Hangzhou Hospital of Traditional Chinese Medicine, Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310007, P.R. China
Published online on: April 10, 2024 https://doi.org/10.3892/mmr.2024.13223
Article Number: 99
Copyright: © Wu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Spontaneous abortion (SA) occurs in woman of child‑bearing age, jeopardizing their physical and mental health. Quercetin is a natural flavonoid, which exhibits a variety of pharmacological activities. However, the role and mechanisms of quercetin in SA still need to be further explored. Animal experiments were performed to examine the effect of quercetin in treating SA. Institute of Cancer Research mice were injected with lipopolysaccharide into the tail vein on the 7th day of gestation to establish a SA model. Gavage was performed during days 3‑8 of gestation with high‑, medium‑ and low‑dose of quercetin. Then the effect of quercetin on embryos was evaluated. Animal experiment showed that quercetin could remarkably reduce the embryo loss rate and increase the mean weight of surviving embryos to some degree. Furthermore, network pharmacology was employed to explore the underlying mechanisms of quercetin in the treatment of SA. Several databases were used to collect the targets of SA and quercetin. Protein‑protein interaction network, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed to elucidate the interactions between SA and quercetin. The relative mRNA expressions of several targets in uterine were detected by quantitative reverse transcriptase polymerase chain reaction (RT‑qPCR). Network pharmacology indicated that the effects of quercetin in treating SA were mainly related to hormone response and the modulation of defense response and inflammatory response, involving signaling pathways such as PI3K‑Akt, VEGF, MAPK and core targets such as AKT1, albumin, caspase‑3. RT‑qPCR showed that quercetin could up‑regulate AKT1, MAPK1, PGR, SGK1 and down‑regulate ESR1, MAPK3. The results showed that quercetin may modulate multiple signaling pathways by targeting core targets to prevent and treat SA.

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1	Zhao AM: Chinese expert consensus on diagnosis and treatment of spontaneous abortion (2020 edition). Chin J Pract Gynecol Obstet. 36:1082–1090. 2020.
2	Quenby S, Gallos ID, Dhillon-Smith RK, Podesek M, Stephenson MD, Fisher J, Brosens JJ, Brewin J, Ramhorst R, Lucas ES, et al: Miscarriage matters: The epidemiological, physical, psychological, and economic costs of early pregnancy loss. Lancet. 397:1658–1667. 2021. View Article : Google Scholar : PubMed/NCBI
3	Dimitriadis E, Menkhorst E, Saito S, Kutteh WH and Brosens JJ: Recurrent pregnancy loss. Nat Rev Dis Primers. 6:982020. View Article : Google Scholar : PubMed/NCBI
4	Larsen EC, Christiansen OB, Kolte AM and Macklon N: New insights into mechanisms behind miscarriage. BMC Med. 11:1542013. View Article : Google Scholar : PubMed/NCBI
5	Li HF, Shen QH, Li XQ, Feng ZF, Chen WM, Qian JH, Shen L, Yu LY and Yang Y: The efficacy of traditional Chinese medicine shoutai pill combined with western medicine in the first trimester of pregnancy in women with unexplained recurrent spontaneous abortion: A systematic review and meta-analysis. Biomed Res Int. 2020:74951612020.PubMed/NCBI
6	Shi YJ, Xie JH and Li XJ: Meta-analysis of pre-pregnancy intervention with Chinese medicinals for tonifying kidney and activating blood in patients with recurrent spontaneous abortion of pre-thrombotic state. Shandong J Tradit Chin Med. 41:744–752. 2022.
7	Wu T, Wang YZ, Li WL and Yu XH: Meta-analysis of tonifying kidney and invigorating spleen in the treatment of recurrent abortion. Chin J Gen Pract. 20:1056–1061. 2022.
