10.5826/dpc.1304a280
Introduction: Acne vulgaris (AV) is the most common skin disease. AV is a skin disease often associated with oxidative stress. Thiols and ischemia modified albumin (IMA) analysis are used as oxidative stress markers.
Objectives: In this study, it was aimed to evaluate the blood levels of thiols and IMA, which are accepted as oxidative stress markers, and to determine the severity of the disease in AV patients whose severity is determined by the global acne score rate (GAS).
Methods: Thiol parameters and IMA values ​​were measured spectrophotometrically in blood samples taken from patients and controls. Determine VAS values ​​in AV patients. The thiol and IMA values ​​obtained were compared between the patient and control groups and their correlation with the patient's VAS values ​​was evaluated.
Results: In our study, in acne patients, native thiol (NT), total thiol (TT) and index 3 (I3=NT/TT*100) were significantly lower than the control group, disulfide (SS), index 1 (I1=SS/NT*100), index 2 (I2=SS/TT*100) and IMA values were found to be significantly higher. GAS values, which are accepted as an indicator of the degree and severity of acne disease, and SS, I1 and I2 showed a positive correlation, while I3 showed a negative correlation.
Conclusion: Our study suggests that oxidative stress associated with AV disease pathogenesis may occur through mechanisms dependent on thiol and IMA levels. Therefore, in AV, oral supplementation or topical application of antioxidants may be a good way to increase drug efficacy or prevent potential harm.
text/xml
2160-9381
3399
en
Mustafa  Tunca
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
IMA
Evaluation of Thiol Disulfide Homeostasis and Ischemia-Modified Albumin Levels as an Indicator of Oxidative Stress in Acne Vulgaris
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Original Article
2023-10-31
2023-04-05
2023-10-31
2024-01-16
e2023280
Dermatol Pract Concept
Introduction: Acne vulgaris (AV) is the most common skin disease. AV is a skin disease often associated with oxidative stress. Thiols and ischemia modified albumin (IMA) analysis are used as oxidative stress markers.
Objectives: In this study, it was aimed to evaluate the blood levels of thiols and IMA, which are accepted as oxidative stress markers, and to determine the severity of the disease in AV patients whose severity is determined by the global acne score rate (GAS).
Methods: Thiol parameters and IMA values ​​were measured spectrophotometrically in blood samples taken from patients and controls. Determine VAS values ​​in AV patients. The thiol and IMA values ​​obtained were compared between the patient and control groups and their correlation with the patient's VAS values ​​was evaluated.
Results: In our study, in acne patients, native thiol (NT), total thiol (TT) and index 3 (I3=NT/TT*100) were significantly lower than the control group, disulfide (SS), index 1 (I1=SS/NT*100), index 2 (I2=SS/TT*100) and IMA values were found to be significantly higher. GAS values, which are accepted as an indicator of the degree and severity of acne disease, and SS, I1 and I2 showed a positive correlation, while I3 showed a negative correlation.
Conclusion: Our study suggests that oxidative stress associated with AV disease pathogenesis may occur through mechanisms dependent on thiol and IMA levels. Therefore, in AV, oral supplementation or topical application of antioxidants may be a good way to increase drug efficacy or prevent potential harm.
Mustafa  Tunca
2023/10/31
10.5826/dpc.1304a280
e2023280
Health Sciences University Gulhane Training and Research Hospital Department of Dermatology, Ankara, Turkey
2160-9381
IMA
en
e2023280
Tunçez Akyürek F, Saylam Kurtipek G, Kurku H, et al. Assessment of ADMA, IMA, and Vitamin A and E Levels in Patients with Acne Vulgaris. J Cosmet Dermatol. 2020;19(12):3408-3413. DOI:10.1111/jocd.13590. PMID: 32623816.
Evaluation of Thiol Disulfide Homeostasis and Ischemia-Modified Albumin Levels as an Indicator of Oxidative Stress in Acne Vulgaris
https://dpcj.org/index.php/dpc/article/download/3399/2356
           Evaluation of Thiol Disulfide Homeostasis
         and Ischemia-Modified Albumin Levels as an
         Indicator of Oxidative Stress in Acne Vulgaris
   Zeynep Büşra Balık1, Ahmet Rıfat Balık2, Esra Fırat Oğuz3, Özcan Erel3, Mustafa Tunca1


