Introduction

The crystal structure of methyl gallate (systematic name:methyl 3,4,5-trihydroxybenzoate), C8H8O5, is composed of essentially planar molecules [maximum departures from the mean carbon and oxygen skeleton plane of 0.0348 (10) ?].The H atoms of the three hydroxyl groups, which function as hydrogen-bond donors and acceptors simultaneously, are oriented in the same direction around the aromatic ring. In addition to two intramolecular hydrogen bonds, each molecule is hydrogen bonded to six others, creating a three-dimensional hydrogen-bonded network.[1] Methyl gallate (Figure 1) is widely found in natural plants, such as Juglans mandshurica, Galla chinensis, Paeoniaanomala, Phyllanthus emblica, Mangifera indica, Plicosepalus acacia, Carica papaya Linn, and Maple (Genus Acer). A large number of cell and animal experiments have shown that methyl gallate has good therapeutic effects, such as anti-tumor, anti-inflammatory,anti-oxidation, anti-microbial, anti-malarial,and so on. Based on its strong anti-oxidant properties, methyl gallate has shown good pharmacological effects in liver protection, neuroprotection, anti-aging, anti-diabetes, anti-platelet and anti-atherosclerosis.[2]

Pharmacological activity[2]

Anti-tumor activity

A number of studies have confirmed that methyl gallate has a strong anti-cancer effect on various cancers through different mechanisms. The uncontrolled proliferation of malignant tumors is one of the characteristics of tumor cells. Inhibition of tumor cell proliferation has become a hot spot in cancer research. Methyl gallate extracted from Syzygium coriaceum leaves directly inhibits the growth of HepG2 cells through cytotoxicity. Methyl gallate can also inhibit the proliferation of A431 skin cancer cells by down-regulating Bcl-2 and up-regulating Cleaved caspase-3 protein expression.

Methyl gallate demonstrates significant potential in inhibiting cancer cell migration and invasion, primarily attributed to its inhibition of tumor EMT, MMPs, and angiogenesis, as well as its modulation of the ERK1/2 signaling pathway. Additionally, MG can suppress tumor proliferation by inhibiting tumor immune Treg cells, and enhance the antitumor effect of the clinical drug cisplatin.

Anti-inflammatory activity

A large number of studies have found that methyl gallate can produce different anti-inflammatory effects on various inflammatory injury models through a variety of mechanisms, including intestinal inflammation,arthritis, nephritis and dermatitis. Methyl gallate inhibited LPS induces phosphorylation of ERK1/2 in RAW264.7 cells in a dose-dependent manner and reduced the production of NO and IL-6 by macrophages. In addition, methyl gallate can also inhibit the production of COX-2 and leukotriene C4 (LTC4) by prostaglandin D2 (PGD2) in bone marrow-derived mast cells (BMMC). The above studies have shown the anti-inflammatory and analgesic potential of methyl gallate.

In summary, methyl gallate exerts significant anti-inflammatory activity by primarily inhibiting autophagy, oxidative stress, as well as modulating the TLR4/NF-κB and MAPK signaling pathways involved in inflammation. It can be utilized for the prevention and treatment of various inflammatory diseases.