8	Ahmad A, Tandon S, Xuan TD and Nooreen Z: A review on Phytoconstituents and Biological activities of Cuscuta species. Biomed Pharmacother. 92:772–795. 2017. View Article : Google Scholar : PubMed/NCBI
9	Donnapee S, Li J, Yang X, Ge AH, Donkor PO, Gao XM and Chang YX: Cuscuta chinensis Lam.: A systematic review on ethnopharmacology, phytochemistry and pharmacology of an important traditional herbal medicine. J Ethnopharmacol. 157:292–308. 2014. View Article : Google Scholar : PubMed/NCBI
10	Lu X, Lin CY, Zhang WQ, Cao R, Qin WH and Fan LL: Chemical components and pharmacological effect of Trib. Lorantheae in China: A review. Chin J Exp Tradit Med Form. 29:209–221. 2023.
11	Yang D, Wang T, Long M and Li P: Quercetin: Its main pharmacological activity and potential application in clinical medicine. Oxid Med Cell Longev. 2020:88253872020. View Article : Google Scholar : PubMed/NCBI
12	Li J, Sun Z, Luo G, Wang S, Cui H, Yao Z, Xiong H, He Y, Qian Y and Fan C: Quercetin attenuates trauma-induced heterotopic ossification by tuning immune cell infiltration and related inflammatory insult. Front Immunol. 12:6492852021. View Article : Google Scholar : PubMed/NCBI
13	Gansukh E, Nile A, Kim DH, Oh JW and Nile SH: New insights into antiviral and cytotoxic potential of quercetin and its derivatives-A biochemical perspective. Food Chem. 334:1275082021. View Article : Google Scholar : PubMed/NCBI
14	Hur HJ, Jeong YH, Lee SH and Sung MJ: Quercitrin ameliorates hyperlipidemia and hepatic steatosis in ovariectomized mice. Life (Basel). 10:2432020.PubMed/NCBI
15	Huang YY, Wang ZH, Deng LH, Wang H and Zheng Q: Oral administration of quercetin or its derivatives inhibit bone loss in animal model of osteoporosis. Oxid Med Cell Longev. 2020:60805972020. View Article : Google Scholar : PubMed/NCBI
16	van der Woude H, Ter Veld MG, Jacobs N, van der Saag PT, Murk AJ and Rietjens IM: The stimulation of cell proliferation by quercetin is mediated by the estrogen receptor. Mol Nutr Food Res. 49:763–771. 2005. View Article : Google Scholar : PubMed/NCBI
17	Patel RV, Mistry BM, Shinde SK, Syed R, Singh V and Shin HS: Therapeutic potential of quercetin as a cardiovascular agent. Eur J Med Chem. 155:889–904. 2018. View Article : Google Scholar : PubMed/NCBI
18	Reyes-Farias M and Carrasco-Pozo C: The anti-cancer effect of quercetin: molecular implications in cancer metabolism. Int J Mol Sci. 20:31772019. View Article : Google Scholar : PubMed/NCBI
19	Liu C, Liu DQ, Tian YK, Mei W, Tian XB, Xu AJ and Zhou YQ: The emerging role of quercetin in the treatment of chronic pain. Curr Neuropharmacol. 20:2346–2353. 2022. View Article : Google Scholar : PubMed/NCBI
20	Hosseini A, Razavi BM, Banach M and Hosseinzadeh H: Quercetin and metabolic syndrome: A review. Phytother Res. 35:5352–5364. 2021. View Article : Google Scholar : PubMed/NCBI
21	Tang F, Tang Q, Tian Y, Fan Q, Huang Y and Tan X: Network pharmacology-based prediction of the active ingredients and potential targets of Mahuang Fuzi Xixin decoction for application to allergic rhinitis. J Ethnopharmacol. 176:402–412. 2015. View Article : Google Scholar : PubMed/NCBI
22	Nogales C, Mamdouh ZM, List M, Kiel C, Casas AI and Schmidt HHHW: Network pharmacology: Curing causal mechanisms instead of treating symptoms. Trends Pharmacol Sci. 43:136–150. 2022. View Article : Google Scholar : PubMed/NCBI
