Investigation of possible protective effects of 4 hydroxy phenylboronic acid on lipopolysaccharide-induced liver injury

Öz

Boron products have been used in the field of health for many years. Boron products have been used in the field of health for many years. Boron products, which were used in the treatment of cancer for the first time in the medical field, have taken their place in medical treatments over the years due to their positive effects on cardiovascular health, bone health, wound healing and immune system. Boronic acids are a group of boron compounds that have recently been studied very popularly in medical research. Boronic acids have been known for their anti-microbial effect for more than 100 years. However, recent studies have shown that boronic acids have not only an antimicrobial effect, but also a strong anti-inflammatory effect and with these effects, they can be used in many inflammatory diseases. Liver injury is one of the diseases in which inflammation is seen. In recent years, the incidence of liver injury have increased extremely due to cancer, chemotherapies, use of antiviral drugs, increased hepatic steatosis and the use of wrong herbal supplements. For this reason, the treatment of liver damage is of greater importance today. In our study, we examined the role of 4-hydroxyphenylboronic acid, a derivative of boronic acid, in LPS-induced liver injury. When we looked at our results, we observed that 4 hydroxy phenylboronic acid treatment decreased the increased cytokine levels. Based on these results, we hope that 4 hydroxyphenylboronic acid will be an agent with the potential to treat liver injury.

Anahtar Kelimeler

• 4 hydroxy phenylboronic acid
• Boron
• LPS
• Liver injury
• BRL-3a

4 hidroksi fenilboronik asidin lipopolisakkarit ile indüklenmiş karaciğer hasarı üzerine muhtemel koruyucu etkilerinin incelenmesi

Öz

Bor ürünleri sağlık alanında uzun yıllardır kullanılmaktadır. Medikal anlamda ilk kez kanser tedavisinde kullanılan bor ürünleri yıllar içinde kardiyovasküler sağlık, kemik sağlığı, yara iyileşmesi ve immün sistem üzerine olan olumlu etkileri sebebiyle medikal tedavilerde yerini almıştır. Boronik asitler ise son zamanlarda medikal araştırmalarda oldukça popüler olarak incelenen bir bor bileşeni grubudur. Boronik asitler 100 yıldan daha uzun bir süredir sahip oldukları anti mikrobiyal etki ile biliniyorlardı. Ancak son zamanlarda yapılan çalışmalar boronik asitlerin sadece antimikrobiyal etkiye değil aynı zamanda anti enflamatuvar etkiye sahip olduklarını göstermiştir. Bu etkileriyle birçok enflamatuvar hastalıkta kullanılabilirler. Karaciğer hasarı da enflamasyonun görüldüğü hastalıklardan biridir. Son yıllarda karaciğer hasarının gerek kanser gerek kemoterapiler ve gerekse de kullanılan antiviral ilaç kullanımına bağlı olarak artışının yanı sıra hepatik steatozis ve yanlış bitkisel destekleyici ürün kullanımıyla birlikte insidansı son derece artmıştır. Bu sebeple karaciğer hasarının tedavi edilmesi günümüzde artık daha büyük önem arz etmektedir. Yaptığımız çalışmada bir boronik asit türevi olan 4 hidroksi fenilboronik asidin LPS ile indüklenmiş karaciğer hasarındaki rolünü inceledik. Sonuçlarımıza baktığımızda 4 hidroksi fenilboronik asit tedavisinin artmış olan sitokin seviyelerini düşürdüğünü gözlemledik. Bu sonuçlarımıza binaen 4 hidroksi fenilboronik asidin karaciğer hasarını tedavi etme potansiyeline sahip bir ajan olacağını ümit etmekteyiz.

