Wound healing is a very complex process, where variety of different pathways is activated, depending on the phase of healing. Improper or interrupted healing might result in development of chronic wounds. Therefore, novel approaches based on detailed knowledge of signalling pathways that are activated during acute or chronic cutaneous wound healing enables quicker and more effective healing. This review outlined new possibilities of cutaneous wound healing by modulation of some signalling molecules, e.g., gasotransmitters, or calcium. Special focus is given to gasotransmitters, since these bioactive signalling molecules that can freely diffuse into the cell and exert antioxidative effects. Calcium is an important booster of immune system and it can significantly contribute to healing process. Special interest is given to chronic wounds caused by diabetes mellitus and overcoming problems with the inflammation.

Department of Burns and Plastic Surgery Faculty of Medicine Masaryk University and University Hospital Brno Czechia

Department of Chemistry Faculty of Natural Sciences University of St Cyril and Methodius Trnava Slovakia

Department of Physiology Faculty of Medicine Masaryk University Brno Czechia

Institute of Clinical and Translational Research Biomedical Research Center SAS Bratislava Slovakia

Zobrazit více v PubMed

Ajit A., Ambika Gopalankutty I. (2021). Adipose-derived stem cell secretome as a cell-free product for cutaneous wound healing. 3 Biotech. 11, 413. 10.1007/s13205-021-02958-7 PubMed DOI PMC

André-Lévigne D., Modarressi A., Pepper M. S., Pittet-Cuénod B. (2017). Reactive oxygen species and NOX enzymes are emerging as key players in cutaneous wound repair. Int. J. Mol. Sci. 18, 2149. 10.3390/ijms18102149 PubMed DOI PMC

Babula P., Krizanova O. (2022). Involvement of calcium signaling in different types of cell death in cancer. Neoplasma 69, 264–273. 10.4149/neo_2022_220127N121 PubMed DOI

Bagheri M., Jahromi B. M., Mirkhani H., Solhjou Z., Noorafshan A., Zamani A., et al. (2011). Azelnidipine, a new calcium channel blocker, promotes skin wound healing in diabetic rats. J. Surg. Res. 169, e101–e107. 10.1016/j.jss.2011.02.039 PubMed DOI

Berlanga J., Fernandez J. I., Lopez E., Lopez P. A., Del Rio A., Valenzuela C., et al. (2013). Heberprot-P: A novel product for treating advanced diabetic foot ulcer. MEDICC Rev. 15, 11–15. 10.1590/s1555-79602013000100004 PubMed DOI

Boateng J. S., Matthews K. H., Stevens H. N. E., Eccleston G. M. (2008). Wound healing dressings and drug delivery systems: A review. J. Pharm. Sci. 97, 2892–2923. 10.1002/jps.21210 PubMed DOI

Borena B. M., Martens A., Broeckx S. Y., Meyer E., Chiers K., Duchateau L., et al. (2015). Regenerative skin wound healing in mammals: State-of-the-Art on growth factor and stem cell based treatments. Cell. Physiol. biochem. 36, 1–23. 10.1159/000374049 PubMed DOI

Cao X., Ding L., Xie Z. Z., Yang Y., Whiteman M., Moore P. K., et al. (2019). A review of hydrogen sulfide synthesis, metabolism, and measurement: Is modulation of hydrogen sulfide a novel therapeutic for cancer? Antioxid. Redox Signal. 31, 1–38. 10.1089/ars.2017.7058 PubMed DOI PMC

Caterina M. J., Pang Z. (2016). TRP channels in skin biology and pathophysiology. Pharmaceuticals 9, E77. 10.3390/ph9040077 PubMed DOI PMC

Chattopadhyay M., Kodela R., Duvalsaint P. L., Kashfi K. (2016). Gastrointestinal safety, chemotherapeutic potential, and classic pharmacological profile of NOSH-naproxen (AVT-219) a dual NO- and H2S-releasing hybrid. Pharmacol. Res. Perspect. 4, e00224. 10.1002/prp2.224 PubMed DOI PMC

