The role and mechanisms of N,N-dimethylglycine sodium in promoting wound healing in mice_Journal of Biomedical Engineering

Authors：

GUO Shuchang ¹ , ZHANG Zhenyang ¹ , QI Baoying ¹ , ZHOU Yuxiao ¹ , LI Meng ¹ , LIANG Tianzhu ¹ , YAN Huan ¹ ,  WANG Qiuyu ^1,2 ,  JIN Lili ¹

1. School of Life Sciences, Liaoning University, Shenyang 110036, P. R. China;
2. School of Life and Health Management, Shenyang City University, Shenyang 110112, P. R. China;

Corresponding?author：

WANG Qiuyu, Email: qiuyuwang@lnu.edu.cn; JIN Lili, Email: lilijin@lnu.edu.cn

Keywords：

N,N-dimethylglycine sodium; Keratinocytes; Immune-inflammatory microenvironment; Wound healing

DOI：

10.7507/1001-5515.202411042

Video：

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N,N-Dimethylglycine (DMG) is a glycine derivative, and its sodium salt (DMG-Na) has been demonstrated to possess various biological activities, including immunomodulation, free radical scavenging, and antioxidation, collectively contributing to the stability of tissue and cellular functions. However, its direct effects and underlying mechanisms in wound healing remain unclear. In this study, a full-thickness excisional wound model was established on the dorsal skin of mice, and wounds were treated locally with DMG-Na. Wound healing progression was assessed by calculating wound closure rates. Histopathological analysis was conducted using hematoxylin-eosin (HE) staining, and keratinocyte proliferation, migration, and differentiation were evaluated using CCK-8 assays, scratch wound assays, and quantitative reverse transcription PCR (qRT-PCR). Inflammation-related cytokine expression in keratinocytes was analyzed via ELISA and qRT-PCR. Results revealed that DMG-Na treatment significantly accelerated wound healing in mice and improved overall wound closure quality. The wound healing rates on days 3, 6, and 9 were 49.18%, 68.87%, and 90.55%, respectively, with statistically significant differences compared to the control group (P<0.05). DMG-Na treatment downregulated the mRNA levels of keratinocyte differentiation markers while enhancing cell proliferation and migration (P<0.05). Furthermore, DMG-Na decreased the secretion of LPS-induced keratinocyte inflammatory cytokines, including IL-1β, IL-6, IL-8, TNF-α, and CXCL10 (P<0.05). These findings indicate that DMG-Na regulates inflammatory responses and promotes keratinocyte proliferation and migration, thereby facilitating the healing of skin wounds.

Citation： GUO Shuchang, ZHANG Zhenyang, QI Baoying, ZHOU Yuxiao, LI Meng, LIANG Tianzhu, YAN Huan, WANG Qiuyu, JIN Lili. The role and mechanisms of N,N-dimethylglycine sodium in promoting wound healing in mice. Journal of Biomedical Engineering, 2025, 42(4): 824-831. doi: 10.7507/1001-5515.202411042 Copy

