Skip to main content
Evidence-based Complementary and Alternative Medicine : eCAM logoLink to Evidence-based Complementary and Alternative Medicine : eCAM
. 2022 Jan 17;2022:9523071. doi: 10.1155/2022/9523071

Pharmacological Effects and Underlying Mechanisms of Licorice-Derived Flavonoids

Yufan Wu 1, Zhuxian Wang 1, Qunqun Du 1, Zhaoming Zhu 1, Tingting Chen 1, Yaqi Xue 1, Yuan Wang 1, Quanfu Zeng 1, Chunyan Shen 1, Cuiping Jiang 1, Li Liu 1, Hongxia Zhu 2,, Qiang Liu 1,
PMCID: PMC8786487  PMID: 35082907

Abstract

Glycyrrhizae Radix et Rhizoma is the most frequently prescribed natural medicine in China and has been used for more than 2,000 years. The flavonoids of licorice have garnered considerable attention in recent decades due to their structural diversity and myriad pharmacological effects, especially as novel therapeutic agents against inflammation and cancer. Although many articles have been published to summarize different pharmacological activities of licorice in recent years, the systematic summary for flavonoid components is not comprehensive. Therefore, in this review, we summarized the pharmacological and mechanistic data from recent researches on licorice flavonoids and their bioactive components.

1. Introduction

Glycyrrhizae Radix et Rhizoma is the most frequently prescribed natural medicine in China and has been widely used for more than 2,000 years. The genus Glycyrrhiza is composed of approximately 30 species [1], of which G. inflate Bat., G. uralensis Fisch., and G. glabra L. are the origins of licorice according to the pharmacopeia of the People's Republic of China [2]. As it does not represent a hazard to the public, it is widely used in food, tobacco, and cosmetics as condiments and ingredients [3]. As a herbal medicine, G. Radix et Rhizoma is mainly used to treat respiratory and gastrointestinal symptoms and to quench thirst during fasting [4]. Furthermore, it is also prescribed as part of both holistic and mainstream medicine for various diseases, which can be attributed to its extensive pharmacological activities including anti-inflammatory, anticancer, antioxidant, antidiabetic, antiulcer, antiallergy, and antiviral effects [5, 6].

Over 400 compounds have been identified in licorice, including triterpene saponins, flavonoids [7], coumarins, phenolics, pterocarpan, and others [8]. In addition, 300 flavonoids with a basic C6-C3-C6 skeleton derived from licorice are currently known, including flavanones, flavones, flavonols, chalcones, isoflavones, isoflavanones, isoflavans, and isoflavenes [911], which have considerable structural diversity [5] and exhibit anti-inflammatory, antioxidant [12], antitumor [13], antibacterial, antiviral [1416], gastroprotective [17], and other effects (shown in Figure 1). For instance, licochalcone A inhibits the growth and metastasis of colonic tumors by downregulating inflammatory mediators and modifying the tumor microenvironment [18]. The chemical structures and main components of licorice flavonoids are summarized in Figure 2.

Figure 1.

Figure 1

Pharmacological activities of licorice flavonoids.

Figure 2.

Figure 2

(a) Flavanone, flavone, flavonol, and chalcone structure from licorice. (b) Isoflavone, isoflavanone, isoflavan, and isoflavene structure from licorice.

There is a substantial body of research on the biological activities, molecular and cellular mechanisms, and the active components of licorice flavonoids. Although many articles have been published to summarize different pharmacological activities of licorice in recent years, most of them tended to focus on triterpenoid components or one aspect of the effect, and the systematic summary for flavonoid components is not comprehensive. The purpose of this review is to summarize the pharmacological effects and mechanisms of action from recent researches on licorice flavonoids and their bioactive components.

2. Anti-Inflammation

Inflammation is the protective response to harmful stimuli such as mechanical injury, pathogens, damaged cells, or other irritants and involves local blood vessels, immune cells, and molecular factors. The inflammatory response restricts and eliminates invading pathogens, removes and/or absorbs necrotic tissues and cells, and repairs injured tissues. Based on the clinical course and predominant cell types, it can be classified as acute or chronic. Acute inflammation is mediated by the rapid infiltration of granulocytes into the affected tissues and has a finite duration, whereas chronic inflammation is a prolonged condition induced by the direct infiltration of mononuclear immune cells like macrophages, monocytes, lymphocytes, and so forth [19]. At the molecular level, the inflammatory response is mediated by cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), vascular endothelial growth factor (VEGF), nitric oxide (NO), prostaglandin (PG), and leukotriene (LT) [2022], along with the nuclear factor kappa B (NF-κB) [23, 24], Janus kinase/signal transducers and activators of transcription (JAK/STAT) [25], Nrf2/Keap1/ARE [19], and toll-like receptors (TLRs) pathways [26].

2.1. Effect on Inflammatory Diseases

The flavonoid structure is endowed with excellent anti-inflammatory property; for instance, viscosine, a flavonoid from Dodonaea viscosa showed anti-inflammatory and antipyretic properties as it reduced the concentration of PGE2 in brain through its mPGES-1 inhibitory action [27]. In the same way, licorice flavonoids display favorable anti-inflammatory effect and have shown therapeutic effects in pneumonia, hepatitis, ulcerative colitis, gastritis, and other inflammatory diseases [28]. Total flavonoids (TFF) from G. uralensis alleviated localized inflammation in the carrageenan-stimulated rat paw edema model and dimethylbenzene (DMB) induced ear vasodilatation assay in a dose-dependent manner [29]. Likewise, licorice flavonoids mitigated the acute pulmonary inflammation induced by intratracheal administration of lipopolysaccharides (LPS) at the doses of 3, 10, and 300 mg/kg, as indicated by reduced infiltration of macrophages, lymphocytes, and especially neutrophils in the accumulated bronchoalveolar lavage fluid (BALF) [30].

The main anti-inflammatory active flavonoids of licorice include the chalcones like licochalcone A and licochalcone B, and isoliquiritigenin, isoflavones such as isoangustone A, and isoflavans such as glabridin and licoricidin [31]. Licochalcone A, licochalcone B, 5-(1,1-dimethylallyl)-3,4,40-trihydroxy-2-methoxychalcone, and echinatin suppressed the LPS-induced production of reactive oxygen species (ROS) in RAW 264.7 macrophages in a dose-dependent manner and downregulated the levels of prostaglandin E2 (PGE2), IL-6, and NO in LPS-stimulated macrophages [32]. Moreover, isoliquiritigenin mitigated high-fat-diet-induced inflammation in a mouse model by significantly reducing the infiltration of inflammatory cells into the white adipose tissue of epididymis (eWAT) [33]. Glabridin also exhibited an anti-inflammatory effect against diabetes-related vascular dysfunction by downregulating LPS-induced NO production, as well as the expression of inducible nitric oxide synthase (iNOS) gene under high-glucose conditions [34].

In vitro and in vivo studies on the anti-inflammatory effects of licorice flavonoids are summarized in Tables 1 and 2, respectively.

Table 1.

The anti-inflammatory properties of licorice flavonoids in vitro.

Compounds Dose Inflammation Cell line/tissue Inhibition References
Licochalcone A 5–20 μM LPS-induced inflammatory reactions RAW 264.7 cell Reduced the concentration of TNF-α, IL-6, and IL-1β [35]
3 and 10 μM LPS-induced inflammatory reactions RAW 264.7 cell Dose-dependently inhibited LPS-induced ROS production and reduced the generation of NO, IL-6, and PGE2 [32]
15 nM IL-1β-stimulated inflammation Normal human dermal fibroblasts Exhibited the 50% inhibition of COX-2-dependent PGE2 production [36]
5–20 μM IL-1β/TNF-α-stimulated inflammation Primary chondrocytes Inhibited PGE2, NO, iNOS, COX-2, matrix metalloproteinase-1 (MMP-1), MMP-13, and MMP-3 production in chondrocytes [37]
Licochalcone C 50 μM LPS- (10 μg/mL) and interferon-γ (IFN-γ) (20 ng/mL) stimulated inflammation in THP-1 cell Human myeloid leukemia mononuclear cell (THP-1) Attenuated inflammatory response by diminishing the expression and activity of iNOS, by modulating extracellular O2 generation and by restraining the activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) [38]
Isoliquiritigenin 2.5–10 μg/ml LPS- (0.1 μg/ml) induced proinflammatory mediators production J774A.1 murine macrophage cell line Inhibited NO, IL-1β, and IL-6 production dose-dependently [39]
10 μM 2,4-Dinitrochlorobenzene (DNCB) induced atopic dermatitis THP-1 cell line Suppressed the differentiation of CD54 and CD86 and restrained the activation of extracellular signal-regulated kinase (ERK) and p38-α mitogen-activated protein kinase (p38-α) [40]
Glabridin 5–10 μg/ml LPS (0.1 μg/ml) induced proinflammatory mediators production J774A.1 murine macrophage cell line Moderate inhibition in NO levels with a maximum inhibition of 33% at the highest tested concentration [39]
5–20 μM LPS (1 μg/mL) stimulated inflammation HaCaT cell line At 20 μM, the inhibition reached 47%, 53%, and 68% for IL-1β, IL-6, and p65, respectively; and the suppression reached 53%, 55%, and 45% for IL-17A, IL-22, and IL-23 [41]
1–10 μM TNF-α (10−10 M) induced increase of PGE2 and NO in osteoblasts MC3T3-E1 cells The release of PGE2 and the increase of NO in osteoblasts were decreased significantly [42]
Liquiritin 50 and 100 μM LPS (100 ng/mL) stimulated microglial cell model Murine BV2 cell line Inhibited the increase of NO and proinflammatory mediators iNOS, COX-2, IL-1β, TNF-α, and IL-6 [43]
Liquiritigenin 50 and 100 μM LPS- (100 ng/mL) induced microglial cell model Murine BV2 cell line Suppressed the augment of NO and proinflammatory mediators COX-2, iNOS, IL-1β, IL-6, and TNF-α [43]
20 and 40 μM IL-1β (10 ng/ml) induced inflammation Chondrocytes from 1-week-old Sprague-Dawley rats Inhibited the IL-1β-induced expression of NO and PGE2 [44]
Licoricidin 0.5–1 μg/ml LPS-stimulated secretion of cytokines and MMPs by human monocyte-derived macrophages Human monoblastic leukemia cell line Inhibited the secretion of IL-6, chemokine ligand 5, and MMP-7, MMP-8, and MMP-9 [45]

Table 2.

The anti-inflammatory properties of licorice flavonoids in vivo.

Compounds Dose and administration Inflammation tissues/diseases Animal Outcomes References
Total flavonoids 50 and 100 mg/kg once a day for 10 weeks (i.g.) Azoxymethane/dextran sulfate sodium (AOM/DSS) stimulated colonic inflammation Female C57BL/6 mice weighing 16–18 g Greatly suppressed colitis and colorectal tumorigenesis by suppressing the production of inflammatory cytokines and phosphorylation [46]
1.56 g crude drugs per kilogram per day for 3 weeks (i.g.) Arthritis induced by injection of complete Freund's adjuvant (CFA) Sprague-Dawley (SD) rats (200 ± 20 g) Exhibited therapeutic effects on acute inflammation, chronic inflammation, and inflammatory pain and reduced IL-1β and TNF-α in plasma level [47]
3–30 mg/kg (i.g.) for 5 times with an interval of 6 h before LPS instillation and for 2 times with an interval of 8 h after LPS instillation LPS (2 mg/ml) induced acute inflammation of lung ICR mice Significantly attenuated LPS-induced pulmonary inflammation by suppressing inflammatory cells infiltration and inflammatory mediator release and reduced neutrophil-mediated oxidative injury [30]
500 and 250 mg/kg (i.g.) with 40 min before carrageenan injection 1% (w/v) carrageenan-induced paw edema SD rats (180–220 g) Significantly ameliorated edema and reduced the expression of TNF-α, IL-1β, and iNOS at a dose of 500 mg/kg [29]
Licochalcone A 20, 40, and 80 mg/kg (i.p.) at 1 h prior to LPS administration/1 h after LPS challenge LPS-induced lung injury/acute kidney BALB/c mice/female C57BL/6 mice Attenuated lung/kidney histopathologic changes and inhibited the production of TNF-α and IL-1β induced by LPS [35, 48]
50 mg/kg (i.p.) at 1 h before OVA challenges on days 25–27 Ovalbumin (OVA) stimulated inflammation on noninfectious asthma Female BALB/c mice, weighing about 16–18 g Inhibited T-helper type 2 cytokines like IL-4, IL-13, and IL-5 in bronchoalveolar lavage fluid and decreased serum levels of OVA-specific IgG and IgE [49]
Isoliquiritigenin 20 mg/kg (i.p.) administered at 30 min, 12 h, and 24 h prior to LPS treatment/5–20 mg/kg given 1 h before LPS challenge LPS-induced neuroinflammation/acute lung injury Male Wistar rats/BALB/c mice Reversed LPS-induced increase in expression of TNF-α and IL-1β and decreased NF-κB activity [50, 51]
Treated with 1% isoliquiritigenin on dorsal skin daily from day 6 to day 18 Repetitive application of DNCB-induced atopic dermatitis-like skin lesion 6–8-week-old BALB/c mice Suppressed the IgE and Th2 cytokines increase in blood and inhibited the expressions of IL-6, TNF-α, and IL-4 at the site of skin lesion [40]
Gavaged 7.5–75 mg/kg at 24 hours and 1 h prior to indomethacin challenge Indomethacin (10 mg/kg) induced small intestinal damage Wild-type male C57BL/6 mice (7-week-old) Reversed indomethacin-induced increase in cleaved caspase-1 and mature IL-1β protein levels [52]
Glabridin Glabridin (10, 30, and 50 mg/kg/d) pretreated on shaved back for 7 days Imiquimod-induced psoriasis-like inflammation BALB/c mice averagely weighted 20–25 g Significantly downregulated the mRNA expressions of IL-1β, IL-6, IL-17A, IL-22, IL-23, and p65 [41]
Gavaged 10 or 50 mg/kg/d 1 week before colitis induction and parallel with DSS-feeding for 7 days Dextran sulfate sodium (DSS, 5%) induced colonic inflammation Adult male Wistar rats/six-week-old female BALB/c mice Ameliorated the disruption of the colonic architecture and reduced myeloperoxidase (MPO) activity and production of inflammatory mediators in colon [53, 54]

2.2. Mechanism Underlying Anti-Inflammatory Effect

The inflammatory process is highly synchronized and progresses sequentially through cell migration and infiltration, enzyme activation, fluid extravasation, inflammatory mediator release, tissue breakdown, and repair [55]. The mechanisms, factors, and pathways that induce and exacerbate inflammation are highly complex, and licorice flavonoids restrain the inflammatory mediators and cytokines by targeting multiple immune-related pathways (Figure 3).

Figure 3.

Figure 3

The main signaling pathway of anti-inflammation of licorice flavonoids.

2.2.1. NF-κB Signaling Pathway

The NF-κB axis is the representative proinflammatory signaling pathway, and the activation of the transcription factor NF-κB culminates in the expression of genes encoding proinflammatory cytokines like TNF-α and IL-1 [24], adhesion molecules, chemokines, COX-2, MMPs, and iNOS [56]. Given the crucial role of NF-κB in the pathogenesis of inflammation, its blockade is a rational therapeutic strategy against various chronic inflammatory conditions.

Isoliquiritigenin exerts its anti-inflammatory effects by suppressing NF-κB activity, consequently leading to a decrease in the levels of TNF-α, IL-6, IL-1β, and IL-8 and other proinflammatory factors [57, 58]. Another study showed that isoliquiritigenin inhibited NF-κB and the downstream iNOS, TNF-α, COX-2, and IL-6 in RAW 264.7 cells via downregulation of extracellular signal-regulated kinase 1/2 (ERK1/2), nuclear factor kappa B kinase (IKK), and p38 phosphorylation [59]. Likewise, licochalcone A, licochalcone D, and licochalcone B significantly inhibited LPS-induced transcriptional activation of NF-κB and phosphorylation at serine 276 by suppressing protein kinase A (PKA) [60]. In addition, licochalcone E inhibited the nuclear translocation of NF-κB and decreased the levels of its multiple downstream targets such as iNOS, vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) in LPS-stimulated H9c2 cells [61]. Licochalcone E also ameliorated chronic allergic contact dermatitis and inhibited the production of IL-12p40 in a dose-dependent manner by downregulating NF-κB, indicating its therapeutic potential in skin inflammatory disorders [62].