Anahtar Kelimeler

• 4 hidroksi fenilboronik asit
• Bor
• LPS
• Karaciğer hasarı
• BRL-3a

Kaynakça

1. [1] Merian, E.,(2004) Nonmetals, Particular Aspects. Wiley-VCH, ISBN: 3-527-30459-2, WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
2. [2] Axtell J. C., Saleh L. M., Qian E. A., Wixtrom A. I. and Spokoyny A. M., (2018), Synthesis and applications of perfunctionalized boron clusters. Inorganic Chemistry. 57(5): p.2333-2350, DOI:10.1021/acs.inorgchem.7b02912
3. [3] Pitochelli, A. R. and F. M. Hawthorne,(1960), The isolation of the icosahedral B12H12-2 Ion. Journal of the American Chemical Society. 82(12): p. 3228-3229.
4. [4] Nielsen, F. H. and C. D. Eckhert,(2019), Boron. Advances in Nutrition. 11(2): p. 461-462. DOI:10.1093/advances/nmz110
5. [5] Marriott, B. P., Birt D. F., Stallings V. A. and Yates A. A.,(2020) Present Knowledge in Nutrition: Clinical and Applied Topics in Nutrition. ISBN: 9780128184608, Academic Press.
6. [6] Emsley, J.,(2011) Nature's building blocks: an AZ guide to the elements. ISBN: 978-0199605637 Oxford University Press.
7. [7] Khaliq, H., Z. Juming, and P. K. Mei,(2018), The physiological role of boron on health. Biological Trace Element Research. 186(1): p. 31-51. DOI: 10.1007/s12011-018-1284-3.
8. [8] Doğan, A., Demirci S., Bayir Y., Halici Z., Karakus E., Aydin A., Cadirci E., Albayrak A., Demirci E., Karaman A., Ayan A. K., Gundogdu C. and Sahin F. (2014), Boron containing poly-(lactide-co-glycolide)(PLGA) scaffolds for bone tissue engineering. Materials Science and Engineering: C. 44: p. 246-253.DOI: 10.1016/j.msec.2014.08.035.

9. [9] Atila, A., Halici Z., Cadirci E., Karakus E., Palabiyik S. S., Ay N., Bakan F. and Yilmaz S.,(2016), Study of the boron levels in serum after implantation of different ratios nano-hexagonal boron nitride–hydroxy apatite in rat femurs. Materials Science and Engineering: C. 58: p. 1082-1089. DOI:10.1016/j.msec.2015.09.041
10. [10] Yayla, M., Cadirci E., Halici Z., Bakan F., Ay N., Demirci S., Karaman A. and Sahin F.,(2020), Regenerative effect of resorbable scaffold embedded boron-nitride/hydroxyapatite nanoparticles in rat parietal bone. Journal of Nanoscience and Nanotechnology. 20(2): p. 680-691. DOI: 10.1166/jnn.2020.17128
11. [11] Demirci, S., Doğan A., Karakuş E., Halıcı Z., Topçu A., Demirci E. and Sahin F.,(2015), Boron and poloxamer (F68 and F127) containing hydrogel formulation for burn wound healing. Biological Trace Element Research. 168(1): p. 169-180. DOI: 10.1007/s12011-015-0338-z
12. [12] Bouchareb, R., Katz M., Saadallah N., Sassi Y., Ali S. and Lebeche D.,(2020), Boron improves cardiac contractility and fibrotic remodeling following myocardial infarction injury. Scientific Reports. 10(1): p. 1-11. DOI: 10.1038/s41598-020-73864-w
13. [13] Nielsen, F. H. and S. L. Meacham,(2011), Growing evidence for human health benefits of boron. Journal of Evidence-Based Complementary & Alternative Medicine. 16(3): p. 169-180. DOI:10.1177/2156587211407638
14. [14] Einsele, H.,(2010), Bortezomib. Small Molecules in Oncology: p. 173-187. DOI: 10.1007/978-3-642-01222-8_12
