Tag: oxidative stress

Polyphenols as possible alternative agents in chronic fatigue: a review

Abstract:

Chronic fatigue syndrome (CFS) is a pathological state of extreme tiredness that lasts more than six months and may possess an impact on the social, emotional, or occupational functioning of an individual. CFS is characterized by profound disabling fatigue associated with infectious, rheumatological, and neurological symptoms.

The current pharmacological treatment for CFS does not offer a complete cure for the disease, and none of the available treatments show promising results.

The exact mechanism of the pathogenesis of the disease is still unknown, with current suggestions indicating the overlapping roles of the immune system, central nervous system, and neuroendocrine system.

However, the pathological mechanism revolves around inflammatory and oxidative stress markers.

Polyphenols are the most abundant secondary metabolites of plant origin, with potent antioxidant and anti-inflammatory effects, and can exert protective activity against a whole range of disorders.

The current review is aimed at highlighting the emerging role of polyphenols in CFS from both preclinical and clinical studies. Numerous agents of this class have shown promising results in different in vitro and in vivo models of chronic fatigue/CFS, predominantly by counteracting oxidative stress and the inflammatory cascade.

The clinical data in this regard is still very limited and needs expanding through randomized, placebo-controlled studies to draw final conclusions on whether polyphenols may be a class of clinically effective nutraceuticals in patients with CFS.

Source: Ullah, H., Khan, A., Riccioni, C. et al. Polyphenols as possible alternative agents in chronic fatigue: a review. Phytochem Rev (2022). https://doi.org/10.1007/s11101-022-09838-9 (Full text)

Targeting endothelial dysfunction and oxidative stress in Long-COVID

Comment:

We thank Dr. Hsu and Dr. Lai for their interest in our work on COVID-19 and Long-COVID.

We fully agree with them on the fact that several factors need to be pondered in order to evaluate the risk of developing Long-COVID , . However, we respectfully believe that these considerations are not pertinent to our study . Indeed, we designed the LINCOLN (l-Arginine and Vitamin C improves Long-COVID) survey to determine whether a supplementation combining l-Arginine (to improve endothelial function) and Vitamin C (to reduce oxidation) could have favorable effects in patients with Long-COVID . Thus, in our study we did not assess the risk of developing Long-COVID; in fact, as clearly specified in our article, all the enrolled patients had Long-COVID when the survey was administered. Nevertheless, potential differences in health conditions between the group that had received l-Arginine + Vitamin C and the group that had received the alternative treatment were ruled out by their family physicians. When comparing the two groups, we did not observe any significant difference in terms of age, sex, hospitalization due to COVID-19, and time from SARS-Cov-2 negativization. Moreover, bearing in mind the limitations that all surveys have, we had concluded our article stating that further dedicated interventional studies were warranted to endorse our findings.

Of note, we have previously conducted a randomized, double-blind, placebo-controlled, parallel-group, clinical trial testing the effects of l-Arginine oral supplementation in patients hospitalized for COVID-19, demonstrating that this treatment significantly decreases the length of hospitalization and reduces the respiratory support . Additionally, we have identified endothelial exosomes enriched in miR-24 as a reliable biomarker to predict cerebrovascular complications of COVID-19 , corroborating the fundamental role of endothelial dysfunction in the pathobiology of COVID-19 and its clinical sequelae .

Source: Trimarco V, Izzo R, Mone P, Trimarco B, Santulli G. Targeting endothelial dysfunction and oxidative stress in Long-COVID. Pharmacol Res. 2022 Sep 13;184:106451. doi: 10.1016/j.phrs.2022.106451. Epub ahead of print. PMID: 36108875; PMCID: PMC9467917. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9467917/ (Full text)

The potential role of ischaemia-reperfusion injury in chronic, relapsing diseases such as rheumatoid arthritis, Long COVID, and ME/CFS: evidence, mechanisms, and therapeutic implications

Abstract:

Ischaemia-reperfusion (I-R) injury, initiated via bursts of reactive oxygen species produced during the reoxygenation phase following hypoxia, is well known in a variety of acute circumstances. We argue here that I-R injury also underpins elements of the pathology of a variety of chronic, inflammatory diseases, including rheumatoid arthritis, ME/CFS and, our chief focus and most proximally, Long COVID.

