Molecular Targets for the Novel Therapies of Inflammation and Wound Care
,
Abstract
Anti-inflammatory drugs, particularly steroidal and non-steroidal, are already the sole treatment options for inflammatory illnesses. Chronic use of these medicines has been linked to gastrointestinal, cardiovascular, as well as other serious side effects. New anti-inflammatory and wound healing drugs with selective effect and lower toxicity are desperately needed. Novel therapies acting on different molecular targets have shown promising resultsRelevant studies (2003-2024) were identified through electronic searches of PubMed and Google scholar. The search used the keywords, including the following inflammation, wound care, signalling pathways, molecular targets of inflammation. Neutrophils and macrophages play a significant role in the release of mediators and phagocytosis at the site, Nf-kB signaling pathway and the JAK/Stat signaling pathway stimulate the production of mediators including IL-6, IL-1, and TNF-α, although their overproduction can have a variety of consequences. Cell therapy, MicroRNA, plasma protein therapy, COX-2 inhibitor with stem cells, combination of AMD3100 and Tacrolimus and combination of siRNAs with Plurogel for increasing wound healing time are among the approved and continuing clinical trial novel therapies mentioned. This study shows that these new therapeutics can interact with numerous targets and modify the dysregulated inflammatory pathways and mediators associated with normal and chronic wounds more effectively than standard anti-inflammatory medication treatments.
1. Kunnumakkara AB, Sailo BL, Banik K, et al. Chronic diseases, inflammation, and spices: how are they linked? J Transl Med. 2018 5;16(1):1–25.
2. Takeuchi O, Akira S. Pattern Recognition Receptors and Inflammation. Cell. 2010;140(6):805–20.
3. Pawelec G, Goldeck D, Derhovanessian E. Inflammation, ageing and chronic disease. Curr Opin Immunol. 2014;29(1):23–8.
4. Simmons DL. What makes a good anti-inflammatory drug target? Drug Discov Today. 2006;11(5–6):210–9.
5. Prasad S, Sung B, Aggarwal BB. Age-associated chronic diseases require age-old medicine: Role of chronic inflammation. Prev Med (Baltim). 2012;54(SUPPL.):S29–37.
6. Patil KR, Mahajan UB, Unger BS, et al. Animal Models of Inflammation for Screening of Anti-inflammatory Drugs: Implications for the Discovery and Development of Phytopharmaceuticals. Int J Mol Sci. 2019;20(18):4367.
7. Seong SY, Matzinger P. Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses. Nat Rev Immunol. 2004;4(6):469–78.
8. Brusselle G, Bracke K. Targeting immune pathways for therapy in asthma and chronic obstructive pulmonary disease. Ann Am Thorac Soc. 2014;11:S322–8.
9. Gudkov A V., Komarova EA. p53 and the Carcinogenicity of Chronic Inflammation. Cold Spring Harb Perspect Med. 2016;6(11):a026161.
10. Takeda K, Yamamoto M. Current views of toll-like receptor signaling pathways. Gastroenterol Res Pract. 2010;2010:240365.
11. Rubartelli A, Lotze MT. Inside, outside, upside down: damage-associated molecular-pattern molecules (DAMPs) and redox. Trends Immunol. 2007;28(10):429–36.
12. Machowska A, Carrero JJ, Lindholm B, Stenvinkel P. Therapeutics targeting persistent inflammation in chronic kidney disease. Transl Res. 2016;167(1):204–13.
13. Goldstein BI, Kemp DE, Soczynska JK, McIntyre RS. Inflammation and the Phenomenology, Pathophysiology, Comorbidity, and Treatment of Bipolar Disorder: A Systematic Review of the Literature. J Clin Psychiatry. 2009;70(8):1078-90.
14. Hoffmann A, Natoli G, Ghosh G. Transcriptional regulation via the NF-κB signaling module. Oncogene. 2006;25(51):6706–16.
15. Medzhitov R. Inflammation 2010: New Adventures of an Old Flame. Cell. 2010;140(6):771–6.
16. Fonder MA, Lazarus GS, Cowan DA, Aronson-Cook B, Kohli AR, Mamelak AJ. Treating the chronic wound: A practical approach to the care of nonhealing wounds and wound care dressings. J Am Acad Dermatol. 2008;58(2):185–206.
17. Peña OA, Martin P. Cellular and molecular mechanisms of skin wound healing. Nat Rev Mol Cell Biol. 2024;1–8.
18. Powers JG, Higham C, Broussard K, Phillips TJ. Wound healing and treating wounds: Chronic wound care and management. J Am Acad Dermatol. 2016;74(4):607–25.