1.	劉國昇. 保護好人體最大的器官——皮膚. 健康向導, 2021, 27(6): 44-45.
2.	Gottrup F. A specialized wound-healing center concept: importance of a multidisciplinary department structure and surgical treatment facilities in the treatment of chronic wounds. Am J Surg, 2004, 187(5A): 38S-43S.
3.	袁皓, 楊童玲. 新生兒醫源性皮膚損傷處理的專家共識. 中國循證兒科雜志, 2021, 16(4): 255-261.
4.	張曉翠, 尹雪梅, 張學穎, 等. 新生兒病房護士對新生兒醫源性皮膚損傷及其高危因素認知的現狀調查. 天津護理, 2024, 32(2): 159-163.
5.	武榮偉, 王堠崟, 王遠鑫, 等. 2000—2020年中國縣域人口老齡化分布格局及其影響因素. 熱帶地理, 2024, 44(8): 1500-1512.
6.	喻強. 農村公共衛生服務發展中存在的問題及對策. 現代農村科技, 2024(8): 2-3.
7.	Landén N X, Li D, St?hle M. Transition from inflammation to proliferation: a critical step during wound healing. Cell Mol Life Sci, 2016, 73(20): 3861-3885.
8.	蔣曉蕾, 朱立宏. 復方黃柏液激活Notch1/Twist1軸對皮膚潰瘍大鼠傷口愈合的影響. 中國免疫學雜志, 2023, 39(12): 2560-2565.
9.	Lin S Y, Wang Q X, Huang X T, et al. Wounds under diabetic milieu: The role of immune cellar components and signaling pathways. Biomed Pharmacother, 2023, 157: 114052.
10.	Pastar I, Stojadinovic O, Yin NC, et al. Epithelialization in wound healing: a comprehensive review. Adv Wound Care, 2014, 3(7): 445-464.
11.	Tüzün Y, Antonov M, Dolar N, et al. Keratinocyte cytokine and chemokine receptors. Dermatol Clin, 2007, 25(4): 467-476.
12.	Gordon S, Taylor P. Monocyte and macrophage heterogeneity. Nat Rev Immunol, 2005, 5: 953-964.
13.	Mittal M, Siddiqui M R, Tran K, et al. Reactive oxygen species in inflammation and tissue injury. Antioxid Redox Signal, 2014, 20(7): 1126-1167.
14.	Lewis C J, Stevenson A, Fear M W, et al. A review of epigenetic regulation in wound healing: Implications for the future of wound care. Wound Repair Regen, 2020, 28(6): 710-718.
15.	Kalmar I D, Verstegen M W, Maenner K, et al. Tolerance and safety evaluation of N,N-dimethylglycine, a naturally occurring organic compound, as a feed additive in broiler diets. Br J Nutr, 2012, 107(11): 1635-1644.
16.	Cools A, Maes D, Buyse J, et al. Effect of N,N-dimethylglycine supplementation in parturition feed for sows on metabolism, nutrient digestibility and reproductive performance. Animal, 2010, 4(12): 2004-2011.
17.	Kalmar I D, Cools A, Buyse J, et al. Dietary N,N-dimethylglycine supplementation improves nutrient digestibility and attenuates pulmonary hypertension syndrome in broilers. J Anim Physiol Anim Nutr (Berl), 2010, 94(6): e339-347.
18.	Takahashi T, Sasaki K, Somfai T, et al. N, N-Dimethylglycine decreases oxidative stress and improves in vitro development of bovine embryos. J Reprod Dev, 2016, 6(2): 209-212.
19.	Lin J C, Chan M H, Lee M Y, et al. N,N-dimethylglycine differentially modulates psychotomimetic and antidepressant-like effects of ketamine in mice. Prog Neuropsychopharmacol Biol Psychiatry, 2016, 71: 7-13.
20.	Hsieh C P, Chen S T, Lee M Y, et al. N, N-dimethylglycine protects behavioral disturbances and synaptic deficits induced by repeated ketamine exposure in mice. Neurscience, 2021, 472: 128-137.
21.	Dhanjal D S, Bhardwaj S, Chopra C, et al. Millennium nutrient N,N-dimethylglycine (DMG) and its effectiveness in autism spectrum disorders. Curr Med Chem, 2022, 29(15): 2632-2651.
22.	Hsieh C P, Chen H, Chan M H, et al. N,N-dimethylglycine prevents toluene-induced impairment in recognition memory and synaptic plasticity in mice. Toxicology, 2020, 446: 152613.
23.	Lendvai A, Béke G, Hollósi E, et al. N,N-dimethylglycine sodium salt exerts marked anti-inflammatory effects in various dermatitis models and activates human epidermal keratinocytes by increasing proliferation, migration, and growth factor release. Int J Mol Sci, 2023, 24(14): 11264.