23	He RP, Jin Z, Ma RY, Hu FD and Dai JY: Network pharmacology unveils spleen-fortifying effect of Codonopsis Radix on different gastric diseases based on theory of ‘same treatment for different diseases’ in traditional Chinese medicine. Chin Herb Med. 13:189–201. 2020.PubMed/NCBI
24	Shi QQ, Yan MQ, Yu HH, Chen QQ, Chen SH and Lyu GY: Effect of Yunkang oral liquid on preventing LPS-induced abortion and regulating immune tolerance in mice. Zhongguo Zhong Yao Za Zhi. 44:1227–1232. 2019.(In Chinese). PubMed/NCBI
25	Chen LL, Song C, Zhang Y, Li Y, Zhao YH, Lin FY, Han DD, Dai MH, Li W and Pan PH: Quercetin protects against LPS-induced lung injury in mice via SIRT1-mediated suppression of PKM2 nuclear accumulation. Eur J Pharmacol. 936:1753522022. View Article : Google Scholar : PubMed/NCBI
26	Li Q, Yin L, Si Y, Zhang C, Meng Y and Yang W: The bioflavonoid quercetin improves pathophysiology in a rat model of preeclampsia. Biomed Pharmacother. 127:1101222020. View Article : Google Scholar : PubMed/NCBI
27	Wierwille WW and Ellsworth LA: Evaluation of driver drowsiness by trained raters. Accid Anal Prev. 26:571–581. 1994. View Article : Google Scholar : PubMed/NCBI
28	Kim S, Chen J, Cheng T, Gindulyte A, He J, He S, Li Q, Shoemaker BA, Thiessen PA, Yu B, et al: PubChem 2023 update. Nucleic Acids Res. 51(D1): D1373–D1380. 2023. View Article : Google Scholar : PubMed/NCBI
29	Wang X, Shen Y, Wang S, Li S, Zhang W, Liu X, Lai L, Pei J and Li H: PharmMapper 2017 update: a web server for potential drug target identification with a comprehensive target pharmacophore database. Nucleic Acids Res. 45((W1)): W356–W360. 2017. View Article : Google Scholar : PubMed/NCBI
30	UniProt Consortium: UniProt: The universal protein knowledgebase in 2023. Nucleic Acids Res. 51(D1): D523–D531. 2023. View Article : Google Scholar : PubMed/NCBI
31	Hamosh A, Amberger JS, Bocchini C, Scott AF and Rasmussen SA: Online mendelian inheritance in man (OMIM^®): Victor McKusick's magnum opus. Am J Med Genet A. 185:3259–3265. 2021. View Article : Google Scholar : PubMed/NCBI
32	Stelzer G, Rosen N, Plaschkes I, Zimmerman S, Twik M, Fishilevich S, Stein TI, Nudel R, Lieder I, Mazor Y, et al: The GeneCards suite: From gene data mining to disease genome sequence analyses. Curr Protoc Bioinformatics. 54:1.30.1–1.30.33. 2016. View Article : Google Scholar : PubMed/NCBI
33	Piñero J, Ramírez-Anguita JM, Saüch-Pitarch J, Ronzano F, Centeno E, Sanz F and Furlong LI: The DisGeNET knowledge platform for disease genomics: 2019 Update. Nucleic Acids Res. 48(D1): D845–D855. 2020.PubMed/NCBI
34	Bardou P, Mariette J, Escudié F, Djemiel C and Klopp C: Jvenn: An interactive Venn diagram viewer. BMC Bioinformatics. 15:2932014. View Article : Google Scholar : PubMed/NCBI
35	Szklarczyk D, Kirsch R, Koutrouli M, Nastou K, Mehryary F, Hachilif R, Gable AL, Fang T, Doncheva NT, Pyysalo S, et al: The STRING database in 2023: Protein-protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Res. 51(D1): D638–D646. 2023. View Article : Google Scholar : PubMed/NCBI
36	Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B and Ideker T: Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res. 13:2498–2504. 2003. View Article : Google Scholar : PubMed/NCBI
37	Wang D and Wang XL: Mechanism of diosgenin in treatment of atherosclerosis based on network pharmacology, molecular docking and experimental validation. Chin Tradit Herb Drugs. 53:7783–7794. 2022.
