Reactivation of herpesvirus type 6 and IgA/IgM-mediated responses to activin-A underpin long COVID, including affective symptoms and chronic fatigue syndrome

Acta Neuropsychiatrica, Journal Year: 2024, Volume and Issue: 36(3), P. 172 - 184

Published: April 4, 2024

Persistent infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), reactivation of dormant viruses, and immune-oxidative responses are involved in long COVID.

Language: Английский

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Melatonin modulates tumor metabolism and mitigates metastasis

Expert Review of Endocrinology & Metabolism, Journal Year: 2023, Volume and Issue: 18(4), P. 321 - 336

Published: July 4, 2023

Melatonin, originally isolated from the mammalian pineal gland, was subsequently identified in many animal cell types and plants. While melatonin discovered to inhibit cancer more than 5 decades ago, its anti-cancer potential has not been fully exploited despite lack of serious toxicity over a very wide dose range, high safety margin, efficacy.This review elucidates mechanisms by which interferes with tumor growth metastasis, including ability alter metabolism, epithelial-mesenchymal transition, reverse chemoresistance, function synergistically conventional cancer-inhibiting drugs while limiting their side effects. In contrast as potent antioxidant normal cells, it may induce oxidative stress contributing oncostatic actions.Considering large amount experimental data supporting melatonin's multiple varied inhibitory effects on numerous types, coupled virtual this molecule, thoroughly tested an agent clinical trials. There seems be significant resistance such investigations, possibly because is inexpensive non-patentable, result there would limited financial gain for use.

Language: Английский

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Melatonin, BAG-1 and cortisol circadian interactions in tumor pathogenesis and patterned immune responses

Exploration of Targeted Anti-tumor Therapy, Journal Year: 2023, Volume and Issue: unknown, P. 962 - 993

Published: Oct. 25, 2023

A dysregulated circadian rhythm is significantly associated with cancer risk, as aging. Both aging and dysregulation show suppressed pineal melatonin, which indicated in many studies to be linked risk progression. Another independently investigated aspect of the cortisol awakening response (CAR), stress-associated hypothalamus-pituitary-adrenal (HPA) axis activation. CAR HPA activity are primarily mediated via activation glucocorticoid receptor (GR), drives patterned gene expression binding promotors element (GRE)-expressing genes. Recent data shows that GR can prevented from nuclear translocation by B cell lymphoma-2 (Bcl-2)-associated athanogene 1 (BAG-1), translocates mitochondria, where it have diverse effects. Melatonin also suppresses maintaining a complex heat shock protein 90 (Hsp90). Melatonin, directly and/or epigenetically, upregulate BAG-1, suggesting dramatic 10-fold decrease melatonin adolescence ninth decade life will attenuate capacity night-time modulate effects early morning CAR. The interactions melatonin/BAG-1/Hsp90 proposed underpin how risk. This may differential melatonin/BAG-1/Hsp90/GR different cells microenvironments across body, tumors emerge. provides model pathogenesis better integrates previously disparate bodies data, including immune regulated tumor microenvironment, at least partly regulation tryptophan-melatonin pathway. has number future research treatment implications.

Language: Английский

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Polycystic Ovary Syndrome Pathophysiology: Integrating Systemic, CNS and Circadian Processes

Frontiers in Bioscience-Landmark, Journal Year: 2024, Volume and Issue: 29(1), P. 24 - 24

Published: Jan. 18, 2024

The conceptualization of polycystic ovary syndrome (PCOS) has primarily focused on hormonal alterations driven by changes within the hypothalamus and ovarian granulosa cells, with treatment contraceptive pill weight loss. However, a growing body data implicates wider systemic central nervous system (CNS) in pathoetiology pathophysiology PCOS, consequent implications for targeted treatments. It is proposed that there significant role night-time interactions factors acting to regulate whether rising level cortisol over night during morning awakening response (CAR) able induce nuclear translocation glucocorticoid receptor (GR), thereby influencing how immune glial systems cellular function preparation coming day. Factors affording protection PCOS also inhibit GR including gut microbiome-derived butyrate, pineal/local melatonin as well regulated bcl2-associated athanogene (BAG)-1. A pathophysiological attributed aryl hydrocarbon (AhR), which shows heightened levels activity PCOS. AhR activated ligands many processes, white adipocyte-derived kynurenine, implicating obesity occurring ovaries. activation consequences physiological hypothalamic paraventricular nucleus, cells adipocytes, partly mediated upregulation mitochondrial N-acetylserotonin/melatonin ratio, decreasing availability whilst increasing local stress plasticity nucleus. This article reviews detail CNS highlighting pineal melatonergic pathway, nucleus tanycytes/astrocytes, hypothalamus-pituitary-adrenal (HPA) axis pathophysiology. integrates wide array previously disparate biological underpinnings associates other currently classified medical conditions, such depression, bipolar disorder, type 1 diabetes mellitus autism spectrum. Numerous future research are detailed.