Ischaemia may be initiated via fibrin amyloid microclot blockage of capillaries, for instance as exercise is started; reperfusion is a necessary corollary when it finishes. We rehearse the mechanistic evidence for these occurrences here, in terms of their manifestation as oxidative stress, hyperinflammation, mast cell activation, the production of marker metabolites and related activities.

Such microclot-based phenomena can explain both the breathlessness/fatigue and the post-exertional malaise that may be observed in these conditions, as well as many other observables. The recognition of these processes implies, mechanistically, that therapeutic benefit is potentially to be had from antioxidants, from anti-inflammatories, from iron chelators, and via suitable, safe fibrinolytics, and/or anti-clotting agents. We review the considerable existing evidence that is consistent with this, and with the biochemical mechanisms involved.

Source: Kell DB, Pretorius E. The potential role of ischaemia-reperfusion injury in chronic, relapsing diseases such as rheumatoid arthritis, Long COVID, and ME/CFS: evidence, mechanisms, and therapeutic implications. Biochem J. 2022 Aug 31;479(16):1653-1708. doi: 10.1042/BCJ20220154. PMID: 36043493. https://portlandpress.com/biochemj/article/479/16/1653/231696/The-potential-role-of-ischaemia-reperfusion-injury (Full text)

Lowered Quality of Life in Long COVID Is Predicted by Affective Symptoms, Chronic Fatigue Syndrome, Inflammation and Neuroimmunotoxic Pathways

Abstract:

The physio-affective phenome of Long COVID-19 is predicted by (a) immune-inflammatory biomarkers of the acute infectious phase, including peak body temperature (PBT) and oxygen saturation (SpO2), and (b) the subsequent activation of immune and oxidative stress pathways during Long COVID. The purpose of this study was to delineate the effects of PBT and SpO2 during acute infection, as well as the increased neurotoxicity on the physical, psychological, social and environmental domains of health-related quality of life (HR-QoL) in people with Long COVID.

We recruited 86 participants with Long COVID and 39 normal controls, assessed the WHO-QoL-BREF (World Health Organization Quality of Life Instrument-Abridged Version, Geneva, Switzerland) and the physio-affective phenome of Long COVID (comprising depression, anxiety and fibromyalgia-fatigue rating scales) and measured PBT and SpO2 during acute infection, and neurotoxicity (NT, comprising serum interleukin (IL)-1β, IL-18 and caspase-1, advanced oxidation protein products and myeloperoxidase, calcium and insulin resistance) in Long COVID.

We found that 70.3% of the variance in HR-QoL was explained by the regression on the physio-affective phenome, lowered calcium and increased NT, whilst 61.5% of the variance in the physio-affective phenome was explained by calcium, NT, increased PBT, lowered SpO2, female sex and vaccination with AstraZeneca and Pfizer. The effects of PBT and SpO2 on lowered HR-QoL were mediated by increased NT and lowered calcium yielding increased severity of the physio-affective phenome which largely affects HR-QoL.

In conclusion, lowered HR-Qol in Long COVID is largely predicted by the severity of neuro-immune and neuro-oxidative pathways during acute and Long COVID.

Source: Maes M, Al-Rubaye HT, Almulla AF, Al-Hadrawi DS, Stoyanova K, Kubera M, Al-Hakeim HK. Lowered Quality of Life in Long COVID Is Predicted by Affective Symptoms, Chronic Fatigue Syndrome, Inflammation and Neuroimmunotoxic Pathways. Int J Environ Res Public Health. 2022 Aug 19;19(16):10362. doi: 10.3390/ijerph191610362. PMID: 36011997. https://www.mdpi.com/1660-4601/19/16/10362/htm (Full text)

In Schizophrenia, Chronic Fatigue Syndrome- and Fibromyalgia-Like Symptoms are Driven by Breakdown of the Paracellular Pathway with Increased Zonulin and Immune Activation-Associated Neurotoxicity

Abstract:

Background: A meaningful part of schizophrenia patients suffer from physiosomatic symptoms (formerly named psychosomatic) which are reminiscent of chronic fatigue syndrome and fibromyalgia (FF) and are associated with signs of immune activation and increased levels of tryptophan catabolites (TRYCATs).

