E-IJD® - ORIGINAL ARTICLE
|Year : 2022 | Volume
| Issue : 5 | Page : 624
|Assessment of oxidative/nitrosative stress and raftlin in vitiligo
Mehmet K Mulayim1, Ergul B Kurutas2, Hulya Nazik1, Perihan Ozturk1
1 Department of Dermatology, Faculty of Medicine, Kahramanmaras Sutcu Imam University, Kahramanmaras, Turkey
2 Department of Biochemistry, Faculty of Medicine, Kahramanmaras Sutcu Imam University, Kahramanmaras, Turkey
|Date of Web Publication||29-Dec-2022|
Mehmet K Mulayim
Department of Dermatology, Sutcu Imam University Faculty of Medicine, Avsar Campus, 46100, Onikisubat, Kahramanmaras
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Vitiligo is a chronic skin disease characterized by white macules on the skin due to loss of melanocytes. Although there are many theories about the etiopathogenesis of the disease, oxidative stress is identified as an important determinant in the etiology of vitiligo. In recent years, Raftlin has been shown to play a role in many inflammatory diseases. Aims: The aim of this study was to compare the patients with vitiligo and the control group to determine both oxidative/nitrosative stress markers and Raftlin levels. Materials and Methods: This study was designed prospectively between September 2017 and April 2018. Twenty-two patients diagnosed with vitiligo and 15 healthy people as the control group were included in the study. Blood samples collected to determine oxidative/nitrosative stress, the antioxidant enzyme, and Raftlin levels were sent to the biochemistry laboratory. Results: In patients with vitiligo, the activities of catalase, superoxide dismutase, glutathione peroxidase, and glutathione S transferase were significantly lower than in the control group (P < 0.0001). In vitiligo patients, the levels of malondialdehyde, nitric oxide, nitrotyrosine (3-NTx), and Raftlin were significantly higher than in the control group (P < 0.0001). Conclusions: The results of the study support that oxidative stress and nitrosative stress may play a role in the pathogenesis of vitiligo. In addition, the Raftlin level, a new biomarker of inflammatory diseases, was found high in patients with vitiligo.
Keywords: Nitrosative stress, oxidative stress, pathogenesis, raftlin, vitiligo
|How to cite this article:|
Mulayim MK, Kurutas EB, Nazik H, Ozturk P. Assessment of oxidative/nitrosative stress and raftlin in vitiligo. Indian J Dermatol 2022;67:624
|How to cite this URL:|
Mulayim MK, Kurutas EB, Nazik H, Ozturk P. Assessment of oxidative/nitrosative stress and raftlin in vitiligo. Indian J Dermatol [serial online] 2022 [cited 2023 Feb 7];67:624. Available from: https://www.e-ijd.org/text.asp?2022/67/5/624/366143
| Introduction|| |
Vitiligo is a chronic skin disease characterized by the appearance of white macules on the skin, mucosa, and scalp due to the loss of melanocytes. Both sexes are affected equally. Its prevalence ranges from 0.1% to 8.8% worldwide.
The pathogenesis of vitiligo has not yet been fully elucidated. There are different theories to explain the loss of melanocyte activity. These are autoimmune theory, cytotoxic theory, biochemical theory, oxidant-antioxidant theory, viral theory, growth factor theory, chronic pressure theory, nerve theory, genetic theory, and convergence theory.,
In recent years, oxidative stress has become prominent in the etiology of vitiligo. An increase in reactive oxygen species (ROS) was observed in the lesional and non-lesional skin of the vitiligo patients. Nitric oxide (NO) and nitrotyrosine (3-NTx) are known as reactive nitrogen species (RNS). Low ROS/RNS levels are required for various biological processes. Increased ROS/RNS formation and/or decreased antioxidant defense may damage cellular components in a process called oxidative/nitrosative stress.
This possible damage of ROS may be prevented by antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione S transferase (GST). Lipid peroxidation is one of the most important expressions of ROS-induced oxidative stress. Malondialdehyde (MDA) is an indicator of lipid peroxidation which increases in a variety of diseases. Increased oxidative stress has been proposed as a mechanism that plays a role in the etiopathogenesis of vitiligo by inducing melanocyte destruction due to excessive production of ROS.