2.2.2. Nuclear Factor-Erythroid 2 Related Factor 2 (Nrf2) Signaling Pathway

A recent study showed that licochalcone A alleviated the symptoms of arthritis by suppressing the proliferation of the inflammatory cells. Mechanistically, licochalcone A slowed cell cycle transition and enhanced apoptosis, inhibited proinflammatory cytokine secretion, and upregulated antioxidant enzyme expression by activating the Keap1-Nrf2 signaling pathway. It promoted Nrf2 accumulation and nuclear translocation and increased p62 phosphorylation [63]. Isoliquiritigenin protected against cigarette-smoke-induced chronic obstructive pulmonary disease (COPD) via suppression of inflammation and oxidative stress by targeting the Nrf2 and NF-κB signaling pathways [64]. In addition, isoliquiritigenin also downregulated NADPH oxidase 2 (NOX2) and NOX4 levels, promoted the dissociation of Keap1 and Nrf2, and activated the NAD(P)H quinone dehydrogenase 1 (NQO1), heme oxygenase-1 (HO-1), glutamate-cysteine ligase (GCLC), and GCLM genes [65]. Another study showed that isoliquiritin can activate Nrf2 signaling in murine macrophages by suppressing Keap1 and increasing Nrf2 translocation and increasing the expression levels of UGT1A1, HO-1, and NQO1, eventually suppressing the inflammatory responses [66]. Taken together, licorice flavonoids exert a potent anti-inflammatory effect through Nrf2 pathway activation.

2.2.3. Other Signaling Pathways

As discussed in Section 2.2.2, the anti-inflammatory effects of licorice flavonoids are driven by complex mechanisms and multiple signaling pathways. Isoliquiritigenin mitigated DSS-induced colitis in a mouse model by inhibiting the mitogen-activated protein kinase (MAPK) signaling pathway via suppression of ERK1/2 and p38 phosphorylation. Likewise, liquiritin also targeted the MAPK pathway in rheumatoid arthritis (RA) by downregulating the B-cell lymphoma-2 (Bcl-2)/Bcl-2-associated X (Bax) ratio, c-Jun N-terminal kinase (JNK), and p38 phosphorylation, as well as VEGF expression [67, 68]. Moreover, isoliquiritigenin significantly decreased the levels of toll-like receptor 4 (TLR4) protein and its downstream targets including myeloid differentiation primary response 88 (MYD88), a phosphorylated inhibitor of nuclear factor kappa B (p-IκBα), and p-NF-κB. Isoliquiritigenin-mediated blockade of the TLR4/MYD88 pathway had neuroprotective and anti-inflammatory effects in a kainic acid (KA) stimulated model of epileptogenesis [69]. Zhu et al. found that isoliquiritigenin inhibited receptor activator of nuclear factor-κB ligand (RANKL) stimulated osteoclastogenesis and inflammatory bone loss by inhibiting receptor activator of IκBα/NF-κB, MAPK, nuclear factor-κB-TNF receptor-associated factor 6 (RANK-TRAF6), and activator protein-1(AP-1) signaling pathways [70]. Licochalcone A blocked the induction of caspase-1 and IL-1β in human SZ95 sebocytes and primary mouse macrophages infected with Propionibacterium acnes and controlled P. acnes-induced skin inflammation by targeting NOD-, LRR-, and pyrin-domain-containing protein 3 (NLRP3) inflammasome [71]. Total flavonoids of Radix Glycyrrhiza inhibited the LPS/IFN-γ-induced inflammatory response in RAW 264.7 macrophages by inhibiting iNOS expression via the ERK/NF-κB/miR-155 pathway [72].

3. Anticancer

3.1. Anticancer Effect

Cancer results from human cells that slip from reining, having been recruited and to some extent transformed into pathological organisms or building the block of tumor [73]. Licorice flavonoids have established anticancer effects, and the underlying mechanisms are diverse. For instance, 70% ethanol-extracted total flavonoids markedly reduced tumor mass of breast cancer cell MDA-MB-231 xenografts by suppressing iNOS expression [72]. In addition, licochalcone A inhibited the growth and proliferation of HepG2 cells by blocking the MAPK signaling pathway [74]. Furthermore, several licorice flavonoids have exhibited proapoptotic [7577] and antimetastatic [18, 78] effects in diverse cancer cell lines and animal models. In this section, we have summarized the effects and underlying mechanisms of licorice flavonoids on solid tumors and cancer cells.

3.1.1. Hepatocellular Carcinoma

Studies have demonstrated the anti-liver-cancer effects of glabridin [79], licochalcone A [80], licochalcone B [81], and isoliquiritigenin [78]. Glabridin significantly blocked cell proliferation in Huh7 human hepatoma cells and induced apoptosis through poly ADP-ribose polymerase (PARP) cleavage, caspase-3, caspase-8, and caspase-9 activation and increased microtubule-associated protein 1 light chain 3-II (LC3-II) and Beclin-1 protein expression [76]. Moreover, it restrained the migration and invasion of hepatocellular carcinoma cells and effectively prevented the formation of hepatoma xenografts in a mouse model [79]. Recent studies showed that isoliquiritigenin inhibited the proliferation, migration, and metastasis of Hep3B human liver cancer cells and exhibited cytotoxic effects on HepG2 and Hep3B cells, indicating that it can block hepatocellular carcinoma genesis and metastasis [78, 82]. The antihepatocellular carcinoma effect of liquiritigenin was embodied in enhancing apoptotic rate, inhibiting cell viability, and inducing overrelease of lactate dehydrogenase and up-regulated intracellular ROS level and caspase 3 activity in HepG2 and PLC/PRL/5 cells [83]. Both licochalcone A and licochalcone B blocked the growth of HepG2 cells via terminating cell cycle at G2/M phase and induced apoptosis by modulating the expression of genes involved in cell cycles [80, 81].

3.1.2. Lung Cancer

Lung cancer is one of the most prevalent malignancies and is associated with a poor prognosis. Despite advances in chemotherapy over the past two decades, the survival rates of patients are still dismal. Studies show that flavonoids isolated from Glycyrrhiza, such as liquiritin, isoliquiritigenin [84], and licochalcones [85], can effectively control lung cancer progression. Licochalcone A induced apoptosis in non-small cell lung cancer (NSCLC) cells by promoting autophagy and simultaneously enhancing the expression of the endoplasmic reticulum stress-related mediator C/EBP homologous protein (CHOP), which is known to clear damaged cells by triggering both apoptotic and autophagic pathways [85]. In addition, it suppressed cell growth and induced apoptosis in A549 and H460 NSCLC cell lines [86]. Licochalcone B and licochalcone D displayed proapoptotic and antiproliferative effects in epidermal growth factor receptor (EGFR) mutant NSCLC cell line HCC827 via caspases activation, PARP cleavage, and relevant proteins modulation [13, 87]. Furthermore, glabridin exhibited suppression of cell metastasis by deterring migration and invasion of A549 cells and decreasing A549-mediated angiogenesis both in vitro and in vivo [88]. Echinatin restrained gefitinib-sensitive/resistant NSCLC cells by inhibiting cell multiplication and inducing ROS production in EGFR mutant NSCLC cell line HCC827 and human lung epithelial cell line NL20 [89]. Finally, the combination of liquiritin, isoliquiritigenin, and isoliquiritin induced apoptosis in the A549 NSCLC cell line by inhibiting the p53-dependent pathway and also affecting the downstream targets of Akt [84].

3.1.3. Gastric Cancer

Several licorice flavonoids including licochalcone A [90], liquiritin [91], and liquiritigenin [92] have shown therapeutic effects against gastric cancer, of which licochalcone A shows the highest cytotoxicity in gastric cancer cells [90]. In normal cells, glucose is metabolized into H2O and CO2 that generate ATP to meet the energy requirements. However, tumor cells largely depend on aerobic glycolysis, wherein glucose is converted to pyruvate and lactate, for their energy needs. This phenomenon is known as the Warburg effect and results in the accumulation of lactate which creates a highly acidic tumor microenvironment, leading to enhanced chemoresistance, migration, and metastasis of the tumor cells [93, 94]. Licochalcone A suppressed hexokinase 2 (HK2) induced glycolysis in the human gastric BGC-823 cells, which not only inhibited proliferation and clonogenic survival [95] but also induced apoptosis in the tumor cells [96]. Furthermore, liquiritin monotherapy moderately inhibited the proliferation and migration of cisplatin (DDP) resistant [91] or TNF-related apoptosis-inducing ligand (TRAIL) resistant [97] gastric cancer cells and induced apoptosis. The combination therapy of liquiritin and DPP significantly increased apoptosis and autophagy rates in vitro and in vivo by enhancing cleavage of caspase-8/-9/-3 and PARP and upregulating LC3B and Beclin-1 [91]. The combined application of liquiritin and TRAIL synergistically impeded the growth and proliferation of gastric cancer cells in vitro and the xenograft growth in nude mice through caspase activation [97]. Thus, liquiritin can significantly augment the therapeutic effects of other anticancer drugs and should be considered as an adjuvant in the treatment of human gastric cancer.

3.1.4. Breast Cancer

Breast carcinoma is the most frequently diagnosed malignancy in women worldwide and is associated with high morbidity and mortality. The majority of breast-cancer-related deaths have been attributed to the metastasis of tumor cells to distant tissues, such as the brain or bone [98]. Licorice flavonoids including isoliquiritigenin [99], licochalcone A [100], and licochalcone E [101] can deter breast cancer progression through different mechanisms and signaling networks. Isoliquiritigenin inhibited the transcription and enzymatic activity of aromatase CYP19 that is involved in the synthesis of estrogen, which increases the risk of breast cancer [99]. It also inhibited the growth of MDA-MB-231 and MCF-7 cells by blocking the arachidonic acid (AA) metabolic network, which plays a crucial role in the growth of breast tumors [102]. In addition, isoliquiritigenin also inhibits key mediators and enzymes involved in breast carcinoma invasion and metastasis, such as VEGF, MMP-9, MMP-2, and hypoxia-inducible factor-1α (HIF-1α) [103]. Glabridin attenuated the cancer stem cells (CSCs) like properties of breast carcinoma cells, which is likely the major underlying cause of breast cancer metastasis and recurrence, by inhibiting the miR-148a/transforming growth factor-beta (TGF-β) drosophila mothers against decapentaplegic protein 2 (SMAD2) pathway both in vitro and in vivo [104]. Finally, licochalcone A displays proapoptotic and antiproliferative effects in breast cancer cells via modulation of transcription factor Sp1 (Sp1) and apoptosis-related proteins [100]. It also suppressed the proliferation, migration, and invasion of MDA-MB-231 breast carcinoma cells by increasing ROS production that triggered apoptosis and by regulating epithelial-mesenchymal transition factors like E-cadherin and vimentin [105].

3.1.5. Other Tumors

The antitumor properties of licorice flavonoids have also been reported for the cancers of the colon [75], oral/esophageal squamous epithelium [106, 107], prostate [108], bladder [109], ovary [110], cervix, uterus [111], glioma [112], melanoma [113], uterine leiomyoma [114], and pleural mesothelioma [115]. The effects of flavonoid compounds against these tumors are summarized in Table 3.

Table 3.

Anticancer/tumor effects of licorice flavonoid and its active components in experimental models.

Cancer Compounds Dose and administration Result References
Colon Isoangustone A 5–20 μM incubated Induced apoptosis in colorectal cancer cells [116]
Total flavonoids Gavaged (50 and 100 mg/kg) once a day for 28 days Restrained AOM/DSS-induced colitis-associated tumorigenesis, reduced activation of p53 and NF-κB, and suppressed phosphorylated-Janus kinases 2 (p-JAK2) and phosphorylated-signal transducer and activator of transcription 3 (p-STAT3) production [46]
Liquiritigenin 50 and 100 μM incubated Exerted significant inhibitory effects on HCT116 colorectal cancer cell invasion and blocked the epithelial-mesenchymal transition (EMT) process [117]
Oral/esophageal squamous Licochalcone A 10–40 μM incubated Inhibited HN22 and HSC4 oral squamous cell carcinoma cells growth concentration- and time-dependently [118]
Licochalcone B 10–30 μM incubated Arrested cell cycle at G1 phase, significantly inhibited cell proliferation, and induced apoptosis in oral squamous cell carcinoma cells [119]
Licochalcone C 10–30 μM incubated for 48 h Significantly decreased cell viability of esophageal squamous cell carcinoma (ESCC) cells in a dose- and time-dependent manner [120]
Licochalcone H 10–30 μM incubated Induced cell cycle arrest and apoptosis, reduced cell activity, and colony-forming ability in HSC2 and HSC3 oral squamous cell carcinoma cells [77]
Glabridin 20–80 μM incubated Inhibited cell proliferation in human tongue squamous carcinoma cell lines (SCC-9 and SAS) and induced several features of apoptosis [121]
Isoliquiritigenin 25 and 50 μM incubated Induced cell cycle G2/M phase arrest, DNA damage, and apoptosis in oral squamous cell carcinoma cells [122]
Prostate Licochalcone A 6.5 and 12.5 μM incubated Induced caspase-dependent and autophagy-related cell death in LNCaP cells [123]
Isoliquiritigenin 25 and 50 μM incubated Suppressed cell proliferation, induced cell apoptosis, and arrested G2/M cell cycle in human prostate cancer PC-3 and 22RV1 cells [124]
Bladder Licochalcone A 10–40 μM incubated Exerted antiproliferative effect on human bladder cancer cells and induced G2/M cell cycle arrest and apoptotic cell death [125]
Ovary Isoliquiritigenin 5 and 10 μM incubated Inhibited epithelial-to-mesenchymal transition, migration, and invasion in SKOV3 and OVCAR5 ovarian cancer cells and extended the life span of animals bearing SKOV3/Luc cells consequently [126]
Cervix uteri Liquiritin 40–80 μM incubated Suppressed the migration, invasion, and cloning ability of cervical cancer cells and showed little cytotoxicity to human normal cells [111]
Glioma Licochalcone A 10–30 μM incubated Inhibited glioma cell growth in U87 glioma cell lines and U87 glioma cell xenograft male athymic mice [127]
Melanoma Isoliquiritigenin 20–80 μM incubated Effectively induced apoptosis and inhibited proliferation in mouse melanoma B16F10 cells [128]
Uterine leiomyoma Isoliquiritigenin 10–40 μM incubated in vivo; 1 and 5 mg/ml (i.p.) three times a week for 9 weeks on ICR mice Exerted inhibition of estrogen-induced uterine leiomyoma growth both in vitro and in vivo [114]
Pleural mesothelioma Licochalcone A 10–40 μM incubated Induced apoptosis through suppressing Sp1 expression in malignant pleural mesothelioma cell MSTO-211H and H28 [115]
Osteosarcoma Licochalcone A 20–60 μM incubated with human osteosarcoma cells; 10 mg/ml (i.p.) twice a week for 5 weeks on BALB/c nude mice Inhibited cell proliferation and induced apoptosis in human osteosarcoma cells by reduction of cell viability, activation of caspases, and loss of mitochondrial membrane potentials [129]

3.2. Mechanism Underlying Anticancer Effect

Phytochemicals and other natural products can effectively inhibit the growth of tumor cells, augment the antitumor immune responses, and alleviate the side effects of radiotherapy. Several studies have shown that plant-derived bioactive compounds target pathways involved in tumor cell proliferation, differentiation, and metastasis, induce apoptosis, inhibit extracellular matrix enzymes, modulate the expression of transcription factors, and inhibit neoangiogenesis. In addition, several phytochemicals can promote the survival and expansion of antitumor immune cells and reverse the immunosuppressive tumor microenvironment [130]. Licorice flavonoids typically target the MAPK/JNK and PI3K/AKT pathways and also directly regulate the expression of genes involved in metastasis and apoptosis, as shown in Figure 4.

Figure 4.

Figure 4

The main antitumor signaling pathway of licorice flavonoids.

3.2.1. MAPK/JNK Signaling Pathway

ERK, p38, and JNK are the key mediators of the MAPK signaling pathway in mammalian cells [131]. JNK contains a dual phosphorylated functional region that can bind to the N-terminal activation region of c-Jun and phosphorylate the serine residues at positions 63 and 73 [132]. It is activated by different stress-related stimuli and relays the signals through multiple pathways that regulate cancer genesis and progression [133]. Glabridin inhibited the proliferation of human liver cancer and oral cancer cells and induced apoptosis via the p38 MAPK and JNK1/2 pathways [76, 121]. Licochalcone A inhibited hepatocellular cell migration and invasion by downregulating uPA expression and activity through the inhibition of NF-κB nuclear translocation and transcription of its downstream targets and that of the MKK4/JNK signaling pathway as well [134]. The antihepatocellular carcinoma effect of liquiritigenin has been attributed to MAPK inactivation, increased phosphorylation of JNK and p38, reduced expression of B-cell lymphoma-extra large (Bcl-xL) and Bcl-2, suppression of ERK, and decreased nuclear translocation of phosphorylated ERKs [83]. Licochalcone C induced apoptosis in human esophageal squamous cell carcinoma cells via ER stress response and ROS generation, which triggered mitochondrial dysfunction via JNK/p38 MAPK pathway activation [120].

