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ORIGINAL ARTICLE |
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| Year : 2022 | Volume
: 67
| Issue : 6 | Page : 657-661 |
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| Oxidative stress-related miRNAs in patients with severe acne vulgaris |
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Betul Calis1, Fatma Humeyra Yerlikaya2, Arzu Ataseven3, Selami Aykut Temiz3, Duygu Eryavuz Onmaz2
1 Department of Biochemistry, Meram Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey
2 Department of Biochemistry, Faculty of Medicine, Selcuk University, Konya, Konya, Turkey
3 Department of Dermatology, Meram Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey
| Date of Web Publication | 23-Feb-2023 |
Correspondence Address:
Duygu Eryavuz Onmaz
Department of Biochemistry, Selcuk University Faculty of Medicine, Selcuk University Faculty of Medicine Alaaddin Keykubat Campus, 42075 Selcuklu, Konya
Turkey
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/ijd.ijd_467_22
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 Abstract | | |
Background: Acne vulgaris is a common chronic inflammatory skin disease in adolescents and oxidative stress plays an important role in acne pathology. However, the pathology of acne has not yet been fully elucidated. miRNAs are small noncoding RNAs, and there is increasing evidence for their role in the pathogenesis of skin diseases such as psoriasis, atopic dermatitis, and other inflammatory diseases. Aims and Objectives: The aim of the study was to investigate serum malondialdehyde (MDA) and glutathione (GSH) levels with plasma miRNA expression profile related with oxidative stress in patients with severe acne vulgaris. Materials and Methods: Fifty seven female patients with severe acne and 40 healthy women were included in the study. Plasma miRNA-31, miRNA-200a, and miRNA-21 levels were evaluated by using real-time quantitative polymerase chain rection analysis. MDA and GSH levels were measured as per the manufacturer's procedures using commercial ELISA kits. Results: Plasma miRNA-21 levels were statistically significantly higher in patients with severe acne compared to the control group (P =0.003). Plasma miRNA-200a (P =0.303) and miRNA-31 (P =.652) levels were slightly higher in patients with severe acne compared to the control group, but this difference was not statistically significant. Serum MDA levels (P =.047) were higher in patients with severe acne compared to control group, while serum GSH levels (P =.001) were lower. Conclusion: These results show that oxidative damage is involved in acne etiopathogenesis and especially miRNA-21 may have an important role in the pathogenesis of acne vulgaris.
Keywords: Acne vulgaris, glutathione, miRNA, malondialdehyde, oxidative stress
How to cite this article:
Calis B, Yerlikaya FH, Ataseven A, Temiz SA, Onmaz DE. Oxidative stress-related miRNAs in patients with severe acne vulgaris. Indian J Dermatol 2022;67:657-61 |
How to cite this URL:
Calis B, Yerlikaya FH, Ataseven A, Temiz SA, Onmaz DE. Oxidative stress-related miRNAs in patients with severe acne vulgaris. Indian J Dermatol [serial online] 2022 [cited 2023 Mar 23];67:657-61. Available from: https://www.e-ijd.org/text.asp?2022/67/6/657/370301 |
| Introduction | |  |
Acne vulgaris is a chronic inflammatory, recurrent skin disease affecting the pilosebaceous unit. Acne is one of the 10 most common diseases worldwide, affecting more than 80% of adolescents.[1] Although acne is not a life-threatening disease, it significantly reduces the quality of life by causing emotional disturbances such as depression, social withdrawal, poor self-image, and anxiety.[2] The pathogenesis is multifactorial and includes four primary factors: abnormal hyper keratinization leading to comedo formation, increased sebum production, proliferation and follicular colonization of propionibacterium acnes, inflammatory response, and increased release of reactive oxygen species induced by immune system activation.[1],[3] P. acnes produce chemotactic mediators for neutrophils and cause the release of hydrolytic enzymes associated with damage to the follicular wall as a result of its phagocytosis, thus triggering the inflammatory process. In addition, it has been reported that reactive oxygen derivatives released against microorganisms from neutrophils in the follicular wall contribute to the development of inflammation and are involved in the pathogenesis of the disease.[4],[5],[6] Oxidative stress is caused by the imbalance between the production of reactive oxygen/nitrogen derivatives and the antioxidant defense system and is involved in the pathogenesis of many diseases such as cardiovascular diseases, diabetes, cancer, and neurodegenerative diseases. Moreover, a growing body of evidence indicates that it also plays an important role in the pathogenesis of acne.