{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,26]],"date-time":"2026-07-26T04:30:11Z","timestamp":1785040211623,"version":"3.55.0"},"reference-count":109,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2021,8,12]],"date-time":"2021-08-12T00:00:00Z","timestamp":1628726400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004569","name":"Ministerstwo Nauki i Szkolnictwa Wy\u017cszego","doi-asserted-by":"publisher","award":["MNiSW\/2019\/106\/DIR\/NN3"],"award-info":[{"award-number":["MNiSW\/2019\/106\/DIR\/NN3"]}],"id":[{"id":"10.13039\/501100004569","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004166","name":"Warszawski Uniwersytet Medyczny","doi-asserted-by":"publisher","award":["1M15\/NM1\/17"],"award-info":[{"award-number":["1M15\/NM1\/17"]}],"id":[{"id":"10.13039\/501100004166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In this study, we aimed to investigate the influence of N-acetylcysteine (NAC) on the gene expression profile, neoangiogenesis, neutrophils and macrophages in a rat model of incisional wounds. Before creating wounds on the backs of 24 Sprague\u2013Dawley rats, intradermal injections were made. Lidocaine\u2013epinephrin solutions were supplemented with 0.015%, 0.03% or 0.045% solutions of NAC, or nothing (control group). Scars were harvested on the 3rd, 7th, 14th and 60th day post-surgery. We performed immunohistochemical staining in order to visualize macrophages (anti-CD68), neutrophils (anti-MPO) and newly formed blood vessels (anti-CD31). Additionally, RT-qPCR was used to measure the relative expression of 88 genes involved in the wound healing process. On the 14th day, the number of cells stained with anti-CD68 and anti-CD31 antibodies was significantly larger in the tissues treated with 0.03% NAC compared with the control. Among the selected genes, 52 were upregulated and six were downregulated at different time points. Interestingly, NAC exerted a significant effect on the expression of 45 genes 60 days after its administration. In summation, a 0.03% NAC addition to the pre-incisional anesthetic solution improves neovasculature and increases the macrophages\u2019 concentration at the wound site on the 14th day, as well as altering the expression of numerous genes that are responsible for the regenerative processes.<\/jats:p>","DOI":"10.3390\/ijms22168659","type":"journal-article","created":{"date-parts":[[2021,8,12]],"date-time":"2021-08-12T10:54:41Z","timestamp":1628765681000},"page":"8659","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Single Dose of N-Acetylcysteine in Local Anesthesia Increases Expression of HIF1\u03b1, MAPK1, TGF\u03b21 and Growth Factors in Rat Wound Healing"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3051-5446","authenticated-orcid":false,"given":"Wiktor","family":"Paskal","sequence":"first","affiliation":[{"name":"Department of Methodology, Medical University of Warsaw, 02-091 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Micha\u0142","family":"Kopka","sequence":"additional","affiliation":[{"name":"Department of Methodology, Medical University of Warsaw, 02-091 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7591-9482","authenticated-orcid":false,"given":"Albert","family":"Stachura","sequence":"additional","affiliation":[{"name":"Department of Methodology, Medical University of Warsaw, 02-091 Warsaw, Poland"},{"name":"Doctoral School, Medical University of Warsaw, 02-091 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0557-1588","authenticated-orcid":false,"given":"Adriana M.","family":"Paskal","sequence":"additional","affiliation":[{"name":"Department of Methodology, Medical University of Warsaw, 02-091 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piotr","family":"Pietruski","sequence":"additional","affiliation":[{"name":"Centre of Postgraduate Medical Education, Department of Replantation and Reconstructive Surgery, Gruca Teaching Hospital, 05-400 Otwock, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4679-9669","authenticated-orcid":false,"given":"Kacper","family":"Pe\u0142ka","sequence":"additional","affiliation":[{"name":"Department of Methodology, Medical University of Warsaw, 02-091 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan E.","family":"Woessner","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Arkansas, Fayetteville, AR 