Tag: lipid peroxidation

Oxidative Stress is a shared characteristic of ME/CFS and Long COVID

Abstract:

More than 65 million individuals worldwide are estimated to have Long COVID (LC), a complex multisystemic condition, wherein patients of all ages report fatigue, post-exertional malaise, and other symptoms resembling myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). With no current treatments or reliable diagnostic markers, there is an urgent need to define the molecular underpinnings of these conditions.

By studying bioenergetic characteristics of peripheral blood lymphocytes in over 16 healthy controls, 15 ME/CFS, and 15 LC, we find both ME/CFS and LC donors exhibit signs of elevated oxidative stress, relative to healthy controls, especially in the memory subset. Using a combination of flow cytometry, bulk RNA-seq analysis, mass spectrometry, and systems chemistry analysis, we also observed aberrations in ROS clearance pathways including elevated glutathione levels, decreases in mitochondrial superoxide dismutase levels, and glutathione peroxidase 4 mediated lipid oxidative damage.

Critically, these changes in redox pathways show striking sex-specific trends. While females diagnosed with ME/CFS exhibit higher total ROS and mitochondrial calcium levels, males with an ME/CFS diagnosis have normal ROS levels, but larger changes in lipid oxidative damage. Further analyses show that higher ROS levels correlates with hyperproliferation of T cells in females, consistent with the known role of elevated ROS levels in the initiation of proliferation. This hyperproliferation of T cells can be attenuated by metformin, suggesting this FDA-approved drug as a possible treatment, as also suggested by a recent clinical study of LC patients.

Thus, we report that both ME/CFS and LC are mechanistically related and could be diagnosed with quantitative blood cell measurements. We also suggest that effective, patient tailored drugs might be discovered using standard lymphocyte stimulation assays.

Source: Vishnu Shankar, Julie Wilhelmy, Basil Michael, Layla Cervantes, Vamsee Mallajosyula, Ronald Davis, Michael Snyder, Shady Younis,
William H Robinson, Sadasivan Shankar, Paul Mischel, Hector Bonilla, Mark Davis. Oxidative Stress is a shared characteristic of ME/CFS and Long COVID. bioRxiv 2024.05.04.592477; doi: https://doi.org/10.1101/2024.05.04.592477  https://www.biorxiv.org/content/10.1101/2024.05.04.592477v1https://www.biorxiv.org/content/10.1101/2024.05.04.592477v1 (Full text available as PDF file)

Quantitative Proteomics of COVID-19 Recovered Patients Identifies Long-Term Changes in Sperm Proteins Leading to Cellular Stress in Spermatozoa

Abstract:

Following an initial recovery, COVID-19 survivors struggle with a spectrum of persistent medical complications, including fatigue, breathlessness, weight loss, hair loss, and attention deficits. Additionally, there is growing evidence of adverse effects of COVID-19 on the male reproductive system. This investigation seeks to understand the long-term ramifications on male fertility by examining hormonal profiles, semen parameters, and sperm proteome of recovered COVID-19 patients compared to controls.

The serum hormone profiles between the two groups showed minimal variations except for prolactin, cortisol, and testosterone levels. Testosterone levels were slightly lower, while prolactin and cortisol were elevated in COVID-19 cases compared to controls.

Though semen parameters exhibited no significant disparities between the COVID-19 and control groups, quantitative proteomics analysis revealed changes in sperm proteins. It identified 190 differentially expressed proteins, of which 161 were upregulated and 29 downregulated in COVID-19 cases.

Western blotting analysis validated the differential expression of serpin B4 and calpain 2. Bioinformatics analysis signifies cellular stress in the spermatozoa of COVID-19 recovered patients and thus, SOD and MDA levels in semen were measured. MDA levels were found to be significantly elevated, indicating lipid peroxidation in COVID-19 samples.

While the effects of COVID-19 on semen parameters may exhibit a potential for reversal within a short duration, the alterations it inflicts on sperm proteome are persisting consequences on male fertility. This study paves the path for further research and emphasizes the significance of comprehending the complex molecular processes underlying the long-term consequences of COVID-19 on male reproductive health.