1 Health Sciences University Gulhane Training and Research Hospital Department of Dermatology, Ankara, Turkey
2 Health Sciences University Gulhane Training and Research Hospital Department of Medical Biochemistry, Ankara, Turkey
3 Ankara City Hospital Department of Medical Biochemistry, Ankara, Turkey



Key words: acne vulgaris, oxidative stress, thiols, IMA
Citation: Balık ZB, Balık AR, Oğuz EF, Erel Ö, Tunca M. Evaluation of Thiol Disulfide Homeostasis and Ischemia-Modified
Albumin Levels as an Indicator of Oxidative Stress in Acne Vulgaris. Dermatol Pract Concept. 2023;13(4):e2023280. DOI: https://
doi.org/10.5826/dpc.1304a280
Accepted: July 4, 2023; Published: October 2023
Copyright: ©2023 Balık et al. This is an open-access article distributed under the terms of the Creative Commons
Attribution-NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted
noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited.
Funding: None.
Competing Interests: None.
Authorship: All authors have contributed significantly to this publication.
Corresponding Author: Zeynep Büşra Balık: Health Sciences University Gulhane Training and Research Hospital Department of
Dermatology, Ankara/Turkey, E-mail: zeynepbusrakucuker@gmail.com




  ABSTRACT             Introduction: Acne vulgaris (AV) is the most common skin disease. AV is a skin disease often associ-
                       ated with oxidative stress. Thiols and ischemia modified albumin (IMA) analysis are used as oxidative
                       stress markers.
                       Objectives: In this study, it was aimed to evaluate the blood levels of thiols and IMA, which are ac-
                       cepted as oxidative stress markers, and to determine the severity of the disease in AV patients whose
                       severity is determined by the global acne score rate (GAS).
                       Methods: Thiol parameters and IMA values were
                                                                   ​​  measured spectrophotometrically in blood samples
                       taken from patients and controls. Determine GAS values in
                                                                              ​​ AV patients. The thiol and IMA values ob-
                                                                                                                       ​​
                       tained were compared between the patient and control groups and their correlation with the patient’s
                       GAS values was
                                   ​​  evaluated.
                       Results: In our study, in acne patients, native thiol (NT), total thiol (TT) and index 3 (I3=NT/TT*100)
                       were significantly lower than the control group, disulfide (SS), index 1 (I1=SS/NT*100), index 2 (I2=SS/
                       TT*100) and IMA values were found to be significantly higher. GAS values, which are accepted as an
                       indicator of the degree and severity of acne disease, and SS, I1 and I2 showed a positive correlation,
                       while I3 showed a negative correlation.
                       Conclusions: Our study suggests that oxidative stress associated with AV disease pathogenesis may occur
                       through mechanisms dependent on thiol and IMA levels. Therefore, in AV, oral supplementation or top-
                       ical application of antioxidants may be a good way to increase drug efficacy or prevent potential harm.


