Research Progress of Vitamin K2 Related Signal Pathways: A Literature
Review

Shimin      Li; Xiao      Ouyang
doi:10.2174/1570180819666220929161327
Abstract

Vitamin K2 products were first applied to Japanese children, which can promote the growth of children's bones and eliminate their growing pain. At the same time, it does little harm to the human body, so it has attracted the attention of some scholars. Later, it was also proved to be effective in treating osteoporosis, especially for postmenopausal women. After years of research, some capabilities of VK2 have been discovered; it has been proved that it has great clinical value in treating osteoporosis, reducing intimal lipid deposition, diabetes, tumor, immune diseases, nervous system diseases and other diseases. There is no doubt that VK2 is an essential nutrient for human health, once vitamin K2 is deficient, it will cause a series of diseases. In recent years, some new evidences show that VK2 can also be used in leukemia and other diseases, which shows that VK2 still has great development potential. As a new adjuvant drug, VK2 has attracted worldwide attention and has been used in the clinic for many years. In this article, we mainly summarized the related research of VK2 in recent years, and expounded on several VK2-related signal pathways and the related mechanisms of these signal pathways in treating various diseases.
Keywords: Vitamin K2, Signal paths, Osteoporosis, Tumor, Scleratheroma, Immune system.
« Previous Next »
Graphical Abstract

[1]
Hirota, Y.; Suhara, Y. New aspects of vitamin K research with synthetic ligands: Transcriptional activity via SXR and neural differentiation activity. Int. J. Mol. Sci.,  2019, 20(12), 3006.
 [http://dx.doi.org/10.3390/ijms20123006] [PMID:  31226734]

[2]
Bøe, C.A.; Holo, H. Engineering Lactococcus lactis for increased vitamin K2 production. Front. Bioeng. Biotechnol.,  2020, 8, 191.
 [http://dx.doi.org/10.3389/fbioe.2020.00191]

[3]
Vik, H. Highlighting the substantial body of evidence confirming the importance of vitamin K2 As a cardio-support nutrient, and how the right K2 makes all the difference. Integr. Med. (Encinitas),  2019, 18(6), 24-28.
 [PMID:  32549853]

[4]
Zhang, Z.; Liu, L.; Liu, C.; Sun, Y.; Zhang, D. New aspects of microbial vitamin K2 production by expanding the product spectrum. Microb. Cell Fact.,  2021, 20(1), 84.
 [http://dx.doi.org/10.1186/s12934-021-01574-7]

[5]
Braasch-Turi, M.; Crans, D.C. Synthesis of naphthoquinone derivatives: Menaquinones, lipoquinones and other vitamin K derivatives. Molecules,  2020, 25(19), 4477.
 [http://dx.doi.org/10.3390/molecules25194477]

[6]
Barrett, H.; O’Keeffe, M.; Kavanagh, E.; Walsh, M.; O’Connor, E.M. Is matrix gla protein associated with vascular calcification? a systematic review. Nutrients,  2018, 10(4), 415.
 [http://dx.doi.org/10.3390/nu10040415]

[7]
Brnic, D.; Martinovic, D.; Zivkovic, P.M.; Tokic, D.; Vilovic, M.; Rusic, D.; Hadjina, I.T.; Libers, C.; Glumac, S.; Supe-Domic, D.; Tonkic, A.; Bozic, J. Inactive matrix Gla protein is elevated in patients with inflammatory bowel disease. World J. Gastroenterol.,  2020, 26(32), 4866-4877.
 [http://dx.doi.org/10.3748/wjg.v26.i32.4866] [PMID:  32921963]

[8]
Vilovic, M.; Dogas, Z.; Ticinovic Kurir, T.; Borovac, J.A.; Supe-Domic, D.; Vilovic, T.; Ivkovic, N.; Rusic, D.; Novak, A.; Bozic, J. Bone metabolism parameters and inactive matrix Gla protein in patients with obstructive sleep apnea†. Sleep ,  2019, 43(3), zsz243.
 [http://dx.doi.org/10.1093/sleep/zsz243] [PMID:  31631227]

[9]
Zhang, L.; Yao, J.; Yao, Y.; Boström, K.I. Contributions of the endothelium to vascular calcification. Front. Cell Dev. Biol.,  2021, 9, 620882.
 [http://dx.doi.org/10.3389/fcell.2021.620882]

