Antioxidants

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22 pages, 2223 KiB

Open AccessArticle

PON-1 and PON-2 Polymorphisms and PON-1 Paraoxonase Activity in People Living with HIV-1

by Cadiele Oliana Reichert, Débora Levy, Luciana Morganti Ferreira Maselli, Joel da Cunha, Sandra Fátima Menosi Gualandro and Sérgio Paulo Bydlowski

Antioxidants 2025, 14(2), 209; https://doi.org/10.3390/antiox14020209 - 12 Feb 2025

Viewed by 697

Abstract

Antiretroviral therapy (ART) has significantly improved the life expectancy of people living with HIV-1 (PLWH). However, prolonged ART use is linked to metabolic alterations and oxidative stress. The paraoxonase (PON) enzymes, especially PON-1 and PON-2, are critical in maintaining antioxidant balance. Their activity [...] Read more.

Antiretroviral therapy (ART) has significantly improved the life expectancy of people living with HIV-1 (PLWH). However, prolonged ART use is linked to metabolic alterations and oxidative stress. The paraoxonase (PON) enzymes, especially PON-1 and PON-2, are critical in maintaining antioxidant balance. Their activity can be influenced by polymorphisms such as Q192R and L55M in PON-1 and A148G and S311C in PON-2. This study examines the impact of these polymorphisms on paraoxonase activity, lipid metabolism, and infection markers in PLWH under various ART regimens. This is a case-control study with 525 participants, 175 healthy controls (HC) and 350 PLWH divided into subgroups: T0 (ART-naïve, n = 48), T1 (ART with reverse transcriptase inhibitors, n = 159), and T2 (ART with protease inhibitors, n = 143). Paraoxonase activity was higher in PLWH (123.0; IQR: 62.0–168.0) compared to HC (91.0; IQR: 48.0–136.0, p < 0.001) but similar between HC and T0 (p = 0.594). T1 (125.0; IQR: 65.5–166.0) and T2 (123.0; IQR: 61.0–182.0) showed higher activity than HC (p = 0.002 and 0.003). Among 61 complete genotypes, 13 were unique to PLWH and 6 to HC (p < 0.001). L55L was more frequent in HC (49.7% vs. 36.9% in PLWH), while M55M was higher in PLWH (p = 0.004). The S311C genotype was more frequent in HC (39.2%) than PLWH (24.9%) (p = 0.003). The L55L genotype conferred 59.9% protection against HIV-1 (OR: 0.401; 95% CI: 0.228–0.704), while the M allele increased susceptibility by ~69% (OR: 1.694; 95% CI: 1.173–2.446). The M55M genotype and/or M allele may be linked to HIV-1 susceptibility. Prolonged ART use elevates PON-1 activity in PLWH. Full article

(This article belongs to the Special Issue Antioxidant Role of High-Density Lipoprotein)

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13 pages, 1431 KiB

Open AccessArticle

The Role of Paraoxonase-1 Activity, Apolipoprotein B Levels, and Apolipoprotein B/Apolipoprotein A-I Ratio as Risk Markers for Aortic Stenosis in Patients with a Bicuspid Aortic Valve

by Maria Kwiatkowska, Agnieszka Mickiewicz, Aleksandra Krzesińska, Agnieszka Kuchta, Maciej Jankowski, Marcin Gruchała and Marcin Fijałkowski

Antioxidants 2025, 14(2), 167; https://doi.org/10.3390/antiox14020167 - 30 Jan 2025

Viewed by 689

Abstract

The bicuspid aortic valve (BAV) is commonly associated with the early degeneration of the aortic valve. Up to 45% of BAV patients over the age of 50 develop aortic stenosis (AS). Although published data indicate a robust interplay between lipids and calcific AS [...] Read more.

