MYMD-1, a Novel Immunometabolic Regulator, Ameliorates Autoimmune Thyroiditis via Suppression of Th1 Responses and TNF-α Release

Dalmazi, Giulia Di; Chalan, Paulina; Caturegli, Patrizio

doi:10.4049/jimmunol.1801238

Cited by 15 publications

(10 citation statements)

References 52 publications

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“…Another study showed that CD19 positive B cells were one major B cell component in PD [ 28 ]. Similarly, CD19 was related to autoimmunity of the thyroid [ 29 ]. All of these findings could support the (auto-) immune relationship between PD and HT.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic Analysis Reveals Genetic Cross-Talk between Periodontitis and Hypothyroidism

et al. 2022

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Background. Aim of this bioinformatics study based on transcriptomic analysis was to reveal the cross-talk between periodontitis (PD) and hypothyroidism (HT). Methods. The gene expression datasets GSE18152 and GSE176153 of HT and GSE10334, GSE16134, and GSE173078 of PD were downloaded through the Gene Expression Omnibus (GEO) database. Differential Expression Genes (DEG) between cases and controls in each microarray were assessed by using the “limma” (linear models for microarray data) R package (|log2 fold change (FC)| >0 and P -value <0.05). To analyze the cross-talk effect between HT and PD, the intersection of DEG of HT and PD was selected. To investigate the biological function of cross-talk genes, the gene ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were applied. Protein-Protein Interaction (PPI) network was constructed using Cytoscape software. Top 10 cross-talk genes were screened, and the expression values of these 10 genes were extracted. ROC analysis was performed by using the pROC package and GGplot2 package of R language to predict the classification accuracy. Results. The overlapping DEG between HT and PD were 107 cross-talk genes. The results revealed that developmental process ( P -value =1.06E-21) was the most significantly enriched biological process, followed by cell differentiation ( P -value =8.49E-18) and immune system process ( P -value =6.78E-11). KEGG analysis showed that Complement and coagulation cascades ( P -value =2.29E-05), Hematopoietic cell lineage ( P -value =2.66E-05), Phospholipase D signaling pathway ( P -value =0.034367878) and Chemokine signaling pathway ( P -value =0.04946333) were significantly enriched. The top 10 genes with most connections were LCE1B, LCE2B, LCE2A, LCE2C, LCE1C, LCE1F, ITGAM, C1QB, TREM2, and CD19. The AUC values of the two datasets of HT were both greater than 65% (GSE18152 = 81.42%, GSE176153 = 68.75%). AUC values of three datasets of PD were all greater than 60% (GSE10334 = 69.23%, GSE16134 = 73.72%, GSE173078 = 81.6%). Conclusions. A genetic cross-talk between HT and PD was detected, whereby LCE family genes appeared to play the most important role.

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Section: Discussionmentioning

confidence: 99%

Transcriptomic Analysis Reveals Genetic Cross-Talk between Periodontitis and Hypothyroidism

et al. 2022

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“…Isomyosamine has been investigated in vitro and in animal models suggesting various mechanisms and potential indications for development. A study utilizing a mice model of spontaneous thyroiditis suggests that Isomyosamine ameliorates thyroiditis acting on specific lymphoid subsets via the reduction of Th1 responses and TNF-a release 4 . Another study in mice and in vitro showed improvement of the course of experimental autoimmune encephalomyelitis (EAE) induced by immunization with myelin oligodendrocyte glycoprotein and suppressed activation of effector T cells without causing global immunosuppression or toxicity 5 .…”

Section: Discussionmentioning

confidence: 99%

“…TNF-α is the protein in the body that causes inflammation and helps activate the process of aging. In preclinical studies and recently published reports, Isomyosamine could suppress in vitro the release of TNF-α from splenic CD4 T cells and reducing disease incidence and severity in mouse models of autoimmune thyroiditis and multiple sclerosis [2,4], in the absence of measurable toxicity. These models, based on a relatively short administration (12 weeks for thyroiditis and 3 weeks for experimental autoimmune encephalomyelitis; EAE), included the mechanism of reducing the number of infiltrating Th1 CD4 T cells and follicular B cells [4][5].…”

Section: Introductionmentioning

confidence: 94%

“…Isomyosamine, an isomer of myosmine, is a synthetic alkaloid derived from tobacco plant, which has been shown to inhibit the production and release of cytokines, including IFN-γ, IL-2, IL-10, and TNF-α, from human peripheral blood mononuclear cells in a dose-dependent manner 4 . TNF-α is the protein in the body that causes inflammation and helps activate the process of aging.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A Double-blind, Placebo-controlled, Randomized, Single Ascending, and Multiple Dose Phase 1 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Oral Dose Isomyosamine Capsules in Healthy Adult Subjects

