The role of mediators in the formation of leading pathological processes in psoriatic arthritis

The lecture analyzes the results of research on the role of humoral and cellular mediators, their interaction, as well as the imbalance of angiogenic factors in psoriatic arthritis. The information is presented with identification of the leading typical pathological processes: inflammation and microcirculation disorders, formed due to the activation of protein cascades and interaction of molecular proinflammatory mediators and angiogenic factors. It is known that the clinical phenotypes of psoriatic arthritis are diverse. A deeper understanding of the pathogenesis and changes in the predominant pathological process can become the basis for the development of a personalized treatment strategy based on the pathogenesis to minimize iatrogenic complications and economic costs, as well as for the introduction of modern diagnostic methods for verification, differentiation, and monitoring of psoriatic arthritis in order to timely correct drug treatment.

1. Cigolini C., Fattorini F., Gentileschi S., Terenzi R., Carli L. Psoriatic arthritis: one year in review 2022. Clin. Exp. Rheumatol. 2022;40(9):1611–1619. DOI: 10.55563/clinexprheumatol/x3sfxe.

2. Antony A.S., Allard A., Rambojun A., Lovell C.R., Shaddick G., Robinson G. et al. Psoriatic Nail Dystrophy Is Associated with Erosive Disease in the Distal Interphalangeal Joints in Psoriatic Arthritis: A Retrospective Cohort Study. J. Rheumatol. 2019;46(9):1097–1102. DOI: 10.3899/jrheum.180796.

3. Mistegård J., Gudbjornsson B., Lindqvist U., Laasonen L., Ejstrup L., Ståhle M. et al. Comorbidities in a Cohort of 66 Patients With Psoriatic Arthritis Mutilans-Results From the Nordic PAM Study. Front. Med. (Lausanne). 2021;8:629741. DOI: 10.3389/fmed.2021.629741.

4. Poddubnyy D., Jadon D.R., Van den Bosch F., Mease P.J., Gladman D.D. Axial involvement in psoriatic arthritis: An update for rheumatologists. Semin. Arthritis. Rheum. 2021;51(4):880– 887. DOI: 10.1016/j.semarthrit.2021.06.006.

5. Araujo E.G., Schett G. Enthesitis in psoriatic arthritis (Part 1): pathophysiology. Rheumatology (Oxford). 2020;59(Suppl. 1):i10–i14. DOI: 10.1093/rheumatology/keaa039.

6. Girolimetto N., Giovannini I., Crepaldi G., De Marco G., Tinazzi I., Possemato N. et al. Psoriatic dactylitis: current perspectives and new insights in ultrasonography and magnetic resonance imaging. J. Clin. Med. 2021;10(12):2604. DOI: 10.3390/jcm10122604.

7. Sudoł-Szopińska I., Pracoń G. Diagnostic imaging of psoriatic arthritis. Part II: magnetic resonance imaging and ultrasonography. J. Ultrason. 2016;16(65):163–174. DOI: 10.15557/JoU.2016.0018.

8. De Vicente Delmás A., Sanchez-Bilbao L., Calvo-Río V., Martínez-López D., Herrero-Morant A., Galíndez-Agirregoikoa E. et al. Uveitis in psoriatic arthritis: study of 406 patients in a single university center and literature review. RMD Open. 2023;9(1):e002781. DOI: 10.1136/rmdopen-2022-002781.

9. Li Y., Guo J., Cao Z., Wu J. Causal Association Between Inflammatory Bowel Disease and Psoriasis: A Two-Sample Bidirectional Mendelian Randomization Study. Front. Immunol. 2022;13:916645. DOI: 10.3389/fimmu.2022.916645.

10. Kim W.B., Jerome D., Yeung J. Diagnosis and management of psoriasis. Can. Fam. Physician. 2017;63(4):278–285.

11. Taylor W., Gladman D., Helliwell P., Marchesoni A., Mease P., Mielants H. Classification criteria for psoriatic arthritis: development of new criteria from a large international study. Arthritis Rheum. 2006;54(8):2665–2673. DOI: 10.1002/art.21972.

12. Dai L.Y., Gong D.D., Zhao J.X. Clinical characteristics of psoriatic arthritis with positive rheumatoid factor or anti-cyclic citrullinated peptide antibody. Beijing Da Xue Bao Yi Xue Ban. 2019;51(6):1008–1013. DOI: 10.19723/j.issn.1671-167X.2019.06.005.