Chen C. J., Kajita H., Takaya K., Aramaki-Hattori N., Sakai S., Asou T., et al. (2022). Single-cell RNA-seq analysis reveals cellular functional heterogeneity in dermis between fibrotic and regenerative wound healing fates. Front. Immunol. 13, 875407. 10.3389/fimmu.2022.875407 PubMed DOI PMC

Cheng J., Gan G. H., Shen Z. Q., Gao L., Zhang G. Y., Hu J. M. (2021). Red light-triggered intracellular carbon monoxide release enables selective eradication of MRSA infection. Angew. Chem. Int. Ed. Engl. 60, 13513–13520. 10.1002/anie.202104024 PubMed DOI

Cheng J., Zheng B., Cheng S., Zhang G. Y., Hu J. M. (2020). Metal-free carbon monoxidereleasing micelles undergo tandem photochemical reactions for cutaneous wound healing. Chem. Sci. 11, 4499–4507. 10.1039/d0sc00135j PubMed DOI PMC

Cheng Z. J., Kishore R. (2020). Potential role of hydrogen sulfide in diabetes-impaired angiogenesis and ischemic tissue repair. Redox Biol. 37, 101704. 10.1016/j.redox.2020.101704 PubMed DOI PMC

Choi J., Hong G., Kwon T., Lim J. O. (2018). Fabrication of oxygen releasing scaffold by embedding H2O2-PLGA microspheres into alginate-based hydrogel sponge and its application for wound healing. Appl. Sci. (Basel). 8, 1492. 10.3390/app8091492 DOI

Csordas G., Hajnoczky G. (2009). SR/ER-mitochondrial local communication: Calcium and ROS. Biochim. Biophys. Acta 1787, 1352–1362. 10.1016/j.bbabio.2009.06.004 PubMed DOI PMC

Degovics D., Hartmann P., Nemeth I. B., Arva-Nagy N., Kaszonyi E., Szel E., et al. (2019). A novel target for the promotion of dermal wound healing: Ryanodine receptors. Toxicol. Appl. Pharmacol. 366, 17–24. 10.1016/j.taap.2019.01.021 PubMed DOI

Dehkordi A. N., Babaheydari F. M., Chehelgerdi M., Dehkordi S. R. (2019). Skin tissue engineering: Wound healing based on stem-cell-based therapeutic strategies. Stem Cell Res. Ther. 10, 111. 10.1186/s13287-019-1212-2 PubMed DOI PMC

Demidova-Rice T. N., Hamblin M. R., Herman I. M. (2012). Acute and impaired wound healing: Pathophysiology and current methods for drug delivery, part 1: Normal and chronic wounds: Biology, causes, and approaches to care. Adv. Skin. Wound Care 25, 304–314. 10.1097/01.ASW.0000416006.55218.d0 PubMed DOI PMC

Denda S., Kumamoto J., Takei K., Tsutsumi M., Aoki H., Denda M. (2012). Ryanodine receptors are expressed in epidermal keratinocytes and associated with keratinocyte differentiation and epidermal permeability barrier homeostasis. J. Invest. Dermatol. 132, 69–75. 10.1038/jid.2011.256 PubMed DOI

Dissanayake A., Vandal A. C., Boyle V., Park D., Milne B., Grech R., et al. (2020). Does intensive glycaemic control promote healing in diabetic foot ulcers? - a feasibility study. Bmj Open 10, e029009. 10.1136/bmjopen-2019-029009 PubMed DOI PMC

Eligini S., Arenaz I., Barbieri S. S., Faleri M. L., Crisci M., Tremoli E., et al. (2009). Cyclooxygenase-2 mediates hydrogen peroxide-induced wound repair in human endothelial cells. Free Radic. Biol. Med. 46, 1428–1436. 10.1016/j.freeradbiomed.2009.02.026 PubMed DOI

