Magnesium sulfate (MgSO4) possesses the advantages of being readily accessible, cost-effective, and having low toxicity. It has potential applications as a neuroprotective agent. The mechanisms underlying the effects of Mg2+ treatment on depression and its neuroprotective properties remain poorly elucidated.
In this study, we employed chronic mild unpredictable stress (CMS)-induced mice were orally administered with MgSO4 or pioglitazone. The CMS-induced depressive-like behaviors of mice were monitored. After sacrifice, the levels of Mg2+ and inflammatory cytokines were observed. Blood-brain barrier (BBB) permeability and the M1-to-M2 shift of microglia in mouse hippocampus were detected. The expression of proteins in IKK/NF-κB and NLRP3 inflammasome signal pathway were analyzed.
We found that CMS induced depressive-like behaviors as well as hypomagnesemia in mice, which were accompanied with hypersecretion of inflammatory cytokines in hippocampus of mice. These animals induced by CMS exhibited hippocampal neuroinflammation characterized by an elevated number of Iba+ microglia with enlarged cell bodies and increased branching structures. In CMS-induced mice, MgSO4 alleviated CMS-induced depressive-like behaviors and hypomagnesemia, reduced the levels of inflammatory cytokines in both serum and hippocampus, decreased the number of Iba+ microglia, modulated microglia polarization and repaired the BBB damage. MgSO4 also significantly facilitates the M1-to-M2 shift in CMS-induced mouse hippocampus and lipopolysaccharide (LPS)-induced BV2 microglia. Mechanically, we found that MgSO4 inhibited microglia activation and BBB damage, possibly by suppressing IKK/NF-κB and NLRP3 inflammasome signaling pathways.
Our findings showed that MgSO4 supplementation played an active role in the prevention and treatment of depression.
Copyright © 2025 Wang, Hu, Li, Hu, Zhang, Qiao, Tang and Wang.

The role of the conjunctiva in the pathophysiology of Sjögren's syndrome (SS) related dry eye disease (DED) remains obscure especially in the view of functional conjunctival epithelia. In order to illustrate effects of conjunctiva in SS, we investigated the interactions between parenchymal cells and immune cells in the conjunctiva with single-cell RNA sequencing technique.
Freshly collected conjunctiva from a canonical SS model was prepared for 10 × Genomics single-cell RNA sequencing and T cell receptor (TCR) sequencing. Conjunctiva was collected for Western blot, immunofluorescence, multiplex immunohistochemical (mIHC), and flow cytometry. Phenol red thread test, lissamine staining, and qRT-PCR were applied to evaluate signs of DED.
DED phenotype was validated in the SS model. Loss of water-secreting keratinocyte was projected in scRNA-seq data and proved by mIHC test in SS mice. The proportion of Lgr4+ basal epithelial cells with poor ability to differentiate into mature keratinocyte increased, and Wnt/β-catenin signaling was upregulated in it under regulation of TGF-β derived from macrophages. Such macrophages promoted angiogenesis through secretion of VEGFA to activate endothelial cells. Immuno-fibroblasts had an increased population, which were implicated in specifically activated T cell chemotaxis.
In SS conjunctiva, a TGF-β-Wnt/β-catenin axis downregulated the formation of functional keratinocytes accompanied by infiltration of pro-angiogenetic and pro-fibrotic macrophage and pro-inflammatory T cell.

Tissue-resident memory CD8 T (TRM) cells provide protection from infection at barrier sites. In the small intestine, TRM cells are found in at least two distinct subpopulations: one with higher expression of effector molecules and another with greater memory potential1. However, the origins of this diversity remain unknown. Here we proposed that distinct tissue niches drive the phenotypic heterogeneity of TRM cells. To test this, we leveraged spatial transcriptomics of human samples, a mouse model of acute systemic viral infection and a newly established strategy for pooled optically encoded gene perturbations to profile the locations, interactions and transcriptomes of pathogen-specific TRM cell differentiation at single-transcript resolution. We developed computational approaches to capture cellular locations along three anatomical axes of the small intestine and to visualize the spatiotemporal distribution of cell types and gene expression. Our study reveals that the regionalized signalling of the intestinal architecture supports two distinct TRM cell states: differentiated TRM cells and progenitor-like TRM cells, located in the upper villus and lower villus, respectively. This diversity is mediated by distinct ligand-receptor activities, cytokine gradients and specialized cellular contacts. Blocking TGFβ or CXCL9 and CXCL10 sensing by antigen-specific CD8 T cells revealed a model consistent with anatomically delineated, early fate specification. Ultimately, our framework for the study of tissue immune networks reveals that T cell location and functional state are fundamentally intertwined.
© 2025. The Author(s).

Nanrilkefusp alfa (nanril; SOT101) is an interleukin (IL)-15 receptor βγ superagonist that stimulates natural killer (NK) and CD8+ T cells, thereby promoting an innate and adaptive anti-tumor inflammatory microenvironment in mouse tumor models either in monotherapy or combined with an anti-programmed cell death protein 1 (PD-1) antibody. In cynomolgus monkeys, a clinical schedule was identified, which translated into the design of a phase 1/1b clinical trial, AURELIO-03 (NCT04234113). In 51 patients with advanced/metastatic solid tumors, nanril increased the proportions of CD8+ T cells and NK cells in peripheral blood and tumors. It had a favorable safety profile when administered subcutaneously on days 1, 2, 8, and 9 of each 21-day cycle as monotherapy (0.25-15 μg/kg) or combined (1.5-12 μg/kg) with the anti-PD-1 pembrolizumab (200 mg). The most frequent treatment-emergent adverse events were pyrexia, injection site reactions, and chills. Furthermore, early clinical efficacy was observed, including in immune checkpoint blockade-resistant/refractory patients.
Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.

ABSTRACT Dietary lipids play an essential role in regulating the function of the gut microbiota and gastrointestinal tract, and these luminal interactions contribute to mediating host metabolism. PAHSAs are a class of lipids with anti-diabetic and anti-inflammatory properties, but whether the gut microbiota contributes to their beneficial effects on host metabolism is unknown. Here, we report that treating high fat diet (HFD)-fed germ-free mice with PAHSAs does not improve insulin sensitivity. However, transfer of feces from PAHSA-treated, but not Vehicle-treated, chow-fed mice increases insulin-sensitivity in HFD-fed germ free mice. Thus, the gut microbiota is necessary for and can transmit the insulin-sensitizing effects of PAHSAs in HFD-fed germ-free mice. Functional analyses of the cecal metagenome and lipidome of PAHSA-treated mice identified multiple lipid species that associate with the gut commensal Bacteroides thetaiotaomicron ( Bt ) and with insulin sensitivity resulting from PAHSA treatment. Bt supplementation in HFD-fed female mice prevented weight gain, reduced adiposity, improved glucose tolerance, fortified the colonic mucus barrier and reduced systemic inflammation versus chow-fed controls, effects that were not observed in HFD-fed male mice. Furthermore, ovariectomy partially reversed the beneficial Bt effects on host metabolism, indicating a role for sex hormones in mediating probiotic effects. Altogether, these studies highlight the fact that lipids can modulate the gut microbiota resulting in improvement in host metabolism and that PAHSA-induced changes in the microbiota result in at least some of their insulin-sensitizing effects in female mice.