13. Gialouri C.G., Fragoulis G.E. Disease activity indices in psoriatic arthritis: current and evolving concepts. Clin. Rheumatol. 2021;40(11):4427–4435. DOI: 10.1007/s10067-021- 05774-9.

14. Roe K. An inflammation classification system using cytokine parameters. Scand. J. Immunol. 2021;93(2):e12970. DOI: 10.1111/sji.12970.

15. Черешнев В.А., Гусев Е.Ю., Зотова Н.В. Фундаментально-прикладные аспекты системного воспаления с точки зрения физиологического и типичного патологического процесса. Российский физиологический журнал имени И.М. Сеченова. 2010;96(7):696–707.

16. Gialouri C.G., Evangelatos G., Pappa M., Karamanakos A., Iliopoulos A., Tektonidou M.G. et al. Normal C-reactive protein in active psoriatic arthritis: results from real-world clinical practice. Ther. Adv. Musculoskelet. Dis. 2022;14:1–8. DOI: 10.1177/1759720X221122417.

17. Singh S.K., Ngwa D.N., Agrawal A. Complement activation by c-reactive protein is critical for protection of mice against pneumococcal infection. Front. Immunol. 2020;11:1812. DOI: 10.3389/fimmu.2020.01812.

18. Chirco K.R., Potempa L.A. C-reactive protein as a mediator of complement activation and inflammatory signaling in age-related macular degeneration. Front. Immunol. 2018;9:539. DOI: 10.3389/fimmu.2018.00539.

19. Ryu J., Lee C.W., Shin J.A., Park C.S., Kim J.J., Park S.J. et al. FcgammaRIIa mediates C-reactive protein-induced inflammatory responses of human vascular smooth muscle cells by activating NADPH oxidase 4. Cardiovasc. Res. 2007;75(3):555–565. DOI: 10.1016/j.cardiores.2007.04.027.

20. Wu Y., Potempa L.A., El Kebir D., Filep J.G. C-reactive protein and inflammation: conformational changes affect function. Biol. Chem. 2015;396(11):1181–1197. DOI: 10.1515/hsz-2015-0149.

21. Ji S.R., Wu Y., Zhu L., Potempa L.A., Sheng F.L., Lu W. et al. Cell membranes and liposomes dissociate C-reactive protein (CRP) to form a new, biologically active structural intermediate: mCRP(m). FASEB J. 2007;21(1):284–294. DOI: 10.1096/fj.06-6722com.

22. Sproston N.R., Ashworth J.J. Role of C-reactive protein at sites of inflammation and infection. Front. Immunol. 2018;9:754. DOI: 10.3389/fimmu.2018.00754.

23. Kim K.W., Kim B.M., Moon H.W., Lee S.H., Kim H.R. Role of C-reactive protein in osteoclastogenesis in rheumatoid arthritis. Arthritis. Res. Ther. 2015;17(1):41. DOI: 10.1186/s13075-015-0563-z.

24. Gershov D., Kim S., Brot N., Elkon K.B. C-Reactive protein binds to apoptotic cells, protects the cells from assembly of the terminal complement components, and sustains an antiinflammatory innate immune response: implications for systemic autoimmunity. J. Exp. Med. 2000;192(9):1353–1364. DOI: 10.1084/jem.192.9.1353.

25. Chimenti M.S., Perricone C., Graceffa D., Di Muzio G., Ballanti E., Guarino M.D. et al. Complement system in psoriatic arthritis: a useful marker in response prediction and monitoring of anti-TNF treatment. Clin. Exp. Rheumatol. 2012;30(1):23–30.

26. Coss S.L., Zhou D., Chua G.T., Aziz R.A., Hoffman R.P., Wu Y.L. et al. The complement system and human autoimmune diseases. J. Autoimmun. 2023;137:102979. DOI: 10.1016/j.jaut.2022.102979.

27. Cavalli S., Lonati P.A., Gerosa M., Caporali R., Cimaz R., Chighizola C.B. Beyond systemic lupus erythematosus and anti-phospholipid syndrome: the relevance of complement from pathogenesis to pregnancy outcome in other systemic rheumatologic diseases. Front. Pharmacol. 2022;13:841785. DOI: 10.3389/fphar.2022.841785.