72701, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle P.","family":"Quinn","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Arkansas, Fayetteville, AR 72701, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryszard","family":"Galus","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology, Medical University of Warsaw, 02-091 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0659-7322","authenticated-orcid":false,"given":"Jaros\u0142aw","family":"Wejman","sequence":"additional","affiliation":[{"name":"Department of Pathology, Centre of Postgraduate Medical Education, 00-416 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0683-1791","authenticated-orcid":false,"given":"Pawe\u0142","family":"W\u0142odarski","sequence":"additional","affiliation":[{"name":"Department of Methodology, Medical University of Warsaw, 02-091 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1152\/physrev.00067.2017","article-title":"Wound Healing: A Cellular Perspective","volume":"99","author":"Rodrigues","year":"2019","journal-title":"Physiol. Rev."},{"key":"ref_2","first-page":"54","article-title":"Inflammation as an orchestrator of cutaneous scar formation: A review of the literature","volume":"7","author":"Wilgus","year":"2020","journal-title":"Plast. Aesthetic Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1111\/j.1524-475X.2008.00410.x","article-title":"Growth factors and cytokines in wound healing","volume":"16","author":"Barrientos","year":"2008","journal-title":"Wound Repair Regen."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1111\/wrr.12205","article-title":"Clinical application of growth factors and cytokines in wound healing","volume":"22","author":"Barrientos","year":"2014","journal-title":"Wound Repair Regen."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"455","DOI":"10.2165\/11534570-000000000-00000","article-title":"Benefit-risk assessment of becaplermin in the treatment of diabetic foot ulcers","volume":"33","author":"Papanas","year":"2010","journal-title":"Drug Saf."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"163","DOI":"10.2165\/11631850-000000000-00000","article-title":"Delivery of growth factors for tissue regeneration and wound healing","volume":"26","author":"Koria","year":"2012","journal-title":"BioDrugs"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1093\/toxsci\/kfq364","article-title":"The cytoprotective effect of N-acetyl-L-cysteine against ROS-induced cytotoxicity is independent of its ability to enhance glutathione synthesis","volume":"120","author":"Zhang","year":"2011","journal-title":"Toxicol. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.pharmthera.2013.09.006","article-title":"Existing and potential therapeutic uses for N-acetylcysteine: The need for conversion to intracellular glutathione for antioxidant benefits","volume":"141","author":"Rushworth","year":"2014","journal-title":"Pharmacol. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"7563","DOI":"10.3390\/ijms15057563","article-title":"Topical N-acetylcysteine accelerates wound healing in vitro and in vivo via the PKC\/Stat3 pathway","volume":"15","author":"Tsai","year":"2014","journal-title":"Int. J. Mol. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1111\/j.1365-2230.2010.03823.x","article-title":"N-acetyl cysteine promotes angiogenesis and clearance of free oxygen radicals, thus improving wound healing in an alloxan-induced diabetic mouse model of incisional wound","volume":"35","author":"Aktunc","year":"2010","journal-title":"Clin. Exp. Dermatol."},{"key":"ref_11","first-page":"91","article-title":"Topical and Systemic Effects of N-acetyl Cysteine on Wound Healing in a Diabetic Rat Model","volume":"31","author":"Ozkaya","year":"2019","journal-title":"Wounds"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"419","DOI":"10.3389\/fphys.2018.00419","article-title":"The Role of Macrophages in Acute and Chronic Wound Healing and Interventions to Promote Pro-wound Healing Phenotypes","volume":"9","author":"Krzyszczyk","year":"2018","journal-title":"Front. Physiol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Paskal, W., Paskal, A.M., Pietruski, P., Stachura, A., Pe\u0142ka, K., Woessner, A.E., Quinn, K.P., Kopka, M., Galus, R., and Wejman, J. (2021). N-Acetylcysteine Added to Local Anesthesia Reduces Scar Area and Width in Early Wound Healing\u2014An Animal Model Study. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22147549"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1111\/exd.12553","article-title":"An automated image processing method to quantify collagen fiber organization within cutaneous scar tissue","volume":"24","author":"Quinn","year":"2015","journal-title":"Exp. Dermatol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/BF02340831","article-title":"The time-dependent rearrangement of the epithelial basement membrane in human skin wounds--immunohistochemical localization of collagen IV and VII","volume":"105","author":"Betz","year":"1992","journal-title":"Int. J. Leg. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4103\/1947-2714.92892","article-title":"Collagen IV in normal skin and in pathological processes","volume":"4","author":"Howard","year":"2012","journal-title":"North. Am. J. Med Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1111\/jcmm.12255","article-title":"Improved repair of dermal wounds in mice lacking microRNA-155","volume":"18","author":"Araldi","year":"2014","journal-title":"J. Cell. Mol. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"847","DOI":"10.2119\/molmed.2014.00186","article-title":"Downregulation of miRNAs during Delayed Wound Healing in Diabetes: Role of Dicer","volume":"21","author":"Bhattacharya","year":"2016","journal-title":"Mol. Med."},{"key":"ref_19","first-page":"958695","article-title":"Myofibroblast expression in skin wounds is enhanced by collagen III suppression","volume":"2015","author":"Hawary","year":"2015","journal-title":"Biomed. Res. Int."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1159\/000322399","article-title":"Diminished type III collagen promotes myofibroblast differentiation and increases scar deposition in cutaneous wound healing","volume":"194","author":"Volk","year":"2011","journal-title":"Cells Tissues Organs"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2482","DOI":"10.1091\/mbc.e02-11-0743","article-title":"Calponin repeats regulate actin filament stability and formation of podosomes in smooth muscle cells","volume":"14","author":"Gimona","year":"2003","journal-title":"Mol. Biol. Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1146\/annurev-physiol-022516-034356","article-title":"Mechanisms of Organ Injury and Repair by Macrophages","volume":"79","author":"Vannella","year":"2017","journal-title":"Annu. Rev. Physiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1126\/science.3041594","article-title":"Wound macrophages express TGF-alpha and other growth factors in vivo: Analysis by mRNA phenotyping","volume":"241","author":"Rappolee","year":"1988","journal-title":"Science"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1161\/01.STR.0000252129.18605.c8","article-title":"Macrophage-derived matrix metalloproteinase-2 and -9 promote the progression of cerebral aneurysms in rats","volume":"38","author":"Aoki","year":"2007","journal-title":"Stroke"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Ridiandries, A., Tan, J.T.M., and Bursill, C.A. (2018). The Role of Chemokines in Wound Healing. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19103217"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1089\/wound.2014.0568","article-title":"Chemokines in Wound Healing and as Potential Therapeutic Targets for Reducing Cutaneous Scarring","volume":"4","author":"Rees","year":"2015","journal-title":"Adv. Wound Care"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.jdds.2016.09.001","article-title":"Critical role of tumor necrosis factor-\u03b1 in the early process of wound healing in skin","volume":"21","author":"Ritsu","year":"2017","journal-title":"J. Dermatol. Dermatol. Surg."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1016\/j.matbio.2018.01.004","article-title":"CCN4\/WISP1 controls cutaneous wound healing by modulating proliferation, migration and ECM expression in dermal fibroblasts via alpha5beta1 and TNFalpha","volume":"68","author":"Ono","year":"2018","journal-title":"Matrix Biol."},{"key":"ref_29","unstructured":"Oppenheim, J.J., Feldman, M., Durum, S.K., Hirano, T., Vilcek, J., and Nicola, N.A. (2001). Cytokine Reference: A Compendium of Cytokines and Other Mediators of Host Defense, Academic Press."