It is widely accepted that the pathophysiology and treatment of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) could be considerably improved. The heterogeneity of ME/CFS and the ...confusion over its classification have undoubtedly contributed to this, although this would seem a consequence of the complexity of the array of ME/CFS presentations and high levels of diverse comorbidities. This article reviews the biological underpinnings of ME/CFS presentations, including the interacting roles of the gut microbiome/permeability, endogenous opioidergic system, immune cell mitochondria, autonomic nervous system, microRNA-155, viral infection/re-awakening and leptin as well as melatonin and the circadian rhythm. This details not only relevant pathophysiological processes and treatment options, but also highlights future research directions. Due to the complexity of interacting systems in ME/CFS pathophysiology, clarification as to its biological underpinnings is likely to considerably contribute to the understanding and treatment of other complex and poorly managed conditions, including fibromyalgia, depression, migraine, and dementia. The gut and immune cell mitochondria are proposed to be two important hubs that interact with the circadian rhythm in driving ME/CFS pathophysiology.
This paper reviews the body of evidence that not only tryptophan and consequent 5-HT depletion, but also induction of indoleamine 2,3-dioxygenase (IDO) and the detrimental effects of tryptophan ...catabolites (TRYCATs) play a role in the pathophysiology of depression. IDO is induced by interferon (IFN)γ, interleukin-6 and tumor necrosis factor-α, lipopolysaccharides and oxidative stress, factors that play a role in the pathophysiology of depression. TRYCATs, like kynurenine and quinolinic acid, are depressogenic and anxiogenic; activate oxidative pathways; cause mitochondrial dysfunctions; and have neuroexcitatory and neurotoxic effects that may lead to neurodegeneration. The TRYCAT pathway is also activated following induction of tryptophan 2,3-dioxygenase (TDO) by glucocorticoids, which are elevated in depression. There is evidence that activation of IDO reduces plasma tryptophan and increases TRYCAT synthesis in depressive states and that TDO activation may play a role as well. The development of depressive symptoms during IFNα-based immunotherapy is strongly associated with IDO activation, increased production of detrimental TRYCATs and lowered levels of tryptophan. Women show greater IDO activation and TRYCAT production following immune challenge than men. In the early puerperium, IDO activation and TRYCAT production are associated with the development of affective symptoms. Clinical depression is accompanied by lowered levels of neuroprotective TRYCATs or increased levels or neurotoxic TRYCATs, and lowered plasma tryptophan, which is associated with indices of immune activation and glucocorticoid hypersecretion. Lowered tryptophan and increased TRYCATs induce T cell unresponsiveness and therefore may exert a negative feedback on the primary inflammatory response in depression. It is concluded that activation of the TRYCAT pathway by IDO and TDO may be associated with the development of depressive symptoms through tryptophan depletion and the detrimental effects of TRYCATs. Therefore, the TRYCAT pathway should be a new drug target in depression. Direct inhibitors of IDO are less likely to be useful drugs than agents, such as kynurenine hydroxylase inhibitors; drugs which block the primary immune response; compounds that increase the protective effects of kynurenic acid; and specific antioxidants that target IDO activation, the immune and oxidative pathways, and 5-HT as well.
► Induction of the tryptophan catabolite (TRYCAT) pathway is associated with the onset of depression. ► Activation of IDO and TDO may induce this pathway and increase the synthesis of detrimental TRYCATs. ► IDO is induced by proinflammatory cytokines, TDO by glucocorticoids, both increased in depression. ► Activation of IDO and TDO deplete plasma tryptophan and consequently brain 5-HT. ► The TRYCAT pathway is new drug target in depression.