[10]
Bus, K.; Szterk, A. Relationship between structure and biological activity of various vitamin K forms. Foods,  2021, 10(12), 3136.
 [http://dx.doi.org/10.3390/foods10123136]

[11]
Wei, F.F.; Huang, Q.F.; Zhang, Z.Y.; Van Keer, K.; Thijs, L.; Trenson, S.; Yang, W.Y.; Cauwenberghs, N.; Mujaj, B.; Kuznetsova, T.; Allegaert, K.; Struijker-Boudier, H.A.J.; Verhamme, P.; Vermeer, C.; Staessen, J.A. Inactive matrix Gla protein is a novel circulating biomarker predicting retinal arteriolar narrowing in humans. Sci. Rep.,  2018, 8(1), 15088.
 [http://dx.doi.org/10.1038/s41598-018-33257-6] [PMID:  30305657]

[12]
Aoun, M.; Makki, M.; Azar, H.; Matta, H.; Chelala, D.N. High dephosphorylated-uncarboxylated MGP in hemodialysis patients: Risk factors and response to vitamin K2, A pre-post intervention clinical trial. BMC Nephrol.,  2017, 18(1), 191.
 [http://dx.doi.org/10.1186/s12882-017-0609-3]

[13]
Oikonomaki, T.; Papasotiriou, M.; Ntrinias, T.; Kalogeropoulou, C.; Zabakis, P.; Kalavrizioti, D.; Papadakis, I.; Goumenos, D.S.; Papachristou, E. The effect of vitamin K2 supplementation on vascular calcification in haemodialysis patients: A 1-year follow-up randomized trial. Int. Urol. Nephrol.,  2019, 51(11), 2037-2044.
 [http://dx.doi.org/10.1007/s11255-019-02275-2] [PMID:  31529295]

[14]
De Vriese, A.S.; Caluwé, R.; Pyfferoen, L.; De Bacquer, D.; De Boeck, K.; Delanote, J.; De Surgeloose, D.; Van Hoenacker, P.; Van Vlem, B.; Verbeke, F. Multicenter randomized controlled trial of vitamin K antagonist replacement by rivaroxaban with or without vitamin K2 in hemodialysis patients with atrial fibrillation: The valkyrie study. J. Am. Soc. Nephrol.,  2020, 31(1), 186-196.
 [http://dx.doi.org/10.1681/ASN.2019060579] [PMID:  31704740]

[15]
Mansour, A.G.; Ahdab, R.; Daaboul, Y.; Korjian, S.; Morrison, D.A.; Hariri, E.; Salem, M.; El Khoury, C.; Riachi, N.; Aoun Bahous, S. Vitamin K2 status and arterial stiffness among untreated migraine patients: A case‐control study. Headache,  2020, 60(3), 589-599.
 [http://dx.doi.org/10.1111/head.13715] [PMID:  31769041]

[16]
Lang, F.; Leibrock, C.; Pandyra, A.A.; Stournaras, C.; Wagner, C.A.; Föller, M. Phosphate Homeostasis, Inflammation and the Regulation of FGF-23. Kidney Blood Press. Res.,  2018, 43(6), 1742-1748.
 [http://dx.doi.org/10.1159/000495393] [PMID:  30504710]

[17]
Weng, S.J.; Yan, D.Y. gu, L.J.; Chen, L.; Xie, Z.J.; Wu, Z.Y.; Tang, J.H.; Shen, Z.J.; Li, H.; Bai, B.L.; Boodhun, V.; Yang, L. Combined treatment with vitamin K2 and PTH enhanced bone formation in ovariectomized rats and increased differentiation of osteoblast in vitro. Chem. Biol. Interact.,  2019, 300, 101-110.
 [http://dx.doi.org/10.1016/j.cbi.2019.01.012] [PMID:  30639440]

[18]
Choi, H.J.; Yu, J.; Choi, H.; An, J.H.; Kim, S.W.; Park, K.S.; Jang, H.C.; Kim, S.Y.; Shin, C.S. Vitamin K2 supplementation improves insulin sensitivity via osteocalcin metabolism: A placebo-controlled trial. Diabetes Care,  2011, 34(9), e147.
 [http://dx.doi.org/10.2337/dc11-0551] [PMID:  21868771]

