Type 1 diabetes (T1D) is an autoimmune disease that leads to the progressive destruction of pancreatic β cells, resulting in insulin deficiency and hyperglycemia. Current treatments focus on insulin replacement, but novel therapeutic approaches targeting β cell regeneration are needed. Dual-specificity tyrosine-phosphorylation-regulated kinases 1A (DYRK1A) and 1B (DYRK1B) play key roles in cell cycle regulation and β cell proliferation.
In this study, FX8474, a novel DYRK1 inhibitor, was evaluated in a streptozotocin (STZ)-induced diabetic mouse model. Mice were treated orally for 7 days, and pharmacokinetics, glucose regulation, and immune cell profiling were assessed.
Pharmacokinetic analysis confirmed the oral bioavailability of FX8474, and treatment was associated with improved fasted glucose levels and glucose tolerance after a 7-day treatment. Immunophenotyping indicated that FX8474 treatment increases CD4+ memory T cell populations while decreasing CD4+ effector cells, as well as restores CD8+ T cell phenotypes to levels observed in healthy mice.
FX8474 has a modest effect on glucose regulation and immune cell composition, warranting further investigation into its potential therapeutic applications.
Copyright © 2025 Tumas, Mingaila, Baranauskas, Baltrukonytė, Orla, Krasko, Pocevičiūtė, Berlina, Belenky, Vilenchik, Vaitkevičienė, Potapova and Burokas.

Prolonged or broad-spectrum antibiotic courses are associated with intestinal dysbiosis and cytopenias, and depletion of hematopoietic progenitor populations after antibiotics is associated with loss of peripheral immune cells, leading to increased susceptibility to systemic infections. We evaluated the bone marrow hematopoietic compartment in a murine model of antibiotic exposure. Single-cell RNA sequencing revealed a substantial and previously unrecognized depletion of bone marrow B cells at all stages of development in antibiotic-treated mice, further confirmed by flow cytometric analysis. Depletion of the microbiota was associated with rapid changes in the peripheral B-cell compartment, yet fecal microbiota transfer did not rescue either peripheral or bone marrow B cells to a greater degree than natural recovery from antibiotic treatment. Antibiotic-mediated loss of B-cell progenitors was secondary to enhanced apoptosis and occurred independent of disrupted systemic type I and II interferon signaling, previously implicated in the maintenance of other hematopoietic compartments. Instead, the depletion of prosurvival MYC signaling was implicated in the depletion of circulating lymphocytes and bone marrow B-cell progenitor populations during antibiotic treatment. Furthermore, in vitro exposure of bone marrow cells to antibiotics demonstrated significantly decreased viability of B cells. We conclude that both microbiota depletion and cytotoxic effects of prolonged broad-spectrum antibiotic treatment disrupt cytokine and cell survival signaling critical for B-cell progenitor maintenance. These results contribute to our understanding of the compartment-specific mechanisms by which the microbiota maintains the hematopoietic system and suggest critical pathways for maintenance of bone marrow progenitors during prolonged antibiotic treatment.
© 2025 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

Oropharyngeal candidiasis (OPC) is an opportunistic infection caused by Candida albicans. IL-17-mediated immunity driven by Th17 cells plays a crucial role in defense against this infection. However, the location and mechanism by which the Th17 immune response is induced during OPC remain unclear. Here, we show that C. albicans in the gut enhances protection against OPC. Intestinal C. albicans is taken up by the mucosal immune system and triggers a systemic C. albicans-responsive Th17 cell response. Upon oral infection with C. albicans, these Th17 cells migrate from the gut to the oral region and accumulate in the tongue tissue, resulting in antifungal immune responses. The pathobiont-reactive Th17 cells developed in the gut strongly provide IL-17A not only locally in the mouth but also systemically in the serum upon OPC. Our findings highlight that fungal pathogen-responsive Th17 cells in the gut-mouth axis enhance protection against OPC.
© 2025 The Author(s).

Hyperlipidemia induces cellular dysfunction and is strongly linked to various diseases. The transient receptor potential channel melastatin 2 (TRPM2) plays a critical role in endothelial injury, immune cell activation, and neuronal death. We reveal that TRPM2 expression in human peripheral leukocytes strongly correlates with plasma lipid levels. In middle-aged Apoe-/- mice, global, myeloid, and endothelial TRPM2 knockout or TRPM2 inhibition abolishes the hyperlipidemia-induced exacerbation of ischemic brain injury suggesting that TRPM2 overactivity caused by hyperlipidemia predisposes these cells to dysfunction during ischemia. Using a clinically relevant ischemic brain injury mouse model, we demonstrate TRPM2's pivotal role in mediating hyperlipidemia's detrimental effects on myeloid cells and neurovascular units. Our findings suggest that TRPM2 is a promising therapeutic target for alleviating neurodegenerative diseases exacerbated by hyperlipidemia, such as ischemic stroke. These results also highlight TRPM2 expression in peripheral blood as a potential biomarker for predicting stroke outcomes in hyperlipidemic patients.
Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved.

Rubber accelerators are used in the vulcanization of rubber. However, rubber accelerators for example tetraethylthiuram disulfide (TETD) and zinc diethyldithiocarbamate (ZDEC) may cause contact allergy. Concomitant reactions between ZDEC and TETD have been observed in patients which could be explained by co- or cross-reactivity.
To investigate cross-reactivity between TETD and ZDEC and vice versa.
Groups of mice were sensitized with TETD or ZDEC based on reported EC3-values. Proliferation of lymphocytes were measured on day 5. To test cross-reactivity, mice were sensitized and challenged 3 weeks later with TETD or ZDEC. The inflammatory response was measured by changes in ear thickness and the proliferative response in CD4+ and CD8+ T cells in the submandibular and cervical draining lymph nodes.
Sensitization of mice with doses of ZDEC 3%, TETD 5.6% or TETD 16.2% induced significant increased ear thickness and proliferation of CD4+ and CD8+ T cells. Challenge with ZDEC or TETD in these groups induced significant increased ear thickness. Challenge with ZDEC in mice sensitized to TETD 5.6% or TETD 16.2% induced significant increased proliferation of CD4+ and CD8+ T cells.
We show cross-reactivity between TETD and ZDEC. Patients sensitized to TETD or ZDEC should avoid exposure to both ZDEC and TETD.
© 2024 The Author(s). Contact Dermatitis published by John Wiley & Sons Ltd.