One of the major lipid rafts, Raftlin, was first identified in Raji B cells and is essential to the integrity of the lipid rafts. Raftlin has been shown to play an important role in many processes, such as membrane viscosity, signal transduction, and regulation of apoptosis. In addition, Raftlin plays a role in the toll-like receptor 3 activation and autoimmune response. The role of lipid raft in the pathophysiology of inflammatory responses led to our assumption that Raftlin may play a role in the pathogenesis of vitiligo.
As far as we know, although there are studies on oxidative stress in vitiligo, there is no study in which both oxidative stress and nitrosative stress are studied and the Raftlin level is examined. This study aims to compare oxidative/nitrosative stress markers (MDA/NO and 3-NTx), antioxidant (SOD, CAT, GPx, and GST) response levels and Raftlin levels, a new biomarker in inflammatory diseases, of the vitiligo patients with the control group.
| Materials and Methods|| |
This study was approved by the Scientific and Clinical Researches Ethics Committee of the Kahramanmaras Sutcu Imam University Medical Faculty. The legal guardians of those under the age of 18 and all subjects who were included in the study provided informed written consent.
The study included 22 patients who attended the dermatology outpatient clinic of the Kahramanmaras Sutcu Imam University Medical Faculty Hospital between September 2017 and April 2018 and were diagnosed with vitiligo by clinical examination and Wood's lamp examination. All of the patient groups were non-segmental vitiligo patients. Patients who used systemic or topical treatment at least 1 month before starting the study were excluded from the study. Fifteen healthy people without any systemic or dermatological diseases were included as the control group. There was no family history of vitiligo in the first- and second-degree relatives of the healthy controls. There was no smoking, alcohol use, or any medication use in the patient and control groups. Calculating with GPower 3.1 (http://www.gpower.hhu.de/) gives a power of 80% with alpha = 0.05 when comparing the two means using student t test with a total sample size of 18 patients (patient/control: 9/9).
Blood samples were taken from 22 patients and 15 control individuals. The samples were centrifuged at 3000 g for 10 min at 4°C. The plasma was separated and the buffy coat was discarded by aspiration. The erythrocytes were washed four times with cold physiological saline solution and stored at −70°C until analysis. The CAT activity in the erythrocyte was measured in samples by the method applied by Beutler. The decomposition of the substrate hydrogen peroxide was monitored spectrophotometrically at 240 nm. The activity of CAT was expressed as U/g Hb. The SOD activities in the erythrocyte were estimated using the method described by Fridovich. The SOD activity was expressed as U/g Hb. The GST activity was measured spectrophotometrically at 340 nm by the method of Habig et al. with 1-Chloro-2,4-dinitrobenzene as a substrate. GST was calculated as U/g Hb. The lipid peroxidation level in the plasma samples was expressed in MDA. The measurement was based on the method of Ohkawa. The MDA levels were expressed as nmol/mL. NO, 3-NTx, and the Raftlin levels in the plasma samples were determined with sandwich enzyme linked immunosorbent assay kits (MyBioSource human ELISA kits, USA), according to the manufacturers' protocol. The 3-NTx levels were given as nmol/L.
The SPSS 22.0 (SPSS, Chicago, IL) software package was used to evaluate the data obtained in the study. Continuous data were summarized as mean and standard deviation while categorical data were summarized as counts and percentages. The Chi-square test was used for categorical variables and the Mann–Whitney U test for numerical variables. The receiver operating characteristic (ROC) curve was used to investigate the accuracy of Raftlin, CAT, SOD, MDA, GPx, GST, NO, and 3-NTx in indicating vitiligo. To investigate the accuracy of the test, sensitivity, specificity, and 95% confidence intervals were calculated and presented in a tabular form. Any P values below 0.05 were considered statistically significant.
| Results|| |
A total of 37 cases, namely 22 (59.5%) patients with vitiligo and 15 (40.5%) control groups, were included in the study. Within the vitiligo group, 45.5% (n = 10) of the patients were female and 54.5% (n = 12) were male. Within the control group, 53.3% (n = 8) of the individuals were female and 46.7% (n = 7) were male. The mean ages of the vitiligo group and the control group were 35.6 ± 16.8 years (min-max: 10–65 years) and 29.6 ± 9.2 years (min-max: 17–47 years), respectively. There was no statistically significant difference between the groups regarding gender and age (the P values were 0.222 and 0.435, respectively).