3.2.2. PI3K/AKT Pathway

The PI3K/AKT pathway is frequently dysregulated in multiple tumor cells [135]. It consists of several bifurcating and converging kinase cascades and is therefore a highly attractive therapeutic target [135, 136]. Several studies have shown that licorice flavonoids exert their antitumor effects by suppressing the PI3K/AKT pathway. Isoliquiritigenin not only inhibited cell cycle transition, proliferation, and migration of Hep3B cells but also inactivated the PI3K/AKT pathway in human breast tumor cells that resulted in growth retardation and apoptosis [78, 102]. Licochalcone A suppressed glycolysis and induced apoptosis in gastric cancer cells by inhibiting hexokinase 2 (HK2) and the AKT signaling pathway [95]. It also induced apoptosis in breast cancer cells and mitigated their migration and invasion by inhibiting Akt phosphorylation [105] and exhibited a proapoptotic effect in the BCC-823 gastric cancer cells through the PI3K/AKT-mediated pathway [109]. Liquiritigenin exerted significant inhibitory effects on the invasiveness and epithelial-mesenchymal transition of colorectal cancer cells by downregulating runt-related transcription factor 2 (Runx2) and inactivating the PI3K/AKT signaling pathway [117].

3.2.3. Induction of Apoptosis in Tumor Cells

Apoptosis is a form of genetically programmed cell death characterized by membrane blebbing, cell shrinkage, and chromosomal DNA fragmentation. Most chemotherapeutic drugs and phytochemicals inhibit tumor growth by inducing the apoptotic cascade in cancer cells by targeting the enzymes, genes, and cytokines [137]. There are two major apoptotic pathways in the eukaryotic cell: the intrinsic mitochondrial-dependent pathway and the extrinsic death receptor-mediated pathway involving caspase activation [138]. Bax and Bak are members of the Bcl-2 family and the core regulators of the intrinsic apoptotic pathway. They are activated and oligomerized in the outer mitochondrial membrane and induce membrane depolarization under apoptotic stimuli [139]. Cysteine aspartic proteases or caspases are involved in inflammation, programmed cell death, and immune disorders [138].

Licochalcone A can induce apoptosis in the human hepatoma [80], lung cancer [86], osteosarcoma [129], bladder cancer [125], and prostate cancer [123] cells. It triggered the apoptotic cascade in HepG2 cells and human bladder cancer cells by upregulating Bcl-2, Bax, caspase-3, and caspase-8. It also decreased the expression levels of Bcl-2 and Bcl-xL in lung cancer cell lines, resulting in apoptosis. The cytotoxic effects of licochalcone A against human osteosarcoma cells and LNCaP prostate cancer cells are also mediated through the intrinsic apoptotic pathway and caspase-dependent cell death. Liquiritin triggered apoptosis in gastric cancer cells via both the intrinsic Bcl-2/Bax and extrinsic Fas-associated protein with death domain (FADD) regulated pathways, which culminated in cleavage of caspase-8 and caspase-9 [111]. It also induced apoptosis and autophagy in cancer cells when used in combination with cisplatin by enhancing caspase-8/-9/-3 and PARP cleavage [91].

4. Antioxidation

4.1. Antioxidant Effect

The antioxidant capacity of flavonoids is related to the molecular structure, associating with the position and the total number of -OH groups, conjugation and resonance effects, modification of the surrounding environment of thermodynamically favorable antioxidant sites, and the particular antioxidant mechanism of the compound [140].

Phenolic compounds derived from the roots and stolons of G. glabra exhibited considerable antioxidant action, as measured by the peroxynitrite assay, of which isoliquiritigenin, hispaglabridin B, and paratocarpin were the most potent antioxidants [141]. Liu et al. have reported that licorice extract (20, 40, and 60 mg/kg) containing licochalcone A, licoisoflavone, isolicocflavonol, and glycyrol reduced paraquat-induced oxidative stress in lung tissues by downregulating MDA level and increasing the SOD activity [142]. Polyphenols extracted from Glycyrrhiza also reduced the serum levels of total cholesterol, triglycerides, LDL cholesterol (LDL-C), and very-LDL-C by directly suppressing cholesterol biosynthesis and by indirectly eliminating free radicals and lowering LDL oxidation [143]. Additionally, flavonoid fraction from G. glabra showed remarkable antioxidant activity manifested by assays of low IC50 values in DPPH (20.9 mg/mL), NO radical scavenging (195.2 mg/mL), and hydrogen peroxide scavenging capacity (3.4 mg/mL) [144].

Furthermore, licochalcone B and licochalcone A significantly inhibited lipid peroxidation in rat liver microsomes and restrained LPS-induced ROS production in RAW 264.7 cells [32]. Glabridin reduced low-density lipoprotein (LDL) oxidation in vitro and in vivo [145]. Isoliquiritin exhibited a protective effect on neurodegenerative disorders through oxidative stress downregulation, intracellular [Ca2+]i overloading inhibition, and the mitochondrial apoptotic pathways suppression [146]. In addition, liquiritin alleviated cerebral ischemia/reperfusion injury in mice, as indicated by decreased infarct volume and less neurological deficit, through antioxidant and antiapoptosis mechanisms. It reduced the levels of malondialdehyde (MDA) and carbonyl, increased the ratio of glutathione (GSH/GSSG), and significantly decreased the percentage of apoptotic cells in the infarct region [147].

Other relevant reports with regard to antioxidation of licorice flavonoids and the specific structures are listed in Table 4.

Table 4.

The antioxidant properties of licorice flavonoids.

Compounds Model Dose and effects References
Isoliquiritigenin LPS-induced acute lung injury mice Treatment with isoliquiritigenin (30 mg/kg) enhanced the production of ROS, MPO, and MDA, ameliorating low expression of GSH and SOD caused by LPS stimulation [148]
LPS-induced cognitive impairment rats Isoliquiritigenin (20 mg/kg) pretreatment appeared antioxidant capacity through reversing the downregulation of SOD and GSH-PX activity and reducing the content of MDA [149]
Streptozotocin (STZ) induced diabetic retinopathy Isoliquiritigenin (20 mg/kg/day) treatment markedly reduced diabetes-induced lipid peroxidation by 27.8%, upregulated retinal GSH 1.57-fold, and restored total retinal antioxidant capacity 2.15-fold [150]
Caenorhabditis elegans Isoliquiritigenin (50 μg/ml) reduced heat shock protein-16.2 (HSP-16.2) expression level by 30.8% under mild oxidative stress and increased the survival rate of C. elegans from 10.8% of control group to 97.4% under lethal oxidative stress [151]
Liquiritigenin Serum deprivation in HepG2, H4IIE, and AML12 cells induced oxidative stress Mitochondrial dysfunction, oxidative stress like ROS formation, and resultant cell death caused by nutrition deprivation were prohibited by liquiritigenin (100 μM) pretreatment [152]
Citrinin (CTN) induced, oxidative-stress-mediated disruption of embryonic development in mouse blastocysts CTN-triggered ROS generation for sequent apoptosis and injury of blastocysts was restrained by the preincubation of liquiritigenin (20–40 μM) [153]
Glabridin Methotrexate (MTX) triggered liver injury Glabridin (20 or 40 mg/kg) lower oxidative stress stimulated by MTX through upregulation of MDA level, as well as reduction of GSH level and SOD activity [154]
Diabetic vascular complications mouse Glabridin prevented the antiatherogenic capacity of paraoxonase 2 (PON2) by the interaction of glabridin-PON2 that protected PON2 from oxidation [155]
Licochalcone A HepG2 cell and L-02 cell Licochalcone A inhibited peroxyl radical-induced oxidation of DCFH to DCF in HepG2 cells in a dose-dependent manner and upregulated protein expression of SOD1, CAT, and GPx1 at 2–8 μg/ml [74]

4.2. Antioxidant Mechanism

Nrf2 controls the expression of antioxidant enzymes in management of oxidant stress [154]. Flavonoids derived from licorice exhibited reliable antioxidant activity through the regulation of Nrf2 protein expression. Isoliquiritigenin exerted its antioxidant effects by upregulating the transcription factors SKN-1/Nrf2 and DAF-16/FOXO, which activated genes involved in the antioxidant responses [151]. It also inhibited cigarette-smoke-induced oxidative stress in COPD by reversing MPO activity and decreasing MDA levels, upregulating Nrf2, and downregulating NF-κB [64]. Isoliquiritigenin notably activated AMPK/Nrf2/ARE signaling and exhibited ROS producing inhibition in peritoneal macrophages of wild-type mice but not in Nrf2−/− mice, illustrating that the antioxidative capacity of isoliquiritigenin relied on Nrf2 activation [148]. In addition, licochalcone A prevented ROS-driven oxidative stress in primary human fibroblasts in vitro by activating the cytoprotective phase II enzymes and stimulating the antioxidant transcription factor Nrf2 [156]. Glabridin displayed the antioxidant defense mechanism of liver via upregulating Nrf2 protein expression to lower the ROS formation and ameliorate oxidative stress exerting the hepatoprotective effect against MTX [154].

Furthermore, ultraweak photon emission analysis revealed significantly lower ultraviolet A (UV-A) stimulated luminescence in vivo following treatment with licochalcone A-rich licorice extract, which is indicative of lower oxidation [156]. Liquiritin abrogated oxidative injury in B65 neuroblastoma cells by increasing the expression of glucose-6-phosphate dehydrogenase in a dose-dependent manner [157]. Liquiritigenin, as an AMPK activator, protected hepatocytes against oxidant hepatic injury and mitochondrial dysfunction caused by nutrition deficiency which was attributed to LKB1-AMPK pathway activation and FXR induction [152]. Glabridin inhibits LDL oxidation by its direct antioxidant activity as well as by the removal of oxidized LDL through its paraoxonase activity [158]. Further research is needed to elucidate the exact mechanisms, as well as the structure-bioactivity relationship of licorice flavonoids to expand their applications as antioxidants.

5. Antibacterial, Antiviral, and Antiprotozoan Activity

Viral and other microbial infections play a critical role in many prevalent diseases, especially in developing countries [6]. Natural bioactive flavonoids derived from medicinal herbs and plants have been widely demonstrated to have antibacterial, antiviral, and antiprotozoan activity and can enhance the protective immune systems of human [159]. It is important to develop safe and effective antibacterial or antiviral agents, and licorice flavonoids have attracted much attention due to their excellent activity [6].

5.1. Effect on Diverse Microorganisms

Isoflavonoids such as 6,8-diisoprenyl-5,7,4′-thrihhydroxyisoflavone effectively inhibited the Gram-positive bacteria Streptococcus mutans, while gancaonin G displayed moderate antimicrobial activity [160]. Flavonoids from licorice, including glabrol, licochalcone A, licochalcone C, and licochalcone E, showed a favorable potential on Methicillin-resistant Staphylococcus aureus (MRSA) with low cytotoxicity for mammalian cells [161]. The flavonoid-rich fraction of the aqueous Glycyrrhiza extract has a potent anti-herpes-simplex-virus (HSV) activity; in addition, liquiritin, apioside, isoliquiritin apioside, lucurzid, and isoliquiritin have also been reported to be effective against HSV [162]. Licochalcone A displayed in vitro schistosomicidal effect on Schistosoma mansoni adult worms by affording lethal concentration for LC50 of 9.52 ± 0.9 and 9.12 ± 1.1 μM against male and female adult worms, respectively, and it reduced the total number of S. mansoni eggs and impeded eggs produced by S. mansoni adult worms [163].

The studies associated with the effects of licorice flavonoids and their active constituents on bacteria, viruses, and protozoa are summarized in Table 5.

Table 5.

The antibacterial, antiviral, and antiprotozoan effects of licorice flavonoids.

Effects Compounds Microorganism Dose and effect References
Antibacterial effects 1-Methoxyficifolinol, licorisoflavan A, and 6,8-diprenylgenistein Streptococcus mutans Showed bactericidal effects at the concentration of ≥4 μg/ml [164]
Flavonoid of G. uralensis extracts Streptococcus mutans and Candida albicans The inhibition zones of S. mutans and C. albicans increased in order: 50 μg/ml < 100 μg/ml < 150 μg/ml < 200 μg/ml [165]
Licoricidin and glabridin Streptococcus mutans Licoricidin had an MIC of 6.25 μg/mL and an MBC between 6.25 and 25 μg/mL; glabridin showed an MIC from 6.25 to 12.5 μg/mL and an MBC between 6.25 and 25 μg/mL against one reference (ATCC 25175) and four clinical (12A, 33A, INB, and T8) strains of S. mutans [166]
Flavonoid-rich extract of G. glabra Helicobacter pylori At minimum inhibitory concentration (MIC) of 100 μg/ml [167]
Flavonoids of G. glabra, namely, licoricone, glycyrin, and glyzarin Acinetobacter baumannii Significantly reduced quorum sensing regulated virulence factors of A. baumannii at 0.5 mg/ml [168]
Isoliquiritigenin and liquiritigenin MRSA MIC of both components exhibited significant anti-MRSA activity (50–100 μg/ml) against clinical isolates of MRSA [169]
Licochalcone A Bacillus subtilis The vegetative cell growth of B. subtilis was inhibited in a concentration-dependent manner and was completely prevented by 3 μg/ml [170]
Licochalcone A Candida albicans Reduced C. albicans biofilm growth at 625 μM in vitro; and mice treated with licochalcone A exhibited a markable reduction in total photon flux and CFU/ml/mg of tongue tissue sample [171]
Nisin/glabridin, nisin/licoricidin, and nisin/licochalcone A Enterococcus faecalis Efficiently restrained the growth of E. faecalis, with MICs ranging from 6.25 to 25 μg/mL [172]
6-Aldehydo-isoophiopogonone and liquiritigenin Multidrug-resistant human bacterial Staphylococcus aureus 6-Aldehydo-isoophiopogonone and liquiritigenin showed activity against S. aureus with a zone inhibition of 10 ± 0.2 mm and 10 ± 0.3 mm [173]
Glabridin Amphotericin B resistant Candida albicans At an MIC of 31.25–250 μg/mL [174]
Liquiritin Phytophthora capsici Suppressed the P. capsici mycelial growth with EC50 of 658.4 mg/L and caused P. capsici sporangia to shrink and collapse [175]
Antiviral effects Echinantin and isoliquiritigenin Influenza A viruses Showed strong inhibitory effects on various neuraminidases from influenza viral strains, H1N1, H9N2, novel H1N1 (WT), and oseltamivir-resistant novel H1N1 (H274Y) expressed in 293T cells [176]
Licocoumarone, glyasperin C, 2′-methoxyisoliquiritigenin, glycyrin, licoflavonol, and glyasperin D Rotaviruses, specially G5P [7] and G8P [7] The 50% effective inhibitory concentrations (EC50) of the six compounds were 18.7–69.5 μM against G5P [7] and 14.7–88.1 μM against G8P [7] [177]
Quercetin of G. uralensis Herpes simplex virus-1 (HSV-1) Showed 50% decrease for 10 μg/ml quercetin and 90% decrease for 30 μg/ml of quercetin in plaque formation in Vero cells when incubated with infected cell lysates treated with quercetin; dose-dependently suppressed HSV-1 infection in Raw 264.7 cells [178]
Kanzonol Y Dengue virus (DENV) Exhibited anti-dengue-virus activity due to the outstanding docking properties with DENV protease, DENV RNA-dependent RNA polymerase, and DENV envelope protein [179]
Isobavachalcone Porcine reproductive and respiratory syndrome virus (PRRSV) Had potential anti-PRRSV activity and inhibited PRRSV replication at the postentry stage of PRRSV infection [180]
Antiprotozoan effects Licochalcone A Chloroquine-susceptible (3D7) and chloroquine-resistant (Ddz) strains of Plasmodium falciparum Had potent antiplasmodial efficacy against chloroquine-susceptible (3D7) and chloroquine-resistant (Ddz) strains of Plasmodium falciparum in vitro [181]

5.2. Mechanism Underlying Antimicrobial Action

In terms of mechanism, glabrol rapidly disrupted the proton movie force and membrane permeability of S. aureus possibly through binding to peptidoglycan, phosphatidylglycerol, and cardiolipin [161]. The flavonoid-rich extract of G. glabra inhibited Helicobacter pylori by downregulating DNA gyrase, dihydrofolate reductase, and protein synthesis [167]. The virulence of Acinetobacter baumannii was attenuated by the flavonoid-rich quorum quenching fraction of G. glabra via downregulation of autoinducer synthase and abaI expression [168]. Besides, liquiritin induced autophagy, apoptosis, and reduction of intracellular Ca2+ content of Phytophthora capsici and inhibited P. capsici pathogenicity via reducing PcCRN4 and Pc76RTF expressions as well as stimulating the plant defense which was reflected in the activated transcriptional expression of defense-related genes CaPR1, CaDEF1, and CaSAR82 and the increased antioxidant enzyme activity [175].