The bicuspid aortic valve (BAV) is commonly associated with the early degeneration of the aortic valve. Up to 45% of BAV patients over the age of 50 develop aortic stenosis (AS). Although published data indicate a robust interplay between lipids and calcific AS in tricuspid aortic valve patients, the studies on the BAV population are lacking. We aimed to evaluate the association between selected lipid markers and the occurrence of AS in BAV patients. Methods: The study included 76 adults (21 female) with a BAV diagnosed by echocardiography, divided by age and AS diagnosis. Biochemical parameters concentrations in serum were measured: high density lipoprotein cholesterol (HDL-C) levels by standard enzymatic colorimetric tests, low density lipoprotein cholesterol (LDL-C) levels by the Friedewald formula, apolipoprotein A-I (Apo AI) and apolipoprotein B (Apo B) serum concentration by the nephelometric method, and paraoxonase-1 activity (PON-1 ASE) and arylesterase activity (PON-1 ARE) based on paraoxon and phenyl acetate hydrolysis. Results: A total of 54 patients (15 female) were more than 45 years old and 22 (6 female) were 45 or less years old. BAV patients with AS aged ≤45 had higher levels of Apo B, compared to those without AS [110.5 (102–132) vs. 95.6 (77–101) mg/d; p 0.044]. Similarly, Apo B/Apo AI ratio was higher in BAV patients with AS aged ≤45, compared to those without AS [(0.8 (0.7–1) vs. 0.6 (0.5–0.7); p 0.029]. In the group aged ≤45, Apo B showed a positive correlation with the aortic valve peak transvalvular velocity (AV Vmax) measurement (R Spearman 0.6, p 0.004). We found also that, among young BAV patients, those with AS had a lower level of PON-1 ARE compared to the cohort without AS [63.4 (52–80) vs. 85.3 (70–102); p 0.012]. We did not find any differences in lipid parameters in patients aged >45. Conclusions The metabolic link between Apo B level and Apo B/AI ratio with AS presence in BAV patients under 45 years of age suggests a significant impact of these parameters on the earlier development of AS in the BAV population. Molecules associated with high density lipoprotein and its antioxidant function, such as PON1, are valuable markers for AS development, compared to HDL-C and LDL-C levels. Full article

(This article belongs to the Special Issue Antioxidant Role of High-Density Lipoprotein)

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13 pages, 712 KiB

Open AccessArticle

Oxidative Status and Lipid Metabolism Analytes in Dogs with Mast Cell Tumors: A Preliminary Study

by Argyrios Ginoudis, Dimitra Pardali, Mathios E. Mylonakis, Androniki Tamvakis, Asta Tvarijonaviciute, Evgenia Lymperaki, Jose Joaquin Ceron and Zoe Polizopoulou

Antioxidants 2024, 13(12), 1473; https://doi.org/10.3390/antiox13121473 - 29 Nov 2024

Viewed by 1317

Abstract

Mast cell tumors (MCTs) are common skin neoplasms in dogs. Prognostic indicators include histologic grade, clinical stage, high Ki-67 index, elevated argyrophilic nucleolus organizer regions (AgNOR) index, c-kit mutations, and recurrence after surgery. Blood serum redox status has been shown to correlate with [...] Read more.

Mast cell tumors (MCTs) are common skin neoplasms in dogs. Prognostic indicators include histologic grade, clinical stage, high Ki-67 index, elevated argyrophilic nucleolus organizer regions (AgNOR) index, c-kit mutations, and recurrence after surgery. Blood serum redox status has been shown to correlate with prognostic factors in canine lymphoma and mammary tumors. This study aimed to assess the correlation between established prognostic factors and serum redox status and lipid metabolism analytes in dogs with MCTs. Dogs with cutaneous (n = 33) or subcutaneous (n = 6) MCTs, without comorbidities, were studied. Staging was evaluated based on cytology of regional lymph nodes and ultrasound-guided liver and spleen aspiration cytology. Histologic grading and immunohistochemical staining for Ki-67 and KIT patterns were performed on excised tumor specimens. Dogs were categorized by Patnaik grading (1–3), Kiupel grading (low/high), metastatic status, Ki-67 positive nuclei per cm² (>23 or ≤23), and KIT pattern (I, II–III). Paraoxonase-1, Butyrylcholinesterase, Cupric Reducing Antioxidant Capacity (CUPRAC), Diacron Reactive Oxygen Metabolites (d-ROMs), and oxy-adsorbent levels were measured before any therapeutic intervention. ANOVA and independent t-tests were used to detect differences in the mean values among groups. Paraoxonase-1 activity was significantly lower in Patnaik grade 3 (p = 0.003) and Kiupel high-grade (p = 0.022) MCTs. No significant differences were found in CUPRAC, d-ROMs, or oxy-adsorbent levels across different prognostic groups. This study found a significant correlation between histologic grading and Paraoxonase-1 activity, suggesting a potential role of Paraoxonase-1 as a prognostic biomarker in canine MCTs. Full article

