Abstract
Introduction
Excessive inflammation results in adverse pregnancy outcomes, including embryonic resorption, fetal growth restriction, and preeclampsia. This study investigated whether curcumin, a highly safe anti-inflammation drug, had protective effect on lipopolysaccharide (LPS)-treated pregnant mice.
Method
A mouse model of LPS-induced adverse pregnancy outcomes was generated by daily administering LPS from GD 13.5 to GD 16.5. Curcumin was given from GD 0.5. The effects of curcumin on maternal hypertension, proteinuria, pregnancy outcomes, as well as proinflammatory factors, chemokines, Akt, JNK, and P38 levels in placenta were examined.
Results
Systolic blood pressure (156.6 ± 5.056 versus 125.5 ± 3.617 mmHg; P < 0.05) and proteinuria (22.36 ± 2.22 versus 12.70 ± 1.04 mg/L; P < 0.05) were decreased in the LPS+curcumin-treated group, as compared with the LPS-treated group. Curcumin also increased the number of live pups, fetal weight, and placental weight, while it decreased fetal resorption rate. Moreover, increased placental TNF-α, IL-1β, and IL-6 expressions in LPS-treated group were significantly suppressed after curcumin administration. Furthermore, decreased p-Akt level in placenta induced by LPS was improved by curcumin. Of note, the expression of p-Akt increased by curcumin was accompanied by the decreased chemokines MCP-1 and MIP-1 levels and fewer CD68-positive macrophages in the placenta.
Conclusion
Curcumin inhibited the expression of proinflammatory factors and macrophage infiltration in placenta and ameliorated LPS-induced adverse pregnancy outcomes in mice by inhibiting inflammation via upregulation of phosphorylated Akt.
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References
Cappelletti M, Della Bella S, Ferrazzi E, Mavilio D, Divanovic S. Inflammation and preterm birth. J Leukoc Biol. 2016;99(1):67–78.
Fox C, Eichelberger K. Maternal microbiome and pregnancy outcomes. Fertil Steril. 2015;104(6):1358–63.
Kunnen A, van Pampus MG, Aarnoudse JG, van der Schans CP, Abbas F, Faas MM. The effect of Porphyromonas gingivalis lipopolysaccharide on pregnancyin the rat. Oral Dis. 2014;20(6):591–601.
Cotechini T, Komisarenko M, Sperou A, Macdonald-Goodfellow S, Adams MA, Graham CH. Inflammation in rat pregnancy inhibits spiral artery remodeling leading to fetal growth restriction and features of preeclampsia. J Exp Med. 2014;211(1):165–79.
Xue P, Zheng M, Gong P, Lin C, Zhou J, Li Y, Shen L, Diao Z, Yan G, Sun H, Hu Y. Single administration of ultra-low-dose lipopolysaccharide in rat early pregnancy induces TLR4 activation in the placenta contributing to preeclampsia. PLoS One. 2015;10(4):e0124001.
Collins S, Ramsay M, Slack MP, Campbell H, Flynn S, Litt D, Ladhani SN. Risk of invasive Haemophilus influenzae infection during pregnancy and association with adverse fetal outcomes. JAMA. 2014;311(11):1125–32.
Straley ME, Togher KL, Nolan AM, Kenny LC, O’Keeffe GW. LPS alters placental inflammatory and endocrine mediators and inhibits fetal neurite growth in affected offspring during late gestation. Placenta. 2014;35(8):533–8.
Barrera D, Díaz L, Noyola-Martínez N, Halhali A. Vitamin D and inflammatory cytokines in healthy and preeclamptic pregnancies. Nutrients. 2015;7(8):6465–90.
Gan Y, Zheng S, Baak JP, Zhao S, Zheng Y, Luo N, Liao W, Fu C. Prediction of the anti-inflammatory mechanisms of curcumin by module-based protein interaction network analysis. Acta Pharm Sin B. 2015;5(6):590–5.
Rajitha B, Belalcazar A, Nagaraju GP, Shaib WL, Snyder JP, Shoji M, Pattnaik S, Alam A, El-Rayes BF. Inhibition of NF-κB translocation by curcumin analogs induces G0/G1 arrest and downregulates thymidylate synthase in colorectal cancer. Cancer Lett. 2016;373(2):227–33.
Langhorst J, Wulfert H, Lauche R, Klose P, Cramer H, Dobos GJ, Korzenik J. Systematic review of complementary and alternative medicine treatments in inflammatory bowel diseases. J Crohns Colitis. 2015;9(1):86–106.
Ghosh SS, Gehr TW, Ghosh S. Curcumin and chronic kidney disease (CKD): major mode of action through stimulating endogenous intestinal alkaline phosphatase. Molecules. 2014;19(12):20139–56.
Nakagawa Y, Mukai S, Yamada S, Matsuoka M, Tarumi E, Hashimoto T, Tamura C, Imaizumi A, Nishihira J, Nakamura T. Short-term effects of highly-bioavailable curcumin for treating knee osteoarthritis: a randomized, double-blind, placebo-controlled prospective study. J Orthop Sci. 2014;19(6):933–9.
Cheppudira B, Fowler M, McGhee L, Greer A, Mares A, Petz L, Devore D, Loyd DR, Clifford JL. Curcumin: a novel therapeutic for burn pain and wound healing. Expert Opin Investig Drugs. 2013;22(10):1295–303.
Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB. Bioavailability of curcumin: problems and promises. Mol Pharm. 2007;4(6):807–18.
Ganiger S, Malleshappa HN, Krishnappa H, Rajashekhar G, Ramakrishna Rao V, Sullivan F. A two generation reproductive toxicity study with curcumin, turmeric yellow, in Wistar rats. Food Chem Toxicol. 2007;45(1):64–9.