Aims: To examine whether FF symptoms in schizophrenia are associated with breakdown of the paracellular pathway, zonulin, lowered natural IgM responses to oxidative specific epitopes (OSEs); and whether FF symptoms belong to the behavioral-cognitive-physical-psychosocial-(BCPS)-worsening index consisting of indices of a general cognitive decline (G-CoDe), symptomatome of schizophrenia, and quality of life (QoL)-phenomenome.

Methods: FF symptoms were assessed using the Fibromyalgia and Chronic Fatigue Rating scale in 80 schizophrenia patients and 40 healthy controls and serum cytokines/chemokines, IgA levels to TRYCATs, IgM to OSEs, zonulin and transcellular/paracellular (TRANS/PARA) molecules were assayed using ELISA methods.

Results: A large part (42.3%) of the variance in the total FF score was explained by the regression on the PARA/TRANS ratio, pro-inflammatory cytokines, IgM to zonulin, IgA to TRYCATs (all positively) and IgM to OSEs (inversely). There were highly significant correlations between the total FF score and G-CoDe, symtopmatome, QoL phenomenome and BCPS-worsening score. FF symptoms belong to a common core shared by G-CoDe, symtopmatome, and QoL phenomenome.

Discussion: The physio-somatic symptoms of schizophrenia are driven by various pathways including increased zonulin, breakdown of the paracellular tight-junctions pathway, immune activation with induction of the TRYCAT pathway, and consequent neurotoxicity. It is concluded that FF symptoms are part of the phenome of schizophrenia and BCPS-worsening as well.

Source: Maes M, Andrés-Rodríguez L, Vojdani A, Sirivichayakul S, Barbosa DS, Kanchanatawan B. In Schizophrenia, Chronic Fatigue Syndrome- and Fibromyalgia-Like Symptoms are Driven by Breakdown of the Paracellular Pathway with Increased Zonulin and Immune Activation-Associated Neurotoxicity. CNS Neurol Disord Drug Targets. 2022 Aug 6. doi: 10.2174/1871527321666220806100600. Epub ahead of print. PMID: 35946099.

Rationale for Nicotinamide Adenine Dinucleotide (NAD+) Metabolome Disruption as a Pathogenic Mechanism of Post-Acute COVID-19 Syndrome

Abstract:

Many acute COVID-19 convalescents experience a persistent sequelae of infection, called post-acute COVID-19 syndrome (PACS). With incidence ranging between 31% and 69%, PACS is becoming increasingly acknowledged as a new disease state in the context of SARS-CoV-2 infection. As SARS-CoV-2 infection can affect several organ systems to varying degrees and durations, the cellular and molecular abnormalities contributing to PACS pathogenesis remain unclear.

Despite our limited understanding of how SARS-CoV-2 infection promotes this persistent disease state, mitochondrial dysfunction has been increasingly recognized as a contributing factor to acute SARS-CoV-2 infection and, more recently, to PACS pathogenesis. The biological mechanisms contributing to this phenomena have not been well established in previous literature; however, in this review, we summarize the evidence that NAD+ metabolome disruption and subsequent mitochondrial dysfunction following SARS-CoV-2 genome integration may contribute to PACS biological pathogenesis.

We also briefly examine the coordinated and complex relationship between increased oxidative stress, inflammation, and mitochondrial dysfunction and speculate as to how SARS-CoV-2-mediated NAD+ depletion may be causing these abnormalities in PACS. As such, we present evidence supporting the therapeutic potential of intravenous administration of NAD+ as a novel treatment intervention for PACS symptom management.

Source: Block T, Kuo J. Rationale for Nicotinamide Adenine Dinucleotide (NAD+) Metabolome Disruption as a Pathogenic Mechanism of Post-Acute COVID-19 Syndrome. Clin Pathol. 2022 Jun 24;15:2632010X221106986. doi: 10.1177/2632010X221106986. PMID: 35769168; PMCID: PMC9234841. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9234841/ (Full text)

Could the kynurenine pathway be the key missing piece of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) complex puzzle?

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex and debilitating disease with a substantial social and economic impact on individuals and their community. Despite its importance and deteriorating impact, progresses in diagnosis and treatment of ME/CFS is limited. This is due to the unclear pathophysiology of the disease and consequently lack of prognostic biomarkers.