15. [15] Das, B.C ., Thapa P., Karki R., Schinke C., Das S., Kambhampati S., Banerjee S. K., Van Veldhuizen P., Verma A., Weiss L. M. and Evans T.,(2013), Boron chemicals in diagnosis and therapeutics. Future Medicinal Chemistry. 5(6): p. 653-676. DOI: 10.4155/fmc.13.38
16. [16] Leśnikowski, Z. J.,(2016), Recent developments with boron as a platform for novel drug design. Expert Opinion on Drug Discovery. 11(6): p. 569-578. DOI: 10.1080/17460441.2016.1174687
17. [17] Barth, R. F., Coderre J. A., Vicente M. G. H. and Blue T. E.,(2005), Boron neutron capture therapy of cancer: current status and future prospects. Clinical Cancer Research. 11(11): p. 3987-4002. DOI: 10.1158/1078-0432.CCR-05-0035
18. [18] Hawthorne, M.F.,(1998), New horizons for therapy based on the boron neutron capture reaction. Molecular Medicine Today. 4(4): p. 174-181. DOI: 10.1016/s1357-4310(98)01226-x
19. [19] Hawthorne, M. F. and A. Maderna,(1999), Applications of radiolabeled boron clusters to the diagnosis and treatment of cancer. Chemical Reviews. 99(12): p. 3421-3434. DOI: 10.1021/cr980442h
20. [20] Qian, E. A., Wixtrom A. I., Axtell J. C., Saebi A., Jung D., Rehak P., Han Y., Moully E. H., Mosallaei D., Chow S., Messina M. S., Wang J. Y., Royappa A. T., Rheingold A. L., Maynard H. D., Král P. and Spokoyny A. M.,(2017), Atomically precise organomimetic cluster nanomolecules assembled via perfluoroaryl-thiol SN Ar chemistry. Nature Chemistry. 9(4): p. 333-340. DOI: 10.1038/nchem.2686
21. [21] Hawthorne, M. F.,(1993), The role of chemistry in the development of boron neutron capture therapy of cancer. Angewandte Chemie International Edition in English. 32(7): p. 950-984. DOI:10.1002/ANIE.199309501
22. [22] Lam, P. Y., Clark C. G., Saubern S., Adams J., Winters M. P., Chan D. M. and Combs A.,(1998), New aryl/heteroaryl CN bond cross-coupling reactions via arylboronic acid/cupric acetate arylation. Tetrahedron Letters. 39(19): p. 2941-2944. DOI:/10.1016/S0040-4039(98)00504-8
23. [23] Miyaura, N. and A. Suzuki,(1995), Palladium-catalyzed cross-coupling reactions of organoboron compounds. Chemical Reviews. 95(7): p. 2457-2483. DOI:/10.1021/cr00039a007
24. [24] Hall, D. G.,(2005), Structure, properties, and preparation of boronic acid derivatives. Overview of their reactions and applications. Boronic Acids. DOI:10.1002/3527606548.ch1
25. [25] Cambre, J. N. and Sumerlin B. S.,(2011), Biomedical applications of boronic acid polymers. Polymer. 52(21): p. 4631-4643. DOI:10.1016/j.polymer.2011.07.057
26. [26] Kiener, P. A. and Waley S. G.,(1978), Reversible inhibitors of penicillinases. Biochemical Journal. 169(1): p. 197-204. DOI: 10.1042/bj1690197
27. [27] Ulusoy, S. and Akalin R. B.,(Boronik asit moleküllerinin Pseudomonas aeruginosa’da virülens faktörlerinin üretimine etkisi. Journal of Boron. 3(3): p. 166-173. DOI:10.30728/boron.345186
28. [28] Yoshimori, M., Shibayama H., Imadome K. I., Kawano F., Ohashi A., Nishio M., Shimizu N., Kurata M., Fujiwara S. and Arai A.,(2021), Antineoplastic and anti-inflammatory effects of bortezomib on systemic chronic active EBV infection. Blood Advances. 5(7): p. 1805-1815. DOI: 10.1182/bloodadvances.2020002417