Source: Chopra P, Tomar AK, Thapliyal A, Ranjan P, Datta SK, Yadav S. Quantitative Proteomics of COVID-19 Recovered Patients Identifies Long-Term Changes in Sperm Proteins Leading to Cellular Stress in Spermatozoa. Reprod Sci. 2024 Apr 24. doi: 10.1007/s43032-024-01560-5. Epub ahead of print. PMID: 38658489. https://pubmed.ncbi.nlm.nih.gov/38658489/

Hyperbaric Oxygen Therapy Counters Oxidative Stress/Inflammation-Driven Symptoms in Long COVID-19 Patients: Preliminary Outcomes

Abstract:

Long COVID-19 patients show systemic inflammation and persistent symptoms such as fatigue and malaise, profoundly affecting their quality of life. Since improving oxygenation can oppose inflammation at multiple tissue levels, we hypothesized that hyperbaric oxygen therapy (HBOT) could arrest inflammation progression and thus relieve symptoms of COVID-19.
We evaluated oxy-inflammation biomarkers in long COVID-19 subjects treated with HBOT and monitored with non-invasive methods. Five subjects (two athletes and three patients with other comorbidities) were assigned to receive HBOT: 100% inspired O2 at 2.4 ATA in a multiplace hyperbaric chamber for 90 min (three athletes: 15 HBOT × 5 days/wk for 3 weeks; two patients affected by Idiopathic Sudden Sensorineural Hearing Loss: 30 HBOT × 5 days/wk for 6 weeks; and one patient with osteomyelitis: 30 HBOT × 5 days/wk for week for 6 weeks and, after a 30-day break, followed by a second cycle of 20 HBOT).
Using saliva and/or urine samples, reactive oxygen species (ROS), antioxidant capacity, cytokines, lipids peroxidation, DNA damage, and renal status were assessed at T1_pre (basal level) and at T2_pre (basal level after treatment), and the results showed attenuated ROS production, lipid peroxidation, DNA damage, NO metabolites, and inflammation biomarker levels, especially in the athletes post-treatment. Thus, HBOT may represent an alternative non-invasive method for treating long COVID-19-induced long-lasting manifestations of oxy-inflammation.
Source: Mrakic-Sposta S, Vezzoli A, Garetto G, Paganini M, Camporesi E, Giacon TA, Dellanoce C, Agrimi J, Bosco G. Hyperbaric Oxygen Therapy Counters Oxidative Stress/Inflammation-Driven Symptoms in Long COVID-19 Patients: Preliminary Outcomes. Metabolites. 2023; 13(10):1032. https://doi.org/10.3390/metabo13101032 https://www.mdpi.com/2218-1989/13/10/1032 (Full text)

Increase in gut permeability and oxidized ldl is associated with post-acute sequelae of SARS-CoV-2

Abstract:

Background: Post-acute sequelae of SARS-CoV-2 (PASC) is marked by persistent or newly developing symptoms beyond 4 weeks of infection. Investigating gut integrity, oxidized lipids and inflammatory markers is important for understanding PASC pathogenesis.

Methods: A cross-sectional study including COVID+ with PASC, COVID+ without PASC, and COVID-negative (COVID-) participants. We measured plasma markers by enzyme-linked immunosorbent assay to assess intestinal permeability (ZONULIN), microbial translocation (lipopolysaccharide-binding protein or LBP), systemic inflammation (high-sensitivity C-reactive protein or hs-CRP), and oxidized low-density lipoprotein (Ox-LDL).

Results: 415 participants were enrolled in this study; 37.83% (n=157) had prior COVID diagnosis and among COVID+, 54% (n=85) had PASC. The median zonulin among COVID- was 3.37 (IQR: 2.13, 4.91) mg/mL, 3.43 (IQR: 1.65, 5.25) mg/mL among COVID+ no PASC, and highest [4.76 (IQR: 3.2, 7.35) mg/mL] among COVID+ PASC+ (p<.0001). The median ox-LDL among COVID- was 47.02 (IQR: 35.52, 62.77) U/L, 57.24 (IQR: 40.7, 75.37) U/L among COVID+ No PASC, and the highest [76.75 (IQR: 59.95, 103.28) U/L] among COVID+ PASC+ (p<.0001). COVID+ PASC+ was positively associated with zonulin (p=0.0002) and ox-LDL (p<.0001), and COVID- was negatively associated with ox-LDL (p=0.01), compared to COVID+ No PASC. Every unit increase in zonulin was associated with 44% higher predicted odds of having PASC [aOR: 1.44 (95%CI: 1.1, 1.9)] and every one-unit increase in ox-LDL was associated with more than four-fold increased odds of having PASC [aOR: 2.44 (95%CI: 1.67, 3.55)].

Conclusions: PASC is associated with increased gut permeability and oxidized lipids. Further studies are needed to clarify whether these relationships are causal which could lead to targeted therapeutics.

Source: Mouchati C, Durieux JC, Zisis SN, Labbato D, Rodgers MA, Ailstock K, Reinert BL, Funderburg NT, McComsey GA. Increase in gut permeability and oxidized ldl is associated with post-acute sequelae of SARS-CoV-2. Front Immunol. 2023 May 12;14:1182544. doi: 10.3389/fimmu.2023.1182544. PMID: 37251403; PMCID: PMC10217362. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10217362/ (Full text)

 

Could mitochondrial dysfunction be a differentiating marker between chronic fatigue syndrome and fibromyalgia?