In the first part, the following mechanisms involved in different forms of cell death are considered, with a view to identifying potential therapeutic targets: tumour necrosis factor receptors ...(TNFRs) and their engagement by tumour necrosis factor-alpha (TNF-α); poly ADP-ribose polymerase (PARP)-1 cleavage; the apoptosis signalling kinase (ASK)-c-Jun N-terminal kinase (JNK) axis; lysosomal permeability; activation of programmed necrotic cell death; oxidative stress, caspase-3 inhibition and parthanatos; activation of inflammasomes by reactive oxygen species and the development of pyroptosis; oxidative stress, calcium dyshomeostasis and iron in the development of lysosomal-mediated necrosis and lysosomal membrane permeability; and oxidative stress, lipid peroxidation, iron dyshomeostasis and ferroptosis. In the second part, there is a consideration of the role of lethal and sub-lethal activation of these pathways in the pathogenesis and pathophysiology of neurodegenerative and neuroprogressive disorders, with particular reference to the TNF-α-TNFR signalling axis; dysregulation of ASK-1-JNK signalling; prolonged or chronic PARP-1 activation; the role of pyroptosis and chronic inflammasome activation; and the roles of lysosomal permeabilisation, necroptosis and ferroptosis. Finally, it is suggested that, in addition to targeting oxidative stress and inflammatory processes generally, neuropsychiatric disorders may respond to therapeutic targeting of TNF-α, PARP-1, the Nod-like receptor NLRP3 inflammasome and the necrosomal molecular switch receptor-interacting protein kinase-3, since their widespread activation can drive and/or exacerbate peripheral inflammation and neuroinflammation even in the absence of cell death. To this end, the use is proposed of a combination of the tetracycline derivative minocycline and
N
-acetylcysteine as adjunctive treatment for a range of neuropsychiatric disorders.
Objective
Somatization is a symptom cluster characterized by ‘psychosomatic’ symptoms, that is, medically unexplained symptoms, and is a common component of other conditions, including depression and ...myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This article reviews the data regarding the pathophysiological foundations of ‘psychosomatic’ symptoms and the implications that this has for conceptualization of what may more appropriately be termed physio‐somatic symptoms.
Method
This narrative review used papers published in PubMed, Scopus, and Google Scholar electronic databases using the keywords: depression and chronic fatigue, depression and somatization, somatization and chronic fatigue syndrome, each combined with inflammation, inflammatory, tryptophan, and cell‐mediated immune (CMI).
Results
The physio‐somatic symptoms of depression, ME/CFS, and somatization are associated with specific biomarkers of inflammation and CMI activation, which are correlated with, and causally linked to, changes in the tryptophan catabolite (TRYCAT) pathway. Oxidative and nitrosative stress induces damage that increases neoepitopes and autoimmunity that contribute to the immuno‐inflammatory processes. These pathways are all known to cause physio‐somatic symptoms, including fatigue, malaise, autonomic symptoms, hyperalgesia, intestinal hypermotility, peripheral neuropathy, etc.
Conclusion
Biological underpinnings, such as immune‐inflammatory pathways, may explain, at least in part, the occurrence of physio‐somatic symptoms in depression, somatization, or myalgic encephalomyelitis/chronic fatigue syndrome and thus the clinical overlap among these disorders.
In some patients with major depressive disorder (MDD), individual illness characteristics appear consistent with those of a neuroprogressive illness. Features of neuroprogression include poorer ...symptomatic, treatment and functional outcomes in patients with earlier disease onset and increased number and length of depressive episodes. In such patients, longer and more frequent depressive episodes appear to increase vulnerability for further episodes, precipitating an accelerating and progressive illness course leading to functional decline. Evidence from clinical, biochemical and neuroimaging studies appear to support this model and are informing novel therapeutic approaches. This paper reviews current knowledge of the neuroprogressive processes that may occur in MDD, including structural brain consequences and potential molecular mechanisms including the role of neurotransmitter systems, inflammatory, oxidative and nitrosative stress pathways, neurotrophins and regulation of neurogenesis, cortisol and the hypothalamic-pituitary-adrenal axis modulation, mitochondrial dysfunction and epigenetic and dietary influences. Evidence-based novel treatments informed by this knowledge are discussed.