28. Pouw R.B., Ricklin D. Tipping the balance: intricate roles of the complement system in disease and therapy. Semin. Immunopathol. 2021;43(6):757–771. DOI: 10.1007/s00281-021-00892-7.

29. Nurmohamed M.T., Heslinga M., Kitas G.D. Cardiovascular comorbidity in rheumatic diseases. Nat. Rev. Rheumatol. 2015;11(12):693–704. DOI: 10.1038/nrrheum.2015.112.

30. Engström G., Hedblad B., Janzon L., Lindgärde F. Complement C3 and C4 in plasma and incidence of myocardial infarction and stroke: a population-based cohort study. Eur. J. Cardiovasc. Prev. Rehabil. 2007;14(3):392–397. DOI: 10.1097/01.hjr.0000244582.30421.b2.

31. Arias de la Rosa I., Font P., Escudero-Contreras A., López-Montilla M.D., Pérez-Sánchez C., Ábalos-Aguilera MC. et al. Complement component 3 as biomarker of disease activity and cardiometabolic risk factor in rheumatoid arthritis and spondyloarthritis. Ther. Adv. Chronic. Dis. 2020;11:1–12. DOI: 10.1177/2040622320965067.

32. Soley B.S., Silva L.M., Mendes D.A.G.B., Báfica A., Pesquero J.B., Bader M. et al. B1 and B2 kinin receptor blockade improves psoriasis-like disease. Br. J. Pharmacol. 2020;177(15):3535–3551. DOI: 10.1111/bph.15077.

33. Golias Ch., Charalabopoulos A., Stagikas D., Charalabopoulos K., Batistatou A. The kinin system-bradykinin: biological effects and clinical implications. Multiple role of the kinin system-bradykinin. Hippokratia. 2007;11(3):124–128.

34. Costa-Neto C.M., Dillenburg-Pilla P., Heinrich T.A., Parreiras-e-Silva L.T., Pereira M.G., Reis R.I. et al. Participation of kallikrein-kinin system in different pathologies. Int. Immunopharmacol. 2008;8(2):135–142. DOI: 10.1016/j.intimp.2007.08.003.

35. Choi S.I., Hwang S.W. Depolarizing effectors of bradykinin signaling in nociceptor excitation in pain perception. Biomol. Ther. (Seoul). 2018;26(3):255–267. DOI: 10.4062/biomolther.2017.127.

36. Ramjeeawon A., Choy E. Neuropathic-like pain in psoriatic arthritis: evidence of abnormal pain processing. Clin. Rheumatol. 2019;38(11):3153–3159. DOI: 10.1007/s10067-019- 04656-5.

37. Grinnell-Merrick L.L., Lydon E.J., Mixon A.M., Saalfeld W. Evaluating Inflammatory Versus Mechanical Back Pain in Individuals with Psoriatic Arthritis: A Review of the Literature. Rheumatol. Ther. 2020;7(4):667–684. DOI: 10.1007/s40744-020-00234-3.

38. Cassim B., Shaw O.M., Mazur M., Misso N.L., Naran A., Langlands D.R. et al. Kallikreins, kininogens and kinin receptors on circulating and synovial fluid neutrophils: role in kinin generation in rheumatoid arthritis. Rheumatology (Oxford). 2009;48(5):490–496. DOI: 10.1093/rheumatology/kep016.

39. Tan D.B.A., Tedja C., Kuster L., Raymond W.D., Harsanyi A., Chowalloor P.V. et al. The relationship between clinical phenotype and kallikrein-kinin bioregulation in different forms of arthritis. BMC Musculoskelet. Disord. 2023;24(1):396. DOI: 10.1186/s12891-023-06388-9.

40. Tsou P.S., Lu C., Gurrea-Rubio M., Muraoka S., Campbell P.L., Wu Q. et al. Soluble CD13 induces inflammatory arthritis by activating the bradykinin receptor B1. J. Clin. Invest. 2022;132(11):e151827. DOI: 10.1172/JCI151827.

41. Di Minno M.N., Iervolino S., Peluso R., Di Minno A., Ambrosino P., Scarpa R. Hemostatic and fibrinolytic changes are related to inflammatory conditions in patients with psoriatic arthritis-effect of different treatments. J. Rheumatol. 2014;41(4):714–722. DOI: 10.3899/jrheum.130850.

42. Visser M.J.E., Venter C., Roberts T.J., Tarr G., Pretorius E. Psoriatic disease is associated with systemic inflammation, endothelial activation, and altered haemostatic function. Sci. Rep. 2021;11(1):13043. DOI: 10.1038/s41598-021-90684-8.