24.	Béke G, Lendvai A, Hollósi E, et al. Topically applied N,N-dimethylglycine sodium salt enhances human skin blood flow by inducing endothelial nitric oxide release. J Invest Dermatol, 2024, 144(12): 2823-2827.
25.	李姝嬌. 多肽AWRK6促進糖尿病小鼠皮膚創面愈合的作用及機制研究. 沈陽: 遼寧大學, 2023.
26.	熊翱, 熊仁平, 彭艷, 等. 原代滑膜細胞培養及同時提取微量總RNA和蛋白質的方法在體外細胞分子生物學研究中的應用. 中華骨與關節外科雜志, 2022, 15(4): 276-282.
27.	Yao H, Hu Y, Tong H, et al. Dimethylglycine alleviates metabolic dysfunction-associated fatty liver disease by improving the circulating estrogen level via gut staphylococcus. J Agric Food hem, 2024, 72(5): 2708-2717.
28.	Picaud J C, De Magistris A, Mussap M, et al. Urine NMR metabolomics profile of preterm infants with necrotizing enterocolitis over the first two months of life: a pilot longitudinal case-control study. Front Mol Biosci, 2021, 8: 680159.
29.	Michail K, Baghdasarian A, Narwaley M, A et al. Scavenging of free-radical metabolites of aniline xenobiotics and drugs by amino acid derivatives: toxicological implications of radical-transfer reactions. Chem Res Toxicol, 2013, 26(12): 1872-1883.
30.	Zhang J, Jiang C, Liu X, et al. The metabolomic profiling identifies N, N-dimethylglycine as a facilitator of dorsal root ganglia neuron axon regeneration after injury. FASEB J, 2022, 36(5): e22305.
31.	Morasso M I, Tomic-Canic M. Epidermal stem cells: the cradle of epidermal determination, differentiation and wound healing. Biol Cell, 2005, 97(3): 173-183.
32.	Xu W, Dielubanza E, Maisel A, et al. Staphylococcus aureus impairs cutaneous wound healing by activating the expression of a gap junction protein, connexin-43 in keratinocytes. Cell Mol Life Sci, 2021, 78(3): 935-947.
33.	唐鳳玲. 溶膠-凝膠生物活性玻璃調控角質形成細胞屏障功能及其機制研究. 廣州: 華南理工大學, 2020.
34.	Masse I, Barbollat-Boutrand L, Kharbili M E, et al. GATA3 inhibits proliferation and induces expression of both early and late differentiation markers in keratinocytes of the human epidermis. Arch Dermatol Res, 2014, 306(2): 201-208.
35.	廖倩, 于春水, 汪瀚文. 皮膚屏障中分化蛋白的研究進展. 實用皮膚病學雜志, 2017, 10(6): 354-356.
36.	黃鈺淇, 李里, 鐘維, 等. sprouty4蛋白對角質形成細胞增殖及分化的影響. 皮膚性病診療學雜志, 2020, 27(3): 147-150.
37.	Kroeze K-L, Boink M A, Sampat-Sardjoepersad S C, et al. Autocrine regulation of re-epithelialization after wounding by chemokine receptors CCR1, CCR10, CXCR1, CXCR2, and CXCR3. J Invest Dermatol, 2012, 132(1): 216-225.
38.	Krausgruber T, Fortelny N, Fife-Gernedl V, et al. Structural cells are key regulators of organ-specific immune responses. Nature, 2020, 583(7815): 296-302.
39.	Feliciani C, Gupta A K, Sauder D N. Keratinocytes and cytokine/growth factors. Crit Rev Oral Biol Med, 1996, 7(4): 300-318.
40.	Herold K, Mrowka R. Inflammation-Dysregulated inflammatory response and strategies for treatment. Acta Physiol, 2019, 226(3): e13284.
41.	Niebuhr M, Baumert K, Werfel T. TLR-2-mediated cytokine and chemokine secretion in human keratinocytes. Exp Dermatol, 2010, 19(10): 873-877.
42.	Mulder P P G, Vlig M, Fasse E, et al. Burn-injured skin is marked by a prolonged local acute inflammatory response of innate immune cells and pro-inflammatory cytokines. Front Immunol, 2022, 13: 1034420.
43.	Rodrigues A E, Dolivo D, Li Y, et al. Comparison of thermal burn-induced and excisional-induced scarring in animal models: a review of the literature. Adv Wound Care, 2022, 11(3): 150-162.
44.	Sadeghipour H, Torabi R, Gottschall J, et al. Blockade of IgM-mediated inflammation alters wound progression in a swine model of partial-thickness burn. J Burn Care Res, 2017, 38(3): 148-160.
45.	Petreaca M L, Do D, Dhall S, et al. Deletion of a tumor necrosis superfamily gene in mice leads to impaired healing that mimics chronic wounds in humans. Wound Repair Regen, 2012, 20(3): 353-366.