Language: Английский

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Therapeutic potential of melatonin in targeting molecular pathways of organ fibrosis

Pharmacological Reports, Journal Year: 2023, Volume and Issue: 76(1), P. 25 - 50

Published: Nov. 23, 2023

Language: Английский

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A More Holistic Perspective of Alzheimer's Disease: Roles of Gut Microbiome, Adipocytes, HPA Axis, Melatonergic Pathway and Astrocyte Mitochondria in the Emergence of Autoimmunity

Frontiers in Bioscience-Landmark, Journal Year: 2023, Volume and Issue: 28(12), P. 355 - 355

Published: Dec. 28, 2023

Alzheimer's disease is widely regarded as poorly treated due to poor conceptualization. For 40 years, pathophysiology has focused on two culprits, amyloid-β induced plaques and hyperphosphorylated tau associated tangles, with no significant treatment advance. This confounded by data showing be an endogenous antimicrobial that increased in a wide array of diverse medical conditions heightened inflammation. article reviews the wider bodies pertaining pathophysiology, highlighting role suppressed astrocyte mitochondrial function melatonergic pathway core hub driving neuronal loss dementia. It proposed over aging becomes dysregulated, at least partly mediated systemic processes involving 10-fold decrease pineal melatonin leading attenuated capacity night-time dampen residual daytime Suppressed also attenuates melatonin's inhibition glucocorticoid receptor nuclear translocation, thereby changing not only stress/hypothalamus-pituitary-adrenal (HPA) axis consequences but cortisol awakening response, which 'primes body for coming day'. Gut microbiome-derived butyrate inhibits well inducing pathway. prevents autocrine paracrine effects limiting levels effects. production induction lactate, decreasing metabolism The lactate melatonin, coupled suppression decreases mitophagy, major histocompatibility complex (MHC)-1. MHC-1 initiates chemoattraction CD8+ t cells, destruction being driven 'autoimmune'/'immune-mediated' processes. may therefore conceptualized initiated act astrocytes hub, leaving neurons deplete appropriate metabolic substrates co-ordinated antioxidants. culminates 'immune-mediated' cell death. Future research treatment/prevention implications are indicated.

Language: Английский

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Reactivation of herpesvirus type-6 and IgA/IgM-mediated responses to activin-A underpin Long COVID, including affective symptoms and chronic fatigue syndrome

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: July 24, 2023

Abstract Background Persistent infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), reactivation of dormant viruses, and immune-oxidative responses are involved in Long COVID. Objectives To investigate whether COVID depressive, anxiety chronic fatigue (CFS) symptoms, associated IgA/IgM/IgG to SARS-CoV-2, human Herpesvirus type 6 (HHV-6), Epstein-Barr Virus (EBV), biomarkers. Methods We examined 90 patients healthy controls. measured serum against HHV-6 EBV their deoxyuridine 5′-triphosphate nucleotidohydrolase (duTPase), activin-A, C-reactive protein (CRP), advanced oxidation products (AOPP), insulin resistance (HOMA2-IR). Results showed significant elevations IgG/IgM-SARS-CoV-2, IgG/IgM-HHV-6 HHV-6-duTPase, IgA/IgM-activin-A, CRP, AOPP, HOMA2-IR. Neural network analysis yielded a highly predictive accuracy 80.6% for the diagnosis (sensitivity: 78.9%, specificity: 81.8%, area under ROC curve=0.876); topmost predictors were: IGA-activin-A, IgG-HHV-6, IgM-HHV-6-duTPase, IgG-SARS-CoV-2, IgM-HHV-6 (all positively) factor extracted from all IgA levels viral antigens (inversely). The top-5 affective symptoms due education, IgA-activin-A (predictive r=0.636). CFS were descending order: IgG-HHV-6-duTPase, IgM-activin-A, IgM-SARS-CoV-2, accuracy: r=0.709). Conclusion Reactivation HHV-6, SARS-CoV-2 persistence, autoimmune reactions activin-A combined activated pathways play major role pathophysiology as well severity

