Tag: NF-kB

Dissecting the Molecular Mechanisms Surrounding Post-COVID-19 Syndrome and Neurological Features

Abstract:

Many of the survivors of the novel coronavirus disease (COVID-19) are suffering from persistent symptoms, causing significant morbidity and decreasing their quality of life, termed “post-COVID-19 syndrome” or “long COVID”. Understanding the mechanisms surrounding PCS is vital to developing the diagnosis, biomarkers, and possible treatments.

Here, we describe the prevalence and manifestations of PCS, and similarities with previous SARS epidemics. Furthermore, we look at the molecular mechanisms behind the neurological features of PCS, where we highlight important neural mechanisms that may potentially be involved and pharmacologically targeted, such as glutamate reuptake in astrocytes, the role of NMDA receptors and transporters (EAAT2), ROS signaling, astrogliosis triggered by NF-κB signaling, KNDy neurons, and hypothalamic networks involving Kiss1 (a ligand for the G-protein-coupled receptor 54 (GPR54)), among others. We highlight the possible role of reactive gliosis following SARS-CoV-2 CNS injury, as well as the potential role of the hypothalamus network in PCS manifestations.

Source: Mohamed MS, Johansson A, Jonsson J, Schiöth HB. Dissecting the Molecular Mechanisms Surrounding Post-COVID-19 Syndrome and Neurological Features. Int J Mol Sci. 2022 Apr 12;23(8):4275. doi: 10.3390/ijms23084275. PMID: 35457093. https://www.mdpi.com/1422-0067/23/8/4275/htm (Full text)

Electroacupuncture improves cognitive function by inhibiting NF-κB activity in rats with chronic fatigue syndrome

Abstract:

in English, Chinese

Objective: To observe the effect of electroacupuncture (EA) on the expression of NF-κB p65 in hippocampus and the morphology of hippocampus in rats with chronic fatigue syndrome (CFS), so as to explore its mechanism in improving cognitive dysfunction of CFS.

Methods: Forty-eight SD rats were randomly divided into control, model, EA and inhibitor groups (n=12 in each group). The CFS model was established by multi-factor compound stress stimulation method. Rats of the EA group received EA (50 Hz, 1 mA) at “Baihui” (GV20), Emotional Area I and bilateral Sensory Area for 30 min, once daily for 15 days. For rats in the inhibitor group, pyrrolidine dithiocarbamate (100 mg·kg-1·d-1) was injected intraperitoneally, once a day for 15 days. Learning and memory ability was evaluated by Morris water maze test. HE staining was used to observe the morphology of hippocampus. Western blot was used to determine the expression level of NF-κB p65 in hippocampus.

Results: After mode-ling, the general status score was increased （P<0.01）, the escape latency was prolonged(P<0.01), the times of crossing the platform was decreased(P<0.01), and the expression level of NF-κB p65 in hippocampus tissue was significantly increased (P<0.05) in the model group compared with the control group. Compared with the model group, the general status score was decreased （P<0.01）, the escape latency was shortened(P<0.01), the times of crossing the platform was increased(P<0.01), and the expression level of NF-κB p65 in hippocampus tissue was significantly decreased (P<0.05) in the EA and inhibitor groups. HE staining showed that in the model group, the hippocampal nerve cells were arranged disorderly, the structure was loose, and the number of apoptotic bodies and inflammatory cells was significantly increased. The degree of tissue damage of the EA and inhibitor groups was milder than that of the model group.

Conclusion: EA can improve the cognitive function in CFS rats, which may be associated with its effect in inhibiting the expression of NF-κB and reducing the inflammation response in hippocampus.

Source: Feng CW, Qu YY, Sun ZR, Wang YL, Zhang P, Wang QY, Lin WJ, Zhang L, Yang TS. [Electroacupuncture improves cognitive function by inhibiting NF-κB activity in rats with chronic fatigue syndrome]. Zhen Ci Yan Jiu. 2021 Sep 25;46(9):775-81. Chinese. doi: 10.13702/j.1000-0607.200827. PMID: 34558244. https://pubmed.ncbi.nlm.nih.gov/34558244/ [Article in Chinese]

Increased nuclear factor-κB and loss of p53 are key mechanisms in Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS)

Abstract:

Fukuda’s criteria are adequate to make a distinction between Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS) and chronic fatigue (CF), but ME/CFS patients should be subdivided into those with (termed ME) and without (termed CFS) post exertional malaise [Maes et al. 2012].

ME/CFS is considered to be a neuro-immune disease. ME/CFS is characterized by activated immuno-inflammatory pathways, including increased levels of pro-inflammatory cytokines, nuclear factor κB (NF-κB) and aberrations in mitochondrial functions, including lowered ATP. These processes may explain typical symptoms of ME/CFS, e.g. fatigue, malaise, hyperalgesia, and neurologic and autonomic symptoms.

