View of Evaluation of Paraoxonase-1 (PON-1) in Relation with Rheumatoid Arthritis Patients

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Received 15 April, 2021; Accepted 08 June 2021.

13902 http://annalsofrscb.ro

Evaluation of Paraoxonase-1 (PON-1) in Relation with Rheumatoid Arthritis Patients

Huda Najah Abd and Adhraa Baqir Hassan

University of Kufa, Faculty of Science, Department of Biology, Najaf, Iraq Email: [email protected], Mobile: +0964-7801103720

Abstract

The current investigation involved 60 Rheumatoid arthritis patients who were randomly recruited from (Al-Sadder Teaching Hospital in Al-Najaf Province, Iraq) and a group of 20 supposedly control groups. The research was conducted from November 2020 to April 2021. The patients and control groups were between the ages of 40 and 70.

Biomarker PON-1 of Rheumatoid arthritis patients decreased significantly (p≤0.05) in comparison to the controlled group. Biomarker PON-1 of Rheumatoid arthritis patients at various ages displayed a considerable decrease (p≤0.05) in comparison to the controlled group. PON-1 of Rheumatoid arthritis patients in both males and females displays considerable decrease (p≤0.05) in comparison to the controlled group. PON-1 of Rheumatoid arthritis patients in BMI decreased significantly (p≤0.05) in comparison to the controlled group. Patients with Rheumatoid arthritis had a positive considerable connection (P≤ 0.05) between their age (year) and PON-1. BMI and biomarker (PON-1) of

Rheumatoid arthritis patients have a significant positive relation (P≤ 0.05).

Keyword: Rheumatoid arthritis, Biomarker PON-1, Elisa, and Al-Najaf Province

1- Introduction

Rheumatoid arthritis (RA) is an inflammatory disease that lasts for a long time and has a large impact on the physical activity andmentaland somatic health of apatient, The risk tends to be highest in the first year after RA diagnosis and stabilizes at a lower level with minor annual rises during the subsequent years2,3 RA is unpredictable attacks of synovitis and joint pain (Hansen et al.,2016). PON1, an enzyme carried by high-density lipoproteins (HDLs), has antioxidant and anti-inflammatory properties, as well as the ability to detoxify xenobiotics like organophosphates, Recent epidemiological investigations have shown that it acts as a preventive factor against atherogenesis, The potential relevance of PON1 activity and polymorphisms as a risk factor for ischemic stroke, one of the most common neurological illnesses linked with arteriosclerosis, has received a lot of attention (Menini and Guliucci, 2014). PON1 (paraoxonase 1) is a highly selective enzyme that acts on organophosphates

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Received 15 April, 2021; Accepted 08 June 2021.

(from which the term paraoxonase comes), arylesters, and lactones. PON1 is carried in the bloodstream with high-density lipoproteins (HDL) and protects lipoproteins, especially low-density lipoproteins (LDL), against oxidative damage ( Bednarska-Makaruketal.,2013).

2- Materials and methods

The study was conducted on randomly selected 60 Rheumatoid Arthritispatients (13 Males and 47 Females) in "Al-Sadder Teaching City in Al-Najaf province-Iraq". It was carried out from Octobar 2020 to April2021. The age of patients was range of 40-70y. Consultant doctors diagnosed Rheumatoid Arthritis. The names, sexes, ages, weights, and heights of the patients were obtained through a questionnaire. As a healthy group, 20 plainly controlled participants (7 males and 13 females) were involved. Their ages were similar to those of the patients.

3- Results 3-1 Paraoxonase-1 level

The findings shown in Figure (1) refer to a considerable decrease (P≤0.05) in the level of (PON1) in rheumatoid arthritis patients (µg/mL)in comparing with control groups (µg/ml).

Figure (1): PON-1 levels(µg/ml) in Rheumatoid arthritis patients and controlled groups

Comparing the level of biomarkers between rheumatoid arthritis and controlled groups due to age

The findings displayed in table (1) indicate that there is a considerable decrease (P≤ 0.05( in serum all biomarker level PON-1 in patients at different ages, level Paraoxonase-1 is asignificant

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Received 25 April 2021; Accepted 08 May 2021.

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decrease (p≤ 0.05) in patients of various ages as compared to control groups.

Table(1): Levels of biomarkers in patients and controlled groups at various ages

Comparing the level of biomarker PON1 between rheumatoid arthritis and controlled groups due to gender

The findings displayed in Table (2) reveal that there is a considerable decrease (p≤ 0.05) in serum biomarker level PON-1in both males and females patients as well as controlled groups.

Table(2): Levels of PON-1 in patients and controlled groups of both genders

Comparison between miscarried women, according to weights

The results indicate that there is a significant increase (p≤0. 05) GDF 15 of weight groups (>76kg) (347.27±32.48) in compared with weight groups (<65kg, 66-75kg) (240.81±27.22, 355.72±29.41).