Original Article | Dermatol Pract Concept. 2023;13(4):e2023280                                                                    1
Introduction                                                       Methods
Acne vulgaris (AV) is the most common skin disease. In             Study Population
general, AV is a time-varying disease of the skin. It can also     A total of 43 patients were identified at the beginning of the
cause years of physical (wound growth) and psychological           study. One patient was excluded because he used benzoyl
discomfort [1]. In addition to other causes such as hyperker-      peroxide for acne and six patients used the topical agents.
atosis, increased sebum secretion and immune system, recent        Six patients were excluded from the study because they were
research has linked oxidative stress to AV diseases [2-5]. It      taking medication for different types of acne. Another 30 pa-
has been reported that sebum oxidation and oxidative stress        tients completed the study. In addition, those under the age
in the pilosebaceous unit provide an environment that can          of 18 and over the age of 65, those with metabolic disease,
cause some acne-causing bacteria [6]. An imbalance in the          those with severe or chronic diseases, those with blood dis-
production of oxygen-derived prooxidants, also known as            eases, those with malignancies, those who are pregnant and
reactive oxygen species (ROS), is thought to cause oxidative       breastfeeding, and those who received medical treatment for
stress and the potency of ROS [7].                                 diseases other than acne were excluded from the study.
    It is well documented that oxidative stress is involved in        Thirty healthy individuals were included in the study as
the pathogenesis of many diseases, including skin diseases.        the control group. Demographic characteristics of all par-
Various markers are available to measure oxidative stress.         ticipants were recorded. This study was approved by the
Recent studies have shown that ischemia modified albumin           Ethics Committee (approval number: 19/369) and written
(IMA) is not only an indicator of ischemia, but also a marker      informed consent was obtained from all participants in ac-
of oxidative stress. The N-terminal region of the albumin          cordance with the principles of the Declaration of Helsinki.
molecule binds divalent heavy metals such as nickel, copper,
cobalt. Hydroxylated radicals damage the N-terminal region
                                                                   Determination of Global Acne Scores (GAS)
of the albumin molecule and albumin cannot bind divalent
                                                                   To determine the severity of acne, it is divided into facial
heavy metals [8].
                                                                   and upper chest and under-back sections, and a coefficient
    Another indicator of exposure to oxidative stress is thi-
                                                                   is given for each area, including the width and density of the
ols. Thiols are susceptible to oxidation due to “-SH’’ groups.
                                                                   area and the distribution of pilosebaceous units (forehead,
Thiols are evaluated under three groups. The first of these
                                                                   right cheek and left cheek = 2, nose and chin = 1, chest and
are native thiols (NT). Native thiols oxidize to a second thiol
                                                                   upper back = 3). Acne lesions were also graded 0-4 according
group called disulfides (SS) when exposed to ROS. Therefore,
                                                                   to their type (no lesion = 0, ≥1 comedones = 1, ≥1 papules =
the decrease of native thiol groups and increase of disulfide
                                                                   2, ≥1 pustules = 3, ≥1 nodules = 4). Each region was analyzed
groups after oxidation is considered as an indicator of strong
                                                                   separately, and the global acne score was calculated by mul-
oxidative stress. The sum of the native thiols and disulfides
                                                                   tiplying the region coefficient by the maximum number of
forms the third thiol group called total thiols (TT) [9].
                                                                   lesions in that region to determine the score of each region.
    Global Acne Score (GAS) is an index that aims to deter-
                                                                   Acne severity was determined by the total number of acne
mine the severity of pain in patients by measuring AV disease
                                                                   scars (0 = no acne, 1-18 = mild acne, 19-30 = moderate acne,
[10]. In this measure to determine severity of acne, the face is
                                                                   31-38 = severe acne, >39 = severe acne) [11].
divided into upper chest and lower back sections and a coef-
ficient is given for each area, including the width of the area
where dense pilosebaceous units are found [11].                    Sample Collection and Measurement of Parameters
                                                                   After a 12-hour fast, take venous blood from the partici-
                                                                   pants in the vein. Blood collected for analysis was centri-
Objectives
                                                                   fuged at 3500xg for 10 minutes. The separated sera were
Many studies have been conducted on Thiol and IMA [9,12].          divided into Eppendorf dishes and stored in a deep freezer
However, until now, the effects of oxidative stress in AV pa-      at -80°C until analysis. On the day of examination, all blood
tients have not been evaluated by simultaneous measurement         samples were simultaneously removed from the refrigerator
of thiol and IMA levels. In this study, we aimed to evaluate       and thawed at room temperature for 20 minutes. Then the
the oxidative stress level in AV patients using biochemical        blood is homogenized and prepared for analysis using the
parameters. In addition, we aim to determine the severity of       vortexing technique.
AV disease with the GAS method and evaluate it according              Blood samples from patients and controls were tested
to its correlation with the indicators.                            spectrophotometrically for IMA and Thiols (NT, TT and SS)