[19]
Zhang, Y.; Ma, C.; Zhao, J.; Xu, H.; Hou, Q.; Zhang, H. Lactobacillus casei Zhang and vitamin K2 prevent intestinal tumorigenesis in mice via adiponectin-elevated different signaling pathways. Oncotarget,  2017, 8(15), 24719-24727.
 [http://dx.doi.org/10.18632/oncotarget.15791] [PMID:  28445967]

[20]
Xiao, H.; Chen, J.; Duan, L.; Li, S. Role of emerging vitamin K- dependent proteins: Growth arrest specific protein 6, Gla rich protein and periostin (Review). Int. J. Mol. Med.,  2020, 47(3), 2.
 [http://dx.doi.org/10.3892/ijmm.2020.4835] [PMID:  33448308]

[21]
Kashem, M.A.; Li, H.; Toledo, N.P.; Omange, R.W.; Liang, B.; Liu, L.R.; Li, L.; Yang, X.; Yuan, X.Y.; Kindrachuk, J.; Plummer, F.A.; Luo, M. Toll-like interleukin 1 receptor regulator is an important modulator of inflammation responsive genes. Front. Immunol.,  2019, 10, 272.
 [http://dx.doi.org/10.3389/fimmu.2019.00272] [PMID:  30873160]

[22]
Friebel, J.; Moritz, E.; Witkowski, M.; Jakobs, K.; Strässler, E.; Dörner, A.; Steffens, D.; Puccini, M.; Lammel, S.; Glauben, R.; Nowak, F.; Kränkel, N.; Haghikia, A.; Moos, V.; Schutheiss, H.P.; Felix, S.B.; Landmesser, U.; Rauch, B.H.; Rauch, U. Pleiotropic effects of the Protease-Activated Receptor 1 (PAR1) inhibitor, vorapaxar, on atherosclerosis and vascular inflammation. Cells,  2021, 10(12), 3517.
 [http://dx.doi.org/10.3390/cells10123517] [PMID:  34944024]

[23]
Wang, Z.; Wang, Z.; Zhu, J.; Long, X.; Yan, J. Vitamin K2 can suppress the expression of Toll-like receptor 2 (TLR2) and TLR4, and inhibit calcification of aortic intima in ApoE -/- mice as well as smooth muscle cells. Vascular,  2018, 26(1), 18-26.
 [http://dx.doi.org/10.1177/1708538117713395] [PMID:  28587577]

[24]
Basu, A.; Sridharan, S. Regulation of anti-apoptotic Bcl-2 family protein Mcl-1 by S6 kinase 2. PLoS One,  2017, 12(3), e0173854.
 [http://dx.doi.org/10.1371/journal.pone.0173854]

[25]
Proudfoot, D.; Skepper, J.N.; Hegyi, L.; Bennett, M.R.; Shanahan, C.M.; Weissberg, P.L. Apoptosis regulates human vascular calcification in vitro: Evidence for initiation of vascular calcification by apoptotic bodies. Circ. Res.,  2000, 87(11), 1055-1062.
 [http://dx.doi.org/10.1161/01.RES.87.11.1055] [PMID:  11090552]

[26]
Son, B.K.; Kozaki, K.; Iijima, K.; Eto, M.; Kojima, T.; Ota, H.; Senda, Y.; Maemura, K.; Nakano, T.; Akishita, M.; Ouchi, Y. Statins protect human aortic smooth muscle cells from inorganic phosphate-induced calcification by restoring Gas6-Axl survival pathway. Circ. Res.,  2006, 98(8), 1024-1031.
 [http://dx.doi.org/10.1161/01.RES.0000218859.90970.8d] [PMID:  16556867]

[27]
Qiu, C.; Zheng, H.; Tao, H.; Yu, W.; Jiang, X.; Li, A.; Jin, H.; Lv, A.; Li, H. Vitamin K2 inhibits rat vascular smooth muscle cell calcification by restoring the Gas6/Axl/Akt anti-apoptotic pathway. Mol. Cell. Biochem.,  2017, 433(1-2), 149-159.
 [http://dx.doi.org/10.1007/s11010-017-3023-z] [PMID:  28386842]

[28]
Akbulut, A.C.; Wasilewski, G.B.; Rapp, N.; Forin, F.; Singer, H.; Czogalla-Nitsche, K.J.; Schurgers, L.J. Menaquinone-7 supplementation improves osteogenesis in pluripotent stem cell derived mesenchymal stem cells. Front. Cell Dev. Biol.,  2021, 8, 618760.
 [http://dx.doi.org/10.3389/fcell.2020.618760] [PMID:  33585456]