38	Zhou Y, Zhou B, Pache L, Chang M, Khodabakhshi AH, Tanaseichuk O, Benner C and Chanda SK: Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun. 10:15232019. View Article : Google Scholar : PubMed/NCBI
39	Vaitsopoulou CI, Kolibianakis EM, Bosdou JK, Neofytou E, Lymperi S, Makedos A, Savvaidou D, Chatzimeletiou K, Grimbizis GF, Lambropoulos A and Tarlatzis BC: Expression of genes that regulate follicle development and maturation during ovarian stimulation in poor responders. Reprod Biomed Online. 42:248–259. 2021. View Article : Google Scholar : PubMed/NCBI
40	Brown MB, von Chamier M, Allam AB and Reyes L: M1/M2 macrophage polarity in normal and complicated pregnancy. Front Immunol. 5:6062014. View Article : Google Scholar : PubMed/NCBI
41	Chavan AR, Griffith OW and Wagner GP: The inflammation paradox in the evolution of mammalian pregnancy: Turning a foe into a friend. Curr Opin Genet Dev. 47:24–32. 2017. View Article : Google Scholar : PubMed/NCBI
42	Li Y, Zhang D, Xu L, Dong L, Zheng J, Lin Y, Huang J, Zhang Y, Tao Y, Zang X, et al: Cell-cell contact with proinflammatory macrophages enhances the immunotherapeutic effect of mesenchymal stem cells in two abortion models. Cell Mol Immunol. 16:908–920. 2019. View Article : Google Scholar : PubMed/NCBI
43	Liu PS, Chen YT, Li X, Hsueh PC, Tzeng SF, Chen H, Shi PZ, Xie X, Parik S, Planque M, et al: CD40 signal rewires fatty acid and glutamine metabolism for stimulating macrophage anti-tumorigenic functions. Nat Immunol. 24:452–462. 2023. View Article : Google Scholar : PubMed/NCBI
44	Wang L and He C: Nrf2-mediated anti-inflammatory polarization of macrophages as therapeutic targets for osteoarthritis. Front Immunol. 13:9671932022. View Article : Google Scholar : PubMed/NCBI
45	Zhang W, Fu ZT, Liu CG, Wang BL, Liu RD and Fan RH: Stimultaneous determination of six flavonoids in Semen Cuscutae by UPLC-MS/MS. J Shenyang Med Coll. 20:377–380. 2018.
46	Su BW, Wang H, Li YH, Pei HH, Zhu KX and Lu D: Contents of avicularin, quercetrin amd quercetin in Taxilli Herba harvested from different areas and time points. Chin J Hosp Pharm. 37:1922–1926. 2017.
47	Sun XM, Song H, Yan XJ, Hu Y, Xu BL, Zhao LZ and Li WL: Screening and determination of estrogen-like quality markers of Cuscuta chinensis. Chin Tradit Herb Drugs. 51:2671–2679. 2020.
48	Wu H, Hao LL, Li WL and Jin Y: Analysis of medication rules of traditional Chinese medicine in treatment of immunological recurrent abortion by data driven approach. Liaoning J Tradit Chin Med. 47:52–55. 2020.
49	Zhang J, Chen L, Zheng CH, Wang J, Xie D and Zhou YX: Effect of shoutai pills on Th1/Th2 cytokines in serum and endometrium of rats with stimulated ovulation. Curr Med Sci. 39:285–290. 2019. View Article : Google Scholar : PubMed/NCBI
50	Li YQ, Zhao F, Ji MM, Li K and Wang YH: Efficacy of Jiawei Shoutai Pill in the treatment of threatened miscarriage and its effect on reproductive immuno-endocrine function. Lishizhen Med Mater Med Res. 31:2971–2973. 2020.