The median, minimum, and maximum values of Raftlin, CAT, SOD, MDA, GPx, GST, NO, and 3-NTx of the patient and the control groups are shown in [Table 1].
|Table 1: Median, minimum, and maximum values of Raftlin, CAT, SOD, MDA, GPx, GST, NO, and 3-NTx of the patient and control groups|
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The mean standard deviation of the Raftlin values was statistically significantly higher in the vitiligo group (P < 0.0001) (ROC curve analysis for Raftlin is presented graphically in [Figure 1]). The mean standard deviation of the CAT values was statistically significantly lower in the vitiligo group (P < 0.0001). The mean standard deviation of the SOD values was statistically significantly lower in the vitiligo group (P < 0.0001). The mean standard deviation of the MDA values was statistically significantly higher in the vitiligo group (P < 0.0001) (ROC curve analysis for MDA is presented graphically in [Figure 2]). The mean standard deviation of the GPx values was statistically significantly lower in the vitiligo group (P < 0.0001). The mean standard deviation of the GST values was statistically significantly lower in the vitiligo group (P < 0.0001). The mean standard deviation of the NO values was statistically significantly higher in the vitiligo group (P < 0.0001) (ROC curve analysis for NO is presented graphically in [Figure 3]). The mean standard deviation of the 3-NTx values was statistically significantly higher in the vitiligo group (P < 0.0001) (ROC curve analysis for 3-NTx is presented graphically in [Figure 4]).
|Figure 2: ROC curve for malondialdehyde area under the curve value of 1.0|
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|Figure 3: ROC curve for nitric oxide area under the curve value of 0.982|
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|Figure 4: ROC curve for nitrotyrosine area under the curve value of 0.997|
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While the CAT, SOD, GPx, and GST values were significantly lower, Raftlin, MDA, NO, and 3-NTx values were significantly higher in the vitiligo group compared with the control group. The cut-off, sensitivity, specificity, and area under the curve (AUC) values of Raftlin, MDA, NO, and 3-NTx, which are found to be statistically significant in indicating vitiligo, are given in [Table 2]. In this table, markers with AUC values below 0.5 (CAT, SOD, GPx, and GST) were not used.
|Table 2: Cut-off, sensitivity, specificity, AUC, 95% CI, and P values of Raftlin, MDA, NO, and 3-NTx in indicating vitiligo|
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| Discussion|| |
The etiology and pathogenesis of vitiligo remain unclear. Understanding etiopathogenesis may help prevent treatment failure and find new treatment modalities. Although there are many theories about the etiopathogenesis of vitiligo, there is strong evidence that oxidative stress plays a pivotal role in the onset and progression of the disease.
As far as we know, this study is the first study measuring both oxidative/nitrosative stress markers such as SOD, CAT, MDA, GPx, GST, NO, and 3-NTx, as well as Raftlin levels, a new biomarker of inflammatory diseases, in patients with vitiligo. The results of our study show that both oxidative stress and nitrosative stress are increased and Raftlin levels are enhanced in vitiligo.
Both oxidative and nitrosative stress are associated with the formation of free radicals. In 1956, Denham Harman, an American gerontologist, first described free radicals as compounds involved in processes that lead to cell damage, mutagenesis, tumor development, and biological aging. Free radical production in the cell occurs continuously during metabolism. These radicals, ROS (such as superoxide anion, hydroxyl radical, and hydrogen peroxide) and RNS (such as, NO and peroxynitrite anion), are highly reactive and therefore potentially harmful biomolecules. ROS and RNS are essential for physiological processes such as signal transduction, gene transcription, and host defense but are also associated with pathological conditions. Cellular oxygen is highly reactive and is reduced to less reactive hydrogen peroxide via the SOD enzyme, which is reduced to water and oxygen by the CAT enzyme. In addition, ROS is neutralized by enzymes such as, GPx and GST. Therefore, the measurement of levels and/or enzymatic activity of SOD, CAT, GPx, and GST are an useful indicator of cellular oxidative stress.,
Different research groups have reported conflicting results regarding SOD, CAT, GPx, GST, NO, 3-NTx, and MDA levels in vitiligo patients. Passi et al. showed that oxidative stress causes damage to epidermal cells and suggested that antioxidant therapy may play a role in the treatment of vitiligo.