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"288","DOI":"10.2353\/ajpath.2008.070726","article-title":"Galectin-3 expression and secretion links macrophages to the promotion of renal fibrosis","volume":"172","author":"Henderson","year":"2008","journal-title":"Am. J. Pathol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1006\/jsre.1994.1045","article-title":"Systemic Administration of Interferon-\u03b3 Impairs Wound Healing","volume":"56","author":"Miles","year":"1994","journal-title":"J. Surg. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.legalmed.2015.02.007","article-title":"The mRNA expressions and immunohistochemistry of factors involved in angiogenesis and lymphangiogenesis in the early stage of rat skin incision wounds","volume":"17","author":"Kameyama","year":"2015","journal-title":"Leg. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e92691","DOI":"10.1371\/journal.pone.0092691","article-title":"Granulocyte\/macrophage colony-stimulating factor influences angiogenesis by regulating the coordinated expression of VEGF and the Ang\/Tie system","volume":"9","author":"Zhao","year":"2014","journal-title":"PLoS ONE"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1693","DOI":"10.1172\/JCI1020","article-title":"MIP-1alpha as a critical macrophage chemoattractant in murine wound repair","volume":"101","author":"DiPietro","year":"1998","journal-title":"J. Clin. Investig."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2400","DOI":"10.2741\/2853","article-title":"The role of chemokines in neutrophil biology","volume":"13","author":"Kobayashi","year":"2008","journal-title":"Front. Biosci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1089\/wound.2013.0461","article-title":"Regenerative Wound Healing: The Role of Interleukin-10","volume":"3","author":"King","year":"2014","journal-title":"Adv. Wound Care"},{"key":"ref_37","first-page":"19","article-title":"Interferon-gamma-induced inhibition of wound healing in vivo and in vitro","volume":"90","author":"Laato","year":"2001","journal-title":"Ann. Chir. Gynaecol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1111\/j.1468-3083.2011.04415.x","article-title":"Cytokines, chemokines and growth factors in wound healing","volume":"26","author":"Behm","year":"2012","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1848","DOI":"10.4049\/jimmunol.172.3.1848","article-title":"The essential involvement of cross-talk between IFN-gamma and TGF-beta in the skin wound-healing process","volume":"172","author":"Ishida","year":"2004","journal-title":"J. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"40","DOI":"10.3389\/fcvm.2017.00040","article-title":"CD40L and Its Receptors in Atherothrombosis-An Update","volume":"4","author":"Michel","year":"2017","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1038\/sj.jid.5700701","article-title":"Inflammation in wound repair: Molecular and cellular mechanisms","volume":"127","author":"Eming","year":"2007","journal-title":"J. Investig. Dermatol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2579","DOI":"10.2337\/db12-1450","article-title":"Blocking interleukin-1beta induces a healing-associated wound macrophage phenotype and improves healing in type 2 diabetes","volume":"62","author":"Mirza","year":"2013","journal-title":"Diabetes"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1534","DOI":"10.1213\/ANE.0b013e3181f691eb","article-title":"The Role of Interleukin-1 in Wound Biology. Part II: In Vivo and Human Translational Studies","volume":"111","author":"Hu","year":"2010","journal-title":"Anesth. Analg."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"656","DOI":"10.9738\/INTSURG-D-14-00227.1","article-title":"Topical N-acetylcysteine improves wound healing comparable to dexpanthenol: An experimental study","volume":"100","author":"Oguz","year":"2015","journal-title":"Int. Surg."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1038\/labinvest.2008.36","article-title":"Regulation of scar formation by vascular endothelial growth factor","volume":"88","author":"Wilgus","year":"2008","journal-title":"Lab. Investig. A J. Tech. Methods Pathol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1089\/wound.2013.0520","article-title":"The Role of Hypoxia-Inducible Factor in Wound Healing","volume":"3","author":"Hong","year":"2014","journal-title":"Adv. Wound Care"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1111\/j.1524-475X.2007.00278.x","article-title":"Sustained expression of Hif-1alpha in the diabetic environment promotes angiogenesis and cutaneous wound repair","volume":"15","author":"Mace","year":"2007","journal-title":"Wound Repair Regen."