Abstract:

Chronic fatigue syndrome (CFS) and fibromyalgia (FM) are complex and serious illnesses that affect approximately 2.5% and 5% of the general population worldwide, respectively. The etiology is unknown; however, recent studies suggest that mitochondrial dysfunction has been involved in the pathophysiology of both conditions. We have investigated the possible association between mitochondrial biogenesis and oxidative stress in patients with CFS and FM.

We studied 23 CFS patients, 20 FM patients, and 15 healthy controls. Peripheral blood mononuclear cell showed decreased levels of Coenzyme Q10 from CFS patients (p<0.001 compared with controls) and from FM subjects (p<0.001 compared with controls) and ATP levels for CFS patients (p<0.001 compared with controls) and for FM subjects (p<0.001 compared with controls).

On the contrary, CFS/FM patients had significantly increased levels of lipid peroxidation, respectively (p<0.001 for both CFS and FM patients with regard to controls) that were indicative of oxidative stress-induced damage. Mitochondrial citrate synthase activity was significantly lower in FM patients (p<0.001) and, however, in CFS, it resulted in similar levels than controls. Mitochondrial DNA content (mtDNA/gDNA ratio) was normal in CFS and reduced in FM patients versus healthy controls, respectively (p<0.001). Expression levels of peroxisome proliferator-activated receptor gamma-coactivator 1-alpha and transcription factor A, mitochondrial by immunoblotting were significantly lower in FM patients (p<0.001) and were normal in CFS subjects compared with healthy controls.

These data lead to the hypothesis that mitochondrial dysfunction-dependent events could be a marker of differentiation between CFS and FM, indicating the mitochondria as a new potential therapeutic target for these conditions.

 

Source: Castro-Marrero J, Cordero MD, Sáez-Francas N, Jimenez-Gutierrez C, Aguilar-Montilla FJ, Aliste L, Alegre-Martin J. Could mitochondrial dysfunction be a differentiating marker between chronic fatigue syndrome and fibromyalgia? Antioxid Redox Signal. 2013 Nov 20;19(15):1855-60. doi: 10.1089/ars.2013.5346. Epub 2013 May 29. https://www.ncbi.nlm.nih.gov/pubmed/23600892

 

Lipid and protein oxidation in female patients with chronic fatigue syndrome

Abstract:

INTRODUCTION: Chronic fatigue syndrome (CFS) is a widely recognized problem, characterized by prolonged, debilitating fatigue and a characteristic group of accompanying symptoms, that occurs four times more frequently in women than in men. The aim of the study was to determine the existence of oxidative stress and its possible consequences in female patients with CFS.

MATERIAL AND METHODS: Twenty-four women aged 15-45 who fulfilled the diagnostic criteria for CFS with no comorbidities were recruited and were age matched to a control group of 19 healthy women. After conducting the routine laboratory tests, levels of the lipid oxidation product malondialdehyde (MDA) and protein oxidation protein carbonyl (CO) were determined.

RESULTS: The CFS group had higher levels of triglycerides (p = 0.03), MDA (p = 0.03) and CO (p = 0.002) and lower levels of HDL cholesterol (p = 0.001) than the control group. There were no significant differences in the levels of total protein, total cholesterol or LDL cholesterol.

CONCLUSIONS: The CFS group had an unfavorable lipid profile and signs of oxidative stress induced damage to lipids and proteins. These results might be indicative of early proatherogenic processes in this group of patients who are otherwise at low risk for atherosclerosis. Antioxidant treatment and life style changes are indicated for women with CFS, as well as closer observation in order to assess the degree of atherosclerosis.

 

Source: Tomic S, Brkic S, Maric D, Mikic AN. Lipid and protein oxidation in female patients with chronic fatigue syndrome. Arch Med Sci. 2012 Nov 9;8(5):886-91. doi: 10.5114/aoms.2012.31620. Epub 2012 Nov 7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3506242/ (Full article)

 

Lipid peroxidation is elevated in female patients with chronic fatigue syndrome

Abstract:

BACKGROUND: Chronic fatigue syndrome is a debilitating disease of unclear cause and pathogenesis. It affects mostly women from lower socioeconomic classes. There is mounting evidence that oxidative stress, specifically lipid peroxidation (LPO) contributes to the disease process. We investigated levels of LPO and its possible consequences for these patients.

MATERIAL/METHODS: Forty women aged 15-45 years who fulfilled the 1994 Centers for Disease Control’s diagnostic criteria for chronic fatigue syndrome (CFS) with no comorbidities were recruited and were age matched to a control group of 40 healthy women. Levels of total cholesterol (TC), triglycerides (TG), LDL cholesterol (LDLc), HDL cholesterol (HDLc), and malondialdehyde (MDA) levels were measured.