Hsuuw YD, Chang CK, Chan WH, Yu JS. Curcumin prevents methylglyoxal-induced oxidative stress and apoptosis in mouse embryonic stem cells and blastocysts. J Cell Physiol. 2005;205(3):379–86.
Zhou J, Wang Z, Zhao X, Wang J, Sun H, Hu Y. An increase of Treg cells in the peripheral blood is associated with a better in vitro fertilization treatment outcome. Am J Reprod Immunol. 2012;68(2):100–6.
Zhou J, Xiao D, Hu Y, Wang Z, Paradis A, Mata-Greenwood E, Zhang L. Gestational hypoxia induces preeclampsia-like symptoms via heightened endothelin-1 signaling in pregnant rats. Hypertension. 2013;62(3):599–607.
Hartley JD, Ferguson BJ, Moffett A. The role of shed placental DNA in the systemic inflammatory syndrome of preeclampsia. Am J Obstet Gynecol. 2015;213(3):268–77.
Vizi ES, Szelényi J, Selmeczy ZS, Papp Z, Németh ZH, Haskó G. Enhanced tumor necrosis factor-alpha-specific and decreased interleukin-10-specific immune responses to LPS during the third trimester of pregnancy in mice. J Endocrinol. 2001;171(2):355–61.
Shaw J, Tang Z, Schneider H, Saljé K, Hansson SR, Guller S. Inflammatory processes are specifically enhanced in endothelial cells by placental-derived TNF-α: implications in preeclampsia (PE). Placenta. 2016;43:1–8.
Qian L, Wang H, Wu F, Li M, Chen W, Lv L. Vitamin D3 alters Toll-like receptor 4 signaling in monocytes of pregnant women at risk for preeclampsia. Int J Clin Exp Med. 2015;8(10):18041–9 (eCollection 2015).
Henderson JT, Whitlock EP, O’Conner E, Senger CA, Thompson JH, Rowland MG. Low-dose aspirin for the prevention of morbidity and mortality from preeclampsia: a systematic evidence review for the US Preventive Services Task Force. Rockville (MD): Agency for Healthcare Research and Quality (US); 2014 (Report No.: 14-05207-EF-1).
Henderson JT, Whitlock EP, O’Connor E, Senger CA, Thompson JH, Rowland MG. Low-dose aspirin for prevention of morbidity and mortality from preeclampsia: a systematic evidence review for the US Preventive Services Task Force. Ann Intern Med. 2014;160(10):695–703.
Ganjali S, Sahebkar A, Mahdipour E, Jamialahmadi K, Torabi S, Akhlaghi S, Ferns G, Parizadeh SM, Ghayour-Mobarhan M. Investigation of the effects of curcumin on serum cytokines in obese individuals: a randomized controlled trial. Sci World J. 2014;2014:898361.
Yekollu SK, Thomas R, O’Sullivan B. Targeting curcusomes to inflammatory dendritic cells inhibits NF-κB and improves insulin resistance in obese mice. Diabetes. 2011;60(11):2928–38.
Maradana MR, Thomas R, O’Sullivan BJ. Targeted delivery of curcumin for treating type 2 diabetes. Mol Nutr Food Res. 2013;57(9):1550–6.
Murphy CJ, Tang H, Van Kirk EA, Shen Y, Murdoch WJ. Reproductive effects of a pegylated curcumin. Reprod Toxicol. 2012;34(1):120–4.
An R, Zhao L, Xi C, Li H, Shen G, Liu H, Zhang S, Sun L. Melatonin attenuates sepsis-induced cardiac dysfunction via a PI3K/Akt-dependent mechanism. Basic Res Cardiol. 2016;111(1):8.
Shalini V, Pushpan CK, Sindhu G, Jayalekshmy A, Helen A. Tricin, flavonoid from Njavara reduces inflammatory responses in hPBMCs by modulating the p38MAPK and PI3K/Akt pathways and prevents inflammation associated endothelial dysfunction in HUVECs. Immunobiology. 2016;221(2):137–44.
Kizhakkayil J, Thayyullathil F, Chathoth S, Hago A, Patel M, Galadari S. Modulation of curcumin-induced Akt phosphorylation and apoptosis by PI3K inhibitor in MCF-7 cells. Biochem Biophys Res Commun. 2010;394(3):476–81.
Covarrubias AJ, Aksoylar HI, Yu J, Snyder NW, Worth AJ, Iyer SS, Wang J, Ben-Sahra I, Byles V, Polynne-Stapornkul T, Espinosa EC, Lamming D, Manning BD, Zhang Y, Blair IA, Horng T. Akt-mTORC1 signaling regulates Acly to integrate metabolic input to control of macrophage activation. Elife. 2016;5:e11612 (pii: e11612).
Liu T, Li C, Sun H, Luo T, Tan Y, Tian D, Guo Z. Curcumin inhibits monocyte chemoattractant protein-1 expression and enhances cholesterol efflux by suppressing the c-Jun N-terminal kinase pathway in macrophage. Inflamm Res. 2014;63(10):841–50.
Acknowledgements
This study was supported by Chinese National Natural Science Foundation (81200450, 81571504, and 81270713), Nanjing Medical Science and technique Development Foundation (QRX11166), Jiangsu Provincial Special Program of Medical Science (BL2014003).
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Responsible Editor: Liwu Li.
J. Zhou and H. Miao contributed equally to this work.
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Zhou, J., Miao, H., Li, X. et al. Curcumin inhibits placental inflammation to ameliorate LPS-induced adverse pregnancy outcomes in mice via upregulation of phosphorylated Akt. Inflamm. Res. 66, 177–185 (2017). https://doi.org/10.1007/s00011-016-1004-4
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DOI: https://doi.org/10.1007/s00011-016-1004-4