[29]
Pagani, S.; Bellan, M.; Mauro, D.; Castello, L.M.; Avanzi, G.C.; Lewis, M.J.; Sainaghi, P.P.; Pitzalis, C.; Nerviani, A. New insights into the role of Tyro3, Axl, and Mer receptors in rheumatoid arthritis. Dis. Markers,  2020, 2020, 1-9.
 [http://dx.doi.org/10.1155/2020/1614627] [PMID:  32051695]

[30]
Huang, C.; Wen, Z.; Niu, J.; Lin, S.; Wang, W. Steroid-induced osteonecrosis of the femoral head: Novel insight into the roles of bone endothelial cells in pathogenesis and treatment. Front. Cell Dev. Biol.,  2021, 9, 777697.
 [http://dx.doi.org/10.3389/fcell.2021.777697]

[31]
Weinstein, R.S.; Wan, C.; Liu, Q.; Wang, Y.; Almeida, M.; O’Brien, C.A.; Thostenson, J.; Roberson, P.K.; Boskey, A.L.; Clemens, T.L.; Manolagas, S.C. Endogenous glucocorticoids decrease skeletal angiogenesis, vascularity, hydration, and strength in aged mice. Aging Cell,  2010, 9(2), 147-161.
 [http://dx.doi.org/10.1111/j.1474-9726.2009.00545.x] [PMID:  20047574]

[32]
Tsugawa, N.; Shiraki, M. Vitamin K nutrition and bone health. Nutrients,  2020, 12(7), 1909.
 [http://dx.doi.org/10.3390/nu12071909] [PMID:  32605143]

[33]
Zhang, Y.; Yin, J.; Ding, H.; Zhang, C.; Gao, Y.S. Vitamin K2 ameliorates damage of blood vessels by glucocorticoid: A potential mechanism for its protective effects in glucocorticoid-induced osteonecrosis of the femoral head in a rat model. Int. J. Biol. Sci.,  2016, 12(7), 776-785.
 [http://dx.doi.org/10.7150/ijbs.15248]

[34]
Lee, J.H.; Park, A.; Oh, K.J.; Lee, S.C.; Kim, W.K.; Bae, K.H. The Role of adipose tissue mitochondria: Regulation of mitochondrial function for the treatment of metabolic diseases. Int. J. Mol. Sci.,  2019, 20(19), 4924.
 [http://dx.doi.org/10.3390/ijms20194924]

[35]
Park, A.; Oh, M.; Lee, S.J.; Oh, K.J.; Lee, E.W.; Lee, S.C.; Bae, K.H.; Han, B.S.; Kim, W.K. Mitochondrial transplantation as a novel therapeutic strategy for mitochondrial diseases. Int. J. Mol. Sci.,  2021, 22(9), 4793.
 [http://dx.doi.org/10.3390/ijms22094793] [PMID:  33946468]

[36]
Murphy, M.P.; Siegel, R.M. Mitochondrial ROS fire up T cell activation. Immunity,  2013, 38(2), 201-202.
 [http://dx.doi.org/10.1016/j.immuni.2013.02.005] [PMID:  23438817]

[37]
Fuhrmann, D.C.; Brüne, B. Mitochondrial composition and function under the control of hypoxia. Redox Biol.,  2017, 12, 208-215.
 [http://dx.doi.org/10.1016/j.redox.2017.02.012] [PMID:  28259101]

[38]
Solevåg, A.L.; Schmölzer, G.M.; Cheung, P.Y. Novel interventions to reduce oxidative-stress related brain injury in neonatal asphyxia. Free Radic. Biol. Med.,  2019, 142, 113-122.
 [http://dx.doi.org/10.1016/j.freeradbiomed.2019.04.028] [PMID:  31039399]

[39]
McGarry, T.; Biniecka, M.; Veale, D.J.; Fearon, U. Hypoxia, oxidative stress and inflammation. Free Radic. Biol. Med.,  2018, 125, 15-24.
 [http://dx.doi.org/10.1016/j.freeradbiomed.2018.03.042] [PMID:  29601945]

[40]
Jaafaru, M.S.; Nordin, N.; Rosli, R.; Shaari, K.; Bako, H.Y.; Noor, N.M.; Abdull Razis, A.F. Prospective role of mitochondrial apoptotic pathway in mediating GMG-ITC to reduce cytotoxicity in H2O2-induced oxidative stress in differentiated SH-SY5Y cells. Biomed. Pharmacother.,  2019, 119, 109445.
 [http://dx.doi.org/10.1016/j.biopha.2019.109445] [PMID:  31541852]