The G. inflata-derived chalcones inactivated the influenza A virus by inhibiting neuraminidase A [176]. Licocoumarone, licoflavonol, glyasperin D, and 2′-methoxyisoliquiritigenin exhibited antirotavirus activity, especially against G5P [7] and G8P [7] by suppressing both viral absorption and replication [177]. HSV-1 infection was suppressed by the quercetins extracted from G. uralensis via the inhibition of TLR-3, the inflammatory transcriptional factor NF-κB, and interferon regulatory factor 3 (IRF3) [178].

Additionally, licochalcone A induced the death of adult Schistosoma mansoni by blocking superoxide dismutase activity, which increased the production of superoxide and other free radicals that directly damaged the worm tegument and membranes [163].

6. Antidiabetic Effect

6.1. Effect on Diabetes and Its Complications

Diabetes is a metabolic disease characterized by high blood sugar levels over a prolonged period. Clinical studies show that diabetes increases the risk of several complications such as renal damage, cataract, glaucoma, neuropathy, ischemic stroke, and gangrene among others. Many researchers have turned to discovering new drugs from natural products or traditional Chinese medicine owing to the specific toxic side effects of medications and insulin resistance [9].

Licorice flavonoids have shown significant antidiabetic effects. For instance, the ethanol extract of G. glabra can alleviate chronic hyperglycemia and diabetic nephropathy; in addition, the ethanol extract of G. uralensis inhibited the activity of liver microsomal diacylglycerol acyltransferase in obese and diabetic rats, and that of G. inflata was effective against diabetic nephropathy and diabetes-related vascular complications and endothelial dysfunction [182]. The flavonoid oil and ethanol extracts of licorice showed hypoglycemic and abdominal lipid-lowering effects in obese diabetic KK-Ay mice, which is clinically significant, since type 2 diabetes, hyperglycemia, obesity, and abdominal adiposity always develop simultaneously [183]. Moreover, licorice flavonoid oil exhibited therapeutic effects against diabetes and hyperglycemia in the KK-Ay mice by regulating glucose metabolism through AMPK pathway and the insulin levels in skeletal muscle [184]. In addition, licochalcone E promoted blood glucose elimination in hyperglycemic zebrafish, which restored calcium metabolism and impeded the generation of advanced glycation end-products (AGEs) [185]. Other studies on the antidiabetic effects of licorice flavonoids and their active components are summarized in Table 6.

Table 6.

The antihyperglycemic effects of licorice flavonoids.

Compounds Dose and administration Result References
Isoangustone A 1–20 mmol/L incubated with human renal mesangial cells (HRMC) for three days High glucose-inflammatory mesangial hyperplasia and matrix dilation were retarded by the accumulation of type IV collagen, and diabetes-related renal inflammation was reduced by attenuating inflammatory ICAM-1 expression and monocyte chemotactic protein-1 (MCP-1) production in the mesangium [186]
Isoliquiritigenin 1–20 μM incubated with HRMC for 3 days Prevented mesangial fibrosis and glomerulosclerosis generating into renal failure and end-stage renal diseases through diminishing high glucose-related mesangial matrix accumulation [187]
Glabridin 3T3‐L1 adipocytes incubated with 5–20 μM of glabridin 1 hour before 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD, 10 nM) challenge for 3 days Restored TCDD-descended insulin‐stimulated glucose uptake and production of glucose transporter 4 (GLUT4) and insulin receptor substrate 1 (IRS1) [188]
Isoliquiritigenin 20 mg/kg/day to diabetic rats for 8 weeks Ameliorated diabetes-induced retinal injury in STZ-induced diabetic rats [150]
Liquiritigenin 4–16 mg/kg liquiritigenin-treated mice after fructose feeding Reduced fructose-diet-induced lipid accumulation and cardiac fibrosis that exerted protective response in high-fructose-diet-triggered cardiac injury [189]

6.2. Antidiabetic Mechanism

Protein tyrosine phosphatase 1B (PTP1B), a major negative regulator of the insulin-signaling cascade, is a promising therapeutic target for diabetes. Licorice flavonoids, including glycybenzofuran, licocoumarone, glycyrrhisoflavone, glisoflavone, isoliquiritigenin, licoflavone A, apigenin, glycycoumarin, and isoglycycoumarin [190], inhibited PTP1B activity with varying affinities and activated the insulin-signaling pathway [191]. Isoliquiritigenin blocked mesangial proliferation and matrix deposition during diabetic nephropathy by inactivating TGF-β RI and TGF-β RII and inhibiting the downstream SMAD signaling pathway [187]. STZ-induced diabetes was also alleviated by isoliquiritigenin via attenuation of oxidative stress, inflammation, and endothelial damage, downregulation of miR-195, restoration of retinal SIRT-1 levels, and tissue structure [150]. In addition, liquiritigenin significantly decreased high-fructose-diet-stimulated cardiac injury by mitigating tissue inflammation and fibrosis via suppression of the NF-κB signaling pathway [189].

7. Treatment of Gastrointestinal Diseases

7.1. Gastrointestinal Protective Effect

The gastrointestinal tract of almost 50% of the global population is colonized by H. pylori, which is one of the most frequent causes of peptic ulcers [192]. Flavonoids of Glycyrrhiza, including licochalcone A (G. inflata), glabridin and glabrene (G. glabra), licoricidin, and licoisoflavone B (G. uralensis), inhibited the growth of H. pylori in vitro [193]. GutGard®, a flavonoid-rich fraction of G. glabra, inhibited H. pylori growth as per the microbroth dilution and agar dilution methods, with glabridin exhibiting the potent antibacterial effect [167]. Another study showed a special licorice extract (s-lico) that lowered the content of glycyrrhizin while enhancing the ratio of licochalcone A significantly inhibited H. pylori-induced gastritis as well tumorigenesis in vivo [194]. Apart from H. pylori infection, nonsteroid anti-inflammatory drugs (NSAIDs) abuse, irregular diet, excessive alcohol consumption, and smoking may also induce gastric or duodenal ulcers [192]. The hydroalcoholic extract of G. glabra significantly ameliorated HCL/ethanol-induced ulcer and also exerted a therapeutic effect on ulcers caused by indomethacin [195]. Isoliquiritigenin inhibited the occurrence of indomethacin-stimulated gastric ulcers through a favorable stomach distribution, ameliorated the gastric and hemorrhagic lesion sizes, and increased gastric mucus secretion as indicated by stronger Alcian blue staining intensity [196].

Both glabridin and licochalcone A have demonstrated therapeutic effects against inflammatory bowel disease (IBD). Gladridin mitigated the inflammation and colon damage in DSS-induced ulcerative colitis and improved hypertrophy and edema in the serosa and muscularis with lymphoid follicles hyperplasia [53]. Moreover, licochalcone A effectively alleviated colitis induced by DSS by reducing colon length, MPO activity, proinflammatory cytokine levels, and oxidative stress [197].

7.2. Gastrointestinal Protective Mechanism

The therapeutic effects of licorice flavonoids against gastric ulcer or gastritis induced by H. pylori may relate to restrain 35S methionine incorporating into H. pylori ATCC 700392 strain and inhibition of DNA gyrase and dihydrofolate reductase [167]. In addition, licorice flavonoids reversed the expressions of iNOS, COX-2, IL-8, and VEGF increased by H. pylori infection and significantly improved H. pylori- or hypoxia-induced angiogenesis [194]. Licorice flavonoids also alleviated NSAIDs- or chemical-induced gastric damage by regulating the content of small molecules metabolites like arachidonic acid, histamine, sphingosine-1-phosphate (S1P), tryptophan, and so forth, which mitigated inflammation and amino acid metabolism and increased gastric mucosal defensive factors [17, 195, 196]. Furthermore, glabridin reduced TNF-α levels and the expressions of iNOS and MPO genes in the colon tissues in a rat model of colitis, which was accompanied by a decrease in NO and an increase in cAMP levels [53]. Licochalcone A alleviated DSS-induced ulcerative colitis by restoring the expression levels of IκB kinase α (IKKα), p65 NF-κB, and p-IκB, upregulating γ-glutamyl cysteine ligase (GCL), Nrf2, and HO-1, and downregulating Kelch-like ECH-associated protein 1 (Keap1) in the colonic tissues [197].

8. Effect on Skin Disorders

8.1. Skin Protective Effect

Cho et al. found that topical application of licochalcone E decreased ear edema and thickness, epidermal detachment, and focal microabscesses in the oxazolone-induced chronic dermatitis mouse model in a dose-dependent manner. Mechanistically, licochalcone E decreased the expression of IL-12p40 and IFN-γ in the affected mice, which mitigated other symptoms of inflammation as well [62]. Atopic dermatitis (AD) is a common chronic inflammatory skin disorder that is currently treated with steroids, which have severe side effects in most of the patients. Isoliquiritigenin ameliorated AD-like symptoms in a mouse model, reduced scratching behavior and the severity of skin lesions [40], and can be considered as a safer alternative to steroid therapy. Furthermore, Wu et al. have reported that isoliquiritigenin ameliorated the inflammatory process in various psoriasis models, including VEGF transgenic mouse, the imiquimod-induced psoriasis-like mouse, and the human keratinocytes HaCaT and NHEK cell [57].

The therapeutic effects of topically applied licorice flavonoids on sensitive skin or inflammatory dermatosis have been demonstrated in recent clinical trials [198, 199]. The incorporation of licochalcone A in the skin care regimens was well tolerated by the sensitive skin of rosacea patients. After 8 weeks of treatment, redness was significantly reduced and other signs of rosacea were also neutralized. A randomized, prospective, investigator-blinded study showed that a moisturizer formulation containing licochalcone A improved facial dermatitis, erythema, and skin hydration compared to 0.02% triamcinolone acetonide [200].

Tyrosinase is a kind of oxidase, which is the rate-limiting enzyme that controls the production of melanin in human body. Once melanin overproduces, it will lead to a variety of skin diseases [201]. Licorice flavonoid is a natural skin-lighting agent, especially the component glabridin which is regarded as the “whitening gold,” and it exhibited reversibly inhibition of tyrosinase in a noncompetitive manner by a multiphase kinetic process with IC50 of 0.43 μmol/L; besides, it bound to tyrosinase with a static process and a stable complex of glabridin-tyrosinase may be generated [201]. In general, glabridin is consumed as a constituent of licorice extract; for instance, glabridin-40, one of glabridin-rich licorice extracts, is widely applied in cosmetic products as a skin-whitening and is used as an antioxidant and anti-inflammatory agent [202].

8.2. Skin Protective Mechanism

Licochalcone E improved inflammatory skin disorders by inhibiting NF-κB activation and nuclear translocation through IκBα dephosphorylation [62]. Furthermore, licochalcone E exhibited anti-inflammatory effects on mouse skin and murine macrophages by suppressing AP-1 and NF-κB transcriptional activity, inactivation of AKT and MAPK, and downregulation of iNOS, COX-2, and proinflammatory cytokines [203]. Isoliquiritigenin ameliorated DNCB-stimulated atopic dermatitis through decreasing Th2 and IgE cytokines, inhibiting proinflammatory cytokines, eliminating p38-α and ERK activation, and upregulating CD54 and CD86 in human monocyte model THP-1 [40]. Isoliquiritigenin suppressed psoriasis-like symptoms through the inhibition of NF-κB activity which consequently led to the less expressions of proinflammation cytokines IL-6 and IL-8 [57]. The skin-lighting mechanism of glabridin has been deduced by molecular docking experiment where glabridin may interact between the hydroxyl group of glabridin and the active site residues (mainly His-85) attributing to a type of stereospecific blockade effect or deformation of the catalytic core domain, which resulted in suppressing the oxidant activity of tyrosinase to substrate L-3,4-dihydroxyphenylalanine (L-DOPA) [201].

9. Effect on Obesity

9.1. Antiobesity Effect

Obesity is characterized by the excess accumulation of lipid metabolites in adipose and nonadipose tissues [204] and is currently a pressing health issue worldwide due to its association with a high risk of cardiovascular diseases, type 2 diabetes, hypertension, and cancer [205]. Glabridin reduced the body weight of obese mice by decreasing food intake and increasing energy expenditure [206]. In addition, licorice flavonoid oil prevented and regulated diet-induced obesity and total body fat in human subjects by restoring the expression levels of the related lipid metabolism [207]. White adipose tissues are energy depots, whereas brown adipose tissues convert energy to heat via thermogenesis and improve triglyceride clearance and glucose metabolism [208, 209]. Inducible brown adipocytes can be developed in white adipose tissues through the browning process, which is a viable strategy for treating obesity and its complications [210]. Licochalcone E has demonstrated an inhibitory effect in early adipogenesis, as indicated by enhanced adipocyte differentiation, reduction in adipocyte size, and increased population of small adipocytes in white adipose tissues [211].

9.2. Antiobesity Mechanism

Glabridin inhibited the expression of lipogenic genes such as fatty acid synthase (FAS), sterol regulatory element-binding protein-1c (SREBP-1c), stearoyl-CoA desaturase-1 (SCD-1), and acetyl-CoA carboxylase (ACC) in the white adipose tissues and liver of several animal models of obesity and upregulated fatty acid oxidation genes in the muscle, eventually leading to a decrease in body weight and fat cell size through AMPK activation [206]. Licochalcone E upregulated PPARγ by activating the AKT pathway and facilitated adipocyte differentiation and increased the number of small adipocytes, thereby ameliorating hyperglycemia and hyperlipidemia under diabetic conditions [211]. Licochalcone A activated the sirt-1/AMPK pathway to enhance lipolysis and β-oxidation and reduce fatty acid chain synthesis [210]. Moreover, it upregulated the expression of brown fat markers including PR domain containing 16 (PRDM16), uncoupling protein 1 (UCP1), and PPARγ coactivator-1 (PGC-1α), which reduced obesity and restored metabolic homeostasis by altering brown fat phenotype [212].

10. Conclusion

Licorice is the most frequently prescribed herbal medicine in China, and it consists of abundant flavonoid components with a multitude of pharmacological effects. In recent years, licorice flavonoids have been isolated and characterized, and the mechanisms underlying their pharmacological effects have been elucidated. The therapeutic effects of licorice flavonoids against gastrointestinal and skin diseases have even been clinically tested. Other biological properties of licorice flavonoids including the antiviral, antibacterial, antidiabetic, antiasthma, and anticancer effects have been demonstrated at the cellular and animal level and need to be validated in clinical trials. Furthermore, the molecular mechanisms underlying the pharmacological action of licorice flavonoids need to be lucubrated due to the complex interaction between diverse components and organisms. In this review, the pharmacological properties of licorice flavonoids in various pathological conditions and the possible mechanisms of action were detailly summarized. The article expands the application of licorice flavonoids, which provides a preference for further research on material basis, bioactivity, and mechanism of licorice flavonoids in the future.

Contributor Information

Hongxia Zhu, Email: gzzhx2012@163.com.

Qiang Liu, Email: liuqiang@smu.edu.cn.

Conflicts of Interest

The authors declare that there are no conflicts of interest.

