Researchers have synthesized complex menthyl esters and uncovered the mechanism by which they interact with the liver X receptor.
Researchers developed menthyl esters with significant anti-inflammatory and anti-obesity effects, which may offer new treatment options for chronic inflammatory diseases and metabolic disorders.
Recent therapeutic advances and commercial successes have often been attributed to modified derivatives of natural products. Menthol, a naturally occurring cyclic monoterpene alcohol, is found in various plants, particularly members of the mint family such as peppermint and spearmint. It is widely used in confectionery, chewing gum and oral care products. Notably, menthol also possesses significant medicinal properties, including analgesic, anti-inflammatory and anti-cancer effects.
In a recent study, a team of researchers led by Professor Gen-ichiro Arimura from the Department of Biological Science and Technology at Tokyo University of Science in Japan developed and investigated menthyl esters of valine (MV) and isoleucine (MI). These are obtained from menthol by replacing its hydroxyl group with valine or isoleucine.
Their research results were recently published in the journal immunologyProf. Arimura explains the motivation behind the present work as follows: “I have always been fascinated by the functional components of plants that contribute to human health. The discovery of new molecules from natural materials inspired our research team to develop these amino acids. acid Derivatives of menthol.”
Anti-inflammatory properties of menthyl esters
The researchers began with the synthesis of menthyl esters of six Amino acids characterized by less reactive side chains. They then investigated the properties of these esters using in vitro cell line studies. Finally, they conducted experiments in mice to study the effects of these compounds under induced disease conditions. The exceptional anti-inflammatory profiles of MV and MI were determined by assessing tumor necrosis factor-α (TNF) transcript levels in stimulated macrophage cells. Notably, both MV and MI performed better than menthol in the anti-inflammatory test. RNA Sequence analysis revealed that 18 genes involved in inflammatory and immune responses were effectively suppressed.
Excited by their results, the researchers went a step further and investigated the mechanism of action of the menthyl esters. They discovered that the liver X receptor (LXR) – an intracellular nuclear receptor – played an important role in the anti-inflammatory effects, independently of the cold-sensitive transient receptor TRPM8, which mainly recognizes menthol. When they looked deeper into the LXR-dependent activation of MV and MI, they found that the Scd1 gene, central to lipid metabolism, was upregulated by LXR. In addition, the anti-inflammatory effects were further confirmed in mice with induced intestinal colitis by suppressing the transcription levels of the Tnf and Il6 genes by MV or MI in an LXR-dependent manner.
Possible anti-obesity effects
Driven by the discovery of the intracellular machinery of LXR-SCD1, Prof. Arimura and his team hypothesized that menthyl esters have anti-obesity properties. They found that these esters inhibited adipogenesis – fat accumulation – especially at the stage of mitotic clonal expansion in 3T3-L1 adipocyte cells. In animal studies, diet-induced obesity was alleviated and adipogenesis was suppressed in mice.
Menthyl esters possess unique advantages compared to other anti-inflammatory or anti-obesity compounds currently being researched or used. Their specific mechanisms of action, which contribute to their dual anti-inflammatory and anti-obesity effects, distinguish them from other compounds and could make them particularly effective in treating both inflammatory diseases and metabolic disorders. They could benefit specific populations such as those with chronic inflammation, metabolic syndrome, or obesity-related complications.
“Although this study focused on their functions and mechanisms of action in diseases mimicking inflammation and obesity, we expect that these compounds will also be effective against a wide range of lifestyle-related diseases caused by metabolic syndrome, such as diabetes and hypertension, as well as allergic symptoms,” says Prof. Arimura optimistically.
In conclusion, this study highlights the importance and value of multifaceted molecules derived from naturally occurring substances. Future research using these novel and superior menthyl esters may lead to therapeutic compounds to address the increasing health problems associated with obesity and inflammatory diseases.
Reference: “The Powerful Potential of Amino Acid Menthyl Esters for Anti-Inflammatory and Anti-Obesity Therapies” by Seidai Takasawa, Kosuke Kimura, Masato Miyanaga, Takuya Uemura, Masakazu Hachisu, Shinichi Miyagawa, Abdelaziz Ramadan, Satoru Sukegawa, Masaki Kobayashi, Seisuke Kimura, Kenji Matsui, Mitsunori Shiroishi, Kaori Terashita, Chiharu Nishiyama, Takuya Yashiro, Kazuki Nagata, Yoshikazu Higami and Gen-ichiro Arimura, May 8, 2024, immunology.
DOI: 10.1111/imm.13798
This work was supported in part by a grant from the Japan Society for the Promotion of Science (JSPS) KAKENHI (20H02951 and 24K01723) and by a research fellowship from the Tokyo University of Science to Gen-ichiro Arimura.