(This article belongs to the Special Issue Antioxidant Role of High-Density Lipoprotein)

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15 pages, 1028 KiB

Open AccessArticle

Healthier Lipid Profiles of Japanese Adults, Especially in Women with Elevated High-Density Lipoprotein Cholesterol (HDL-C), Are Associated with Low HDL-C Peroxide Content

by Loni Berkowitz-Fiebich, Shelby M. Flaherty, Shinobu Kitayama, Mayumi Karasawa, Norito Kawakami, Attilio Rigotti and Christopher L. Coe

Antioxidants 2024, 13(12), 1434; https://doi.org/10.3390/antiox13121434 - 22 Nov 2024

Viewed by 1420

Abstract

Japanese adults typically have healthier lipid profiles than American and European adults and a lower prevalence and later onset of atherosclerotic cardiovascular disease (ASCVD). Many Japanese also have uniquely elevated levels of high-density lipoprotein cholesterol (HDL-C). The following analysis examined the relationship between [...] Read more.

Japanese adults typically have healthier lipid profiles than American and European adults and a lower prevalence and later onset of atherosclerotic cardiovascular disease (ASCVD). Many Japanese also have uniquely elevated levels of high-density lipoprotein cholesterol (HDL-C). The following analysis examined the relationship between HDL-C level and HDL-C peroxide content, a bioindicator of unhealthy lipid metabolism in Japanese adults. Blood samples were collected from 463 participants, 31–84 years of age, who lived in Tokyo. A second blood sample was collected 5 years later from 241 of the participants, allowing us to evaluate the temporal stability of the inverse correlation between HDL-C level and HDL-C peroxide content. Glucoregulation and inflammatory activity were assessed because both can be associated with dyslipidemia and HDL-C dysfunction. Obesity and central adiposity were also considered. Overall, women had healthier HDL-C profiles than men. Elevated HDL-C (>90 mg/dL) was common (16.6%) and found more often in women. Higher HDL-C peroxide content was associated with older age and central adiposity and incremented further when HA1c and CRP were higher. When assessed 5 years later, lower HDL-C peroxide content continued to be evident in adults with higher HDL-C. While similar associations have been described for other populations, most Japanese adults typically had healthier levels of HDL-C with lower HDL-C peroxide content than previously reported for American adults. Full article

(This article belongs to the Special Issue Antioxidant Role of High-Density Lipoprotein)

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Review

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27 pages, 2606 KiB

Open AccessReview

HDL-Cholesterol and Triglycerides Dynamics: Essential Players in Metabolic Syndrome

by Sebastià Alcover, Lisaidy Ramos-Regalado, Gabriela Girón, Natàlia Muñoz-García and Gemma Vilahur

Antioxidants 2025, 14(4), 434; https://doi.org/10.3390/antiox14040434 - 3 Apr 2025

Viewed by 761

Abstract

Metabolic syndrome (MetS) is a complex cluster of interrelated metabolic disorders that significantly elevate the risk of cardiovascular disease, making it a pressing public health concern worldwide. Among the key features of MetS, dyslipidemia—characterized by altered levels of high-density lipoprotein cholesterol (HDL-C) and [...] Read more.

