4-Methylumbelliferone

Chem Biol Interact. 2014 Jun 5;216:9-16.

Long-term supplementation of umbelliferone and 4-methylumbelliferone alleviates high-fat diet induced hypertriglyceridemia and hyperglycemia in mice.[Pubmed: 24661945]

This study was conducted to evaluate the effects of umbelliferone (UF) and 4-Methylumbelliferone (mUF) on high-fat diet-induced hypertriglyceridemia and hyperglycemia in mice.
METHODS AND RESULTS:
The mice were assigned to normal control, high-fat control, and high-fat with UF or 4-Methylumbelliferone groups. For UF or mUF groups, the high-fat diet was supplemented with UF or 4-Methylumbelliferone at 0.02% (wt/wt) for 12weeks. Both UF and 4-Methylumbelliferone significantly decreased plasma triglyceride, free fatty acid and glucose levels, adipocyte size, white adipose tissue weights, and hepatic phosphatidate phosphohydrolase activity and significantly increased plasma adiponectin levels and hepatic fatty acid β-oxidation activity compared with the high-fat control group. UF and 4-Methylumbelliferone improved glucose intolerance and hepatic steatosis in the high-fat fed mice. Long-term high-fat diet intake induced an increase in hepatic CYP2E1 activity and lipid peroxide and cytosolic hydrogen peroxide contents and suppressed superoxide dismutase and glutathione peroxidase activities, which were reversed by UF and 4-Methylumbelliferone supplementation.
CONCLUSIONS:
These results indicate that UF and 4-Methylumbelliferone similarly ameliorate hypertriglyceridemia and hyperglycemia partly by modulating hepatic lipid metabolism and the antioxidant defense system along with increasing adiponectin levels.

J Comp Physiol B. 2014 Aug;184(6):699-708.

Antioxidative properties of 4-methylumbelliferone are related to antibacterial activity in the silkworm (Bombyx mori) digestive tract.[Pubmed: 24997539]

Umbelliferones have gained significant attention due to their tumor-inhibitory effects in vitro. This study was undertaken to examine the impact of umbelliferones in an invertebrate model organism, Bombyx mori, to assess the underlying antimicrobial activities via antioxidation in vivo.
METHODS AND RESULTS:
Oral administration of 4 mM 4-Methylumbelliferone (4-MU), a model umbelliferone drug, in B. Mori larvae caused a rapid increase in reactive oxygen species, such as hydrogen peroxide (H2O2) and antimicrobial activity in the digestive tract. In addition, a significant increase in total antioxidant capacity as well as superoxide anion radical-inhibiting activity and reduced glutathione were detected. The antioxidant defense system was activated following induction of H2O2, resulting in a significant rise in catalase (50-66 %) and glutathione peroxidase (175 %) activities, which were helpful in defending digestive tract cells against oxidative injury.
CONCLUSIONS:
These results help in understanding the anticancer mechanism of 4-MU based on its antioxidation in organisms.

Front Immunol. 2015 Mar 23;6:123.

4-methylumbelliferone treatment and hyaluronan inhibition as a therapeutic strategy in inflammation, autoimmunity, and cancer.[Pubmed: 25852691]

Hyaluronan (HA) is a prominent component of the extracellular matrix at many sites of chronic inflammation, including type 1 diabetes (T1D), multiple sclerosis, and numerous malignancies. Recent publications have demonstrated that when HA synthesis is inhibited using 4-Methylumbelliferone (4-MU), beneficial effects are observed in several animal models of these diseases. Notably, 4-MU is an already approved drug in Europe and Asia called "hymecromone" where it is used to treat biliary spasm. However, there is uncertainty regarding how 4-MU treatment provides benefit in these animal models and the potential long-term consequences of HA inhibition.
CONCLUSIONS:
Here, we review what is known about how HA contributes to immune dysregulation and tumor progression. Then, we review what is known about 4-MU and hymecromone in terms of mechanism of action, pharmacokinetics, and safety. Finally, we review recent studies detailing the use of 4-MU to treat animal models of cancer and autoimmunity.

Biomed Res. 2013 Apr;34(2):97-103.

4-Methylumbelliferone inhibits the phosphorylation of hyaluronan synthase 2 induced by 12-O-tetradecanoyl-phorbol-13-acetate.[Pubmed: 23594483]

METHODS AND RESULTS:
The effect of 4-Methylumbelliferone (MU), a hyaluronan synthase-suppressor, on O-linked β-Nacetylglucosaminylation (O-GlcNAcylation) was investigated in cultured human skin fibroblasts, and we found that 4-Methylumbelliferone stimulated O-GlcNAcylation of the cellular proteins. Since O-GlcNAcylation affects protein phosphorylation via Ser/Thr kinases, we examined the effect of 4-Methylumbelliferone on both the phosphorylation of hyaluronan synthase 2 (HAS2) and hyaluronan production. The cells were cultured in the presence or absence of 12-O-tetradecanoyl-phorbol-13-acetate (TPA) and 4-Methylumbelliferone independently or in combination. The protein fraction of each cell culture was extracted and divided into 2 parts-phosphorylated and non-phosphorylated fractions-by immobilized metal-affinity chromatography. The hyaluronan level in the medium was determined by an ELISA-like assay. Addition of 4-Methylumbelliferone decreased the level of hyaluronan in the medium and that of HAS2 in the phosphorylated protein fraction. On the contrary, the addition of TPA increased the levels of both of them. Interestingly, the combination of TPA and 4-Methylumbelliferone lowered the levels of them in treated cells as compared to those in untreated control cells.
CONCLUSIONS:
These results suggest that TPA activated protein kinase C (PKC), which stimulates the phosphorylation of HAS2, and increased hyaluronan production. Further, 4-Methylumbelliferone may inhibit the phosphorylation of HAS2 by PKC through the stimulation of O-GlcNAcylation.

Comp Biochem Physiol C Toxicol Pharmacol. 2014 Jan;159:31-7.

Antioxidative capacity in the fat body of Bombyx mori is increased following oral administration of 4-methylumbelliferone.[Pubmed: 24080584]

Plant sources of umbelliferones have tumor-inhibitory effects at the cellular level. However, their physiological functions in animals are largely unresolved.
METHODS AND RESULTS:
In this study, we provide evidence to show that 4-Methylumbelliferone (4-MU) participates in the regulation of antioxidative capacity in the fat body of Bombyx mori, a tissue similar to mammalian liver in this model invertebrate. Larvae (3rd day of the 5th instar) were orally exposed to 4 mM 4-MU, an umbelliferone, which swiftly induced the generation of a large number of ROS (e.g. H2O2 increased 6 to 8-fold), and 4-MU was detected in the fat body 8 min after administration. In addition, the activities of CAT and GPx were up-regulated 4 to 11-fold and 2 to 16-fold, respectively, and were helpful in defending fat body cells against oxidative injury in combination with NADPH. Furthermore, significant increases in the contents of T-AOC (up to approx. 2-fold), antioxidants of ASAFR (by 2 to 4-fold) and GSH were detected.