Arican et al. and Yildirim et al. reported that the SOD activity in the erythrocytes was significantly higher in patients with vitiligo than in the control group. Dell'Anna et al. found higher SOD activity in the leukocytes of vitiligo patients. Similarly, Maresca et al., Hazneci et al., Jain et al., and Ozel Turkcu et al. observed that blood SOD activity was significantly higher in vitiligo patients than in healthy controls. Taştan et al. reported that there was no statistically significant difference in the SOD activity between the lesional tissue and the non-lesional tissue in vitiligo patients. However, Koca et al. showed that the SOD activity in the blood of patients with vitiligo is lower than in the control group. In our study, the SOD activity in the erythrocytes was statistically significantly lower in patients with vitiligo than in the control group. We believe that the discrepancies observed in the results may be associated with differences in serum, leukocyte, erythrocyte and epidermis levels, duration and activity of the disease, and differences in laboratory techniques.
Many studies on the effectiveness of CAT enzyme activity in vitiligo have been carried out in tissue, blood, and serum. Liu et al., Maresca et al., and Ozel Turkcu et al. observed that the patients with vitiligo have lower serum CAT activity than the control group. Dell'Anna et al. reported that the CAT activity is low in the leukocytes of vitiligo patients. Arican et al. reported that the CAT activity is low in the erythrocytes of localized vitiligo patients. Low CAT activity was observed in the lesional and normal skin of segmental vitiligo, as well as in the cultured melanocytes, leading to the accumulation of epidermal hydrogen peroxide., Hazneci et al. and Sravani et al. reported that the CAT activity is low in the skin and blood of vitiligo patients. Schallreuter et al. found decreased CAT activity in the affected and unaffected skin of vitiligo patients. In line with other studies, the CAT activity in patients with vitiligo was also statistically significantly lower than in the control group in our study.
ROS is neutralized by GPx in a reaction that converts cellular antioxidant glutathione from its reduced state to its oxidized form. In studies of vitiligo mouse models, it was found that GPx, SOD, and CAT enzyme activities that clear free oxygen radicals causing oxidative stress were low. A study reported that in patients with vitiligo up to the age of 46, the GPx activity was lower compared with the control group, while there was no significant difference in the vitiligo group after the age of 46 compared with the control group. Jalel et al. showed that patients with vitiligo have low GPx enzyme activity. In accordance with other studies, in our study, the GPx activity in the erythrocytes was statistically significantly lower in vitiligo patients than in the control group.
GST consists of isoenzymes involved in the defense mechanisms against oxidative stress. GST may detoxify various compounds produced by damage to cells caused by ROS. Liu et al. reported that the absence of the GST gene (especially the GST-T1 and M1 genes) could be a risk factor for vitiligo. In our study, the GST activity in the erythrocytes was also statistically significantly lower in vitiligo patients than in the control group.
MDA is a product of ROS-induced lipid peroxidation and is considered a specific indicator of oxidative stress. Picardo et al. and Tastan et al. found that MDA levels are normal in the erythrocytes of vitiligo patients. Arican et al., Yıldırım et al., and Koca et al. showed that serum MDA levels were high in vitiligo patients. In another study, the MDA level was reported to be high in the tissues of patients with vitiligo. Laddha et al. reported the importance of oxidative stress and high lipid peroxidation levels in vitiligo patients. In accordance with other studies, in our study, the MDA level in the vitiligo group was also statistically significantly higher than in the control group. In addition, our study shows that the MDA level has an auxiliary diagnostic value for vitiligo with high sensitivity and specificity compared with the ROC curve analysis.
The results of our study support that oxidative stress may play a role in the etiopathogenesis of vitiligo due to both decreased activity of antioxidant enzymes such as, SOD, CAT, GPx, and GST and increased MDA levels which indicate lipid peroxidation due to oxidative stress.
