The powerful potential of amino acid menthyl esters for anti-inflammatory and anti-obesity therapies.
Seidai TakasawaKosuke KimuraMasato MiyanagaTakuya UemuraMasakazu HachisuShinichi MiyagawaAbdelaziz RamadanSatoru SukegawaMasaki KobayashiSeisuke KimuraKenji MatsuiMitsunori ShiroishiKaori TerashitaChiharu NishiyamaTakuya YashiroKazuki NagataYoshikazu HigamiGen-Ichiro ArimuraPublished in: Immunology (2024)
Our newly developed menthyl esters of valine and isoleucine exhibit anti-inflammatory properties beyond those of the well-known menthol in macrophages stimulated by lipopolysaccharide (LPS) and in a mouse model of colitis induced by sodium dextran sulfate. Unlike menthol, which acts primarily through the cold-sensitive TRPM8 channel, these menthyl esters displayed unique mechanisms that operate independently of this receptor. They readily penetrated target cells and efficiently suppressed LPS-stimulated tumour necrosis factor-alpha (Tnf) expression mediated by liver X receptor (LXR), a key nuclear receptor that regulates intracellular cholesterol and lipid balance. The menthyl esters showed affinity for LXR and enhanced the transcriptional activity through their non-competitive and potentially synergistic agonistic effect. This effect can be attributed to the crucial involvement of SCD1, an enzyme regulated by LXR, which is central to lipid metabolism and plays a key role in the anti-inflammatory response. In addition, we discovered that the menthyl esters showed remarkable efficacy in suppressing adipogenesis in 3T3-L1 adipocytes at the mitotic clonal expansion stage in an LXR-independent manner as well as in mice subjected to diet-induced obesity. These multiple capabilities of our compounds establish them as formidable allies in the fight against inflammation and obesity, paving the way for a range of potential therapeutic applications.
Keyphrases
- high fat diet induced
- anti inflammatory
- inflammatory response
- insulin resistance
- metabolic syndrome
- weight loss
- type diabetes
- mouse model
- weight gain
- amino acid
- lipopolysaccharide induced
- lps induced
- toll like receptor
- adipose tissue
- induced apoptosis
- oxidative stress
- rheumatoid arthritis
- signaling pathway
- binding protein
- poor prognosis
- gene expression
- transcription factor
- physical activity
- cell cycle
- cell cycle arrest
- cell death
- body mass index
- cell proliferation
- long non coding rna
- immune response
- mass spectrometry
- climate change
- risk assessment
- drug delivery