The Anti-Inflammatory Properties of Licorice (Glycyrrhiza glabra)-Derived Compounds in Intestinal Disorders

Intestinal diseases, such as inflammatory bowel diseases (IBDs) and colorectal cancer (CRC), are a significant source of morbidity and mortality worldwide. Epidemiological data have shown that IBD patients are at an increased risk for the development of CRC. IBD-associated cancer develops against a background of chronic inflammation and oxidative stress, and their products contribute to cancer development and progression. Therefore, the discovery of novel drugs for the treatment of intestinal diseases is urgently needed. Licorice (Glycyrrhiza glabra) has been largely used for thousands of years in traditional Chinese medicine. Licorice and its derived compounds possess antiallergic, antibacterial, antiviral, anti-inflammatory, and antitumor effects. 

Licorice (Glycyrrhiza glabra) has been used in traditional Chinese medicine for thousands of years. Clinically, it is used widely to treat immune systems, respiratory, and digestive diseases, and no severe side effects have been reported so far. In addition, Licorice-derived compounds possesses antiallergic, antibacterial, antiviral, anti-inflammatory, and anticarcinogenic effects

G, GA, and DPG-Mediated Anti-Inflammation Regulation

As stated previously, Licorice compounds such as G, GA, and DPG have anti-inflammatory, antioxidant, antiviral, immunomodulatory, and antitumor properties. Inflammation is an evolutionarily conserved, tightly regulated protective mechanism that comprehends immune, vascular, and cellular biochemical reactions. The normal inflammatory response is temporally restricted and, in general, beneficial to the host. Chronic inflammatory response, on the other hand, is a risk factor for the development of several diseases such as ischemic heart disease, stroke, cancer, and diabetes mellitus, among others . Taking this into account, natural compounds have been widely used to treat all sorts of inflammatory conditions.

The anti-inflammatory effects of G and GA have long been reported. G has exerted anti-inflammatory actions by inhibiting the generation of reactive oxygen species (ROS) by neutrophils, the most potent inflammatory mediator at the site of inflammation. Moreover, G has enhanced interleukin (IL)-10 production by liver dendritic cells in mice with hepatitis . GA has presented anti-inflammatory and anticarcinogen effects on several tumor cell lines such as human hepatoma (HLE), promyelocytic leukemia (HL-60), stomach cancer (KATO III), and prostate cancer (LNCaP e DU-145) by both DNA fragmentation and gene deregulation required for oxidative stress control.

More recently, one study exposed the U251 GBM cell line to different concentrations of GA (1 mM, 2 mM, and 4 mM), and the authors observed that the inhibition of cell proliferation and colony formation, apoptosis stimulation, and significant decrease in p65 protein, which is responsible for the activation of the nuclear factor kappa B (NF-κB) pathway. The NF-κB pathway is constantly activated in GBM and is responsible for the aggressiveness of the disease and regulation of the expression of anti-apoptotic genes, and cell adhesion and invasion factors . Thus, some studies have suggested that the inhibition of the NF-κB pathway could decrease the resistance of tumor cells to chemotherapy and contribute to increasing the survival of patients with GBM.

Recently, a study has shown that DPG exposure has anti-tumoral effects on GBM cell lines (U87MG and T98G) through cell proliferation decrease and apoptosis stimulation. Furthermore, DPG anti-tumoral effect was related to NF-κB pathway suppression by IRAK2 and TRAF6 mediating miR-16 and miR-146a, respectively. Finally, the authors have also shown that DPG was able to inhibit the subpopulation of stem cells essential for tumor formation, survival, and recurrence .

3. G, GA, and DPG-Mediated Crosstalk between Inflammation and Oxidative Stress Pathways

Oxidative stress consists of an imbalance of endogenous pro-oxidant and antioxidant activities, characterized by excessive formation of high ROS and reactive nitrogen species (RNS). Small amounts of ROS are synthesized physiologically and act on cell homeostasis; however, in the disease context, the excessive synthesis of ROS disrupts the antioxidant defense system, causing cellular apoptosis . This condition is commonly associated with oxidative changes such as lipid peroxidation, protein carbonylation, carbonyl adduct, nitration, and DNA impairment as well as the induction of inflammatory processes, leading to several diseases. Cyclooxygenase type 2 (Cox-2) and inducible nitric oxide synthase (iNOS) enzymes, responsible for the release of pro-inflammatory mediators, prostaglandin E2 (Pge-2), and nitric oxide (NO), play relevant roles in oxidative and acute inflammatory processes.

The high mobility group box 1 (Hmgb1) cytokine plays an important role in the pathologic process of endothelial permeability under oxidative stress . DPG and G have presented antioxidant effects due to their negative modulation of Hmgb1 in the DSS-induced colitis mice model. It has been shown that G inhibits Hmgb1-cytokine secretion by blocking the Cytochrome C release and caspase-3 activity, consequently inhibiting apoptosis in inflammation-related stroke rat models. In addition, the G compound decreases the iNOS, TNF-α, IL-1β, and IL-6 expression levels by the modulation of p38 mitogen-activated protein kinases (p38-MAPK) and c-Jun N-terminal kinase (p-JNK) signaling pathways in brain vascular cells and by preventing oxidative stress and apoptosis through the inhibition of p38-MAPK, p-JNK, and NF-κB signaling pathways in lung cells.

Accordingly, the G compound can inhibit oxidative stress and inflammatory response by attenuating the activity of the Hmgb1 and NF-κB signaling pathways, with decreased levels of malondialdehyde (MDA) and cytokines (TNF-α, IL-1β and IL-6) in lung cells. Moreover, G increases glutathione-S-transferase (GSTs) levels, decreases MDA, and negatively regulates the expression of TNF-α, IL-6, iNOS, and monocyte chemotactic protein-1 (MCP-1) in liver cells. G compound has been shown to suppress NF-κB pathway through inhibiting the toll-like receptor 4 (TLR4) in renal cells and reducing the formation of intracellular ROS. Moreover, an activation of the AMP/nuclear factor erythroid-2-related factor-2 (NRF2) pathways in vitro was observed, positively regulating the antioxidant enzymes, HO-1, NQO-1, and GCLC and negatively regulating TNF-α, IL-1β, and IL-6 .

According to descriptions, GA also suppresses oxidative stress and neuroinflammation induced by A1C13 through TLR4/NF-κB signaling pathway inhibition . In accordance, one study has observed that GA was able to attenuate oxidative stress and neuroinflammation induced by rotenone reducing the activation of the ionized calcium-binding adapter molecule-1 (Iba-1), preventing glutathione depletion, lipid peroxidation inhibition, and attenuation of the induction of COX-2 and iNOS. In addition, a restored mitochondrial complex I and IV, a reduction in the generation of ROS, the release of Cytochrome C, and ultimately cell apoptosis inhibition after exposure to GA in brain tissue of adult Sprague Dawley Rats were observed .

GA can suppresses lipopolysaccharide (LPS)-induced oxidative stress, inflammation, and apoptosis through activation of the extracellular signal-regulated kinase (ERK) pathway, and inhibition of the NF-κB in renal cells. GA also suppresses oxidative stress and inflammation through activation of the NRF-2 and HO-1 pathways and IκB and NF-κB p65 signaling inhibition in cardiac cells.