Anti-oxidant activity

Polyphenols have significant antioxidant effects, which can reduce oxygen free radicals in the human body, inhibit oxidative stress, and play a role in anti-aging, liver protection, neuroprotection, and anti-atherosclerosis. Methyl gallate derived from natural plant sources exhibits high antioxidant activity, making it a valuable natural source of antioxidants. Methyl gallate can change the mitochondrial-dependent apoptosis signaling pathway and rescue hepatocytes by inhibiting tert-butyl hydroperoxide (t-BHP) induced oxidative stress, which has the potential to treat non-alcoholic fatty liver disease by regulating oxidative stress. By scavenging intracellular reactive oxygen species (ROS), inhibiting lipid peroxidation and reducing glutathione digestion, methyl gallate effectively prevented H2O2 induced oxidative stress and DNA damage in MDCK cells. Similarly, it also has an oxidative stress protective effect on human umbilical vein endothelial cells. In terms of neuroprotection, methyl gallate can be used to treat neurodegenerative diseases related to oxidative stress and apoptosis. It showed neuroprotective effects by reducing Aβ toxicity-induced ROS-mediated mitochondrial dysfunction and DNA damage in Neuro2A cells through antioxidant capacity and inhibition of acetylcholinesterase activity. Similarly, methyl gallate also counteracts oxidative stress in neonatal cardiomyocytes by scavenging ROS, increasing endogenous glutathione, protecting mitochondria and cellular DNA, and inhibiting intrinsic apoptotic pathways. Methyl gallate can also inhibit lipid accumulation, reduce intracellular ROS by inhibiting ERK1/2 phosphorylation and activate Nrf2, HO-1 and PRDX3 to protecting adipocytes from oxidative stress. Among them, the regulation of the ERK1/2 pathway by methyl gallate may be a critical node for its anti-tumor, anti-inflammatory, and anti-oxidative pharmacological effects. Besides, methyl gallate can inhibit the expression of HUVECs and VCAM-1 induced by TNF-α, and reduce the biomarkers of early atherosclerosis.

Anti-microbial activity

Methyl gallate mainly plays an antibacterial role by increasing the expression of immune-related factors, disrupting bacterial protein homeostasis, destroying bacterial membrane integrity, and enhancing the antibacterial effect of antibiotics. It was found that methyl gallate played a huge pharmacological role in the treatment of bacterial infections, whether it was treated alone or in combination. Additionally, this provides direction for the development of anti-HSV-2, anti-HIV, and anti-dengue virus drugs.

Other pharmacological activities

Methyl gallate has the ability to resist obesity. Methyl gallate regulates Wnt/β-catenin signaling to antagonize PPARγ expression, down-regulate lipid accumulation and adipogenesis, and play a role in the treatment of obesity. Reduces the intercellular lipid content of 3T3-L1 adipocytes, increase the amount of glycerol released into the medium, activate lipolysis, and actively inhibit lipid formation. Methyl gallate has diuretic,diuretic sodium and diuretic potassium effects, depending on the activation of muscarinic acetylcholine receptors. Another study has demonstrated that methyl gallate possesses anti-urolithiasis properties as it can inhibit the formation of total calcium oxalate (CaOx) crystals in in vitro experiments. Methyl gallate also exhibits other potent pharmacological activities. Methyl gallate reduced lower limb ischemia induced bydiabetic rats and promoted angiogenesis by increasing the expressionlevels of HIF-1α, VEGF, FGF-2 and miR-146 a and down-regulating the level of NF-Κb. Methyl gallate inhibiting melanin production by inducing the phosphorylation of glycogen synthase kinase (GSK) 3β, increasing the level of β-catenin, and reducing the expression of MITF and tyrosinase. Methyl gallate significantly attenuates restraint stress-induced weight loss, hypoglycemia and depressive behaviors, and prevented hypoglycemiafrom exerting its antidepressant like effect. Methyl gallate inhibits the glycation reaction between BSA and glucose and exerts anti-aging effect. Methyl gallate also exhibits anti-leishmanial activity, and its mechanism is associated with stimulating infected macrophages to produce TNF-α,IL-12, ROS, and NO, while reducing IL-6 and arginase activity in infected macrophages.

References

[1]Bebout D, Pagola S. Methyl gallate. Acta Crystallogr Sect E Struct Rep Online. 2009;65(Pt 2):o317-o318. Published 2009 Jan 14. doi:10.1107/S1600536809001123

[2]Liang H, Huang Q, Zou L, Wei P, Lu J, Zhang Y. Methyl gallate: Review of pharmacological activity. Pharmacol Res. 2023;194:106849. doi:10.1016/j.phrs.2023.106849