Pharmacological significance of MitoQ in ameliorating mitochondria-related diseases

Abstract:

The Mitochondria is a critical sub-cellular organelle that plays an integral part in a normal cellular process. Besides ATP production, the mitochondria participate in various key cellular processes such as cell signalingepigenetic regulation leading to cell proliferation, migration, apoptosis, differentiation, and autophagy – highlighting their importance to cellular health. However, mitochondrial dysfunction has serious organismal consequences, playing critical roles in the pathophysiology of many diseases, including neurodegenerative disorders, cardiovascular diseases, cancer, pulmonary and liver diseases. In recent years, mitochondrial dysfunction has spurred a surge of interest in developing mitochondria-targeted therapies.

MitoQ is a selective antioxidant that concentrates in the mitochondria and prevents oxidative damage to the mitochondria. The therapeutic relevance of MitoQ has been studied in various diseased conditions to determine its efficacy in either slowing disease progression or alleviating symptoms. In this review, we discussed mitochondrial dysfunction in selected diseases and the therapeutic benefit of MitoQ in numerous studies.

Source: Lateef Adegboyega Sulaimon, Lukman Olalekan Afolabi, Rahmat Adetutu Adisa, Akinrinade George Ayankojo, Mariam Olanrewaju Afolabi, Abiodun Mohammed Adewolu, Xiaochun Wan. Pharmacological significance of MitoQ in ameliorating mitochondria-related diseases. Advances in Redox Research, 2022 [In Press, Journal pre-proof]  https://www.sciencedirect.com/science/article/pii/S2667137922000091 (Full text)

Chronic Fatigue Exhibits heterogeneous autoimmunity characteristics which reflect etiology

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is considered to be associated with post-viral complications and mental stress, but the role of autoimmunity also remains promising. A comparison of autoimmune profiles in chronic fatigue of different origin may bring insights on the pathogenesis of this disease.
Thirty-three patients with CFS/ME were divided into three subgroups. The first group included Herpesviridae carriers (group V), the second group included stress-related causes of chronic fatigue (distress, group D), and the third group included idiopathic CFS/ME (group I). Were evaluated thirty-six neural and visceral autoantigens with the ELISA ELI-test (Biomarker, Russia) and compared to 20 healthy donors, either without any fatigue (group H), or “healthy but tired” (group HTd) with episodes of fatigue related to job burnout not fitting the CFS/ME criteria. β2-glycoprotein-I autoantibodies were increased in CFS/ME patients, but not in healthy participants, that alludes the link between CFS/ME and antiphospholipid syndrome (APS) earlier suspected by Berg et al. (1999).
In CFS/ME patients, an increase in levels of autoantibodies towards the non-specific components of tissue debris (double-stranded DNA, collagen) was shown. Both CFS and HTd subgroups had elevated level of autoantibodies against serotonin receptors, glial fibrillary acidic protein and protein S100. Only group V showed an elevation in the autoantibodies towards voltage-gated calcium channels, and only group D had elevated levels of dopamine-, glutamate- and GABA-receptor autoantibodies, as well as NF200-protein autoantibodies. Therefore, increased autoimmune reactions to the multiple neural antigens and to adrenal medullar antigen, but not to other tissue-specific somatic ones were revealed.
An increase in autoantibody levels towards some neural and non-tissue-specific antigens strongly correlated with a CFS/ME diagnosis. Autoimmune reactions were described in all subtypes of the clinically significant chronic fatigue. Visceral complaints in CFS/ME patients may be secondary to the neuroendocrine involvement and autoimmune dysautonomia. CFS may be closely interrelated with antiphospholipid syndrome, that requires further study.
Source: Danilenko OV, Gavrilova NY, Churilov LP. Chronic Fatigue Exhibits Heterogeneous Autoimmunity Characteristics Which Reflect Etiology. Pathophysiology. 2022; 29(2):187-199. https://doi.org/10.3390/pathophysiology29020016 https://www.mdpi.com/1873-149X/29/2/16/htm (Full text)

Therapeutic Implications of the Microbial Hypothesis of Mental Illness

Abstract:

There is increasingly compelling evidence that microorganisms may play an etiological role in the emergence of mental illness in a subset of the population. Historically, most work has focused on the neurotrophic herpesviruses, herpes simplex virus type 1 (HSV-1), cytomegalovirus (CMV), and Epstein-Barr virus (EBV) as well as the protozoan, Toxoplasma gondii. In this chapter, we provide an umbrella review of this literature and additionally highlight prospective studies that allow more mechanistic conclusions to be drawn.