[7],[8] MicroRNAs (miRNAs) are short noncoding RNAs, approximately 22 nucleotides long, that play a role in gene silencing by directing Argonaute proteins to target sites in the 3' untranslated region (UTR) of mRNAs.[9] miRNAs regulate important cellular functions such as proliferation, differentiation, cell cycle, and apoptosis.[10] miRNA networks and oxidative stress play an intertwined role in many pathological processes. Recent studies have revealed that specific miRNAs contribute to the regulation of oxidative stress and that irregularities in this modulation may be associated with various pathologies.[11],[12],[13],[14] Oxidative stress affects the expression levels of miRNAs, while miRNAs also affect the expression levels of genes involved in oxidative stress response.[11] Malondialdehyde (MDA) is the end product of lipid peroxidation and is one of the well-known markers of oxidative stress. Increased free radicals cause an increase in MDA levels.[15] MDA changes the physical structure of the cell membrane and is indirectly involved in protein, DNA, and RNA synthesis.[16] Glutathione (GSH) is one of the most abundant, nonprotein thiols in mammalian tissues at millimolar levels, playing a direct role in the neutralization of free radicals.[17] It has many important functions in combating oxidative stress, immune function, and fibrogenesis.[18] Our aim in this study was to investigate the levels of oxidative stress–related miRNAs miRNA-31, miRNA-200a, miRNA-21, and oxidant-antioxidant status markers MDA and GSH levels in patients with severe acne.
| Materials and Methods | | |
Study design
Subjects
This is a case-control study included 57 women with severe acne and 40 healthy women without acne vulgaris who applied to Konya Necmettin Erbakan University Meram Medical Faculty Hospital Dermatology Polyclinic. In this study, probability sampling technique was used. There were 78 patients with severe acne who were registered in the Dermatology Polyclinic of Konya Necmettin Erbakan University and were followed up regularly. However, the following patients were excluded from the study: 18 patients receiving topical or systemic medication, two patients taking vitamin or antioxidant supplements, and one patient who did not give consent. Thus, the sample size of the patients group was determined as 57. After the exclusion criteria were applied, the control group was selected as age and sex-matched healthy individuals with the patient group. All patients were evaluated as per the Global Acne Grading Score (GAGS) and severe acne patients were included in the study.[19] Exclusion criteria were receiving topical or systemic medication in the last 3 months, have any additional dermatological and/or systemic disease, smoking or drink alcohol, follow a specific diet, taking vitamin or antioxidant supplements, and do regularly exercise. After 12 hours of fasting, the venous blood samples of the patients were taken into tubes with EDTA and gel. Serum and plasma samples were separated and stored at -80°C until analysis. Before the study, all participants were informed about the study and their written informed consent was obtained. The study was approved by local ethics committee (Necmettin Erbakan University ethics committee Number: 2017/1009, Date: 22/09/2017).
Laboratory tests
The serum levels of urea, creatinine, total cholesterol, triglycerides, high-density lipoprotein-cholesterol (HDL-C), very low-density lipoprotein (VLDL-C), glucose, alanine aminotransferase (ALT) and aspartate amino transferase (AST), hemoglobin, and hsCRP levels were analyzed with an Synchron LX System (Beckman Coulter, Fullerton CA, USA) using commercially available kits as per manufacturer's instructions. Low-density lipoprotein (LDL-C) was calculated using Friedewald's formula.
miRNA expression profiling
Total RNA extracted from plasma samples via High Pure miRNA Isolation Kit (Roche Life Science, Mannheim, Germany). Total RNA was reversely transcribed to cDNA by using miScript II RT Kit (Qiagen, Hilden, Germany). Obtained cDNA samples are PreAmplified via miScript Microfluidics PreAMP Kit (Qiagen, Hilden, Germany). Quantitative real-time polymerase chain reaction analysis was carried out using miScript miRNA Assays (Qiagen, Hilden, Germany) with Dynamic Array (Fluidigm, South San Francisco, CA, USA) on BioMark System (Fluidigm, South San Francisco, CA, USA) as per manufacturer's protocol. The relative gene expression was calculated with the comparison of cycle times for target polymerase chain reaction using this equation: relative gene expression = 2−(ΔCtsample − ΔCtcontrol).