43. Ogdie A., Kay McGill N., Shin D.B., Takeshita J., Jon Love T., Noe M.H. et al. Risk of venous thromboembolism in patients with psoriatic arthritis, psoriasis and rheumatoid arthritis: a general population-based cohort study. Eur. Heart J. 2018;39(39):3608–3614. DOI: 10.1093/eurheartj/ehx145.

44. Nohawica M., Nowak-Terpilowska A., Adamska K., Wyganowska-Swiatkowska M. Simulated in vitro hypoxic conditions from psoriatic arthritis cartilage change plasminogen activating system urokinase and serpine functionality. Adv. Dermatol. Alergol. 2022;39(5):944–952. DOI: 10.5114/ada.2022.113405.

45. Coras R., Kavanaugh A., Boyd T., Huynh Q., Pedersen B., Armando A.M. et al. Pro- and anti-inflammatory eicosanoids in psoriatic arthritis. Metabolomics. 2019;15(4):65. DOI: 10.1007/s11306-019-1527-0.

46. Wójcik P., Biernacki M., Wroński A., Łuczaj W., Waeg G., Žarković N. et al. Altered lipid metabolism in blood mononuclear cells of psoriatic patients indicates differential changes in psoriasis vulgaris and psoriatic arthritis. Int. J. Mol. Sci. 2019;20(17):4249. DOI: 10.3390/ijms20174249.

47. Łuczaj W., Gęgotek A., Skrzydlewska E. Antioxidants and HNE in redox homeostasis. Free Radic. Biol. Med. 2017;111:87– 101. DOI: 10.1016/j.freeradbiomed.2016.11.033.

48. Cheng H., Huang H., Guo Z., Chang Y., Li Z. Role of prostaglandin E2 in tissue repair and regeneration. Theranostics. 2021;11(18):8836–8854. DOI: 10.7150/thno.63396.

49. Samuels J.S., Holland L., López M., Meyers K., Cumbie W.G., McClain A. et al. Prostaglandin E2 and IL-23 interconnects STAT3 and RoRγ pathways to initiate Th17 CD4+ T-cell development during rheumatoid arthritis. Inflamm. Res. 2018;67(7):589–596. DOI: 10.1007/s00011-018-1153-8.

50. Diao G., Huang J., Zheng X., Sun X., Tian M., Han J. et al. Prostaglandin E2 serves a dual role in regulating the migration of dendritic cells. Int. J. Mol. Med. 2021;47(1):207–218. DOI: 10.3892/ijmm.2020.4801.

51. Timmermann M., Högger P. Oxidative stress and 8-iso-prostaglandin F(2alpha) induce ectodomain shedding of CD163 and release of tumor necrosis factor-alpha from human monocytes. Free Radic. Biol. Med. 2005;39(1):98–107. DOI: 10.1016/j.freeradbiomed.2005.02.031.

52. Antón R., Camacho M., Puig L., Vila L. Hepoxilin B3 and its enzymatically formed derivative trioxilin B3 are incorporated into phospholipids in psoriatic lesions. J. Invest. Dermatol. 2002;118(1):139–146. DOI: 10.1046/j.0022-202x.2001.01593.x.

53. Arnardottir H.H., Dalli J., Norling L.V., Colas R.A., Perretti M., Serhan C.N. Resolvin D3 Is Dysregulated in Arthritis and Reduces Arthritic Inflammation. J. Immunol. 2016;197(6):2362–2368. DOI: 10.4049/jimmunol.1502268.

54. Rea I.M., Gibson D.S., McGilligan V., McNerlan S.E., Alexander H.D., Ross O.A. Age and age-related diseases: role of inflammation triggers and cytokines. Front. Immunol. 2018;9:586. DOI: 10.3389/fimmu.2018.00586.

55. Faustman D.L., Davis M. TNF Receptor 2 and disease: autoimmunity and regenerative medicine. Front. Immunol. 2013;4:478. DOI: 10.3389/fimmu.2013.00478.

56. Fitzgerald O., Winchester R. Psoriatic arthritis: from pathogenesis to therapy. Arthritis. Res. Ther. 2009;11(1):214. DOI: 10.1186/ar2580.

