Fig. 1

Potential role of EBV reactivation in the development and progression of MS and therapeutic option of fluvoxamine

EBV directly infects resting B cells and epithelial cells, subsequently residing in the infected memory B cells in peripheral blood. These cells express latent membrane protein 2 (LMP-2) and EBV nuclear antigens (EBNAs). Under stress conditions, these B cells can trigger EBV reactivation, leading to severe systemic inflammation, neuronal demyelination, and the potential onset of MS. The interaction of the XBP-1 (X-box binding protein 1) with Sig1R (sigma-1 receptor) on the endoplasmic reticulum (ER) may be implicated in EBV reactivation. Consequently, this hypothesis suggests that sigma-1 receptor agonists like fluvoxamine could help in preventing EBV reactivation, thereby offering therapeutic advantages in the management and progression of MS. This figure incorporates elements from Figure 2 in , with minor modifications, and was designed using resources from Biorender.com.

Abstract:      Accumulating evidence suggests that the Epstein-Barr virus (EBV) plays a key role in the development of multiple sclerosis (MS). Additionally, depressive symptoms often precede the onset of MS. Given the role of the XBP1-sigma-1 receptor complex in the endoplasmic reticulum during EBV reactivation, the author proposes that fluvoxamine, an antidepressant with sigma-1 receptor agonism, could be a suitable therapeutic drug for MS.

Hashimoto K. Viewpoints Sigma-1 receptor agonist fluvoxamine for multiple sclerosis. Brain Behav Immun Health. 2024 Mar 13;37:100752. doi: 10.1016/j.bbih.2024.100752. PMID: 38524897; PMCID: PMC10957369.

https://pubmed.ncbi.nlm.nih.gov/38524897/

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Post-exercise recovery is essential to resolve metabolic perturbations and promote long-term cellular remodeling in response to exercise. Here, we report that muscle-generated brain-derived neurotrophic factor (BDNF) elicits post-exercise recovery and metabolic reprogramming in skeletal muscle. BDNF increased the post-exercise expression of the gene encoding PPARδ (peroxisome proliferator-activated receptor δ), a transcription factor that is a master regulator of lipid metabolism. After exercise, mice with muscle-specific Bdnf knockout (MBKO) exhibited impairments in PPARδ-regulated metabolic gene expression, decreased intramuscular lipid content, reduced β-oxidation, and dysregulated mitochondrial dynamics. Moreover, MBKO mice required a longer period to recover from a bout of exercise and did not show increases in exercise-induced endurance capacity. Feeding naïve mice with the bioavailable BDNF mimetic 7,8-dihydroxyflavone resulted in effects that mimicked exercise-induced adaptations, including improved exercise capacity. Together, our findings reveal that BDNF is an essential myokine for exercise-induced metabolic recovery and remodeling in skeletal muscle.

Chan WS, Ng CF, Pang BPS, Hang M, Tse MCL, Iu ECY, Ooi XC, Yang X, Kim JK, Lee CW, Chan CB. Exercise-induced BDNF promotes PPARδ-dependent reprogramming of lipid metabolism in skeletal muscle during exercise recovery. Sci Signal. 2024 Mar 19;17(828):eadh2783. doi: 10.1126/scisignal.adh2783. Epub 2024 Mar 19. PMID: 38502732.

https://pubmed.ncbi.nlm.nih.gov/38502732/

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Abstract:

Introduction: The etiology of multiple sclerosis (MS) remains unknown. Pathogenesis likely relies on a complex interaction between multiple environmental, genetic, and behavioral risk factors. However, a growing body of literature supports the role of a preceding Epstein-Barr virus (EBV) infection in the majority of cases.

Areas covered: In this narrative review, we summarize the latest findings regarding the potential role of EBV as a predisposing event inducing new onset of MS. EBV interactions with the genetic background and other infectious agents such as human endogenous retrovirus are explored. Additional data regarding the role of EBV regarding the rate of mid- and long-term disease progression is also discussed. Lastly, the effect of currently approved disease-modifying therapies (DMT) for MS treatment on the EBV-based molecular mechanisms and the development of new EBV-specific therapies are further reviewed.

Expert opinion: Recent strong epidemiological findings support that EBV may be the primary inducing event in certain individuals that shortly thereafter develop MS. More studies are needed in order to better understand the significant variability in susceptibility based on environmental factors such as EBV exposure. Future investigations should focus on determining the specific EBV-related risk antigen(s) and phenotyping people with likely EBV-induced MS. Targeting EBV via several different avenues, including development of an EBV vaccine, may become the mainstay of MS treatment in the future.