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor encoded by
NFE2L2
. Under oxidative stress, Nrf2 does not undergo its normal cytoplasmic degradation but instead travels ...to the nucleus, where it binds to a DNA promoter and initiates transcription of anti-oxidative genes. Nrf2 upregulation is associated with increased cellular levels of glutathione disulfide, glutathione peroxidase, glutathione transferases, thioredoxin and thioredoxin reductase. Given its key role in governing the cellular antioxidant response, upregulation of Nrf2 has been suggested as a common therapeutic target in neuropsychiatric illnesses such as major depressive disorder, bipolar disorder and schizophrenia, which are associated with chronic oxidative and nitrosative stress, characterised by elevated levels of reactive oxygen species, nitric oxide and peroxynitrite. These processes lead to extensive lipid peroxidation, protein oxidation and carbonylation, and oxidative damage to nuclear and mitochondrial DNA. Intake of
N
-acetylcysteine, coenzyme Q
10
and melatonin is accompanied by increased Nrf2 activity.
N
-acetylcysteine intake is associated with improved cerebral mitochondrial function, decreased central oxidative and nitrosative stress, reduced neuroinflammation, alleviation of endoplasmic reticular stress and suppression of the unfolded protein response. Coenzyme Q
10
, which acts as a superoxide scavenger in neuroglial mitochondria, instigates mitohormesis, ameliorates lipid peroxidation in the inner mitochondrial membrane, activates uncoupling proteins, promotes mitochondrial biogenesis and has positive effects on the plasma membrane redox system. Melatonin, which scavenges mitochondrial free radicals, inhibits mitochondrial nitric oxide synthase, restores mitochondrial calcium homeostasis, deacetylates and activates mitochondrial SIRT3, ameliorates increased permeability of the blood-brain barrier and intestine and counters neuroinflammation and glutamate excitotoxicity.
Objective
To conduct a systematic review and meta‐analysis of studies that measured cytokine and chemokine levels in individuals with major depressive disorder (MDD) compared to healthy controls ...(HCs).
Method
The PubMed/MEDLINE, EMBASE, and PsycINFO databases were searched up until May 30, 2016. Effect sizes were estimated with random‐effects models.
Result
Eighty‐two studies comprising 3212 participants with MDD and 2798 HCs met inclusion criteria. Peripheral levels of interleukin‐6 (IL‐6), tumor necrosis factor (TNF)‐alpha, IL‐10, the soluble IL‐2 receptor, C‐C chemokine ligand 2, IL‐13, IL‐18, IL‐12, the IL‐1 receptor antagonist, and the soluble TNF receptor 2 were elevated in patients with MDD compared to HCs, whereas interferon‐gamma levels were lower in MDD (Hedge's g = −0.477, P = 0.043). Levels of IL‐1β, IL‐2, IL‐4, IL‐8, the soluble IL‐6 receptor (sIL‐6R), IL‐5, CCL‐3, IL‐17, and transforming growth factor‐beta 1 were not significantly altered in individuals with MDD compared to HCs. Heterogeneity was large (I2: 51.6–97.7%), and sources of heterogeneity were explored (e.g., age, smoking status, and body mass index).
Conclusion
Our results further characterize a cytokine/chemokine profile associated with MDD. Future studies are warranted to further elucidate sources of heterogeneity, as well as biosignature cytokines secreted by other immune cells.