57. Merola J.F., Espinoza LR., Fleischmann R. Distinguishing rheumatoid arthritis from psoriatic arthritis. RMD Open. 2018;4(2):e000656. DOI: 10.1136/rmdopen-2018-000656.

58. Lee B.W., Moon S.J. Inflammatory cytokines in psoriatic arthritis: understanding pathogenesis and implications for treatment. Int. J. Mol. Sci. 2023;24(14):11662. DOI: 10.3390/ijms241411662.

59. Fragoulis G.E., Siebert S. The role of IL-23 and the use of IL-23 inhibitors in psoriatic arthritis. Musculoskeletal Care. 2022;20(Suppl. 1):S12–S21. DOI: 10.1002/msc.1694.

60. Iznardo H., Puig L. Exploring the role of IL-36 cytokines as a new target in psoriatic disease. Int. J. Mol. Sci. 2021;22(9):4344. DOI: 10.3390/ijms22094344.

61. Blauvelt A., Chiricozzi A. The immunologic role of IL-17 in psoriasis and psoriatic arthritis pathogenesis. Clin. Rev. Allergy. Immunol. 2018;55(3):379–390. DOI: 10.1007/s12016-018-8702-3.

62. Aggarwal B.B. Signalling pathways of the TNF superfamily: a double-edged sword. Nat. Rev. Immunol. 2003;3(9):745–756. DOI 10.1038/nri1184.

63. Bodmer J.L., Schneider P., Tschopp J. The molecular architecture of the TNF superfamily. Trends Biochem. Sci. 2002;27(1):19–26. DOI: 10.1016/s0968-0004(01)01995-8.

64. Brenner D., Blaser H., Mak T.W. Regulation of tumour necrosis factor signalling: live or let die. Nat. Rev. Immunol. 2015;15(6):362–374. DOI: 10.1038/nri3834.

65. Boras E., Slevin M., Alexander M.Y., Aljohi A., Gilmore W., Ashworth J. et al. Monomeric C-reactive protein and Notch-3 co-operatively increase angiogenesis through PI3K signaling pathway. Cytokine. 2014;69(2):165–179. DOI: 10.1016/j.cyto.2014.05.027.

66. Narazaki, M. The two-faced cytokine IL-6 in host defense and diseases. Int. J. Mol. Sci. 2018;19(11):3528. DOI 10.3390/ijms19113528.

67. Rose-John S. Interleukin-6 family cytokines. Cold. Spring. Harb. Perspect. Biol. 2018;10(2):a028415. DOI 10.1101/cshperspect.a028415.

68. Blauvelt A., Chiricozzi A. The immunologic role of IL-17 in psoriasis and psoriatic arthritis pathogenesis. Clin. Rev. Allergy. Immunol. 2018;55(3):379–390. DOI: 10.1007/s12016-018-8702-3.

69. Boutet M.A., Nerviani A., Pitzalis C. IL-36, IL-37, and IL38 Cytokines in Skin and Joint Inflammation: A Comprehensive Review of Their Therapeutic Potential. Int. J. Mol. Sci. 2019;20(6):1257. DOI: 10.3390/ijms20061257.

70. Bettiol A., Fagni F., Mattioli I., Bagni G., Vitiello G., Grassi A. et al. Serum interleukin-36 α as a candidate biomarker to distinguish behçet’s syndrome and psoriatic arthritis. Int. J. Mol. Sci. 2023;24(10):8817. DOI: 10.3390/ijms24108817.

71. Wang C., Hu J., Shi J. Role of interleukin-36 in inflammatory joint diseases. Zhejiang Da XueXue Bao Yi Xue Ban. 2023;52(2):249–259. DOI: 10.3724/zdxbyxb-2023-0034.

72. Kaplan A.P., Joseph K. Pathogenic mechanisms of bradykinin mediated diseases: dysregulation of an innate inflammatory pathway. Adv. Immunol. 2014;121:41–89. DOI: 10.1016/B978-0-12-800100-4.00002-7.

73. Oncul S., Afshar-Kharghan V. The interaction between the complement system and hemostatic factors. Curr. Opin. Hematol. 2020;27(5):341–352. DOI: 10.1097/MOH.0000000000000605.

74. Risau W. Mechanisms of angiogenesis. Nature. 1997;386(6626):671–674. DOI: 10.1038/386671a0.

75. Cantatore F.P., Maruotti N., Corrado A., Ribatti D. Angiogenesis dysregulation in psoriatic arthritis: molecular mechanisms. Biomed. Res. Int. 2017;2017:5312813. DOI: 10.1155/2017/5312813.