Here we hypothesize that increased NF-κB together with a loss of p53 are key phenomena in ME/CFS that further explain ME/CFS symptoms, such as fatigue and neurocognitive dysfunction, and explain ME symptoms, such as post-exertional malaise following mental and physical activities. Inactivation of p53 impairs aerobic mitochondrial functions and causes greater dependence on anaerobic glycolysis, elevates lactate levels, reduces mitochondrial density in skeletal muscle and reduces endurance during physical exercise. Lowered p53 and increased NF-κB are associated with elevated reactive oxygen species. Increased NF-κB induces the production of pro-inflammatory cytokines, which increase glycolysis and further compromise mitochondrial functions.

All these factors together may contribute to mitochondrial exhaustion and indicate that the demand for extra ATP upon the commencement of increased activity cannot be met. In conditions of chronic inflammation and oxidative stress, high NF-κB and low p53 may conspire to promote neuron and glial cell survival at a price of severely compromised metabolic brain function. Future research should examine p53 signaling in ME/CFS.

Copyright © 2012. Published by Elsevier Ltd.

 

Source: Morris G, Maes M. Increased nuclear factor-κB and loss of p53 are key mechanisms in Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS). Med Hypotheses. 2012 Nov;79(5):607-13. doi: 10.1016/j.mehy.2012.07.034. Epub 2012 Aug 27. https://www.ncbi.nlm.nih.gov/pubmed/22951418

 

Will vitamin D supplementation ameliorate diseases characterized by chronic inflammation and fatigue?

Abstract:

Chronic NF-κB activation has been supposed as a key event in chronic fatigue syndrome (CFS) and many other better-defined pro-inflammatory diseases. Knowledge about the impact of deficiency vitamin D on chronic NF-κB activation could open a new disease approach. Whereas NF-κB activation leads at first to a pro-inflammatory immune response, later on a vitamin D-dependent anti-inflammatory response ensues. Binding of the active vitamin D metabolite 1,25(OH)(2)D(3) to vitamin D receptor (VDR) yields a transcription factor which represses NF-κB activation, and additionally modulates and down-regulates adaptive, but enhances innate immune responses, and improves redox balance, thus counterbalancing inflammation on multiple levels. However, this built-in late counterbalance against inflammation works only when stores of calcium and 25(OH)D(3) are abundant. Therefore a connection between lowered vitamin D-metabolism and persistent NF-κB activation, augmented nitrosative-oxidative stress, redox imbalance, chronic inflammation, and concomitant fatigue can be postulated. In order to confirm this hypothesis, randomized controlled clinical studies about the clinical effects of supplementation of calcium and vitamin D(3) would be necessary in diseases characterized by persistent NF-κB activation and chronic inflammation and fatigue.

Copyright © 2010 Elsevier Ltd. All rights reserved.

 

Source: Hoeck AD, Pall ML. Will vitamin D supplementation ameliorate diseases characterized by chronic inflammation and fatigue? Med Hypotheses. 2011 Feb;76(2):208-13. doi: 10.1016/j.mehy.2010.09.032. Epub 2010 Oct 25. https://www.ncbi.nlm.nih.gov/pubmed/20980105

 

Post-radiation syndrome as a NO/ONOO- cycle, chronic fatigue syndrome-like disease

Abstract:

Post-radiation syndrome is proposed to be chronic fatigue syndrome (CFS) or a chronic fatigue syndrome-like illness, initiated by exposure to ionizing radiation. This view is supported by the nitric oxide/peroxynitrite (NO/ONOO-) cycle mechanism, the putative etiologic mechanism for CFS and related illnesses.

Ionizing radiation may initiate illness by increasing nitric oxide levels via increased activity of the transcription factor NF-kappaB and consequent increased synthesis of the inducible nitric oxide synthase. Two types of components of the nitric oxide/peroxynitrite cycle have been studied in post-radiation syndrome patients and shown to be elevated.

The symptoms and signs of post-radiation syndrome and its chronicity are similar or identical to those of chronic fatigue syndrome and can be explained as being a consequence of nitric oxide/peroxynitrite cycle etiology. While the data available to test this view are limited, it provides for the first time a comprehensive explanation for post-radiation syndrome.

 

Source: Pall ML. Post-radiation syndrome as a NO/ONOO- cycle, chronic fatigue syndrome-like disease. Med Hypotheses. 2008 Oct;71(4):537-41. doi: 10.1016/j.mehy.2008.05.023. Epub 2008 Jul 29. https://www.ncbi.nlm.nih.gov/pubmed/18667279

 

Not in the mind of neurasthenic lazybones but in the cell nucleus: patients with chronic fatigue syndrome have increased production of nuclear factor kappa beta

Abstract:

There is now some evidence that chronic fatigue syndrome is accompanied by an activation of the inflammatory response system and by increased oxidative and nitrosative stress. Nuclear factor kappa beta (NFkappabeta) is the major upstream, intracellular mechanism which regulates inflammatory and oxidative stress mediators. In order to examine the role of NFkappabeta in the pathophysiology of CFS, this study examines the production of NFkappabeta p50 in unstimulated, 10 ng/mL TNF-alpha (tumor necrosis factor alpha) and 50 ng/mL PMA (phorbolmyristate acetate) stimulated peripheral blood lymphocytes of 18 unmedicated patients with CFS and 18 age-sex matched controls.