RESULTS: Although initial statistical analyses showed no differences between groups (P=.345), when subdivided according to the level of MDA, a difference was found in the subgroup of high-level MDA (P=.034). There was a negative correlation between HDLc and MDA levels (r=0.3; P=.046), a positive correlation between TG and MDA levels (r=0.4; P=.006), and lower levels of HDL cholesterol in the CFS group (P=.036).

CONCLUSIONS: High levels of MDA, positively correlated with TG and lower HDL levels, might be indicative of proatherogenic events in female CFS patients, a group not otherwise considered a risk for atherosclerosis.

 

Source: Brkic S, Tomic S, Maric D, Novakov Mikic A, Turkulov V. Lipid peroxidation is elevated in female patients with chronic fatigue syndrome. Med Sci Monit. 2010 Dec;16(12):CR628-32. https://www.ncbi.nlm.nih.gov/pubmed/21119582

 

Antioxidant status and lipoprotein peroxidation in chronic fatigue syndrome

Abstract:

The aetiology and pathogenesis of the Chronic Fatigue Syndrome (CFS) are still largely unresolved. Accompanying metabolic disorders such as selective n-6 fatty acid depletion suggest that oxidative stress and more specifically lipid peroxidation might play a role in its pathogenesis.

In order to investigate this hypothesis, oxidant-antioxidant status and its impact on lipoprotein peroxidation in vitro was examined in 61 patients with unexplained fatigue lasting more than 1 month. They were subdivided into 2 groups: group CFS+ (33 subjects) fulfilled the 1988 Center of Disease Control criteria for CFS and group CFS- did not but was similar as regards age, sex distribution and clinical characteristics.

Antioxidant status was similar in the 2 groups except for lower serum transferrin in the CFS + (mean (95 % CI) 2.41 (2.28-2.54) versus 2.73 (2.54-2.92) g/L in the CFS-, p = 0.009) and higher lipoprotein peroxidation in vitro: 6630 (5949-7312) versus 5581 (4852-6310) nmol MDA/mg LDL and VLDL cholesterol x minutes, p = 0.035). CFS intensified the influence of LDL cholesterol (p = 0.012) and of transferrin (p = 0.045) on peroxidation in vitro, suggesting additional pro-oxidant effects.

These results indicate that patients with CFS have increased susceptibility of LDL and VLDL to copper-induced peroxidation and that this is related both to their lower levels of serum transferrin and to other unidentified pro-oxidising effects of CFS.

 

Source: Manuel y Keenoy B, Moorkens G, Vertommen J, De Leeuw I. Antioxidant status and lipoprotein peroxidation in chronic fatigue syndrome. Life Sci. 2001 Mar 16;68(17):2037-49. http://www.ncbi.nlm.nih.gov/pubmed/11388705

 

Magnesium status and parameters of the oxidant-antioxidant balance in patients with chronic fatigue: effects of supplementation with magnesium

Abstract:

OBJECTIVE: Magnesium deficiency and oxidative stress have both been identified as pathogenic factors in aging and in several age-related diseases. The link between these two factors is unclear in humans although, in experimental animals, severe Mg deficiency has been shown to lead to increased oxidative stress.

METHODS: The relationship between Mg body stores, dietary intakes and supplements on the one hand and parameters of the oxidant-antioxidant balance on the other was investigated in human subjects.

RESULTS: The study population consisted of 93 patients with unexplained chronic fatigue (median age 38 years, 25% male, 16% smokers and 54% with Chronic Fatigue Syndrome (CFS). Mg deficient patients (47%) had lower total antioxidant capacity in plasma (p=0.007) which was related to serum albumin. Mg deficient patients whose Mg body stores did not improve after oral supplementation with Mg (10 mg/kg/day) had persistently lower blood glutathione levels (p=0.003). In vitro production of thiobarbituric acid reactive substances (TBARS) by non-HDL lipoproteins incubated with copper was related to serum cholesterol (p<0.001) but not to Mg or antioxidants and did not improve after Mg supplementation. In contrast, velocity of formation of fluorescent products of peroxidation (slope) correlated with serum vitamin E (p<0.001), which was, in turn, related to Mg dietary intakes. Both slope and serum vitamin E improved after Mg supplementation (p<0.001).

CONCLUSIONS: These results show that the lower antioxidant capacity found in moderate Mg deficiency was not due to a deficit in Mg dietary intakes and was not accompanied by increased lipid susceptibility to in vitro peroxidation. Nevertheless, Mg supplementation was followed by an improvement in Mg body stores, in serum vitamin E and its interrelated stage of lipid peroxidation.

 

Source: Manuel y Keenoy B, Moorkens G, Vertommen J, Noe M, Nève J, De Leeuw I. Magnesium status and parameters of the oxidant-antioxidant balance in patients with chronic fatigue: effects of supplementation with magnesium. J Am Coll Nutr. 2000 Jun;19(3):374-82. http://www.ncbi.nlm.nih.gov/pubmed/10872900