[41]
Miyazawa, S.; Moriya, S.; Kokuba, H.; Hino, H.; Takano, N.; Miyazawa, K. Vitamin K2 induces non-apoptotic cell death along with autophagosome formation in breast cancer cell lines. Breast Cancer,  2020, 27(2), 225-235.
 [http://dx.doi.org/10.1007/s12282-019-01012-y] [PMID:  31625014]

[42]
Farhadi, M.B.; Fereidoni, M. Neuroprotective effect of menaquinone-4 (MK-4) on transient global cerebral ischemia/reperfusion injury in rat. PLoS One,  2020, 15(3), e0229769.
 [http://dx.doi.org/10.1371/journal.pone.0229769]

[43]
Xue, Y.; Deng, Q.; Zhang, Q.; Ma, Z.; Chen, B.; Yu, X.; Peng, H.; Yao, S.; Liu, J.; Ye, Y.; Pan, G. Gigantol ameliorates CCl4-induced liver injury via preventing activation of JNK/cPLA2/12-LOX inflammatory pathway. Sci. Rep.,  2020, 10(1), 22265.
 [http://dx.doi.org/10.1038/s41598-020-79400-0] [PMID:  33335297]

[44]
Dragh, M.A.; Xu, Z.; Al-Allak, Z.S.; Hong, L. Vitamin K2 prevents lymphoma in drosophila. Sci. Rep.,  2017, 7(1), 17047.
 [http://dx.doi.org/10.1038/s41598-017-17270-9] [PMID:  29213118]

[45]
Duan, Y.; Li, F.; Tan, B.; Yao, K.; Yin, Y. Metabolic control of myofibers: Promising therapeutic target for obesity and type 2 diabetes. Obes. Rev.,  2017, 18(6), 647-659.
 [http://dx.doi.org/10.1111/obr.12530] [PMID:  28391659]

[46]
Moriggi, M.; Belloli, S.; Barbacini, P.; Murtaj, V.; Torretta, E.; Chaabane, L.; Canu, T.; Penati, S.; Malosio, M.L.; Esposito, A.; Gelfi, C.; Moresco, R.M.; Capitanio, D. Skeletal muscle proteomic profile revealed gender-related metabolic responses in a diet-induced obesity animal model. Int. J. Mol. Sci.,  2021, 22(9), 4680.
 [http://dx.doi.org/10.3390/ijms22094680] [PMID:  33925229]

[47]
Wright, J.N.; Benavides, G.A.; Johnson, M.S.; Wani, W.; Ouyang, X.; Zou, L.; Collins, H.E.; Zhang, J.; Darley-Usmar, V.; Chatham, J.C. Acute increases in O -GlcNAc indirectly impair mitochondrial bioenergetics through dysregulation of LonP1-mediated mitochondrial protein complex turnover. Am. J. Physiol. Cell Physiol.,  2019, 316(6), C862-C875.
 [http://dx.doi.org/10.1152/ajpcell.00491.2018] [PMID:  30865517]

[48]
Leduc-Gaudet, J.P.; Hussain, S.N.A.; Barreiro, E.; Gouspillou, G. Mitochondrial dynamics and mitophagy in skeletal muscle health and aging. Int. J. Mol. Sci.,  2021, 22(15), 8179.
 [http://dx.doi.org/10.3390/ijms22158179]

[49]
Su, X.; Wang, W.; Fang, C.; Ni, C.; Zhou, J.; Wang, X.; Zhang, L.; Xu, X.; Cao, R.; Lang, H.; Wang, F. Vitamin K2 alleviates insulin resistance in skeletal muscle by improving mitochondrial function Via SIRT1 signaling. Antioxid. Redox Signal.,  2021, 34(2), 99-117.
 [http://dx.doi.org/10.1089/ars.2019.7908] [PMID:  32253917]

[50]
Chalhoub, D.; Boudreau, R.; Greenspan, S.; Newman, A.B.; Zmuda, J.; Frank-Wilson, A.W.; Nagaraj, N.; Hoffman, A.R.; Lane, N.E.; Stefanick, M.L.; Barrett-Connor, E.; Dam, T.; Cawthon, P.M.; Orwoll, E.S.; Cauley, J.A. Associations between lean mass, muscle strength and power, and skeletal size, density and strength in older men. J. Bone Miner. Res.,  2018, 33(9), 1612-1621.
 [http://dx.doi.org/10.1002/jbmr.3458] [PMID:  29701926]

