Hyperthermia and targeting heat shock proteins: innovative approaches for neurodegenerative disorders and Long COVID

Frontiers in Neuroscience, Journal Year: 2025, Volume and Issue: 19

Published: Feb. 4, 2025

Neurodegenerative diseases (NDs) and Long COVID represent critical growing global health challenges, characterized by complex pathophysiological mechanisms including neuronal deterioration, protein misfolding, persistent neuroinflammation. The emergence of innovative therapeutic approaches, such as whole-body hyperthermia (WBH), offers promising potential to modulate underlying in NDs related conditions like COVID. WBH, particularly fever-range, enhances mitochondrial function, induces heat shock proteins (HSPs), modulates neuroinflammation—benefits that pharmacological treatments often struggle replicate. HSPs HSP70 HSP90 play pivotal roles folding, aggregation prevention, cellular protection, directly targeting pathological processes seen Alzheimer's, Parkinson's, Huntington's disease. Preliminary findings also suggest WBH's alleviate neurological symptoms COVID, where neuroinflammation serotonin dysregulation are prominent. Despite the absence robust clinical trials, implications WBH extend immune modulation restoration disrupted physiological pathways. However, dual nature hyperthermia's effects—balancing pro-inflammatory anti-inflammatory responses—emphasizes need for dose-controlled applications stringent patient monitoring minimize risks vulnerable populations. While shows interest, significant challenges remain. These include individual variability response, limited accessibility advanced technologies, standardized protocols. Future research must focus on targeted biomarker identification, personalized treatment strategies optimize efficacy integration into paradigms could mark a transformative step addressing these conditions.

Language: Английский

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Disruptions in serotonin- and kynurenine pathway metabolism in post-COVID: biomarkers and treatment