76. Espinoza L.R., Vasey F.B., Espinoza C.G., Bocanegra T.S., Germain B.F. Vascular changes in psoriatic synovium. A light and electron microscopic study. Arthritis Rheum. 1982;25(6):677–684. DOI: 10.1002/art.1780250611.

77. Tenazinha C., Barros R., Fonseca J.E., Vieira-Sousa E. Histopathology of Psoriatic Arthritis Synovium-A Narrative Review. Front. Med (Lausanne). 2022;9:860813. DOI: 10.3389/fmed.2022.860813.

78. Lazar L.T., Guldberg-Møller J., Lazar B.T., Mogensen M. Nailfold capillaroscopy as diagnostic test in patients with psoriasis and psoriatic arthritis: A systematic review. Microvasc. Res. 2023;147:104476. DOI: 10.1016/j.mvr.2023.104476.

79. Anghel D., Sîrbu C.A., Petrache O.G., Opriș-Belinski D., Negru M.M., Bojincă V.C. et al. Nailfold videocapillaroscopy in patients with rheumatoid arthritis and psoriatic arthropathy on ANTI-TNF-ALPHA therapy. Diagnostics (Basel). 2023;13(12):2079. DOI: 10.3390/diagnostics13122079.

80. Guldberg-Møller J., Henriksen M., Ellegaard K., Haedersdal M., Lazar L.T., Kristensen L.E. et al. Novel application of optical coherence tomography and capillaroscopy in psoriatic arthritis in relationship to psoriasis and hand osteoarthritis. Rheumatol. Adv. Pract. 2021;5(3):rkab065. DOI: 10.1093/rap/rkab065.

81. Sivasankari M., Arora S., Vasdev V., Mary E.M. Nailfold capillaroscopy in psoriasis. Med. J. Armed. Forces India. 2021;77(1):75–81. DOI: 10.1016/j.mjafi.2020.01.013.

82. Li W., Man X.Y., Chen J.Q., Zhou J., Cai S.Q., Zheng M. Targeting VEGF/VEGFR in the treatment of psoriasis. Discov. Med. 2014;18(98):97–104.

83. Fearon U., Reece R., Smith J., Emery P., Veale D.J. Synovial cytokine and growth factor regulation of MMPs/TIMPs: implications for erosions and angiogenesis in early rheumatoid and psoriatic arthritis patients. Ann. N. Y. Acad. Sci. 1999;878:619–621. DOI: 10.1111/j.1749-6632.1999.tb07743.

84. Yamamoto T. Angiogenic and inflammatory properties of psoriatic arthritis. ISRN Dermatology. 2013;2013:2017. DOI: 10.1155/2013/630620.630620.

85. Ballara S.C., Miotla J.M., Paleolog E.M. New vessels, new approaches: angiogenesis as a therapeutic target in musculoskeletal disorders. Int. J. Exp. Pathol. 1999;80(5):235–250. DOI: 10.1046/j.1365-2613.1999.00129.x.

86. Parikh S.M. The angiopoietin-tie2 signaling axis in systemic inflammation. J. Am. Soc. Nephrol. 2017;28(7):1973–1982. DOI: 10.1681/ASN.2017010069.

87. Moss A. The angiopoietin:Tie 2 interaction: a potential target for future therapies in human vascular disease. Cytokine Growth Factor Rev. 2013;24(6):579–592. DOI: 10.1016/j.cytogfr.2013.05.009.

88. Pinto Tasende J.A., Fernandez-Moreno M., Vazquez-Mosquera M.E., Fernandez-Lopez J.C., Oreiro-Villar N., De Toro Santos F.J. et al. Increased synovial immunohistochemistry reactivity of TGF-β1 in erosive peripheral psoriatic arthritis. BMC Musculoskelet. Disord. 2023;24(1):246. DOI: 10.1186/s12891-023-06339-4.

89. Wang J., Xiang H., Lu Y., Wu T. Role and clinical significance of TGFβ1 and TGFβR1 in malignant tumors (Review). Int. J. Mol. Med. 2021;47(4):55. DOI: 10.3892/ijmm.2021.4888.

90. Walger P. Rational use of antibiotics. Internist. (Berl.). 2016;57(6):551–568. DOI: 10.1007/s00108-016-0071-5.