Metabolic syndrome (MetS) is a complex cluster of interrelated metabolic disorders that significantly elevate the risk of cardiovascular disease, making it a pressing public health concern worldwide. Among the key features of MetS, dyslipidemia—characterized by altered levels of high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG)—plays a crucial role in the disorder’s progression. This review aims to elucidate the intricate interplay between HDL-C and TG within the context of lipid metabolism and cardiovascular health, while also addressing the detrimental impact of various cardiovascular risk factors and associated comorbidities. The dynamics of HDL-C and TG are explored, highlighting their reciprocal relationship and respective contributions to the pathophysiology of MetS. Elevated levels of TGs are consistently associated with reduced concentrations of HDL-C, resulting in a lipid profile that promotes the development of vascular disease. Specifically, as TG levels rise, the protective cardiovascular effects of HDL-C are diminished, leading to the increased accumulation of pro-atherogenic TG-rich lipoproteins and low-density lipoprotein particles within the vascular wall, contributing to the progression of atheromas, which can ultimately result in significant ischemic cardiovascular events. Ultimately, this paper underscores the significance of HDL and TG as essential targets for therapeutic intervention, emphasizing their potential in effectively managing MetS and reducing cardiovascular risk. Full article

(This article belongs to the Special Issue Antioxidant Role of High-Density Lipoprotein)

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25 pages, 2512 KiB

Open AccessReview

How Does HDL Participate in Atherogenesis? Antioxidant Activity Versus Role in Reverse Cholesterol Transport

by Paul N. Durrington, Bilal Bashir and Handrean Soran

Antioxidants 2025, 14(4), 430; https://doi.org/10.3390/antiox14040430 - 2 Apr 2025

Viewed by 817

Abstract

Low-density lipoprotein (LDL) chemically modified by reactive oxygen species (ROS), for example, leaking from red blood cells in the vascular compartment, more readily crosses the vascular endothelium than does nonoxidatively modified LDL to enter tissue fluid. Oxidatively modified LDL (oxLDL) may also be [...] Read more.

Low-density lipoprotein (LDL) chemically modified by reactive oxygen species (ROS), for example, leaking from red blood cells in the vascular compartment, more readily crosses the vascular endothelium than does nonoxidatively modified LDL to enter tissue fluid. Oxidatively modified LDL (oxLDL) may also be created in the tissue fluid by ROS leaking from cells by design, for example, by inflammatory white cells, or simply leaking from other cells as a consequence of oxygen metabolism. As well as oxLDL, glycatively modified LDL (glycLDL) is formed in the circulation. High-density lipoprotein (HDL) appears capable of decreasing the burden of lipid peroxides formed on LDL exposed to ROS or to glucose and its metabolites. The mechanism for this that has received the most attention is the antioxidant activity of HDL, which is due in large part to the presence of paraoxonase 1 (PON1). PON1 is intimately associated with its apolipoprotein A1 component and with HDL’s lipid domains into which lipid peroxides from LDL or cell membranes can be transferred. It is frequently overlooked that for PON1 to hydrolyze lipid substrates, it is essential that it remain by virtue of its hydrophobic amino acid sequences within a lipid micellar environment, for example, during its isolation from serum or genetically modified cells in tissue culture. Otherwise, it may retain its capacity to hydrolyze water-soluble substrates, such as phenyl acetate, whilst failing to hydrolyze more lipid-soluble molecules. OxLDL and probably glycLDL, once they have crossed the arterial endothelium by receptor-mediated transcytosis, are rapidly taken up by monocytes in a process that also involves scavenger receptors, leading to subendothelial foam cell formation. These are the precursors of atheroma, inducing more monocytes to cross the endothelium into the lesion and the proliferation and migration of myocytes present in the arterial wall into the developing lesion, where they transform into foam cells and fibroblasts. The atheroma progresses to have a central extracellular lake of cholesteryl ester following necrosis and apoptosis of foam cells with an overlying fibrous cap whilst continuing to grow concentrically around the arterial wall by a process involving oxLDL and glycLDL. Within the arterial wall, additional oxLDL is generated by ROS secreted by inflammatory cells and leakage from cells generally when couplet oxygen is reduced. PON1 is important for the mechanism by which HDL opposes atherogenesis, which may provide a better avenue of inquiry in the identification of vulnerable individuals and the provision of new therapies than have emerged from the emphasis placed on its role in RCT. Full article

