Volume 29, Issue 5 (9-2025)                   IBJ 2025, 29(5): 344-351 | Back to browse issues page


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Tavakoli A, Heidari Keshel S, Valizadeh M. Alterations in the Expression of miR-148a-5p, TGF-β1, and TGF-βR2 in Skin Samples Exposed to Sulfur Mustard.. IBJ 2025; 29 (5) :344-351
URL: http://ibj.pasteur.ac.ir/article-1-5198-en.html
Abstract:  
Background: Sulfur mustard exposure causes chronic cutaneous injuries characterized by inflammation, fibrosis, and delayed wound healing. MiRNAs, such as miR-148a-5p, have been implicated in regulating the TGF-β signaling pathways involved in these processes. This study aimed to evaluate whether alterations in the expression of miR-148a-5p, TGF-β1, and TGF-βR2 are associated with long-term SM-induced skin damage.
Methods: Skin biopsy samples were collected from 20 SM-exposed veterans and 20 healthy controls. Total RNA was extracted, and quantitative real-time PCR was performed to assess the expression levels of miR-148a-5p, TGF-β1, and TGF-βR2. Group differences were analyzed using a t-test, and ROC curves were generated to evaluate diagnostic performance.
Results: Expression levels of miR-148a-5p, TGF-β1, and TGF-βR2 were significantly lower in SM-exposed skin compared with controls (miR-148a-5p: p = 0.0010; TGF-β1: p < 0.0001; TGF-βR2: p < 0.0001). Based on ROC analysis, miR-148a-5p and TGF-βR2 indicated promising discriminative potential, whereas TGF-β1 did not reach statistical significance (AUC = 0.65; p = 0.0877).
Conclusion: Our findings suggest that reduced expression of miR-148a-5p and TGF-βR2 may contribute to SM-related skin injury. Both markers demonstrated potential diagnostic utility and could aid in risk stratification and monitoring in SM-induced skin disease, pending further validation in larger cohorts. 

 
Type of Study: Full Length/Original Article | Subject: Related Fields

References
1. Rosenblatt DH, Small MJ, Kimmell TA, Anderson AW. Background chemistry for chemical warfare agents and decontamination processes in support of delisting waste streams at the US army dugway proving ground. Environmental Assessment Division. Tech Rep. 1996. [DOI:10.2172/258187]
2. Khateri S, Ghanei M, Keshavarz S, Soroush M, Haines D. Incidence of lung, eye, and skin lesions as late complications in 34,000 Iranians with wartime exposure to mustard agent. J Occup Environ Med. 2003;45(11):1136-43. [DOI:10.1097/01.jom.0000094993.20914.d1]
3. Ghasemi BM, Karami GR, Pourfarzam SH, Emadi S, Ghasemi H. Late concurrent ophthalmic, respiratory, coetaneous and psychiatric complications of chemical weapons exposure in 479 war patients. Daneshvar Med. 2007;70(4):81-92.
4. Kavehie B, Faghihzadeh S, Eskandari F, Kazemnejad A, Ghazanfari T, Soroosh MR. Studying the surrogate validity of respiratory indexes in predicting the respiratory illnesses in wounded people exposed to sulfur mustard. Arak Uni Med Sci. 2011;13(4):75-82.
