Research round up

The ME Association ME/CFS (& Long Covid) Weekly Research Round-up

July 23, 2021

The weekly research round-up now includes recent publications about ME/CFS and about Long Covid. We highlight several studies that have particularly caught our interest and follow these with the full list of publications together with their abstracts (summaries).

All research relating to ME/CFS can be located in the ME Association: Index of ME/CFS Published Research. It is a free resource and available to anyone.

This extensive library of research is normally updated at the end of each month, but with the change in staff, it will be updated again by 01 August 2021.

The Index provides an A-Z of published research studies, selected key documents and articles, listed by subject matter, on myalgic encephalomyelitis, myalgic encephalopathy, and/or chronic fatigue syndrome (ME/CFS).

You can use it to easily locate and read any research that you might be interested in regard to, e.g., epidemiology, infection, neurology, post-exertional malaise etc.

You can also find the Research Index in the Research section of the website together with a list of Research Summaries that provide more detailed lay explanations of the more interesting work that has been published to date.

ME/CFS Research Published 10 – 16 July 2021 

Four new research studies on ME/CFS have been published during this period and we have also included ten studies on Long Covid. Not much caught our attention this week, however, we highlight two on ME/CFS from the selection below: 

The third study (3) examined natural killer cells which are important in immune response. More specifically the study looked at the transient receptor potential melastatin 3 channel (TRPM3) located on the membrane of natural killer cells.  

TRPM3 is a calcium-permeable nonselective cation that is expressed in a subset of dorsal root (DRG) and trigeminal ganglia sensory neurons. It plays an important role in modulating glucose homeostasis.  

How TRPM3 is regulated under physiological and pathological conditions is poorly understood but its function is thought to be impaired in ME/CFS. This was a small study of only 15 people with ME/CFS and matched healthy controls. 

The results appear to support an impaired function, but the researchers conclude that stimulation of NK cells with IL-2 significantly enhanced cytotoxic function.  

The fourth study (4) found that the herbal drug Young Yum Pill might improve chronic fatigue syndrome in mice.  

Mice are occasionally used as model organisms in studies of ME/CFS and Fibromyalgia, and more about this can be found here.  

The methodology of the study is questionable particularly around how CFS was induced in mice. However, the herbal drug was determined to reverse metabolic changes, reduce oxidative damage, and improve some immune function parameters in mice. 

1. Pathomechanisms and possible interventions in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) 

Fluge Ø, Tronstad KJ, Mella O. J Clin Invest. 2021 Jul 15;131(14):e150377. 

No abstract available – but full article can be read here

2. Dynamics of endogenous interferon-alpha and -gamma production under the influence of ingaron therapy in patients with chronic epstein – barr viral infection with chronic fatigue syndrome  

Rakityanskaya I.A., Ryabova T.S., Kalashnikova A.A., Manuilov A.S., Bel'skikh A.N., Apchel A.V. Bulletin of the Russian Military Medical Academy. – 2021. – Vol. 23. – N. 2. – P. 17-28. 


The influence of antiviral therapy with ingaron on the dynamics of production of interferons α and γ and clinical effects in patients with chronic viral Epstein – Barr infection was studied. The study involved 51 patients (33 women and 17 men aged 35,27 ± 1,28 years) suffering from chronic infection caused by the Epstein – Barr virus. The duration of the disease from the appearance of the first complaints to laboratory confirmation of the Epstein – Barr virus infection and diagnosis was 2,23 ± 0,21 years. Determined the serum, spontaneous and induced production of cytokines interferons α and γ in serum and in the culture of lymphocytes. Three months after the end of antiviral therapy, in patients with an initially low level of induced interferon-γ, the production of interferon-γ increased. The absence of an increase in the production of induced interferon-γ in patients one and three months after the end of therapy with ingaron indicates the absence of the effect of the drug on the level of endogenous interferon-γ. It has been established that the initially low level of induced interferon-γ can be a marker of the positive effect of the therapy with ingaron. Correlation analysis revealed the effect of baseline interferon-γ induced on the clinical picture of the disease. Thus, initially a high level of induced interferon-γ (2706 ± 1058.94 pg/ml) inversely affects the development of sweating in patients (r = –0.506, p = 0,023; τ = –0.419, р = 0.021), and initially low level of the induced IFN-γ (287.2 ± 64.65 pg/ml) — on development of weakness (r = –0.405, р = 0.045; τ = –0.419, р = 0.037). In general, ingarone can be used in the therapy of patients with chronic Epstein virus — Bar infection at a dose of 500,000 IU every other day, at least 10 injections. 

3. The effect of IL-2 stimulation and treatment of TRPM3 on channel co-localisation with PIP 2 and NK cell function in myalgic encephalomyelitis/chronic fatigue syndrome patients 

Eaton-Fitch N, Cabanas H, du Preez S, Staines D, Marshall-Gradisnik S. J Transl Med. 2021 Jul 15;19(1):306. 


Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a serious multifactorial disorder. The origin remains ambiguous, however reduced natural killer (NK) cell cytotoxicity is a consistent immunological feature of ME/CFS.  

Impaired transient receptor potential melastatin 3 (TRPM3), a phosphatidylinositol dependent channel, and impaired calcium mobilisation have been implicated in ME/CFS pathology.  