29. [29] Zhu, M.,(2019), Inhibitory effects of bortezomib in a subcutaneous tumor model of H22 mouse hepatocarcinoma cells. Pathology-Research and Practice. 215(6): p. 152388. DOI: 10.1016/j.prp.2019.03.017
30. [30] Jiang, L., Song J., Hu X., Zhang H., Huang E., Zhang Y., Deng F. and Wu X. (2017), The proteasome inhibitor bortezomib inhibits inflammatory response of periodontal ligament cells and ameliorates experimental periodontitis in rats. Journal of Periodontology. 88(5): p. 473-483. DOI: 10.1902/jop.2016.160396
31. [31] Liang, Y., Ma S., Zhang Y., Wang Y., Cheng Q., Wu Y., Jin Y, Zheng D, Wu D. and Liu H.,(2014), IL-1β and TLR4 signaling are involved in the aggravated murine acute graft-versus-host disease caused by delayed bortezomib administration. The Journal of Immunology. 192(3): p. 1277-1285. DOI: 10.4049/jimmunol.1203428
32. [32] Han, S. H., Kim J. S., Woo J. H., Jeong S. J., Shin J. S., Ahn Y. S. and Kim J. M.,(2015), The effect of bortezomib on expression of inflammatory cytokines and survival in a murine sepsis model induced by cecal ligation and puncture. Yonsei Medical Journal. 56(1): p. 112-123. DOI: 10.3349/ymj.2015.56.1.112
33. [33] Wen, Z., Lei Z., Yao L., Jiang P., Gu T., Ren F, Liu Y, Gou C, Li X. and Wen T.,(2016), Circulating histones are major mediators of systemic inflammation and cellular injury in patients with acute liver failure. Cell Death & Disease. 7(9): p. e2391-e2391. ; DOI:10.1038/cddis.2016.303
34. [34] Sodeifian, F., Seyedalhosseini Z. S., Kian N., Eftekhari M., Najari S., Mirsaeidi M. and Farsi Y., Nasiri M. J.,(2021), Drug-induced liver injury in COVID-19 patients: A Systematic Review. Frontiers in Medicine: p. 1624. DOI: 10.3389/fmed.2021.731436
35. [35] Abubakar, A. R., Sani I. H., Godman B., Kumar S., Islam S., Jahan I. and Haque M.,(2020), Systematic review on the therapeutic options for COVID-19: clinical evidence of drug efficacy and implications. Infection and Drug Resistance. 13: p. 4673-4695. DOI: 10.2147/IDR.S289037
36. [36] Torre, L. A., Siegel R. L., Ward E. M. and Jemal A.,(2016), Global cancer incidence and mortality rates and trends—an update. Cancer Epidemiology and Prevention Biomarkers. 25(1): p. 16-27. DOI: 10.1158/1055-9965.EPI-15-0578
37. [37] Floyd, J., Mirza I., Sachs B. and Perry M. C.. Hepatotoxicity of chemotherapy.(2006). Seminars in Oncology. Elsevier. DOI: 10.1053/j.seminoncol.2005.11.002
38. [38] Caballero, B.,(2019), Humans against obesity: who will win? Advances in Nutrition. 10(suppl_1): p. S4-S9. DOI: 10.1093/advances/nmy055
39. [39] Manna, P. and S. K. Jain,(2015), Obesity, oxidative stress, adipose tissue dysfunction, and the associated health risks: causes and therapeutic strategies. Metabolic Syndrome and Related Disorders. 13(10): p. 423-444. DOI: 10.1089/met.2015.0095
40. [40] Hurr, C., Simonyan H., Morgan D. A., Rahmouni K. and Young C. N.,(2019), Liver sympathetic denervation reverses obesity‐induced hepatic steatosis. The Journal of Physiology. 597(17): p. 4565-4580. DOI: 10.1113/JP277994
41. [41] Zhang, X., Jiang D., Jiang W., Zhao M. and Gan J.,(2015), Role of TLR4-Mediated PI3K/AKT/GSK-3β signaling pathway in apoptosis of rat hepatocytes. BioMed Research International. DOI: 10.1155/2015/631326