51	Zhou H, Zhen XY, Wang H, Zeng Q, Deng LW and Ding WJ: Exploration of the mechanism differences between Shoutaiwan and Juyuanjian in reversing the pathology of decidual of spontaneous abortion patients based on the ‘uterine collaterals connecting the kidney’ and ‘fetal collaterals connecting the spleen’ theory. Chin J Exp Tradit Med Form. 28:186–200. 2022.
52	Hao XL, Wang DY, Gao J and Luo SP: Effect of modified Shoutai Pills on IL-17 in mice model of spontaneous abortion due to kidney deficiency. World J Integr Tradit West Med. 15:292–295. 2020.
53	Lou YY, Wu XT and Fu P: Effect of Chinese medicine on PI3K signaling pathway at the maternal-fetal interface of recurrent miscarriage of kidney deficiency type. Zhejiang J Tradit Chin Med. 54:564–566. 2019.
54	Zhang MY, Lou YY and Fu P: Effect of Huatai Antai Decoction regulating PI3K signaling pathway on endometrial decidulization in recurrent spontaneous abortion of kidney deficiency type. Zhejiang J Tradit Chin Med. 55:892–894. 2020.
55	Chiang SCC, Owsley E, Panchal N, Chaturvedi V, Terrell CE, Jordan MB, Mehta PA, Davies SM, Akeno N, Booth C and Marsh RA: Quercetin ameliorates XIAP deficiency-associated hyperinflammation. Blood. 140:706–715. 2022. View Article : Google Scholar : PubMed/NCBI
56	da Silva AB, Cerqueira Coelho PL, das Neves Oliveira M, Oliveira JL, Oliveira Amparo JA, da Silva KC, Soares JRP, Pitanga BPS, Dos Santos Souza C, de Faria Lopes GP, et al: The flavonoid rutin and its aglycone quercetin modulate the microglia inflammatory profile improving antiglioma activity. Brain Behav Immun. 85:170–185. 2020. View Article : Google Scholar : PubMed/NCBI
57	Olayinka J, Eduviere A, Adeoluwa O, Fafure A, Adebanjo A and Ozolua R: Quercetin mitigates memory deficits in scopolamine mice model via protection against neuroinflammation and neurodegeneration. Life Sci. 292:1203262022. View Article : Google Scholar : PubMed/NCBI
58	Liu W, Zhang M, Feng J, Fan A, Zhou Y and Xu Y: The influence of quercetin on maternal immunity, oxidative stress, and inflammation in mice with exposure of fine particulate matter during gestation. Int J Environ Res Public Health. 14:5922017. View Article : Google Scholar : PubMed/NCBI
59	Cao L, Tan C, Meng F, Liu P, Reece EA and Zhao Z: Amelioration of intracellular stress and reduction of neural tube defects in embryos of diabetic mice by phytochemical quercetin. Sci Rep. 6:214912016. View Article : Google Scholar : PubMed/NCBI
60	Zhou J, Li L, Pan X, Wang J, Qi Q, Sun H, Li C and Wang L: The effect of a traditional Chinese quadri-combination therapy and its component quercetin on recurrent spontaneous abortion: A clinical trial, network pharmacology and experiments-based study. Front Pharmacol. 13:9656942022. View Article : Google Scholar : PubMed/NCBI
61	Albini A and Noonan DM: Decidual-like NK cell polarization: From cancer killing to cancer nurturing. Cancer Discov. 11:28–33. 2021. View Article : Google Scholar : PubMed/NCBI
62	Hazan AD, Smith SD, Jones RL, Whittle W, Lye SJ and Dunk CE: Vascular-leukocyte interactions: Mechanisms of human decidual spiral artery remodeling in vitro. Am J Pathol. 177:1017–1030. 2010. View Article : Google Scholar : PubMed/NCBI