Next, we focus on clinical trials of anti-microbial medications for the treatment of psychiatric disorders. We critically evaluate six trials that tested the impact of anti-herpes medications on inflammatory outcomes in the context of a medical disorder, nine clinical trials utilizing anti-herpetic medications for the treatment of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) or schizophrenia, and four clinical trials utilizing anti-parasitic medications for the treatment of schizophrenia.

We then turn our attention to evidence for a gut dysbiosis and altered microbiome in psychiatric disorders, and the potential therapeutic effects of probiotics, including an analysis of more than 10 randomized controlled trials of probiotics in the context of schizophrenia, bipolar disorder (BD), and major depressive disorder (MDD).

Source: Savitz J, Yolken RH. Therapeutic Implications of the Microbial Hypothesis of Mental Illness. Curr Top Behav Neurosci. 2022 May 24. doi: 10.1007/7854_2022_368. Epub ahead of print. PMID: 35606640. https://pubmed.ncbi.nlm.nih.gov/35606640/

The Pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Case for Neuroglial Failure

Abstract:

Although myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has a specific and distinctive profile of clinical features, the disease remains an enigma because causal explanation of the pathobiological matrix is lacking. Several potential disease mechanisms have been identified, including immune abnormalities, inflammatory activation, mitochondrial alterations, endothelial and muscular disturbances, cardiovascular anomalies, and dysfunction of the peripheral and central nervous systems. Yet, it remains unclear whether and how these pathways may be related and orchestrated.

Here we explore the hypothesis that a common denominator of the pathobiological processes in ME/CFS may be central nervous system dysfunction due to impaired or pathologically reactive neuroglia (astrocytes, microglia and oligodendrocytes). We will test this hypothesis by reviewing, in reference to the current literature, the two most salient and widely accepted features of ME/CFS, and by investigating how these might be linked to dysfunctional neuroglia.

From this review we conclude that the multifaceted pathobiology of ME/CFS may be attributable in a unifying manner to neuroglial dysfunction. Because the two key features – post exertional malaise and decreased cerebral blood flow – are also recognized in a subset of patients with post-acute sequelae COVID, we suggest that our findings may also be pertinent to this entity.

Source: Renz-Polster H, Tremblay ME, Bienzle D, Fischer JE. The Pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Case for Neuroglial Failure. Front Cell Neurosci. 2022 May 9;16:888232. doi: 10.3389/fncel.2022.888232. PMID: 35614970; PMCID: PMC9124899. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9124899/ (Full text)

Fatigue Doesn’t Always have to be caused by SARS-CoV-2: Case Report

Abstract:

We report on a 17-year-old female adolescent who presented with marked fatigue. The cause of this was found to be Epstein-Barr virus (EBV) infection. Even during the COVID-19 pandemic, fatigue doesn’t always have to be caused by SARS-CoV‑2 but can also be induced by other adolescent-onset diseases (EBV), Up to 13.5 % of EBV sufferers develop chronic fatigue syndrome, which is why it makes sense to determine the exact cause. Diagnosis, therapy and prognosis of infectious mononucleosis are addressed.

Source: Howanietz H, Graf U, Kainz T. Fatigue muss nicht immer SARS-CoV-2-bedingt sein – eine Kasuistik [Fatigue Doesn’t Always have to be caused by SARS-CoV-2: Case Report]. Padiatr Padol. 2022 May 19:1-4. German. doi: 10.1007/s00608-022-00989-8. Epub ahead of print. PMID: 35611157; PMCID: PMC9118809. https://pubmed.ncbi.nlm.nih.gov/35611157/ [Full article in German]

Electroacupuncture at BL15 attenuates chronic fatigue syndrome by downregulating iNOS/NO signaling in C57BL/6 mice

Abstract:

Chronic fatigue syndrome (CFS) has a high incidence due to the increased pressure of daily life and work in modern society. Our previous clinical studies have found the effects of electroacupuncture (EA) on CFS patients, however, the mechanism of EA on CFS is still unknown. In this study, we investigated the effects of EA on cardiac function in a CFS mouse model to explore its underlying mechanism.