42. [42] Guo, X., J. Qiu, and Y. Qian,(2021), 6-shogaol mitigates sepsis-associated hepatic injury through transcriptional regulation. Nutrients. 13(10): p. 3427-3442. DOI: 10.3390/nu13103427
43. [43] Azrad, M., Zeineh N., Weizman A., Veenman L. and Gavish M.,(2019), The TSPO ligands 2-Cl-MGV-1, MGV-1, and PK11195 differentially suppress the inflammatory response of BV-2 microglial cell to LPS. International Journal of Molecular Sciences. 20(3): p. 594-608. DOI: 10.3390/ijms20030594
44. [44] Ayaz, G., Halici Z., Albayrak A., Karakus E. and Cadirci E.,(2017), Evaluation of 5-HT7 receptor trafficking on in vivo and in vitro model of lipopolysaccharide (LPS)-induced inflammatory cell injury in rats and LPS-treated A549 cells. Biochemical Genetics. 55(1): p. 34-47. DOI: 10.1007/s10528-016-9769-2
45. [45] Keskin, H., Tavaci T., Halici H., Yuksel T. N., Ozkaraca M., Bilen A., Kose D., Mendil A.S. and Halici Z.,(2021), Early administration of milrinone ameliorates lung and kidney injury during sepsis in juvenile rats. Pediatrics International. DOI: 10.1111/ped.14917
46. [46] Bilen, A., Calik I., Yayla M., Dincer B., Tavaci T., Cinar I., Bilen H, Cadirci E., Halici Z., Mercantepe F.,(2021), Does daily fasting shielding kidney on hyperglycemia-related inflammatory cytokine via TNF-α, NLRP3, TGF-β1 and VCAM-1 mRNA expression. International Journal of Biological Macromolecules. 190: p. 911-918. DOI: 10.1016/j.ijbiomac.2021.08.216
47. [47] Beheshti, F., Hosseini M., Taheri Sarvtin M., Kamali A. and Anaeigoudari A.,(2021), Protective effect of aminoguanidine against lipopolysaccharide-induced hepatotoxicity and liver dysfunction in rat. Drug and Chemical Toxicology. 44(2): p. 215-221. DOI: 10.1080/01480545.2018.1561712
48. [48] Cinar, I., Yayla M., Tavaci T., Toktay E., Ugan R. A., Bayram P. and Halici H.,(2021), In vivo and in vitro cardioprotective effect of gossypin against isoproterenol-ınduced myocardial infarction injury. Cardiovascular Toxicology: 22(1) p. 1-11. DOI: 10.1007/s12012-021-09698-3
49. [49] Keskin, H., Keskin F., Tavaci T., Halici H., Yuksel T. N., Ozkaraca M., Bilen A. and Halici Z.,(2021), Neuroprotective effect of roflumilast under cerebral ischaemia/reperfusion injury in juvenile rats through NLRP‐mediated inflammatory response inhibition. Clinical and Experimental Pharmacology and Physiology. 48(8) p:1103-1110 DOI:10.1111/1440-1681.13493
50. [50] Dai, W., Zhan X., Peng W., Liu X., Peng W., Mei Q. and Hu X.,(2021), Ficus pandurata hance inhibits ulcerative colitis and colitis-associated secondary liver damage of mice by enhancing antioxidation activity. Oxidative Medicine and Cellular Longevity. DOI: 10.1155/2021/2617881
51. [51] Cheng, D., Wu C., Li Y., Liu Y., Mo J., Fu L. and Peng S.,(2021), METTL3 inhibition ameliorates liver damage in mouse with hepatitis B virus-associated acute-on-chronic liver failure by regulating miR-146a-5p maturation. Biochimica et Biophysica Acta (BBA)-Gene Regulatory Mechanisms: DOI: 10.1016/j.bbagrm.2021.194782