Frontiers in Neurology, Journal Year: 2025, Volume and Issue: 16

Published: Feb. 13, 2025

This opinion article attempts to connect knowledge about post-Covid syndrome (PCS) gained in neuropsychiatry and immunology. It discusses some misunderstandings PCS light of the interplay between serotonergic system kynurenine pathway (KP). From a new perspective, potential biomarkers for further research therapeutic targets are identified.Due severity extent PCS, researchers urgently searching its causes treatments. For neurocognitive autonomic nervous problems such as present it is common encounter dysregulated neurotransmitter systems. Among neurotransmitters, serotonin plays special role immune regulating inflammatory responses by central peripheral mechanisms (1)(2)(3)(4)(5). Serotonin -also known 5-hydroxytryptamine (5-HT) -is with stimulating effect that influences memory, mood, selfconfidence, sleep, emotion, orgasm eating (6)(7)(8)(9).Serotonin not only binds receptors on neurons, but also cells (3,5,10,11). Many studies have indicate receptors, especially 5-HT3 (one receptors), involved pathogenesis chronic conditions (5,10,11). Therapeutic applications receptor antagonists instance been reported rheumatoid arthritis (5,11,12). An essential amino acid KP tryptophan, precursor both (see figure1), we get through food part regular diet (13). The creating an important energy factor modulated infection stress (1,5)and subsets T helper 17 (Th17 cells) produce cytokines signaling function (14).Strong alterations intestinal gene expression upregulate genes viral recognition inflammation pathways downregulate nutrient metabolism, like tryptophan (15). downregulation result serum reduction Various suspect this might be cause complaints (15)(16)(17)(18)(19).In I address question whether disruptions serotonin-and metabolism lead treatment PCS.In study 'Serotonin post-acute sequelae infection' Wong et al. (15) they investigated four human cohorts, animal models organoid cultures. First, conducted among 1540 patients who presented center severe complaints. They identified eight clusters based clinical symptoms, varying from mainly physical problems, loss strength muscles, memory disorders. performed targeted plasma metabolomics 58 representative 3-22 months after found compared 30 healthy controls.For finding three causes: a) diminished absorption tryptophan. Because angiotensin converting enzyme (ACE2) these strongly decreased. Furthermore, COVID-19 virus spike proteins attaches (20,21). As consequence, during infection, has compete over reduced number ACE2 receptors; b) micro-clots thrombocytes. Thrombocytes contain serotonin. reduce thrombocytes thus availability serotonin; c) enhanced monoamine oxidase (MAO) promotes breakdown serotonin.In Sadlier (17), cohort 20 hospitalized were controls, 4-6 6-9 infection. Levels multiple metabolites immunomodulatory properties elevated quinolinate, toxic metabolite. There levels other things glutamate (a neurotransmitter) level was increased.Su (18) longitudinal multi-omic analysis (n=209). followed immediately Covid-19 had less symptoms. measured autoantibodies, specific RNAemia, metabolic profiles, global proteomic blood mononuclear (PBMCs) draws. no 457 controls. What striking stands out reporting neurological symptoms exhibited associated negative regulation circadian sleep/wake cycle. hormone melatonin responsible produced brain (in pineal gland) serotonin.Wong conclude serious greater chance permanently retaining than mild checked Peluso (22) did indeed negatively correlate complaints.However, retrospective Mathé (19) using Liquid Chromatography -Mass Spectrometry (lc-ms/ms) technology 34 at least 6 complaints, which 14 controls.Although colleagues much more extensive most comprehensive all interesting results, agree conclusion reliable biomarker should used routine diagnostic assessment, two arguments.The first reason cannot cross blood-brain barrier appears reaches via cranial nerve, vagus nerve normally uses Acetylcholine (Ach) (9). So, directly related brain. Based models, assume PCS. In vivo, however, technically very difficult measure With possible techniques (microdialysis, functional magnetic resonance imaging (fMRI), fast-scan cyclic voltammetry (FSCV), genetically encoded indicators (GESIs) positron emission tomography (PET) either spatiotemporal resolution too poor or technique invasive or/and expensive .However, vivo you (23). authorsWong can move up hippocampus, control causing disorders our describe into 95 selective reuptake inhibitors (SSRIs) 'Treatment SSRIs' ( 16), give however another explanation. We hypothesize occurs brainstem After all, pons origin serotoninergic there, axons sent throughout (CNS) (6,7). afferent arises (6,7) full attach (20). Hypometabolic areas (24,25).Further corroboration argument rRecent Besteher (26) confirms argument. fMRI scans suffering neuropsychiatric (n = 30) significantly larger gray matter volumes (GMV) controls 20). Such example prefrontal cortex (PFC) -which range higher order cognitive functions limbic (27). predominates (27,28). authors state enlargement GMV could sign recovery neurogenesis compensation (26). However, Another explanation cerebral swelling caused reactions.Using PET -for transmission systems -researchers see exactly what happening enlarged Given persist, seems likely pathology. Moreover, provides plausible positive SSRIs when there something wrong balance those regions (16).Furthermore, Su melatonin, serotonin, reduced. additional support-contrary -that may reduced.The second reject biomarker, variability degree variable cohorts different (15,(17)(18)(19). probably many variables studies. as: time passed measurement: ranging 0 22 months, their exact quantification (especially subjective complaints) subgroups belonged cohort. believe methodology therefore results vary research.Unlike (9,13) better option (14,16). expected if instead levels, case comparative above preferably comparable.Beside given colleagues, fourth cause: KP, create nicotinamide adenine dinucleotide (NAD+), interacts extensively system, activated (14,(29)(30)(31). formation process demands lot 14) figure1) because deficiency (9).In study, decline lasted longer. Therefore, major reduction. Guo (30) show persistently INDO-2, stimulates production (figure 1). Cron (14) (such quinoline), while depleted. Additionally, Cysique significant relationship impairment (29). These overactivity KP. active left Figure 1 2.4. overactive deficiencies hormones neurotransmitters illustrates too. regulates cycle (17,32). sleep (16,33).Too due runaway feedback loop blocks tetrahydrobiopterin (BH4), coenzyme dopamine, turn ensures (nor)epinephrine Norepinephrine sympathetic increases frequency force muscle contractions (34)why symptom SNRI (selective norepinephrine inhibitor) SSRI (16).If look metabolites, quinolinic glutaminergic antagonists. accumulation (35) leads various concentration palpitations (35), often suffer (16,33). That why recommend (16) Nacetylcysteine drug restore (35). (36). stimulatesexcept besides pathological propose would preferable choose 5-hydroxytryptophan (5-HTP, confused 5-HT)5hydroxytryptophan) 5-HTP direct does feed barrier. 2.5.2. reduces -to lesser -norepinephrine presynaptic neuron allows synapse transmit signal postsynaptic longer period Normally usually described depression anxiety (37).Wong mice treated fluoxetine (an SSRI) improved Previously, several took SSRIs, lower developing (38)(39)(40)(41)(42)(43).In exploratory thirds PCS-patients showed considerable even strong being (16). confirmed hypothesis regarding importance formulated seven action one hypothetical mechanism. short: , short. instance, a. influence hypothalamic -pituitary -adrenalaxis (HPA-axis, system) (44-51), b. circulatory (52,53), c. . Bby prolonging clotting theoretically help dissolve microclots (54), d. oxidative e. tThe fluvoxamine shown extra anti-inflammatory effects inhibiting sphingomyelinase (ASM) (55), f. pro-inflammatory interleukin 2 (IL 2) IL CNS (56) -in achieve effects, must then sigma1 agonist receptor) (56),. g. stimulate hippocampus (9,57). Finally, slow down (9).Disruptions -and provide clear direction advancing line inquiry. literature noticed While evident scientists explore focus route (14,(29)(30)(31) (15,(17)(18)(19)36), typically overlook possibility routes related, regard pathology overlooked.Additionally, sSerotonin assessment turned (15,(17)(18)(19)22). Tryptophan option. comparable.Toxic good well, (29).Wong advised do examine (15)(16)(17)36). A randomized controlled trial (RCT) follow under strict conditions, testing pharmacogenetic profile advance, since absorb break quickly slowly lack desired side effects. excluded RCT outside context RCT. sensitive stop increasing dosage threatens tip without affecting requirements RCT.Furthermore recommended Therefore option.This review call collaboration immunologists, neurologists psychiatrists field neuroimmunology. already examples psychiatric diseases immunologically, schizophrenia (58)(59)(60)(61)(62), childhood (61,63,64) still unravel neuroimmunology immunological psychotropic drugs considered. (KP) same building block system. From: Treatment

Language: Английский

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Detrimental Effects of Anti-Nucleocapsid Antibodies in SARS-CoV-2 Infection, Reinfection, and the Post-Acute Sequelae of COVID-19

Pathogens, Journal Year: 2024, Volume and Issue: 13(12), P. 1109 - 1109

Published: Dec. 15, 2024

Antibody-dependent enhancement (ADE) is a phenomenon in which antibodies enhance subsequent viral infections rather than preventing them. Sub-optimal levels of neutralizing individuals infected with dengue virus are known to be associated severe disease upon reinfection different serotype. For Severe Acute Respiratory Syndrome Coronavirus type-2 infection, three types ADE have been proposed: (1) Fc receptor-dependent infection cells expressing receptors, such as macrophages by anti-spike antibodies, (2) receptor-independent epithelial and (3) cytokine production anti-nucleocapsid antibodies. This review focuses on the induced examining its potential role COVID-19 during contribution post-acute sequelae COVID-19, i.e., prolonged symptoms lasting at least months after acute phase disease. We also discuss protective effects recently identified that neutralize Omicron variants.

Language: Английский

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