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.freeradbiomed.2013.11.007","article-title":"Hypoxia-inducible factor 1 contributes to N-acetylcysteine\u2019s protection in stroke","volume":"68","author":"Zhang","year":"2014","journal-title":"Free. Radic. Biol. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2686","DOI":"10.1038\/sj.emboj.7601173","article-title":"Plasminogen activation independent of uPA and tPA maintains wound healing in gene-deficient mice","volume":"25","author":"Lund","year":"2006","journal-title":"EMBO J."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.2174\/1381612822666151210122954","article-title":"Coagulation Factor XIIIA (F13A1): Novel Perspectives in Treatment and Pharmacogenetics","volume":"22","author":"Gemmati","year":"2016","journal-title":"Curr. Pharm. Des."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1089\/wound.2013.0512","article-title":"SERPINE1: A Molecular Switch in the Proliferation-Migration Dichotomy in Wound-\"Activated\" Keratinocytes","volume":"3","author":"Simone","year":"2014","journal-title":"Adv. Wound Care"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1172\/JCI92880","article-title":"Factor XII and uPAR upregulate neutrophil functions to influence wound healing","volume":"128","author":"Stavrou","year":"2018","journal-title":"J. Clin. Investig."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"3691","DOI":"10.1182\/blood.V97.12.3691","article-title":"Wound-healing defects in mice lacking fibrinogen","volume":"97","author":"Drew","year":"2001","journal-title":"Blood"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1002\/1096-9896(2000)9999:9999<::AID-PATH757>3.0.CO;2-G","article-title":"Localization of vascular endothelial growth factor-D in malignant melanoma suggests a role in tumour angiogenesis","volume":"193","author":"Achen","year":"2001","journal-title":"J. Pathol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2074","DOI":"10.1038\/jid.2013.83","article-title":"Vascular endothelial growth factor-d modulates caliber and function of initial lymphatics in the dermis","volume":"133","author":"Levy","year":"2013","journal-title":"J. Investig. Dermatol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1097\/BCR.0b013e318240540a","article-title":"Sugar-coating wound repair: A review of FGF-10 and dermatan sulfate in wound healing and their potential application in burn wounds","volume":"33","author":"Plichta","year":"2012","journal-title":"J. Burn. Care Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2144","DOI":"10.1016\/j.ajpath.2011.09.001","article-title":"A novel enhancer of the wound healing process: The fibroblast growth factor-binding protein","volume":"179","author":"Werner","year":"2011","journal-title":"Am. J. Pathol."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Kashpur, O., LaPointe, D., Ambady, S., Ryder, E.F., and Dominko, T. (2013). FGF2-induced effects on transcriptome associated with regeneration competence in adult human fibroblasts. BMC Genom., 14.","DOI":"10.1186\/1471-2164-14-656"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"470418","DOI":"10.1155\/2013\/470418","article-title":"HGF accelerates wound healing by promoting the dedifferentiation of epidermal cells through beta1-integrin\/ILK pathway","volume":"2013","author":"Li","year":"2013","journal-title":"Biomed. Res. Int."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"A4","DOI":"10.1046\/j.1365-2613.2000.0145e.x","article-title":"Hepatocyte growth factor\/scatter factor (HGF\/SF) increases cutaneous wound healing in the diabetes mouse","volume":"81","author":"Bevan","year":"2000","journal-title":"Int. J. Exp. Pathol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1002\/jcb.240450403","article-title":"Role of platelet-derived growth factor in wound healing","volume":"45","author":"Pierce","year":"1991","journal-title":"J. Cell. Biochem."},{"key":"ref_62","first-page":"4551","article-title":"Enhanced regenerative healing efficacy of a highly skin-permeable growth factor nanocomplex in a full-thickness excisional mouse wound model","volume":"9","author":"Bae","year":"2014","journal-title":"Int. J. Nanomed."