References

  • 1.Zhao Y., Lv B., Feng X., Li C. Perspective on biotransformation and de novo biosynthesis of licorice constituents. Journal of Agricultural and Food Chemistry . 2017;65(51):11147–11156. doi: 10.1021/acs.jafc.7b04470. [DOI] [PubMed] [Google Scholar]
  • 2.Cheng M. Z., Zhang J. Q., Yang L., et al. Recent advances in chemical analysis of licorice (Gan-Cao) Fitoterapia . 2020;149 doi: 10.1016/j.fitote.2020.104803.104803 [DOI] [PubMed] [Google Scholar]
  • 3.Kao T.-C., Wu C.-H., Yen G.-C. Bioactivity and potential health benefits of licorice. Journal of Agricultural and Food Chemistry . 2014;62(3):542–553. doi: 10.1021/jf404939f. [DOI] [PubMed] [Google Scholar]
  • 4.Harding V., Stebbing J. Liquorice: a treatment for all sorts? The Lancet Oncology . 2017;18(9):p. 1155. doi: 10.1016/s1470-2045(17)30628-9. [DOI] [PubMed] [Google Scholar]
  • 5.Wang Z., Zhao X., Zu Y., et al. Licorice flavonoids nanoparticles prepared by liquid antisolvent re-crystallization exhibit higher oral bioavailability and antioxidant activity in rat. Journal of Functional Foods . 2019;57:190–201. doi: 10.1016/j.jff.2019.04.010. [DOI] [Google Scholar]
  • 6.Wang L., Yang R., Yuan B., Liu Y., Liu C. The antiviral and antimicrobial activities of licorice, a widely-used Chinese herb. Acta Pharmaceutica Sinica B . 2015;5(4):310–315. doi: 10.1016/j.apsb.2015.05.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Yang F., Chu T., Zhang Y., Liu X., Sun G., Chen Z. Quality assessment of licorice (Glycyrrhiza glabra L.) from different sources by multiple fingerprint profiles combined with quantitative analysis, antioxidant activity and chemometric methods. Food Chemistry . 2020;324 doi: 10.1016/j.foodchem.2020.126854.126854 [DOI] [PubMed] [Google Scholar]
  • 8.Wang C., Chen L., Xu C., et al. A comprehensive review for phytochemical, pharmacological, and biosynthesis studies on Glycyrrhiza spp. The American journal of Chinese medicine . 2020;48(1):17–45. doi: 10.1142/S0192415X20500020. [DOI] [PubMed] [Google Scholar]
  • 9.Bai L., Li X., He L., et al. Antidiabetic potential of flavonoids from traditional Chinese medicine: a review. The American Journal of Chinese Medicine . 2019;47(5):933–957. doi: 10.1142/s0192415x19500496. [DOI] [PubMed] [Google Scholar]
  • 10.Badshah S. L., Faisal S., Muhammad A., Poulson B. G., Emwas A. H., Jaremko M. Antiviral activities of flavonoids. Biomedicine & Pharmacotherapy . 2021;140 doi: 10.1016/j.biopha.2021.111596.111596 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Guo Z., Niu X., Xiao T., Lu J., Li W., Zhao Y. Chemical profile and inhibition of α-glycosidase and protein tyrosine phosphatase 1B (PTP1B) activities by flavonoids from licorice (Glycyrrhiza uralensis Fisch) Journal of Functional Foods . 2015;14:324–336. doi: 10.1016/j.jff.2014.12.003. [DOI] [Google Scholar]
  • 12.Hou X., Yang S., Zheng Y. Licochalcone A attenuates abdominal aortic aneurysm induced by angiotensin II via regulating the miR‐181b/SIRT1/HO‐1 signaling. Journal of Cellular Physiology . 2019;234(5):7560–7568. doi: 10.1002/jcp.27517. [DOI] [PubMed] [Google Scholar]
  • 13.Oh H.-N., Lee M.-H., Kim E., Yoon G., Chae J.-I., Shim J.-H. Licochalcone B inhibits growth and induces apoptosis of human non-small-cell lung cancer cells by dual targeting of EGFR and MET. Phytomedicine . 2019;63 doi: 10.1016/j.phymed.2019.153014.153014 [DOI] [PubMed] [Google Scholar]
  • 14.Chirumbolo S. Commentary: the antiviral and antimicrobial activities of licorice, a widely-used Chinese herb. Frontiers in Microbiology . 2016;7:p. 531. doi: 10.3389/fmicb.2016.00531. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Ahmad N., Badshah S. L., Junaid M., Ur Rehman A., Muhammad A., Khan K. Structural insights into the zika virus NS1 protein inhibition using a computational approach. Journal of Biomolecular Structure and Dynamics . 2021;39(8):3004–3011. doi: 10.1080/07391102.2020.1759453. [DOI] [PubMed] [Google Scholar]
  • 16.Shahid F., Noreen, Ali R., et al. Identification of potential HCV inhibitors based on the interaction of epigallocatechin-3-gallate with viral envelope proteins. Molecules (Basel, Switzerland) . 2021;26(5):p. 1257. doi: 10.3390/molecules26051257. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Yang Y., Wang S., Bao Y.-r., et al. Anti-ulcer effect and potential mechanism of licoflavone by regulating inflammation mediators and amino acid metabolism. Journal of Ethnopharmacology . 2017;199:175–182. doi: 10.1016/j.jep.2017.01.053. [DOI] [PubMed] [Google Scholar]
  • 18.Kim J.-K., Shin E. K., Park J. H., Kim Y. H., Park J. H. Y. Antitumor and antimetastatic effects of licochalcone a in mouse models. Journal of Molecular Medicine . 2010;88(8):829–838. doi: 10.1007/s00109-010-0625-2. [DOI] [PubMed] [Google Scholar]
  • 19.Ahmed S. M. U., Luo L., Namani A., Wang X. J., Tang X. Nrf2 signaling pathway: pivotal roles in inflammation. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease . 2017;1863(2):585–597. doi: 10.1016/j.bbadis.2016.11.005. [DOI] [PubMed] [Google Scholar]
  • 20.Dinarello C. A. Anti-inflammatory agents: present and future. Cell . 2010;140(6):935–950. doi: 10.1016/j.cell.2010.02.043. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Dinarello C. A. Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. Blood . 2011;117(14):3720–3732. doi: 10.1182/blood-2010-07-273417. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Kongkatitham V., Muangnoi C., Kyokong N., et al. Anti-oxidant and anti-inflammatory effects of new bibenzyl derivatives from Dendrobium parishii in hydrogen peroxide and lipopolysaccharide treated RAW264.7 cells. Phytochemistry Letters . 2018;24:31–38. doi: 10.1016/j.phytol.2018.01.006. [DOI] [Google Scholar]
  • 23.Kumar A., Takada Y., Boriek A. M., Aggarwal B. B. Nuclear factor-κB: its role in health and disease. Journal of Molecular Medicine . 2004;82:434–448. doi: 10.1007/s00109-004-0555-y. [DOI] [PubMed] [Google Scholar]
  • 24.Lawrence T. The nuclear factor NF- κB pathway in inflammation. Cold Spring Harbor Perspectives in Biology . 2009;1(6) doi: 10.1101/cshperspect.a001651.a1651 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Gao Q., Liang X., Shaikh A. S., Zang J., Xu W., Zhang Y. JAK/STAT signal transduction: promising attractive targets for immune, inflammatory and hematopoietic diseases. Current Drug Targets . 2018;19(5):487–500. doi: 10.2174/1389450117666161207163054. [DOI] [PubMed] [Google Scholar]
  • 26.Mohan S., Gupta D. Crosstalk of toll-like receptors signaling and Nrf2 pathway for regulation of inflammation. Biomedicine & Pharmacotherapy . 2018;108:1866–1878. doi: 10.1016/j.biopha.2018.10.019. [DOI] [PubMed] [Google Scholar]
  • 27.Muhammad A., Khan B., Iqbal Z., et al. Viscosine as a potent and safe antipyretic agent evaluated by yeast-induced pyrexia model and molecular docking studies. ACS Omega . 2019;4(10):14188–14192. doi: 10.1021/acsomega.9b01041. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Yinghe D., Xiaoqin L., Juan Z., Wei Y., Jingquan Y. Research progress of anti-inflammatory effect and mechanism of licorice flavonoid. Jiangxi Journal of Traditional Chinese Medicine . 2017;48(2):68–71. [Google Scholar]
  • 29.Yin L., Guan E., Zhang Y., et al. Chemical profile and anti-inflammatory activity of total flavonoids from Glycyrrhiza uralensis Fisch. Iranian Journal of Pharmaceutical Research . 2018;17(2):726–734. [PMC free article] [PubMed] [Google Scholar]
  • 30.Xie Y.-C., Dong X.-W., Wu X.-M., Yan X.-F., Xie Q.-M. Inhibitory effects of flavonoids extracted from licorice on lipopolysaccharide-induced acute pulmonary inflammation in mice. International Immunopharmacology . 2009;9(2):194–200. doi: 10.1016/j.intimp.2008.11.004. [DOI] [PubMed] [Google Scholar]
  • 31.Yang R., Yuan B.-C., Ma Y.-S., Zhou S., Liu Y. The anti-inflammatory activity of licorice, a widely used Chinese herb. Pharmaceutical Biology . 2017;55(1):5–18. doi: 10.1080/13880209.2016.1225775. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Fu Y., Chen J., Li Y.-J., Zheng Y.-F., Li P. Antioxidant and anti-inflammatory activities of six flavonoids separated from licorice. Food Chemistry . 2013;141(2):1063–1071. doi: 10.1016/j.foodchem.2013.03.089. [DOI] [PubMed] [Google Scholar]
  • 33.Honda H., Nagai Y., Matsunaga T., et al. Isoliquiritigenin is a potent inhibitor of NLRP3 inflammasome activation and diet‐induced adipose tissue inflammation. Journal of Leukocyte Biology . 2014;96(6):1087–1100. doi: 10.1189/jlb.3a0114-005rr. [DOI] [PubMed] [Google Scholar]
  • 34.Yehuda I., Madar Z., Leikin-Frenkel A., Tamir S. Glabridin, an isoflavan from licorice root, downregulates iNOS expression and activity under high-glucose stress and inflammation. Molecular Nutrition & Food Research . 2015;59(6):1041–1052. doi: 10.1002/mnfr.201400876. [DOI] [PubMed] [Google Scholar]
  • 35.Chu X., Ci X., Wei M., et al. Licochalcone a inhibits lipopolysaccharide-induced inflammatory response in vitro and in vivo. Journal of Agricultural and Food Chemistry . 2012;60(15):3947–3954. doi: 10.1021/jf2051587. [DOI] [PubMed] [Google Scholar]
  • 36.Furuhashi I., Iwata S., Shibata S., Sato T., Inoue H. Inhibition by licochalcone A, a novel flavonoid isolated from liquorice root, of IL-1b-induced PGE2 production in human skin fibroblasts. Pharmacy and Pharmacology . 2005;57:1661–1666. doi: 10.1211/jpp.57.12.0017. [DOI] [PubMed] [Google Scholar]
  • 37.Jia T., Qiao J., Guan D., Chen T. Anti-inflammatory effects of licochalcone A on IL-1β-stimulated human osteoarthritis chondrocytes. Inflammation . 2017;40(6):1894–1902. doi: 10.1007/s10753-017-0630-5. [DOI] [PubMed] [Google Scholar]
  • 38.Franceschelli S., Pesce M., Vinciguerra I., et al. Licocalchone-C extracted from Glycyrrhiza glabra inhibits lipopolysaccharide-interferon-γ inflammation by improving antioxidant conditions and regulating inducible nitric oxide synthase expression. Molecules . 2011;16(7):5720–5734. doi: 10.3390/molecules16075720. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Thiyagarajan P., Chandrasekaran C. V., Deepak H. B., Agarwal A. Modulation of lipopolysaccharide-induced pro-inflammatory mediators by an extract of Glycyrrhiza glabra and its phytoconstituents. Inflammopharmacology . 2011;19(4):235–241. doi: 10.1007/s10787-011-0080-x. [DOI] [PubMed] [Google Scholar]
  • 40.Yu H., Li H., Li Y., Li M., Chen G. Effect of isoliquiritigenin for the treatment of atopic dermatitis-like skin lesions in mice. Archives of Dermatological Research . 2017;309(10):805–813. doi: 10.1007/s00403-017-1787-3. [DOI] [PubMed] [Google Scholar]
  • 41.Li P., Li Y., Jiang H., et al. Glabridin, an isoflavan from licorice root, ameliorates imiquimod-induced psoriasis-like inflammation of BALB/c mice. International Immunopharmacology . 2018;59:243–251. doi: 10.1016/j.intimp.2018.04.018. [DOI] [PubMed] [Google Scholar]
  • 42.Choi E.-M. The licorice root derived isoflavan glabridin increases the function of osteoblastic mc3t3-E1 cells. Biochemical Pharmacology . 2005;70(3):363–368. doi: 10.1016/j.bcp.2005.04.019. [DOI] [PubMed] [Google Scholar]
  • 43.Yu J.-Y., Ha J., Kim K.-M., Jung Y.-S., Jung J.-C., Oh S. Anti-inflammatory activities of licorice extract and its active compounds, glycyrrhizic acid, liquiritin and liquiritigenin, in BV2 cells and mice liver. Molecules . 2015;20(7):13041–13054. doi: 10.3390/molecules200713041. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Tu C., Ma Y., Song M., Yan J., Xiao Y., Wu H. Liquiritigenin inhibits IL-1β-induced inflammation and cartilage matrix degradation in rat chondrocytes. European Journal of Pharmacology . 2019;858 doi: 10.1016/j.ejphar.2019.172445.172445 [DOI] [PubMed] [Google Scholar]
  • 45.La V. D., Tanabe S.-i., Bergeron C., Gafner S., Grenier D. Modulation of matrix metalloproteinase and cytokine production by licorice isolates licoricidin and licorisoflavan a: potential therapeutic approach for periodontitis. Journal of Periodontology . 2011;82(1):122–128. doi: 10.1902/jop.2010.100342. [DOI] [PubMed] [Google Scholar]
  • 46.Huo X., Liu D., Gao L., Li L., Cao L. Flavonoids extracted from licorice prevents colitis-associated carcinogenesis in AOM/DSS mouse model. International Journal of Molecular Sciences . 2016;17(9) doi: 10.3390/ijms17091343. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Wei M., Ma Y., Liu Y., et al. Urinary metabolomics study on the anti-inflammation effects of flavonoids obtained from Glycyrrhiza. Journal of Chromatography B . 2018;1086:1–10. doi: 10.1016/j.jchromb.2018.04.007. [DOI] [PubMed] [Google Scholar]
  • 48.Hu J., Liu J. Licochalcone A attenuates lipopolysaccharide-induced acute kidney injury by inhibiting NF-κB activation. Inflammation . 2016;39(2):569–574. doi: 10.1007/s10753-015-0281-3. [DOI] [PubMed] [Google Scholar]
  • 49.Chu X., Jiang L., Wei M., et al. Attenuation of allergic airway inflammation in a murine model of asthma by licochalcone a. Immunopharmacology and Immunotoxicology . 2013;35(6):653–661. doi: 10.3109/08923973.2013.834929. [DOI] [PubMed] [Google Scholar]
  • 50.Zhang W., Wang G., Zhou S. Protective effects of isoliquiritigenin on LPS-induced acute lung injury by activating PPAR-γ. Inflammation . 2018;41(4):1290–1296. doi: 10.1007/s10753-018-0777-8. [DOI] [PubMed] [Google Scholar]
  • 51.Zhu X., Liu J., Huang S., et al. Neuroprotective effects of isoliquiritigenin against cognitive impairment via suppression of synaptic dysfunction, neuronal injury, and neuroinflammation in rats with kainic acid-induced seizures. International Immunopharmacology . 2019;72:358–366. doi: 10.1016/j.intimp.2019.04.028. [DOI] [PubMed] [Google Scholar]
  • 52.Nakamura S., Watanabe T., Tanigawa T., et al. Isoliquiritigenin ameliorates indomethacin-induced small intestinal damage by inhibiting NOD-like receptor family, pyrin domain-containing 3 inflammasome activation. Pharmacology . 2018;101(5-6):236–245. doi: 10.1159/000486599. [DOI] [PubMed] [Google Scholar]
  • 53.El-Ashmawy N. E., Khedr N. F., El-Bahrawy H. A., El-Adawy S. A. Downregulation of iNOS and elevation of cAMP mediate the anti-inflammatory effect of glabridin in rats with ulcerative colitis. Inflammopharmacology . 2018;26(2):551–559. doi: 10.1007/s10787-017-0373-9. [DOI] [PubMed] [Google Scholar]
  • 54.Kwon H.-S., Park J. H., Kim D. H., et al. Licochalcone a isolated from licorice suppresses lipopolysaccharide-stimulated inflammatory reactions in RAW264.7 cells and endotoxin shock in mice. Journal of Molecular Medicine . 2008;86(11):1287–1295. doi: 10.1007/s00109-008-0395-2. [DOI] [PubMed] [Google Scholar]
  • 55.Vane J. R., Botting R. M. New insights into the mode of action of anti-inflammatory drugs. Inflammation Research . 1995;44(1):1–10. doi: 10.1007/bf01630479. [DOI] [PubMed] [Google Scholar]