19. Ye W, Yan Y, Tang Y, et al. Orexin-A Attenuates Inflammatory Responses in Lipopolysaccharide-Induced Neural Stem Cells by Regulating NF-KB and Phosphorylation of MAPK/P38/Erk Pathways. J Inflamm Res. 2021;14:2007.
20. Messina S, Vita GL, Aguennouz M, Sframeli M, Romeo S, Rodolico C, Vita G. Activation of NF-kappaB pathway in Duchenne muscular dystrophy: relation to age. Acta Myol. 2011;30(1):16-23.
21. Salminen A, Huuskonen J, Ojala J, Kauppinen A, Kaarniranta K, Suuronen T. Activation of innate immunity system during aging: NF-kB signaling is the molecular culprit of inflamm-aging. Ageing Res Rev. 2008;7(2):83–105.
22. Belacortu Y, Paricio N. Drosophila as a model of wound healing and tissue regeneration in vertebrates. Dev Dyn. 2011;240(11):2379–404.
23. Katsuyama T, Comoglio F, Seimiya M, Cabuy E, Paro R. During Drosophila disc regeneration, JAK/STAT coordinates cell proliferation with Dilp8-mediated developmental delay. Proc Natl Acad Sci. 2015;112(18):E2327–36.
24. Beigel F, Friedrich M, Probst C, et al. Oncostatin M Mediates STAT3-Dependent Intestinal Epithelial Restitution via Increased Cell Proliferation, Decreased Apoptosis and Upregulation of SERPIN Family Members. PLoS One. 2014;9(4):e93498.
25. Feng Y, Sanders AJ, Morgan LD, Harding KG, Jiang WG. Potential roles of suppressor of cytokine signaling in wound healing. Regen Med. 2016;11(2):193–209.
26. Papanas N, Maltezos E. Becaplermin gel in the treatment of diabetic neuropathic foot ulcers. Clin Interv Aging. 2008;3(2):233–40.
27. Wood S, Jayaraman V, Huelsmann EJ, et al. Pro-inflammatory chemokine CCL2 (MCP-1) promotes healing in diabetic wounds by restoring the macrophage response. PLoS One. 2014;9(3):e91574.
28. Kanji S, Das H. Advances of Stem Cell Therapeutics in Cutaneous Wound Healing and Regeneration. Mediators Inflamm. 2017;2017:5217967.
29. Lin Q, Wesson RN, Maeda H, et al. Pharmacological Mobilization of Endogenous Stem Cells Significantly Promotes Skin Regeneration after Full-Thickness Excision: The Synergistic Activity of AMD3100 and Tacrolimus. J Invest Dermatol. 2014;134(9):2458–68.
30. O’Rourke BP, Kramer AH, Cao LL, et al. Fidgetin-Like 2 siRNA Enhances the Wound Healing Capability of a Surfactant Polymer Dressing. Adv Wound Care. 2019;8(3):91.
31. A Phase 3 Clinical Trial to Assess the Effectiveness of BioChaperone PDGF-BB In the Treatment of Chronic Diabetic Foot Ulcer - Full Text View - ClinicalTrials.gov (Internet).
32. Liu CJ, Jones DS, Tsai PC, Venkataramana A, Cochran JR. An engineered dimeric fragment of hepatocyte growth factor is a potent c-MET agonist. FEBS Lett. 2014;588(24):4831–7.
33. Rodgers KE, Bolton LL, Verco S, diZerega GS. NorLeu3-Angiotensin (1-7) (DSC127) as a Therapy for the Healing of Diabetic Foot Ulcers. Adv Wound Care. 2015;4(6):339.
34. Jensen J, Gentzkow G, Berman G, et al. Anti-CTGF Oligonucleotide Reduces Severity of Postsurgical Hypertrophic Scars in a Randomized, Double-Blind, Within-Subject, Placebo-Controlled Study. Plast Reconstr Surg. 2018;142(2):192E-201E.
35. Barakat M, Dipietro LA, Chen L. Limited treatment options for diabetic wounds: barriers to clinical translation despite therapeutic success in murine models. https://home.liebertpub.com/wound. 2021;10(8):436–60.
36. Bohannon M, Liu M, Nadeau P, et al. Topical doxycycline monohydrate hydrogel 1% targeting proteases/PAR2 pathway is a novel therapeutic for atopic dermatitis. Exp Dermatol. 2020;29(12):1171–5.
37. Braude E, Hachem O, Ben-Hamo M, Solomonik I, Braiman L, Tennenbaum T. Ho/03/03 in the treatment of diabetic foot ulcers - Final results of a phase I study. Wound Repair Regen. 2008;16:A33–A33.