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"27406","DOI":"10.1074\/jbc.M101056200","article-title":"Platelet-derived growth factor C (PDGF-C), a novel growth factor that binds to PDGF alpha and beta receptor","volume":"276","author":"Gilbertson","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1111\/j.1524-475X.2007.00274.x","article-title":"Effects of decreased insulin-like growth factor-1 stimulation on hypoxia inducible factor 1-alpha protein synthesis and function during cutaneous repair in diabetic mice","volume":"15","author":"Yu","year":"2007","journal-title":"Wound Repair Regen."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/0014-4827(92)90089-Q","article-title":"Effect of recombinant IGF binding protein-1 on primary cultures of human keratinocytes and fibroblasts: Selective enhancement of IGF-1 but not IGF-2-induced cell proliferation","volume":"202","author":"Kratz","year":"1992","journal-title":"Exp. Cell Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1753","DOI":"10.1016\/j.ijporl.2013.08.009","article-title":"Analysis of gene expression profiles in tympanic membrane following perforation using PCR Array in rats--preliminary investigation","volume":"77","author":"Taranta","year":"2013","journal-title":"Int. J. Pediatric Otorhinolaryngol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1038\/labinvest.2012.162","article-title":"A physiological role for connective tissue growth factor in early wound healing","volume":"93","author":"Alfaro","year":"2013","journal-title":"Lab. Investig. A J. Tech. Methods Pathol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1080\/08977190802025602","article-title":"Connective tissue growth factor: Structure-function relationships of a mosaic, multifunctional protein","volume":"26","author":"Leoni","year":"2008","journal-title":"Growth Factors"},{"key":"ref_69","first-page":"547187","article-title":"NGF accelerates cutaneous wound healing by promoting the migration of dermal fibroblasts via the PI3K\/Akt-Rac1-JNK and ERK pathways","volume":"2014","author":"Chen","year":"2014","journal-title":"Biomed. Res. Int."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1111\/j.1524-475X.2009.00466.x","article-title":"Interactions between extracellular matrix and growth factors in wound healing","volume":"17","author":"Schultz","year":"2009","journal-title":"Wound Repair Regen."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1111\/1523-1747.ep12365637","article-title":"Wound fluids from human pressure ulcers contain elevated matrix metalloproteinase levels and activity compared to surgical wound fluids","volume":"107","author":"Yager","year":"1996","journal-title":"J. Investig. Dermatol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"28612","DOI":"10.1038\/srep28612","article-title":"Inhibition of hypoxia inducible factor-1\u03b1 attenuates abdominal aortic aneurysm progression through the down-regulation of matrix metalloproteinases","volume":"6","author":"Tsai","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1334","DOI":"10.1016\/j.biocel.2007.10.024","article-title":"Metalloproteinases and their inhibitors: Regulators of wound healing","volume":"40","author":"Gill","year":"2008","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"24594","DOI":"10.1074\/jbc.M201984200","article-title":"Galpha12 and Galpha13 negatively regulate the adhesive functions of cadherin","volume":"277","author":"Meigs","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1083\/jcb.201501076","article-title":"Polarized E-cadherin endocytosis directs actomyosin remodeling during embryonic wound repair","volume":"210","author":"Hunter","year":"2015","journal-title":"J. Cell Biol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"10583","DOI":"10.1074\/jbc.M513002200","article-title":"Role of tyrosine kinase Csk in G protein-coupled receptor- and receptor tyrosine kinase-induced fibroblast cell migration","volume":"281","author":"McGarrigle","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1182\/blood.V97.1.297","article-title":"Inhibition of neutrophil elastase prevents cathelicidin activation and impairs clearance of bacteria from wounds","volume":"97","author":"Cole","year":"2001","journal-title":"Blood"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1016\/j.bbadis.2016.05.004","article-title":"Downregulation of miR-205 in migrating epithelial