MDA and GSH analysis
Serum MDA (Cat.No E-BC-K025-S) and GSH (Cat.No E-EL-0026) levels were analyzed using commercial human ELISA kits (Elabscience, Wuhan, China) as per manufacturer's instructions. The absorbance of all wells was measured at 450 nm in an ELx800 Absorbance Microplate Reader (Biotek, Winooski, VT, USA).
Statistical analysis
Statistical analysis was carried out using SPSS statistical software package version 21.0. One-sample Kolmogorov-Smirnov test was used to evaluate the distribution of data. The mean values between the two groups were compared using Student's t-test. Correlation analyses were performed using the Spearman's correlation test. P <.05 was considered to be statistically significant. The Student's t-test is used to compare the means between two groups, while Spearman's correlation used to measure of nonlinear dependence between two random variables.
| Results | | |
There was no statistically significant difference (P =0.102) between the mean age of the patient (22.4 ± 3.7 years) and control (23.4 ± 1.5 years) groups. Demographic characteristics and routine laboratory parameters of the participants were shown in [Table 1] and [Table 2]. | Table 1: Demographic characteristics of patients with acne vulgaris and control group
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 | Table 2: Levels of various biochemical parameters of patients with acne vulgaris and control group
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Plasma miRNA-21 levels were statistically significantly higher in patients with severe acne compared to the control group [(0.55 ± 0.06) vs. (0.30 ± 0.05), P =0.003]. Plasma miRNA-200a (P =0.303) and miRNA-31 (P =.652) levels were slightly higher in patients with severe acne compared to the control group, but this difference was not statistically significant.
Serum MDA levels [(2058.3 ± 28.5) ng/mL vs. (1993.3 ± 14.9) ng/mL, P =0.047] were higher in patients with severe acne compared to control group, while serum GSH levels [(97.2 ± 18.9) μg/mL vs. (112.2 ± 20.8) μg/mL, P =0.001] were lower [Table 3]. | Table 3: miRNA-200a, miRNA-21, miRNA-31, MDA and GSH levels of patients with acne vulgaris and control group
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Moreover, serum MDA levels were positively correlated with miRNA-21 (r = 0.323, P =0.019), miRNA-200a (r = 0.353, P =0.010), and miRNA-31 (r = 0.617, P <.001) levels in the acne group, but there was no significant correlation between GSH and miRNA levels. There was no significant correlation (P >.05) between plasma miRNA levels and serum GSH and MDA levels in the control group.
| Discussion | | |
Acne is a chronic inflammatory skin disease. It is the most common skin condition after dermatitis and has an estimated global prevalence of 9.38%.[20],[21] Acne patients have not only local tissue damage but also increased oxidative stress burden.[8] Recent studies have shown that oxidative stress has an important role in acne initiation and progression. Reactive oxygen derivatives released from accumulated neutrophils by the effect of chemotactic factors secreted by P. acnes cause chemical damage, including healthy tissues, by attacking DNA and/or membrane lipids.[22] Arican et al. measured the levels of catalase (CAT), glucose-6-phosphate dehydrogenase (G6PD), superoxide dismutase (SOD), and MDA, which are markers associated with oxidative stress, in the blood samples of patients with acne. As a result of the study, CAT and G6PD levels were found to be statistically significantly lower in acne patients compared to the control group, while SOD and MDA levels were found to be statistically significantly higher.[23] Sarici et al. reported higher serum MDA levels, increased xanthine oxidase activity, decreased SOD, and CAT activity in acne patients compared to the control group.[24] Al-Shobaili et al.[25] reported high MDA levels and low total antioxidant capacity and SOD and CAT activity in acne patients. Moreover, they reported that MDA levels in patients with severe acne were higher than mild and moderate subgroups. Gürel et al.[26] reported higher ischemia modified albumin levels in patients with acne compared to the control group. Similarly, in our study, MDA levels, an indicator of oxidant status, were statistically significantly higher in patients with severe acne compared to the control group, while GSH levels, an indicator of antioxidant status, were statistically significantly lower [Table 3]. In our study, the levels of miRNAs related with oxidative stress were also investigated. To our best knowledge, this is the first study to investigate the levels of oxidative stress–related miRNAs in patients with severe acne. In recent years, the number of diseases involving miRNAs has increased dramatically and specific miRNAs have received increasing attention as potential biomarkers and therapeutic targets.