Obstructive sleep apnea syndrome (OSAS) is characterized by cycles of decreased blood oxygen saturation followed by reoxygenation due to transient apnea. Cognitive dysfunction is a complication of OSAS, but its mechanisms remain unclear. Eight-week-old C57BL/6J mice were exposed to intermittent hypoxia (IH) to model OSAS, and cognitive function and hippocampal gene expression were analyzed. Three groups were maintained for 28 days: an IH group (oxygen alternating between 10 and 21% in 2 min cycles, 8 h/day), sustained hypoxia group (SH) (10% oxygen, 8 h/day), and control group (21% oxygen). Behavioral tests and RNA sequencing (RNA-seq) analysis were performed. While Y-maze test results showed no differences, the IH group demonstrated impaired memory and learning in passive avoidance tests compared to control and SH groups. RNA-seq revealed coordinated suppression of mitochondrial function genes and oxidative stress response pathways, specifically in the IH group. RT-qPCR showed decreased Lars2, Hmcn1, and Vstm2l expression in the IH group. Pathway analysis showed the suppression of the KEAP1-NFE2L2 antioxidant pathway in the IH group vs. the SH group. Our findings demonstrate that IH induces cognitive dysfunction through suppression of the KEAP1-NFE2L2 antioxidant pathway and downregulation of mitochondrial genes (Lars2, Vstm2l), leading to oxidative stress and mitochondrial dysfunction. These findings advance our understanding of the molecular basis underlying OSAS-related cognitive impairment.

Gut bacteria play pivotal roles in the antitumor effects of immune checkpoint inhibitors (ICIs). However, antimicrobial therapy, often necessary for infections in cancer patients, can reduce the efficacy of ICIs. The potential of probiotics to restore ICI efficacy remains uncertain. This study evaluated the effects of Bifidobacterium longum and Bifidobacterium infantis (BLBI) in a CT-26 subcutaneous tumor mouse model treated with anti-programmed cell death protein 1 antibody (αPD-1) and cefcapene pivoxil (CFPN-PI). BALB/c mice received daily oral gavage of CFPN-PI for 5 days before tumor inoculation, followed by weekly αPD-1 administration and tumor growth monitoring. BLBI was administered via ad libitum feeding, mixed in powdered feed. Gut microbiota composition and fecal short-chain fatty acid concentrations were assessed, along with gene expression and immune cell populations in the tumor microenvironment, using quantitative RT-PCR and flow cytometry, respectively. CFPN-PI alone increased tumor growth and attenuated the antitumor effect of αPD-1. In contrast, BLBI inhibited CFPN-PI-induced tumor growth and improved the efficacy of αPD-1. Probiotic treatment increased the stool propionic acid concentration and the number of tumor-infiltrating conventional type 1 dendritic cells. Relative decreases in Bacteroides and Lachnospiraceae _NK4A136_group species and relative increases in Muribaculaceae and Unclassified_f_Oscillospiraceae species correlated with an improved αPD-1 response. These results suggest that probiotic administration may be a new therapeutic strategy to rescue the attenuated efficacy of ICIs in patients with cancer who require antimicrobial therapy.

Obstructive sleep apnea syndrome (OSAS) is characterized by cycles of decreased blood oxygen saturation followed by reoxygenation due to transient apnea. Cognitive dysfunction is a complication of OSAS, but its mechanisms remain unclear. 8-week-old C57BL/6J mice were exposed to intermittent hypoxia (IH) to model OSAS, and cognitive function and hippocampal gene expression were analyzed. Three groups were maintained for 28 days: IH group (oxygen alternating between 10–21% in 2-minute cycles, 8 hours/day), sustained hypoxia group (SH) (10% oxygen, 8 hours/day), and control group (21% oxygen). Behavioral tests and RNA sequencing (RNA-seq) analysis was performed. While Y-maze test results showed no differences, the IH group demonstrated impaired memory and learning in passive avoidance tests compared to control and SH groups. RNA-seq revealed specific changes in learning/memory-related genes and oxidative stress response genes in the IH group. RT-qPCR showed decreased Lars2, Hmcn1, and Vstm2l expression in the IH group. Pathway analysis showed the suppression of the KEAP1-NFE2L2 antioxidant pathway in the IH group vs. SH group. Our findings demonstrate that IH may cause cognitive dysfunction through oxidative stress and suppressed antioxidant defenses. IH-specific downregulation of Lars2, Hmcn1, and Vstm2l may contribute to OSAS-related cognitive impairment.

Obesity imprints an epigenetic memory in adipose tissue macrophages (ATMs), allowing proinflammatory traits to persist after weight loss. However, mechanisms by which ATMs sustain efferocytosis and influence adipose tissue mass remain unclear. Here, we demonstrate that aberrant messenger RNA splicing, caused by dysfunction of the CWC22/exon junction complex, limits efferocytosis in macrophages during postobesity weight loss. Multiomics and gene-targeting approaches revealed that 51.9% of the obesity-induced differentially spliced genes in ATMs remained altered after weight loss, identifying persistent splicing alterations as a prominent component of obesity memory, with one-quarter of these changes dependent on CWC22. Scarb1 exon skipping increased scavenger receptor class B type II (SR-BII) expression, promoting the formation of SR-BI/SR-BII heterodimers that were subsequently targeted for endoplasmic reticulum–associated degradation. This reduced surface SR-BI in macrophages, suppressed efferocytosis and inosine release from dead cells, and impaired inosine-induced lipolysis in white adipose tissue. Restoring Scarb1 splicing with an antisense oligonucleotide rescued SR-BI expression, efferocytosis, inosine availability, and fat loss in Cwc22 -deficient mice. Immunohistochemical analysis of human adipose tissue specimens revealed predominant nuclear localization of CWC22 in ATMs from lean individuals, whereas this nuclear localization was markedly diminished in ATMs from obese individuals. These findings reveal that aberrant alternative splicing in macrophages underlies resistance to postobesity weight loss and suggest that splicing-targeted therapies may counteract obesity memory.