tongue facilitates skin wound re-epithelialization by derepressing ITGA5","volume":"1862","author":"Wang","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1128\/MCB.20.3.755-759.2000","article-title":"Normal development, wound healing, and adenovirus susceptibility in beta5-deficient mice","volume":"20","author":"Huang","year":"2000","journal-title":"Mol. Cell. Biol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"2241","DOI":"10.1242\/jcs.108.6.2241","article-title":"Expression of the beta 6 integrin subunit in development, neoplasia and tissue repair suggests a role in epithelial remodeling","volume":"108","author":"Breuss","year":"1995","journal-title":"J. Cell Sci."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Gilbert, R.W.D., Vickaryous, M.K., and Viloria-Petit, A.M. (2016). Signalling by Transforming Growth Factor Beta Isoforms in Wound Healing and Tissue Regeneration. J. Dev. Biol., 4.","DOI":"10.3390\/jdb4020021"},{"key":"ref_82","first-page":"18","article-title":"The role of the TGF-beta family in wound healing, burns and scarring: A review","volume":"2","author":"Penn","year":"2012","journal-title":"Int. J. Burn. Trauma"},{"key":"ref_83","first-page":"160","article-title":"Effect of transforming growth factor Beta 1 on wound healing in induced diabetic rats","volume":"7","author":"Elbardisey","year":"2013","journal-title":"Int. J. Health Sci."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"e42","DOI":"10.1016\/j.jcms.2012.08.001","article-title":"Downregulated gene expression of TGF-betas in diabetic oral wound healing","volume":"41","author":"Yamano","year":"2013","journal-title":"J. Cranio Maxillofac. Surg."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1083\/jcb.200507111","article-title":"A \u201ctraffic control\u201d role for TGFbeta3: Orchestrating dermal and epidermal cell motility during wound healing","volume":"172","author":"Bandyopadhyay","year":"2006","journal-title":"J. Cell Biol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1186\/s13287-015-0103-4","article-title":"Wnt and Notch signaling pathway involved in wound healing by targeting c-Myc and Hes1 separately","volume":"6","author":"Shi","year":"2015","journal-title":"Stem Cell Res. Ther."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.devcel.2009.05.011","article-title":"Reciprocal requirements for EDA\/EDAR\/NF-kappaB and Wnt\/beta-catenin signaling pathways in hair follicle induction","volume":"17","author":"Zhang","year":"2009","journal-title":"Dev. Cell"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"3446","DOI":"10.1091\/mbc.e06-02-0102","article-title":"A role for the mitogen-activated protein kinase kinase kinase 1 in epithelial wound healing","volume":"17","author":"Deng","year":"2006","journal-title":"Mol. Biol. Cell"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"12348","DOI":"10.1038\/ncomms12348","article-title":"Cutaneous wound healing through paradoxical MAPK activation by BRAF inhibitors","volume":"7","author":"Li","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/j.jss.2008.04.023","article-title":"The role of vascular endothelial growth factor in wound healing","volume":"153","author":"Bao","year":"2009","journal-title":"J. Surg. Res."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1038\/sj.bjp.0707503","article-title":"PTEN: A promising pharmacological target to enhance epithelial wound healing","volume":"152","author":"Zhao","year":"2007","journal-title":"Br. J. Pharmacol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"179e","DOI":"10.1097\/PRS.0000000000001443","article-title":"Effect of N-Acetylcysteine on Adipose-Derived Stem Cell and Autologous Fat Graft Survival in a Mouse Model","volume":"136","author":"Gillis","year":"2015","journal-title":"Plast. Reconstr. Surg."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Pietruski, P., Paskal, W., Paluch, \u0141., Paskal, A.M., Nitek, \u017b., W\u0142odarski, P., Walecki, J., and Noszczyk, B. (2020). The Impact of N-Acetylcysteine on Autologous Fat Graft: First-in-Human Pilot Study. Aesthetic. Plast. Surg., 1\u20139.","DOI":"10.1007\/s00266-020-01730-1"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1111\/iwj.12557","article-title":"Reactive oxygen species (ROS) and wound healing: The functional role of ROS and emerging ROS-modulating technologies for augmentation of the healing process","volume":"14","author":"Dunnill","year":"2017","journal-title":"Int. Wound J."