2                                                                      Original Article | Dermatol Pract Concept. 2023;13(4):e2023280
                   Table 1. Comparison of parameters between patient and control groups.
     Parameters                   Patient Group (Mean±SD)                          Control Group (Mean±SD)                   P
 Native Thiol                            332.89±51.62                                      372.58±34.43                   0.001
 Total Thiol                             378.29±48.33                                      411.93±37.06                   0.004
 Disulfide                                 22.70±7.64                                       19.68±2.05                    0.041
 Index 1                                   7.10±3.22                                        5.30±0.46                     0.005
 Index 2                                   6.09±2.32                                        4.78±0.38                     0.004
 Index 3                                   87.82±4.65                                       90.43±0.76                    0.005
 IMA                                      0.624±0.010                                      0.618±0.012                    0.034

IMA = Ischemia-modified Albumin; SD = Standard Deviation.

Index 1: Disulfide/Native Thiol*100, Index 2: Disulfide/Total Thiol*100, Index 3: Native Thiol/Total Thiol*100.



 Table 2. Correlation data of Global Acne Score                       was found that NT, TT and I3 values ​​in patient group were
    (GAS) values with measured parameters.                            lower than the control group (P values ​​0.001, 0.004, 0.005,
               Disulfide     Index 1      Index 2      Index 3        respectively).
         r      0.406         0.369        0.369       (-) 0.371          The SS, I1, I2 and IMA patient groups were higher than
 GAS                                                                  the control group (P values 0.041, 0.005, 0.004, 0.034, re-
         P      0.026         0.045        0.045        0.044
                                                                      spectively) (Table 1).
GAS = Global Acne Score.                                                  While GAS values in the patient group were positively
Index 1: Disulfide/Native Thiol*100, Index 2: Disulfide/Total         correlated with SS, I1 and I2, they were negatively correlated
Thiol*100, Index 3: Native Thiol/Total Thiol*100.                     with I3 (Table 2).



on a Siemens Advia 1800 automated analyzer under the
                                                                      Conclusions
same conditions and all results were closed (13,14). Cal-             In our study, NT, TT and I3 decreased in AV patients com-
culate and record indicators for the thiol index (Index 1 =           pared to controls, while SS, I1, I2 and IMA values increased.
I1: SS/NT*100, Index 2 = I2: SS/TT*100, Index 3 = I: NT/              GAS values showed a positive correlation with SS (Figure 1),
TT*100).                                                              I1 and I2, while I3 showed a negative correlation. These
                                                                      results clearly demonstrate a change from NT (-SH) to SS
Statistical Analysis                                                  (-S-S-) due to oxidative stress in AV patients. This change
IBM SPSS Statistic V.22 program was used for all statistical          increases as acne progresses. At the same time, albumin
analyses. Shapiro-Wilk test was used for normality test. Re-          oxidation increases in acne patients, causing IMA levels to
sults are shown as mean ± SD as they are parametric data.             increase.
Student’s t test was used for statistical analysis. Correlations          AV is a chronic disease of the pilosebaceous glands
between statistical variables were made using the Pearson test.       that affects young people. The main mechanisms of acne
The significance value was accepted as P < 0.05 in all tests.         are altered keratinization of pilaris, hypersebum secretion,
                                                                      inflammation, and colonization of pilosebaceous ducts by

Results                                                               Cutibacterium acnes [15]. In all its stages, there is an in-
                                                                      flammatory process. AV is now recognized as a primary in-
In the study, there were no gender (P 0.601) and age                  flammatory disease. Healthy skin in acne patients refers to
(P 0.134) difference between the patient group (age; 22.93            subclinical inflammation before lesions appear [16].
±5 .13, 11 men/29 women) and the control group (age; 24.4                 ROS are toxic molecules that play an important role in
0± 4.37, 13 men/27 women). It was determined that stress              many skin diseases [17,18]. Oxidative stress is known to
in 5 patients, fatty food in 8 patients, menstruation in 2 pa-        affect many aspects of the skin [19]. According to recent
tients, epilation in 1 patient and laser application in 1 patient     studies, tissue damage with reactive oxygen species is one of
caused acne.                                                          the main factors affecting the pathogenesis of acne. Protein
    According to GAS data (19.83 ± 6.103), 12 cases of mild           oxidation, lipid peroxidation, and nitrosative stress increase
acne, 17 cases of moderate acne, and 1 case of severe acne. It        in acne patients and are associated with disease activity [3].