Allergic contact dermatitis (ACD) is a T cell-mediated type of skin inflammation resulting from contact hypersensitivity (CHS) to antigens. There is strong comorbidity between ACD and major ...depression. Keratinocytes release immunomodulatory mediators including pro-inflammatory cytokines and chemokines, which modulate skin inflammation and are crucial cell type for the development of CHS. Our previous studies showed that fluoxetine and desipramine were effective in suppressing CHS in different mouse strains. However, the immune and molecular mechanisms underlying this effect remain to be explored. The aim of the current study was to determine the immune and molecular mechanisms of action of antidepressant drugs engaged in the inhibition of CHS response in the stimulated keratinocyte HaCaT cell line. The results show that LPS, TNF-α/IFN-γ, and DNFB stimulate HaCaT cells to produce large amounts of pro-inflammatory factors including IL-1β, IL-6, CCL2, and CXCL8. HaCaT stimulation was associated with increased expression of ICAM-1, a cell adhesion molecule, and decreased expression of E-cadherin. Imipramine, desipramine, and fluoxetine suppress the production of IL-1β, CCL2, as well as the expression of ICAM-1. LPS and TNF-α/IFN-γ activate p-38 kinase, but antidepressants do not regulate this pathway. LPS decreases E-cadherin protein expression and fluoxetine normalizes these effects. In summary, the antidepressant drugs examined in this study attenuate the stimulated secretion of pro-inflammatory cytokines, chemokines, and modulate adhesion molecule expression by the HaCaT cell line. Therefore, antidepressants may have some clinical efficacy in patients with ACD and patients with comorbid depression and contact allergy.
Background
Reduced physical fitness is a cardiovascular disease (CVD) risk factor in the general population. However, generalising these results to older adults with intellectual disabilities (ID) ...may be inappropriate given their pre‐existing low physical fitness levels and high prevalence of co‐morbidities. Therefore, the aim of this study is to investigate the difference in physical fitness between older adults with ID with and without CVD.
Method
Baseline data of a cohort of older adults with borderline to profound ID (HA‐ID study) were used (n = 684; 61.6 ± 8.2 years; 51.3% male). CVD status (coronary artery disease, heart failure, stroke) was obtained from medical files. Cardiorespiratory fitness (10‐m incremental shuttle walking test), comfortable and fast gait speed (over 5 m distance) and grip strength (hand dynamometer) were measured. Multivariable linear regression models were used to investigate the association between these physical fitness components and the presence of CVD, adjusted for participant characteristics.
Results
Of the 684 participants 78 (11.4%) had CVD. Participants with CVD scored lower on cardiorespiratory fitness (−81.4 m, P = 0.002), comfortable gait speed (−0.3 km/h, P = 0.04) and fast gait speed (−1.1 km/h, P = 0.04). No significant differences were found for grip strength (−0.2 kg, P = 0.89).
Conclusions
Older adults with CVD had significantly lower physical fitness levels than those without CVD, except for grip strength. Longitudinal research is needed to investigate causality.
Xanthomonas axonopodis pv. dieffenbachiae (Xad) is the causal agent of anthurium bacterial blight and listed as an A2 quarantine organism by EPPO. However, the name Xad covers a variety of strains. ...Here, 25 Xad strains and 88 phylogenetically related strains, including Xanthomonas type strains and representatives of other pathovars, were examined using a polyphasic taxonomic approach. Multilocus sequence analysis of seven genes showed that strains isolated from Dieffenbachia, Philodendron and Anthurium cluster into three phylogenetic groups (PG I, II and III), while the type strain of X. axonopodis clustered into a fourth group (PG IV). PG I included the type strains of X. citri subsp. citri, X. citri subsp. malvacearum, X. fuscans subsp. fuscans and X. fuscans subsp. aurantifolii. PG II included the type strains of X. euvesicatoria, X. perforans, X. alfalfae subsp. alfalfae and X. alfalfae subsp. citrumelonis. PG III included the type strains of X. phaseoli. Each PG was shown to represent a single species, based on average nucleotide identity values, DNA–DNA hybridization data and phenotypic characteristics. Therefore, strains named as Xad belong to PG I, PG II and PG III, and not to X. axonopodis (PG IV). Taxonomic proposals are made: emendations of the descriptions of X. citri, X. phaseoli and X. axonopodis, to encompass the strains of PG I, PG III and PG IV, respectively; and reclassification of X. perforans and X. alfalfae as X. euvesicatoria and emendation of the description of X. euvesicatoria to encompass all strains of PG II.
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