Insights into the Role of Glutathione Peroxidase 3 in Non-Neoplastic Diseases

The repeated evolution of similar phenotypes in independent lineages often occurs in response to similar environmental pressures, through similar or different molecular pathways. Recently, a repeatedly occurring mutation R263Q in a conserved domain of the protein Cryptochrome1 (CRY1) was reported in multiple species inhabiting subterranean environments. Cryptochromes regulate circadian rhythms, and glucose and lipid metabolism. Subterranean species show changes to their circadian rhythm and metabolic pathways, making it likely that this mutation in CRY1 contributes to adaptive phenotypic changes. To identify the functional consequences of the CRY1 R263Q mutation, we generated a mouse model homozygous for this mutation. Indirect calorimetry experiments revealed delayed energy expenditure, locomotor activity and feeding patterns of mutant mice in the dark phase, but no further metabolic phenotypes, unlike a full loss of function of CRY1. Gene expression analyses showed altered expression of several canonical circadian genes in the livers of the mutant mice, fortifying the notion that CRY1 R263Q impacts metabolism. Our data provide the first characterization of a novel mutation that has repeatedly evolved in subterranean environments, supporting the idea that shared environmental constraints can drive the evolution of similar phenotypes through similar genetic changes.

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Immunotherapy for type 1 diabetes

Sann,

Rahman,

Thu

2024

Metab Target Organ Damage

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Type 1 diabetes mellitus (T1D) is a chronic autoimmune disorder in which the immune system attacks insulin-producing β cells in the pancreas, leading to insulin deficiency and hyperglycemia. Despite advancements in treatment, managing T1D remains challenging, with patients experiencing diabetes distress and reduced life expectancy. Immunotherapy offers promising strategies for modifying the course of T1D by targeting the immune system’s attack on β cells. A recent highlight is teplizumab, an anti-CD3 monoclonal antibody, which delays the progression of T1D in patients with recent onset by preserving endogenous insulin production. Clinical trials have shown that teplizumab can improve glycemic control and delay the onset of stage 3 T1D for up to two years in at-risk individuals. Other immunotherapies, including targeting B cells with rituximab, have shown potential to preserve β cell function and reduce insulin requirements in recent-onset T1D. Additionally, T cell modulation therapies such as abatacept have been shown to slow the decline in β cell function. Cytokine-directed therapies targeting inflammation have also demonstrated potential in preserving β cell function and improving glycemic control. Combination therapies, such as the use of anti-interleukin (IL)-21 antibodies with liraglutide, may offer synergistic benefits and preserve endogenous insulin secretion. While immunotherapies offer the potential for short-term protection of β cells, ongoing research is needed to refine treatment strategies and identify optimal timing and combinations of therapies. This could lead to safer and more effective management of T1D, potentially reducing reliance on insulin therapy and providing long-term benefits for patients.

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Insights into the Role of Glutathione Peroxidase 3 in Non-Neoplastic Diseases

Cited by 5 publications

References 209 publications

Viral Infections and the Glutathione Peroxidase Family: Mechanisms of Disease Development

Viral Infections and the Glutathione Peroxidase Family: Mechanisms of Disease Development

A repeatedly evolved mutation in Cryptochrome-1 of subterranean animals alters behavioral and molecular circadian rhythms

Immunotherapy for type 1 diabetes

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