Original Article | Dermatol Pract Concept. 2023;13(4):e2023280                                                                    3
                                                                    levels of SOD and GSH compared to healthy controls [3].
                                                                    Moazen et al MDA levels were found to be higher in acne
                                                                    patients [29]. Perryhan et al increased levels of antioxidant
                                                                    enzymes found in scraping samples from acne patients. They
                                                                    think this may be the body’s local response to increased oxi-
                                                                    dative stress. They also found that oxidative stress increased
                                                                    with disease severity [4]. In another study, it was noted that
                                                                    oxidative stress biomarkers were higher in AV lesions and
                                                                    showed a positive correlation with acne severity. In addition,
                                                                    a decrease in antioxidant enzymes (SOD, CAT) has been
                                                                    observed in acne [24]. In one study, Al-Shobaili found that
                                                                    acne patients had higher plasma MDA levels and lower lev-
                                                                    els of the antioxidant enzymes SOD and CAT compared to
                                                                    controls. In addition, it was found that the total antioxidant
Figure 1. Correlation of Global Acne Score (GAS) values with di-    capacity (TAC) in acne patients was lower than in controls.
sulfide results.                                                    Although higher MDA levels were observed in the severe
                                                                    acne group compared to the mild and moderate groups,
                                                                    there was a negative correlation between MDA and CAT in
Propionibacterium acnes is involved in the pathogenesis of          the severe acne group [2]. All these studies using different
acne, secretes some chemokines to stimulate the accumula-           levels of oxidative stress in AV patients support our results
tion of neutrophils, and releases some bacteria such as lyso-       and clearly show that oxidative stress is present in acne and
somal enzymes through phagocytosis, causing inflammation            may play an important role in their disease.
of fur cover follicle epithelial cells. ROS is released by active      Dynamic thiol-disulfide homeostasis has been studied for
neutrophils in inflamed tissues. These oxidants attack and          different organisms. It found that the prevalence of SS was
damage DNA and/or membrane lipids, including those in               higher in people with obesity, lung disease, and inflamma-
healthy tissues [17,20,21]. Reactive oxygen species synthe-         tory diseases such as diabetes [14]. Doru et al NT levels were
sized by neutrophils are closely related to the pathogenesis        found to be lower in patients with ankylosing spondylitis
of many skin diseases [2,22,23]. Squalene, unique to human          [30]. In another study, Kundi et al found a relationship be-
sebum, protects the skin surface from lipid peroxidation, ie        tween disease severity and thiol levels in patients with ath-
substances that cause comedogenic effects, and is present in        erosclerosis and found that mortality was higher in patients
high concentrations in open or closed comedones [21]. In ad-        with low thiol levels [31]. Kaplan et al were determined that
dition, sebocytes and keratinocytes secrete proinflammatory         celiac patients had lower TT and NT levels and higher SS, I1
cytokines (IL-1alpha, IL-8, TNF-alpha) in response to lipo-         and I2 rates compared to controls [32]. It is also the study of
polysaccharide in the Bacillus acnes test. Thus, the inflam-        thiol-disulfide homeostasis, skin diseases such as psoriasis,
matory process contributes to the formation of acne lesions.        seborrheic dermatitis, atopic dermatitis, leukoplakia, lichen
Kart et al have been suggested that oxidative stress plays a        planus and rosacea. A unique aspect of these findings is the
role in the pathogenesis of acne vulgaris through various           implication of thiol-disulfide homeostasis as an indicator of
pathways such as PPAR, TLR and mTOR [24].                           oxidative stress [33]. On the other hand, Güler et al in their
    Arican et al. spectrophotometric measurement of oxi-            study, they found that AV patients had a lower TT and I2 ra-
dative stress such as catalase (CAT), glucose-6-phosphate           tio, similar to our results, and concluded that the antioxidant
dehydrogenase (G6PD), superoxide dismutase (SOD) and                defense of AV, an inflammatory disease, was low [34]. These
malondialdehyde (MDA) in acne patients and determination            studies show that oxidative stress plays an important role in
of oxidative stress in acne patients [23]. Basak et al. decreased   the development of acne and can be used as a biomarker to
leukocyte antioxidant levels and increased lipid peroxidation       evaluate the disease and monitor its treatment.
in AV patients [25]. ElAkawi et al found that antioxidant              High IMA levels are associated with infections, tumors,
levels, such as vitamin A and vitamin E, were reduced in pa-        cirrhosis, etc associated with [35]. In previous studies, IMA
tients with AV [26]. Awad et al found that although acne            levels were evaluated in some skin diseases. High IMA levels
patients had higher MDA levels than controls, total antiox-         in hidradenitis suppurativa, leukoplakia, acute and chronic ur-
idant capacity was lower [27]. Saric et al found that serum         ticaria and Behçet’s disease compared to controls suggest that
MDA and xanthine oxidase (XO) were higher in AV patients            IMA may be a marker of oxidative stress in these diseases [12].
compared to controls [28]. In another study, acne patients          Guler et al found that IMA was higher in AV patients and
had higher levels of MDA and nitric oxide (NO) and lower            suggested that IMA might be a marker of oxidative stress in