[51]
Cariati, I.; Bonanni, R.; Onorato, F.; Mastrogregori, A.; Rossi, D.; Iundusi, R.; Gasbarra, E.; Tancredi, V.; Tarantino, U. Role of physical activity in bone–muscle crosstalk: Biological aspects and clinical implications. J. Funct. Morphol. Kinesiol.,  2021, 6(2), 55.
 [http://dx.doi.org/10.3390/jfmk6020055] [PMID:  34205747]

[52]
Rønning, S.B.; Pedersen, M.E.; Berg, R.S.; Kirkhus, B.; Rødbotten, R. Vitamin K2 improves proliferation and migration of bovine skeletal muscle cells in vitro. PLoS One,  2018, 13(4), e0195432.
 [http://dx.doi.org/10.1371/journal.pone.0195432]

[53]
McFarlin, B.K.; Henning, A.L.; Venable, A.S. Oral consumption of vitamin K2 for 8 weeks associated with increased maximal cardiac output during exercise. Altern. Ther. Health Med.,  2017, 23(4), 26-32.
 [PMID:  28646812]

[54]
Meng, K.; Xu, W.; Miura, T.; Suzuki, S.; Chiyotanda, M.; Tanaka, S.; Sugiyama, K.; Kawashima, H.; Hirano, T. The effects of vitamin K1 and vitamin K2 on the proliferation, cytokine production and regulatory T-cell frequency in peripheral blood mononuclear cells of paediatric atopic dermatitis patients. Exp. Dermatol.,  2018, 27(9), 1058-1060.
 [http://dx.doi.org/10.1111/exd.13671] [PMID:  29697859]

[55]
Kusano, J.; Tanaka, S.; Matsuda, H.; Hara, Y.; Fujii, Y.; Suzuki, S.; Sekiyama, M.; Ando, E.; Sugiyama, K.; Hirano, T. Vitamin K1 and Vitamin K2 immunopharmacological effects on the peripheral lymphocytes of healthy subjects and dialysis patients, as estimated by the lymphocyte immunosuppressant sensitivity test. J. Clin. Pharm. Ther.,  2018, 43(6), 895-902.
 [http://dx.doi.org/10.1111/jcpt.12747] [PMID:  30014604]

[56]
Lasemi, R.; Kundi, M.; Moghadam, N.B.; Moshammer, H.; Hainfellner, J.A. Vitamin K2 in multiple sclerosis patients. Wien. Klin. Wochenschr.,  2018, 130(9-10), 307-313.
 [http://dx.doi.org/10.1007/s00508-018-1328-x] [PMID:  29500722]

[57]
Moriya, M.; Nakatsuji, Y.; Okuno, T.; Hamasaki, T.; Sawada, M.; Sakoda, S. Vitamin K2 ameliorates experimental autoimmune encephalomyelitis in Lewis rats. J. Neuroimmunol.,  2005, 170(1-2), 11-20.
 [http://dx.doi.org/10.1016/j.jneuroim.2005.08.001] [PMID:  16146654]

[58]
Kaltschmidt, C.; Greiner, J.F.W.; Kaltschmidt, B. The transcription factor NF-κB in stem cells and development. Cells,  2021, 10(8), 2042.
 [http://dx.doi.org/10.3390/cells10082042]

[59]
Kaltschmidt, B.; Greiner, J.F.W.; Kadhim, H.M.; Kaltschmidt, C. Subunit-specific role of NF-κB in cancer. Biomedicines,  2018, 6(2), 44.
 [http://dx.doi.org/10.3390/biomedicines6020044]

[60]
Kaltschmidt, C.; Banz-Jansen, C.; Benhidjeb, T.; Beshay, M.; Förster, C.; Greiner, J.; Hamelmann, E.; Jorch, N.; Mertzlufft, F.; Pfitzenmaier, J.; Simon, M.; Schulte am Esch, J.; Vordemvenne, T.; Wähnert, D.; Weissinger, F.; Wilkens, L.; Kaltschmidt, B. A role for NF-κB in organ specific cancer and cancer stem cells. Cancers (Basel),  2019, 11(5), 655.
 [http://dx.doi.org/10.3390/cancers11050655] [PMID:  31083587]