52. [52] Dunn, C., Brunetto M., Reynolds G., Christophides T., Kennedy P. T., Lampertico P., Das A., Lopes A. R., Borrow P., Williams K., Humphreys E., Afford S., Adams D.H., Bertoletti A. and Maini M. K.,(2007), Cytokines induced during chronic hepatitis B virus infection promote a pathway for NK cell–mediated liver damage. The Journal of Experimental Medicine. 204(3): p. 667-680. DOI: 10.1084/jem.20061287
53. [53] Brenner, C., Galluzzi L., Kepp O. and Kroemer G.,(2013), Decoding cell death signals in liver inflammation. Journal of Hepatology. 59(3): p. 583-594. DOI: 10.1016/j.jhep.2013.03.033
54. [54] Essani, N. A., Fisher M. A., and Jaeschke H.,(1997), Inhibition of NF-kappa B activation by dimethyl sulfoxide correlates with suppression of TNF-alpha formation, reduced ICAM-1 gene transcription, and protection against endotoxin-induced liver injury. Shock (Augusta, Ga.). 7(2): p. 90-96. DOI: 10.1097/00024382-199702000-00003
55. [55] Teng, C. Y., Lai Y. L., Huang H. I., Hsu W. H., Yang C. C. and Kuo W. H.,(2012), Tournefortia sarmentosa extract attenuates acetaminophen-induced hepatotoxicity. Pharmaceutical Biology. 50(3): p. 291-396. DOI: 10.3109/13880209.2011.602695
56. [56] Kim, E. A., Kim S. Y., Ye B. R., Kim J., Ko S. C., Lee W. W., Kim K. N., Choi I. W., Jung W. K. and Heo S. J.,(2018), Anti-inflammatory effect of Apo-9′-fucoxanthinone via inhibition of MAPKs and NF-kB signaling pathway in LPS-stimulated RAW 264.7 macrophages and zebrafish model. International Immunopharmacology. 59: p. 339-346. DOI: 10.1016/j.intimp.2018.03.034
57. [57] Pervin, M., Karim M. R., Kuramochi M., Izawa T., Kuwamura M. and Yamate J.,(2018), Macrophage populations and expression of regulatory inflammatory factors in hepatic macrophage-depleted rat livers under lipopolysaccharide (LPS) treatment. Toxicologic Pathology. 46(5): p. 540-552. DOI: 10.1177/0192623318776898
58. [58] Yang, R., Yu H., Chen J., Zhu J., Song C., Zhou L., Sun Y. and Zhang Q.,(2021), Limonin attenuates lps-induced hepatotoxicity by inhibiting pyroptosis via nlrp3/gasdermin d signaling pathway. Journal of Agricultural and Food Chemistry. 69(3): p. 982-991. DOI: 10.1021/acs.jafc.0c06775
59. [59] Zhang, X., Shang X., Jin S., Ma Z., Wang H., Na A., Yang J. and Du J.,(2021), Vitamin D ameliorates high-fat-diet-induced hepatic injury via inhibiting pyroptosis and alters gut microbiota in rats. Archives of Biochemistry and Biophysics. 705: p. 108894. DOI: 10.1016/j.abb.2021.108894
60. [60] Jiang, W., Sun R., Wei H. and Tian Z.,(2005), Toll-like receptor 3 ligand attenuates LPS-induced liver injury by down-regulation of toll-like receptor 4 expression on macrophages. Proceedings of the National Academy of Sciences. 102(47): p. 17077-17082. DOI: 10.1073/pnas.0504570102
61. [61] Olleros, M.L., Vesin D., Fotio A. L., Santiago-Raber M.L., Tauzin S., Szymkowski D. E. and Garcia I.,(2010), Soluble TNF, but not membrane TNF, is critical in LPS-induced hepatitis. Journal of Hepatology. 53(6): p. 1059-1068. DOI: 10.1016/j.jhep.2010.05.029
62. [62] Gantner, F., Leist M., Lohse A. W., Germann P. G. and Tiegs G.,(1995), Concanavalin A—induced T-cell—mediated hepatic injury in mice: the role of tumor necrosis factor. Hepatology. 21(1): p. 190-198. DOI: 10.1016/0270-9139(95)90428-x