4                                                                       Original Article | Dermatol Pract Concept. 2023;13(4):e2023280
AV patients [36]. Ebrahim et al stated that since IMA levels are          7. Kardeh S, Moein SA, Namazi MR, Kardeh B. Evidence for the
elevated in AV patients, serum IMA levels can be considered as               Important Role of Oxidative Stress in the Pathogenesis of Acne.
                                                                             Galen Med J. 2019;8:e1291. DOI:10.31661/gmj.v0i0.1291.
an independent predictor of AV susceptibility and function [37].
                                                                             PMID: 34466486. PMCID: PMC8344136.
Akyurek et al found that citrulline and vitamin A levels in
                                                                          8. Sbarouni E, Georgiadou P, Voudris V. Ischemia modified albumin
AV patients were lower than in controls. They also found                     changes – review and clinical implications. Clin Chem Lab Med.
that IMA plasma levels increased with disease severity. As the               2011;49(2):177-184 DOI:10.1515/CCLM.2011.037. PMID:
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vitamin A decrease [38]. According to all these studies, our re-          9. Erel Ö, Erdoğan S. Thiol-disulfide homeostasis: an integrated
                                                                             approach with biochemical and clinical aspects. Turk J Med
sults show that AV patients have higher IMA levels. However,
                                                                             Sci. 2020;50(7):1728-1738. DOI:10.3906/sag-2003-64. PMID:
there was no correlation between the GAS values we
                                                ​​ used to
                                                                             32233181. PMCID: PMC7672356.
determine the severity of the disease and the IMA values. This           10. Bilaç C, Şahin MT, Öztürkcan S. Disease severity scoring systems
may be due to the low number of educated people.                             in dermatology. TURKDERM. 2016;50(2):42-53. DOI:10.4274
    In a previous study, thiol testing and IMA were examined                 /turkderm.67799.
separately in AV patients. However, our study is simultane-              11. Doshi A, Zaheer A, Stiller M. A comparison of current acne
                                                                             grading systems and proposal of a novel system. Int J Dermatol.
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                                                                             1997;36(6):416-418. DOI:10.1046/j.1365-4362.1997.00099.x.
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                                                                             PMID: 9248884.
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                                                                             ­
nisms dependent on thiol and IMA levels. Given the diverse                   Marker of Oxidative Stress in Dermatological Diseases. Medicina
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                                                                             PMID: 35630086. PMCID: PMC9147831.
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                                                                         13. Bar–Or D, Lau E, Winkler J V. A novel assay for cobalt-­
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                                                                             albumin binding and its potential as a marker for myocardial
Therefore, future studies with larger patient populations                    ­ischemia—a preliminary report. J Emerg Med. 2000;19(4):311-
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                                                                              DOI:10.1016/j.clinbiochem.2014.09.026. PMID: 25304913.
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                                                                         15. Tan JKL, Stein Gold LF, Alexis AF, Harper JC. Current
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                                                                         16.   Kircik LH. Advances in the Understanding of the Pathogenesis
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