[61]
Mandatori, D.; Penolazzi, L.; Pelusi, L.; Lambertini, E.; Michelucci, F.; Porreca, A.; Cerritelli, P.; Pipino, C.; Di Iorio, A.; Bruni, D.; Di Nicola, M.; Buda, R.; Piva, R.; Pandolfi, A. Three-dimensional co-culture system of human osteoblasts and osteoclast precursors from osteoporotic patients as an innovative model to study the role of nutrients: Focus on vitamin K2. Nutrients,  2021, 13(8), 2823.
 [http://dx.doi.org/10.3390/nu13082823] [PMID:  34444982]

[62]
Kieronska-Rudek, A.; Kij, A.; Kaczara, P.; Tworzydlo, A.; Napiorkowski, M.; Sidoryk, K.; Chlopicki, S. Exogenous vitamins K exert anti-inflammatory effects dissociated from their role as substrates for synthesis of endogenous MK-4 in murine macrophages cell line. Cells,  2021, 10(7), 1571.
 [http://dx.doi.org/10.3390/cells10071571] [PMID:  34206530]

[63]
Saputra, W.D.; Aoyama, N.; Komai, M.; Shirakawa, H. Menaquinone-4 suppresses lipopolysaccharide-induced inflammation in MG6 mouse microglia-derived cells by inhibiting the NF-κB signaling pathway. Int. J. Mol. Sci.,  2019, 20(9), 2317.
 [http://dx.doi.org/10.3390/ijms20092317]

[64]
Xu, W.; Chen, S.; Wang, X.; Tahara, K.; Wu, H.; Tanaka, S.; Sugiyama, K.; Sawada, T.; Hirano, T. Suppressive effect of vitamin K2 against mitogen-activated peripheral blood mononuclear cells of rheumatoid arthritis patients Int. J. Clin. Pharmacol. Ther.,  2021, 59(1), 55-62.
 [http://dx.doi.org/10.5414/CP203827] [PMID:  33040843]

[65]
Abdel-Rahman, M.S.; Alkady, E.A.M.; Ahmed, S. Menaquinone-7 as a novel pharmacological therapy in the treatment of rheumatoid arthritis: A clinical study. Eur. J. Pharmacol.,  2015, 761, 273-278.
 [http://dx.doi.org/10.1016/j.ejphar.2015.06.014] [PMID:  26073022]

[66]
Mashukova, A.; Forteza, R.; Shah, V.N.; Salas, P.J. The cell polarity kinase Par1b/MARK2 activation selects specific NF-kB transcripts via phosphorylation of core mediator Med17/TRAP80. Mol. Biol. Cell,  2021, 32(8), 690-702.
 [http://dx.doi.org/10.1091/mbc.E20-10-0646] [PMID:  33596087]

[67]
Xia, J.; Ozaki, I.; Matsuhashi, S.; Kuwashiro, T.; Takahashi, H.; Anzai, K.; Mizuta, T. Mechanisms of PKC-mediated enhancement of HIF-1α activity and its inhibition by vitamin K2 in hepatocellular carcinoma cells. Int. J. Mol. Sci.,  2019, 20(5), 1022.
 [http://dx.doi.org/10.3390/ijms20051022] [PMID:  30813635]

[68]
Park, S.; Lim, W.; Bazer, F.W.; Song, G. Apigenin induces ROS-dependent apoptosis and ER stress in human endometriosis cells. J. Cell. Physiol.,  2018, 233(4), 3055-3065.
 [http://dx.doi.org/10.1002/jcp.26054] [PMID:  28617956]

[69]
Nagumo, Y.; Kandori, S.; Tanuma, K.; Nitta, S.; Chihara, I.; Shiga, M.; Hoshi, A.; Negoro, H.; Kojima, T.; Mathis, B.J.; Funakoshi, Y.; Nishiyama, H. PLD1 promotes tumor invasion by regulation of MMP-13 expression via NF-κB signaling in bladder cancer. Cancer Lett.,  2021, 511, 15-25.
 [http://dx.doi.org/10.1016/j.canlet.2021.04.014] [PMID:  33945837]