5. Kehe K, Szinicz L. Medical aspects of sulphur mustard poisoning. Toxicology. 2005;214(3):198-209. [DOI:10.1016/j.tox.2005.06.014]
6. Jowsey PA, Williams FM, Blain PG. DNA damage responses in cells exposed to sulphur mustard. Toxicol lett. 2012;209(1):1-10. [DOI:10.1016/j.toxlet.2011.11.009]
7. Kehe K, Thiermann H. Clinical picture of sulfur mustard poisoning. Toxicol. 2009;263(1):1. [DOI:10.1016/j.tox.2009.04.038]
8. Graham JS, Schoneboom BA. Historical perspective on effects and treatment of sulfur mustard injuries. Chem Biol Interac. 2013;206(3):512-22. [DOI:10.1016/j.cbi.2013.06.013]
9. Shakarjian MP, Heck DE, Gray JP, Sinko PJ, Gordon MK. Casillas RP, et al. Mechanisms mediating the vesicant actions of sulfur mustard after cutaneous exposure. Toxicol Sci. 2010;114(1):5-19. [DOI:10.1093/toxsci/kfp253]
10. Sepehr A, Aghamohammad S, Ghanavati R, Talebi M, Pourshafie MR, Rohani M. Role of native probiotic Lactobacillus species via TGF-β signaling pathway modulation in CRC. Iran Biomed J. 2023;28(4):168-178. [DOI:10.61186/ibj.4012]
11. Salamati P, Razavi SM. The late clinical and forensic symptoms and signs of sulfur mustard. Burns. 2015;41(6):1370-1. [DOI:10.1016/j.burns.2015.03.006]
12. Poursaleh Z, Ghanei M, Babamahmoodi F, Izadi M, Harandi AA, Emadi SE, et al. Pathogenesis and treatment of skin lesions caused by sulfur mustard. Cutan Ocul Toxicol. 2012;31(3):241-9. [DOI:10.3109/15569527.2011.636119]
13. Feister AJ. Medical defense against mustard gas toxicity: Mechanisms, pharmacology, implications. CRC-Press; 1991.
14. Tahmasbpour E, Emami SR, Ghanei M, Panahi Y. Role of oxidative stress in sulfur mustard-induced pulmonary injury and antioxidant protection. Inhal Toxicol. 2015;27(13):659-72. [DOI:10.3109/08958378.2015.1092184]
15. Mann J, Mann DA. Epigenetic regulation of wound healing and fibrosis. Curr Opin Rheumatol. 2013;25(1):101-7. [DOI:10.1097/BOR.0b013e32835b13e1]
16. Ambros V. The functions of animal microRNAs. Nature. 2004;431(7006):350-5. [DOI:10.1038/nature02871]
17. Cullen BR. Transcription and processing of human microRNA precursors. Mol Cell. 2004;16(6):861-5. [DOI:10.1016/j.molcel.2004.12.002]
18. Li J, Song Y, Wang Y, Luo J, Yu W. MicroRNA-148a suppresses epithelial-to-mesenchymal transition by targeting ROCK1 in non-small cell lung cancer cells. Mol Cell Biochem. 2013;380(1-2):277-82. [DOI:10.1007/s11010-013-1682-y]
19. Valizadeh M, Soleimani M, Irani S, Tavallaei M. Evaluation of changes in miR-20a expression changes in war wounded exposed to mustard gas. J Anim Biol. 2023;15(3):281-91.
20. Valizade M, Irani S, Tavallaei M, Soleimani M. Differential expression of miR-21-5p, miR-20a-5p, TGF-β1, and TGF-β receptor 2 in skin, serum, and lung samples exposed to sulfur mustard. Iran J Allergy Asthma Immunol. 2023;22(4):366-78. [DOI:10.18502/ijaai.v22i4.13609]
21. Wang H, Pan J-Q, Luo L, Ning X-J, Ye Z-P, Yu Z, et al. NF-κB induces miR-148a to sustain TGF-β/Smad signaling activation in glioblastoma. Mol Cancer. 2015:14:2. [DOI:10.1186/1476-4598-14-2]
22. Miscianinov V, Martello A, Rose L, Parish CL, Brown C, Watson A, et al. MicroRNA-148b targets the TGF-β pathway to regulate fibrosis. Matrix Biol. 2018;68(69):47-60.
23. Babalola O, Mamalis A, Lev-Tov H, Jagdeo J. The role of microRNAs in skin fibrosis. Arch Dermatol Res. 2013;305(9):763-76. [DOI:10.1007/s00403-013-1410-1]
24. Deng Z, Fan T, Xiao C, Tian H, Zheng Y, Li C, et al. TGF-β signaling in health, disease and therapeutics. Signal Transduct Target Ther. 2024:9:61. [DOI:10.1038/s41392-024-01764-w]
25. Zhu L, Han X, Gao M, et al. Exosomal miR-148a-3p suppresses TGF-β/Smad4-mediated fibrosis and inflammation. J Transl Med. 2025:23:540.