Language: Английский

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Melatonin suppresses TLR4‐mediated RSV infection in the central nervous cells by inhibiting NLRP3 inflammasome formation and autophagy

Journal of Cellular and Molecular Medicine, Journal Year: 2024, Volume and Issue: 28(9)

Published: April 29, 2024

Abstract Respiratory syncytial virus (RSV) infects neuronal cells in the central nervous system (CNS), resulting neurological symptoms. In present study, we intended to explore mechanism of RSV infection‐induced neuroinflammatory injury from perspective immune response and sought identify effective protective measures against injury. The findings showed that toll‐like receptor 4 (TLR4) was activated after infection human SY5Y cells. Furthermore, TLR4 activation induced autophagy apoptosis cells, promoted formation NOD‐like family pyrin domain containing 3 (NLRP3) inflammasome, increased secretion downstream inflammatory cytokines such as interleukin‐1β (IL‐1β), interleukin‐18 (IL‐18) tumour necrosis factor‐α (TNF‐α). Interestingly, blockade or treatment with exogenous melatonin significantly suppressed well TLR4‐mediated apoptosis, responses. Therefore, infer may act on ameliorate RSV‐induced injury, which provides a new therapeutic target for infection.

Language: Английский

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Why are aging and stress associated with dementia, cancer, and other diverse medical conditions? Role of pineal melatonin interactions with the HPA axis in mitochondrial regulation via BAG-1

Melatonin Research, Journal Year: 2023, Volume and Issue: 6(3), P. 345 - 371

Published: Sept. 29, 2023

Pineal melatonin and the cortisol awakening response (CAR) are integral aspects of circadian rhythm. release during sleep is proposed to optimize mitochondrial function dampen any residual oxidant inflammatory activity. Little known about CAR, which generally thought prepare body for coming day, primarily through activation glucocorticoid receptor (GR). Melatonin, like gut microbiome-derived butyrate, suppresses GR nuclear translocation, indicating that pineal night-time butyrate may interact modulate CAR effects via GR, including priming immune glia cells underpin pathogenesis most medical conditions. Cutting edge research shows can be chaperoned by bcl2-associated athanogene (BAG)-1 mitochondria, where have significant diverse impacts on function. A number lines evidence indicate indirectly increases BAG-1, epigenetic mechanisms, such as derepressing miR-138 inhibition BAG-1. The dramatic decrease in production over aging will therefore but also possibly levels BAG-1 mediated translocation GR. This consequences how ‘prepares day’, differential consequence location cytoplasm, nucleus or with different cell types. interactions melatonin/butyrate/BAG-1/GR especially important hypothalamus, a maintained heightened concentration occurs night due direct melatonin, recess, into third ventricle. interaction types, thereby altering intercellular homeostatic given microenvironment contribute many aging-associated conditions, neurodegenerative conditions cancer. reframes nature rhythm well stress-associated hypothalamus-pituitary-adrenal (HPA) axis both course presentations. has treatment implications across host current

Language: Английский

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Gut Microbiome and Circadian Interactions with Platelets Across Human Diseases, including Alzheimer’s Disease, Amyotrophic Lateral Sclerosis, and Cancer

Current Topics in Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 23(28), P. 2699 - 2719

Published: Oct. 9, 2023

Abstract: Platelets have traditionally been investigated for their role in clot formation the course of cardiovascular diseases and strokes. However, recent work indicates platelets to be an integral aspect wider systemic processes, with relevance pathophysiology a host diverse medical conditions, including neurodegenerative disorders cancer. This article reviews platelet function interactions gut microbiome circadian systems, highlighting mitochondrial melatonergic pathway determining activation, fluxes plasticity. provides number novel conceptualizations mode interaction other cell types, pathoetiology such as cancer, Alzheimer’s disease, amyotrophic lateral sclerosis. It is proposed that platelet-gut axis allows contribute many pathophysiological processes linked dysbiosis permeability. at least partly via sphingosine- 1-phosphate release, which regulates enteric glial cells lymphocyte chemotaxis, indicating etiological wide array conditions alterations microbiome. are also important regulator various microenvironments underpin most human tumor microenvironment, diseases, autoimmune disorders. Platelet serotonin release availability systemically, thereby being determinant dynamic metabolic occurring across types conditions. In addition, future research directions treatment implications proposed.

Language: Английский

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