Fernandes A. R., Mendonca-Martins I., Santos M. F. A., Raposo L. R., Mendes R., Marques J., et al. (2020). Improving the anti-inflammatory response via gold nanoparticle vectorization of CO-releasing molecules. ACS Biomater. Sci. Eng. 6, 1090–1101. 10.1021/acsbiomaterials.9b01936 PubMed DOI

Förstermann U., Sessa W. C. (2012). Nitric oxide synthases: regulation and function. Eur. Heart J. 33, 829–837. 837a.–837d. 10.1093/eurheartj/ehr304 PubMed DOI PMC

Fournet M., Bonte F., Desmouliere A. (2018). Glycation damage: A possible hub for major pathophysiological disorders and aging. Aging Dis. 9, 880–900. 10.14336/AD.2017.1121 PubMed DOI PMC

Gao L., Cheng J., Shen Z. Q., Zhang G. Y., Liu S. Y., Hu J. M. (2022). Orchestrating nitric oxide and carbon monoxide signaling molecules for synergistic treatment of MRSA infections. Angew. Chem. Int. Ed. Engl. 61, e202112782. 10.1002/anie.202112782 PubMed DOI

Garoufalia Z., Papadopetraki A., Karatza E., Vardakostas D., Philippou A., Kouraklis G., et al. (2021). Insulin-like growth factor-I and wound healing, a potential answer to non-healing wounds: A systematic review of the literature and future perspectives. Biomed. Rep. 15, 66. 10.3892/br.2021.1442 PubMed DOI PMC

Goren I., Kohler Y., Aglan A., Pfeilschifter J., Beck K. F., Frank S. (2019). Increase of cystathionine-gamma-lyase (CSE) during late wound repair: Hydrogen sulfide triggers cytokeratin 10 expression in keratinocytes. Nitric Oxide 87, 31–42. 10.1016/j.niox.2019.03.004 PubMed DOI

Görlach A., Bertram K., Hudecova S., Krizanova O. (2015). Calcium and ROS: A mutual interplay. Redox Biol. 26, 260–271. 10.1016/j.redox.2015.08.010 PubMed DOI PMC

Guerrero-Juarez C. F., Dedhia P. H., Jin S., Ruiz-Vega R., Ma D., Liu Y., et al. (2019). Single-cell analysis reveals fibroblast heterogeneity and myeloid-derived adipocyte progenitors in murine skin wounds. Nat. Commun. 10, 650. 10.1038/s41467-018-08247-x PubMed DOI PMC

Halschou-Jensen P. M., Sauer J., Bouchelo uche P., Fabrin J., Brorson S., Ohrt-Nissen S. (2021). Improved healing of diabetic foot ulcers after high-dose vitamin D: A randomized double-blinded clinical trial. Int. J. Low. Extrem. Wounds. 10.1177/15347346211020268 PubMed DOI

Hao Y. P., Zhao W. W., Zhang H., Zheng W. P., Zhou Q. H. (2022). Carboxymethyl chitosanbased hydrogels containing fibroblast growth factors for triggering diabetic wound healing. Carbohydr. Polym. 287, 119336. 10.1016/j.carbpol.2022.119336 PubMed DOI

Hasan N., Lee J., Ahn H. J., Hwang W. R., Bahar M. A., Habibie H., et al. (2022). Nitric oxide-releasing bacterial cellulose/chitosan crosslinked hydrogels for the treatment of polymicrobial wound infections. Pharmaceutics 14, 22. 10.3390/pharmaceutics14010022 PubMed DOI PMC

Hong W. X., Hu M. S., Esquivel M., Liang G. Y., Rennert R. C., Mcardle A., et al. (2014). The role of hypoxia-inducible factor in wound healing. Adv. Wound Care 3, 390–399. 10.1089/wound.2013.0520 PubMed DOI PMC

Hwang S., Shin D. M., Hong J. H. (2020). Intracellular Ca2+-mediated AE2 is involved in the vectorial movement of HaCaT keratinocyte. Int. J. Mol. Sci. 21, E8429. 10.3390/ijms21228429 PubMed DOI PMC