26. Valizadeh M, Soleimani M, Irani S, Tavallaei M. Decreased expression of TGF-β1 and TGF-βR2 in skin lesions induced by sulfur mustard in Iranian war veterans. Iran J Allergy Asthma Immunol. 2015;14(4):332-6.
27. Suo L, Cheng J, Yuan H, Jiang Z, Tash D, Wang L, et al. miR-26a/30d/152 are reliable reference genes for miRNA quantification in skin wound age estimation. Forensic Sci Res. 2023;8(3):230-40. [DOI:10.1093/fsr/owad037]
28. Etich J, Bergmeier V, Pitzler L, Brachvogel B. Identification of a reference gene for the quantification of mRNA and miRNA expression during skin wound healing. Connect Tissue Res. 2017;58(2):196-207. [DOI:10.1080/03008207.2016.1210606]
29. Luo M, Wang L, Zhu W, Fu J, Song F, Fang M, et al. Identification and characterization of skin color microRNAs in koi carp (Cyprinus carpio L.) by Illumina sequencing. BMC Genomics. 2018;19(1):779. [DOI:10.1186/s12864-018-5189-5]
30. Barber RD, Harmer DW, Coleman RA, Clark BJ. GAPDH as a housekeeping gene: Analysis of GAPDH mRNA expression in a panel of 72 human tissues. Physiol Genomics. 2005;11;21(3):389-95. [DOI:10.1152/physiolgenomics.00025.2005]
31. Arai K, Okabe M, Kobashi D, Ichimura K, Fathy M, Oba J, et al. Importance of housekeeping gene optimization for the analysis of mRNA expression during wound healing in a third-degree burn injury model. J Burn Care Res. 2023;44(1):146-57. [DOI:10.1093/jbcr/irac161]
32. Renshaw B. Mechanisms in production of cutaneous injuries by sulfur and nitrogen mustard. Chemical warfare agents and related chemical problems. 1946;4(23):479-518.
33. Smith KJ, Hurst CG, Moeller RB, Skelton HG, Sidell FR. Sulfur mustard: Its continuing threat as a chemical warfare agent, the cutaneous lesions induced, progress in understanding its mechanism of action, its long-term health effects, and new developments for protection and therapy. J Am Acad Dermatol. 1995;32(5):765-76. [DOI:10.1016/0190-9622(95)91457-9]
34. Qabar A, Nelson M, Guzman J, Corun C, Hwang B-J, Steinberg M. Modulation of sulfur mustard induced cell death in human epidermal keratinocytes using IL‐10 and TNF‐α. J Biochem Mol Toxicol. 2005;19(4):213-25. [DOI:10.1002/jbt.20089]
35. Saki S, Monjezi S, Ghaffari F, Orak G, Bavarsad SS, Khedri A, et al. Unraveling the exosome-miR-133a axis: targeting TGF-β signaling via WJ-MSC-derived exosomes for anti-fibrotic therapy in liver fibrosis. Iran Biomed J. 2024;28(5 and 6):235-244. [DOI:10.61186/ibj.4357]
36. Kulkarni AB, Huh CG, Becker D, Geiser A, Lyght M, Flanders KC, et al. Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci USA. 1993;90(2):770-4. [DOI:10.1073/pnas.90.2.770]
37. Shojaei Jeshvaghani Z, Soleimani M, Asgharpour S, Arefian E. Latency-associated transcript-derived MicroRNAs in herpes simplex virus type 1 target SMAD3 and SMAD4 in TGF-β/smad signaling pathway. Iran Biomed J.2021;25(3):169-179. [DOI:10.52547/ibj.25.3.169]

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