Like ROS, RNS may play an important role in the pathogenesis of various diseases. The most important markers of nitrosative stress are NO and 3-NTx. Low NO levels generally have a beneficial effect and protect against cell death. High NO levels may damage cellular components and induce apoptosis. A study showed that NO-induced apoptosis may be the reason for the decrease in the number of melanocytes in vitiligo. It has been stated that NO may cause skin depigmentation by causing auto-destruction of melanocytes in cultured human melanocytes. Yildirim et al. reported that the NO level in erythrocytes increased significantly in patients with vitiligo compared with the control group. Another study reported that there was no statistically significant difference between the NO levels in the tissue of patients with vitiligo and the NO levels of the healthy control group. In our study, the NO level in the vitiligo group was statistically significantly higher than in the control group. In addition, our study shows that the NO level is an auxiliary diagnostic value for vitiligo with high sensitivity and specificity compared with the ROC curve analysis.
The 3-NTx is a characteristic marker of nitrosative stress and a common mark of inflammation. NO and 3-NTx levels have been reported to be high in various skin diseases such as, skin cancers, systemic lupus erythematosus, psoriasis, urticaria, and atopic dermatitis. In addition, levels of 3-NTx have been shown to increase in the tissue with vitiligo. Another study emphasized that 3-NTx may play a role in the pathogenesis of vitiligo due to its effects on mitochondrial Deoxyribonucleic acid (DNA). In our study, the 3-NTx level in the vitiligo group was statistically significantly higher than in the control group. Furthermore, our study shows that the 3-NTx level is an auxiliary diagnostic value for vitiligo with high sensitivity and specificity compared with the ROC curve analysis.
Our study showed that nitrosative stress is increased in vitiligo as a result of high NO and 3-NTx levels in vitiligo patients. This supports that nitrosative stress may play a role in the etiopathogenesis of vitiligo.
Membrane microdomains known as lipid rafts have been shown to act as platforms for the initiation of various receptor signals. Saeki et al. described a new protein called Raftlin (raft-linking protein) as a major protein in lipid rafts. The Raftlin B cell identified in Raji B cells is responsible for regulating the signal transmission of antigen receptors. It was shown that Raftlin modulates the signals of T cell receptors and is also necessary for fine-tuning T cell-mediated immune responses. It has also been shown that excessive Raftlin expression may play a role in the development or progression of T cell-mediated immune diseases. Apart from lipid rafts in B and T cells, Raftlin is also localized in the cytoplasm of human epithelial cells. Tatematsu et al. showed that Raftlin plays a role in both innate and adaptive immunity depending on the cell type.
There is a limited number of studies on Raftlin. As far as we know, there is no similar study conducted in vitiligo patients and therefore, we could not compare our results with those of others. However, some studies on Raftlin have reported that Raftlin plays a possible role in neuronal degeneration in Alzheimer's disease. Lee et al. stated that the level of Raftlin in septic patients is associated with the severity of sepsis and may represent a new marker of endothelial cell dysfunction. The authors also stated that Raftlin may be used as a biomarker to determine the severity of sepsis. Ozer et al. observed that Raftlin levels were significantly higher in patients with appendicitis than in healthy controls and stated that Raftlin may be a new diagnostic parameter that may be used in inflammatory diseases. Bilgen et al. studied Raftlin levels in wound healing and showed that the levels of Raftlin in tissue were significantly higher in patients with a wound than in the control group.
In our study, the Raftlin level was statistically significantly higher in the vitiligo group than in the control group. Moreover, our study shows that the level of Raftlin is an auxiliary diagnostic value for vitiligo with high sensitivity and specificity compared with the ROC curve analysis.
We believe that there is melanocyte destruction in vitiligo because of free radical-mediated inflammation due to oxidative stress and nitrosative stress and Raftlin levels increase due to this inflammation. Raftlin may be a new biomarker in the demonstration of inflammatory diseases such as vitiligo. However, new studies including larger series are warranted on this subject.
The first is that this study had limited number of patients. Another important limitation is the absence of posttreatment oxidative/nitrosative stress markers and Raftlin levels due to the cross-sectional design of the study.
| Conclusion|| |
We can suggest that oxidative and nitrosative stress may play a role in the pathogenesis of vitiligo by causing melanocyte damage. Therefore, we suggest that additional treatments containing antioxidants may be beneficial in vitiligo patients to reduce oxidative stress and nitrosative stress. Furthermore, our results may be considered as a preliminary study for studies with larger populations and pre/posttreatment values to determine the role of Raftlin in vitiligo etiopathogenesis.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
This study was financially supported by the Kahramanmaras Sutcu Imam University Scientific Research Project unit (Project No.: 2016/3-60 M).
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2]
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