Eckert S, Jakimovski D, Zivadinov R, Hicar M, Weinstock-Guttman B. How to and should we target EBV in MS? Expert Rev Clin Immunol. 2024 Mar 15:1-12. doi: 10.1080/1744666X.2024.2328739. Epub ahead of print. PMID: 38477887.

https://pubmed.ncbi.nlm.nih.gov/38477887/

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Long-Term Autoimmune Inflammatory Rheumatic Outcomes of COVID-19

“Preliminary evidence suggests a possible higher incidence of diagnosis of autoimmune inflammatory rheumatic diseases (AIRDs) among patients with a history of COVID-19, but whether this association is specific to SARS-CoV-2 infection is unclear. This study compared the risk for AIRD in patients with a recent SARS-CoV-2 infection versus those with recent influenza infection and those with no infection….

Conclusion:

SARS-CoV-2 infection was associated with increased risk for incident AIRD compared with matched patients without SARS-CoV-2 infection or with influenza infection. The risk for incident AIRD was higher with greater severity of acute COVID-19.“

Kim MS et al., Long-Term Autoimmune Inflammatory Rheumatic Outcomes of CZoVID-19. A Binational Cohort Study. Annals of Internal Medicine (March 5, 2024) https://doi.org/10.7326/M23-1831

https://www.acpjournals.org/doi/10.7326/M23-1831

 

 

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“…Search yielded in total 345 publications, 257 thereof with psychiatric topic, 72 on personality disorder or traits, 43 of which were in humans and epigenetic, 23 thereof were original studies. Lastly, 23 original publications fulfilled the intended search criteria and were included. Those are 13 studies on gene methylation pattern with aggressive, antisocial and impulsive traits, 9 with borderline personality disorder (BPD), and 2 with antisocial personality disorder (ASPD). The results of these studies showed significant associations of PD with methylation aberrances in system-wide genes and suggest evidence for epigenetic processes in the development of personality traits and personality disorders. Environmental factors, of which childhood trauma showed a high impact, interfered with many neurofunctional genes. Methylation alterations in ASPD and BPD repeatedly affected HTR2A, HTR3A, NR3C1, and MAOA genes. …”

Gescher DM, Kahl KG, Hillemacher T, Frieling H, Kuhn J, Frodl T. Epigenetics in Personality Disorders: Today’s Insights. Front Psychiatry. 2018 Nov 19;9:579. doi: 10.3389/fpsyt.2018.00579. PMID: 30510522; PMCID: PMC6252387.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6252387/

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Epigenetic editing was used to reduce the activity of a gene that affects cholesterol levels without changing the DNA sequence — and did so for an extended period, according to a study in mice by Cappelluti and colleagues. The study lays the foundation for the development of in vivo therapeutics that are based on epigenetic silencing. …

Cappelluti, M.A., Mollica Poeta, V., Valsoni, S. et al. Durable and efficient gene silencing in vivo by hit-and-run epigenome editing. Nature (2024). https://doi.org/10.1038/s41586-024-07087-8

https://www.nature.com/articles/s41586-024-07087-8

https://www.nature.com/articles/d41586-024-00563-1

and see also:

Ueda J, Yamazaki T, Funakoshi H. Toward the Development of Epigenome Editing-Based Therapeutics: Potentials and Challenges. Int J Mol Sci. 2023 Mar 1;24(5):4778. doi: 10.3390/ijms24054778. PMID: 36902207; PMCID: PMC10003136.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10003136/

 

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T cells that are specific for B cells infected with Epstein–Barr virus (EBV) are enriched in the cerebrospinal fluid (CSF) of people with early multiple sclerosis (MS), according to new research. The finding adds to evidence that EBV has a role in the pathogenesis of MS, and offers insight into possible mechanisms.

Fyfe, I. T cells implicate Epstein–Barr virus in multiple sclerosis pathogenesis. Nat Rev Neurol (2024). https://doi.org/10.1038/s41582-024-00939-x

https://www.nature.com/articles/s41582-024-00939-x

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“HPV and Tobacco: Dangerous Lesions

Author: Stéphanie Lavaud.     Date: February 23, 2024

PARIS — Cancer and tobacco are a dangerous combination. This adage holds particularly true for cervical cancer, which is induced by high-risk human papillomavirus(HPV). Julia Maruani, MD, a gynecologist in Marseille, France, described this association during a press conference at the French Society of Colposcopy and Cervico-Vaginal Pathology Congress.

4500 Chemical Compounds

To clarify the role of tobacco in cervical cancer, Maruani observed that cigarettes contain nearly 4500 chemical compounds, 60 of which are carcinogenic. “For example, we know that benzopyrene increases viral load, while nitrosamines have a carcinogenic effect,” she said. “And don’t believe that nicotine has no impact. While not directly affecting carcinogenesis, it plays a harmful role in terms of immunosuppression. Tobacco alters all components of immunity: Cellular, humoral, local, and systemic.”