Brager¹,

Chapman²,

Dunn

et al. 2022

Drug Res (Stuttg)

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Background Aging is tightly linked to chronic disease, frailty, and death. Multi-morbidity, defined as the presence in the same patient of three or more conditions such as neoplastic, cardiovascular, neurodegenerative, metabolic, or autoimmune diseases, becomes more common with age. Methods The study was performed in a double-blind fashion. Subjects within each dose cohort (Cohorts 1, 2, 3, and 4) were randomly assigned to receive Isomyosamine doses (between 150 mg to 600 mg or placebo) or placebo in a 3:1 ratio (6 active: 2 placebo). Results Isomyosamine single daily doses each of 150 mg, 300 mg, and 450 mg for 3 days and multiple daily doses of 600 mg for 6 days were safe and well tolerated in healthy subjects. In one dose group, there was a decrease in TNF-α levels found in Isomyosamine treated subjects, but no change in the levels in subjects given placebo. The increase in Isomyosamine exposure was proportional to dose across the dose range of 300 mg to 600 mg when administered as a single dose. There was minimal accumulation of Isomyosamine following 5 days of once daily dosing of Isomyosamine 600 mg. Isomyosamine half-life ranged from approximately 15 minutes to 45 minutes across all doses in the single ascending dose and multiple ascending dose portion of the study. Elimination of Isomyosamine included the renal pathway as a minor route. Conclusion Isomyosamine will continue to be investigated in phase 2 clinical trials for the treatment of sarcopenia/frailty, hashimoto’s thyroiditis and rheumatoid arthritis.

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“…disease. The co-occurrence of rheumatoid arthritis and autoimmune thyroid disease has long been recognized 38,39 , with few, but suggestive reports that TNF-alpha inhibitors might improve thyroid autoimmunity in patients with rheumatic arthritis 40 and inhibition of TNFalpha signalling in a mouse model ameliorated thyroiditis 41 . While we provide here genetically anchored evidence for targeted treatment strategies, the best timepoint for the treatment needs to be established in preclinical models and human trials as both medications might be most effective early in the disease process before much of the thyroid gland is damaged.…”

Section: Drug Repurposing and Adverse Effect Predictionmentioning

confidence: 99%

Complex patterns of multimorbidity associated with severe COVID-19 and Long COVID

Pietzner,

Denaxas,

Yasmeen

et al. 2023

Preprint

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Many diseases with significant health burden and healthcare costs have been neglected in biomedical research, partly due to a lack of data. Here, we systematically harmonized >12 million primary care and hospitalisation health records from ~440,000 UK Biobank participants into 1445 collated disease terms for genetic analyses. This included ~200 diseases with >10,000 cases that are predominantly managed in primary care, like skin and non-serious infectious diseases. We quantify the heritability for these common diseases, identify novel loci with extreme effect sizes, and highlight novel roles of poorly characterised genes, e.g.PNLIPRP3as a sebaceous gland cell-specific gene for rosacea. We characterise the substantial regional pleiotropy with more than 300 independent genomic regions associated with multiple, often seemingly unrelated diseases and use these insights to generate a pan-genome disease network of shared disease loci to prioritise potential pathways contributing to multiple diseases and onset of multimorbidity. We demonstrate the value of primary care data to improve and guide genetic approaches for drug selection, repurposing, and adverse event prediction, e.g.,IGFR1as a putative multi-disease target for, among others, gout and atrial fibrillation, through network augmentation and integration of molecular quantitative trait loci. We make all results publicly available via an interactive webserver (https://www.omicscience.org/apps/phecodes). Our results provide new insights for diseases across diverse clinical specialties and provide a resource for drug discovery and mechanistic understanding.

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MYMD-1, a Novel Immunometabolic Regulator, Ameliorates Autoimmune Thyroiditis via Suppression of Th1 Responses and TNF-α Release

Abstract: This information is current as Release α and TNF-Thyroiditis via Suppression of Th1 Responses Regulator, Ameliorates Autoimmune MYMD-1, a Novel Immunometabolic

Cited by 15 publications

References 52 publications

Transcriptomic Analysis Reveals Genetic Cross-Talk between Periodontitis and Hypothyroidism

Transcriptomic Analysis Reveals Genetic Cross-Talk between Periodontitis and Hypothyroidism

A Double-blind, Placebo-controlled, Randomized, Single Ascending, and Multiple Dose Phase 1 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Oral Dose Isomyosamine Capsules in Healthy Adult Subjects

Complex patterns of multimorbidity associated with severe COVID-19 and Long COVID

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