  • 56.Tak P. P., Firestein G. S. NF-κB: a key role in inflammatory diseases. Journal of Clinical Investigation . 2001;107(1):7–11. doi: 10.1172/jci11830. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Wu Y., Chen X., Ge X., et al. Isoliquiritigenin prevents the progression of psoriasis-like symptoms by inhibiting NF-κB and proinflammatory cytokines. Journal of Molecular Medicine . 2016;94(2):195–206. doi: 10.1007/s00109-015-1338-3. [DOI] [PubMed] [Google Scholar]
  • 58.Liao Y., Tan R.-z., Li J.-c., et al. Isoliquiritigenin attenuates UUO-induced renal inflammation and fibrosis by inhibiting mincle/syk/NF-kappa B signaling pathway. Drug Design, Development and Therapy . 2020;14:1455–1468. doi: 10.2147/dddt.s243420. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59.Kim J.-Y., Park S. J., Yun K.-J., Cho Y.-W., Park H.-J., Lee K.-T. Isoliquiritigenin isolated from the roots of Glycyrrhiza uralensis inhibits LPS-induced iNOS and COX-2 expression via the attenuation of NF-κB in RAW 264.7 macrophages. European Journal of Pharmacology . 2008;584(1):175–184. doi: 10.1016/j.ejphar.2008.01.032. [DOI] [PubMed] [Google Scholar]
  • 60.Furusawa J.-i., Funakoshi-Tago M., Mashino T., et al. Glycyrrhiza inflata-derived chalcones, Licochalcone A, Licochalcone B and Licochalcone D, inhibit phosphorylation of NF-κB p65 in LPS signaling pathway. International Immunopharmacology . 2009;9(4):499–507. doi: 10.1016/j.intimp.2009.01.031. [DOI] [PubMed] [Google Scholar]
  • 61.Franceschelli S., Pesce M., Ferrone A., et al. Biological effect of licochalcone C on the regulation of PI3K/Akt/eNOS and NF-κB/iNOS/NO signaling pathways in H9c2 cells in response to LPS stimulation. International Journal of Molecular Sciences . 2017;18(4):p. 690. doi: 10.3390/ijms18040690. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Cho Y.-C., Lee S. H., Yoon G., et al. Licochalcone E reduces chronic allergic contact dermatitis and inhibits IL-12p40 production through down-regulation of NF-κB. International Immunopharmacology . 2010;10(9):1119–1126. doi: 10.1016/j.intimp.2010.06.015. [DOI] [PubMed] [Google Scholar]
  • 63.Su X., Li T., Liu Z., et al. Licochalcone A activates Keap1-Nrf2 signaling to suppress arthritis via phosphorylation of p62 at serine 349. Free Radical Biology and Medicine . 2018;115:471–483. doi: 10.1016/j.freeradbiomed.2017.12.004. [DOI] [PubMed] [Google Scholar]
  • 64.Yu D., Liu X., Zhang G., Ming Z., Wang T. Isoliquiritigenin inhibits cigarette smoke-induced COPD by attenuating inflammation and oxidative stress via the regulation of the Nrf2 and NF-κB signaling pathways. Frontiers in Pharmacology . 2018;9:p. 1001. doi: 10.3389/fphar.2018.01001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65.Gao Y., Lv X., Yang H., Peng L., Ci X. Isoliquiritigenin exerts antioxidative and anti-inflammatory effects via activating the KEAP-1/Nrf2 pathway and inhibiting the NF-κB and NLRP3 pathways in carrageenan-induced pleurisy. Food & Function . 2020;11(3):2522–2534. doi: 10.1039/c9fo01984g. [DOI] [PubMed] [Google Scholar]
  • 66.Wang R., Zhang C. Y., Bai L. P., et al. Flavonoids derived from liquorice suppress murine macrophage activation by up-regulating heme oxygenase-1 independent of Nrf2 activation. International Immunopharmacology . 2015;28(2):917–924. doi: 10.1016/j.intimp.2015.03.040. [DOI] [PubMed] [Google Scholar]
  • 67.Choi Y. H., Bae J.-K., Chae H.-S., et al. Isoliquiritigenin ameliorates dextran sulfate sodium-induced colitis through the inhibition of MAPK pathway. International Immunopharmacology . 2016;31:223–232. doi: 10.1016/j.intimp.2015.12.024. [DOI] [PubMed] [Google Scholar]
  • 68.Zhai K.-f., Duan H., Cui C.-y., et al. Liquiritin from Glycyrrhiza uralensis attenuating rheumatoid arthritis via reducing inflammation, suppressing angiogenesis, and inhibiting MAPK signaling pathway. Journal of Agricultural and Food Chemistry . 2019;67(10):2856–2864. doi: 10.1021/acs.jafc.9b00185. [DOI] [PubMed] [Google Scholar]
  • 69.Zhu X., Liu J., Chen O., et al. Neuroprotective and anti-inflammatory effects of isoliquiritigenin in kainic acid-induced epileptic rats via the TLR4/MYD88 signaling pathway. Inflammopharmacology . 2019;27(6):1143–1153. doi: 10.1007/s10787-019-00592-7. [DOI] [PubMed] [Google Scholar]
  • 70.Zhu L., Wei H., Wu Y., et al. Licorice isoliquiritigenin suppresses RANKL-induced osteoclastogenesis in vitro and prevents inflammatory bone loss in vivo. The International Journal of Biochemistry & Cell Biology . 2012;44(7):1139–1152. doi: 10.1016/j.biocel.2012.04.003. [DOI] [PubMed] [Google Scholar]
  • 71.Yang G., Lee H. E., Yeon S. H., et al. Licochalcone a attenuates acne symptoms mediated by suppression of NLRP3 inflammasome. Phytotherapy Research . 2018;32(12):2551–2559. doi: 10.1002/ptr.6195. [DOI] [PubMed] [Google Scholar]
  • 72.Jiang Y. X., Dai Y. Y., Pan Y. F., et al. Total flavonoids from Radix Glycyrrhiza exert anti-inflammatory and antitumorigenic effects by inactivating iNOS signaling pathways. Evidence-based Complementary and Alternative Medicine . 2018;2018:10. doi: 10.1155/2018/6714282.6714282 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73.Hausman D. M. What is Cancer? Perspectives in Biology and Medicine . 2019;62(4):778–784. doi: 10.1353/pbm.2019.0046. [DOI] [PubMed] [Google Scholar]
  • 74.Chen X., Liu Z., Meng R., Shi C., Guo N. Antioxidative and anticancer properties of licochalcone a from licorice. Journal of Ethnopharmacology . 2017;198:331–337. doi: 10.1016/j.jep.2017.01.028. [DOI] [PubMed] [Google Scholar]
  • 75.Takahashi T., Takasuka N., Iigo M., et al. Isoliquiritigenin, a flavonoid from licorice, reduces prostaglandin E2 and nitric oxide, causes apoptosis, and suppresses aberrant crypt foci development. Cancer Science . 2004;95(5):448–453. doi: 10.1111/j.1349-7006.2004.tb03230.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 76.Hsieh M.-J., Chen M.-K., Chen C.-J., et al. Glabridin induces apoptosis and autophagy through JNK1/2 pathway in human hepatoma cells. Phytomedicine . 2016;23(4):359–366. doi: 10.1016/j.phymed.2016.01.005. [DOI] [PubMed] [Google Scholar]
  • 77.Nho S. H., Yoon G., Seo J. H., et al. Licochalcone H induces the apoptosis of human oral squamous cell carcinoma cells via regulation of matrin 3. Oncology Reports . 2019;41(1):333–340. doi: 10.3892/or.2018.6784. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 78.Huang Y., Liu C., Zeng W. C., et al. Isoliquiritigenin inhibits the proliferation, migration and metastasis of Hep3B cells via suppressing cyclin D1 and PI3K/AKT pathway. Bioscience Reports . 2020;40(1) doi: 10.1042/BSR20192727. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 79.Hsieh M.-J., Lin C.-W., Yang S.-F., Chen M.-K., Chiou H.-L. Glabridin inhibits migration and invasion by transcriptional inhibition of matrix metalloproteinase 9 through modulation of NF-κB and AP-1 activity in human liver cancer cells. British Journal of Pharmacology . 2014;171(12):3037–3050. doi: 10.1111/bph.12626. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 80.Wang J., Zhang Y.-S., Thakur K., et al. Licochalcone a from licorice root, an inhibitor of human hepatoma cell growth via induction of cell apoptosis and cell cycle arrest. Food and Chemical Toxicology . 2018;120:407–417. doi: 10.1016/j.fct.2018.07.044. [DOI] [PubMed] [Google Scholar]
  • 81.Wang J., Liao A.-M., Thakur K., Zhang J.-G., Huang J.-H., Wei Z.-J. Licochalcone B extracted from Glycyrrhiza uralensis Fisch induces apoptotic effects in human hepatoma cell HepG2. Journal of Agricultural and Food Chemistry . 2019;67(12):3341–3353. doi: 10.1021/acs.jafc.9b00324. [DOI] [PubMed] [Google Scholar]
  • 82.Wang J. R., Luo Y. H., Piao X. J., et al. Mechanisms underlying isoliquiritigenin‐induced apoptosis and cell cycle arrest via ROS‐mediated MAPK/STAT3/NF‐κB pathways in human hepatocellular carcinoma cells. Drug Development Research . 2019;80(4):461–470. doi: 10.1002/ddr.21518. [DOI] [PubMed] [Google Scholar]
  • 83.Wang D., Lu J. H., Liu Y., et al. Liquiritigenin induces tumor cell death through mitogen-activated protein kinase- (MPAKs-) mediated pathway in hepatocellular carcinoma cells. BioMed Research International . 2014;2014:11. doi: 10.1155/2014/965316.965316 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 84.Zhou Y., Ho W. S. Combination of liquiritin, isoliquiritin and isoliquirigenin induce apoptotic cell death through upregulating P53 and P21 in the A549 non-small cell lung cancer cells. Oncology Reports . 2014;31(1):298–304. doi: 10.3892/or.2013.2849. [DOI] [PubMed] [Google Scholar]
  • 85.Tang Z. H., Chen X., Wang Z. Y., et al. Induction of C/EBP homologous protein-mediated apoptosis and autophagy by licochalcone a in non-small cell lung cancer cells. Scientific Reports . 2016;6(1) doi: 10.1038/srep26241. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 86.Qiu C., Zhang T., Zhang W., et al. Licochalcone a inhibits the proliferation of human lung cancer cell lines A549 and H460 by inducing G2/M cell cycle arrest and ER stress. International Journal of Molecular Sciences . 2017;18(8):p. 1761. doi: 10.3390/ijms18081761. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 87.Oh H. N., Lee M. H., Kim E., et al. Licochalcone D induces ROS-dependent apoptosis in gefitinib-sensitive or resistant lung cancer cells by targeting EGFR and MET. Biomolecules . 2020;10(2):p. 297. doi: 10.3390/biom10020297. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 88.Tsai Y.-M., Yang C.-J., Hsu Y.-L., et al. Glabridin inhibits migration, invasion, and angiogenesis of human non-small cell lung cancer A549 cells by inhibiting the FAK/rho signaling pathway. Integrative Cancer Therapies . 2017;10(4):341–349. doi: 10.1177/1534735410384860. [DOI] [PubMed] [Google Scholar]
  • 89.Oh H. N., Lee M. H., Kim E., et al. Dual inhibition of EGFR and MET by echinatin retards cell growth and induces apoptosis of lung cancer cells sensitive or resistant to gefitinib. Phytotherapy Research . 2020;34(2):388–400. doi: 10.1002/ptr.6530. [DOI] [PubMed] [Google Scholar]
  • 90.Xiao X.-y., Hao M., Yang X.-y., et al. Licochalcone a inhibits growth of gastric cancer cells by arresting cell cycle progression and inducing apoptosis. Cancer Letters . 2011;302(1):69–75. doi: 10.1016/j.canlet.2010.12.016. [DOI] [PubMed] [Google Scholar]
  • 91.Wei F., Jiang X., Gao H.-Y., Gao S.-H. Liquiritin induces apoptosis and autophagy in cisplatin (DDP)-resistant gastric cancer cells in vitro and xenograft nude mice in vivo. International Journal of Oncology . 2017;51(5):1383–1394. doi: 10.3892/ijo.2017.4134. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 92.Zhang X. R., Wang S. Y., Sun W., Wei C. Isoliquiritigenin inhibits proliferation and metastasis of MKN28 gastric cancer cells by suppressing the PI3K/AKT/mTOR signaling pathway. Molecular Medicine Reports . 2018;18(3):3429–3436. doi: 10.3892/mmr.2018.9318. [DOI] [PubMed] [Google Scholar]
  • 93.Lee N., Kim D. Cancer metabolism: fueling more than just growth. Molecules and Cells . 2016;39(12):847–854. doi: 10.14348/molcells.2016.0310. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 94.Doherty J. R., Cleveland J. L. Targeting lactate metabolism for cancer therapeutics. Journal of Clinical Investigation . 2013;123(9):3685–3692. doi: 10.1172/jci69741. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 95.Wu J., Zhang X., Wang Y., et al. Licochalcone a suppresses hexokinase 2-mediated tumor glycolysis in gastric cancer via downregulation of the Akt signaling pathway. Oncology Reports . 2018;39(3):1181–1190. doi: 10.3892/or.2017.6155. [DOI] [PubMed] [Google Scholar]
  • 96.Hao W., Yuan X., Yu L., et al. Licochalcone A-induced human gastric cancer BGC-823 cells apoptosis by regulating ROS-mediated MAPKs and PI3K/AKT signaling pathways. Scientific Reports . 2015;5(1) doi: 10.1038/srep10336.10336 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 97.Xie R., Gao C.-c., Yang X.-z., et al. Combining TRAIL and liquiritin exerts synergistic effects against human gastric cancer cells and xenograft in nude mice through potentiating apoptosis and ROS generation. Biomedicine & Pharmacotherapy . 2017;93:948–960. doi: 10.1016/j.biopha.2017.06.095. [DOI] [PubMed] [Google Scholar]
  • 98.White D. E., Muller W. J. Multifaceted roles of integrins in breast cancer metastasis. Journal of Mammary Gland Biology and Neoplasia . 2007;12(2-3):135–142. doi: 10.1007/s10911-007-9045-5. [DOI] [PubMed] [Google Scholar]
  • 99.Ye L., Gho W. M., Chan F. L., Chen S., Leung L. K. Dietary administration of the licorice flavonoid isoliquiritigenin deters the growth of MCF-7 cells overexpressing aromatase. International Journal of Cancer . 2009;124(5):1028–1036. doi: 10.1002/ijc.24046. [DOI] [PubMed] [Google Scholar]
  • 100.Kang T. H., Seo J. H., Oh H., Yoon G., Chae J. I., Shim J. H. Licochalcone a suppresses specificity protein 1 as a novel target in human breast cancer cells. Journal of Cellular Biochemistry . 2017;118(12):4652–4663. doi: 10.1002/jcb.26131. [DOI] [PubMed] [Google Scholar]
  • 101.Kwon S. J., Park S. Y., Kwon G. T., et al. Licochalcone E present in licorice suppresses lung metastasis in the 4T1 mammary orthotopic cancer model. Cancer Prevention Research . 2013;6(6):603–613. doi: 10.1158/1940-6207.capr-13-0012. [DOI] [PubMed] [Google Scholar]
  • 102.Li Y., Zhao H., Wang Y., et al. Isoliquiritigenin induces growth inhibition and apoptosis through downregulating arachidonic acid metabolic network and the deactivation of PI3K/Akt in human breast cancer. Toxicology and Applied Pharmacology . 2013;272(1):37–48. doi: 10.1016/j.taap.2013.05.031. [DOI] [PubMed] [Google Scholar]
  • 103.Wang K.-L., Hsia S.-M., Chan C.-J., et al. Inhibitory effects of isoliquiritigenin on the migration and invasion of human breast cancer cells. Expert Opinion on Therapeutic Targets . 2013;17(4):337–349. doi: 10.1517/14728222.2013.756869. [DOI] [PubMed] [Google Scholar]
  • 104.Jiang F., Li Y., Mu J., et al. Glabridin inhibits cancer stem cell-like properties of human breast cancer cells: an epigenetic regulation of miR-148a/SMAd2 signaling. Molecular Carcinogenesis . 2016;55(5):929–940. doi: 10.1002/mc.22333. [DOI] [PubMed] [Google Scholar]
  • 105.Huang W.-C., Su H.-H., Fang L.-W., Wu S.-J., Liou C.-J. Licochalcone a inhibits cellular motility by suppressing E-cadherin and MAPK signaling in breast cancer. Cells . 2019;8(3):p. 218. doi: 10.3390/cells8030218. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 106.Kwak A.-W., Choi J.-S., Lee M.-H., et al. Retrochalcone echinatin triggers apoptosis of esophageal squamous cell carcinoma via ROS- and ER stress-mediated signaling pathways. Molecules . 2019;24(22):p. 4055. doi: 10.3390/molecules24224055. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 107.Oh H. N., Seo J. H., Lee M. H., et al. Licochalcone C induced apoptosis in human oral squamous cell carcinoma cells by regulation of the JAK2/STAT3 signaling pathway. Journal of Cellular Biochemistry . 2018;119(12):10118–10130. doi: 10.1002/jcb.27349. [DOI] [PubMed] [Google Scholar]