[27] Recent studies have revealed that reactive oxygen derivatives modulate the biogenesis, transcription, and epigenetic modifications and by affecting expression levels of miRNAs are involved in the pathogenesis of various diseases such as cancer, neurodegenerative diseases, and cardiovascular diseases.[28],[29],[30] Reactive oxygen derivatives are commonly produced under inflammatory conditions to activate NF-κB. It has been validated that several miRNAs, including miRNA-21, miRNA-9, and miRNA-146, are directly transcriptionally regulated by NF-κB. Of these, miRNA-21 is one of the most studied oncogenic miRNAs. Reactive oxygen derivatives have been reported to induce miRNA-21 expression and functions, and NF-κB activation is thought to be one of the mechanisms of ROS-mediated miRNA-21 induction.[31] miRNA-21 is expressed at high levels in mammalian cells and is involved in the pathogenesis of different cancer types and various studies have reported that miRNA-21 contributes to apoptosis in both heart and lung tissues under oxidative conditions.[32] It also plays an important role in oxidative stress–related diabetic cardiomyopathy. Studies in different skin conditions have shown that miRNA-21 is upregulated in psoriasis and atopic dermatitis and is expressed both structurally and by inflammatory cells.[33],[34] In our study, it was shown that plasma miRNA-21 levels were statistically significantly increased in patients with severe acne compared to the control group [Table 3]. Another miRNA that has been shown to be regulated by NF-κB is miRNA-31.[35] miRNA-31 is involved in the neoplastic processes of various malignancies, including oral squamous cell carcinoma. Kao et al.[36] reported that miRNA-31 impairs mitochondrial activity and increases oxidative stress by targeting SIRT3 in oral carcinoma. Moreover, miRNA-31 has been reported to play a role in both lung and heart pathologies during oxidative stress. miRNA-31-5p expression has been found to induce hypoxia and oxidative damage in the heart, while miRNA-31-3p has been reported to play a protective role in the lung. After myocardial infarction, miRNA-31 gene silencing has been shown to improve left ventricular dysfunction and be beneficial; however, silencing of miRNA-31-3p has been reported to induce the production of reactive oxygen derivatives in lipopolysaccharide-treated lung cells.[32] In studies on skin diseases, it has been reported that miRNA-31 is the highest expressed miRNA in psoriatic skin keratinocytes. It has been shown that miRNA-31 expression is increased dramatically in psoriasis lesional skin compared to healthy skin and psoriasis nonlesional skin.[37] Transcription factor nuclear factor erythroid-derived 2-like 2 (Nrf2) and its inhibitor Kelch-like ECH-associated protein 1 (Keap1) are important regulators of oxidative stress response. Previous studies have reported that one of the miRNAs targeting the Nrf2 signaling pathway is miRNA-200a. Eades et al.[38] and Yang et al.[39] revealed the miR-200a and miR-28 could modulate Nrf2 expression via directly targeting Keap1 mRNA in breast cancer cells. Mateescu et al.[40] reported that miRNA-200a modulates ROS production by targeting p38a under oxidative stress and potentiates tumor growth and progression. In our study, it was shown that miRNA-31 and miRNA-200a levels were slightly higher in patients with severe acne compared to the control group but this difference was not statistically significant [Table 3].
| Conclusions | | |
Our findings suggest that oxidative damage is involved in the etiopathogenesis of acne and especially, miRNA-21 may have an important role in the pathogenesis of acne vulgaris. Furthermore, our data show that miRNA-21 regulation and the use of antioxidants in combination with various acne treatments may be beneficial, especially in severe acne. However, the limitation of our study is that a limited number of miRNA levels were investigated in a small number of patients. Further studies in a larger population are needed.
Acknowledgments
The authors would like to thank the Necmettin Erbakan University for funding this project.
Author contributions
F Humeyra Yerlikaya: Conceptualization, Funding acquisition, and Project administration; Duygu Eryavuz Onmaz: Data curation, Software, Writing–original draft, and Writing–review & editing; Hayriye Alp: Formal analysis; Berivan Unat: Investigation, Writing–original draft, and Software. All authors read and approved the final version of the manuscript.
Financial support and sponsorship
This work was supported by the Necmettin Erbakan University Scientific Research Projects Coordinator (grant numbers: Proje no: 181318003).
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3] |
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