The unstimulated (F=19.4, df=1/34, p=0.0002), TNF-alpha-(F=14.0, df=1/34, p=0.0009) and PMA-(F=7.9, df=1/34, p=0.008) stimulated production of NFkappabeta were significantly higher in CFS patients than in controls. There were significant and positive correlations between the production of NFkappabeta and the severity of illness as measured with the FibroFatigue scale and with symptoms, such as aches and pain, muscular tension, fatigue, irritability, sadness, and the subjective feeling of infection.

The results show that an intracellular inflammatory response in the white blood cells plays an important role in the pathophysiology of CFS and that previous findings on increased oxidative stress and inflammation in CFS may be attributed to an increased production of NFkappabeta. The results suggest that the symptoms of CFS, such as fatigue, muscular tension, depressive symptoms and the feeling of infection reflect a genuine inflammatory response in those patients. It is suggested that CFS patients should be treated with antioxidants, which inhibit the production of NFkappabeta, such as curcumin, N-Acetyl-Cysteine, quercitin, silimarin, lipoic acid and omega-3 fatty acids.

 

Source: Maes M, Mihaylova I, Bosmans E. Not in the mind of neurasthenic lazybones but in the cell nucleus: patients with chronic fatigue syndrome have increased production of nuclear factor kappa beta. Neuro Endocrinol Lett. 2007 Aug;28(4):456-62. https://www.ncbi.nlm.nih.gov/pubmed/17693979

 

Not in the mind but in the cell: increased production of cyclo-oxygenase-2 and inducible NO synthase in chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) is a medically unexplained disorder, characterized by profound fatigue, infectious, rheumatological and neuropsychiatric symptoms. There is, however, some evidence that CFS is accompanied by signs of increased oxidative stress and inflammation in the peripheral blood. This paper examines the role of the inducible enzymes cyclo-oxygenase (COX-2) and inducible NO synthase (iNOS) in the pathophysiology of CFS.

Toward this end we examined the production of COX-2 and iNOS by peripheral blood lymphocytes (PBMC) in 18 CFS patients and 18 normal volunteers and examined the relationships between those inflammatory markers and the severity of illness as measured by means of the FibroFatigue scale and the production of the transcription factor nuclear factor kappa beta (NFkappabeta).

We found that the production of COX-2 and iNOS was significantly higher in CFS patients than in normal controls. There were significant and positive intercorrelations between COX-2, iNOS and NFkappabeta and between COX-2 and iNOS, on the one hand, and the severity of illness, on the other. The production of COX-2 and iNOS by PBMCs was significantly related to aches and pain, muscular tension, fatigue, concentration difficulties, failing memory, sadness and a subjective experience of infection.

The results suggest that a) an intracellular inflammatory response in the white blood cells plays an important role in the pathophysiology of CFS; b) the inflammatory response in CFS is driven by the transcription factor NFkappabeta; c) symptoms, such as fatigue, pain, cognitive defects and the subjective feeling of infection, indicates the presence of a genuine inflammatory response in CFS patients; and d) CFS patients may be treated with substances that inhibit the production of COX-2 and iNOS.

 

Source: Maes M, Mihaylova I, Kubera M, Bosmans E. Not in the mind but in the cell: increased production of cyclo-oxygenase-2 and inducible NO synthase inchronic fatigue syndrome. Neuro Endocrinol Lett. 2007 Aug;28(4):463-9. https://www.ncbi.nlm.nih.gov/pubmed/17693978

 

Say NO to fibromyalgia and chronic fatigue syndrome: an alternative and complementary therapy to aerobic exercise

Abstract:

Increased shear stress to the endothelium increases activity of endothelial nitric oxide synthase (eNOS) with subsequent release of small quantities (nMol) of nitric oxide (NO) into the circulation. It occurs during moderate aerobic exercise mostly as a result of laminar shear stress and with whole body, periodic acceleration as a result of pulsatile shear stress. The latter is administered by means of a new, non-invasive, passive exercise device.

Moderate exercise has long been known to alleviate the symptoms of fibromyalgia and chronic fatigue syndrome and in the current study, whole body, periodic acceleration did as well. Since NO through action of eNOS has potent anti-inflammatory properties mainly by suppressing nuclear factor kappabeta activity, it is hypothesized that both diseases have chronic inflammation as their basis. Whole body periodic acceleration can be applied separately or supplementary to aerobic exercise in the treatment of fibromyalgia and chronic fatigue syndrome.

 

Source: Sackner MA, Gummels EM, Adams JA. Say NO to fibromyalgia and chronic fatigue syndrome: an alternative and complementary therapy to aerobic exercise. Med Hypotheses. 2004;63(1):118-23. http://www.ncbi.nlm.nih.gov/pubmed/15193362