The mice were randomly divided into three groups: control, CFS, and CFS mice receiving EA (CFS + EA). After behavioral assessments and echocardiographic measurement, blood and heart tissue of the mice were collected for biochemical tests, and then we evaluated the effects of EA on the CFS mouse model when nitric oxide (NO) levels were enhanced by l-arginine.

The results showed that EA ameliorated the injured motor and cardiac function. Meanwhile, EA also inhibited increased expression of inducible nitric oxide synthase (iNOS) at heart tissue and the serum NO levels in mice subjected to sustained forced swimming stress. Furthermore, the NO level in serum increased with l-arginine administration, which blocked the effects of EA on CFS mice. This study suggested that EA could improve the motor function and cardiac function in CFS mice and its effects may be associated with the down-regulation of iNOS/NO signaling.

Source: Zhu Y, Wang J, Yao L, Huang Y, Yang H, Yu X, Chen X, Chen Y. Electroacupuncture at BL15 attenuates chronic fatigue syndrome by downregulating iNOS/NO signaling in C57BL/6 mice. Anat Rec (Hoboken). 2022 May 24. doi: 10.1002/ar.24953. Epub ahead of print. PMID: 35608198. https://pubmed.ncbi.nlm.nih.gov/35608198/

Known unknowns, and as yet medically unexplained diseases

Seen from the outside, the process of scientific exploration of diseases seems chaotic and confusing. Indeed, from within, it is tempting to deduce that clinical academics are chaotic and confused.

To be fair, that is an appropriate deduction. Einstein famously said, ‘If we knew what we were doing, it wouldn’t be called research.’ The vast majority of medical research can be compared to solving a particularly complex crossword puzzle. We start with the ‘easy answers’, then progress to the deducible, before staring endlessly at the problems that don’t make sense to us. The hope is that the pieces we already have will enable us to fill the gaps and produce a semblance of sense.

Practising medicine often does not allow this freedom of thought. If the CRP is falling, the antibiotics are working; if it is rising, they’re not; fracture is a fracture; air under the diaphragm represents burst viscera.

Where, then, do we place conditions that we don’t as yet have diagnostic tests for?

Read the rest of this article HERE.

Source: Known unknowns, and as yet medically unexplained diseases by David Strain. BMA, May 12, 2022. https://www.bma.org.uk/news-and-opinion/known-unknowns-and-as-yet-medically-unexplained-diseases

Chronic fatigue syndrome and occupational status: a retrospective longitudinal study

Dear Sir,

Occupational Medicine recently published a paper from Stevelink et al. [1] called ‘Chronic fatigue syndrome and occupational status: a retrospective longitudinal study’. Unfortunately, the paper features major technical and methodological errors that warrant urgent editorial attention.

To recap: The study started with 508 participants. The primary outcome was occupational status. Many participants had dropped out by follow-up—only 316, or 62%, provided follow-up data. Of those 316, 88% reported no change in employment status. As a group, the participants experienced either no changes or only insignificant ones in a range of secondary outcomes, including fatigue and physical function. The poor follow-up scores on fatigue and physical function alone indicate that the group remained, collectively, severely disabled after treatment.

In several sections of the paper, the authors’ description of their own statistical findings is incorrect. They make a recurring elementary error in their presentation of percentages. The authors repeatedly use the construction ‘X% of patients who did Y at baseline’ when they should have used the construction ‘X% of all 316 patients (i.e. those who provided follow-up data)’. This recurring error involving the core findings undermines the merit and integrity of the entire paper.

For example, in the Abstract, the authors state that ‘53% of patients who were working [at baseline] remained in employment [at follow-up]’. This is not accurate. Their own data (Table 2) show that 185 patients (i.e. 167 + 18) were working at baseline, and that 167 patients were working at both time points. In other words, the proportion working continuously was in fact 90% (i.e. 167 out of 185). The ‘53%’ that the authors refer to is the percentage of the sample who were employed at both time points (i.e. 167 out of 316), which is an entirely different subset. They have either misunderstood the percentage they were writing about, or they have misstated their own finding by linking it to the wrong percentage.