63	Hanna J, Goldman-Wohl D, Hamani Y, Avraham I, Greenfield C, Natanson-Yaron S, Prus D, Cohen-Daniel L, Arnon TI, Manaster I, et al: Decidual NK cells regulate key developmental processes at the human fetal-maternal interface. Nat Med. 12:1065–1074. 2006. View Article : Google Scholar : PubMed/NCBI
64	Hao F, Zhou X and Jin L: Natural killer cells: Functional differences in recurrent spontaneous abortion†. Biol Reprod. 102:524–531. 2020. View Article : Google Scholar : PubMed/NCBI
65	Gaynor LM and Colucci F: Uterine natural killer cells: Functional distinctions and influence on pregnancy in humans and mice. Front Immunol. 8:4672017. View Article : Google Scholar : PubMed/NCBI
66	Bruno A, Ferlazzo G, Albini A and Noonan DM: A think tank of TINK/TANKs: Tumor-infiltrating/tumor-associated natural killer cells in tumor progression and angiogenesis. J Natl Cancer Inst. 106:dju2002014. View Article : Google Scholar : PubMed/NCBI
67	Jabrane-Ferrat N: Features of human decidual NK cells in healthy pregnancy and during viral infection. Front Immunol. 10:13972019. View Article : Google Scholar : PubMed/NCBI
68	Haider S, Lackner AI, Dietrich B, Kunihs V, Haslinger P, Meinhardt G, Maxian T, Saleh L, Fiala C, Pollheimer J, et al: Transforming growth factor-β signaling governs the differentiation program of extravillous trophoblasts in the developing human placenta. Proc Natl Acad Sci USA. 119:e21206671192022. View Article : Google Scholar : PubMed/NCBI
69	Hu Y, Gui Z, Zhou Y, Xia L, Lin K and Xu Y: Quercetin alleviates rat osteoarthritis by inhibiting inflammation and apoptosis of chondrocytes, modulating synovial macrophages polarization to M2 macrophages. Free Radic Biol Med. 145:146–160. 2019. View Article : Google Scholar : PubMed/NCBI
70	Ediriweera MK, Tennekoon KH and Samarakoon SR: Role of the PI3K/AKT/mTOR signaling pathway in ovarian cancer: Biological and therapeutic significance. Semin Cancer Biol. 59:147–160. 2019. View Article : Google Scholar : PubMed/NCBI
71	Fresno Vara JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C and González-Barón M: PI3K/Akt signalling pathway and cancer. Cancer Treat Rev. 30:193–204. 2004. View Article : Google Scholar : PubMed/NCBI
72	Paskeh MDA, Ghadyani F, Hashemi M, Abbaspour A, Zabolian A, Javanshir S, Razzazan M, Mirzaei S, Entezari M, Goharrizi MASB, et al: Biological impact and therapeutic perspective of targeting PI3K/Akt signaling in hepatocellular carcinoma: Promises and challenges. Pharmacol Res. 187:1065532023. View Article : Google Scholar : PubMed/NCBI
73	Ding J, Yang C, Zhang Y, Wang J, Zhang S, Guo D, Yin T and Yang J: M2 macrophage-derived G-CSF promotes trophoblasts EMT, invasion and migration via activating PI3K/Akt/Erk1/2 pathway to mediate normal pregnancy. J Cell Mol Med. 25:2136–2147. 2021. View Article : Google Scholar : PubMed/NCBI
74	Song NR, Chung MY, Kang NJ, Seo SG, Jang TS, Lee HJ and Lee KW: Quercetin suppresses invasion and migration of H-Ras-transformed MCF10A human epithelial cells by inhibiting phosphatidylinositol 3-kinase. Food Chem. 142:66–71. 2014. View Article : Google Scholar : PubMed/NCBI