1. 劉國昇. 保護好人體最大的器官——皮膚. 健康向導, 2021, 27(6): 44-45.
2. Gottrup F. A specialized wound-healing center concept: importance of a multidisciplinary department structure and surgical treatment facilities in the treatment of chronic wounds. Am J Surg, 2004, 187(5A): 38S-43S.
3. 袁皓, 楊童玲. 新生兒醫源性皮膚損傷處理的專家共識. 中國循證兒科雜志, 2021, 16(4): 255-261.
4. 張曉翠, 尹雪梅, 張學穎, 等. 新生兒病房護士對新生兒醫源性皮膚損傷及其高危因素認知的現狀調查. 天津護理, 2024, 32(2): 159-163.
5. 武榮偉, 王堠崟, 王遠鑫, 等. 2000—2020年中國縣域人口老齡化分布格局及其影響因素. 熱帶地理, 2024, 44(8): 1500-1512.
6. 喻強. 農村公共衛生服務發展中存在的問題及對策. 現代農村科技, 2024(8): 2-3.
7. Landén N X, Li D, St?hle M. Transition from inflammation to proliferation: a critical step during wound healing. Cell Mol Life Sci, 2016, 73(20): 3861-3885.
8. 蔣曉蕾, 朱立宏. 復方黃柏液激活Notch1/Twist1軸對皮膚潰瘍大鼠傷口愈合的影響. 中國免疫學雜志, 2023, 39(12): 2560-2565.
9. Lin S Y, Wang Q X, Huang X T, et al. Wounds under diabetic milieu: The role of immune cellar components and signaling pathways. Biomed Pharmacother, 2023, 157: 114052.
10. Pastar I, Stojadinovic O, Yin NC, et al. Epithelialization in wound healing: a comprehensive review. Adv Wound Care, 2014, 3(7): 445-464.
11. Tüzün Y, Antonov M, Dolar N, et al. Keratinocyte cytokine and chemokine receptors. Dermatol Clin, 2007, 25(4): 467-476.
12. Gordon S, Taylor P. Monocyte and macrophage heterogeneity. Nat Rev Immunol, 2005, 5: 953-964.
13. Mittal M, Siddiqui M R, Tran K, et al. Reactive oxygen species in inflammation and tissue injury. Antioxid Redox Signal, 2014, 20(7): 1126-1167.
14. Lewis C J, Stevenson A, Fear M W, et al. A review of epigenetic regulation in wound healing: Implications for the future of wound care. Wound Repair Regen, 2020, 28(6): 710-718.
15. Kalmar I D, Verstegen M W, Maenner K, et al. Tolerance and safety evaluation of N,N-dimethylglycine, a naturally occurring organic compound, as a feed additive in broiler diets. Br J Nutr, 2012, 107(11): 1635-1644.
16. Cools A, Maes D, Buyse J, et al. Effect of N,N-dimethylglycine supplementation in parturition feed for sows on metabolism, nutrient digestibility and reproductive performance. Animal, 2010, 4(12): 2004-2011.
17. Kalmar I D, Cools A, Buyse J, et al. Dietary N,N-dimethylglycine supplementation improves nutrient digestibility and attenuates pulmonary hypertension syndrome in broilers. J Anim Physiol Anim Nutr (Berl), 2010, 94(6): e339-347.
18. Takahashi T, Sasaki K, Somfai T, et al. N, N-Dimethylglycine decreases oxidative stress and improves in vitro development of bovine embryos. J Reprod Dev, 2016, 6(2): 209-212.
19. Lin J C, Chan M H, Lee M Y, et al. N,N-dimethylglycine differentially modulates psychotomimetic and antidepressant-like effects of ketamine in mice. Prog Neuropsychopharmacol Biol Psychiatry, 2016, 71: 7-13.
20. Hsieh C P, Chen S T, Lee M Y, et al. N, N-dimethylglycine protects behavioral disturbances and synaptic deficits induced by repeated ketamine exposure in mice. Neurscience, 2021, 472: 128-137.
21. Dhanjal D S, Bhardwaj S, Chopra C, et al. Millennium nutrient N,N-dimethylglycine (DMG) and its effectiveness in autism spectrum disorders. Curr Med Chem, 2022, 29(15): 2632-2651.
22. Hsieh C P, Chen H, Chan M H, et al. N,N-dimethylglycine prevents toluene-induced impairment in recognition memory and synaptic plasticity in mice. Toxicology, 2020, 446: 152613.
23. Lendvai A, Béke G, Hollósi E, et al. N,N-dimethylglycine sodium salt exerts marked anti-inflammatory effects in various dermatitis models and activates human epidermal keratinocytes by increasing proliferation, migration, and growth factor release. Int J Mol Sci, 2023, 24(14): 11264.
