Critical Understanding of Apoptosis’ Function in Diabetes and Diabetic Wound Healing: Prospective Therapeutic Opportunities
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Abstract
Apoptosis, or programmed cell death, can be triggered by various factors such as radiation, chemicals, and both physiological and pathological conditions. It is essential for many biological processes, including the turnover of normal cells and the growth and functioning of the immune system. However, an imbalance in apoptosis, whether excessive or insufficient, has been linked to several clinical conditions, including cancer, diabetes, and neurodegenerative diseases. One such condition is Type 2 Diabetes Mellitus (T2DM), where damage to β-cell cytoplasm due to the death of pancreatic cells contributes to the complex etiology of non-insulin-dependent diabetes mellitus. To prevent the progression of pancreatic cell disorders, it may be necessary to regulate the apoptosis and proliferation processes of these cells. Apoptosis itself is a complex process with four key stages: induction, detection, effectors, and eradication. Each of these steps requires the coordinated action of multiple molecules, with caspases, the Bcl-2 protein family, and p53 (a tumor suppressor gene) being some of the most important.
With a greater understanding and a comprehensive search through the journal’s databases, and the molecular activities of these biochemical apoptotic markers, it may be feasible to create innovative techniques for the treatment of diabetes and its consequences.
This review presently explains the complications of insulin-dependent and non-insulin-dependent diabetes that may result in angiopathy complications such as diabetic neuropathy, diabetic encephalopathy, diabetic retinopathy, and diabetic wounds. New studies that defined some of the most significant activities of apoptosis in the treatment of wounds were reviewed.
This review highlights the importance of caries by considering the intricate molecular pathways involved in apoptosis, particularly the roles of caspases, Bcl-2 protein clan, p53 varying the care of diabetic wounds and diabetes, and modulation in the supervision of diabetes and diabetic wounds. This underscores the potential for future research to explore and harness the beneficial effects of modifying apoptosis for improved diabetes management strategies.
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1. Kinloch RA, Treherne JM, Furness LM, Hajimohamadreza I. The pharmacology of apoptosis. Trends Pharmacol Sci. 1999 Jan;20(1):35-42. Available from: https://doi.org/10.1016/s0165-6147(98)01277-2
2. Sanyaolu A, Marinkovic A, Prakash S, Williams M, Dixon Y, Okorie C, et al. Diabetes mellitus: An overview of the types, prevalence, comorbidity, complication, genetics, economic implication, and treatment. World J Meta-Anal. 2023 Jun 18;11(5):134-143. Available from: http://dx.doi.org/10.13105/wjma.v11.i5.134
3. Tomic D, Shaw JE, Magliano DJ. The burden and risks of emerging complications of diabetes mellitus. Nat Rev Endocrinol. 2022;18:525–539. Available from: https://doi.org/10.1038/s41574-022-00690-7
4. Harding JL, Pavkov ME, Magliano DJ. The burden and risks of emerging complications of diabetes mellitus. Nat Rev Endocrinol. 2019 Oct;15(10):525-539. Available from: https://doi.org/10.1038/s41574-022-00690-7
5. Li J, Jiang C, Xia J. The role of programmed cell death in diabetic foot ulcers: Pathophysiology and therapeutic implications. Int Wound J. 2024 Feb;21(2):143-155. Available from: https://doi.org/10.1111/iwj.14399
6. Screaton G, Xu XN. T cell life and death signalling via TNF-receptor family members. Curr Opin Immunol. 2000 Jun;12(3):316-322. Available from: https://doi.org/10.1016/s0952-7915(00)00093-5