Jaluvka F., Ihnat P., Madaric J., Vrtkova A., Janosek J., Prochazka V. (2020). Current status of cell-based therapy in patients with critical limb ischemia. Int. J. Mol. Sci. 21, E8999. 10.3390/ijms21238999 PubMed DOI PMC

Kajsik M., Chovancova B., Liskova V., Babula P., Krizanova O. (2022). Slow sulfide donor GYY4137 potentiates effect of paclitaxel on colorectal carcinoma cells. Eur. J. Pharmacol. 922, 174875. 10.1016/j.ejphar.2022.174875 PubMed DOI

Kang I. S., Kim R. I., Kim C. (2021). Carbon monoxide regulates macrophage differentiation and polarization toward the M2 phenotype through upregulation of heme oxygenase 1. Cells 10, 3444. 10.3390/cells10123444 PubMed DOI PMC

Keyes B. E., Liu S., Asare A., Naik S., Levorse J., Polak L., et al. (2016). Impaired epidermal to dendritic T cell signaling slows wound repair in aged skin. Cell 67, 1323–1338. 10.1016/j.cell.2016.10.052 PubMed DOI PMC

Kimura K., Iwano M., Higgins D. F., Yamaguchi Y., Nakatani K., Harada K., et al. (2008). Stable expression of HIF-1alpha in tubular epithelial cells promotes interstitial fibrosis. Am. J. Physiol. Ren. Physiol. 295, F1023–F1029. 10.1152/ajprenal.90209.2008 PubMed DOI PMC

Krischel V., Bruch-Gerharz D., Suschek C., Kröncke K. D., Ruzicka T., Kolb-Bachofen V. (1998). Biphasic effect of exogenous nitric oxide on proliferation and differentiation in skin derived keratinocytes but not fibroblasts. J. Invest. Dermatol. 111, 286–291. 10.1046/j.1523-1747.1998.00268.x PubMed DOI

Kurian S. J., Miraj S. S., Benson R., Munisamy M., Saravu K., Rodrigues G. S., et al. (2021). Vitamin D supplementation in diabetic foot ulcers: A current perspective. Curr. Diabetes Rev. 17, 512–521. 10.2174/1573399816999201012195735 PubMed DOI

Kurkipuro J., Mierau I., Wirth T., Samaranayake H., Smith W., Karkkainen H.-R., et al. (2022). Four in one-Combination therapy using live Lactococcus lactis expressing three therapeutic proteins for the treatment of chronic non-healing wounds. Plos One 17, e0264775. 10.1371/journal.pone.0264775 PubMed DOI PMC

Kutz J. L., Greaney J. L., Santhanam L., Alexander L. M. (2015). Evidence for a functional vasodilatatory role for hydrogen sulphide in the human cutaneous microvasculature. J. Physiol. 593, 2121–2129. 10.1113/JP270054 PubMed DOI PMC

Laloze J., Fievet L., Desmouliere A. (2021). Adipose-derived mesenchymal stromal cells in regenerative medicine: State of play, current clinical trials, and future prospects. Adv. Wound Care 10, 24–48. 10.1089/wound.2020.1175 PubMed DOI PMC

Lansdown A. B. G. (2002). Calcium: A potential central regulator in wound healing in the skin. Wound Repair Regen. 10, 271–285. 10.1046/j.1524-475x.2002.10502.x PubMed DOI

Legrand J. M. D., Martino M. M. (2022). Growth factor and cytokine delivery systems for wound healing. Cold Spring Harb. Perspect. Biol. 14, a041234. 10.1101/cshperspect.a041234 PubMed DOI PMC

Li G., Ko C.-N., Li D., Yang C., Wang W., Yang G.-J., et al. (2021). A small molecule HIF-1 alpha stabilizer that accelerates diabetic wound healing. Nat. Commun. 12, 3363. 10.1038/s41467-021-23448-7 PubMed DOI PMC