38. Simonetti O, Cirioni O, Goteri G, et al. Efficacy of Cathelicidin LL-37 in an MRSA Wound Infection Mouse Model. Antibiot 2021. 2021;10(10):1210.
39. Qiu C, Coutinho P, Frank S, et al. Targeting connexin43 expression accelerates the rate of wound repair. Curr Biol. 2003;13(19):1697–703.
40. Kleinman HK, Sosne G. Thymosin β4 Promotes Dermal Healing. Vitam Horm. 2016;102:251–75.
2. Takeuchi O, Akira S. Pattern Recognition Receptors and Inflammation. Cell. 2010;140(6):805–20.
3. Pawelec G, Goldeck D, Derhovanessian E. Inflammation, ageing and chronic disease. Curr Opin Immunol. 2014;29(1):23–8.
4. Simmons DL. What makes a good anti-inflammatory drug target? Drug Discov Today. 2006;11(5–6):210–9.
5. Prasad S, Sung B, Aggarwal BB. Age-associated chronic diseases require age-old medicine: Role of chronic inflammation. Prev Med (Baltim). 2012;54(SUPPL.):S29–37.
6. Patil KR, Mahajan UB, Unger BS, et al. Animal Models of Inflammation for Screening of Anti-inflammatory Drugs: Implications for the Discovery and Development of Phytopharmaceuticals. Int J Mol Sci. 2019;20(18):4367.
7. Seong SY, Matzinger P. Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses. Nat Rev Immunol. 2004;4(6):469–78.
8. Brusselle G, Bracke K. Targeting immune pathways for therapy in asthma and chronic obstructive pulmonary disease. Ann Am Thorac Soc. 2014;11:S322–8.
9. Gudkov A V., Komarova EA. p53 and the Carcinogenicity of Chronic Inflammation. Cold Spring Harb Perspect Med. 2016;6(11):a026161.
10. Takeda K, Yamamoto M. Current views of toll-like receptor signaling pathways. Gastroenterol Res Pract. 2010;2010:240365.
11. Rubartelli A, Lotze MT. Inside, outside, upside down: damage-associated molecular-pattern molecules (DAMPs) and redox. Trends Immunol. 2007;28(10):429–36.
12. Machowska A, Carrero JJ, Lindholm B, Stenvinkel P. Therapeutics targeting persistent inflammation in chronic kidney disease. Transl Res. 2016;167(1):204–13.
13. Goldstein BI, Kemp DE, Soczynska JK, McIntyre RS. Inflammation and the Phenomenology, Pathophysiology, Comorbidity, and Treatment of Bipolar Disorder: A Systematic Review of the Literature. J Clin Psychiatry. 2009;70(8):1078-90.
14. Hoffmann A, Natoli G, Ghosh G. Transcriptional regulation via the NF-κB signaling module. Oncogene. 2006;25(51):6706–16.
15. Medzhitov R. Inflammation 2010: New Adventures of an Old Flame. Cell. 2010;140(6):771–6.
16. Fonder MA, Lazarus GS, Cowan DA, Aronson-Cook B, Kohli AR, Mamelak AJ. Treating the chronic wound: A practical approach to the care of nonhealing wounds and wound care dressings. J Am Acad Dermatol. 2008;58(2):185–206.
17. Peña OA, Martin P. Cellular and molecular mechanisms of skin wound healing. Nat Rev Mol Cell Biol. 2024;1–8.
18. Powers JG, Higham C, Broussard K, Phillips TJ. Wound healing and treating wounds: Chronic wound care and management. J Am Acad Dermatol. 2016;74(4):607–25.
19. Ye W, Yan Y, Tang Y, et al. Orexin-A Attenuates Inflammatory Responses in Lipopolysaccharide-Induced Neural Stem Cells by Regulating NF-KB and Phosphorylation of MAPK/P38/Erk Pathways. J Inflamm Res. 2021;14:2007.
20. Messina S, Vita GL, Aguennouz M, Sframeli M, Romeo S, Rodolico C, Vita G. Activation of NF-kappaB pathway in Duchenne muscular dystrophy: relation to age. Acta Myol. 2011;30(1):16-23.
21. Salminen A, Huuskonen J, Ojala J, Kauppinen A, Kaarniranta K, Suuronen T. Activation of innate immunity system during aging: NF-kB signaling is the molecular culprit of inflamm-aging. Ageing Res Rev. 2008;7(2):83–105.
22. Belacortu Y, Paricio N. Drosophila as a model of wound healing and tissue regeneration in vertebrates. Dev Dyn. 2011;240(11):2379–404.
