Objective: Extract from cultured Lentinula edodes mycelia (L.E.M.) is a food ingredient possessing various pharmacologic actions such as immunomodulatory properties, antitumor and hepatoprotective effects. In Japan, it has been used as a health food for 30 years or more.
In the present study to evaluate the safety of L.E.M., a genotoxicity study and acute toxicity study were conducted. In addition, the inhibitory effect of drug-metabolizing enzyme by L.E.M. was tested in vitro, to gain insight on the interaction with medicines.
Methods: The genotoxicity study was performed using a bacterial reverse mutation assay and a in vivo mammalian bone marrow cell chromosomal mutation assay. The acute toxicity study was performed using a single-dose oral toxicity test in rats. Inhibitory activity of cytochrome P-450 3A4 (CYP3A4), one of the most important drug-metabolizing enzymes, by L.E.M. was tested using a baculovirus-expressed system.
Results: In the genotoxicity study, mutagenicity was negative for both bacterial reverse mutation assay and in vivo mammalian bone marrow cell chromosomal mutation assay. In the acute toxicity study, no toxic symptoms were observed by single dose oral administration of L.E.M. at a dose of 10,000 mg/kg BW in rats. This implies LD₅₀>10,000 mg/kg BW. No inhibitory activity of CYP3A4 by L.E.M. was observed at in the in vitro screening system to investigate drug-L.E.M. interaction.
Conclusion: It is believed L.E.M. is a safety ingredient for foods used in complementary and alternative medicine, since it was toxicologically safe and showed no inhibitory activity of CYP3A4 in the studies conducted.

In dentistry, orthodontic root resorption is a long-lasting issue with no effective treatment strategy, and its mechanisms, especially those related to senescent cells, remain largely unknown. Here, we used an orthodontic intrusion tooth movement model with an L-loop in rats to demonstrate that mechanical stress-induced senescent cells aggravate apical root resorption, which was prevented by administering senolytics (a dasatinib and quercetin cocktail). Our results indicated that cementoblasts and periodontal ligament cells underwent cellular senescence (p21⁺ or p16⁺) and strongly expressed receptor activator of nuclear factor-kappa B (RANKL) from day three, subsequently inducing tartrate-resistant acid phosphatase (TRAP)-positive odontoclasts and provoking apical root resorption. More p21⁺ senescent cells expressed RANKL than p16⁺ senescent cells. We observed only minor changes in the number of RANKL⁺ non-senescent cells, whereas RANKL⁺ senescent cells markedly increased from day seven. Intriguingly, we also found cathepsin K⁺p21⁺p16⁺ cells in the root resorption fossa, suggesting senescent odontoclasts. Oral administration of dasatinib and quercetin markedly reduced these senescent cells and TRAP⁺ cells, eventually alleviating root resorption. Altogether, these results unveil those aberrant stimuli in orthodontic intrusive tooth movement induced RANKL⁺ early senescent cells, which have a pivotal role in odontoclastogenesis and subsequent root resorption. These findings offer a new therapeutic target to prevent root resorption during orthodontic tooth movement.
Rats ; Animals ; Root Resorption/prevention & control* ; Senotherapeutics ; Stress, Mechanical ; Dasatinib/pharmacology* ; Quercetin/pharmacology* ; Osteoclasts ; Tooth Movement Techniques ; Periodontal Ligament ; RANK Ligand