Indeed, tobacco is the leading modifiable risk factor for cancers, contributing to 13% of all cases. When considering cervical cancer in women, tobacco and HPV are the main risk factors. The same applies to cancers of the pharynx and nasopharynx. “There is an extremely strong association between cancer and tobacco for all sites affected by HPV infection,” said Maruani. …”

https://www.medscape.com/viewarticle/hpv-and-tobacco-dangerous-lesions-2024a10003mf

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Abstract

BACKGROUND

Food allergies are common and are associated with substantial morbidity; the only approved treatment is oral immunotherapy for peanut allergy.

METHODS

In this trial, we assessed whether omalizumab, a monoclonal anti-IgE antibody, would be effective and safe as monotherapy in patients with multiple food allergies. Persons 1 to 55 years of age who were allergic to peanuts and at least two other trial-specified foods (cashew, milk, egg, walnut, wheat, and hazelnut) were screened. Inclusion required a reaction to a food challenge of 100 mg or less of peanut protein and 300 mg or less of the two other foods. Participants were randomly assigned, in a 2:1 ratio, to receive omalizumab or placebo administered subcutaneously (with the dose based on weight and IgE levels) every 2 to 4 weeks for 16 to 20 weeks, after which the challenges were repeated. The primary end point was ingestion of peanut protein in a single dose of 600 mg or more without dose-limiting symptoms. The three key secondary end points were the consumption of cashew, of milk, and of egg in single doses of at least 1000 mg each without dose-limiting symptoms. The first 60 participants (59 of whom were children or adolescents) who completed this first stage were enrolled in a 24-week open-label extension.

RESULTS

Of the 462 persons who were screened, 180 underwent randomization. The analysis population consisted of the 177 children and adolescents (1 to 17 years of age). A total of 79 of the 118 participants (67%) receiving omalizumab met the primary end-point criteria, as compared with 4 of the 59 participants (7%) receiving placebo (P<0.001). Results for the key secondary end points were consistent with those of the primary end point (cashew, 41% vs. 3%; milk, 66% vs. 10%; egg, 68% vs. 0%; P<0.001 for all comparisons). Safety end points did not differ between the groups, aside from more injection-site reactions in the omalizumab group.

CONCLUSIONS

In persons as young as 1 year of age with multiple food allergies, omalizumab treatment for 16 weeks was superior to placebo in increasing the reaction threshold for peanut and other common food allergens. (Funded by the National Institute of Allergy and Infectious Diseases and others; ClinicalTrials.gov number, NCT03881696. opens in new tab.)

 Wood RA et al.,  Omalizumab for the Treatment of Multiple Food Allergies. New England J. Med. , DOI:  10.1056/NEJMoa2312382. (2024).

https://www.nejm.org/doi/full/10.1056/NEJMoa2312382

https://www.nih.gov/news-events/news-releases/antibody-reduces-allergic-reactions-multiple-foods-nih-clinical-trial

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Significance
In the midst of rapid globalization, the peaceful coexistence of cultures requires a deeper understanding of the forces that compel prosocial behavior and thwart xenophobia. Yet, the conditions promoting such outgroup-directed altruism have not been determined. Here we report the results of a double-blind, placebo-controlled experiment showing that enhanced activity of the oxytocin system paired with charitable social cues can help counter the effects of xenophobia by fostering altruism toward refugees. These findings suggest that the combination of oxytocin and peer-derived altruistic norms reduces outgroup rejection even in the most selfish and xenophobic individuals, and thereby would be expected to increase the ease by which people adapt to rapidly changing social ecosystems.

Abstract
Never before have individuals had to adapt to social environments defined by such magnitudes of ethnic diversity and cultural differentiation. However, neurobiological evidence informing about strategies to reduce xenophobic sentiment and foster altruistic cooperation with outsiders is scarce. In a series of experiments settled in the context of the current refugee crisis, we tested the propensity of 183 Caucasian participants to make donations to people in need, half of whom were refugees (outgroup) and half of whom were natives (ingroup). Participants scoring low on xenophobic attitudes exhibited an altruistic preference for the outgroup, which further increased after nasal delivery of the neuropeptide oxytocin. In contrast, participants with higher levels of xenophobia generally failed to exhibit enhanced altruism toward the outgroup. This tendency was only countered by pairing oxytocin with peer-derived altruistic norms, resulting in a 74% increase in refugee-directed donations. Collectively, these findings reveal the underlying sociobiological conditions associated with outgroup-directed altruism by showing that charitable social cues co-occurring with enhanced activity of the oxytocin system reduce the effects of xenophobia by facilitating prosocial behavior toward refugees.

Marsh, N. et al.,   Oxytocin-enforced norm compliance reduced xenophobic outgroup rejection. Proc. Natl. Acad. Sci. USA 114(35): 9314-9319.       https://www.pnas.org/doi/full/10.1073/pnas.1705853114
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