  • 108.Zhang X., Yeung E. D., Wang J., et al. Isoliquiritigenin, a natural anti-oxidant, selectively inhibits the proliferation of prostate cancer cells. Clinical and Experimental Pharmacology and Physiology . 2010;37(8):841–847. doi: 10.1111/j.1440-1681.2010.05395.x. [DOI] [PubMed] [Google Scholar]
  • 109.Yuan X., Li D., Zhao H., et al. Licochalcone A-induced human bladder cancer T24 cells apoptosis triggered by mitochondria dysfunction and endoplasmic reticulum stress. BioMed Research International . 2013;2013:9. doi: 10.1155/2013/474272.474272 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 110.Chen H. Y., Huang T. C., Shieh T. M., Wu C. H., Lin L. C., Hsia S. M. Isoliquiritigenin induces autophagy and inhibits ovarian cancer cell growth. International Journal of Molecular Sciences . 2017;18(10) doi: 10.3390/ijms18102025. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 111.He S.-h., Liu H.-g., Zhou Y.-f., Yue Q.-f. Liquiritin (LT) exhibits suppressive effects against the growth of human cervical cancer cells through activating caspase-3 in vitro and xenograft mice in vivo. Biomedicine & Pharmacotherapy . 2017;92:215–228. doi: 10.1016/j.biopha.2017.05.026. [DOI] [PubMed] [Google Scholar]
  • 112.Lin Y., Sun H., Dang Y., Li Z. Isoliquiritigenin inhibits the proliferation and induces the differentiation of human glioma stem cells. Oncology Reports . 2018;39(2):687–694. doi: 10.3892/or.2017.6154. [DOI] [PubMed] [Google Scholar]
  • 113.Xiang S., Chen H., Luo X., et al. Isoliquiritigenin suppresses human melanoma growth by targeting miR-301b/LRIG1 signaling. Journal of Experimental & Clinical Cancer Research: Climate Research . 2018;37(1):p. 184. doi: 10.1186/s13046-018-0844-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 114.Lin P.-H., Kung H.-L., Chen H.-Y., Huang K.-C., Hsia S.-M. Isoliquiritigenin suppresses E2-induced uterine leiomyoma growth through the modulation of cell death program and the repression of ECM accumulation. Cancers . 2019;11(8):p. 1131. doi: 10.3390/cancers11081131. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 115.Kim K. H., Yoon G., Cho J. J., et al. Licochalcone a induces apoptosis in malignant pleural mesothelioma through downregulation of Sp1 and subsequent activation of mitochondria-related apoptotic pathway. International Journal of Oncology . 2015;46(3):1385–1392. doi: 10.3892/ijo.2015.2839. [DOI] [PubMed] [Google Scholar]
  • 116.Huang W., Tang S., Qiao X., et al. Isoangustone a induces apoptosis in SW480 human colorectal adenocarcinoma cells by disrupting mitochondrial functions. Fitoterapia . 2014;94:36–47. doi: 10.1016/j.fitote.2014.01.016. [DOI] [PubMed] [Google Scholar]
  • 117.Meng F.-C., Lin J.-K. Liquiritigenin inhibits colorectal cancer proliferation, invasion, and epithelial-to-mesenchymal transition by decreasing expression of runt-related transcription factor 2. Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics . 2019;27(2):139–146. doi: 10.3727/096504018x15185747911701. [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
  • 118.Cho J. J., Chae J.-I., Yoon G., et al. Licochalcone a, a natural chalconoid isolated from Glycyrrhiza inflata root, induces apoptosis via Sp1 and Sp1 regulatory proteins in oral squamous cell carcinoma. International Journal of Oncology . 2014;45(2):667–674. doi: 10.3892/ijo.2014.2461. [DOI] [PubMed] [Google Scholar]
  • 119.Oh H., Yoon G., Shin J.-C., et al. Licochalcone B induces apoptosis of human oral squamous cell carcinoma through the extrinsic- and intrinsic-signaling pathways. International Journal of Oncology . 2016;48(4):1749–1757. doi: 10.3892/ijo.2016.3365. [DOI] [PubMed] [Google Scholar]
  • 120.Kwak A.-W., Choi J.-S., Liu K., et al. Licochalcone C induces cell cycle G1 arrest and apoptosis in human esophageal squamous carcinoma cells by activation of the ROS/MAPK signaling pathway. Journal of Chemotherapy . 2020;32(3):132–143. doi: 10.1080/1120009x.2020.1721175. [DOI] [PubMed] [Google Scholar]
  • 121.Chen C.-T., Chen Y.-T., Hsieh Y.-H., et al. Glabridin induces apoptosis and cell cycle arrest in oral cancer cells through the JNK1/2 signaling pathway. Environmental Toxicology . 2018;33(6):679–685. doi: 10.1002/tox.22555. [DOI] [PubMed] [Google Scholar]
  • 122.Hsia S.-M., Yu C.-C., Shih Y.-H., et al. Isoliquiritigenin as a cause of DNA damage and inhibitor of ataxia-telangiectasia mutated expression leading to G2/M phase Arrest and apoptosis in oral squamous cell carcinoma. Head & Neck . 2016;38(S1):E360–E371. doi: 10.1002/hed.24001. [DOI] [PubMed] [Google Scholar]
  • 123.Yo Y.-T., Shieh G.-S., Hsu K.-F., Wu C.-L., Shiau A.-L. Licorice and licochalcone-A induce autophagy in LNCaP prostate cancer cells by suppression of bcl-2 expression and the mTOR pathway. Journal of Agricultural and Food Chemistry . 2009;57(18):8266–8273. doi: 10.1021/jf901054c. [DOI] [PubMed] [Google Scholar]
  • 124.Zhang B., Lai Y., Li Y., et al. Antineoplastic activity of isoliquiritigenin, a chalcone compound, in androgen-independent human prostate cancer cells linked to G2/M cell cycle arrest and cell apoptosis. European Journal of Pharmacology . 2018;821:57–67. doi: 10.1016/j.ejphar.2017.12.053. [DOI] [PubMed] [Google Scholar]
  • 125.Hong S. H., Cha H.-J., Hwang-Bo H., et al. Anti-proliferative and pro-apoptotic effects of licochalcone a through ROS-mediated cell cycle arrest and apoptosis in human bladder cancer cells. International Journal of Molecular Sciences . 2019;20(15):p. 3820. doi: 10.3390/ijms20153820. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 126.Chen C., Huang S., Chen C. L., Su S. B., Fang D. D. Isoliquiritigenin inhibits ovarian cancer metastasis by reversing epithelial-to-mesenchymal transition. Molecules (Basel, Switzerland) . 2019;24:20. doi: 10.3390/molecules24203725. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 127.Lu W. J., Wu G. J., Chen R. J., et al. Licochalcone A attenuates glioma cell growthin vitroandin vivothrough cell cycle arrest. Food & Function . 2018;9(8):4500–4507. doi: 10.1039/c8fo00728d. [DOI] [PubMed] [Google Scholar]
  • 128.Wang Y., Ma J., Yan X., et al. Isoliquiritigenin inhibits proliferation and induces apoptosis via alleviating hypoxia and reducing glycolysis in mouse melanoma B16F10 cells. Recent Patents on Anti-cancer Drug Discovery . 2016;11(2):215–227. doi: 10.2174/1573406412666160307151904. [DOI] [PubMed] [Google Scholar]
  • 129.Lin R. C., Yang S. F., Chiou H. L., et al. Licochalcone A-induced apoptosis through the activation of p38MAPK pathway mediated mitochondrial pathways of apoptosis in human osteosarcoma cells in vitro and in vivo. Cells . 2019;8:11. doi: 10.3390/cells8111441. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 130.Liu L. W., Xu R. T., Zhao M. Research progress in anti-tumor mechanism of natural medicine. Medical Recapitulate . 2015;21(10):1778–1780. [Google Scholar]
  • 131.Schaeffer H. J., Weber M. J. Mitogen-activated protein kinases: specific messages from ubiquitous messengers. Molecular and Cellular Biology . 1999;19(4):2435–2444. doi: 10.1128/mcb.19.4.2435. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 132.Pulverer B. J., Kyriakis J. M., Avruch J., Nikolakaki E., Woodgett J. R. Phosphorylation of C-jun mediated by MAP kinases. Nature . 1991;353(6345):670–674. doi: 10.1038/353670a0. [DOI] [PubMed] [Google Scholar]
  • 133.Ip Y. T., Davis R. J. Signal transduction by the c-Jun N-terminal kinase (JNK)—from inflammation to development. Current Opinion in Cell Biology . 1998;10(2):205–219. doi: 10.1016/s0955-0674(98)80143-9. [DOI] [PubMed] [Google Scholar]
  • 134.Tsai J.-P., Hsiao P.-C., Yang S.-F., et al. Licochalcone A suppresses migration and invasion of human hepatocellular carcinoma cells through downregulation of MKK4/JNK via NF-κB mediated urokinase plasminogen activator expression. PLoS One . 2014;9(1) doi: 10.1371/journal.pone.0086537.e86537 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 135.Guo H., German P., Bai S., et al. The PI3K/AKT pathway and renal cell carcinoma. Journal of Genetics and Genomics . 2015;42(7):343–353. doi: 10.1016/j.jgg.2015.03.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 136.Nozhat Z., Hedayati M. PI3K/AKT pathway and its mediators in thyroid carcinomas. Molecular Diagnosis and Therapy . 2016;20(1):13–26. doi: 10.1007/s40291-015-0175-y. [DOI] [PubMed] [Google Scholar]
  • 137.Doonan F., Cotter T. G. Morphological assessment of apoptosis. Methods . 2008;44(3):200–204. doi: 10.1016/j.ymeth.2007.11.006. [DOI] [PubMed] [Google Scholar]
  • 138.Lee H., Shin E. A., Lee J. H., et al. Caspase inhibitors: a review of recently patented compounds (2013–2015) Expert Opinion on Therapeutic Patents . 2018;28(1):47–59. doi: 10.1080/13543776.2017.1378426. [DOI] [PubMed] [Google Scholar]
  • 139.Peña Blanco A., García Sáez A. J. Bax, Bak and beyond—mitochondrial performance in apoptosis. FEBS Journal . 2017;285(3):416–431. doi: 10.1111/febs.14186. [DOI] [PubMed] [Google Scholar]
  • 140.Ullah A., Munir S., Badshah S. L., et al. Important flavonoids and their role as a therapeutic agent. Molecules . 2020;25(22):p. 5243. doi: 10.3390/molecules25225243. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 141.Chin Y.-W., Jung H.-A., Liu Y., et al. Anti-oxidant constituents of the roots and stolons of licorice (Glycyrrhiza glabra) Journal of Agricultural and Food Chemistry . 2007;55(12):4691–4697. doi: 10.1021/jf0703553. [DOI] [PubMed] [Google Scholar]
  • 142.Liu Z.-J., Zhong J., Zhang M., et al. The alexipharmic mechanisms of five licorice ingredients involved in CYP450 and Nrf2 pathways in paraquat-induced mice acute lung injury. Oxidative Medicine and Cellular Longevity . 2019;2019:20. doi: 10.1155/2019/7283104.7283104 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 143.Hasani-Ranjbar S., Nayebi N., Moradi L., Mehri A., Larijani B., Abdollahi M. The efficacy and safety of herbal medicines used in the treatment of hyperlipidemia; A systematic review. Current Pharmaceutical Design . 2010;16(26):2935–2947. doi: 10.2174/138161210793176464. [DOI] [PubMed] [Google Scholar]
  • 144.Singh P., Singh D., Goel R. K. Protective effect on phenytoin-induced cognition deficit in pentylenetetrazol kindled mice: a repertoire of Glycyrrhiza glabra flavonoid antioxidants. Pharmaceutical Biology . 2016;54(7):1–10. doi: 10.3109/13880209.2015.1063673. [DOI] [PubMed] [Google Scholar]
  • 145.Belinky P. A., Aviram M., Fuhrman B., Rosenblat M., Vaya J. The antioxidative effects of the isoflavan glabridin on endogenous constituents of LDL during its oxidation. Atherosclerosis . 1998;137(1):49–61. doi: 10.1016/s0021-9150(97)00251-7. [DOI] [PubMed] [Google Scholar]
  • 146.Zhou Y.-z., Li X., Gong W.-x., et al. Protective effect of isoliquiritin against corticosterone-induced neurotoxicity in PC12 cells. Food & Function . 2017;8(3):1235–1244. doi: 10.1039/c6fo01503d. [DOI] [PubMed] [Google Scholar]
  • 147.Sun Y.-X., Tang Y., Wu A.-L., et al. Neuroprotective effect of liquiritin against focal cerebral ischemia/reperfusion in mice via its antioxidant and antiapoptosis properties. Journal of Asian Natural Products Research . 2010;12(12):1051–1060. doi: 10.1080/10286020.2010.535520. [DOI] [PubMed] [Google Scholar]
  • 148.Liu Q., Lv H., Wen Z., Ci X., Peng L. Isoliquiritigenin activates nuclear factor erythroid-2 related factor 2 to suppress the NOD-like receptor protein 3 inflammasome and inhibits the NF-κB pathway in macrophages and in acute lung injury. Frontiers in Immunology . 2017;8:p. 1518. doi: 10.3389/fimmu.2017.01518. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 149.Zhu X., Liu J., Chen S., et al. Isoliquiritigenin attenuates lipopolysaccharide-induced cognitive impairment through antioxidant and anti-inflammatory activity. BMC Neuroscience . 2019;20(1):p. 41. doi: 10.1186/s12868-019-0520-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 150.Alzahrani S., Ajwah S. M., Alsharif S. Y., et al. Isoliquiritigenin downregulates miR-195 and attenuates oxidative stress and inflammation in STZ-induced retinal injury. Naunyn-Schmiedeberg’s Archives of Pharmacology . 2020;393(12):2375–2385. doi: 10.1007/s00210-020-01948-5. [DOI] [PubMed] [Google Scholar]
  • 151.Link P., Wink M. Isoliquiritigenin exerts antioxidant activity in Caenorhabditis elegans via insulin-like signaling pathway and SKN-1. Phytomedicine . 2019;55:119–124. doi: 10.1016/j.phymed.2018.07.004. [DOI] [PubMed] [Google Scholar]
  • 152.Jung E. H., Lee J.-H., Kim S. C., Kim Y. W. AMPK activation by liquiritigenin inhibited oxidative hepatic injury and mitochondrial dysfunction induced by nutrition deprivation as mediated with induction of farnesoid X receptor. European Journal of Nutrition . 2017;56(2):635–647. doi: 10.1007/s00394-015-1107-7. [DOI] [PubMed] [Google Scholar]
  • 153.Huang C.-H., Chan W.-H. Protective effects of liquiritigenin against citrinin-triggered, oxidative-stress-mediated apoptosis and disruption of embryonic development in mouse blastocysts. International Journal of Molecular Sciences . 2017;18(12):p. 2538. doi: 10.3390/ijms18122538. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 154.Dogra A., Gupta D., Bag S., et al. Glabridin ameliorates methotrexate-induced liver injury via attenuation of oxidative stress, inflammation, and apoptosis. Life Sciences . 2021;278 doi: 10.1016/j.lfs.2021.119583.119583 [DOI] [PubMed] [Google Scholar]
  • 155.Yehuda I., Madar Z., Leikin-Frenkel A., et al. Glabridin, an isoflavan from licorice root, upregulates paraoxonase 2 expression under hyperglycemia and protects it from oxidation. Molecular Nutrition & Food Research . 2016;60(2):287–299. doi: 10.1002/mnfr.201500441. [DOI] [PubMed] [Google Scholar]
  • 156.Kühnl J., Roggenkamp D., Gehrke S. A., et al. Licochalcone A activates Nrf2in vitroand contributes to licorice extract-induced lowered cutaneous oxidative stressin vivo. Experimental Dermatology . 2015;24(1):42–47. doi: 10.1111/exd.12588. [DOI] [PubMed] [Google Scholar]
  • 157.Nakatani Y., Kobe A., Kuriya M., et al. Neuroprotective effect of liquiritin as an antioxidant via an increase in glucose-6-phosphate dehydrogenase expression on B65 neuroblastoma cells. European Journal of Pharmacology . 2017;815:381–390. doi: 10.1016/j.ejphar.2017.09.040. [DOI] [PubMed] [Google Scholar]
  • 158.Kang M. R., Park K. H., Oh S. J., et al. Cardiovascular protective effect of glabridin: implications in LDL oxidation and inflammation. International Immunopharmacology . 2015;29(2):914–918. doi: 10.1016/j.intimp.2015.10.020. [DOI] [PubMed] [Google Scholar]
  • 159.Villa T. G., Feijoo-Siota L., Rama J. L. R., Ageitos J. M. Antivirals against animal viruses. Biochemical Pharmacology . 2017;133:97–116. doi: 10.1016/j.bcp.2016.09.029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 160.He J., Chen L., Heber D., Shi W., Lu Q.-Y. Antibacterial compounds from Glycyrrhiza uralensis. Journal of Natural Products . 2006;69(1):121–124. doi: 10.1021/np058069d. [DOI] [PubMed] [Google Scholar]