This error is carried over into the section on ‘Key Learning Lessons’, where the authors state that ‘Over half of the patients who were working at baseline were able to remain in work over the follow-up period…’ While 90% is certainly ‘over half’, it seems clear that this phrasing is again incorrectly referring to the 53% subset.

The same error is made with the other key findings. For example, the Abstract states that ‘Of the patients who were not working at baseline, 9% had returned to work at follow-up’. But as above, this is incorrect. A total of 131 patients (i.e. 104 + 27) were recorded as ‘not employed’ at baseline and 27 were recorded as not working at baseline but as working at follow-up. This is 21%, not 9%. Once again, the authors appear to misunderstand their own findings. The ‘9%’ they refer to is a percentage of the sample of 316; it is not, as they have it, a percentage of that subset of the sample who were initially unemployed. This erroneous ‘9%’ conclusion appears as well in the ‘Key Learning Lessons’ and in the Discussion.

And again, the authors state in the Abstract that ‘of those working at baseline, 6% were unable to continue to work at follow-up’, a claim they repeat in the section on ‘Key Learning Lessons’ and in the Discussion. This statement too is wrong. Once more, the authors mistakenly interpret a percentage of the sample of 316 as if it were a percentage of a targeted subset. In this case, they think they are referring to a percentage of patients working at baseline, but they are actually referring to a percentage of the full group that provided follow-up data.

The authors present the raw frequency data in Table 2. Readers can see for themselves how their sample of 316 patients is cross-tabulated into four subsets of interest (i.e. ‘working at baseline and follow-up’; ‘not working at baseline and follow-up’; ‘dropped out of work at follow-up’; ‘returned to work at follow-up’). From Table 2, it is clear that the prose provided in the body of the paper is at odds with the actual data.

It is undeniable that the text of this paper is replete with elementary technical errors, as described. Inevitably, the narrative is distorted by the authors’ failure to understand and correctly explain their own findings. It is unclear to us how these basic and self-evident errors were not picked up during peer review. Although we don’t know the identities of the peer reviewers, we speculate that groupthink and confirmation bias will have played their part. After all, it is generally reasonable for peer reviewers to presume that authors have understood their own computations.

There are several other features of this paper that cause concern. These include the following:

  • The authors state that they evaluated participants using guidance from the UK’s National Institute for Health and Care Excellence (NICE). (Presumably they are referring to the 2007 NICE guidance, not the revision published in October 2021.) But the reference for this statement is a 1991 paper that outlines the so-called ‘Oxford criteria’, a case definition that differs significantly from the 2007 NICE guidance. Moreover, in a paper about the same participant cohort previously published by Occupational Medicine—‘Factors associated with work status in chronic fatigue syndrome’—the authors state explicitly that these patients were diagnosed using the Oxford criteria. This inconsistency is non-trivial, because the differences between these two diagnostic approaches have substantive implications for how the findings should be interpreted. The authors’ confusion over the matter is hard to comprehend and raises fundamental questions about the validity of their research.

  • According to Table 1, there were either no changes or no meaningful changes in average scores for fatigue, physical function and multiple other secondary outcomes between the preliminary sample of 508 and the final follow-up sample of 316. The authors themselves acknowledge that the patients who dropped out before follow-up were likely to have had poorer health than those who remained. Therefore, the fact that Table 1 presents combined averages for the entire preliminary sample—i.e. combined averages for patients who dropped out and those who did not—muddies the waters. Presenting combined baseline scores for all patients will mask any declines that occurred for these variables in the subset who were followed up. It would have been far more appropriate to have isolated and presented the baseline data for the 316 followed up patients alone. Doing so would have reflected the authors’ research question more correctly, as well as enabling readers to make their own like-with-like comparisons.

  • Finally, the authors state that ‘Studies into CFS have placed little emphasis on occupational outcomes, including return to work after illness’. However, they conspicuously fail to mention the PACE trial, a high-profile large-scale British study of interventions for CFS. The PACE trial included employment status as one of four objective outcomes, with the data showing that the interventions used—the same ones as in the Occupational Medicine study—have no effect on occupational outcomes. This previous finding is so salient to the present paper that it is especially curious the authors have chosen to omit it. The omission is all the more disquieting given that the corresponding author of the paper was a lead investigator on the PACE trial itself.

Authors of research papers have an obligation to cite seminal findings from prior studies that have direct implications for the target research question. Not doing so—especially where there is overlapping authorship—falls far short of the common standards expected in scientific reporting.

