Plasmalogens (Pls), a kind of glycerophospholipids, have shown potent biological effects but their role in hippocampus-dependent memory remained mostly elusive. Here, we first report Pls can enhance endogenous expression of brain-derived neurotrophic factor (Bdnf) in the hippocampus and promotes neurogenesis associated with improvement of learning and memory in mice. Genomic and proteomic studies revealed that Pls enhanced recruitment of CREB transcription factor onto the murine Bdnf promoter region via upregulating ERK-Akt signaling pathways in neuronal cells. Reduction of endogenous Pls in murine hippocampus significantly reduced learning and memory associated with the reduction of memory-related protein expression, suggesting that Pls can regulate memory-related gene expression in the hippocampus.

Neuroinflammation (NF) is defined as the activation of brain glial cells that are found in neurodegenerative diseases including Alzheimer's disease (AD). It has been known that an increase in NF could reduce the memory process in the brain but the key factors, associated with NF, behind the dysregulation of memory remained elusive. We previously reported that the NF and aging processes reduced the special phospholipids, plasmalogens (Pls), in the murine brain by a mechanism dependent on the activation of transcription factors, NF-kB and c-MYC. A similar mechanism has also been found in postmortem human brain tissues with AD pathologies and in the AD model mice. Recent evidence showed that these phospholipids enhanced memory and reduced neuro-inflammation in the murine brain. Pls can stimulate the cellular signaling molecules, ERK and Akt, by activating the membrane-bound G protein-coupled receptors (GPCRs). Therefore, recent findings suggest that plasmalogens could be one of the key phospholipids in the brain to enhance memory and inhibit NF.

It is widely known that the immune system becomes slower to respond among elderly people, making them more susceptible to viral infection and cancer. The mechanism of aging-related immune deficiency remained mostly elusive. In this article, we report that plasmalogens (Pls), special phospholipids found to be reduced among the elderly population, critically control cytolytic activity of human NK cells, which is associated with activation of a cell surface receptor, G protein–coupled receptor 21 (GPCR21). We found the extracellular glycosylation site of GPCR21, which is conserved among the mammalian species, to be critically important for the activation of NK cells by Pls. The Pls-GPCR21 signaling cascade induces the expression of Perforin-1, a cytolytic pore-forming protein, via activation of STAT5 transcription factor. Inhibition of STAT5 abrogates GPCR21-mediated cytolytic activation of NK cells against the target cancer cells. In addition, oral ingestion of Pls inhibited cancer growth in SCID mice and inhibited the systemic spread of murine CMV in adult C57BL/6J mice. These findings advocate that Pls-GPCR21 signaling could be critical in maintaining NK cell function, and that the age-related reduction of this signaling cascade could be one of the factors behind immune deficiency in mammals, including humans.

Plasmalogens (Pls) are specialized phospholipids integral to brain health, whose decline due to aging and stress contributes to cognitive impairment and neuroinflammation. This study explores the potential of a novel Pls derivative, KIT-13 (1-O-octadecyl-2-arachidonoyl-sn-glycerol-3-phosphoethanolamine), in mitigating neuroinflammation and enhancing cognition. When administered to mice, KIT-13 exhibited potent memory enhancement attributed to upregulated brain-derived neurotrophic factor (BDNF), a key player in cognitive processes. In vitro experiments with neuronal cells revealed KIT-13’s ability to induce robust cellular signaling, surpassing natural plasmalogens. KIT-13 also promoted neurogenesis and inhibited apoptosis of neuronal-like cells, highlighting its potential in fostering neuronal growth and plasticity. Additionally, KIT-13 treatments reduced pro-inflammatory cytokine expression and attenuated glial activation in the brain. KIT-13’s superior efficacy over natural Pls positions it as a promising therapeutic candidate for neurodegenerative conditions such as Alzheimer’s disease, characterized by cognitive decline and neuroinflammation. This study presents KIT-13 as an innovative approach for addressing cognitive impairment and neuroinflammatory pathologies.

Background: Squamous cell carcinoma of head and neck (SCCHN) is a devastating disease with high morbidity and mortality and the 6th most common cancer worldwide. The 5-year relative survival for advanced-stage disease is below 50%, stressing the need for chemoprevention. In the current study, we investigated the chemopreventive efficacy of the combination of resveratrol and epigallocatechin gallate (EGCG). Methods: We used the 4-Nitroquinoline 1-oxide (4-NQO)-induced oral carcinogenesis model. C57BL/6 mice were exposed to drinking water containing 4-NQO for 10 weeks. From week 11, mice were treated with vehicle, resveratrol, EGCG and their combination until week 22. RNASeq, qPCR and in silico analysis were performed identifying differentially expressed genes and enriched pathways. Results: Resveratrol alone and in combination with EGCG significantly inhibited the number of visible lesions, whereas the number of microscopic lesions and lesion areas were significantly inhibited only by the combination. The expression of Ki-67 was also significantly inhibited in resveratrol and combination groups. Growth differentiation factor 15 (GDF15), Activation transcription factor 3 (ATF3) and several other genes associated with xenobiotic metabolism as significantly upregulated genes, with GDF15 being the most upregulated one. Furthermore, hallmarks of xenobiotic metabolism and several other anticancer pathways were enriched after treatment with resveratrol and the combination. Conclusions: Our data strongly demonstrate the chemopreventive potential of the combination of resveratrol and EGCG and pave the way for further clinical developments.