63. [63] Angurana, S.K., Bansal A., Muralidharan J., Aggarwal R. and Singhi S.,(2021), Cytokine levels in critically ill children with severe sepsis and their relation with the severity of illness and mortality. Journal of Intensive Care Medicine. 36(5): p. 576-583. DOI: 10.1177/0885066620912989
64. [64] Rahim, V.B., Khammar M. T., Rakhshandeh H., Samzadeh-Kermani A., Hosseini A. and Askari V. R.,(2019), Crocin protects cardiomyocytes against LPS-Induced inflammation. Pharmacological Reports. 71(6): p. 1228-1234. DOI: 10.1016/j.pharep.2019.07.007
65. [65] Kim, J. W., Yun H., Choi S. J., Lee S. H., Park S., Lim C. W. and Kim B.,(2017), Evaluating the influence of side stream cigarette smoke at an early stage of non-alcoholic steatohepatitis progression in mice. Toxicological Research. 33(1): p. 31-41. DOI: 10.5487/TR.2017.33.1.031
66. [66] Webster, J. D. and Vucic D.,(2020), The balance of TNF mediated pathways regulates inflammatory cell death signaling in healthy and diseased tissues. Frontiers in Cell and Developmental Biology. 8: p. 365. DOI: 10.3389/fcell.2020.00365
67. [67] Zimmermann, H. W., Trautwein C., and Tacke F.,(2012), Functional role of monocytes and macrophages for the inflammatory response in acute liver injury. Frontiers in Physiology. 3: p. 56. DOI: 10.3389/fphys.2012.00056
68. [68] Balaha, M., Kandeel S., and Barakat W.,(2016), Carvedilol suppresses circulating and hepatic IL-6 responsible for hepatocarcinogenesis of chronically damaged liver in rats. Toxicology and Applied Pharmacology. 311: p. 1-11. DOI: 10.1016/j.taap.2016.10.012
69. [69] Hunter, C. A. and Jones S. A.,(2015), IL-6 as a keystone cytokine in health and disease. Nature Immunology. 16(5): p. 448-457. DOI: 10.1038/ni.3153
70. [70] McMaster, W. G., Kirabo A., Madhur M. S. and Harrison D. G.,(2015), Inflammation, immunity, and hypertensive end-organ damage. Circulation Research. 116(6): p. 1022-1033. DOI: 10.1161/CIRCRESAHA.116.303697
71. [71] Nencioni, A., Schwarzenberg, K., Brauer K. M., Schmidt S. M., Ballestrero A., Grünebach F. and Brossart P.,(2006), Proteasome inhibitor bortezomib modulates TLR4-induced dendritic cell activation. Blood. 108(2): p. 551-558. DOI: 10.1182/blood-2005-08-3494
72. [72] Maeda, D. Y., Peck A. M., Schuler A. D., Quinn M. T., Kirpotina L. N., Wicomb W. N., Fan G. H. and Zebala J. A.,(2014), Discovery of 2-[5-(4-Fluorophenylcarbamoyl) pyridin-2-ylsulfanylmethyl] phenylboronic acid (SX-517): noncompetitive boronic acid antagonist of CXCR1 and CXCR2. Journal of Medicinal Chemistry. 57(20): p. 8378-8397. DOI: 10.1021/jm500827t
73. [73] Cordeiro, N. M., Freitas R. H., Fraga C. A. and Fernandes P. D.,(2016), Discovery of novel orally active tetrahydro-naphthyl-N-acylhydrazones with in vivo anti-TNF-α effect and remarkable anti-inflammatory properties. PLoS One. 11(5): p. e0156271. DOI: 10.1371/journal.pone.0156271
74. [74] Huang, H. B., Xiao K., Lu S., Yang K. l., Ansari A. R., Khaliq H., Song H., Zhong J., Liu H. Z. and Peng K. M.,(2015), Increased thymic cell turnover under boron stress may bypass TLR3/4 pathway in African ostrich. PloS One. 10(6): p. e0129596. DOI: 10.1371/journal.pone.0129596