23. Katsuyama T, Comoglio F, Seimiya M, Cabuy E, Paro R. During Drosophila disc regeneration, JAK/STAT coordinates cell proliferation with Dilp8-mediated developmental delay. Proc Natl Acad Sci. 2015;112(18):E2327–36.
24. Beigel F, Friedrich M, Probst C, et al. Oncostatin M Mediates STAT3-Dependent Intestinal Epithelial Restitution via Increased Cell Proliferation, Decreased Apoptosis and Upregulation of SERPIN Family Members. PLoS One. 2014;9(4):e93498.
25. Feng Y, Sanders AJ, Morgan LD, Harding KG, Jiang WG. Potential roles of suppressor of cytokine signaling in wound healing. Regen Med. 2016;11(2):193–209.
26. Papanas N, Maltezos E. Becaplermin gel in the treatment of diabetic neuropathic foot ulcers. Clin Interv Aging. 2008;3(2):233–40.
27. Wood S, Jayaraman V, Huelsmann EJ, et al. Pro-inflammatory chemokine CCL2 (MCP-1) promotes healing in diabetic wounds by restoring the macrophage response. PLoS One. 2014;9(3):e91574.
28. Kanji S, Das H. Advances of Stem Cell Therapeutics in Cutaneous Wound Healing and Regeneration. Mediators Inflamm. 2017;2017:5217967.
29. Lin Q, Wesson RN, Maeda H, et al. Pharmacological Mobilization of Endogenous Stem Cells Significantly Promotes Skin Regeneration after Full-Thickness Excision: The Synergistic Activity of AMD3100 and Tacrolimus. J Invest Dermatol. 2014;134(9):2458–68.
30. O’Rourke BP, Kramer AH, Cao LL, et al. Fidgetin-Like 2 siRNA Enhances the Wound Healing Capability of a Surfactant Polymer Dressing. Adv Wound Care. 2019;8(3):91.
31. A Phase 3 Clinical Trial to Assess the Effectiveness of BioChaperone PDGF-BB In the Treatment of Chronic Diabetic Foot Ulcer - Full Text View - ClinicalTrials.gov (Internet).
32. Liu CJ, Jones DS, Tsai PC, Venkataramana A, Cochran JR. An engineered dimeric fragment of hepatocyte growth factor is a potent c-MET agonist. FEBS Lett. 2014;588(24):4831–7.
33. Rodgers KE, Bolton LL, Verco S, diZerega GS. NorLeu3-Angiotensin (1-7) (DSC127) as a Therapy for the Healing of Diabetic Foot Ulcers. Adv Wound Care. 2015;4(6):339.
34. Jensen J, Gentzkow G, Berman G, et al. Anti-CTGF Oligonucleotide Reduces Severity of Postsurgical Hypertrophic Scars in a Randomized, Double-Blind, Within-Subject, Placebo-Controlled Study. Plast Reconstr Surg. 2018;142(2):192E-201E.
35. Barakat M, Dipietro LA, Chen L. Limited treatment options for diabetic wounds: barriers to clinical translation despite therapeutic success in murine models. https://home.liebertpub.com/wound. 2021;10(8):436–60.
36. Bohannon M, Liu M, Nadeau P, et al. Topical doxycycline monohydrate hydrogel 1% targeting proteases/PAR2 pathway is a novel therapeutic for atopic dermatitis. Exp Dermatol. 2020;29(12):1171–5.
37. Braude E, Hachem O, Ben-Hamo M, Solomonik I, Braiman L, Tennenbaum T. Ho/03/03 in the treatment of diabetic foot ulcers - Final results of a phase I study. Wound Repair Regen. 2008;16:A33–A33.
38. Simonetti O, Cirioni O, Goteri G, et al. Efficacy of Cathelicidin LL-37 in an MRSA Wound Infection Mouse Model. Antibiot 2021. 2021;10(10):1210.
39. Qiu C, Coutinho P, Frank S, et al. Targeting connexin43 expression accelerates the rate of wound repair. Curr Biol. 2003;13(19):1697–703.
40. Kleinman HK, Sosne G. Thymosin β4 Promotes Dermal Healing. Vitam Horm. 2016;102:251–75.
| Files | ||
| Issue | Vol 12, No 3 (Summer 2024) | |
| Section | Review Article(s) | |
| DOI | https://doi.org/10.18502/jpc.v12i3.16773 | |
| Keywords | ||
| Inflammation Mediators Wound Care | ||
| Rights and permissions | |
|
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Agrawal P, Singh S, Singh N, Mishra G, Sharma M. Molecular Targets for the Novel Therapies of Inflammation and Wound Care. J Pharm Care. 2024;12(3):177-184.