},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Cano Sanchez, M., Lancel, S., Boulanger, E., and Neviere, R. (2018). Targeting Oxidative Stress and Mitochondrial Dysfunction in the Treatment of Impaired Wound Healing: A Systematic Review. Antioxidants, 7.","DOI":"10.3390\/antiox7080098"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1083\/jcb.201305074","article-title":"FOXO1 promotes wound healing through the up-regulation of TGF-\u03b21 and prevention of oxidative stress","volume":"203","author":"Ponugoti","year":"2013","journal-title":"J. Cell Biol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"151","DOI":"10.3109\/08941939.2011.560237","article-title":"N-acetyl-cysteine improves anastomotic wound healing after radiotherapy in rats","volume":"24","author":"Demir","year":"2011","journal-title":"J. Investig. Surg."},{"key":"ref_98","first-page":"17","article-title":"N-acetylcycsteine attenuates the deleterious effects of radiation therapy on inci-sional wound healing in rats","volume":"18","author":"Tascilar","year":"2014","journal-title":"Hippokratia"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"24171","DOI":"10.1074\/jbc.M604507200","article-title":"Transforming growth factor beta1 induces hypoxia-inducible factor-1 stabilization through selective inhibition of PHD2 expression","volume":"281","author":"McMahon","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"38527","DOI":"10.1074\/jbc.M104536200","article-title":"Synergistic Cooperation between Hypoxia and Transforming Growth Factor-\u03b2 Pathways on Human Vascular Endothelial Growth Factor Gene Expression","volume":"276","author":"Botella","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1849","DOI":"10.1111\/j.1471-4159.2008.05287.x","article-title":"Glucose up-regulates HIF-1\u03b1 expression in primary cortical neurons in response to hypoxia through maintaining cellular redox status","volume":"105","author":"Guo","year":"2008","journal-title":"J. Neurochem."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"19426","DOI":"10.1073\/pnas.0805230105","article-title":"Stabilization of HIF-1\u03b1 is critical to improve wound healing in diabetic mice","volume":"105","author":"Botusan","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1096\/fasebj.9.9.7601337","article-title":"The MAPK signaling cascade","volume":"9","author":"Seger","year":"1995","journal-title":"FASEB J."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1039\/D0BM01479F","article-title":"Improvement of the wound healing properties of hydrogels with N-acetylcysteine through their modification with methacrylate-containing polymers","volume":"9","year":"2021","journal-title":"Biomater. Sci."},{"key":"ref_105","first-page":"116","article-title":"Vasoconstrictor agents for local anesthesia","volume":"42","author":"Yagiela","year":"1995","journal-title":"Anesth. Prog."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"908259","DOI":"10.1155\/2013\/908259","article-title":"Thrombospondin and VEGF-R: Is There a Correlation in Inflammatory Bowel Disease?","volume":"2013","author":"Wejman","year":"2013","journal-title":"Mediat. Inflamm."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"16878","DOI":"10.1038\/s41598-017-17204-5","article-title":"QuPath: Open source software for digital pathology image analysis","volume":"7","author":"Bankhead","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/0003-2697(87)90021-2","article-title":"Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction","volume":"162","author":"Chomczynski","year":"1987","journal-title":"Anal. Biochem."},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Yuan, J.S., Reed, A., Chen, F., and Stewart, C.N. (2006). Statistical analysis of real-time PCR data. BMC Bioinform., 7.","DOI":"10.1186\/1471-2105-7-85"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/16\/8659\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:44:36Z","timestamp":1760165076000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/16\/8659"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,12]]},"references-count":109,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["ijms22168659"],"URL":"https:\/\/doi.org\/10.3390\/ijms22168659","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,12]]}}}