Li Y., Fu R. Z., Duan Z. G., Zhu C. H., Fan D. D. (2022). Artificial nonenzymatic antioxidant MXene nanosheet-anchored injectable hydrogel as a mild photothermal-controlled oxygen release platform for diabetic wound healing. Acs Nano 16, 7486–7502. 10.1021/acsnano.1c10575 PubMed DOI

Li Y. J., Shen C. C., Zhou X., Zhang J. H., Lai X. Y., Zhang Y. M. (2022). Local treatment of hydrogen-rich saline promotes wound healing in vivo by inhibiting oxidative stress via nrf-2/HO-1 pathway. Oxid. Med. Cell. Longev. 2022, 2949824. 10.1155/2022/2949824 PubMed DOI PMC

Liang Z. Y., Liu W. K., Wang Z. Q., Zheng P. L., Liu W., Zhao J. F., et al. (2022). Near-infrared laser-controlled nitric oxide-releasing gold nanostar/hollow polydopamine Janus nanoparticles for synergistic elimination of methicillin-resistant Staphylococcus aureus and wound healing. Acta Biomater. 143, 428–444. 10.1016/j.actbio.2022.02.029 PubMed DOI

Lin J., Mo X. X., Yang Y. J., Tang C., Chen J. (2022). Association between vitamin D deficiency and diabetic foot ulcer wound in diabetic subjects: A meta-analysis. Int. Wound J. 10.1111/iwj.13836 PubMed DOI PMC

Liu Y., Liu Y., Deng J., Li W., Nie X. (2021). Fibroblast growth factor in diabetic foot ulcer: Progress and therapeutic prospects. Front. Endocrinol. 12, 744868. 10.3389/fendo.2021.744868 PubMed DOI PMC

Lombardi F., Palumbo P., Augello F. R., Cifone M. G., Cinque B., Giuliani M. (2019). Secretome of adipose tissue-derived stem cells (ASCs) as a novel trend in chronic non-healing wounds: An overview of experimental in vitro and in vivo studies and methodological variables. Int. J. Mol. Sci. 20, E3721. 10.3390/ijms20153721 PubMed DOI PMC

Lopez-Lopez N., Gonzalez-Curiel I., Trevino-Santa Cruz M. B., Rivas-Santiago B., Trujillo-Paez V., Enciso-Moreno J. A., et al. (2014). Expression and vitamin D-mediated regulation of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in healthy skin and in diabetic foot ulcers. Arch. Dermatol. Res. 306, 809–821. 10.1007/s00403-014-1494-2 PubMed DOI

Luo Y., Zhou X., Liu C., Lu R., Jia M., Li P., et al. (2022). Scavenging ROS and inflammation produced during treatment to enhance the wound repair efficacy of photothermal injectable hydrogel. Biomater. Adv. 141, 213096. 10.1016/j.bioadv.2022.213096 PubMed DOI

Man M. Q., Wakefield J. S., Mauro T. M., Elias P. M. (2022a). Regulatory role of nitric oxide in cutaneous inflammation. Inflammation 45, 949–964. 10.1007/s10753-021-01615-8 PubMed DOI PMC

Man M. Q., Wakefield J. S., Mauro T. M., Elias P. M. (2022b). Role of nitric oxide in regulating epidermal permeability barrier function. Exp. Dermatol. 31, 290–298. 10.1111/exd.14470 PubMed DOI PMC

Martin P., Nunan R. (2015). Cellular and molecular mechanisms of repair in acute and chronic wound healing. Br. J. Dermatol. 173, 370–378. 10.1111/bjd.13954 PubMed DOI PMC

Mendoza-Mari Y., Garcia-Ojalvo A., Fernandez-Mayola M., Rodriguez-Rodriguez N., Martinez-Jimenez I., Berlanga-Acosta J. (2022). Epidermal growth factor effect on lipopolysaccharide-induced inflammation in fibroblasts derived from diabetic foot ulcer. Scars Burn. Heal. 8, 20595131211067380. 10.1177/20595131211067380 PubMed DOI PMC