7. Fischer U, Schulze-Osthoff K. Apoptosis-based therapies and drug targets. Cell Death Differ. 2005;12:942-961. Available from: https://doi.org/10.1038/sj.cdd.4401556
8. Fischer U, Schulze-Osthoff K. New approaches and therapeutics targeting apoptosis in disease. Pharmacol Rev. 2005 Jun;57(2):187-215. Available from: https://doi.org/10.1124/pr.57.2.6
9. Talanian RV, Brady KD, Cryns VL. Caspases as targets for anti-inflammatory and anti-apoptotic drug discovery. J Med Chem. 2000 Aug;43(17):3351-3371. Available from: https://doi.org/10.1021/jm000060f
10. Schumacher M, Cerella C, Reuter S, Dicato M, Diederich M. Anti-inflammatory, pro-apoptotic, and anti-proliferative effects of a methanolic neem (Azadirachta indica) leaf extract are mediated via modulation of the nuclear factor-κB pathway. Genes Nutr. 2011 Apr;6(2):149-160. Available from: https://doi.org/10.1007/s12263-010-0194-6
11. Martin DA, Elkon KB. Mechanisms of apoptosis. Rheum Dis Clin North Am. 2004 May;30(2):441-454. Available from: https://www.academia.edu/12492421/Mechanisms_of_apoptosis
12. Kinchen JM, Ravichandran KS. Journey to the grave: Signaling events regulating removal of apoptotic cells. J Cell Sci. 2007 Jul;120(13):2143-2149. Available from: https://doi.org/10.1242/jcs.03463
13. Ashkenazi A, Dixit VM. Apoptosis control by death and decoy receptors. Curr Opin Cell Biol. 1999 Apr;11(2):255-260. Available from: https://doi.org/10.1016/s0955-0674(99)80034-9
14. Koff JL, Ramachandiran S, Bernal-Mizrachi L. A time to kill: Targeting apoptosis in cancer. Int J Mol Sci. 2015 Feb;16(2):2942-2955. Available from: https://doi.org/10.3390/ijms16022942
15. Best PJM. Brief Review. Arterioscler Thromb Vasc Biol. 1999:14-23.
16. Liadis N, Murakami K, Eweida M, Elford AR, Sheu L, Gaisano HY, et al. Caspase-3-dependent β-cell apoptosis in the initiation of autoimmune diabetes mellitus. Mol Cell Biol. 2005;25(9):3620-3629. Available from: https://doi.org/10.1128/mcb.25.9.3620-3629.2005
17. Amaravadi R. Autophagy can contribute to cell death when combining targeted therapy. Cancer Biol Ther. 2009;8:130-133. Available from: https://doi.org/10.4161/cbt.8.21.10416
18. Koh TJ, DiPietro LA. Inflammation and wound healing: the role of the macrophage. Expert Rev Mol Med. 2011;13:e23. Available from: https://doi.org/10.1017/s1462399411001943
19. Martin DA, et al. Apoptosis: Biphasic dose responses. Crit Rev Toxicol. 2001;17.
20. Kang PM, Izumo S. Apoptosis in heart: Basic mechanisms and implications in cardiovascular diseases. Trends Mol Med. 2003;9(4):177-182. Available from: https://doi.org/10.1016/s1471-4914(03)00025-x
21. Bosman FT, Visser BC, van Oeveren J. Apoptosis: Pathophysiology of programmed cell death. Pathol Res Pract. 1996;192:676-683. Available from: https://doi.org/10.1016/s0344-0338(96)80089-6
22. Xu G, Shi Y. Apoptosis signaling pathways and lymphocyte homeostasis. Cell Res. 2007;17(8):759-771. Available from: https://doi.org/10.1038/cr.2007.52
23. Huang NF, Zac-Varghese S, Luke S. Apoptosis in wound healing. Available from: https://www.hmpgloballearningnetwork.com/site/wounds/article/1746
24. Gabay C, Lamacchia C, Palmer G. IL-1 pathways in inflammation and human diseases. Nat Rev Rheumatol. 2010;6(4):232-241. Available from: https://doi.org/10.1038/nrrheum.2010.4
25. Haanen C, Vermes I. Apoptosis and inflammation. Mediators Inflamm. 1995;4(1):5-15. Available from: https://doi.org/10.1155/s0962935195000020
26. Rai NK, Suryabhan, Ansari M, Kumar M, Shukla VK, Tripathi K. Effect of glycaemic control on apoptosis in diabetic wounds. J Wound Care. 2005;14(7):277-281. Available from: https://doi.org/10.12968/jowc.2005.14.6.26792