To investigate pathophysiology of ME/CFS, several potential pathologic hallmarks have been investigated; however, these studies have failed to report a consistent result. These failures in introducing the underlying reason for ME/CFS have stimulated considering other possible contributing mechanisms such as tryptophan (TRP) metabolism and in particular kynurenine pathway (KP).

KP plays a central role in cellular energy production through the production of nicotinamide adenine dinucleotide (NADH). In addition, this pathway has been shown to mediate immune response and neuroinflammation through its metabolites. This review, we will discuss the pathology and management of ME/CFS and provide evidence pertaining KP abnormalities and symptoms that are classic characteristics of ME/CFS. Targeting the KP regulation may provide innovative approaches to the management of ME/CFS.

Source: Kavyani B, Lidbury BA, Schloeffel R, Fisher PR, Missailidis D, Annesley SJ, Dehhaghi M, Heng B, Guillemin GJ. Could the kynurenine pathway be the key missing piece of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) complex puzzle? Cell Mol Life Sci. 2022 Jul 11;79(8):412. doi: 10.1007/s00018-022-04380-5. PMID: 35821534. https://link.springer.com/article/10.1007/s00018-022-04380-5  (Full text)

Intracellular Nutritional Biomarker Differences in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Subjects and Healthy Controls

Abstract:

Objectives

A comparison of the nutritional biomarkers between ME/CFS subjects and healthy controls (HC) was undertaken on secondary data collected from an IRB approved cross-sectional study in ME/CFS patients.

Methods

ME/CFS participants were recruited per the 2018 revised Canadian Clinical Case Definition for ME/CFS along with age matched HCs. Self-reported information on demographics and supplement use was collected, and body mass index calculated. HEI was calculated from Willet FFQ and multiple day 24-hour recall data, and severity of fatigue measured by Multidimensional Fatigue Inventory (MFI). Lymphocyte transformation assay by SpectraCell Lab (Houston, TX) was employed for intracellular micronutrient status. A series of two-tailed Mann-Whitney U tests (ɑ = 0.05) were performed for the non-parametric data expressed as mean ± standard error of the mean. All statistical analyses were conducted in IBM SPSS Statistics version 25 (Armonk, NY).

Results

Out of the 21 participants (11 ME/CFS and 10 HC), 82% of ME/CFS and 50% of HC were female. Higher fatigue scores were observed in ME/CFS (16.64 ± 1.36) than HC (10.78 ± 2.14). ME/CFS had better HEI scores (63.36 ± 13.44) than the HC (38.55 ± 12.29). However, despite better diet quality and supplementation, ME/CFS group showed lower intracellular Vitamin B3 and manganese (Mn) (86.3 ± 2.42 and 53.6 ± 2.81 respectively) but higher calcium (Ca) (57.5 ± 3.55) as compared to HC (97.2 ± 2.31, 64.5 ± 1.87 and 46.5 ± 0.96 respectively).

Conclusions

The results align with the current literature on indications of mitochondrial dysfunction in ME/CFS. Reduced intracellular vit B3 provides suboptimal production of the NAD(P)(H)-cofactor family, thus affecting mitochondrial function and consequently energy production. The aberration in energy metabolism is compounded by other factors, such as reduced Mn but higher Ca intracellular levels seen in this study indicating disruptions in oxidative stress pathways, resulting in debilitating fatigue experienced by individuals with ME/CFS.

Source: Priya Krishnakumar, Camila Jaramillo, Shawn Kurian, Wendy Levy, Cara Milman, Nadine Mikati, Fatma Huffman, Maria Abreu, Amanpreet Cheema, Intracellular Nutritional Biomarker Differences in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Subjects and Healthy Controls, Current Developments in Nutrition, Volume 6, Issue Supplement_1, June 2022, Page 745, https://doi.org/10.1093/cdn/nzac062.014

Long COVID and the Autonomic Nervous System: The Journey from Dysautonomia to Therapeutic Neuro-Modulation through the Retrospective Analysis of 152 Patients

Abstract:

Introduction. The severity and prevalence of Post-Acute COVID-19 Sequela (PACS) or long-COVID syndrome (long COVID) should not be a surprise. Long-COVID symptoms may be explained by oxidative stress and parasympathetic and sympathetic (P&S) dysfunction. This is a retrospective, hypothesis generating, outcomes study.
Methods. From two suburban practices in northeastern United States, 152 long COVID patients were exposed to the following practices: (1) first, they were P&S tested (P&S Monitor 4.0; Physio PS, Inc., Atlanta, GA, USA) prior to being infected with COVID-19 due to other causes of autonomic dysfunction; (2) received a pre-COVID-19 follow-up P&S test after autonomic therapy; (3) then, they were infected with COVID-19; (4) P&S tested within three months of surviving the COVID-19 infection with long-COVID symptoms; and, finally, (5) post-COVID-19, follow-up P&S tested, again, after autonomic therapy. All the patients completed autonomic questionnaires with each test. This cohort included 88 females (57.8%), with an average age of 47.0 years (ranging from 14 to 79 years), and an average BMI of 26.9 #/in2. Results. More pre-COVID-19 patients presented with sympathetic withdrawal than parasympathetic excess. Post-COVID-19, these patients presented with this ratio reversed and, on average, 49.9% more autonomic symptoms than they did pre-COVID-19.
Discussion. Both parasympathetic excess and sympathetic withdrawal are separate and treatable autonomic dysfunctions and autonomic treatment significantly reduces the prevalence of autonomic symptoms.
Conclusion. SARS-CoV-2, via its oxidative stress, can lead to P&S dysfunction, which, in turn, affects the control and coordination of all systems throughout the whole body and may explain all of the symptoms of long-COVID syndrome. Autonomic therapy leads to positive outcomes and patient quality of life may be restored.
Source: Colombo J, Weintraub MI, Munoz R, Verma A, Ahmad G, Kaczmarski K, Santos L, DePace NL. Long COVID and the Autonomic Nervous System: The Journey from Dysautonomia to Therapeutic Neuro-Modulation through the Retrospective Analysis of 152 Patients. NeuroSci. 2022; 3(2):300-310. https://doi.org/10.3390/neurosci3020021 https://www.mdpi.com/2673-4087/3/2/21/htm (Full text)

Aberrations in the Cross-Talks Among Redox, Nuclear Factor-κB, and Wnt/β-Catenin Pathway Signaling Underpin Myalgic Encephalomyelitis and Chronic Fatigue Syndrome

Abstract:

There is evidence that chronic fatigue spectrum disorders (CFAS-D) including Myalgic Encephalomyelitis (ME), chronic fatigue syndrome (CFS) and chronic fatigue with physiosomatic symptoms including when due to comorbid medical disease are characterized by neuroimmune and neuro-oxidative biomarkers.

The present study was performed to delineate the protein-protein interaction (PPI) network of CFAS-D and to discover the pathways, molecular patterns and domains enriched in their PPI network.

We performed network, enrichment and annotation analysis using differentially expressed proteins and metabolics, which were established in CFAS-D patients.

PPI network analysis revealed that the backbone of the highly connective CFAS-D network comprises NFKB1, CTNNB1, ALB, peroxides, NOS2, TNF, and IL6, and that the network comprises interconnected immune-oxidative-nitrosative and Wnt/catenin subnetworks.

MultiOmics enrichment analysis shows that the CFAS-D network is highly significantly associated with cellular (antioxidant) detoxification, hydrogen peroxide metabolic process, peroxidase and oxidoreductase activity, IL10 anti-inflammatory signaling, and neurodegenerative, canonical Wnt, the catenin complex, cadherin domains, cell-cell junctions and TLR2/4 pathways; and the transcription factors NF-κB and RELA.

The top-10 DOID annotations of the CFAS-D network include four intestinal, three immune system disorders, cancer and infectious disease.

Custom GO term annotation analysis revealed that the CFAS-D network is associated with a response to a toxic substance, lipopolysaccharides, bacterium or virus.

In conclusion, CFAS-D may be triggered by a variety of stimuli and their effects are mediated by aberrations in the cross-talks between redox, NF-κB, and Wnt/catenin signaling pathways leading to dysfunctions in multicellular organismal homeostatic processes.

Source: Michael Maes, Marta Kubera and Magdalena Kotańska. Aberrations in the Cross-Talks Among Redox, Nuclear Factor-κB, and Wnt/β-Catenin Pathway Signaling Underpin Myalgic Encephalomyelitis and Chronic Fatigue Syndrome. Frontiers in Psychiatry 13: 822382. https://www.frontiersin.org/articles/10.3389/fpsyt.2022.822382/full  (Full text)