This investigation aimed to examine the localisation of TRPM3 at the NK cell plasma membrane and co-localisation with phosphatidylinositol 4,5-bisphosphate (PIP2).  

The effect of IL-2 priming and treatment using pregnenolone sulfate (PregS) and ononetin on TRPM3 co-localisation and NK cell cytotoxicity in ME/CFS patients and healthy controls (HC) was also investigated. 

Methods: NK cells were isolated from 15 ME/CFS patients and 15 age- and sex-matched HC. Immunofluorescent technique was used to determine co-localisation of TRPM3 with the NK cell membrane and with PIP2 of ME/CFS patients and HC.  

Flow cytometry was used to determine NK cell cytotoxicity. Following IL-2 stimulation and treatment with PregS and ononetin changes in co-localisation and NK cell cytotoxicity were measured. 

Results: Overnight treatment of NK cells with PregS and ononetin resulted in reduced co-localisation of TRPM3 with PIP2 and actin in HC. Co-localisation of TRPM3 with PIP2 in NK cells was significantly reduced in ME/CFS patients compared with HC following priming with IL-2.  

A significant increase in co-localisation of TRPM3 with PIP2 was reported following overnight treatment with ononetin within ME/CFS patients and between groups.  

Baseline NK cell cytotoxicity was significantly reduced in ME/CFS patients; however, no changes were observed following overnight incubation with IL-2, PregS and ononetin between HC and ME/CFS patients. IL-2 stimulation significantly enhanced NK cell cytotoxicity in HC and ME/CFS patients. 

Conclusion: Significant changes in co-localisation suggest PIP2-dependent TRPM3 function may be impaired in ME/CFS patients.  

Stimulation of NK cells with IL-2 significantly enhanced cytotoxic function in ME/CFS patients demonstrating normal function compared with HC. A crosstalk exists between IL-2 and TRPM3 intracellular signalling pathways which are dependent on Ca2+ influx and PIP2.  

While IL-2R responds to IL-2 binding in vitro, Ca2+ dysregulation and impaired intracellular signalling pathways impede NK cell function in ME/CFS patients. 

4. A proprietary herbal drug Young Yum Pill ameliorates chronic fatigue syndrome in mice 

Yin C, Fu X, Chou J, Li J, Chen Y, Bai J, Wu J, Wu Y, Wang X, Yu ZL. Phytomedicine. 2021 Jul 15;88:153602. 


Background: Chronic fatigue syndrome (CFS) is a complex disease with few effective and safe therapies. Young Yum Pill (YYP), a proprietary herbal drug, has been used to relieve CFS-like symptoms. The pharmacological basis of this application of YYP is unknown. 

Purpose: This study aimed to investigate the pharmacological effects and mechanisms of action of YYP in a mouse model of CFS. 

Study design and methods: A food restriction and exhaustive swimming-induced mouse CFS model was used to evaluate the effects of YYP. Lymphocyte proliferation was assessed by MTT assays. T-lymphocyte subsets were analyzed by flow cytometry. Serum biochemical parameters were determined using commercial kits. Protein levels were measured by immunoblotting. 

Results: Intragastric administration of YYP (2.85, 5.70, 11.40 g/kg) daily for 21 consecutive days significantly prolonged swimming time and diminished body weight loss of CFS mice. Mechanistic investigations revealed that YYP increased thymus and spleen indices of CFS mice, enhanced proliferation of lipopolysaccharide- or concanavalin A-stimulated spleen lymphocytes, and increased CD3+CD4+ and CD3+CD8+ T-cells in the spleen.  

YYP increased glycogen content in gastrocnemius muscle and liver, and lowered levels of triglyceride, lactic acid, and urea nitrogen in sera of CFS mice. YYP suppressed the elevation of serum level of malondialdehyde, the increase of activities of lactic dehydrogenase and creatine phosphokinase, and the decrease of activity of the serum antioxidant enzyme superoxide dismutase in CFS mice. Moreover, YYP upregulated protein level of activated AMPK in gastrocnemius muscle and liver of CFS mice. 

Conclusions: YYP ameliorates CFS by reversing metabolic changes, reducing oxidative damage, and improving some immune function parameters in mice. This study provides pharmacological justifications for the use of YYP in treating fatigue, including CFS. 

Long-COVID Research References  

  1. Refining “Long-COVID” by a Prospective Multimodal Evaluation of Patients with Long-Term Symptoms Attributed to SARS-CoV-2 Infection 
  1. Symptoms, complications and management of long COVID: a review 
  1. Long COVID and kids: scientists race to find answers 
  1. ‘Reluctant pioneer': A qualitative study of doctors' experiences as patients with long COVID 
  1. Post-acute and long-COVID-19 symptoms in patients with mild diseases: a systematic review 
  1. Antibody Response to SARS-CoV-2 is Associated with Long-term Clinical Outcome in Patients with COVID-19: a Longitudinal Study 
  1. Post-acute and long-COVID-19 symptoms in patients with mild diseases: a systematic review 
  1. A longitudinal SARS-CoV-2 biorepository for COVID-19 survivors with and without post-acute sequelae 
  1. Current issues of treatment and rehabilitation of patients with neurological disorders and the consequences of COVID-19. Resolution of Advisory Board 
  1. COVID-19 long haulers 

Katrina Pears, Research Correspondent, ME Association 

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