27. Martin SJ. Caspases: Executioners of Apoptosis. Pathobiology of Hum Dis. 2014;16:145-152. Available from: https://cir.nii.ac.jp/crid/1360855569585741184
28. Reed JC. Apoptosis-regulating proteins as targets for drug discovery. Trends Mol Med. 2001;7(8):314-319. Available from: https://doi.org/10.1016/s1471-4914(01)02026-3
29. Arroba AI, Frago LM, Argente J, Chowen JA. Activation of caspase 8 in the pituitaries of streptozotocin-induced diabetic rats: Implication in increased apoptosis of lactotrophs. Endocrinology. 2005;146:4417-4424. Available from: https://doi.org/10.1210/en.2005-0517
30. Baba K, Minatoguchi S, Sano H, Kagawa T, Murata I, Takemura G, et al. Involvement of apoptosis in patients with diabetic nephropathy: A study on plasma soluble Fas levels and pathological findings. Nephrology. 2004;9:94-99. Available from: https://doi.org/10.1111/j.1440-1797.2004.00238.x
31. Tomita T. Apoptosis in pancreatic β-islet cells in Type 2 diabetes. Bosn J Basic Med Sci. 2016;16(3):162-179. Available from: https://doi.org/10.17305/bjbms.2016.919
32. Lee SC, Pervaiz S. Apoptosis in the pathophysiology of diabetes mellitus. Int J Biochem Cell Biol. 2007;39(3):497-504. Available from: https://doi.org/10.1016/j.biocel.2006.09.007
33. Sha J, Sui B, Su X, Meng Q, Chenggang Z. Alteration of oxidative stress and inflammatory cytokines induces apoptosis in diabetic nephropathy. Mol Med Rep. 2017;16(6):7715-7723. Available from: https://doi.org/10.3892/mmr.2017.7522
34. Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell. 1997;91(2):231-241. Available from: https://doi.org/10.1016/s0092-8674(00)80405-5
35. Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Humans with Type 2 Diabetes. Diabetes. 2003;52(1):102-110. Available from: https://doi.org/10.2337/diabetes.52.1.102
36. Elghazi L, Bernal-Mizrachi E. Akt and PTEN: β-cell mass and pancreas plasticity. Trends Endocrinol Metab. 2009;20(5):243-251. Available from: https://doi.org/10.1016/j.tem.2009.03.002
37. Xu Y, Chen F. Antioxidant, anti-inflammatory, and anti-apoptotic activities of Nesfatin-1: A review. J Inflamm Res. 2020;13:607-617. Available from: https://doi.org/10.2147/jir.s273446
38. Burgess JL, Wyant WA, Abujamra BA, Kirsner RS, Jozic I. Diabetic wound-healing science. Medicina. 2021;57(10):1072. Available from: https://doi.org/10.3390/medicina57101072
39. Riwaldt S, Corydon TJ, Pantalone D, Sahana J, Wise P, Wehland M, et al. Role of apoptosis in wound healing and apoptosis alterations in microgravity. Front Bioeng Biotechnol. 2021;9:1-22. Available from: https://doi.org/10.3389/fbioe.2021.679650
40. Bratton DL, Fadok VA, Richter DA, Kailey JM, Guthrie LA, Henson PM. Appearance of phosphatidylserine on apoptotic cells requires calcium-mediated nonspecific flip-flop and is enhanced by loss of the amino phospholipid translocase. J Biol Chem. 1997;272(42):26159-26165. Available from: https://doi.org/10.1074/jbc.272.42.26159
41. King KL, Cidlowski JA. Cell cycle and apoptosis: common pathways to life and death. J Cell Biochem. 1995;58(2):175-180. Available from: https://doi.org/10.1002/jcb.240580206
42. Kimball AS, Davis FM, Joshi AD, Schaller MA, Bermick J, Xing X, et al. The histone methyltransferase Setdb2 modulates macrophage phenotype and uric acid production in diabetic wound repair. Immunity. 2019;51(2):258-271. Available from: https://doi.org/10.1016/j.immuni.2019.06.015
43. Cho H, Blatchley MR, Duh EJ, Gerecht S. Acellular and cellular approaches to improve diabetic wound healing. Adv Drug Deliv Rev. 2019;146:267-288. Available from: https://doi.org/10.1016/j.addr.2018.07.019