Montell C., Birnbaumer L., Flockerzi V., Bindels R. J., Brudorf E. A., Caterina M. J., et al. (2002). A unified nomenclature for the superfamily of TRP cation channels. Mol. Cell 9, 229–231. 10.1016/s1097-2765(02)00448-3 PubMed DOI

Moran M. M. (2018). TRP channels as potential drug targets. Annu. Rev. Pharmacol. Toxicol. 58, 309–330. 10.1146/annurev-pharmtox-010617-052832 PubMed DOI

Murphy E. C., Friedman A. J. (2019). Hydrogen peroxide and cutaneous biology: Translational applications, benefits, and risks. J. Am. Acad. Dermatol. 81, 1379–1386. 10.1016/j.jaad.2019.05.030 PubMed DOI

Muzumdar S., Hiebert H., Haertel E., Greenwald M. B., Bloch W., Werner S., et al. (2019). Nrf2-Mediated expansion of pilosebaceous cells accelerates cutaneous wound healing. Am. J. Pathol. 189, 568–579. 10.1016/j.ajpath.2018.11.017 PubMed DOI

Nidegawa Y., Sumioka T., Okada Y., Miyajima M., Reinach P. S., Saika S., et al. (2014). Impairment of corneal epithelial wound healing in a TRPV1-deficient mouse. Invest. Ophthalmol. Vis. Sci. 55, 3295–3302. 10.1167/iovs.13-13077 PubMed DOI

O'toole E. A. (2001). Extracellular matrix and keratinocyte migration. Clin. Exp. Dermatol. 26, 525–530. 10.1046/j.1365-2230.2001.00891.x PubMed DOI

Patel S., Srivastava S., Singh M. R., Singh D. (2019). Mechanistic insight into diabetic wounds: Pathogenesis, molecular targets and treatment strategies to pace wound healing. Biomed. Pharmacother. 112, 108615. 10.1016/j.biopha.2019.108615 PubMed DOI

Pinto R. V., Carvalho S., Antunes F., Pires J., Pinto M. L. (2022). Emerging nitric oxide and hydrogen sulfide releasing carriers for skin wound healing therapy. Chemmedchem 17, e202100429. 10.1002/cmdc.202100429 PubMed DOI

Putra A., Ibrahim S., Muhar A. M., Kuntardjo N., Dirja B. T., Pasongka Z., et al. (2022). Topical gel of mesenchymal stem cells-conditioned medium under TNF-alpha precondition accelerates wound closure healing in full-thickness skin defect animal model. J. Med. Life 15, 214–221. 10.25122/jml-2019-0103 PubMed DOI PMC

Rezuchova I., Hudecova S., Soltysova A., Matuskova M., Durinikova E., Chovancova B., et al. (2019). Type 3 inositol 1, 4, 5-trisphosphate receptor has antiapoptotic and proliferative role in cancer cells. Cell Death Dis. 10, 186. 10.1038/s41419-019-1433-4 PubMed DOI PMC

Rinnerthaler M., Richter K. (2018). The influence of calcium on the skin pH and epidermal barrier during aging. Curr. Probl. Dermatol. 54, 79–86. 10.1159/000489521 PubMed DOI

Roy S., Khanna S., Nallu K., Hunt T. K., Sen C. K. (2006). Dermal wound healing is subject to redox control. Mol. Ther. 13, 211–220. 10.1016/j.ymthe.2005.07.684 PubMed DOI PMC

Sarkandi A. F., Montazer M., Rad M. M. (2022). Oxygenated-bacterial-cellulose nanofibers with hydrogel, antimicrobial, and controlled oxygen release properties for rapid wound healing. J. Appl. Polym. Sci. 139, 51974. 10.1002/app.51974 DOI

Schneider A., Wang X. Y., Kaplan D. L., Garlick J. A., Egles C. (2009). Biofunctionalized electrospun silk mats as a topical bioactive dressing for accelerated wound healing. Acta Biomater. 5, 2570–2578. 10.1016/j.actbio.2008.12.013 PubMed DOI PMC