Figure (3).

Table (3): Weight groups of aborted women

* means significant difference at (P≤ 0.05) Parameters

Groups

Weight groups of Aborted Women Chi-

Square

P- value

<65 kg 66-75 kg >76 kg

Range

N=22 388.520

N=20 485.53

N=18 395.50

1390 4

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GDF15 92.65-481.17 95-580.53 165-561.25

Mean

8.881 0.012 (pg/ml)

±SE

240.81±27.22 355.72±29.41 347.27±32.48*

Comparing the level of Paraoxonase-1 between rheumatoid arthritis and controlled groups due to BMI

The findings shown in Figures (2),(3),(4) refer to a considerable decrease (P≤ 0.05) in the level of PON1 in patients of all weight groups (natural, overweight, and obese) when compared to controlled groups.

Figure (2): PON1 levels (µg/ml) in normal weight patients and controlled groups

Figure (3): PON1levels (µg/ml)of patients and control groups in overweight

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Figure (4): PON1levels (µg/ml) in obese weight patients and controlled groups Correlation Coefficient between age, gender and weight with biomarkers in Rheumatoid arthritis patients

Table (3) shows that there is a significant positive connection (P 0.05) between rheumatoid arthritis patients' age (year) and biomarker PON-1 (µg/ml) (r=0.596). Table (3) shows that the BMI (kg/m2) and PON-1 (µg/ml) levels of rheumatoid arthritis patients have a considerable positive connection

(P≤0.05) (R=0.60). Table (3) shows that there is a substantial positive connection (P 0.05) between the levels of PON-1 (µg/ml) in rheumatoid arthritis patients (R=+ 0.593), (R= 0.125).

Table(4-3):Correlation Coefficient between age, gender and weight with biomarkers in Rheumatoid arthritis patients.

Parameters Statistical Age (year)

BMI

(kg/m²) Gender PON

(µg/mL) Age

(year)

R 1

Sig.

BMI (kg/m²)

R 0.074 1

Sig. 0.410

Gender R 0.054 0.004 1

Sig. 0.621 0.971

POL (µg/mL)

R 0.596^* 0.60^* 0.082 1

Sig. 0.041 0.048 0.446

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5- Discussion

The results of figure (4-1) show a considerable reduction (p≤ 0.05) in PON-1 levels in people with RA in comparison to controlled group.

The previous studies that HDL levels of PON1 protein were shown to be less in people who suffer from active inflammatory RA, that was linked with to aberrant HDL low antioxidant potential (Watanabe et al.,2012; El-Banna et al .,2014 ). Genetic modulation of PON-1 activity is connected to "PON-1 activity, atherogenic lipid profile, and atherosclerotic plaque load", recommending that genetic modulation of PON-1 activity has a role in the raised cardiovascular burden documented in RA(Charles-Schoeman et al.,2013;Rodríguez-Carrioetal.,2016; Zaragoza-García et al.,2020).

Some studies revealed that PON1 enzyme is known to diminish the buildup of oxidized lipids in LDL,as well as HDL, which reduces the buildup of lipid peroxides in LDL due to its ability to decrease hydroperoxides (Wu et al.,2018). PON1 activities may speed up the progression of atherosclerosis in those who have knee osteoarthritis. Reduced PON-1 activity in people with RA might hasten the onset of atherosclerosis in those with knee osteoarthritis (El-Banna et al.,2014). The present study revealed in figure(4-1) that PON-1 activity is linked to cardiovascular events in RA ( Tang et al .,2012).

In patients with RA, PON1 activity is lower than in healthy persons, which is followed by an increase in lipid peroxidation products and/or other oxidative stress indicators (Shahmohamadnejad et al

.,2014). Reactive oxygen species (ROS) are produced in excess by activated inflammatory cells in RA patients, contributing to oxidative stress and tissue damage (Da Fonseca et al .,2019). The activity of the PON-1 enzyme has been discovered to be a deterministic dangerous factor for microvascular problems in RA (Sabah et al.,2015). It was also predicted that preserving serum PON-1 activity by treating the sick people using antioxidant substances at therapeutic concentrations might prevent renal vascular damage in RA. PON was shown to be adversely linked with RA in a research by (Baskol et al.,2011). These findings might indicate that changes in oxidative/ antioxidative state are to blame for the reduction in PON1 activity seen in RA, Previous research has shown that poor PON1 activity in RA patients may be due to damage to PON1 proteins caused by high levels of reactive oxygen species generated in RA patients, rather than a lack of synthesis (Charles et al.,2013).