Even putting these additional matters aside, the technical errors that undermine this paper’s reporting of percentages render its key conclusions meaningless. The sentences used to describe the findings are simply incorrect, and the entire thrust of the paper’s narrative is thereby contaminated. We believe that allowing the authors to publish a correction to these sentences would create only further confusion.

We therefore call on the journal to retract the paper.

Read the rest of this article HERE.

Source: Hughes BM, Tuller D. Chronic fatigue syndrome and occupational status: a retrospective longitudinal study. Occup Med (Lond). 2022 May 23;72(4):e1-e2. doi: 10.1093/occmed/kqac007. PMID: 35604311. https://academic.oup.com/occmed/article/72/4/e1/6590617?login=false (Full article)

An Unexpected Journey: The Lived Experiences of Patients with Long-Term Cognitive Sequelae After Recovering from COVID-19

Abstract:

This current study explored the lived experiences of patients with long-term cognitive sequelae after recovering from COVID-19. A qualitative design with in-depth interviews and an analysis inspired by Ricoeur’s interpretation theory was utilised. Contracting COVID-19 and suffering long-term sequelae presented as a life-altering event with significant consequences for one’s social, psychological and vocational being in the world in the months following the infection.

Patients living with long-term cognitive sequelae after COVID-19 were in an unknown life situation characterised by feelings of anxiety, uncertainty and concerns about the future, significantly disrupting their life trajectory and forcing them to change their ways of life. While awaiting studies on treatment, symptom management and recovery after persistent sequelae of COVID-19, clinicians and researchers may find inspiration in experiences of other health conditions with similar phenomenology, such as ME/chronic fatigue syndrome and chronic headaches.

Source: Loft MI, Foged EM, Koreska M. An Unexpected Journey: The Lived Experiences of Patients with Long-Term Cognitive Sequelae After Recovering from COVID-19. Qual Health Res. 2022 May 21:10497323221099467. doi: 10.1177/10497323221099467. Epub ahead of print. PMID: 35603563. https://pubmed.ncbi.nlm.nih.gov/35603563/

Impaired exercise capacity in post-COVID syndrome: the role of VWF-ADAMTS13 axis

Abstract:

Post-COVID syndrome (PCS) or Long-COVID is an increasingly recognised complication of acute SARS-CoV-2 infection, characterised by persistent fatigue, reduced exercise tolerance chest pain, shortness of breath and cognitive slowing. Acute COVID-19 is strongly linked with increased risk of thrombosis; a prothrombotic state, quantified by elevated Von Willebrand Factor (VWF) Antigen (Ag):ADAMTS13 ratio, and is associated with severity of acute COVID-19 infection. We investigated if patients with PCS also had evidence of a pro-thrombotic state associating with symptom severity.

In a large cohort of patients referred to a dedicated post-COVID-19 clinic, thrombotic risk including VWF(Ag):ADAMTS13 ratio, was investigated. An elevated VWF(Ag):ADAMTS13 ratio (≥1.5) was raised in nearly one-third of the cohort and four times more likely in patients with impaired exercise capacity as evidenced by desaturation ≥3% and/or rise in lactate level more than 1 from baseline on 1-minute sit to stand test and/or 6-minute walk test (p<0.0001). 20% (56/276) had impaired exercise capacity, of which 55% (31/56) had a raised VWF(Ag):ADAMTS13 ratio ≥1.5 (p<0.0001). FVIII and VWF(Ag) were elevated in 26% and 18% respectively and support a hypercoagulable state in some patients with PCS.

These findings suggest possible ongoing microvascular/endothelial dysfunction in the pathogenesis of PCS and highlight a potential role for antithrombotic therapy in the management of these patients.

Source: Prasannan N, Heightman M, Hillman T, Wall E, Bell R, Kessler A, Neave L, Doyle AJ, Devaraj A, Singh D, Dehbi HM, Scully M. Impaired exercise capacity in post-COVID syndrome: the role of VWF-ADAMTS13 axis. Blood Adv. 2022 May 11:bloodadvances.2021006944. doi: 10.1182/bloodadvances.2021006944. Epub ahead of print. PMID: 35543533; PMCID: PMC9098525. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9098525/ (Full text)