Sen C. K., Roy S. (2008). Redox signals in wound healing. Biochim. Biophys. Acta 1780, 1348–1361. 10.1016/j.bbagen.2008.01.006 PubMed DOI PMC

Shefa U., Yeo S. G., Kim M. S., Song I. O., Jung J., Jeong N. Y., et al. (2017). Role of gasotransmitters in oxidative stresses, neuroinflammation, and neuronal repair. Biomed. Res. Int. 2017, 1689341. 10.1155/2017/1689341 PubMed DOI PMC

Shiekh P. A., Singh A., Kumar A. (2020). Exosome laden oxygen releasing antioxidant and antibacterial cryogel wound dressing OxOBand alleviate diabetic and infectious wound healing. Biomaterials 249, 120020. 10.1016/j.biomaterials.2020.120020 PubMed DOI

Subramaniam T., Fauzi M. B., Lokanathan Y., Law J. X. (2021). The role of calcium in wound healing. Int. J. Mol. Sci. 22, 6486. 10.3390/ijms22126486 PubMed DOI PMC

Suntar I., Cetinkaya S., Panieri E., Saha S., Buttari B., Profumo E., et al. (2021). An overview of Nrf2 signaling pathway and its role in inflammation. Molecules 26, E5474. 10.3390/molecules25225474 PubMed DOI PMC

Takagi T., Okayama T., Asai J., Mizushima K., Hirai Y., Uchiyama K., et al. (2022). Topical application of sustained released-carbon monoxide promotes cutaneous wound healing in diabetic mice. Biochem. Pharmacol. 199, 115016. 10.1016/j.bcp.2022.115016 PubMed DOI

Tiwari S., Pratyush D. D., Gupta S. K., Singh S. K. (2014). Vitamin D deficiency is associated with inflammatory cytokine concentrations in patients with diabetic foot infection. Br. J. Nutr. 112, 1938–1943. 10.1017/S0007114514003018 PubMed DOI

Tu C. L., Chang W. H., Bikle D. D. (2005). Phospholipase cgamma1 is required for activation of store-operated channels in human keratinocytes. J. Invest. Dermatol. 124, 187–197. 10.1111/j.0022-202X.2004.23544.x PubMed DOI

Tu C. X., Lu H. D., Zhou T., Zhang W. Y., Deng L. W., Cao W. B., et al. (2022). Promoting the healing of infected diabetic wound by an anti-bacterial and nano-enzyme-containing hydrogel with inflammation-suppressing, ROS-scavenging, oxygen and nitric oxide-generating properties. Biomaterials 286, 121597. 10.1016/j.biomaterials.2022.121597 PubMed DOI

Urban M. V., Rath T., Radtke C. (2019). Hydrogen peroxide (H2O2): A review of its use in surgery. Wien. Med. Wochenschr. 169, 222–225. 10.1007/s10354-017-0610-2 PubMed DOI

Vu R., Jin S., Sun P., Haensel D., Nguyen Q. H., Dragan M., et al. (2022). Defining epidermal basal cell States during skin homeostasis and wound healing using single-cell transcriptomics. Cell Rep. 40, 3932–3947. 10.1016/j.celrep.2020.02.091 PubMed DOI PMC

Wang G. (2021a). Lipid-dependent sequential allosteric activation of heat-sensing TRPV1 channels by anchor-stereoselective "hot" vanilloid compounds and analogs. Biochem. Biophys. Rep. 28, 101109. 10.1016/j.bbrep.2021.101109 PubMed DOI PMC

Wang Y. D., Wan L. Q., Zhang Z. Z., Li J., Qu M. L., Zhou Q. J. (2021b). Topical calcitriol application promotes diabetic corneal wound healing and reinnervation through inhibiting NLRP3 inflammasome activation. Exp. Eye Res. 209, 108668. 10.1016/j.exer.2021.108668 PubMed DOI

Wu J., Li Y., He C. C., Kang J. M., Ye J. J., Xiao Z. C., et al. (2016). Novel H2S releasing nanofibrous coating for in vivo dermal wound regeneration. ACS Appl. Mat. Interfaces 8, 27474–27481. 10.1021/acsami.6b06466 PubMed DOI