44. Bainbridge P. Wound healing and the role of fibroblasts. J Wound Care. 2013;22(8):407-408. Available from: https://doi.org/10.12968/jowc.2013.22.8.407
45. Han G, Ceilley R. Chronic wound healing: A review of current management and treatments. Adv Ther. 2017;34(6):599-610. Available from: https://doi.org/10.1007/s12325-017-0478-y
46. Mutschler W. Physiologie und pathophysiologie der heilung von defektwunden. Unfallchirurg. 2012;115:767-773. Available from: https://doi.org/10.1007/s00113-012-2208-x
47. Darby IA, Bisucci T, Hewitson TD, MacLellan DG. Apoptosis is increased in a model of diabetes-impaired wound healing in genetically diabetic mice. Int J Biochem Cell Biol. 1997;29:191-200. Available from: https://doi.org/10.1016/s1357-2725(96)00131-8
48. Brown DL, Kao WWY, Greenhalgh DG. Apoptosis down-regulates inflammation under the advancing epithelial wound edge: Delayed patterns in diabetes and improvement with topical growth factors. Surgery. 1997;121:372-380. Available from: https://doi.org/10.1016/s0039-6060(97)90306-8
49. Davis FM, Kimball A, Boniakowski A, Gallagher K. Dysfunctional wound healing in diabetic foot ulcers: New crossroads. Curr Diabetes Rep. 2018;18:2. Available from: https://doi.org/10.1007/s11892-018-0970-z
50. Rai NK, Ansari M, Kumar M, Shukla VK, Tripathi K. Apoptosis: A basic physiologic process in wound healing. Int J Lower Extrem Wounds. 2005;4(3):138-144. Available from: https://doi.org/10.1177/1534734605280018
51. Greenhalgh DG. The role of apoptosis in wound healing. Int J Biochem Cell Biol. 1998;30(11):1019-1030. Available from: https://doi.org/10.1016/s1357-2725(98)00058-2
52. Gantwerker EA, Hom DB. Skin: Histology and physiology of wound healing. Facial Plast Surg Clin North Am. 2011;19(3):441-453. Available from: https://doi.org/10.1016/j.fsc.2011.06.009
53. Sorg H, Tilkorn DJ, Hager S, Hauser J, Mirastschijski U. Skin wound healing: An update on the current knowledge and concepts. Eur Surg Res. 2017;58(1-2):81-94. Available from: https://doi.org/10.1159/000454919
54. Geske FJ, Gerschenson LE. The biology of apoptosis. Hum Pathol. 2001;32(10):1029-1038. Available from: https://doi.org/10.1053/hupa.2001.28250
55. Yamazaki R, Kusunoki N, Matsuzaki T, Hashimoto S, Kawai S. Nonsteroidal anti-inflammatory drugs induce apoptosis in association with activation of peroxisome proliferator-activated receptor-γ in rheumatoid synovial cells. J Pharmacol Exp Ther. 2002;302(1):18-25. Available from: https://doi.org/10.1124/jpet.302.1.18
56. Gharagozloo M, Kalantari H, Rezaei A, Maracy MR, Salehi M, Bahador A, et al. Immune-mediated cochleovestibular disease. Bratisl Med J. 2015;116(5):296-301.
57. Broughton G, Janis JE, Attinger CE. Wound healing: An overview. Plast Reconstr Surg. 2006;117:1-32. Available from: https://doi.org/10.1097/01.prs.0000222562.60260.f9
58. Melnikova I, Golden J. Apoptosis-targeting therapies. Nat Rev Drug Discov. 2004;3(11):905-906. Available from: https://doi.org/10.1038/nrd1554
59. Chen Y, Li Y, Xu H, Li G, Ma Y, Pang YJ. Morin mitigates oxidative stress, apoptosis and inflammation in cerebral ischemic rats. Afr J Tradit Complement Altern Med. 2017;14:348-355. Available from: https://doi.org/10.21010/ajtcam.v14i2.36
60. Velnar T, Bailey T, Smrkolj V. The wound healing process: An overview of the cellular and molecular mechanisms. J Int Med Res. 2009;37(5):1528-1542. Available from: https://doi.org/10.1177/147323000903700531
61. Wang PH, Huang BS, Horng HC, Yeh CC, Chen YJ. Wound healing. J Chin Med Assoc. 2018;81(2):94-101. Available from: https://doi.org/10.1016/j.jcma.2017.11.002
62. Elmore S. Apoptosis: A review of programmed cell death. Toxicol Pathol. 2007;35:495-516. Available from: https://doi.org/10.1080/01926230701320337