(This article belongs to the Special Issue Antioxidant Role of High-Density Lipoprotein)

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29 pages, 3002 KiB

Open AccessReview

The Molecular Bases of Anti-Oxidative and Anti-Inflammatory Properties of Paraoxonase 1

by Hieronim Jakubowski

Antioxidants 2024, 13(11), 1292; https://doi.org/10.3390/antiox13111292 - 25 Oct 2024

Cited by 3 | Viewed by 1452

Abstract

The anti-oxidative and anti-inflammatory properties of high-density lipoprotein (HDL) are thought to be mediated by paraoxonase 1 (PON1), a calcium-dependent hydrolytic enzyme carried on a subfraction of HDL that also carries other anti-oxidative and anti-inflammatory proteins. In humans and mice, low PON1 activity [...] Read more.

The anti-oxidative and anti-inflammatory properties of high-density lipoprotein (HDL) are thought to be mediated by paraoxonase 1 (PON1), a calcium-dependent hydrolytic enzyme carried on a subfraction of HDL that also carries other anti-oxidative and anti-inflammatory proteins. In humans and mice, low PON1 activity is associated with elevated oxidized lipids and homocysteine (Hcy)-thiolactone, as well as proteins that are modified by these metabolites, which can cause oxidative stress and inflammation. PON1-dependent metabolic changes can lead to atherothrombotic cardiovascular disease, Alzheimer’s disease, and cancer. The molecular bases underlying these associations are not fully understood. Biochemical, proteomic, and metabolic studies have significantly expanded our understanding of the mechanisms by which low PON1 leads to disease and high PON1 is protective. The studies discussed in this review highlight the changes in gene expression affecting proteostasis as a cause of the pro-oxidative and pro-inflammatory phenotypes associated with attenuated PON1 activity. Accumulating evidence supports the conclusion that PON1 regulates the expression of anti-oxidative and anti-inflammatory proteins, and that the disruption of these processes leads to disease. Full article

(This article belongs to the Special Issue Antioxidant Role of High-Density Lipoprotein)

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14 pages, 940 KiB

Open AccessReview

Protective Role of High-Density Lipoprotein in Multiple Sclerosis

by Agnieszka Damiza-Detmer, Małgorzata Pawełczyk and Andrzej Głąbiński

Antioxidants 2024, 13(11), 1276; https://doi.org/10.3390/antiox13111276 - 23 Oct 2024

Viewed by 1785

Abstract

Multiple sclerosis (MS) is a chronic, progressive demyelinating disease with a most likely autoimmune background and a neurodegenerative component. Besides the demyelinating process caused by autoreactive antibodies, an increased permeability in the blood–brain barrier (BBB) also plays a key role. Recently, there has [...] Read more.

Multiple sclerosis (MS) is a chronic, progressive demyelinating disease with a most likely autoimmune background and a neurodegenerative component. Besides the demyelinating process caused by autoreactive antibodies, an increased permeability in the blood–brain barrier (BBB) also plays a key role. Recently, there has been growing interest in assessing lipid profile alterations in patients with MS. As a result of myelin destruction, there is an increase in the level of cholesterol released from cells, which in turn causes disruptions in lipid metabolism homeostasis both in the central nervous system (CNS) and peripheral tissues. Currently, there is a growing body of evidence suggesting a protective role of HDL in MS through its effect on the BBB by decreasing its permeability. This follows from the impact of HDL on the endothelium and its anti-inflammatory effect, mostly by interacting with adhesion molecules like vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), and E-selectin. HDL, through its action via sphingosine-1-phosphate, exerts an inhibitory effect on leukocyte migration, and its antioxidant properties contribute to the improvement of the BBB function. In this review, we want to summarize these studies and focus on HDL as a mediator of the anti-inflammatory response in MS. Full article

(This article belongs to the Special Issue Antioxidant Role of High-Density Lipoprotein)

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