The results of table (4-1) show a considerable reduction (p≤ 0.05) in PON-1 levels in people with RA in comparison to controlled group. Studies revealed that age is a fundamental factor of PON1 activity , low PON1 activity during development when decrease PON1 risk factor for immune disease by RA(Li et al.,2012). decreased PON activity and increased levels in HDL from adult in RA

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patients(Aslan et al.,2011). PON-1 activity has been shown in several research to have a deleterious impact on age-related disorders as well as the pace of aging. It has previously been shown that free radical-induced lipid oxidation plays a role in aging and the development of oxidative stress, and that the degree of lipid peroxidation corresponds with free radical progression. ( Nair and Rajamohan,2012).

Plasma PON1 arylesterase activity decreases as people get older, starting with children. (Mehdi and Rizvi ,2012).

The results of table (2) show a considerable reduction (p≤ 0.05) in PON-1 levels in RA patients comparing with control group. The antioxidant activity of HDL is greatly supplied by PON1, and blood PON1 activity in females is greater than in men. This difference is attributable to sex hormones, as estradiol boosts PON1 activity without affecting liverPON1 protein production. (Ahmad and scott ,2011). The results of figure (2),(3),(4) show a considerable reduction (p 0.05) in PON-1 level in people with RA in comparison to controlled group. Obese weights had considerably lower PON activity than control participants, indicating that oxidative stress is greater in obese weights compared to controls (Bajnok et al.,2008). According to several research, there is a link between HDL-PON and lipid hydroperoxides in HDL and LDL of healthy and obese people, suggesting that people with lower PON activity are more vulnerable to oxidative damage. In obese people, decreased PON1 activity is linked to low HDL cholesterol levels, and body mass index is an independent predictor of PON1 activity ( Ferretti et al .,2005). The results of table (3) show a considerable reduction (p0.05) in PON-1 level in people with RA in comparison to controlled groups. PON-1 activity has been shown to decrease in those who are at risk of developing atherosclerosis. PON-1 activity has been shown to decrease in those who are at risk of developing atherosclerosis( Rosenblat et al .,2006). According to several research, PON1 prevents the oxidative modification of LDL and provides a significant portion of the antioxidative activity attributed to HDL. HDL is far more abundant in the arterial wall than LDL, therefore it should be perfectly positioned to shield LDL from oxidative alteration ( Deakin et al .,2005).

Conclusions

Lower level of PON-1 connected to an increase in Rheumatoid arthritis risk factors, according to the current study. According to the study, there is a link between Rheumatoid arthritis sufferers and their age. Both males and females have lower levels of biomarkers PON-1. 4. According to the findings, there is a link between Rheumatoid arthritis sufferers and a rise in BMI. Age, gender, and BMI have a substantial positive association with biomarker PON-1which could indicate that these biomarker have a role in Rheumatoid arthritis risk factors.

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References

1. Aslan, M., Horoz, M., Sabuncu, T., Celik, H., Selek, S.(2011).Serum paraoxonase enzyme activity and oxidative stress in obese subjects. Pol Arch Med Wewn ,121:181-186.

2. Bajnok, L., Seres, I., Varga, Z., Jeges, S., Peti, A., Karanyi ,Z.( 2008).relationship of serum resistin level to traits of metabolic syndrome and serum paraoxonase 1 activity in a population with a broad range of body mass index. Exp Clin Endocrinol Diabetes,116:592–9.

3. Baskol, G., Demir, H., Baskol, M., Kilic, E., Ates, F., Kocer ,D.( 2005). Assessment of paraoxonase 1 activity and malondialdehyde levels in patients with rheumatoid arthritis. Clin Biochem, 38:951-5.

4. Bednarska-Makaruk, M. E., Krzywkowski, T., Graban, A., Lipczyńska-Łojkowska, W.,

Bochyńska, A., Rodo, M., ... & Ryglewicz, D. K. (2013). Paraoxonase 1 (PON1) gene-108C> T and p. Q192R polymorphisms and arylesterase activity of the enzyme in patients with dementia.

Folia Neuropathol, 51(2), 111-119.

5. Charles-Schoeman, C., Lee, Y.Y., Shahbazian, A., Gorn, A.H., Fitzgerald, J., Ranganath, V.K., Taylor, M., Ragavendra, N., McMahon, M., Elashoff, D.(2013).Association of paraoxonase 1 gene polymorphism and enzyme activity with carotid plaque in rheumatoid arthritis. Arthritis Rheum. 65, 2765–2772.

6. Da Fonseca L.J.S., Nunes-Souza V., Goulart M.O.F., Rabelo, L.A9. 2019).Oxidative stress in rheumatoid arthritis: What the future might hold regarding novel biomarkers and add-on therapies. Oxid. Med. Cell Longev,2019:7536805. doi: 10.1155/2019/7536805.

7. Deakin, S., Moren, X., James, RW.(2005). Very low density lipoproteins provide a vector for secretion of paraoxonase-1 from cells. Atherosclerosis, 179: 17–25.