75	Halder JB, Zhao X, Soker S, Paria BC, Klagsbrun M, Das SK and Dey SK: Differential expression of VEGF isoforms and VEGF(164)-specific receptor neuropilin-1 in the mouse uterus suggests a role for VEGF(164) in vascular permeability and angiogenesis during implantation. Genesis. 26:213–224. 2000. View Article : Google Scholar : PubMed/NCBI
76	Nagashima T, Li Q, Clementi C, Lydon JP, DeMayo FJ and Matzuk MM: BMPR2 is required for postimplantation uterine function and pregnancy maintenance. J Clin Invest. 123:2539–2550. 2013. View Article : Google Scholar : PubMed/NCBI
77	Perdicaro DJ, Rodriguez Lanzi C, Gambarte Tudela J, Miatello RM, Oteiza PI and Vazquez Prieto MA: Quercetin attenuates adipose hypertrophy, in part through activation of adipogenesis in rats fed a high-fat diet. J Nutr Biochem. 79:1083522020. View Article : Google Scholar : PubMed/NCBI
78	Zhang J, Liu X and Gao Y: Abnormal H3K27 histone methylation of RASA1 gene leads to unexplained recurrent spontaneous abortion by regulating Ras-MAPK pathway in trophoblast cells. Mol Biol Rep. 48:5109–5119. 2021. View Article : Google Scholar : PubMed/NCBI
79	Cui S, Wu Q, Wang J, Li M, Qian J and Li S: Quercetin inhibits LPS-induced macrophage migration by suppressing the iNOS/FAK/paxillin pathway and modulating the cytoskeleton. Cell Adh Migr. 13:1–12. 2019. View Article : Google Scholar : PubMed/NCBI
80	Mor G, Aldo P and Alvero AB: The unique immunological and microbial aspects of pregnancy. Nat Rev Immunol. 17:469–482. 2017. View Article : Google Scholar : PubMed/NCBI
81	Ma LN, Huang XB, Muyayalo KP, Mor G and Liao AH: Lactic acid: A novel signaling molecule in early pregnancy? Front Immunol. 11:2792020. View Article : Google Scholar : PubMed/NCBI
82	He Y, Sun MM, Zhang GG, Yang J, Chen KS, Xu WW and Li B: Targeting PI3K/Akt signal transduction for cancer therapy. Signal Transduct Target Ther. 6:4252021. View Article : Google Scholar : PubMed/NCBI
83	Downward J: Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer. 3:11–22. 2003. View Article : Google Scholar : PubMed/NCBI
84	Shah S, Brock EJ, Ji K and Mattingly RR: Ras and Rap1: A tale of two GTPases. Semin Cancer Biol. 54:29–39. 2019. View Article : Google Scholar : PubMed/NCBI
85	Campbell BB, Galati MA, Stone SC, Riemenschneider AN, Edwards M, Sudhaman S, Siddaway R, Komosa M, Nunes NM, Nobre L, et al: Mutations in the RAS/MAPK pathway drive replication repair-deficient hypermutated tumors and confer sensitivity to MEK inhibition. Cancer Discov. 11:1454–1467. 2021. View Article : Google Scholar : PubMed/NCBI
86	Endo M, Yamamoto H, Setsu N, Kohashi K, Takahashi Y, Ishii T, Iida K, Matsumoto Y, Hakozaki M, Aoki M, et al: Prognostic significance of AKT/mTOR and MAPK pathways and antitumor effect of mTOR inhibitor in NF1-related and sporadic malignant peripheral nerve sheath tumors. Clin Cancer Res. 19:450–461. 2013. View Article : Google Scholar : PubMed/NCBI
87	Chuai Y, Rizzuto I, Zhang X, Li Y, Dai G, Otter SJ, Bharathan R, Stewart A and Wang A: Vascular endothelial growth factor (VEGF) targeting therapy for persistent, recurrent, or metastatic cervical cancer. Cochrane Database Syst Rev. 3:CD0133482021.PubMed/NCBI