24. Béke G, Lendvai A, Hollósi E, et al. Topically applied N,N-dimethylglycine sodium salt enhances human skin blood flow by inducing endothelial nitric oxide release. J Invest Dermatol, 2024, 144(12): 2823-2827.
25. 李姝嬌. 多肽AWRK6促進糖尿病小鼠皮膚創面愈合的作用及機制研究. 沈陽: 遼寧大學, 2023.
26. 熊翱, 熊仁平, 彭艷, 等. 原代滑膜細胞培養及同時提取微量總RNA和蛋白質的方法在體外細胞分子生物學研究中的應用. 中華骨與關節外科雜志, 2022, 15(4): 276-282.
27. Yao H, Hu Y, Tong H, et al. Dimethylglycine alleviates metabolic dysfunction-associated fatty liver disease by improving the circulating estrogen level via gut staphylococcus. J Agric Food hem, 2024, 72(5): 2708-2717.
28. Picaud J C, De Magistris A, Mussap M, et al. Urine NMR metabolomics profile of preterm infants with necrotizing enterocolitis over the first two months of life: a pilot longitudinal case-control study. Front Mol Biosci, 2021, 8: 680159.
29. Michail K, Baghdasarian A, Narwaley M, A et al. Scavenging of free-radical metabolites of aniline xenobiotics and drugs by amino acid derivatives: toxicological implications of radical-transfer reactions. Chem Res Toxicol, 2013, 26(12): 1872-1883.
30. Zhang J, Jiang C, Liu X, et al. The metabolomic profiling identifies N, N-dimethylglycine as a facilitator of dorsal root ganglia neuron axon regeneration after injury. FASEB J, 2022, 36(5): e22305.
31. Morasso M I, Tomic-Canic M. Epidermal stem cells: the cradle of epidermal determination, differentiation and wound healing. Biol Cell, 2005, 97(3): 173-183.
32. Xu W, Dielubanza E, Maisel A, et al. Staphylococcus aureus impairs cutaneous wound healing by activating the expression of a gap junction protein, connexin-43 in keratinocytes. Cell Mol Life Sci, 2021, 78(3): 935-947.
33. 唐鳳玲. 溶膠-凝膠生物活性玻璃調控角質形成細胞屏障功能及其機制研究. 廣州: 華南理工大學, 2020.
34. Masse I, Barbollat-Boutrand L, Kharbili M E, et al. GATA3 inhibits proliferation and induces expression of both early and late differentiation markers in keratinocytes of the human epidermis. Arch Dermatol Res, 2014, 306(2): 201-208.
35. 廖倩, 于春水, 汪瀚文. 皮膚屏障中分化蛋白的研究進展. 實用皮膚病學雜志, 2017, 10(6): 354-356.
36. 黃鈺淇, 李里, 鐘維, 等. sprouty4蛋白對角質形成細胞增殖及分化的影響. 皮膚性病診療學雜志, 2020, 27(3): 147-150.
37. Kroeze K-L, Boink M A, Sampat-Sardjoepersad S C, et al. Autocrine regulation of re-epithelialization after wounding by chemokine receptors CCR1, CCR10, CXCR1, CXCR2, and CXCR3. J Invest Dermatol, 2012, 132(1): 216-225.
38. Krausgruber T, Fortelny N, Fife-Gernedl V, et al. Structural cells are key regulators of organ-specific immune responses. Nature, 2020, 583(7815): 296-302.
39. Feliciani C, Gupta A K, Sauder D N. Keratinocytes and cytokine/growth factors. Crit Rev Oral Biol Med, 1996, 7(4): 300-318.
40. Herold K, Mrowka R. Inflammation-Dysregulated inflammatory response and strategies for treatment. Acta Physiol, 2019, 226(3): e13284.
41. Niebuhr M, Baumert K, Werfel T. TLR-2-mediated cytokine and chemokine secretion in human keratinocytes. Exp Dermatol, 2010, 19(10): 873-877.
42. Mulder P P G, Vlig M, Fasse E, et al. Burn-injured skin is marked by a prolonged local acute inflammatory response of innate immune cells and pro-inflammatory cytokines. Front Immunol, 2022, 13: 1034420.
43. Rodrigues A E, Dolivo D, Li Y, et al. Comparison of thermal burn-induced and excisional-induced scarring in animal models: a review of the literature. Adv Wound Care, 2022, 11(3): 150-162.
44. Sadeghipour H, Torabi R, Gottschall J, et al. Blockade of IgM-mediated inflammation alters wound progression in a swine model of partial-thickness burn. J Burn Care Res, 2017, 38(3): 148-160.
45. Petreaca M L, Do D, Dhall S, et al. Deletion of a tumor necrosis superfamily gene in mice leads to impaired healing that mimics chronic wounds in humans. Wound Repair Regen, 2012, 20(3): 353-366.

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