  • 161.Wu S.-C., Yang Z.-Q., Liu F., et al. Antibacterial effect and mode of action of flavonoids from licorice against methicillin-resistant Staphylococcus aureus. Frontiers in Microbiology . 2019;10:p. 2489. doi: 10.3389/fmicb.2019.02489. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 162.Fukuchi K., Okudaira N., Adachi K., et al. Antiviral and antitumor activity of licorice root extracts. In Vivo . 2016;30(6):777–786. doi: 10.21873/invivo.10994. [DOI] [PubMed] [Google Scholar]
  • 163.Souza R. L., Gonçalves U. O., Badoco F. R., et al. Licochalcone a induces morphological and biochemical alterations in schistosoma mansoni adult worms. Biomedicine & Pharmacotherapy . 2017;96:64–71. doi: 10.1016/j.biopha.2017.09.128. [DOI] [PubMed] [Google Scholar]
  • 164.Ahn S.-J., Park S.-N., Lee Y. J., et al. In vitro antimicrobial activities of 1-methoxyficifolinol, licorisoflavan A, and 6,8-diprenylgenistein against Streptococcus mutans. Caries Research . 2015;49(1):78–89. doi: 10.1159/000362676. [DOI] [PubMed] [Google Scholar]
  • 165.Yang S.-Y., Choi Y.-R., Lee M.-J., Kang M.-K. Antimicrobial effects against oral pathogens and cytotoxicity of Glycyrrhiza uralensis extract. Plants . 2020;9(7):p. 838. doi: 10.3390/plants9070838. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 166.Vaillancourt K., LeBel G., Pellerin G., Lagha A. B., Grenier D. Effects of the licorice isoflavans licoricidin and glabridin on the growth, adherence properties, and acid production of Streptococcus mutans, and assessment of their biocompatibility. Antibiotics (Basel) . 2021;10(2):p. 163. doi: 10.3390/antibiotics10020163. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 167.Asha M. K., Debraj D., Prashanth D. s., et al. In vitro anti-Helicobacter pylori activity of a flavonoid rich extract of Glycyrrhiza glabra and its probable mechanisms of action. Journal of Ethnopharmacology . 2013;145(2):581–586. doi: 10.1016/j.jep.2012.11.033. [DOI] [PubMed] [Google Scholar]
  • 168.Bhargava N., Singh S. P., Sharma A., Sharma P., Capalash N. Attenuation of quorum sensing-mediated virulence of acinetobacter baumannii by Glycyrrhiza glabra flavonoids. Future Microbiology . 2015;10(12):1953–1968. doi: 10.2217/fmb.15.107. [DOI] [PubMed] [Google Scholar]
  • 169.Gaur R., Gupta V. K., Singh P., Pal A., Darokar M. P., Bhakuni R. S. Drug resistance reversal potential of isoliquiritigenin and liquiritigenin isolated from Glycyrrhiza glabra against methicillin-resistant Staphylococcus aureus (MRSA) Phytotherapy Research . 2016;30(10):1708–1715. doi: 10.1002/ptr.5677. [DOI] [PubMed] [Google Scholar]
  • 170.Tsukiyama R.-I., Katsura H., Tokuriki N., Kobayashi M. Antibacterial activity of licochalcone a against spore-forming bacteria. Antimicrobial Agents and Chemotherapy . 2002;46(5):1226–1230. doi: 10.1128/aac.46.5.1226-1230.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 171.Seleem D., Benso B., Noguti J., Pardi V., Murata R. M. In vitro and in vivo antifungal activity of lichochalcone-A against Candida albicans biofilms. PLoS One . 2016;11(6) doi: 10.1371/journal.pone.0157188.e157188 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 172.Grenier D., Marcoux E., Azelmat J., Ben Lagha A., Gauthier P. Biocompatible combinations of nisin and licorice polyphenols exert synergistic bactericidal effects against Enterococcus faecalis and inhibit NF-κB activation in monocytes. AMB Express . 2020;10(1):p. 120. doi: 10.1186/s13568-020-01056-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 173.Rahman H., Khan I., Hussain A., et al. Glycyrrhiza glabra HPLC fractions: identification of aldehydo isoophiopogonone and liquirtigenin having activity against multidrug resistant bacteria. BMC Complementary and Alternative Medicine . 2018;18(1):p. 140. doi: 10.1186/s12906-018-2207-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 174.Fatima A., Gupta V. K., Luqman S., et al. Antifungal activity of Glycyrrhiza glabra extracts and its active constituent glabridin. Phytotherapy Research . 2009;23(8):1190–1193. doi: 10.1002/ptr.2726. [DOI] [PubMed] [Google Scholar]
  • 175.Liu P., Cai Y., Zhang J., et al. Antifungal activity of liquiritin in Phytophthora capsici comprises not only membrane-damage-mediated autophagy, apoptosis, and Ca2+ reduction but also an induced defense responses in pepper. Ecotoxicology and Environmental Safety . 2021;209 doi: 10.1016/j.ecoenv.2020.111813.111813 [DOI] [PubMed] [Google Scholar]
  • 176.Dao T. T., Nguyen P. H., Lee H. S., et al. Chalcones as novel influenza a (H1N1) neuraminidase inhibitors from Glycyrrhiza inflata. Bioorganic & Medicinal Chemistry Letters . 2011;21(1):294–298. doi: 10.1016/j.bmcl.2010.11.016. [DOI] [PubMed] [Google Scholar]
  • 177.Kwon H.-J., Kim H.-H., Ryu Y. B., et al. In vitro anti-rotavirus activity of polyphenol compounds isolated from the roots of Glycyrrhiza uralensis. Bioorganic & Medicinal Chemistry . 2010;18(21):7668–7674. doi: 10.1016/j.bmc.2010.07.073. [DOI] [PubMed] [Google Scholar]
  • 178.Lee S., Lee H. H., Shin Y. S., Kang H., Cho H. The anti-HSV-1 effect of quercetin is dependent on the suppression of TLR-3 in raw 264.7 cells. Archives of Pharmacal Research . 2017;40(5):623–630. doi: 10.1007/s12272-017-0898-x. [DOI] [PubMed] [Google Scholar]
  • 179.Powers C. N., Setzer W. N. An in-silico investigation of phytochemicals as antiviral agents against dengue fever. Combinatorial Chemistry & High Throughput Screening . 2016;19(7):516–536. doi: 10.2174/1386207319666160506123715. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 180.Wang H.-M., Liu T.-X., Wang T.-Y., et al. Isobavachalcone inhibits post-entry stages of the porcine reproductive and respiratory syndrome virus life cycle. Archives of Virology . 2018;163(5):1263–1270. doi: 10.1007/s00705-018-3755-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 181.El-Saber Batiha G., Magdy Beshbishy A., El-Mleeh A., Abdel-Daim M. M., Prasad Devkota H. Traditional uses, bioactive chemical constituents, and pharmacological and toxicological activities of Glycyrrhiza glabra L. (Fabaceae) Biomolecules . 2020;10(3):p. 352. doi: 10.3390/biom10030352. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 182.Yang L., Jiang Y., Zhang Z., Hou J., Tian S., Liu Y. The anti-diabetic activity of licorice, a widely used Chinese herb. Journal of Ethnopharmacology . 2020;263 doi: 10.1016/j.jep.2020.113216.113216 [DOI] [PubMed] [Google Scholar]
  • 183.Nakagawa K., Kishida H., Arai N., Nishiyama T., Mae T. Licorice flavonoids suppress abdominal fat accumulation and increase in blood glucose level in obese diabetic KK-ay mice. Biological and Pharmaceutical Bulletin . 2004;27(11):1775–1778. doi: 10.1248/bpb.27.1775. [DOI] [PubMed] [Google Scholar]
  • 184.Yoshioka Y., Yamashita Y., Kishida H., Nakagawa K., Ashida H. Licorice flavonoid oil enhances muscle mass in KK-A mice. Life Sciences . 2018;205:91–96. doi: 10.1016/j.lfs.2018.05.024. [DOI] [PubMed] [Google Scholar]
  • 185.Carnovali M., Luzi L., Terruzzi I., Banfi G., Mariotti M. Liquiritigenin reduces blood glucose level and bone adverse effects in hyperglycemic adult zebrafish. Nutrients . 2019;11(5):p. 1042. doi: 10.3390/nu11051042. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 186.Li J., Lim S. S., Lee E.-S., et al. Isoangustone a suppresses mesangial fibrosis and inflammation in human renal mesangial cells. Experimental Biology and Medicine . 2011;236(4):435–444. doi: 10.1258/ebm.2010.010325. [DOI] [PubMed] [Google Scholar]
  • 187.Li J., Kang S.-W., Kim J.-L., Sung H.-Y., Kwun I.-S., Kang Y.-H. Isoliquiritigenin entails blockade of TGF-β1-SMAD signaling for retarding high glucose-induced mesangial matrix accumulation. Journal of Agricultural and Food Chemistry . 2010;58(5):3205–3212. doi: 10.1021/jf9040723. [DOI] [PubMed] [Google Scholar]
  • 188.Choi E. M., Suh K. S., Jung W.-W., et al. Glabridin attenuates antiadipogenic activity induced by 2,3,7,8-tetrachlorodibenzo-P-dioxin in murine 3T3-L1 adipocytes. Journal of Applied Toxicology . 2018;38(11):1426–1436. doi: 10.1002/jat.3664. [DOI] [PubMed] [Google Scholar]
  • 189.Xie X.-W. Liquiritigenin attenuates cardiac injury induced by high fructose-feeding through fibrosis and inflammation suppression. Biomedicine & Pharmacotherapy . 2017;86:694–704. doi: 10.1016/j.biopha.2016.12.066. [DOI] [PubMed] [Google Scholar]
  • 190.Li S., Li W., Wang Y., Asada Y., Koike K. Prenylflavonoids from Glycyrrhiza uralensis and their protein tyrosine phosphatase-1B inhibitory activities. Bioorganic & Medicinal Chemistry Letters . 2010;20(18):5398–5401. doi: 10.1016/j.bmcl.2010.07.110. [DOI] [PubMed] [Google Scholar]
  • 191.Li W., Li S., Higai K., et al. Evaluation of licorice flavonoids as protein tyrosine phosphatase 1B inhibitors. Bioorganic & Medicinal Chemistry Letters . 2013;23(21):5836–5839. doi: 10.1016/j.bmcl.2013.08.102. [DOI] [PubMed] [Google Scholar]
  • 192.Kuna L., Jakab J., Smolic R., Raguz-Lucic N., Vcev A., Smolic M. Peptic ulcer disease: a brief review of conventional therapy and herbal treatment options. Journal of Clinical Medicine . 2019;8(2) doi: 10.3390/jcm8020179. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 193.Fukai T., Marumo A., Kaitou K., Kanda T., Terada S., Nomura T. Anti-Helicobacter pylori flavonoids from licorice extract. Life Sciences . 2002;71(12):1449–1463. doi: 10.1016/s0024-3205(02)01864-7. [DOI] [PubMed] [Google Scholar]
  • 194.Park J.-M., Park S.-H., Hong K.-S., et al. Special licorice extracts containing lowered glycyrrhizin and enhanced licochalcone A PreventedHelicobacter pylori-initiated, salt diet-promoted gastric tumorigenesis. Helicobacter . 2014;19(3):221–236. doi: 10.1111/hel.12121. [DOI] [PubMed] [Google Scholar]
  • 195.Jalilzadeh-Amin G., Najarnezhad V., Anassori E., Mostafavi M., Keshipour H. Antiulcer properties of Glycyrrhiza glabra L. extract on experimental models of gastric ulcer in mice. Iranian Journal of Pharmaceutical Research . 2015;14(4):1163–1170. [PMC free article] [PubMed] [Google Scholar]
  • 196.Choi Y. H., Kim Y. J., Chae H. S., Chin Y. W. In Vivo gastroprotective effect along with pharmacokinetics, tissue distribution and metabolism of isoliquiritigenin in mice. Planta Medica . 2015;81(7):586–593. doi: 10.1055/s-0035-1545914. [DOI] [PubMed] [Google Scholar]
  • 197.Liu D., Huo X., Gao L., Zhang J., Ni H., Cao L. NF-κB and Nrf2 pathways contribute to the protective effect of Licochalcone A on dextran sulphate sodium-induced ulcerative colitis in mice. Biomedicine & Pharmacotherapy . 2018;102:922–929. doi: 10.1016/j.biopha.2018.03.130. [DOI] [PubMed] [Google Scholar]
  • 198.Sulzberger M., Worthmann A.-C., Holtzmann U., et al. Effective treatment for sensitive skin: 4-T-butylcyclohexanol and licochalcone a. Journal of the European Academy of Dermatology and Venereology . 2016;30:9–17. doi: 10.1111/jdv.13529. [DOI] [PubMed] [Google Scholar]
  • 199.Weber T. M., Ceilley R. I., Buerger A., et al. Skin tolerance, efficacy, and quality of life of patients with red facial skin using a skin care regimen containing licochalcone a. Journal of Cosmetic Dermatology . 2006;5(3):227–232. doi: 10.1111/j.1473-2165.2006.00261.x. [DOI] [PubMed] [Google Scholar]
  • 200.Boonchai W., Varothai S., Winayanuwattikun W., Phaitoonvatanakij S., Chaweekulrat P., Kasemsarn P. Randomized investigator‐blinded comparative study of moisturizer containing 4-T-butylcyclohexanol and licochalcone a versus 0.02% triamcinolone acetonide cream in facial dermatitis. Journal of Cosmetic Dermatology . 2018;17(6):1130–1135. doi: 10.1111/jocd.12499. [DOI] [PubMed] [Google Scholar]
  • 201.Chen J., Yu X., Huang Y. Inhibitory mechanisms of glabridin on tyrosinase. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy . 2016;168:111–117. doi: 10.1016/j.saa.2016.06.008. [DOI] [PubMed] [Google Scholar]
  • 202.Wang W. P., Hul J., Sui H., Zhao Y. S., Feng J., Liu C. Glabridin nanosuspension for enhanced skin penetration: formulation optimization, in vitro and in vivo evaluation. Die Pharmazie . 2016;71(5):252–257. [PubMed] [Google Scholar]
  • 203.Lee H., Cho H., Lim D., Kang Y.-H., Lee K., Park J. Mechanisms by which licochalcone E exhibits potent anti-inflammatory properties: studies with phorbol ester-treated mouse skin and lipopolysaccharide-stimulated murine macrophages. International Journal of Molecular Sciences . 2013;14(6):10926–10943. doi: 10.3390/ijms140610926. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 204.Kopelman P. G. Obesity as a medical problem. Nature . 2000;404(6778):635–643. doi: 10.1038/35007508. [DOI] [PubMed] [Google Scholar]
  • 205.Gadde K. M., Martin C. K., Berthoud H.-R., Heymsfield S. B. Obesity: pathophysiology and management. Journal of the American College of Cardiology . 2018;71(1):69–84. doi: 10.1016/j.jacc.2017.11.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 206.Lee J.-W., Choe S. S., Jang H., et al. AMPK activation with glabridin ameliorates adiposity and lipid dysregulation in obesity. Journal of Lipid Research . 2012;53(7):1277–1286. doi: 10.1194/jlr.m022897. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 207.Mori N., Nakanishi S., Shiomi S., et al. Enhancement of fat oxidation by licorice flavonoid oil in healthy humans during light exercise. Journal of Nutritional Science & Vitaminology . 2015;61(5):406–416. doi: 10.3177/jnsv.61.406. [DOI] [PubMed] [Google Scholar]
  • 208.Bartelt A., Bruns O. T., Reimer R., et al. Brown adipose tissue activity controls triglyceride clearance. Nature Medicine . 2011;17(2):200–205. doi: 10.1038/nm.2297. [DOI] [PubMed] [Google Scholar]
  • 209.Nedergaard J., Bengtsson T., Cannon B. New powers of Brown fat: fighting the metabolic syndrome. Cell Metabolism . 2011;13(3):238–240. doi: 10.1016/j.cmet.2011.02.009. [DOI] [PubMed] [Google Scholar]
  • 210.Lee H. E., Yang G., Han S.-H., et al. Anti-obesity potential of Glycyrrhiza uralensis and licochalcone a through induction of adipocyte browning. Biochemical and Biophysical Research Communications . 2018;503(3):2117–2123. doi: 10.1016/j.bbrc.2018.07.168. [DOI] [PubMed] [Google Scholar]
  • 211.Park H. G., Bak E. J., Woo G.-H., et al. Licochalcone E has an antidiabetic effect. The Journal of Nutritional Biochemistry . 2012;23(7):759–767. doi: 10.1016/j.jnutbio.2011.03.021. [DOI] [PubMed] [Google Scholar]
  • 212.Liou C.-J., Lee Y.-K., Ting N.-C., et al. Protective effects of licochalcone a ameliorates obesity and non-alcoholic fatty liver disease via promotion of the sirt-1/AMPK pathway in mice fed a high-fat diet. Cells . 2019;8(5):p. 447. doi: 10.3390/cells8050447. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Evidence-based Complementary and Alternative Medicine : eCAM are provided here courtesy of Wiley

RESOURCES