8. El-Banna ,H., Jiman-Fatani,A.( 2014). Anti-cyclic citrullinated peptide antibodies and paraoxonase-1 polymorphism in rheumatoid arthritis. BMC Musculoskelet Disord,15:379.

9. Ferretti, G., Bacchetti ,T., Moroni ,C., Savino, S., Liuzzi, A., Balzola, F(2005). Paraoxonase activity in high-density lipoproteins: A comparison between healthy and obese females. J Clin Endocrinol Metab.90:1728–33.

10. Goličnik, M., & Bavec, A. (2020). Evaluation of the paraoxonase-1 kinetic parameters of the lactonase activity by nonlinear fit of progress curves. Journal of enzyme inhibition and medicinal chemistry, 35(1), 261-264.

11. Hansen, S. M., Hetland, M. L., Pedersen, J., Østergaard, M., Rubak, T. S., & Bjorner, J. B.

(9)

(2016). Effect of rheumatoid arthritis on longterm sickness absence in 1994-2011: a Danish cohort study. The Journal of rheumatology, 43(4), 707-715.

12. Li ,WF., Matthews, C., Disteche, CM., Costa, LG., Furlong, CE.( 2012). Paraoxonase (PON1) gene in human: sequencing, chromosomal localization and developmental expression.

Pharmacogenetics,7:137–44.

13. Mehdi ,MM., Rizvi, SI.( 2012).Human plasma paraoxonase 1 arylesterase activity during aging:

Correlation with Susceptibility of LDL Oxidation. Archives of Medical Research,43(6):438–

443.

14. Menini, T., & Gugliucci, A. (2014). Paraoxonase 1 in neurological disorders. Redox Report, 19(2), 49-58.

15. Rodríguez-Carrio, J., López-Mejías, R., Alperi-López, M., López, P., Ballina-García, F.J., González-Gay, M.Á., Suárez, A. Paraoxonase 1 Activity Is Modulated by the rs662

Polymorphism and IgG Anti-High-Density Lipoprotein Antibodies in Patients With Rheumatoid Arthritis: Potential Implications for Cardiovascular Disease. Arthritis Rheumatol.

2016, 68, 1367–1376.

16. Rosenblat, M., Karry, R., Aviram, M(2006).. Paraoxonase 1 (PON1) is a more potent antioxidant and stimulant of macrophage cholesterol efflux, when present in HDL than in lipoprotein-deficient serum: Relevance to diabetes. Atherosclerosis, 187: 74–81.

17. Sabah, AM., Reham ,S,, Eman, S.( 2015). Role of paraoxonase activity and oxidative stress in renal vascular damage in rheumatoid arthritis. Clinical Medicine and Diag– nostics, 5(2): 26–

34.

18. Shahmohamadnejad ,S., Vaisi-Raygani,A., Shakiba ,Y., Kian, A., Rahimi, Z., Bahrehmand ,F., Shakiba, E., Pourmotabbed ,T.(2015). Association between butyrylcholinesterase activity and phenotypes, paraoxonase192 rs662 gene polymorphism and their enzymatic activity with severity of rheumatoid arthritis: Correlation with systemic inflammatory markers and oxidative stress, preliminary report. Clin. Biochem ,48:63–69. doi: 10.1016/j.clinbiochem.2014.08.016.

19. Tang ,WH., Hartiala, J., Fan, Y., Wu, Y., Stewart AF., Erdmann, J. (2012).Clinical and genetic association of serum paraoxonase and arylesterase activities with cardiovascular risk.

Arterioscler Thromb Vasc Biol,32:2803–12.

20. Watanabe, J., Charles-Schoeman, C., Miao, Y., Elashoff, D., Lee, YY., Katselis, G.(2012).

Proteomic profiling following immunoaffinity capture of high-density lipoprotein: association

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of acute-phase proteins and complement factors with proinflammatory high-density lipoprotein in rheumatoid arthritis. Arthritis Rheum.64:1828–37

21. Wu, C., Wu, D., Lin, M., Zhong ,Ya.(2018). The Associations between Paraoxonase 1 L55M/Q192R Genetic Polymorphisms and the Susceptibilities of Diabetic Macroangiopathy and Diabetic Microangiopathy: A Meta-Analysis. Diabetes Ther. 9(4):1669– 1688.

doi:10.1007/s13300-018-0466-5.

22. Zaragoza-García, O., Guzmán-Guzmán, I.P., Moreno-Godínez, M.E., Navarro-Zarza, J.E., Antonio-Vejar, V., Ramírez, M., Parra-Rojas, I. PON-1 haplotype (-108C > T, L55M, and Q192R) modulates the serum levels and activity PONase promoting an atherogenic lipid profile in rheumatoid arthritis patients. Clin. Rheumatol. 2020, 1–12.