[70]
Yasushi, I.; Zhang, H.; Hamajima, H.; Kawaguchi, Y.; Eguchi, Y.; Mizuta, T.; Yamamoto, K.; Fujimoto, K.; Ozaki, I. Inhibition of matrix metalloproteinase expression by menatetrenone, a vitamin K2 analogue. Oncol. Rep.,  2009, 22(3), 599-604.
 [http://dx.doi.org/10.3892/or_00000478] [PMID:  19639210]

[71]
Carr, B.I.; Akkiz, H.; Bag, H.G.; Karaoğullarından, U.; Yalçın, K.; Ekin, N.; Özakyol, A.; Altıntaş, E.; Balaban, H.Y.; Şimşek, H.; Uyanıkoğlu, A.; Balkan, A.; Kuran, S.; Üsküdar, O.; Ülger, Y.; Güney, B.; Delik, A. Serum levels of gamma-glutamyl transpeptidase in relation to HCC human biology and prognosis. J. Transl. Sci.,  2021, 7(3)
 [http://dx.doi.org/10.15761/JTS.1000446]

[72]
Enomoto, H.; Nakamura, H.; Nishikawa, H.; Nishiguchi, S.; Iijima, H. Hepatoma-derived growth factor: An overview and its role as a potential therapeutic target molecule for digestive malignancies. Int. J. Mol. Sci.,  2020, 21(12), 4216.
 [http://dx.doi.org/10.3390/ijms21124216]

[73]
Zhang, A.; Long, W.; Guo, Z.; Guo, Z.; Cao, B.B. Downregulation of hepatoma-derived growth factor suppresses the malignant phenotype of U87 human glioma cells. Oncol. Rep.,  2012, 28(1), 62-68.
 [http://dx.doi.org/10.3892/or.2012.1768] [PMID:  22576797]

[74]
Zhang, C.; Chang, X.; Chen, D.; Yang, F.; Li, Z.; Li, D.; Yu, N.; Yan, L.; Liu, H.; Xu, Z. Downregulation of HDGF inhibits the tumorigenesis of bladder cancer cells by inactivating the PI3K-AKT signaling pathway. Cancer Manag. Res.,  2019, 11, 7909-7923.
 [http://dx.doi.org/10.2147/CMAR.S215341] [PMID:  31692549]

[75]
Dasari, S.; Samy, A.L.P.A.; Kajdacsy-Balla, A.; Bosland, M.C.; Munirathinam, G. Vitamin K2, a menaquinone present in dairy products targets castration-resistant prostate cancer cell-line by activating apoptosis signaling. Food Chem. Toxicol.,  2018, 115, 218-227.
 [http://dx.doi.org/10.1016/j.fct.2018.02.018] [PMID:  29432837]

[76]
Xv, F.; Chen, J.; Duan, L.; Li, S. Research progress on the anticancer effects of vitamin K2.(Review) Oncol. Lett.,  2018, 15(6), 8926-8934.
 [http://dx.doi.org/10.3892/ol.2018.8502] [PMID:  29805627]

[77]
Kaneda, M.; Zhang, D.; Bhattacharjee, R.; Nakahama, K.; Arii, S.; Morita, I. Vitamin K2 suppresses malignancy of HuH7 hepatoma cells via inhibition of connexin 43. Cancer Lett.,  2008, 263(1), 53-60.
 [http://dx.doi.org/10.1016/j.canlet.2007.12.019] [PMID:  18249064]

[78]
Yamakawa, H.; Setoguchi, S.; Goto, S.; Watase, D.; Terada, K.; Nagata-Akaho, N.; Toki, E.; Koga, M.; Matsunaga, K.; Karube, Y.; Takata, J. Growth inhibitory effects of ester derivatives of menahydroquinone-4, the reduced form of vitamin K2(20), on all-trans retinoic acid-resistant HL60 cell line. Pharmaceutics,  2021, 13(5), 758.
 [http://dx.doi.org/10.3390/pharmaceutics13050758] [PMID:  34065416]
Rights & Permissions Print Cite
Journal Information
For Authors
For Editors
For Reviewers
Explore Articles
Open Access
Open Access Articles
For Visitors
DOI https://dx.doi.org/10.2174/1570180819666220929161327	Print ISSN 1570-1808
Publisher Name Bentham Science Publisher	Online ISSN 1875-628X
Letters in Drug Design & Discovery

Research Progress of Vitamin K2 Related Signal Pathways: A Literature Review

Abstract Play Pause

Graphical Abstract

Related Journals

Related Books

Abstract