Xiao T., Yan Z., Xiao S., Xia Y. (2020). Proinflammatory cytokines regulate epidermal stem cells in wound epithelialization. Stem Cell Res. Ther. 11, 232. 10.1186/s13287-020-01755-y PubMed DOI PMC

Xu M. T., Hua Y. Y., Qi Y., Meng G. L., Yang S. J. (2019). Exogenous hydrogen sulphide supplement accelerates skin wound healing via oxidative stress inhibition and vascular endothelial growth factor enhancement. Exp. Dermatol. 28, 776–785. 10.1111/exd.13930 PubMed DOI

Xu M. T., Zhang L. L., Song S., Pan L. L., Arslan I. M., Chen Y., et al. (2021). Hydrogen sulfide: Recent progress and perspectives for the treatment of dermatological diseases. J. Adv. Res. 27, 11–17. 10.1016/j.jare.2020.02.003 PubMed DOI PMC

Yamasaki K., Edington H. D. J., Mcclosky C., Tzeng E., Lizonova A., Kovesdi I., et al. (1998). Reversal of impaired wound repair in iNOS-deficient mice by topical adenoviral-mediated iNOS gene transfer. J. Clin. Invest. 101, 967–971. 10.1172/JCI2067 PubMed DOI PMC

Yammine K., Hayek F., Assi C. (2020). Is there an association between vitamin D and diabetic foot disease? A meta-analysis. Wound Repair Regen. 28, 90–96. 10.1111/wrr.12762 PubMed DOI

Yu J., Zhang R. L., Chen B. H., Liu X. L., Jia Q., Wang X. F., et al. (2022). Injectable reactive oxygen species-responsive hydrogel dressing with sustained nitric oxide release for bacterial ablation and wound healing. Adv. Funct. Mat. 32, 2202857. 10.1002/adfm.202202857 DOI

Zeng R. J., Lin C. Q., Lin Z. H., Chen H., Lu W. Y., Lin C. M., et al. (2018). Approaches to cutaneous wound healing: Basics and future directions. Cell Tissue Res. 374, 217–232. 10.1007/s00441-018-2830-1 PubMed DOI

Zhan R. X., Yang S. W., He W. F., Wang F., Tan J. L., Zhou J. Y., et al. (2015). Nitric oxide enhances keratinocyte cell migration by regulating rho GTPase via cGMP-PKG signalling. Plos One 10, e0121551. 10.1371/journal.pone.0121551 PubMed DOI PMC

Zhang T., Han Z. Y., Zhang W., Wang J., Xu L. (2020). Cyanoacrylate-encapsulated calcium peroxide achieved oxygen-sustained release and promoted wound healing. Int. J. Polym. Mater. Polym. Biomaterials 69, 703–708. 10.1080/00914037.2019.1600518 DOI

Zhao H. C., Lu S. X., Chai J. H., Zhang Y. C., Ma X. L., Chen J. C., et al. (2017). Hydrogen sulfide improves diabetic wound healing in ob/ob mice via attenuating inflammation. J. Diabetes Complicat. 31, 1363–1369. 10.1016/j.jdiacomp.2017.06.011 PubMed DOI

Zhao X., Liu L., An T. Z., Xian M., Luckanagul J. A., Su Z. H., et al. (2020). A hydrogen sulfide-releasing alginate dressing for effective wound healing. Acta Biomater. 104, 85–94. 10.1016/j.actbio.2019.12.032 PubMed DOI

Zhu G., Wang Q., Lu S., Niu Y. (2017). Hydrogen peroxide: A potential wound therapeutic target. Med. Princ. Pract. 26, 301–308. 10.1159/000475501 PubMed DOI PMC

Changes in gene expression in pressure ulcers debrided by different approaches - a pilot study

Chronic venous insufficiency and venous leg ulcers: Aetiology, on the pathophysiology-based treatment